OA20251A

OA20251A - Fused benzoxazepinones as ion channel modulators

Info

Publication number: OA20251A
Application number: OA1201600490
Authority: OA
Inventors: Britton Kenneth Corkey; Elfatih Elzein; Robert H. Jiang; Rao V. Kalla; Dmitry Koltun; Xiaofen Li; Ruben Martinez; Eric Q Parkhill; Thao Perry; Jeff Zablocki; Chandrasekar Venkataramani; Michael Graupe; Juan Guerrero
Original assignee: Gilead Sciences, Inc.
Filing date: 2016-12-16
Publication date: 2022-04-14

Abstract

The present disclosure relates to compounds that are sodium channel inhibitors and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes. In particular embodiments, the structure of the compounds is given by Formula I :

Description

FUSED BENZOXAZEPINONES AS ION CHANNEL MODULATORS

Cross-Reference to Related Applications

[0001] This application claims the benefït under 35 U.S.C. § 119(e) to U.S. Provisional Application Serial Numbers 61/503,980, filed on July 1, 2011 and 61/582,160, filed on December 30, 2011, the entirety of which are both incorporated herein by reference.

Field

[0002] The présent disclosure relates to novel compounds and to their use in the treatment of various diseases, including cardiovascular diseases and diabètes. The disclosure also relates to methods for préparation of the compounds and to pharmaceutical compositions comprising such compounds.

Background

[0003] The late sodium current (INaL) is a sustained component of the fast Na+ current of cardiac myocytes and neurons. Many common neurological and cardiac conditions are associated with abnormal (INaL) enhancement, which contributes to the pathogenesis of both electrical and contactile dysfunction in mammals. See, for example, Pathophysiology and Pharmacology of the Cardiac “Late Sodium Current”, Pharmacology and Therapeutics 119 (2008) 326-339. Accordingly, compounds that selectively inhibit (INaL) in mammals are useful in treating such disease states.

[0004] One example of a sélective inhibitor of (INaL) is RANEXA®, a compound approved by the FDA for the treatment of chronic stable angina pectoris. RANEXA® has also been shown to be usefùl for the treatment of a variety of cardiovascular diseases, including ischemia-reperfusion injury, arrhythmia and unstable angina, and also for the treatment of diabètes. It would be désirable to provide novel compounds that selectively inhibit (INaL) in mammals and that hâve the similar or improved selectivity over peak INa inhibition of the cardiac sodium channel as RANEXA®.

4824-4563-0480.1

Summary

[0005] Accordingly, typical embodiments the présent disclosure provide novel compounds that function as late sodium channel blockers. In one embodiment, the disclosure provides compounds of Formula I:

I wherein:

Z¹ and Z² are each independently selected from the group consisting of CR⁷ and

N;

Z³ and Z⁴ are each independently selected from the group consisting of CR⁷, C-QR¹ and N, provided that one of Z³ and Z⁴ is C-Q-R¹ and the other of Z³ and Z⁴ is CR⁷ or N and further provided that only one of Z¹, Z² and Z⁴ is N;

X is -O- or -NR⁶-;

Y is -C(O)-, -C(Rⁿ)2- or -S(O)₂-;

Q is a covalent bond, -O-C0-2 alkylene, -NRⁿ-Co-2 alkylene, C2 alkylene,

C2 alkenylene or C2 alkynylene;

R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl;

wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -s(O)2-r²⁰, -oS(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Ci-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group

4824-4563-0480.1 consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, C1-6 alkyl,

C1-3 haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰,

-C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -C1-6 alkylene-R⁵, -L-R⁵, -L-C1-6 alkylene-R⁵, -C1-6 alkylene-L-R⁵ or -C1-6 alkylene-L-Ci-6 alkylene-R⁵;

wherein each -C1-6 alkylene is optionally substituted by one substituent independently selected from the group consisting of C2-4 alkynyl, halo, -NO2, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C2-4 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

_L i_s .q-, -S-, -C(O)-, -NHS(O)₂-, -S(O)2NH-, -C(O)NH-, or -NHC(O)-; provided that when Y is -C(Rⁿ)2-, then R² is -L-R⁵, -L-C1-6 alkylene-R⁵, -C1-6 alkyleneL-R⁵ or -C1-6 alkylene-L-Ci-6 alkylene-R⁵ and L is not -C(O)-; and when R² is -L-R⁵ or -L-C1-6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂or -NHC(O)-;

each R³ is independently hydrogen, deuterium, C1-6 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ci-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂,

4824-4563-0480.1

Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,

-N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and

-O-R²⁰; and wherein said Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

or when Y is -C(O)-, then R² and one of R³ can join together with the atom to which they are attached to form a heterocyclyl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, -O-R²⁰, -N(R²⁰)(R²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said Ci-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;

each R⁴ is independently hydrogen, deuterium, C1-6 alkyl, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁶), cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C1-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted

4824-4563-0480.1 with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO2,

-N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²),

-CN and -O-R²⁰;

or two R³ or two R⁴ together with the carbon atom to which they are attached form an oxo;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C2-4 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -OR²⁰;

wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R⁶ is hydrogen, C1-6 alkyl or cycloalkyl;

wherein said C1-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R⁷ is hydrogen, halo, -O-R²⁰ or C1-6 alkyl;

R¹¹ is hydrogen or C1-4 alkyl;

4824-4563-0480.1

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ch alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Ci-4 alkyl, aryl and cycloalkyl;

wherein the C1-4 alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkoxy, -CF3 and -OCF3;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof;

provided that when Y is -C(O)-, X is -O-, each R⁴ is hydrogen, R and R together with the atom to which they are attached form a piperazine which is optionally substituted with tert-butoxycarbonyl and Q is a bond, then R¹ is not unsubstituted phenyl or morpholinyl; and that when Y is -S(O)2-, X is -O-, R² is benzyl, each R is hydrogen, Z⁴ is C-Q-R¹, Q is a bond and R¹ is aryl or heteroaryl, then both R⁴are hydrogen.

4824-4563-0480.1

[0006] In certain embodiments, the disclosure provides compounds of Formula IA:

IA wherein:

Cy is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl;

Q is a covalent bond, -O-C0-2 alkylene, -NRⁿ-Co-2 alkylene, C2 alkylene,

C2 alkenylene or C2 alkynylene;

m is 0, 1, 2 or 3;

n is 0, 1, 2, 3, 4 or 5;

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(û)2-R²⁶, -S(O)2R²⁰, -O-S(O)₂-R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -ΝΟ2, aryl, heterocyclyl, heteroaryl, C1-6 alkyl, Ci-₃haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -C1-6 alkylene-R⁵, -L-R⁵, -L-C1-6 alkylene-R⁵, -Ci-₆ alkylene-L-R⁵ or -C1-6 alkylene-L-Ci-6 alkylene-R⁵;

wherein each -C1-6 alkylene is optionally substituted by one substituent independently selected from the group consisting of C2-4 alkynyl, halo, -NO2, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R²⁰)(R²²), -N(R²⁰)-S(0)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and

4824-4563-0480.1 wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C2-4 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-; provided that when R² is -L-R⁵ or -L-C1-6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NHC(O)-; and each R³ is independently hydrogen, deuterium, C1-6 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

or R² and one of R³ can join together with the atom to which they are attached to form a heterocyclyl;

4824-4563-0480.1 wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl,

-O-R²⁰, -N(R²⁰)(R²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said Ci-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;

each R⁴ is independently hydrogen, deuterium, Ci-6 alkyl, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁶), cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO2, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C2-4 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, -N(R )C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -OR²⁰;

4824-4563-0480.1 wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NOs,

Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²),

-C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R¹⁷ is halo, -O-R²⁰ or C1-6 alkyl;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1.4 alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with C1-4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, C1-4 alkyl, aryl and cycloalkyl;

4824-4563-0480.1 wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from f to 3 substituents independently selected from the group consisting of hydroxyl, halo, Ci.₄ alkoxy, -CF3 and -OCF3;

provided that when each R⁴ is hydrogen, R² and R³ together with the atom to which they are attached form a piperazine which is optionally substituted with tert-butoxycarbonyl, Q is a bond and Cy is phenyl or morpholinyl, then n is 1, 2, 3, 4 or 5.

[0007] Some embodiments provide a method of using the compounds of Formula I, IA, IB, Π, IIA, ΠΒ, ΙΠ, ΙΤΙΑ, IV, V, VI, VIII, VIIIA, IX, X, XII or ΧΙΠ, or additional Formula(s) described throughout, in the treatment of a disease or condition in a mammal that is amenable to treatment by a late sodium channel blocker. Such diseases include cardiovascular diseases such as atrial and ventricular arrhythmias, heart failure (including congestive heart failure, diastolic heart failure, systolic heart failure, acute heart failure), Prinzmetal’s (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, ischemia, récurrent ischemia, reperfüsion injury, myocardial infarction, acute coronary syndrome, peripheral arterial disease and intermittent claudication. Such diseases may also include diabètes and conditions related to diabètes, e.g. diabetic peripheral neuropathy. Such diseases may also include conditions affecting the neuromuscular system resulting in pain, seizures or paralysis. Therefore, it is contemplated that the compounds ofthe disclosure and their pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers and/or tautomer forms are potentially of use as médicaments for the treatment of the aforementioned diseases.

[0008] In certain embodiments, the disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a compound ofthe disclosure (e.g. a compound of Formula I or additional Formulas described throughout), and at least one pharmaceutically acceptable excipient.

[0009] In certain embodiments, the compound is:

4-((3-methyloxetan-3-yl)methyl)-7-(4-(trifluoromethoxy)pheny 1)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-1);

4824-4563-0480.1

4-(2-(pyrrolidin-1 -yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-3);

4-((5-cyclobutyl-1,3,4-oxadiazoI-2-yl)methyl)-7-(4-(trifIuoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-4);

4-((2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-5);

4-(quinolin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-7);

(R)-2-(pyrimidin-2-ylmethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1Hbenzo[f]pyrazino[2, l-c][l,4]oxazepin-6(2H)-one (Π-8);

4-(cyclopropylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-10);

(S)-3-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f] [1,4] oxazepin-5(2H)-one (Π-12);

(R)-3-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-13);

6-((5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)methyl)picolinonitrile (11-14);

7-(4-(trifluoromethoxy)phenyl)-4-((6-(trifluoromethyl)pyridin-2-yl)methyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-15);

7-(4-(trifluoromethoxy)phenyl)-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-16);

4-((6-methylpyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5 (2H)-one (Π-17);

(2R, 1 laS)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,l 1,1 latetrahydrobenzo[f]pyrrolo[2,l-c][l,4]oxazepin-5(lH)-one (11-21);

(R)-2-(2,2-difluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1Hbenzo[f]pyrazino[2,1 -c][ 1,4]oxazepin-6(2H)-one (11-22);

4824-4563-0480.1 (R)-2-ethyl-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro- 1Hbenzo[f]pyrazino[2, l-c][l,4]oxazepin-6(2H)-one (11-23);

(S)-2-(2,2-difluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-lHbenzo[f]pyrazino[2,1 -c][ 1,4]oxazepin-6(2H)-one (Π-24);

(S)-2-ethyl-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-lHbenzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one (11-25);

4-(pyrazin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-31);

4-((5-methyloxazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-33);

7-(4-(trifluoromethoxy)phenyl)-4-(2-(2,5,5-trimethyl-l,3-dioxan-2-yl)ethyl)-3,4dihy drobenzo [f] [1,4] oxazepin-5 (2H)-one (Π-3 5);

tert-butyl (2R, 11 aR)-5-oxo-7-(4-(trifluoromethyl)phenyl)-1,2,3,5,11,11 ahexahydrobenzo[f]pyrrolo[2,1 -c][ l,4]oxazepin-2-ylcarbamate (Π-39);

4-((5-(pyridin-2-yl)isoxazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (Π-41 );

4-((4,6-dimethoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-42);

ethyl 3-((5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)methyl)benzoate (11-43);

4-(2-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo [f] [ 1,4] oxazepin- 5 (2H)-one (Π-44);

4-(3,4-difluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-45);

4-(2-chlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-47);

4-(2,6-dichlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-48);

4824-4563-0480.1

4-(2,6-difluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f] [ 1,4]oxazepin5(2H)-one (Π-49);

4-(2-(lH-pyrazol-l-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-50);

(2S, 1 laS)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,11,11atetrahydrobenzo [fjpyrrolo [2,1 -c] [ 1,4]oxazepin-5 ( 1 H)-one (II- 51);

4-(2-(pyridin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-54);

4-(2-fluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f|[l,4]oxazepin5(2H)-one (Π-57);

(R)-7-(4-(trifluoromethyl)phenyl)-2,3,11,11 a-tetrahydrobenzo[f]pyrrolo[2,1 c] [ 1,4]oxazepin-5( lH)-one (Π-59);

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-61);

4-(4-fl_Uorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f] [ 1,4]oxazepin5(2H)-one (11-62);

4-((l-methyl-lH-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-64);

4-((5-chloropyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-65);

4-(pyridin-4-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (11-67);

4-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (11-68);

4-(2-(pyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-69);

4-(pyridin-3 -ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo [f] [ 1,4] oxazepin-5 (2H)-one (Π-70);

4824-4563-0480.1

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [1,4] oxazepin-5 (2H)-one (Π-72);

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo [f] [ 1,4] oxazepin-5 (2H)-one (Π-73 );

4-((3-methylpyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Π-75);

(R)-2-(2,2,2-trifluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-lHbenzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one (11-83);

4-(pyrimidin-2-ylmethyl)-7-p-tolyl-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-87);

7-(4-chlorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one (11-88);

7-(4-isopropylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-89);

7-(4-ethylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (H-91);

7-(4-cyclopiOpylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-92);

(R)_4-(l-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-95);

7-(4-isobutoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-97);

7_(4-tert-buÎylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-98);

7_(4-_Cy_Clopropoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-102);

7-(4_fluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one (11-104);

7-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-105);

4824-4563-0480.1

7-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (H-106);

4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethoxy)phenyl)-3,4dihydrobenzo[f] [1,4] oxazepin-5 (2H)-one (Π-107);

7-(2-chloro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-110);

7-(4-(trifluoromethoxy)phenyl)-4-((4-(trifluoromethyl)pyrimidin-2-yl)methyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-113);

7-(4-(trifluoromethoxy)phenyl)-4-((5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2yl)methyl)-3,4-dihydrobenzo[f][l,4]oxazepm-5(2H)-one (II-l 15);

7-(4-chloro-2-fluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-117);

l-(4-(5-oxo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepin-7yl)phenyl)cyclopentanecarbonitrile (Π-122);

7-(4-ethoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f] [ 1,4]oxazepin-5(2H)one (11-123);

7-(4-(difluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo [f] [ 1,4]oxazepin-5 (2H)-one (Π-124);

4-(imidazo[l,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-129);

4_((4-morpholinopyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-133),

4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (11-134);

4-(imidazo[l,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f] [1,4] oxazepin-5 (2H)-one (Π-13 5);

7-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-136);

4824-4563-0480.1

4-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [1,4] oxazepin-5 (2H)-one (Π-137);

4-((4-methylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-138);

4-((4-(piperidin-1 -yl)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [1,4] oxazepin-5(2H)-one (Π-139);

4-((4-(dimethylamino)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo [f] [ 1,4] oxazepin-5 (2H)-one (Π-140);

4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II141);

4-((3-methoxypyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihy drobenzo [f] [ 1,4] oxazepin-5 (2H)-one (Π-143);

7-(4-(cyclobutylmethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (H-144);

7-(2-methyl-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-145);

7-(2-methyl-4-(trifluoromethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (H-146);

4-((l-(difluoromethyl)-lH-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo [f] [ 1,4] oxazepin- 5 (2H)-one (Π-147);

7-(4-(trifluoromethoxy)phenyl)-4-((3 -(trifluoromethyl)-lH-pyrazol-l-yl)methyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (H-148);

4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-150);

4-(pyridin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethyl)phenyl)-3,4dihydrobenzo [f] [ 1,4] oxazepin-5(2H)-one (Π-151 );

4-((1-cyclopentyl-lH-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-152);

4824-4563-0480.1

4-((l-ethyl-lH-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-153);

4-((l-methyl-lH-imidazol-4-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo [f] [ 1,4] oxazepin-5(2H)-one (Π-154);

4-((4-methyl-lH-pyrazol-l-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Π-155);

4-((4-chloro-lH-pyrazol-l-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-156);

7-(4-(difluoromethyl)phenyl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-157);

7-(4-chloro-3-fluorophenyl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-158);

7-(4-(difluoromethoxy)phenyl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-159);

4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo [f] [ 1,4]oxazepin-5 (2H)-one (Π-160);

4-(pyrimidin-2-ylmethyl)-7-(2,3,4-trifluorophenyl)-3,4-dihydrobenzo[f] [ 1,4]oxazepin5(2H)-one (11-162);

7-(3,4-difluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f] [ 1,4]oxazepin5(2H)-one (11-163);

4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (Π-164);

4-benzyl-9-fluoro-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-165);

4-benzyl-9-fluoro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-166);

4-benzyl-8-fluoro-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-167);

4824-4563-0480.1

4-benzyl-8-fluoro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-168);

7-(4-chIoro-3-fluorophenyl)-4-((3-fluoropyridin-2-yl)methyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-169);

7-(2-fluoro-4-(trifluoromethyl)phenyl)-4-((3-fluoropyridin-2-yl)methyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-170);

4-(5-oxo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepin-7-yl)phenyl trifluoromethanesulfonate (II-171);

4-((5-methyIpyrazin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-172);

2,2,3,3-tetradeutero-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-174);

4-((6-methylpyrazin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5 (2H)-one (Π-175);

4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-176);

N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)ethyl)benzenesulfonamide (II-177);

N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)ethyl)cyclopropanesulfonamide (II-179);

4-((l-methyl-lH-imidazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[ 1,4]oxazepin-5(2H)-one (Π-186);

4-((l-benzyl-lH-imidazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-187);

4-(imidazo[ 1,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-189),

N-cyclopropyl-3-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)propane-1 -sulfonamide (II-190);

4824-4563-0480.1

N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)ethyl)pyrimidine-2-carboxamide (II-192);

7-(4-(4-fluorophenoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo [f] [ 1,4] oxazepin-5 (2H)-one (Π-193);

7-(4-phenoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one (11-194);

7-(3-phenoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f|[l,4]oxazepin-5(2H)one (11-195);

7-(4-tert-butylcyclohex-1 -enyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (V-l);

7-cyclohexenyl-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (V-3);

7-(4-methylcyclohex-l-enyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5 (2H)-one (V-5);

7-(2-tert-butoxypyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (VI-4);

7-( 1 -methyl-2-oxo-1,2-dihydropyridin-4-yI)-4-(pyridin-2-ylmethyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (VI-12);

4-(pyridin-2-ylmethyl)-7-(5-(trifluoromethyl)pyridin-2-yl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VI-26);

7-(2-isopropylthiazol-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (VI-30);

4-(pyridin-2-ylmethyl)-7-(5-(trifluoromethyl)thiophen-2-yl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VI-31);

7-(5-cyclopropylthiophen-2-yl)-4-(pyridin-2-ylmethy 1)-3,4dihydrobenzo [f] [ 1,4]oxazepin-5(2H)-one (VI-3 2);

7-(5-cyclopropylthiophen-2-yl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VI-36); and

4824-4563-0480.1

4-(pyrimidin-2-ylmethyl)-7-(5-(trifluoromethyl)thiophen-2-yl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VI-37);

4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethoxy)phenyl)ethynyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (VHI-4);

7-(phenylethynyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VIII-5);

4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethyl)phenyl)ethynyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VIII-6);

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VHI-7);

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenethyl)-3,4dihydrobenzo [f] [ 1,4] oxazepin-5 (2H)-one ( VHI-8);

4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethyl)phenethyl)-3,4dihydrobenzo[f][l,4]oxazepm-5(2H)-one (VIII-9);

(E)-4-benzyl-7-(4-(trifluoromethyl)styryl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VIII-10); and

4-benzyl-7-(4-(trifluoromethyl)phenethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VIII-11);

2-((pyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2Hbenzo[b][l,4,5]oxathiazepin-sulfone (IX-2);

2-((5-chloropyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydiO-2Hbenzo[b] [1,4,5 ]oxathiazepin-sulfone (IX-3);

4-(2-(benzyIoxy)ethyl)-I-methyI-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-lHbenzo[e][ 1,4]diazepine-2,5-dione (X-7);

4-benzy l-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1 H-benzo[e] [ 1,4]diazepine-2,5 -dione (X-8);

4-benzyl-1 -methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro- lH-benzo[e] [ 1,4]diazepine2,5-dione (X-ll);

4824-4563-0480.1

5-benzyl-8-(4-(trifluoromethyl)phenyl)-4H-benzo[f]imidazo[l,2-a][l,4]diazepin-6(5H)one (X-12);

4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3 -f] [ 1,4]oxazepin-5(2H)one (XII-1);

4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[2,3-f][l,4]oxazepin-5(2H)one (XII-2);

4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrido[2,3-f][l,4]oxazepin-5(2H)-one (XII-3);

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3f][l,4]oxazepin-5(2H)-one (XII-5);

4-((4-methylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydropyrido[4,3-f][l,4]oxazepin-5(2H)-one (XII-8);

4-(cyclopropylmethyl)-7-(4-(trifIuoromethoxy)phenyl)-3,4-dihydropyrido[4,3f][l,4]oxazepin-5(2H)-one (XII-9);

4-((3-methoxypyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydropyrido[4,3 -f] [ 1,4]oxazepin-5(2H)-one (XII-10);

4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3f][l,4]oxazepin-5(2H)-one (XII-11);

4-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydropyrido[4,3-f][ 1,4]oxazepin-5(2H)-one (XII-14);

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenylamino)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (ΧΠΙ-1);

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenoxy)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (ΧΠΙ-2);

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenylamino)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (XIII-3);

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenylamino)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (XIII-4);

4824-4563-0480.1

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenylamino)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (ΧΠΙ-6); or

7-(methyl(4-(trifluoromethoxy)phenyl)amino)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (ΧΠΙ-10);

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.

[0010] In other embodiments, the compound is:

4-(2,2-difluoroethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (II-6);

4-(2-methoxyethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-11);

(R)-3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-19);

4-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-46);

(S)-3-isopropyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepm-5(2H)one (11-77);

3-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-142);

N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)ethyl)ethanesulfonamide (11-178); or

4-(3-(azetidin-l-ylsulfonyl)propyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-191);

[0011] In other embodiments, the compound is:

pyrimidin-2-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f|[l,4]oxazepin-4(5H)yl)methanone (III-1);

4824-4563-0480.1 phenyl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)methanone (III-4);

( 1 -methylcyclopropyl)(7-(4-(trifluoromethoxy)phenyl)-2,3 dihydrobenzo[f][ 1,4]oxazepin-4(5H)-yl)methanone (HI-10);

(3,3 -difluorocyclobutyl)(7-(4-(trifluoromethoxy)pheny 1)-2,3 dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (ΙΠ-11);

( 1 -methyl- lH-pyrazol-4-yl)(7-(4-(trifluoromethoxy)phenyi)-2,3 dihydrobenzo[f][ 1,4]oxazepin-4(5H)-yl)methanone (III-12);

(lH-pyrazol-3-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin4(5H)-yl)methanone (III-15);

pyrazin-2-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f|[l,4]oxazepin-4(5H)yl)methanone (III-23);

pyridazin-3-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f] [ 1,4]oxazepin-4(5H)yl)methanone (III-24);

2-(pyridin-2-yl)-l-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin4(5H)-yl)ethanone (III-29);

2-(pyrimidin-2-yl)-1 -(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f] [ 1,4]oxazepin4(5H)-yl)ethanone (III-30);

( 1 -methyl-1 H-imidazol-5 -yl)(7-(4-(trifluoromethyl)phenyl)-2,3 dihydrobenzo[f][ 1,4]oxazepin-4(5H)-yl)methanone (ΙΠ-32);

(lH-imidazol-2-yl)(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin4(5H)-yl)methanone (III-33);

(l-methyl-lH-imidazol-2-yl)(7-(4-(trifluoromethyl)phenyl)-2,3dihydrobenzo[f][ 1,4]oxazepin-4(5H)-yl)methanone (ΙΠ-37);

(R)-(2-methyl-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)(pyrimidm-2-yl)m^eth^anone (ΠΙ-3 8);

tert-butyl 2-(7-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepine-4carbonyl)-5,6-dihydroimidazo[l,2-a]pyrazine-7(8H)-carboxylate (III-40);

4824-4563-0480.1 (lH-l,2,4-triazol-3-yl)(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin4(5H)-yl)methanone (III-50); or ( 1,5-dimethyl-1 H-pyrazol-3 -yl)(7-(4-(trifluoromethoxy)phenyl)-2,3 dihydrobenzo [f] [ 1,4]oxazepin-4(5H)-yl)methanone (ΙΠ-5 8);

[0012] The inventions of this disclosure are described throughout. In addition, spécifie embodiments of the invention are as disclosed herein.

Detailed Description

1. Définitions and General Parameters

[0013] As used in the présent spécification, the following words and phrases are generally intended to hâve the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0014] The term “alkyl” refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms, or from 1 to 15 carbon atoms, or from 1 to 10 carbon atoms, or from 1 to 8 carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. This term is exemplified by groups such as methyl, ethyl, npropyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.

[0015] The term “substituted alkyl” refers to :

1) an alkyl group as defined above, having 1, 2, 3, 4 or 5 substituents, (in some embodiments, 1, 2 or 3 substituents) selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-heterocyclyl, -S(O)-aryl,-S(O)-heteroaryl, -S(O)₂-alkyl, -S(O)₂-cycloalkyl, -S(O)₂-heterocyclyl, -S(O)₂-aryl and -S(O)₂-heteroaryl. Unless

4824-4563-0480.1 otherwise constrained by the définition, ail substituents may optionally be further substituted by 1, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)_nR^a, in which R^a is alkyl, aryl or heteroaryl and n is 0, 1 or 2; or

2) an alkyl group as defined above that is interrupted by 1-10 atoms (e.g. 1, 2,

3, 4 or 5 atoms) independently chosen from oxygen, sulfur and NR^a, where R^a is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. Ail substituents may be optionally further substituted by alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)_nR^a, in which R^a is alkyl, aryl or heteroaryl and n is 0, 1 or 2; or

3) an alkyl group as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-10 atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above.

[0016] The term “lower alkyl” refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5 or 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tbutyl, n-hexyl, and the like.

[0017] The term “substituted lower alkyl” refers to lower alkyl as defined above having 1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents), as defined for substituted alkyl or a lower alkyl group as defined above that is interrupted by 1, 2, 3, 4 or 5 atoms as defined for substituted alkyl or a lower alkyl group as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1, 2, 3, 4 or 5 atoms as defined above.

[0018] The term “alkylene” refers to a diradical of a branched or unbranched saturated hydrocarbon chain, in some embodiments, having from 1 to 20 carbon atoms (e.g. 1-10 carbon atoms or 1, 2, 3, 4, 5 or 6 carbon atoms). This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), the propylene isomers (e.g., -CH2CH2CH2and -CH(CH₃)CH₂-), and the like.

4824-4563-0480.1

[0019] The term “lower alkylene” refers to a diradical of a branched or unbranched saturated hydrocarbon chain, in some embodiments, having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0020] The term “substituted alkylene” refers to an alkylene group as defined above having 1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents) as defined for substituted alkyl.

[0021] The term “aralkyl” refers to an aryl group covalently linked to an alkylene group, where aryl and alkylene are defined herein. “Optionally substituted aralkyl” refers to an optionally substituted aryl group covalently linked to an optionally substituted alkylene group. Such aralkyl groups are exemplified by benzyl, phenylethyl, 3-(4methoxyphenyl)propyl, and the like.

[0022] The term “aralkyloxy” refers to the group -O-aralkyl. “Optionally substituted aralkyloxy” refers to an optionally substituted aralkyl group covalently linked to an optionally substituted alkylene group. Such aralkyl groups are exemplified by benzyloxy, phenylethyloxy, and the like.

[0023] The term “alkenyl” refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms (in some embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) and having from 1 to 6 carboncarbon double bonds, e.g. 1, 2 or 3 carbon-carbon double bonds. In some embodiments, alkenyl groups include ethenyl (or vinyl, i.e. -CH=CH2>, 1-propylene (or allyl, i.e.

-CH₂CH=CH₂), isopropylene (-C(CH₃)=CH₂), and the like.

[0024] The term “lower alkenyl” refers to alkenyl as defined above having from 2 to 6 carbon atoms.

[0025] The term “substituted alkenyl” refers to an alkenyl group as defined above having 1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents) as defined for substituted alkyl.

[0026] The term “alkenylene” refers to a diradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms (in some embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) and having from 1 to 6 carboncarbon double bonds, e.g. 1, 2 or 3 carbon-carbon double bonds.

4824-4563-0480.1

[0027] The term “alkynyl” refers to a monoradical of an unsaturated hydrocarbon, in some embodiments, having from 2 to 20 carbon atoms (in some embodiments, from 2 to carbon atoms, e.g. 2 to 6 carbon atoms) and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2 or 3 carbon-carbon triple bonds. In some embodiments, alkynyl groups include ethynyl (-C^CH), propargyl (or propynyl, i.e. -C=CCH₃), and the like.

[0028] The term “substituted alkynyl” refers to an alkynyl group as defined above having 1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents) as defined for substituted alkyl.

[0029] The term “alkynylene” refers to a diradical of an unsaturated hydrocarbon, in some embodiments, having from 2 to 20 carbon atoms (in some embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2 or 3 carbon-carbon triple bonds.

[0030] The term “hydroxy” or “hydroxyl” refers to a group -OH.

[0031] The term “alkoxy” refers to the group R-O-, where R is alkyl or -Y-Z, in which Y is alkylene and Z is alkenyl or alkynyl, where alkyl, alkenyl and alkynyl are as defined herein. In some embodiments, alkoxy groups are alkyl-O- and includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, 1,2-dimethylbutoxy, and the like.

[0032] The term “lower alkoxy” refers to the group R-O- in which R is optionally substituted lower alkyl. This term is exemplified by groups such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, n-hexyloxy, and the like.

[0033] The term “substituted alkoxy” refers to the group R-O-, where R is substituted alkyl or -Y-Z, in which Y is substituted alkylene and Z is substituted alkenyl or substituted alkynyl, where substituted alkyl, substituted alkenyl and substituted alkynyl are as defined herein.

[0034] The term “C1-3 haloalkyl” refers to an alkyl group having from 1 to 3 carbon atoms covalently bonded to from 1 to 7, or from 1 to 6, or from 1 to 3, halogen(s), where alkyl and halogen are defined herein. In some embodiments, C1-3 haloalkyl includes, by way of example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-tnfluoroethyl, 2,2difluoroethyl, 2-fluoroethyl, 3,3,3-trifluoropropyl, 3,3-difluoropropyl, 3-fluoropropyl.

4824-4563-0480.1

[0035] The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20 carbon atoms, or from 3 to 10 carbon atoms, having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like or multiple ring structures such as adamantanyl and bicyclo[2.2.1]heptanyl or cyclic alkyl groups to which is fùsed an aryl group, for example indanyl, and the like, provided that the point of attachment is through the cyclic alkyl group.

[0036] The term “cycloalkenyl” refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings and having at least one double bond and in some embodiments, from 1 to 2 double bonds.

[0037] The terms “substituted cycloalkyl” and “susbstituted cycloalkenyl” refer to cycloalkyl or cycloalkenyl groups having 1, 2, 3, 4 or 5 substituents (in some embodiments, 1, 2 or 3 substituents), selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-heterocyclyl, -S(O)-aryl,-S(O)heteroaryl, -S(O)₂-alkyl, -S(O)₂-cycloalkyl, -S(O)₂-heterocyclyl, -S(O)₂-aryl and -S(O)₂heteroaryl. The term “substituted cycloalkyl” also includes cycloalkyl groups wherein one or more of the annular carbon atoms of the cycloalkyl group has an oxo group bonded thereto. In addition, a substituent on the cycloalkyl or cycloalkenyl may be attached to the same carbon atom as, or is geminal to, the attachment of the substituted cycloalkyl or cycloalkenyl to the 6,7-ring system. Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by 1, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)_nR^a, in which R^a is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

[0038] The term “cycloalkoxy” refers to the group cycloalkyl-O-,

[0039] The term “substituted cycloalkoxy” refers to the group substituted cycloalkyl-O-,

[0040] The term “cycloalkenyloxy” refers to the group cycloalkenyl-O-,

4824-4563-0480.1

[0041] The term “substituted cycloalkenyloxy” refers to the group substituted cycloalkenyl-O-,

[0042] The term “aryl” refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl) or multiple condensed (fused) rings (e.g., naphthyl, fluorenyl and anthryl). In some embodiments, aryls include phenyl, fluorenyl, naphthyl, anthryl, and the like.

[0043] Unless otherwise constrained by the définition for the aryl substituent, such aryl groups can optionally be substituted with 1, 2, 3, 4 or 5 substituents (in some embodiments, 1, 2 or 3 substituents), selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-heterocyclyl, -S(O)-aryl,-S(O)heteroaryl, -S(O)₂-alkyl, -S(O)₂-cycloalkyl, -S(O)₂-heterocyclyl, -S(O)₂-aryl and -S(O)₂heteroaryl. Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by 1, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino^ cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)_nR^a, in which R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

[0044] The term “aryloxy” refers to the group aryl-O- wherein the aryl group is as defined above, and includes optionally substituted aryl groups as also defined above. The term “arylthio” refers to the group R-S-, where R is as defined for aryl.

[0045] The term “heterocyclyl,” “heterocycle,” or “heterocyclic” refers to a monoradical saturated group having a single ring or multiple condensed rings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, and from 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring. In some embodiments, the heterocyclyl,” “heterocycle,” or “heterocyclic” group is linked to the remainder ofthe molécule through one ofthe heteroatoms within the ring.

[0046] Unless otherwise constrained by the définition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5 substituents (in some

4824-4563-0480.1 embodiments, 1, 2 or 3 substituents), selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-heterocyclyl, -S(O)-aryl,-S(O)heteroaryl, -S(O)₂-alkyl, -S(O)₂-cycloalkyl, -S(O)₂-heterocyclyl, -S(O)₂-aryl and -S(O)₂heteroaryl. In addition, a substituent on the heterocyclic group may be attached to the same carbon atom as, or is geminal to, the attachment of the substituted heterocyclic eroup to the 6,7-ring system. Unless otherwise constrained by the définition, ail substituents may optionally be fùrther substituted by 1, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)_nR^a, in which R^a is alkyl, aryl or heteroaryl and n is 0, 1 or 2. Examples of heterocyclics include tetrahydrofuranyl, morpholino, piperidinyl, and the like.

[0047] The term “heterocyclooxy” refers to the group -O-heterocyclyl.

[0048] The term “heteroaryl” refers to a group comprising single or multiple rings comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring. The term “heteroaryl” is generic to the terms “aromatic heteroaryl” and “partially saturated heteroaryl”. The term “aromatic heteroaryl” refers to a heteroaryl in which at least one ring is aromatic, regardless ofthe point of attachment. Examples of aromatic heteroaryls include pyrrole, thiophene, pyridine, quinoline, pteridine.

[0049] The term “partially saturated heteroaryl” refers to a heteroaryl having a structure équivalent to an underlying aromatic heteroaryl which has had one or more double bonds in an aromatic ring of the underlying aromatic heteroaryl saturated. Examples of partially saturated heteroaryls include dihydropyrrole, dihydropyridine, chroman, 2-oxo-l,2dihydropyridin-4-yl, and the like.

[0050] Unless otherwise constrained by the définition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents) selected from the group consisting alkyl, alkenyl,

4824-4563-0480.1 alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-heterocyclyl, -S(O)-aryl,-S(O)heteroaryl, -S(O)2-alkyl, -S(O)₂-cycloalkyl, -S(O)₂-heterocyclyl, -S(O)₂-aryl and -S(O)₂heteroaryl. Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by 1, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)nR^a, in which R is alkyl, aryl or heteroaryl and n is 0, 1 or 2. Such heteroaryl groups can hâve a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazole or benzothienyl). Examples of nitrogen heterocyclyls and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, and the like as well as N-alkoxynitrogen containing heteroaryl compounds.

[0051] The term “heteroaryloxy” refers to the group heteroaryl-O-.

[0052] The term “amino” refers to the group -NH₂.

[0053] The term “substituted amino” refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl provided that both R groups are not hydrogen or a group -YZ, in which Y is optionally substituted alkylene and Z is alkenyl, cycloalkenyl or alkynyl. Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by 1, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)nR^a, in which R^a is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

4824-4563-0480.1

[0054] The term “alkyl amine” refers to R-NH2 in which R is optionally substituted alkyl.

[0055] The term “dialkyl amine” refers to R-NHR in which each R is independently an optionally substituted alkyl.

[0056] The term “trialkyl amine” refers to NR3 in which each R is independently an optionally substituted alkyl.

[0057] The term “cyano” refers to the group -CN.

[0059] The term “keto” or “oxo” refers to a group =0.

[0060] The term “carboxy” refers to a group -C(O)-OH.

[0061] The term “ester” or “carboxyester” refers to the group -C(O)OR, where R is alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, which may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano or -S(O)_nR , in which R^a is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

[0062] The term “acyl” dénotés the group -C(O)R, in which R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by 1, 2 or j substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)_nR^a, in which R^a is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

[0063] The term “carboxyalkyl” refers to the groups -C(O)O-alkyl or -C(O)Ocycloalkyl, where alkyl and cycloalkyl are as defined herein, and may be optionally further substituted by alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)_nR^a, in which R^a is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

[0064] The term “aminocarbonyl” refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, or where both R groups are joined to form a heterocyclic group (e.g., morpholino). Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by 1, 2

4824-4563-0480.1 or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)_nR^a, in which R^a is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

[0065] The term “acyloxy” refers to the group -OC(O)-R, in which R is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)nR , in which R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

[0066] The term “acylamino” refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl. Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)_nR , in which R^a is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

[0067] The term “alkoxycarbonylamino” refers to the group -N(R^d)C(O)OR in which R is alkyl and R^d is hydrogen or alkyl. Unless otherwise constrained by the définition, each alkyl may optionally be further substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)_nR^a, in which R^a is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

[0068] The term “aminocarbonylamino” refers to the group -NR^CC(O)NRR, wherein R is hydrogen or alkyl and each R is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl. Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)_nR^a, in which R^a is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

[0069] The term “thiol” refers to the group -SH.

4824-4563-0480.1

[0070] The term “thiocarbonyl” refers to a group =S.

[0071] The term “alkylthio” refers to the group -S-alkyl.

[0072] The term “substituted alkylthio” refers to the group -S-substituted alkyl.

[0073] The term “heterocyclylthio” refers to the group -S-heterocyclyl.

[0074] The term “arylthio” refers to the group -S-aryl.

[0075] The term “heteroarylthiol” refers to the group -S-heteroaryl wherein the heteroaryl group is as defined above including optionally substituted heteroaryl groups as also defined above.

[0076] The term “sulfoxide” refers to a group -S(O)R, in which R is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. “Substituted sulfoxide” refers to a group -S(O)R, in which R is substituted alkyl, substituted cycloalkyl, substituted heterocyclyl, substituted aryl or substituted heteroaryl, as defined herein.

[0077] The term “sulfone” refers to a group -S(O)2R, in which R is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. “Substituted sulfone” refers to a group -S(O)₂R, in which R is substituted alkyl, substituted cycloalkyl, substituted heterocyclyl, substituted aryl or substituted heteroaryl, as defined herein.

[0078] The term “aminosulfonyl” refers to the group -S(O)2NRR, wherein each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl. Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)_nR , in which R^a is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

[0079] The term “hydroxyamino” refers to the group -NHOH.

[0080] The term “alkoxyamino” refers to the group -NHOR in which R is optionally substituted alkyl.

[0081] The term “halogen” or “halo” refers to fluoro, bromo, chloro and iodo.

[0082] “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.

4824-4563-0480.1

[0083] A “substituted” group includes embodiments in which a monoradical substituent is bound to a single atom of the substituted group (e.g. forming a branch), and also includes embodiments in which the substituent may be a diradical bridging group bound to two adjacent atoms of the substituted group, thereby forming a fused ring on the substituted group.

[0084] Where a given group (moiety) is described herein as being attached to a second group and the site of attachment is not explicit, the given group may be attached at any available site ofthe given group to any available site ofthe second group. For example, a “lower alkyl-substituted phenyl”, where the attachment sites are not explicit, may hâve any available site of the lower alkyl group attached to any available site of the phenyl group. In this regard, an “available site” is a site of the group at which a hydrogen of the group may be replaced with a substituent.

[0085] It is understood that in ail substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, etc.) are not intended for inclusion herein. Also not included are infinité numbers of substituents, whether the substituents are the same or different. In such cases, the maximum number of such substituents is three. Each of the above définitions is thus constrained by a limitation that, for example, substituted aryl groups are limited to -substituted aryl-(substituted aryl)-substituted aryl.

[0086] A compound of a given formula (e.g. the compound of Formula I, which also includes Formula IA, IB, II, ΠΑ, ΙΠ, ΙΠΑ, IV, V, VI, VIII, VIIIA, IX, X, XI and XIII) is intended to encompass the compounds of the disclosure, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, isomers, tautomers, solvatés, isotopes, hydrates, polymorphs, and prodrugs of such compounds. Additionally, the compounds ofthe disclosure may possess one or more asymmetric centers, and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers présent in any given compound of a given formula dépends upon the number of asymmetric centers présent (there are 2ⁿ stereoisomers possible where n is the number of asymmetric centers). The individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage ofthe synthesis or by resolution ofthe compound by conventional means. The individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic

4824-4563-0480.1 and non-racemic mixtures of stereoisomers are encompassed within the scope of the présent disclosure, ail of which are intended to be depicted by the structures of this spécification unless otherwise specifically indicated.

(0087] “Isomers” are different compounds that hâve the same molecular formula.

Isomers include stereoisomers, enantiomers and diastereomers.

[0088] “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space.

[0089] “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. Aid mixture of a pair of enantiomers is a racemic mixture. The term (±) is used to designate a racemic mixture where appropriate.

[0090] “Diastereoisomers” are stereoisomers that hâve at least two asymmetric atoms, but which are not mirror-images of each other.

[0091] The absolute stereochemistry is specifïed according to the Cahn Ingold Prelog R S system. When the compound is a pure enantiomer the stereochemistry at each chiral carbon may be specifïed by either R or S. Resolved compounds whose absolute configuration is unknown are designated (+) or (-) depending on the direction (dextro- or laevorotary) that they rotate the plane of polarized light at the wavelength ofthe sodium

D line.

[0092] Some ofthe compounds exist as tautomeric isomers. Tautomeric isomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless ofthe nature ofthe equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers. Non-limiting examples of amide-compnsing and imidic acid-comprising tautomers are shown below:

4824-4563-0480.1

[0093] The term “therapeutically effective amount” refers to an amount that is sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and âge ofthe subject, the severity ofthe disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.

[0094] The term “polymorph” refers to different crystal structures of a crystalline compound. The different polymorphs may resuit from différences in crystal packing (packing polymorphism) or différences in packing between different conformers ofthe same molécule (conformational polymorphism).

[0095] The term “solvaté” refers to a complex formed by the combining of a compound of Formula I, IA, IB, II, ΠΑ, ΠΒ, ΙΠ, ΠΙΑ, IV, V, VI, VIII, VÏÏIA, IX, X, ΧΠ or ΧΠΙ and a solvent.

[0096] The term “hydrate” refers to the complex formed by the combining of a compound of Formula I, IA, IB, Π, ΠΑ, ΠΒ, ΙΠ, ΙΠΑ, IV, V, VI, VIII, VHIA, IX, X, XII or ΧΙΠ and water.

[0097] The term “prodrug” refers to compounds of Formula I, IA, IB, II, ΠΑ, ΠΒ, III, ΙΠΑ, IV, V, VI, VIII, VIIIA, IX, X, ΧΠ or ΧΙΠ that include Chemical groups which, in vivo, can be converted and/or can be split off from the remainder of the molécule to provide for the active drug, a pharmaceutically acceptable sait thereof or a biologically active métabolite thereof.

[0098] Any formula or structure given herein, including Formula I, IA, IB, Π, ΠΑ, ΠΒ, ΙΠ ΠΙΑ, IV, V, VI, VIII VIIIA, IX, X, XII or ΧΙΠ compounds, is also intended to represent unlabeled forms as well as isotopically labeled forms ofthe compounds. Isotopically labeled compounds hâve structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds ofthe disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to ²H (deuterium, D), ³H (tritium), ⁿC, ¹³C, ¹⁴C, ¹⁵N, i8p 3ip 32p 35g ³⁶(2| and ¹²⁵I. Various isotopically labeled compounds ofthe présent disclosure, for example those into which radioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated. Such isotopically labelled compounds may be useful in metabohc studies,

4824-4563-0480.1 reaction kinetic studies, détection or imaging techniques, such as positron émission tomography (PET) or single-photon émission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0099] The disclosure also included compounds of Formula I, IA, IB, Π, IIA, IIB, III, IIIA, IV, V, VI, VIII, VIIIA, IX, X, XII or XIII in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molécule. Such compounds exhibit increased résistance to metabolism and are thus usefùl for increasing the half life of any compound of Formula I when administered to a mammal. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens hâve been replaced by deuterium.

[0100] Deuterium labelled or substituted therapeutic compounds ofthe disclosure may hâve improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excrétion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resuiting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. An ¹⁸F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds ofthis disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and préparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I.

[0101] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds ofthis disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as H or hydrogen, the position is understood to hâve hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds ofthis disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

4824-4563-0480.1

[0102] The term “treatment” or “treating” means administration of a compound of the invention, by or at the direction of a competent caregiver, to a mammal having a disease for purposes including:

(i) preventing the disease, that is, causing the clinical symptoms ofthe disease not to develop;

(ii ) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or (iii ) relieving the disease, that is, causing the régression of clinical symptoms.

[0103] In many cases, the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.

[0104] The term “pharmaceutically acceptable sait” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts denved from inorgamc bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnésium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, tnaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two ofthe substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group. Amines are of general structure

4824-4563-0480.1

N(R³⁰)(R³¹)(R³²), wherein mono-substituted amines hâve 2 ofthe three substituents on nitrogen (R³⁰, R³¹ and R³²) as hydrogen, di-substituted amines hâve 1 ofthe three substituents on nitrogen (R³⁰, R³¹ and R³²) as hydrogen, whereas tri-substituted amines hâve none ofthe three substituents on nitrogen (R³⁰, R³¹ and R³²) as hydrogen. R³⁰, R³¹and R³² are selected from a variety of substituents such as hydrogen, optionally substituted alkyl, aryl, heteroayl, cycloalkyl, cycloalkenyl, heterocyclyl and the like. The above-mentioned amines refer to the compounds wherein either one, two or three substituents on the nitrogen are as listed in the name. For example, the term “cycloalkenyl amine” refers to cycloalkenyl-NH₂, wherein “cycloalkenyl is as defined herein. The term “diheteroarylamine” refers to NH(heteroaryl)₂, wherein “heteroaryl” is as defined herein and so on.

[0105] Spécifie examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, Nalkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, Nethylpiperidine, and the like.

[0106] Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycohc acid, pyruvic acid, oxahc acid, malic acid, malonic acid, succinic acid, maleic acid, fùmaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfomc acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.

[0107] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and ail solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonie and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known m the art. Except insofar as any conventional media or agent is incompatible with the active ingrédient, its use in the therapeutic compositions is contemplated. Supplementary active ingrédients can also be incorporated into the compositions.

4824-4563-0480.1

[0108] “Coronary diseases” or “cardiovascular diseases” refer to diseases of the cardiovasculature arising from any one or more than one of, for example, heart failure (including congestive heart failure, diastolic heart failure and systolic heart failure), acute heart failure, ischemia, récurrent ischemia, myocardial infarction, arrhythmias, angina (including exercise-induced angina, variant angina, stable angina, unstable angina), acute coronary syndrome, diabètes and intermittent claudication.

[0109] “Intermittent claudication” means the pain associated with peripheral artery disease. “Peripheral artery disease” or PAD is a type of occlusive peripheral vascular disease (PVD). PAD affects the arteries outside the heart and brain. The most common symptom of PAD is a painful cramping in the hips, thighs or calves when walking, climbing stairs or exercising. The pain is called intermittent claudication. When listing the symptom intermittent claudication, it is intended to include both PAD and PVD.

[0110] Arrhythmia refers to any abnormal heart rate. Bradycardia refers to abnormally slow heart rate whereas tachycardia refers to an abnormally rapid heart rate. As used herein, the treatment of arrhythmia is intended to include the treatment of supra ventricular tachycardias such as atrial fibrillation, atrial flutter, AV nodal reentrant tachycardia, atrial tachycardia and the ventricular tachycardias (VTs), including idiopathic ventricular tachycardia, ventricular fibrillation, pre-excitation syndrome and Torsade de Pointes (TdP).

2. Nomenclature

[0111] Names of compounds of the présent disclosure are provided using ACD/Name software for naming Chemical compounds (Advanced Chemistry Development, Inc., Toronto, Canada). Other compounds or radicals may be named with common names or systematic or non-systematic names. The naming and numbering of the compounds of the disclosure is illustrated with a représentative compound of Formula I:

which is named 4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5 (2H)-one.

4824-4563-0480.1

3. Compounds

[0112] Accordingly, typical embodiments the présent disclosure provide novel compounds that function as late sodium channel blockers. In one embodiment, the disclosure provides compounds of Formula I:

wherein:

N;

Z³ and Z⁴ are each independently selected from the group consisting of CR⁷, C-QR¹ and N, provided that one of Z³ and Z⁴ is C-Q-R¹ and the other of Z³ and Z⁴ is CR⁷ or N and further provided that only one of Z¹, Z² and Z⁴ is N,

X is -O- or -NR⁶-;

Y is -C(O)-, -C(Rⁿ)2- or -S(O)₂-;

Q is a covalent bond, -O-C0-2 alkylene, -NR¹ ‘-Co-2 alkylene, C₂ alkylene,

C₂ alkenylene or C2 alkynylene;

R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl, wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, -CN, -SF₅, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2-R²⁰, -OS(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Ci-6 alkyl, C₂-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Ci-₆ alkyl, C₂-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two

4824-4563-0480.1 or three substituents independently selected from the group consisting of halo, -NCh, aryl, heterocyclyl, heteroaryl, C1-6 alkyl,

C1-3 haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰,

-C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -Ci-6 alkylene-R⁵, -L-R⁵, -L-C1-6 alkylene-R⁵, -Ci^ alkylene-L-R⁵ or -Ci-₆alkylene-L-Ci-6 alkylene-R⁵;

wherein each -C1-6 alkylene is optionally substituted by one substituent independently selected from the group consisting of C2-4 alkynyl, halo, -NO2, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C₂-4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH-, or -NHC(O)-; provided that when Y is -C(Rⁿ)2-, then R² is -L-R⁵, -L-C1-6 alkylene-R⁵, -C1-6 alkyleneL-R⁵ or -C1-6 alkylene-L-Ci-6 alkylene-R⁵ and L is not -C(O)-> and when R² is -L-R⁵ or -L-C1-6 alkylene-R⁵, thenL is not -O-, -S-, -NHS(O)₂or -NHC(O)-;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents

4824-4563-0480.1 independently selected from the group consisting of halo, -NO2,

C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,

-N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and

-O-R²⁰; and wherein said C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O_R2°.

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-₆ alkyl, -O-R²⁰, -N(R²⁰)(R²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said C1-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;

each R⁴ is independently hydrogen, deuterium, C1-6 alkyl, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁶), cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein said C1-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and

4824-4563-0480.1 wherein said Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C2-4 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -OR²⁰;

wherein said alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C^ alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R⁶ is hydrogen, C1-6 alkyl or cycloalkyl, wherein said Ci^ alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

4824-4563-0480.1

R⁷ is hydrogen, halo, -O-R²⁰ or Ci-6 alkyl;

R¹¹ is hydrogen or Ci-4 alkyl;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Ci-₆ alkyl, C₂.₆ alkenyl, C₂-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cw alkyl, C2-6 alkenyl, C₂.₆ alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, acylamino, oxo, -NO₂, -S(O)₂R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with C1-4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Ci-4 alkyl, aryl and cycloalkyl;

wherein the C1-4 alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkoxy, -CF₃ and -OCF₃, or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof;

provided that when Y is -C(O)-, X is -O-, each R⁴ is hydrogen, R² and R³ together with the atom to which they are attached form a piperazine which is optionally substituted with tert-butoxycarbonyl and Q is a bond, then R¹ is not unsubstituted phenyl or morpholinyl; and that when Y is -S(O)₂-, X is -O-, R² is benzyl, each R³is hydrogen, Z⁴ is C-Q-R¹, Q is a bond and R¹ is aryl or heteroaryl, then both R⁴are hydrogen.

4824-4563-0480.1

[0113] In another embodiment, the disclosure provides compounds of Formula I.

R²

R⁴

I wherein:

N;

Z³ and Z⁴ are each independently selected from the group consisting of CR⁷, C-Q_Ri and N, provided that one of Z³ and Z⁴ is C-Q-R¹ and the other of Z³ and Z⁴ is CR⁷ or N and further provided that only one of Z¹, Z² and Z is N,

X is -O- or -NR⁶-;

Y is -C(O)-;

Q is a covalent bond, -0-Co-₂ alkylene, -NR^u-Co-₂ alkylene, C₂ alkylene,

C₂ alkenylene or C₂ alkynylene;

R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl;

wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl are optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of halo, -NO₂, -CN, -SF₅, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2-R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C₂-4 alkenyl, C₂-₄alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Ci-6 alkyl, C₂-4 alkenyl, C₂-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, Ci-6 alkyl, C1-3 haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

4824-4563-0480.1

R² is -Ci-6 alkylene-R⁵, -L-R⁵, -L-Ci-6 alkylene-R⁵, -Ci-6 alkylene-L-R⁵ or -Ci-₆ alkylene-L-Ci-6 alkylene-R⁵;

wherein each -Ci-6 alkylene is optionally substituted by one substituent independently selected from the group consisting of C₂-₄ alkynyl, halo, -NO₂, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-₆ alkyl, C₂-₄alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰, _{L IS} -o-, -S-, -C(O>, -NHS(O)z-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-; provided that when R² is -L-R^! or -L-Cw alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NHC(O)-; and each R³ is independently hydrogen, deuterium, Ci-₆ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C^ alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, θ -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and

-O-R²⁰; and wherein said Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected

4824-4563-0480.1 from the group consisting of halo, -NO2, -N(R²⁰)(R²²),

-C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, -O-R²⁰, -N(R²⁰)(R²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said C1-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO2, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

4824-4563-0480.1

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C2-4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -OR²⁰;

wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R⁶ is hydrogen, C1-6 alkyl or cycloalkyl;

wherein said C1-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R⁷ is hydrogen, halo, -O-R²⁰ or C1-6 alkyl;

R¹¹ is hydrogen or C1-4 alkyl;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C1-6 alkyl, C₂-6 alkenyl, C₂-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C1-6 alkyl, C₂-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl,

4824-4563-0480.1 halo, Ci-4 alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3,

-OCF3, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with C1-4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, Ci-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, C1-4 alkyl, aryl and cycloalkyl;

provided that when X is -O-, each R⁴ is hydrogen, R² and R³ together with the atom to which they are attached form a piperazine which is optionally substituted with tert-butoxycarbonyl and Q is a bond, then R¹ is not unsubstituted phenyl or morpholinyl.

[0114] In another embodiment, the disclosure provides compounds of Formula I:

R²

R⁴

I wherein Z¹, Z², Z³, Z⁴, X, R³ and R⁴ are as defined herein;

Yis -C(R¹¹)₂-;

R² is -L-R³, -L-Ci-6 alkylene-R³, -Ci-ô alkylene-L-R⁵ or -C1-6 alkylene-L-Ci-6 alkylene-R⁵;

4824-4563-0480.1 wherein each -Ci-6 alkylene is optionally substituted by one substituent independently selected from the group consisting of C2-4 alkynyl, halo,

-NO2, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C2-4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

L is -O-, -S-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-; and

R¹¹ is hydrogen or C1-4 alkyl.

[0115] In yet another embodiment, the disclosure provides compounds of Formula I:

,R² wherein Z¹, Z², Z³, Z⁴, X, R², R³ and R⁴ are as defined herein; and

Y is -S(O)₂-;

provided that when X is -O-, R² is benzyl, each R³ is hydrogen, Z⁴ is C-Q-R¹, Q is a bond and R¹ is aryl or heteroaryl, then both R⁴ are hydrogen.

[0116] In some embodiments, R¹ is aryl, cycloalkyl, cycloalkenyl or heteroaryl, wherein said aryl, cycloalkenyl or heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -O-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)OR²², -S(O)2-R²⁰, -O-S(O)2-R²⁰, C1-6 alkyl, cycloalkyl and heterocyclyl; and

4824-4563-0480.1 wherein said Ci-6 alkyl or cycloalkyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -CN and -O-R²⁰.

[0117] In some embodiments, each R³ is independently hydrogen, deuterium or Ci-6 alkyl.

[0118] In some embodiments, each R⁴ is independently hydrogen, deuterium or Ci-6 alkyl.

[0119] In some embodiments, R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-₆ alkyl, halo, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -O-R²⁰;

wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, Ci-6 alkyl, aryl, heterocyclyl and heteroaryl; and wherein said Ci-₆ alkyl is optionally further substituted with one, two or three halo.

[0120] In some embodiments, R² and one of R³ can join together with the atom to which they are attached to form a heterocyclyl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, -OR²⁰, -N(R²⁰)(R²²) and -C(O)-OR²⁰; and wherein said Ci-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl.

[0121] In certain embodiments of each of the formulas disclosed herein, each -Ci-6 alkylene of R² is unsubstituted -Ci-6 alkylene.

[0122] In certain embodiments, the compound is not tert-butyl 6-oxo-8-phenyl3,4,12,12a-tetrahydro-lH-benzo[f]pyrazino[2,1 -c][ 1,4]oxazepine-2(6H)-carboxylate, tert

4824-4563-0480.1 butyl 6-oxo-9-phenyl-3,4,12,12a-tetrahydro- lH-benzo[f]pyrazino [2,1 -c] [ 1,4]oxazepine2(6H)-carboxylate, 8-phenyl-3,4,12,12a-tetrahydro-lH-benzo[f|pyrazino[2,lc][l,4]oxazepin-6(2H)-one, 9-phenyl-3,4,12,12a-tetrahydro-lH-benzo[f]pyrazino[2,lc][ 1,4]oxazepin-6(2H)-one, 8-morpholino-1,2,3,4,12,12ahexahydrobenzo[e]pyrazino[l,2-a]azepin-6(llH)-one, tert-butyl 8-morpholino-6-oxo3,4,6,11,12,12a-hexahydrobenzo[e]pyrazino[l,2-a]azepine-2(lH)-carboxylate, tert-butyl 2-morpholino-12-oxo-5,6,6a,7,9,10-hexahydropyrazino[l,2-a]pyrido[3,2-e]azepine8(12H)-carboxylate, 2-morpholino-6,6a,7,8,9,10-hexahydropyrazino[l,2-a]pyrido[3,2e]azepin-12(5H)-one, 2-morpholino-8,9,10,10a, 11,12-hexahydropyrazino [1,2a]pyrido[2,3-e]azepin-5(7H)-one or tert-butyl 2-morpholino-5-oxo-7,8,10,10a,l 1,12hexahydropyrazino[l,2-a]pyrido[2,3-e]azepine-9(5H)-carboxylate.

[0123] In alternative embodiments, the disclosure provides compounds of Formula I:

wherein:

N;

Z³ and Z⁴ are each independently selected from the group consisting of CR⁷, C-QR¹ and N, provided that one ofZ³ and Z⁴ is C-Q-R¹ and the other of Z³ and Z⁴ is CR⁷ or N and further provided that only one of Z¹, Z² and Z⁴ is N;

X is -O- or -NR⁶-;

Y is -C(O)-, -CCR¹¹)!- or -S(O)₂-;

Q is a covalent bond, -0-Co-₂ alkylene, -NR^-Co-z alkylene or C₂ alkynylene,

R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl;

wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CN, -SFs, -Si(CH3)3,

-O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)-N(R²⁰)(R²²),

4824-4563-04SU.1

-N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2-R²⁰, -oS(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C₂.₄ alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Ci-6 alkyl, C₂.₄ alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Ci-6 alkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -C1-6 alkylene-R⁵, -L-R⁵, -L-C1-6 alkylene-R⁵, -Ci-6 alkylene-L-R⁵ or -C1-6 alkylene-L-Ci-6 alkylene-R⁵;

L i_s -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-; provided that when Y is -CCR¹ ^2-, then R² is -L-R⁵, -L-C1-6 alkylene-R⁵, -Ci-₆alkylene-L-R⁵ or -C1-6 alkylene-L-Ci-6 alkylene-R⁵;

each R³ is independently hydrogen, deuterium, C1-15 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ci-15 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, -N(R²⁰)(R²²),

4824-4563-0480.1

-C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of C1-15 alkyl, -O-R²⁰, -N(R²⁰)(R²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said C1-15 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;

each R⁴ is independently hydrogen, deuterium, C1-15 alkyl, C1-4 alkoxy, -C(O)OR²⁶, -C(O)-N(R²⁶)(R²⁶), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C1-15 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(0)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

4824-4563-0480.1

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C2-4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R⁶ is hydrogen, C1-15 alkyl, -C(O)-R²⁰, -C(O)-OR²⁶, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted

4824-4563-0480.1 with one, two or three substituents independently selected from the group consisting of halo, -NO2, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

R⁷ is hydrogen, halo or C1-6 alkyl;

R¹¹ is hydrogen or C1-4 alkyl;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF₃, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Ci-₄alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, Ci-3 alkoxy, -CF3, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Ci-₄alkyl, aryl and cycloalkyl; and wherein the Ci-₄ alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Ci-₄ alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, hydrate, solvaté, stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or prodrug thereof;

provided that when Y is -C(O)-, X is -O-, each R⁴ is hydrogen, R² and R together with the atom to which they are attached form a piperazine which is optionally substituted

4824-4563-0480.1 with tert-butoxycarbonyl and Q is a bond, then R¹ is not unsubstituted phenyl or morpholinyl; and that when Y is -S(O)2-, X is -O-, R² is benzyl, each R³ is hydrogen, Z⁴ is C-Q-R¹, Q is a bond and R¹ is aryl or heteroaryl, then both R⁴ are hydrogen.

[0124] In some embodiments, R¹ is aryl, cycloalkyl, cycloalkenyl or heteroaryl;

wherein said aryl, cycloalkenyl or heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -O-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)OR²², -S(O)2-R²⁰, -O-S(O)2-R²⁰, Ci-6 alkyl, cycloalkyl and heterocyclyl; and wherein said Cm alkyl or cycloalkyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -CN and -O-R²⁰.

[0125] In some embodiments, each R³ is independently hydrogen, deuterium or Ci-i5 alkyl.

[0126] In some embodiments, each R⁴ is independently hydrogen, deuterium or C1-15 alkyl.

[0127] In some embodiments, R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, halo, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, Cm alkyl, aryl, heterocyclyl and heteroaryl; and wherein said Cm alkyl is optionally further substituted with one, two or three halo.

[0128] In some embodiments, Y is -C(O)- and R² and one of R³ can join together with the atom to which they are attached to form a heterocyclyl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of C1-15 alkyl, -O-R²⁰, -N(R²⁰)(R²²) and -C(O)-OR²⁰; and

4824-4563-0480.1 wherein said C1-15 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl.

In some embodiments, the disclosure provides compounds of Formula IA:

[0129]

wherein:

Cy is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl;

Q is a covalent bond, -O-C0-2 alkylene, -NR^-Co^ alkylene, C2 alkylene,

C2 alkenylene or C2 alkynylene;

m is 0, 1, 2 or 3;

n is 0, 1, 2, 3, 4 or 5;

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF₅, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2r²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C₂-4 alkenyl, C₂-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Ci-₆ alkyl, C₂-₄ alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, aryl, heterocyclyl, heteroaryl, C1-6 alkyl, Ci-₃haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -C1-6 alkylene-R⁵, -L-R⁵, -L-C1-6 alkylene-R⁵, -C1-6 alkylene-L-R or -C1-6 alkylene-L-Ci-6 alkylene-R⁵;

wherein each -C1-6 alkylene is optionally substituted by one substituent independently selected from the group consisting of C2-4 alkynyl, halo, -NO2, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)61

4824-4563-0480.1

N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C2-4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-; provided that when R² is -L-R⁵ or -L-C1-6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)2- or -NHC(O)-; and each R³ is independently hydrogen, deuterium, C1-6 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C1-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R , -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO2, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

4824-4563-0480.1 wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂,

C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²),

-C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰,

R¹⁷ is halo, -O-R²⁰ or C1-6 alkyl;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Ci-₆ alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, acylamino, oxo, -NO2, -S(O)₂R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with C1-4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO_2;

-S(O)₂R²⁶, -CN, C1.3 alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Ci-₄alkyl, aryl and cycloalkyl;

4824-4563-0480.1 wherein the Ci-4 alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkoxy, -CF₃ and -OCF₃;

[0130] In certain embodiments, the disclosure provides compounds of Formula II:

wherein:

m is 0, 1, 2 or 3;

n is 0, 1, 2, 3, 4 or 5;

each R¹⁰ is independently selected from the group consisting of halo, -NO₂, -CN, -SF₅, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C₂-4 alkenyl, C₂-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, aryl, heterocyclyl, heteroaryl, C1-6 alkyl, Ci-₃haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein each -C1-6 alkylene is optionally substituted by one substituent independently selected from the group consisting of C2-4 alkynyl, halo,

4824-4563-0480.1

-NO₂, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C₂-₄alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-Ci-6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NHC(O)-;

each R³ is independently hydrogen, deuterium, Ci-6 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ci-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

4824-4563-0480.1 or R² and one of R³ can join together with the atom to which they are attached to form a heterocyclyl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, -O-R²⁰, -N(R²⁰)(R²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said Ci-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO2, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C2-4 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, -N(R²⁰)

4824-4563-0480.1

C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -OR²⁰;

wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R¹⁷ is halo, -O-R²⁰ or C1-6 alkyl;

wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Ci-₄alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Ci-₄alkyl, aryl and cycloalkyl;

4824-4563-0480.1 wherein the Ci-₄ alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Ci-₄ alkoxy, -CF3 and -OCF3;

provided that when m is 0, each R⁴ is hydrogen, R² and R³ together with the atom to which they are attached form a piperazine which is optionally substituted with tert-butoxycarbonyl and Q is a bond, then n is 1, 2 or 3.

[0131] In some embodiments, R² is -C1-6 alkylene-R⁵ or -C1-6 alkylene-L-R³.

[0132] In some embodiments, each -C1-6 alkylene of R² is optionally substituted by one substituent independently selected from the group consisting of C2-4 alkynyl, halo, -NO2, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)-N(R²⁰)(R²²), -N(R²⁰)-S(O)2R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C2-₄ alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)N(R²⁰)(R²²), -CN and -O-R²⁰.

[0133] In some embodiments, each -C1-6 alkylene of R² is unsubstituted.

[0134] In some embodiments, R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, halo, cycloalkyl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-OR²⁰, -CN and -O-R²⁰;

wherein said C1-6 alkyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of halo, C1-6 alkyl and aryl; and wherein said C1-6 alkyl is optionally fùrther substituted with one, two or three halo.

[0135] In some embodiments, R² and one of R³ can join together with the atom to which they are attached to form a heterocyclyl;

-O-R²⁰, -N(R²⁰)(R²²) and -C(O)-OR²⁰; and wherein said Ci-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl.

4824-4563-0480.1

[0137] In some embodiments, n is 1, 2 or 3; and each R¹⁰ is independently selected from the group consisting of halo, -O-R²⁰, -OS(O)2-R²⁰, Ci-4 alkyl and cycloalkyl; and wherein said alkyl and cycloalkyl are optionally substituted with one, two or three halo or -CN; and

4824-4563-0480.1

R²⁰ is independently selected from the group consisting of Ci-6 alkyl, cycloalkyl and aryl; and wherein the alkyl and aryl are optionally substituted with one, two or three halo or cycloalkyl.

[0138] In some embodiments, n is 1, 2 or 3; and each R¹⁰ is independently 2-fluoro, 3fluoro, 4-fluoro, 2-chloro, 4-chloro, 2-methyl, 4-methyl, 4-ethyl, 4-isopropyl, 4-tert-butyl, 4-difluoromethyl, 4-trifluoromethyl, 4-cyclopropyl, 4-isobutoxy, 4-difluoromethoxy, 4trifluoromethoxy, 4-(2,2,2-trifluoroethoxy), 4-trifluoromethyl sulfoxyl, 4-(2,2,2trifluoroethyl), 4-cyclopropoxy, 4-cyclobutylmethoxy, 4-fluorophenoxy, 4-phenoxy or 3phenoxy.

[0139] In some embodiments, each R³ is independently hydrogen, deuterium or Ci-6 alkyl optionally substituted with heteroaryl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, -N(R²⁰)(R²²) and -N(R²⁰)-C(O)-OR²⁰; and wherein said Ci-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl; and

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Ci-6 alkyl and heteroaryl.

[0140] In some embodiments, each R³ is independently hydrogen, deuterium or Ci-6 alkyl optionally substituted with heteroaryl; and each R⁴ is independently hydrogen, deuterium or Ci-6 alkyl optionally substituted with heteroaryl.

[0141] In some embodiments, each R³ is independently hydrogen, deuterium or Ci-6 alkyl optionally substituted with heteroaryl;

m is 0 or 1 ; and

R¹⁷ is halo.

4824-4563-0480.1

[0142] In some embodiments, each R³ is independently hydrogen, deuterium, methyl, isopropyl or pyridin-2-ylmethyl;

m is 0 or 1; and

R¹⁷ is fluoro.

[0143] In some embodiments, each R⁴ is independently hydrogen, deuterium or Ci-6 alkyl.

[0144] In some embodiments, each R³ is independently hydrogen, deuterium or Ci-₆alkyl optionally substituted with heteroaryl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, -N(R²⁰)(R²²) and -N(R²⁰)-C(O)-OR²⁰; and wherein said Ci-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl; and each R⁴ is independently hydrogen, deuterium or Ci-6 alkyl optionally substituted with heteroaryl.

[0145] In certain embodiments, the disclosure provides compounds of Formula IIA:

wherein:

n is 0, 1, 2 or 3;

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Ci-6 alkyl, C2-4 alkenyl, C₂-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and

4824-4563-0480.1 wherein said Ci-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo,

-NO2, aryl, heterocyclyl, heteroaryl, C1-6 alkyl, C1-3 haloalkyl, cycloalkyl,

-N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

_L i_s -o-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-, provided ' that when R² is -L-R⁵ or -L-C1-6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NHC(O)-;

each R³ is independently hydrogen or C1-6 alkyl;

each R⁴ is independently hydrogen or C1-6 alkyl;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

4824-4563-0480.1

wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, acylamino, oxo, -NO₂, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with C1-4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂.

-S(O)₂R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, C1-4 alkyl, aryl and cycloalkyl;

wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkoxy, -CF₃ and -OCF₃;

[0146] In certain embodiments, the disclosure provides compounds of Formula IIB:

wherein:

n is 0, 1, 2 or 3;

each R¹⁰ is independently selected from the group consisting of halo, -NO₂, -CN, -SF₅, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2

4824-4563-0480.1

R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Ci-6 alkyl, C2-₄ alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;

wherein said C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, aryl, heterocyclyl, heteroaryl, Ci-β alkyl, C1-3 haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -C1-6 alkylene-R⁵;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C2-4 alkynyl, halo, -NO2, -N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, -N(R²⁰)-C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)N(R²⁰)(R²²), -CN, oxo and -O-R²⁰; and wherein said Ci-6 alkyl is optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF₃, -OCH₂CF₃ and -C(O)-NH₂; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂.

-S(O)₂R²⁶, -CN, C1-3 alkoxy, -CF₃ and -OCF₃; and

4824-4563-0480.1 each R²⁶ is independently selected from the group consisting of hydrogen, Ci-4 alkyl, aryl and cycloalkyl;

wherein the Ci-4 alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cim alkoxy, -CF3 and -OCF3;

[0147] In some embodiments, n is 1, 2 or 3; and each R¹⁰ is independently selected from the group consisting of halo, -O-R²⁰, -OS(O)₂-R²⁰, C1-4 alkyl and cycloalkyl; and wherein said alkyl and cycloalkyl are optionally substituted with one, two or three halo or -CN; and

R²⁰ is C1-6 alkyl, cycloalkyl or aryl; and wherein the alkyl and aryl are optionally substituted with one, two or three halo or cycloalkyl.

[0148] In some embodiments, n is 1, 2 or 3; and each R¹⁰ is independently 2-fluoro, 3fluoro, 4-fluoro, 2-chloro, 4-chloro, 2-methyl, 4-methyl, 4-ethyl, 4-isopropyl, 4-tert-butyl, 4-difluoromethyl, 4-trifluoromethyl, 4-cyclopropyl, 4-isobutoxy, 4-difluoromethoxy, 4trifluoromethoxy, 4-(2,2,2-trifluoroethoxy), 4-trifluoromethylsulfoxyl, 4-(2,2,2trifluoroethyl), 4-cyclopropoxy, 4-cyclobutylmethoxy, 4-fluorophenoxy, 4-phenoxy or 3phenoxy.

[0149] In some embodiments, the compound is selected from the group consisting of: 4-((3-methyloxetan-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo [f] [ 1,4] oxazepin-5 (2H)-one (Π-1 );

4-(2-(pyrrolidin-l-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-3);

4-((5-cyclobutyl-l,3,4-oxadiazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-4);

4-((2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-5);

4824-4563-0480.1

4-(quinolin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (II-7);

(R)-2-(pyrimidin-2-ylmethyl)-8-(4-(trifluoromethyl)pheny 1)-3,4,12,12a-tetrahydro-l Hbenzo[f]pyrazino[2,1 -c][ 1,4]oxazepin-6(2H)-one (II-8);

4-(cyclopropylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-10);

(S)-3-methyI-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (Π-12);

(R)-3-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f] [ 1,4] oxazepin-5 (2H)-one (II-13);

7-(4-(trifluoromethoxy)phenyl)-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-16);

4-((6-methylpyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (Π-17);

(2R, 1 laS)-2-amino-7-(4-(trifluoromethyl)pheny 1)-2,3,11,1 latetrahydrobenzo[f]pyrrolo[2,l-c][l,4]oxazepin-5(lH)-one (11-21);

(R)-2-(2,2-difluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-lHbenzo[f]pyrazino[2, l-c][l,4]oxazepin-6(2H)-one (11-22);

(R)-2-ethyl-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro- 1Hbenzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one (11-23);

(S)-2-(2,2-difluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-lHbenzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one (11-24);

4824-4563-0480.1

4-((5 -methyloxazol-2-yl)methyl)-7-(4-(trifluoromethoxy)pheny 1)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5 (2H)-one (Π-3 3 );

7-(4-(trifluoromethoxy)phenyl)-4-(2-(2,5,5-trimethyl-l,3-dioxan-2-yl)ethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-35);

tert-butyl (2R, 1 laR)-5-oxo-7-(4-(trifluorornethyl)phenyl)-l,2,3,5,11,11ahexahydrobenzo[f]pyrrolo[2,l-c][l,4]oxazepin-2-ylcarbamate (11-39);

4-((5-(pyridin-2-yl)isoxazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (H-41 );

4-(2-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-44);

4-(3,4-difluorobenzyl)-7-(4-(trifluoromethoxy)pheny l)-3,4-dihydrobenzo[f] [ 1,4] oxazepin5(2H)-one (11-45);

4-(2,6-dichlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-48);

4-(2,6-difluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-49);

4-(2-( 1 H-pyrazol-1 -yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-50);

(2S,1 laS)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,l 1,1 latetrahydrobenzo[f]pyrrolo[2,l-c][l,4]oxazepin-5(lH)-one (Π-51);

4824-4563-0480.1

4-(2-(pyridin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (11-54);

4-(2-fluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-57);

(R)-7-(4-(trifluoromethyl)phenyl)-2,3,11,11 a-tetrahydrobenzo[f]pyrrolo[2,1 c] [ 1,4]oxazepin-5( lH)-one (H-59);

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-61);

4-(4-fluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-62);

4-((l-methyl-lH-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (H-64);

4-((5-chloropyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-65);

4-(pyridin-4-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (Π-67);

4-((5-cyclopropyl-l,3,4-oxadiazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-68);

4-(2-(pyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-69);

4-(pyridin-3-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzoff] [ 1,4]oxazepin-5(2H)-one (Π-70);

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (ïï-72);

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (Π-73);

4-((3-methylpyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-75);

4824-4563-0480.1 (R)-2-(2,2,2-trifluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-lHbenzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one (11-83);

7-(4-ethylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo [f] [ 1,4]oxazepin-5 (2H)-one (Π-91);

7-(4-cyclopropylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-92);

(R)-4-(l-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-95);

7-(4-tert-butylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f] [ 1,4]oxazepin5(2H)-one (11-98);

7-(4-cyclopropoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f] [ 1,4]oxazepin5(2H)-one (11-102);

7-(4-fluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one (11-104);

7-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihy drobenzo [f] [ 1,4] oxazepin-5 (2H)-one (Π-10 5 ) ;

7-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (II-106);

4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethoxy)phenyl)-3,4dihydrobenzo [f] [ 1,4]oxazepin-5 (2H)-one (Π-107);

4824-4563-0480.1

7-(4-(trifluoromethoxy)phenyl)-4-((5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2yl)methyl)-3,4-dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (II-115);

l-(4-(5-oxo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepin-7yl)phenyl)cyclopentanecarbonitrile (II-122);

7-(4-ethoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepm-5(2H)one (11-123);

7-(4-(difluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-124);

4-(imidazo[l,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-129);

4-((4-morpholinopyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5 (2H)-one (Π-133);

4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (H-134);

4-(imidazo[l,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-13 5);

7-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (Π-13 6);

4-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-137);

4-((4-methylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (Π-13 8);

4-((4-(piperidin-l-yl)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)pheny 1)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-139);

4824-4563-0480.1

4-((4-(dimethylamino)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [1,4] oxazepin-5 (2H)-one (Π-140);

4-((3-methoxypyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (Π-143);

7-(4-(cyclobutylmethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (Π-144);

7-(2-methyl-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f] [1,4] oxazepin-5 (2H)-one (Π-145);

7-(2-methyl-4-(trifluoromethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (Π-146);

4-((l-(difluoromethyl)-lH-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (Π-147);

7-(4-(trifluoromethoxy)phenyl)-4-((3-(trifluoromethyl)-lH-pyrazol-l-yl)methyl)-3,4dihydrobenzoff] [1,4]oxazepin-5(2H)-one (Π-148);

4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethyl)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (Π-150);

4-(pyridin-2-ylmethy 1)-7-(4-(2,2,2-trifluoroethyl)pheny 1)-3,4dihydrobenzo[f][ 1,4] oxazepin-5 (2H)-one (Π-151);

4-(( 1 -cyclopentyl-1 H-pyrazol-3 -yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-152);

4-((l-ethyl-lH-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo [f] [ 1,4]oxazepin-5 (2H)-one (Π-15 3 );

4-((1 -methyl-1 H-imidazol-4-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-154);

4-((4-methyl- IH-pyrazol-1 -yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-155);

4824-4563-0480.1

4-((4-chloro-lH-pyrazol-l-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo [f] [ 1,4] oxazepin-5 (2H)-one (Π-156);

7-(4-(difluoromethyl)phenyl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (Π-157);

7-(4-(difluoromethoxy)phenyl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f] [ 1,4]oxazepin5(2H)-one (11-159);

4-(( 1 -methyl-1 H-pyrazol-4-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-160);

7-(3,4-difluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-163);

4-((3 -fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)pheny 1)-3,4dihydrobenzo [f] [ 1,4]oxazepin-5 (2H)-one (Π-164);

4-benzyl-8-fluoro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (Π-168);

7-(4-chloro-3-fluorophenyl)-4-((3-fluoropyridin-2-yl)methyl)-3,4dihydrobenzo[f|[ 1,4]oxazepin-5(2H)-one (Π-169);

7-(2-fluoro-4-(trifluoromethyl)phenyl)-4-((3-fluoropyridin-2-yl)methyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-170);

4824-4563-0480.1

4-((5 -methylpyrazin-2-yl)methyl)-7-(4-(trifluoromethoxy)pheny 1)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (Π-172);

2,2,3,3-tetradeutero-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-174);

4-((6-methylpyrazin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1, 4] oxazepin-5 (2H)-one (Π-175);

4-((3 -fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (Π-176);

N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)ethyl)benzenesulfonamide (II-l 77);

4-((l-methyl-lH-imidazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4] oxazepin-5(2H)-one (Π-186);

4-(imidazo[l,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Π-189);

N-cyclopropyl-3-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3dihydrobenzo[f] [1,4] oxazepin-4(5H)-yl)propane-1 -sulfonamide (II-190);

7-(4-(4-fluorophenoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (H-193);

7-(4-phenoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one (11-194); and

4824-4563-0480.1

[0150] In other embodiments, the disclosure provides compounds of Formula II:

wherein:

m is 0 or 1;

n is 0, 1, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(_R ²0)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Ci-₆ alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, phenyl, heterocyclyl, heteroaryl, C1-6 alkyl, cycloalkyl,

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(0)NH- or -NHC(O)-;

wherein said C1-15 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo,

4824-4563-0480.1

-NCh, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰,

-C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,

-N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and

-O-R²⁰; and wherein said Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO2, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C2-4 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO2, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R¹⁷ is halo or C1-6 alkyl;

4824-4563-0480.1

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF₃, -OCH2CF3, -C(0)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally fùrther substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cim alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, Ci-3 alkoxy, -CF₃, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, C1-4 alkyl, aryl and cycloalkyl; and wherein the C1-4 alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkoxy, -CF₃ and -OCF₃;

provided the compound is not tert-butyl 6-oxo-8-phenyl-3,4,12,12a-tetrahydrolH-benzo[f]pyrazino[2,l-c][l,4]oxazepine-2(6H)-carboxylate, tert-butyl 6-oxo-9phenyl-3,4,12,12a-tetrahydro-lH-benzo[f]pyrazino[2,l-c][l,4]oxazepine-2(6H)carboxylate, 8-phenyl-3,4,12,12a-tetrahydro-lH-benzo[f]pyrazino[2,1c][l,4]oxazepin-6(2H)-one, or 9-phenyl-3,4,12,12a-tetrahydro-lHbenzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one.

[0151] In some embodiments, R² is -C1-6 alkylene-R⁵ or -C1-6 alkylene-L-R⁵.

[0152] In some embodiments, R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

4824-4563-0480.1 wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, halo, cycloalkyl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²),

-C(O)-OR²⁰, -CN and -O-R²⁰;

wherein said Ci-6 alkyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, Ci-6 alkyl and aryl; and wherein said Ci-6 alkyl is optionally further substituted with one, two or three halo.

[0153] In some embodiments, R² and one of R³ can join together with the atom to which they are attached to form a heterocyclyl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of C1-15 alkyl, -O-R²⁰, -N(R²⁰)(R²²) and -C(O)-OR²⁰; and wherein said C1-15 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl.

4824-4563-0480.1

R² and one of R³ together with the carbon atoms to which they are attached form a

4824-4563-0480.1

[0155] In some embodiments, n is 1, 2 or 3; and each R¹⁰ is independently selected from the group consisting of halo, -O-R²⁰, -OS(O)2-R²⁰, Ci-4 alkyl and cycloalkyl; and wherein said alkyl is optionally substituted with one, two or three halo; and

R²⁰ is independently selected from the group consisting of C1-C15 alkyl and cycloalkyl; and wherein the alkyl is optionally substituted with one, two or three halo or cycloalkyl.

[0156] In some embodiments, n is 1, 2 or 3; and each R¹⁰ is independently 2-fluoro, 3fluoro, 4-fluoro, 2-chloro, 4-chloro, 2-methyl, 4-methyl, 4-ethyl, 4-isopropyl, 4-tert-butyl, 4-difluoromethyl, 4-trifluoromethyl, 4-cyclopropyl, 4-isobutoxy, 4-difluoromethoxy, 4trifluoromethoxy, 4-(2,2,2-trifluoroethoxy), 4-trifluoromethylsulfoxyl, 4-(2,2,2trifluoroethyl), 4-cyclopropoxy or 4-cyclobutylmethoxy.

[0157] In some embodiments, each R³ is independently hydrogen, deuterium or C1-15 alkyl optionally substituted with heteroaryl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-is alkyl, -N(R²⁰)(R²²) and -N(R²⁰)-C(O)-OR²⁰; and wherein said C1-15 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl; and

4824-4563-0480.1

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C1-C15 alkyl and heteroaryl.

[0158] In some embodiments, each R³ is independently hydrogen, deuterium or C1-15 alkyl optionally substituted with heteroaryl.

[0159] In some embodiments, each R³ is independently hydrogen, deuterium, methyl, isopropyl or pyridin-2-ylmethyl.

[0160] In some embodiments, each R⁴ is independently hydrogen, deuterium or C1-15 alkyl.

[0161] In some embodiments, each R⁴ is independently hydrogen, deuterium or methyl.

[0162] In some embodiments, m is 0.

[0163] In some embodiments, m is 1; and R¹⁷ is halo.

[0164] In some embodiments, m is 1; and R¹⁷ is fluoro.

[0165] In certain embodiments, the disclosure provides compounds of Formula III.

(R¹°)n4r I

V^R / r³ '0—γ-R⁴

R⁴ wherein:

n is 0, 1, 2, 3, 4 or 5:

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Ci-₆ alkyl, C₂-4 alkenyl, C₂-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, phenyl, heterocyclyl, heteroaryl, C1-6 alkyl, C1-3 haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

4824-4563-0480.1

R² is -L-R⁵, -L-Ci-6 alkylene-R⁵, -Ci-6 alkylene-L-R⁵ or -Ci-6 alkylene-L-Ci-6 alkylene-R⁵;

wherein each -Ci-6 alkylene is optionally substituted by one substituent independently selected from the group consisting of C₂.₄ alkynyl, halo, -NO₂, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C₂.₄alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

L is -O-, -S-, -NHS(O)₂-, -S(O)₂NH-, -C(0)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-Ci-6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NHC(O)-;

wherein said C1-15 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R²⁰)(R²²),

4824-4563-0480.1

-C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

each R⁴ is independently hydrogen, deuterium, C1-15 alkyl, Ci-4 alkoxy, -C(O)OR²⁶, -C(O)-N(R²⁶)(R²⁶), -N(R²⁰)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ci-u alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C₂.₄ alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Ci-₆ alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents

C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²),

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-₄ alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1.3 alkoxy, -CF3, -OCF3, -OCH2CF3, -C(0)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂, -S(O)₂R²⁶, -CN, Ci-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF3 and -OCF3;

4824-4563-0480.1 or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.

[0166] In other embodiments, the disclosure provides compounds of Formula III:

(R¹°)nT I

V^R /R³o—Vr⁴

R⁴ wherein:

n is 0, 1, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C₂-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, phenyl, heterocyclyl, heteroaryl, C1-6 alkyl, cycloalkyl,

R² is -L-R⁵, -L-C1-6 alkylene-R⁵, -C1-6 alkylene-L-R⁵ or -C1-6 alkylene-L-Ci-6 alkylene-R⁵;

_L i_s .q-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2,

4824-4563-0480.1

Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,

-N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO2, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

4824-4563-0480.1 wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C2-4 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF₃, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally fùrther substituted with Ci-4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cu alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and

4824-4563-0480.1 each R²⁶ is independently selected from the group consisting of hydrogen, Ci-₄ alkyl, aryl and cycloalkyl; and wherein the Cim alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Ci-₄ alkoxy, -CF3 and -OCF3;

or a pharmaceutically acceptable sait, ester, hydrate, solvaté, stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or prodrug thereof.

[0167] In some embodiments, R² is -C(O)-R⁵ or -C(O)-Ci-6 alkylene-R⁵; and

R⁵ is cycloalkyl, aryl or heteroaryl;

wherein said cycloalkyl or heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-₆ alkyl, halo and -C(O)-OR²⁰.

[0168] In some embodiments, R⁵ is cycloalkyl, aryl or heteroaryl;

wherein said cycloalkyl or heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, halo and -C(O)-OR²⁰.

[0169] In some embodiments, each -C1-6 alkylene of R² is unsubstituted.

[0171] In some embodiments, n is 1; and

R¹⁰ is -O-R²⁰ or Cm alkyl;

100

4824-4563-0480.1 wherein said alkyl is optionally substituted with one, two or three halo; and

R²⁰ is C1-C15 alkyl;

wherein the alkyl is optionally substituted with one, two or three halo.

[0172] In some embodiments, n is 1; and R¹⁰ is 4-trifluoromethyl or 4-trifluoromethoxy.

[0173] In some embodiments, the compound is selected from the group consisting of:

pyrimidin-2-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)methanone (III-l);

phenyl(7-(4-(trifhioromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)methanone (III-4);

(l-methylcyclopropyl)(7-(4-(trifluoromethoxy)phenyl)-2,3dihydrobenzo[f] [ 1,4]oxazepin-4(5H)-yl)methanone (III-10);

(3,3 -difluorocyclobutyl)(7-(4-(trifluoromethoxy)phenyl)-2,3 dihydrobenzo[f][l,4]oxazepm-4(5H)-yl)methanone (ΙΠ-11);

(l-methyl-lH-pyrazol-4-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3dihydrobenzo[f] [ 1,4]oxazepin-4(5H)-yl)methanone (III-12);

( 1 H-pyrazol-3 -yl)(7-(4-(trifluoromethoxy)phenyl)-2,3 -dihydrobenzo [f] [ 1,4]oxazepin4(5H)-yl)methanone (III-15);

pyrazin-2-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f] [ 1,4]oxazepin-4(5H)yl)methanone (III-23);

2-(pyrimidin-2-yl)-1 -(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f[ [ 1,4]oxazepin4(5H)-yl)ethanone (III-30);

( 1 -methyl-1 H-imidazol- 5 -yl)(7-(4-(trifluoromethyl)pheny 1)-2,3 dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (ΙΠ-32);

101

4824-4563-0480.1 (lH-imidazol-2-yl)(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin4(5H)-yl)methanone (III-33);

( 1 -methyl-1 H-imidazol-2-yl)(7-(4-(trifluoromethyl)phenyl)-2,3 dihydrobenzo[f] [ 1,4]oxazepin-4(5H)-yl)methanone (IH-37);

(R)-(2-methyl-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)(pyrimidin-2-yl)methanone (III-38);

( 1 H-1,2,4-triazol-3 -yl)(7-(4-(trifluoromethyl)phenyl)-2,3 -dihydrobenzo [f] [ 1,4] oxazepin4(5H)-yl)methanone (III-50); and ( 1,5-dimethyl-1 H-pyrazol-3-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3dihydrobenzo[f] [ 1,4]oxazepin-4(5H)-yl)methanone (IH-58);

[0174] In certain embodiments, the disclosure provides compounds of Formula IV:

IV wherein:

n is 0, 1, 2, 3, 4 or 5:

each R¹⁰ is independently selected from the group consisting of halo, -NO₂, -CN, -SF₅, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C2.₄ alkenyl, C₂-₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C1-6 alkyl, C₂.₄ alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, phenyl, heterocyclyl, heteroaryl, C1-6 alkyl, Ci-₃ haloalkyl,

102

4824-4563-0480.1 cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -Ci-6 alkylene-R³, -L-R⁵, -L-Ci-6 alkylene-R³, -Ci-6 alkylene-L-R⁵ or -Ci-6 alkylene-L-Ci-6 alkylene-R⁵;

wherein each -Ci-6 alkylene is optionally substituted by one substituent independently selected from the group consisting of C2-4 alkynyl, halo, -NO2, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C2-4 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

L i_s -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-Ci-6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)2- or -NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two

103

4824-4563-0480.1 or three substituents independently selected from the group consisting of halo, aryl, -NO2, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and

-O-R²⁰;

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF₃, -OCH2CF3, -C(O)-NH2, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally fùrther substituted with C1-4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, C1-4 alkyl, aryl and cycloalkyl; and wherein the C1-4 alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkoxy, -CF3 and -OCF3;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof

[0175] In other embodiments, the disclosure provides compounds of Formula IV:

104

4824-4563-0480.1

IV n is 0, 1, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO₂, -CN, -SF₅, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, phenyl, heterocyclyl, heteroaryl, C1-6 alkyl, cycloalkyl,

R² is -C1-6 alkylene-R⁵, -L-R⁵, -L-C1-6 alkylene-R⁵, -C1-6 alkylene-L-R⁵ or -Ci-6 alkylene-L-Ci-6 alkylene-R⁵;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(0)NH- or -NHC(O)-;

S(O)R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fürther substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two

105

4824-4563-0480.1 or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and

-O-R²⁰;

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, acylamino, oxo, -NO₂, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, -OCH2CF3, -C(0)-NH2, aryl, cycloalkyl and heteroaryl, and wherein said heteroaryl is optionally fùrther substituted with Ci-₄alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Ci-₄alkyl, aryl and cycloalkyl; and wherein the Ci-₄ alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Ci-₄ alkoxy, -CF3 and -OCF3;

or a pharmaceutically acceptable sait, ester, hydrate, solvaté, stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or prodrug thereof

[0176] In some embodiments, each -C1-6 alkylene of R² is unsubstituted.

[0177] In certain embodiments, the disclosure provides compounds of Formula V:

106

4824-4563-0480.1

wherein:

A is cycloalkenyl;

n is 0, 1, 2, 3, 4 or 5;

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF₅, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Ci-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, phenyl, heterocyclyl, heteroaryl, C1-6 alkyl, Ci-₃ haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -Ci-6 alkylene-R⁵, -L-R⁵, -L-C1-6 alkylene-R⁵, -C1-6 alkylene-L-R⁵ or -Ci-6 alkylene-L-Ci-6 alkylene-R⁵;

wherein each -C1-6 alkylene is optionally substituted by one substituent independently selected from the group consisting of C2-4 alkynyl, halo, -NO2, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C2-4 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

107

4824-4563-0480.1

L is -O-, -S-, -C(O)-, -NHS(0)₂-, -SlObMI-, -C(0)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-Ci-6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)2- or

-NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C2-4 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-₄ alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF₃, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or

108

4824-4563-0480.1 when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂,

-S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, C1-4 alkyl, aryl and cycloalkyl; and wherein the C1-4 alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkoxy, -CF3 and -OCF3;

[0178] In other embodiments, the disclosure provides compounds of Formula V:

wherein:

A is cycloalkenyl;

n is 0, 1, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)₂-R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, phenyl, heterocyclyl, heteroaryl, Ci-6 alkyl, cycloalkyl,

R² is -C1-6 alkylene-R³, -L-R³, -L-C1-6 alkylene-R⁵, -C1-6 alkylene-L-R⁵ or -C1-6 alkylene-L-Ci-6 alkylene-R⁵;

109

4824-4563-0480.1

L is -O-, -S-, -C(O)-, -NHS(Oh-, -S(O>2NH-, -C(0)NH- or -NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C2-4 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF₃, -OCH2CF3, -C(0)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally fùrther substituted with C1-4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with

110

4824-4563-0480.1 one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO?,

-S(O)2K²⁶, -CN, Ci-3 alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Ci-₄alkyl, aryl and cycloalkyl; and wherein the Ci-4 alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Ci-₄ alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, hydrate, soivate, stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or prodrug thereof.

[0179] In some embodiments, R² is -Ci-6 alkylene-R⁵.

[0180] In some embodiments, R⁵ is heteroaryl.

[0181] In some embodiments, each -Ci-6 alkylene of R² is unsubstituted.

[0182]

N \\

In some embodiments, R² is N

[0183] In some embodiments, A is cyclohex-l-enyl.

[0184] In some embodiments, A is cyclohex-l-enyl; n is 0 or 1; and R¹⁰ is 4-methyl or 4-/e/7-butyl.

[0185] In some embodiments, the compound is selected from the group consisting of

7-(4-tert-butylcyclohex-1 -enyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (V-1);

7-cyclohexenyl-4-(pyrimidin-2-ylmethy l)-3,4-dihy drobenzo [f] [ 1,4] oxazepin-5 (2H)-one (V-3); and

7-(4-methylcyclohex-1 -enyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (V-5);

[0186] In certain embodiments, the disclosure provides compounds of Formula VI:

111

4824-4563-0480.1

wherein:

B is heterocyclyl or heteroaryl;

n is 0, 1, 2, 3, 4 or 5:

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF₅, -Sî(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)₂-N(R²⁰)(R²²), C1-6 alkyl, C2-4 alkenyl, C₂-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, phenyl, heterocyclyl, heteroaryl, Ci-6 alkyl, Ci-₃ haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -C1-6 alkylene-R⁵, -L-R⁵, -L-Ci-e alkylene-R⁵, -C1-6 alkylene-L-R⁵ or -C1-6 alkylene-L-Ci-6 alkylene-R⁵;

wherein each -C1-6 alkylene is optionally substituted by one substituent independently selected from the group consisting of C2-4 alkynyl, halo, -NO2, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R²⁰)(R²²), -N(R²⁰)-S(0)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C2-4 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

112

4824-4563-0480.1

L is -O-, -S-, -C(O)-, -NHS(O)2-, -S(O)₂NH-, -C(0)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-Ci-6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)2- or

-NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C2-4 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰, wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, acylamino, oxo, -NO₂, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, -OCH2CF3, -C(0)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Ci-₄alkyl or cycloalkyl; or

113

4824-4563-0480.1 when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Ci-₄alkyl, aryl and cycloalkyl; and wherein the Ci-₄ alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cu alkoxy, -CF₃ and -OCF₃;

[0187] In other embodiments, the disclosure provides compounds of Formula VI:

wherein:

B is heterocyclyl or heteroaryl;

n is 0, 1, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF₅, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Ci-6 alkyl, C₂.₄ alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C1-6 alkyl, C₂.₄ alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, C1-6 alkyl, cycloalkyl,

R² is -Ci-6 alkylene-R⁵, -L-R⁵, -L-Ci-6 alkylene-R⁵, -C1-6 alkylene-L-R⁵ or -C1-6 alkylene-L-Ci-6 alkylene-R⁵;

114

4824-4563-0480.1

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(0)NH- or -NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF₃, -OCH2CF3, -C(O)-NH2, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally fùrther substituted with C1.4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with

115

4824-4563-0480.1 one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂,

-S(O)₂R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, C1.4 alkyl, aryl and cycloalkyl; and wherein the C1-4 alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkoxy, -CF3 and -OCF3;

[0188] In some embodiments, B is heteroaryl.

[0189] In some embodiments, B is 2-oxo-l,2-dihydropyridin-4-yl, pyridin-4-yl, pyridin2-yl, thiazol-4-yl or thiophen-2-yl.

[0190] In some embodiments, each -Ci-6 alkylene of R² is unsubstituted.

[0191] In some embodiments, R² is -C1-6 alkylene-R⁵.

[0192] In some embodiments, R⁵ is heteroaryl.

I\W xrY / [0193] In some embodiments, R² is ^{N 7} .

[0194] In some embodiments, n is 1;

R¹⁰ is cycloalkyl, -O-R²⁰ or Ci-₄ alkyl;

wherein said alkyl is optionally substituted with one, two or three halo; and

R²⁰ is C1-C15 alkyl.

[0195] In some embodiments, n is 1;

R¹⁰ is -O-R²⁰ or C1-4 alkyl;

wherein said alkyl is optionally substituted with one, two or three halo; and

R²⁰ is C1-C15 alkyl.

116

4824-4563-0480.1

[0196] In some embodiments, B is 2-oxo-l,2-dihydropyridin-4-yl, pyridin-4-yl, 5(trifluoromethyl)pyridin-2-yl, 2-isopropylthiazol-4-yl, 5-(trifluoromethyl)thiophen-2-yl or

5-cyclopropylthiophen-2-yl.

[0197] In some embodiments, the compound is selected from the group consisting of:

7-( 1 -methyl-2-oxo-1,2-dihydropyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4dihydrobenzo [f] [ 1,4]oxazepin-5(2H)-one (VI-12);

4-(pyridm-2-ylmethyl)-7-(5-(trifluoromethyl)pyridin-2-yl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (VI-26);

7-(5-cyclopropylthiophen-2-yl)-4-(pyridin-2-ylmethy l)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VI-32);

[0198] In certain embodiments, the disclosure provides compounds of Formula VIII:

wherein:

n is 0, 1, 2, 3, 4 or 5;

4824-4563-0480.1 === represents a single, double or triple bond;

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF₅, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)₂-R²⁰, -S(O)2-N(R²⁰)(R²²), Ci-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Ci-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, aryl, heterocyclyl, heteroaryl, C1-6 alkyl, C1-3 haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-C1-6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)2- or -NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C2-4 alkynyl, halo, -NO2, cycloalkyl,

118

4824-4563-0480.1 aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -OR²⁰;

wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

wherein the Ci-₆ alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1.4 alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, -OCH2CF3, -C(O)-NH2, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally fùrther substituted with C1-4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, C1-4 alkyl, aryl and cycloalkyl;

119

[0199] In some embodiments, each -Ci-6 alkylene of R² is unsubstituted.

χΓΑ x

[0200] In some embodiments, R² is N—z , F or X

[0201] In some embodiments, n is 0 or 1; and R¹⁰ is 4-trifluoromethyl or 4-trifluoromethoxy.

[0202] In some embodiments, the compound is selected from the group consisting of 4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethoxy)phenyl)ethynyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VHI-4);

7-(phenylethynyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (VIII-5);

4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethyl)phenyl)ethynyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VHI-6);

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VIII-7);

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenethyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (VIII-8);

4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethyl)phenethyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (VIII-9);

120

4824-4563-0480.1

[0203]

In other embodiments, the disclosure provides compounds of Formula VIIIA:

wherein:

n is 0, 1, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²0)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C₂-₄ alkenyl, C₂-₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C1-6 alkyl, C2-₄ alkenyl, C₂-₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, _NÛ2, phenyl, heterocyclyl, heteroaryl, C1-6 alkyl, cycloalkyl,

R² is -C1-6 alkylene-R⁵, -L-R⁵, -L-C1-6 alkylene-R⁵, -Ci^ alkylene-L-R⁵ or -C1-6 alkylene-L-Ci-6 alkylene-R⁵;

_L i_s .0-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(0)NH- or -NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C2-₄ alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and

121

4824-4563-0480.1 wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C1-15 alkyl, C2-15 alkenyl, C₂-is alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C1-15 alkyl, C₂-i5 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, -OCH2CF3, -C(0)-NH2, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with C1-4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Ci-₄alkyl, aryl and cycloalkyl; and wherein the Ci-₄ alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Ci-₄ alkoxy, -CF₃ and -OCF₃;

[0204] In some embodiments, R² is -C1-6 alkylene-R⁵.

[0205] In some embodiments, R⁵ is heteroaryl.

122

4824-4563-0480.1

[0206] In some embodiments, R² is N—-z .

[0207] In some embodiments, n is 0 or 1 ;

R¹⁰ is -O-R²⁰ or Ci-4 alkyl;

wherein the alkyl is optionally substituted with three halo; and

R²⁰ is C1-C15 alkyl; and wherein the alkyl is optionally substituted with one, two or three halo.

[0208] In some embodiments, n is 0 or 1; and R¹⁰ is 4-trifluoromethyl or 4-trifluoromethoxy.

[0209] In some embodiments, the compound is selected from the group consisting of:

4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethoxy)phenyl)ethynyl)-3,4dihydrobenzo [f] [ 1,4] oxazepin- 5 (2H)-one (VHI-4);

7-(phenylethynyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VIII-5); and

4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethyl)phenyl)ethyny 1)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VHI-6);

[0210] In certain embodiments, the disclosure provides compounds of Formula IX:

wherein:

n is 0, 1, 2, 3, 4 or 5;

each R¹⁰ is independently selected from the group consisting of halo, -NO₂, -CN, -SF₅, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Ci-6 alkyl, C₂-₄ alkenyl, C₂-₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and

123

4824-4563-0480.1 wherein said Ci-6 alkyl, C₂.₄ alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo,

-NO₂, aryl, heterocyclyl, heteroaryl, Ci-6 alkyl, Ci-shaloalkyl, cycloalkyl,

R² is -Ci-6 alkylene-R⁵, -L-R⁵, -L-Ci-6 alkylene-R⁵, -Ci-6 alkylene-L-R⁵ or -Ci-6 alkylene-L-Ci-6 alkylene-R⁵;

_L i_s -o-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-Ci-6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C₂.₄ alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -OR²⁰;

wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂,

124

4824-4563-0480.1

Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²),

-C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF3, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Ci-₄alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2.

-S(O)₂R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Ci-4 alkyl, aryl and cycloalkyl;

wherein the Ci-₄ alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Ci-₄ alkoxy, -CF3 and -OCF3;

[0211] In other embodiments, the disclosure provides compounds of Formula IX:

125

4824-4563-0480.1

IX wherein:

n is 0, 1, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(_R ²0)(_R ²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Ci-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C1-6 alkyl, C2-4 alkenyl, C₂-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, C1-6 alkyl, cycloalkyl,

L _is -o-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally lurther substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and

126

4824-4563-0480.1 wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1.4 alkyl, acylamino, oxo, -NO₂, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with C1-4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, C1-4 alkyl, aryl and cycloalkyl; and wherein the C1-4 alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkoxy, -CF₃ and -OCF₃;

[0212] In some embodiments, each -C1-6 alkylene of R² is unsubstituted.

[0213] In some embodiments, R² is -C1-6 alkylene-R⁵.

127

4824-4563-0480.1

[0214] In some embodiments, R² is not benzyl.

[0215] In some embodiments, R⁵ is heteroaryl;

wherein said heteroaryl is optionally fùrther substituted with halo.

[0216] In some embodiments, R² is selected from the group consisting of

[0217] In some embodiments, R¹⁰ is 4-trifluoromethyl.

[0218] In some embodiments, the compound is selected from the group consisting of:

2-((pyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2Hbenzo[b][l,4,5]oxathiazepin-sulfone (IX-2); and

2-((5-chloropyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2Hbenzo[b][l,4,5]oxathiazepin-sulfone (IX-3);

[0219] In certain embodiments, the disclosure provides compounds of Formula X:

wherein:

n is 0, 1, 2, 3, 4 or 5;

R¹⁰ is independently selected from the group consisting of halo, -NO₂, -CN, -SF5, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Ci-6 alkyl, C₂-₄ alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Ci-6 alkyl, C₂.₄ alkenyl, C₂-₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three

128

4824-4563-0480.1 substituents independently selected from the group consisting of halo,

-NO2, phenyl, heterocyclyl, heteroaryl, C1-6 alkyl, C1-3 haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -C1-6 alkylene-R⁵, -L-R⁵, -L-C1-6 alkylene-R⁵, -Ci-6 alkylene-L-R⁵ or -Ci-6 alkylene-L-Ci-6 alkylene-R⁵;

_L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-C1-6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NHC(O)-;

each R⁴ is independently hydrogen, deuterium, C1-15 alkyl, Ci-₄ alkoxy, -C(O)OR²⁶, -C(O)-N(R²⁶)(R²⁶), -N(R²⁰)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,

129

4824-4563-0480.1

-N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and

or two R⁴ together with the carbon atom to which they are attached form an oxo;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C2-4 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Ci-₆ alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R⁶ is hydrogen, C1-6 alkyl or cycloalkyl;

4824-4563-0480.1

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Ci-is alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, -OCH2CF3, -C(O)-NH2, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally fùrther substituted with Ci-₄alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, C1.3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

[0220] In other embodiments, the disclosure provides compounds of Formula X:

wherein:

n is 0, 1, 2 or 3;

131

4824-4563-0480.1

R¹⁰ is independently selected from the group consisting of halo, -NO₂, -CN, -SF5,

-Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C1-6 alkyl, C2-4 alkenyl, C₂-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, phenyl, heterocyclyl, heteroaryl, C1-6 alkyl, cycloalkyl,

R² is -C1-6 alkylene-R⁵, -L-R⁵, -L-C1-6 alkylene-R⁵, -C1-6 alkylene-L-R⁵ or -Ci-₆alkylene-L-Ci-6 alkylene-R⁵;

L is -O-, -S-, -C(O)-, -NHS(O)2-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci^ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂,

132

4824-4563-0480.1

-N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²),

-CN and -O-R²⁰;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,

133

4824-4563-0480.1

-N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and

-O-R²⁰; and wherein said Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-₄ alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, -OCH2CF3, -C(O)-NH2, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cim alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Ci-₄ alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkoxy, -CF3 and -OCF3;

134

4824-4563-0480.1

[0221] In some embodiments, each -Ci-6 alkylene of R² is unsubstituted.

[0222] In some embodiments, R² is -Ci-6 alkylene-R⁵.

[0223] In some embodiments, R⁵ is aryl.

[0224] In some embodiments, R² is ' '—or

[0225] In some embodiments, R¹⁰ is 4-trifluoromethyl or 4-trifluoromethoxy.

[0226] In some embodiments, each R⁴ is independently hydrogen, deuterium or Ci-6 alkyl optionally substituted with heteroaryl, or two R⁴ together with the carbon atom to which they are attached form an oxo.

[0227] In some embodiments, two R⁴ together with the carbon atom to which they are attached form an oxo.

[0228] In some embodiments, R⁶ is hydrogen or Ci-6 alkyl.

[0229] In some embodiments, R⁶ is hydrogen or methyl.

[0230] In some embodiments, the compound is selected from the group consisting of:

4-(2-(benzyloxy)ethyl)-l-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-lHbenzo[e] [ 1,4] diazepine-2,5 -dione (X-7);

4-benzy l-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1 H-benzo [e] [ 1,4] diazepine-2,5 -dione (X-8);

4-benzyl-1 -methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro- lH-benzo[e] [ l,4]diazepine2,5-dione (X-l 1); and

5-benzyl-8-(4-(trifluoromethyl)phenyl)-4H-benzo[f|imidazo[l,2-a][l,4]diazepin-6(5H)one (X-l2);

[0231] In certain embodiments, the disclosure provides compounds of Formula XII:

135

4824-4563-0480.1

wherein:

N;

Z⁴ is CR⁷ or N; provided that only one of Z¹, Z² and Z⁴ is N;

n is 0, 1, 2, 3, 4 or 5;

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²o_)(R ²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C₂.₄ alkenyl, C₂-₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Ci-6 alkyl, C₂-₄ alkenyl, C₂-₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Ci-6 alkyl, C1-3 haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein each -Ci-6 alkylene is optionally substituted by one substituent independently selected from the group consisting of C₂.₄ alkynyl, halo, -NO₂, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R²⁰)(R²²), -N(R²⁰)-S(0)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C2-₄alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl,

136

4824-4563-0480.1

-N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and

-O-R²⁰;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-, provided that when R² is -L-R³ or -L-Ci-6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C2-4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰, wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R⁷ is hydrogen, halo or C1-6 alkyl;

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-₄ alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3

137

4824-4563-0480.1 alkoxy, -CF3, -OCF₃, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with C1-4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2.

-S(O)₂R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, C1-4 alkyl, aryl and cycloalkyl; and wherein the Ci-₄ alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkoxy, -CF₃ and -OCF₃;

[0232] In other embodiments, the disclosure provides compounds of Formula XII:

wherein:

N;

Z⁴ is CR⁷ or N; provided that only one of Z¹, Z² and Z⁴ is N;

n is 0, 1, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF₅, -Sî(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Ci-6 alkyl, C₂-₄ alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and

138

-NO2, phenyl, heterocyclyl, heteroaryl, C1-6 alkyl, cycloalkyl,

R² is -C1-6 alkylene-R⁵, -L-R⁵, -L-C1-6 alkylene-R⁵, -C1-6 alkylene-L-R⁵ or -C1-6 alkylene-L-Ci-é alkylene-R⁵;

_L i_s -Q-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C2-4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R⁷ is hydrogen, halo or C1-6 alkyl;

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or

139

4824-4563-0480.1 three substituents independently selected from the group consisting of hydroxyl, halo, Ci-₄ alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF₃, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from f to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF3 and -OCF₃;

[0233] In some embodiments, R² is -C1-6 alkylene-R⁵ or -Cm alkylene-L-Ci-6 alkyleneR⁵.

[0234] In some embodiments, each -Cm alkylene of R² is unsubstituted.

[0235] In some embodiments, R⁵ is cycloalkyl, aryl or heteroaryl;

wherein said heteroaryl is optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, halo and -O-R²⁰.

/=\ ^ν—λ N^/ ytX J X y ) aA [0236] In some embodiments, R² is '—⁴ , ^N , ^N ,

Y, χν a^ \ F or ^X N-Y

140

4824-4563-0480.1

[0237] In some embodiments, n is 0 or 1;

R¹⁰ is -O-R²⁰ or Ci-₄ alkyl;

wherein the alkyl is optionally substituted with three halo; and

[0238] In some embodiments, n is 0 or 1; and R¹⁰ is 4-trifluoromethyl or 4-trifluoromethoxy.

[0239] In some embodiments, the compound is selected from the group consisting of

4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][l,4]oxazepin-5(2H)one (XII-1);

4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[2,3-f][I,4]oxazepin-5(2H)one (XII-2);

4-((4-methylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydropyrido [4,3 -f] [ 1,4]oxazepin-5 (2H)-one (XII-8);

4-(cyclopropylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3f][l,4]oxazepin-5(2H)-one (XII-9);

4-((3-methoxypyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydropyrido[4,3-f][l,4]oxazepin-5(2H)-one (XII-10);

4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3f][l,4]oxazepin-5(2H)-one (XII-11); and

141

4824-4563-0480.1

[0240] In certain embodiments, the disclosure provides compounds of Formula XIII:

XIII wherein:

Q is a -O-C0-2 alkylene- or -NR¹¹-Co-2 alkylene-;

n is 1, 2, 3, 4 or 5;

R¹⁰ is halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)S(O)2-R²⁶, -S(O)2-R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Ci-6 alkyl, C2-₄ alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, aryl, heterocyclyl, heteroaryl, C1-6 alkyl, Ci-₃haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein each -C1-6 alkylene is optionally substituted by one substituent independently selected from the group consisting of C2-4 alkynyl, halo, -NO2, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C2-4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

142

4824-4563-0480.1

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(0)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-Ci-6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or

-NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C2-4 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -OR²⁰;

wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R¹¹ is hydrogen or Ci-₄ alkyl;

wherein the C1-6 alkyl, C₂-6 alkenyl, C₂-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-₄ alkyl, acylamino, oxo, -NO₂, -S(O)₂R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and

143

4824-4563-0480.1 wherein said heteroaryl is optionally fùrther substituted with Ci-₄ alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, Ci-3 alkoxy, -CF3, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Ci-₄alkyl, aryl and cycloalkyl;

wherein the Ci-₄ alkyl, aryl and cycloalkyl may be fùrther substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Ci-₄ alkoxy, -CF₃ and -OCF₃;

[0241] In other embodiments, the disclosure provides compounds of Formula XIII:

r;

XIII wherein:

Q is a -O-Co-2 alkylene- or -NRⁿ-Co-2 alkylene-;

n is 1, 2 or 3;

R¹⁰ is halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)S(O)2-R²⁶, -S(O)2-R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C₂-₄ alkenyl, C₂-₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C1-6 alkyl, C2-₄ alkenyl, C2-₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, phenyl, heterocyclyl, heteroaryl, C1-6 alkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

144

4824-4563-0480.1

R² is -Ci-6 alkylene-R⁵, -L-R⁵, -L-Ci-6 alkylene-R⁵, -Ci-6 alkylene-L-R³ or -Ci-6 alkylene-L-Ci-6 alkylene-R⁵;

L i_s -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C₂-4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-₆ alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R¹¹ is hydrogen or C1-4 alkyl;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C1-15 alkyl, C₂-is alkenyl, C₂-i5 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C1-15 alkyl, C₂-i5 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1.4 alkyl, acylamino, oxo, -NO₂, -S(O)₂R²⁶, -CN, C1.3 alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and

145

4824-4563-0480.1 wherein said heteroaryl is optionally fùrther substituted with C1-4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, C1.4 alkyl, aryl and cycloalkyl; and wherein the C1-4 alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkoxy, -CF₃ and -OCF₃;

[0242] In some embodiments, Q is a -O-, -NH- or -NR¹¹-.

]0243] In some embodiments, R¹¹ is methyl

[0244] In some embodiments, each -C1-6 alkylene of R² is unsubstituted.

]0245] In some embodiments, R² is -C1-6 alkylene-R⁵.

[0246] In some embodiments, R⁵ is heteroaryl.

X W X

[0247] In some embodiments, R² is ' or ^N

[0248] In some embodiments, n is 1;

R¹⁰ is -O-R²⁰;

[0249] In some embodiments, R¹⁰ is 4-trifluoromethoxy.

[0250] In some embodiments, the compound is selected from the group consisting of: 4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenylamino)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (ΧΠΙ-1);

146

4824-4563-0480.1

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenoxy)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (ΧΠΙ-2);

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenylamino)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (ΧΠΙ-3);

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenylarnino)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one (ΧΠΙ-4);

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenylamino)-3,4dihydrobenzo[f][l,4]oxazepm-5(2H)-one (ΧΠΙ-6); and

7-(methyl(4-(trifluoromethoxy)phenyl)amino)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f] [ 1,4] oxazepin-5 (2H)-one (ΧΠΙ-10);

[0251] In certain alternative embodiments, the disclosure provides compounds of Formula IB:

wherein:

R¹ is aryl, cycloalkenyl, heterocyclyl or heteroaryl;

wherein said aryl, cycloalkenyl, heterocyclyl or heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R , -C(O)-R , -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Ci-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C1-6 alkyl, C2-4 alkenyl, C₂-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo,

147

4824-4563-0480.1

-NO₂, phenyl, heterocyclyl, heteroaryl, Ci-6 alkyl, cycloalkyl,

R² is hydrogen, C1-15 alkyl, -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁸), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C1-15 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C₂-4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Ci6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CF3, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -OR²⁰;

Q is a covalent bond or C₂ alkynylene;

Y is -C(O)-, -CH₂-, -C(NR⁵)- or -S(O)₂-;

X is -O- or -NR⁶-;

each R³ is independently hydrogen, C1-15 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ci-is alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents

148

C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,

-N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

each R⁴ is independently hydrogen, C1-15 alkyl, C1-4 alkoxy, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁸), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and

149

4824-4563-0480.1 wherein said Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R⁵ is hydrogen, C1-15 alkyl, C1-4 alkoxy, -C(O)-O-R²⁶, -C(O)-N(R²⁶)(R²⁸), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2û)(R²²), -CN and -O-R²⁰; and wherein said Ci-₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO2, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

or R² and R⁵ can join together with the atom to which they are attached to form a heterocyclyl or heteroaryl;

wherein said heterocyclyl or heteroaryl is optionally substituted with one, two or three substituents independently selected from the group consisting

150

4824-4563-0480.1 ofCi-is alkyl, cycloalkyl, heteroaryl, -O-R²⁰, -N(R²⁰)(R²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said C1-15 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;

R⁶ is hydrogen, Ci-is alkyl, -C(O)-R²⁰, -C(O)-OR²⁶, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C1-15 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NOa, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and

151

4824-4563-0480.1 wherein said heteroaryl is optionally further substituted with Ci-₄ alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, Ci-3 alkoxy, -CF3, -OCF₃, aryl, heteroaryl and cycloalkyl; and

R²⁶ and R²⁸ are in each instance independently selected from the group consisting of hydrogen, Ci-₄ alkyl, aryl and cycloalkyl; and wherein the Ci-₄ alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Ci-₄ alkoxy, -CF3 and -OCF3;

[0252] In certain alternative embodiments, when Y is -C(O)-, X is -O-, each R⁴ is hydrogen, R² and R³ together with the atom to which they are attached form a piperazine which is optionally substituted with tert-butoxycarbonyl and Q is a bond, then R¹ is not unsubstituted phenyl or morpholinyl; and that when Y is -S(O)₂-, X is -O-, R² is benzyl, each R³ is hydrogen, Z⁴ is C-Q-R¹, Q is a bond and R¹ is aryl or heteroaryl, then both R⁴are hydrogen.

[0253] In certain alternative embodiments, the disclosure provides compounds of Formula IIA:

wherein:

n is 0, 1, 2 or 3 :

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶,

152

4824-4563-0480.1

-S(O)₂-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, C2.₄ alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Ci-6 alkyl, C₂-₄ alkenyl, C₂-₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Cm alkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is hydrogen, C1-15 alkyl, -C(O)-R²⁰, -C(O)-OR²⁶, -C(0)-N(R )(R ), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C1-15 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C₂-₄ alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Ci-₆ alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰, and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CF3, -N(R²⁰)(R²²), -C(O)-R , -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -OR²⁰;

153

4824-4563-0480.1 wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

each R⁴ is independently hydrogen, C1-15 alkyl, Ci-4 alkoxy, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁸), -N(R²⁰)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,

154

4824-4563-0480.1

-N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and

-O-R²⁰; and wherein said Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, acylamino, -NO2, -S(O)₂R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(0)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally fùrther substituted with C1-4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO2. -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and R²⁶ and R²⁸ are in each instance independently selected from the group consisting of hydrogen, Ci-4 alkyl, aryl and cycloalkyl; and wherein the Ci-4 alkyl, aryl and cycloalkyl may be fùrther substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkoxy, -CF₃ and -OCF₃;

[0254] In some embodiments, R² is hydrogen or C1-15 alkyl;

155

4824-4563-0480.1 wherein said alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, heterocyclyl, heteroaryl, cycloalkyl and -O-R²⁰;

wherein said aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, Ci-6 alkyl, heterocyclyl, heteroaryl, cycloalkyl, -C(O)-OR²⁰, -CN and -O-R²⁰; and wherein said Ci-6 alkyl,or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo and -CF₃;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of C1-15 alkyl, -N(R²⁰)(R²²) and -N(R²⁰)-C(O)-OR²⁰; and wherein said C1-15 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl; and

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Ci-Ci5 alkyl and heteroaryl.

156

4824-4563-0480.1

[0256] In some embodiments, n is 1 or 2; and

157

4824-4563-0480.1 each R¹⁰ is independently selected from the group consisting of halo, -O-R²⁰, Ci-4 alkyl and cycloalkyl; and wherein said alkyl is optionally substituted with one, two or three halo; and

R²⁰ is independently selected from the group consisting of C1-C15 alkyl and cycloalkyl; and wherein the alkyl is optionally substituted with one, two or three halo.

[0257] In some embodiments, n is 1 or 2; and each R¹⁰ is independently selected from the group consisting of 2-fluoro, 3-fluoro, 4-fluoro, 2-chloro, 4-chloro, 4-ethyl, 4isopropyl, 4-tert-butyl, 4-trifluoromethyl, 4-cyclopropyl, 4-isobutoxy, 4-trifluoromethoxy, 4-(2,2,2-trifluoroethoxy) and 4-cyclopropoxy.

[0258] In some embodiments, each R³ is independently hydrogen or C1-15 alkyl;

[0259] In some embodiments, each R³ is independently hydrogen or C1.15 alkyl.

[0260] In some embodiments, each R³ is independently hydrogen, methyl or isopropyl.

[0261] In some embodiments, the compound is selected from the group consisting of

4-((3 -methyloxetan-3 -yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

4-(2-(pyrrolidin-l-yl)ethyl)-7-(4-(trifluoromethoxy)pheny 1)-3,4dihydrobenzo[f[ [1,4] oxazepin-5 (2H)-one;

158

4824-4563-0480.1

4-((5-cyclobutyl-l,3,4-oxadiazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihy drobenzo [f] [ 1,4]oxazepin-5(2H)-one;

4-((2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihy drobenzo [f] [ 1,4]oxazepin-5(2H)-one;

4-(2,2-difluoroethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one;

4-(quinolin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one;

(R)-2-(pyrimidin-2-ylmethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-lHbenzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one;

4-(cyclopropylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

4-(2-methoxyethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one;

(S)-3-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihy drobenzo [f] [ 1,4]oxazepin-5(2H)-one;

(R)-3-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyI)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one;

6-((5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)methyl)picolinonitrile;

7-(4-(trifluoromethoxy)phenyl)-4-((6-(trifluoromethyl)pyridin-2-yl)methyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one;

7-(4-(trifluoromethoxy)phenyl)-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

4-((6-methylpyridin-2-yl)methyl)-7-(4-(trifiuoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

(R)-3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one, (2R, 1 laS)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,11,1 latetrahydrobenzo[f]pyrrolo[2,l-c][l,4]oxazepin-5(lH)-one;

159

4824-4563-0480.1 (R)-2-(2,2-difluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1Hbenzo[f]pyrazino[2,1 -c] [ 1,4]oxazepin-6(2H)-one;

(R)-2-ethyl-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-lHbenzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one;

(S)-2-(2,2-difluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-lHbenzo[f] pyrazino [2,1 -c] [ 1,4]oxazepin-6(2H)-one;

(S)-2-ethyl-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahy dro-1Hbenzo[f]pyrazino[2,1 -c][l ,4]oxazepin-6(2H)-one;

4-(pyrazin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one;

4-((5-methyloxazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one;

7.(4.(trifluoromethoxy)phenyl)-4-(2-(2,5,5-trimethyl-l,3-dioxan-2-yl)ethyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one;

tert-butyl (2R, 11 aR)-5-oxo-7-(4-(trifluoromethyl)phenyl)-1,2,3,5,11,11ahexahydrobenzo[f]pyrrolo[2, l-c][l,4]oxazepin-2-ylcarbamate, 4-((5-(pyridin-2-yl)isoxazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

4_((46-dimethoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-j,4dihydrobenzo[f] [1,4] oxazepin-5 (2H)-one;

ethyl 3-((5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[fj[l,4]oxazepin-4(5H)yl)methyl)benzoate;

4-(2-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one;

4-(3,4-difluorobenzy l)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihy drobenzo [f] [ 1,4] oxazepin5(2H)-one;

4-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one, 4-(2-chlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one;

160

4824-4563-0480.1

4-(2,6-dichlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one;

4-(2,6-difluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one;

4-(2-(1 H-pyrazol-1 -yl)ethy l)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one;

(2S,1 laS)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,l 1,1 latetrahydrobenzo[f]pyrrolo[2,1 -c] [ 1,4]oxazepin- 5(1 H)-one;

4-(2-(pyridin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihy drobenzo[f] [1,4] oxazepin-5 (2H)-one;

4-(2-fluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one;

(R)-7-(4-(trifluoromethyl)phenyl)-2,3,11,11 a-tetrahydrobenzo[f]pyrrolo[2,1 c] [ 1,4]oxazepin-5( lH)-one;

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one;

4_(4-fl_Uorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one;

4-(( 1 -methyl-1 H-pyrazol-3 -yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one;

4-((5-chloropyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

4-(pyridin-4-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

4-((5-cyclopropyl-l,3,4-oxadiazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo [f] [ 1,4]oxazepin-5 (2H)-one;

4-(2-(pyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one;

161

4824-4563-0480.1

4-(pyridin-3-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one;

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

4-((3-methylpyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

(S)-3-isopropyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one;

(R)-2-(2,2,2-trifluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-lHbenzo[f]pyrazino[2,1 -c] [ 1,4]oxazepin-6(2H)-one;

4-(pyrimidin-2-ylmethyl)-7-p-tolyl-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

7-(4-chlorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one;

7-(44sopropylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f] [ 1,4]oxazepin5(2H)-one;

7-(4-ethylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one;

7_(4._Cy_Clopropylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one;

(R)_4-(l-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

7-(4-isobutoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one;

7-(4_tert-butylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one;

7_(4-_Cyclopropoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one;

162

4824-4563-0480.1

7-(4-fluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one;

7-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

7-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihy drobenzo [f] [ 1,4]oxazepin-5 (2H)-one;

4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

7-(2-chloro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihy drobenzo [f][ 1,4] oxazepin-5 (2H)-one;

7_(4_(trifluoromethoxy)phenyl)-4-((4-(trifluoromethyl)pyrimidin-2-yl)methyl)-3A dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

7-(4-(trifluoromethoxy)phenyl)-4-((5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2yl)methyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

7-(4-chloro-2-fluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one; and

4-(imidazo[l,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihy drobenzo [f] [1,4] oxazepin-5 (2H)-one;

[0262] In certain alternative embodiments, the disclosure provides compounds of Formula III A:

wherein:

n is 0, 1, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO₂, -CN, -SF₅, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²),

163

4824-4563-0480.1

-C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)₂-R²⁶,

-S(O)₂-R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C2.₄ alkenyl, C₂-₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Ci-6 alkyl, C₂.₄ alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Ci-6 alkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is hydrogen, C1-15 alkyl, -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)-N(R )(R ), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ci-is alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C₂-₄ alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Ci-₆ alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-₆ alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CF3, -N(R²⁰)(R²²), -C(O)-R , -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -OR²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C1-15 alkyl, C₂-i₅ alkenyl, C₂-i₅ alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C1-15 alkyl, C₂-is alkenyl, C₂-is alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or

164

4824-4563-0480.1 three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, acylamino, -NO₂, -S(O)2R²⁶, -CN, C1-3 alkoxy,

-CF₃, -OCF₃, -OCH₂CF₃, -C(0)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Ci-₄alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF₃, aryl, heteroaryl and cycloalkyl; and

R²⁶ and R²⁸ are in each instance independently selected from the group consisting of hydrogen, Ci-₄ alkyl, aryl and cycloalkyl; and wherein the Ci-₄ alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkoxy, -CF₃ and -OCF₃;

[0263] In some embodiments, R² is -C(O)-R²⁰; and

R²⁰ is heteroaryl.

[0264]

In some embodiments, R² is

[0265] In some embodiments, n is 1; and

R¹⁰ is -O-R²⁰; and

[0266] In some embodiments, n is 1; and R¹⁰ is 4-trifluoromethoxy.

[0267] In some embodiments, the compound is pyrimidin-2-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin4(5H)-yl)methanone

165

4824-4563-0480.1 or a pharmaceutically acceptable sait, ester, hydrate, solvaté, stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or prodrug thereof.

[0268] In certain alternative embodiments, the disclosure provides compounds of

Formula IV:

n is 0, 1, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C₂-₄ alkenyl, C₂-₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C1-6 alkyl, C₂-₄ alkenyl, C₂-₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, phenyl, heterocyclyl, heteroaryl, C1-6 alkyl, cycloalkyl,

R² is hydrogen, C1-15 alkyl, -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)-N(R )(R ), -N(R²⁰)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C1-15 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C2-4 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

166

4824-4563-0480.1

Cm alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²),

-C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -OR²⁰;

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-₄ alkyl, acylamino, -NO2, -S(O>2R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF3, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Ci-₄alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, Ci-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and R²⁶ and R²⁸ are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl, and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF3;

167

4824-4563-0480.1

[0269] In certain alternative embodiments, the disclosure provides compounds of

Formula V:

wherein:

A is cycloalkenyl;

n is 0, 1, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO₂, -CN, -SF₅, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Ci-6 alkyl, C₂-₄ alkenyl, C₂-₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C1-6 alkyl, C2-₄ alkenyl, C2-₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, phenyl, heterocyclyl, heteroaryl, C1-6 alkyl, cycloalkyl,

R² is hydrogen, C1-15 alkyl, -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)-N(R² )(R ), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ci-is alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C2-₄ alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -O-R²⁰;

wherein said Ci-₆ alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and

168

4824-4563-0480.1 wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, -CF₃, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -OR²⁰;

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, acylamino, -NO₂, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF3, -OCH2CF3, -C(0)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with C1-4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF₃, aryl, heteroaryl and cycloalkyl; and R²⁶ and R²⁸ are in each instance independently selected from the group consisting of hydrogen, C1-4 alkyl, aryl and cycloalkyl; and wherein the C1-4 alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkoxy, -CF₃ and -OCF₃;

[0270] In some embodiments, A is cyclohex-l-enyl.

[0271] In some embodiments, R² is C1-15 alkyl;

wherein said alkyl is optionally substituted with heteroaryl.

169

4824-4563-0480.1

[0272] In some embodiments, R² is

[0273] In some embodiments, n is 0 or 1; and

R¹⁰ is Ci-4 alkyl.

[0274] In some embodiments, A is cyclohex-1-enyl;

n is 0 or 1; and

R¹⁰ is 4-methyl or 4-terZ-butyl.

[0275] In some embodiments, the compound is selected from the group consisting of 7-(4-tert-butylcyclohex-l-enyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

7-cyclohexenyl-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one; and

7-(4-methylcyclohex-1 -eny l)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one;

]0276] In certain alternative embodiments, the disclosure provides compounds of

Formula VI:

wherein:

B is heterocyclyl or heteroaryl;

n is 0, 1, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO₂, -CN, -SF₅, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Ci-6 alkyl, C2.₄ alkenyl, C₂-₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and

170

4824-4563-0480.1 wherein said Ci-6 alkyl, C₂-₄ alkenyl, C₂-₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo,

-NOz, phenyl, heterocyclyl, heteroaryl, C1-6 alkyl, cycloalkyl,

wherein said Ci-is alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C₂-₄ alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -O-R²⁰;

wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)-R , -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -OR²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF3, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl;

171

4824-4563-0480.1 wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, Ci-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and R²⁶ and R²⁸ are in each instance independently selected from the group consisting of hydrogen, C1-4 alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from f to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF3 and -OCF3;

[0277] In some embodiments, B is heterocyclyl.

[0278] In some embodiments, B is 2-oxo-l,2-dihydropyridin-4-yl.

[0279] In some embodiments, B is heteroaryl.

[0280] In some embodiments, B is pyridin-4-yl.

[0281] In some embodiments, R² is C1-15 alkyl;

wherein said alkyl is optionally substituted with heteroaryl.

X z/

[0282] In some embodiments, R² is ^N

[0283] In some embodiments, n is 1;

R¹⁰ is -O-R²⁰ or Cm alkyl; and

R²⁰ is C1-C15 alkyl.

[0284] In some embodiments, B is 2-tert-butoxypyridin-4-yl.

[0285] In some embodiments, B is l-methyl-2-oxo-l,2-dihydropyridin-4-yl.

[0286] In some embodiments, the compound is selected from the group consisting of

172

4824-4563-0480.1

7-(2-tert-butoxypyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one; and

7-( 1 -methyl-2-oxo-1,2-dihydropyridin-4-y l)-4-(pyridin-2-ylmethy l)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one;

[0287] In certain alternative embodiments, the disclosure provides compounds of Formula VIIIA:

wherein:

n is 0, 1, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, phenyl, heterocyclyl, heteroaryl, C1-6 alkyl, cycloalkyl,

wherein said C1-15 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C₂-₄ alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -O-R²⁰;

173

4824-4563-0480.1 wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2,

C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²),

-C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -OR²⁰;

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF3, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with C1-4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-₄ alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO₂,

-S(O)₂R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and R²⁶ and R²⁸ are in each instance independently selected from the group consisting of hydrogen, Ci-₄ alkyl, aryl and cycloalkyl; and wherein the Ci-₄ alkyl, aryl and cycloalkyl may be further substituted with 30 from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Ci-₄ alkoxy, -CF₃ and -OCF3;

174

[0288] In some embodiments, R² is C1-15 alkyl;

wherein said alkyl is optionally substituted with heteroaryl.

[0289] In some embodiments, R² is N-—/ .

[0290] In some embodiments, n is 0 or 1;

R¹⁰ is -O-R²⁰ or Ci-₄ alkyl;

wherein the alkyl is optionally substituted with three halo; and

R²⁰ is Ci-Ci5 alkyl; and wherein the alkyl is optionally substituted with one, two or three halo.

[0291] In some embodiments, n is 0 or 1; and R¹⁰ is 4-trifluoromethyl or 4trifluoromethoxy.

[0292] In some embodiments, the compound is selected from the group consisting of 4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethoxy)phenyl)ethynyl)-3,4dihy drobenzo [f] [ 1,4] oxazepin- 5 (2H)-one;

7-(phenylethynyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one; and

4-(pyrimidm-2-ylmethyl)-7-((4-(trifluoromethyl)phenyl)ethynyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

[0293] In certain alternative embodiments, the disclosure provides compounds of Formula IX:

wherein:

175

4824-4563-0480.1 n is 0, 1, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO₂, -CN, -SF₅, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, C2-₄ alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, C₂-₄ alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Cm alkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said C1-15 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C₂.₄ alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -O-R²⁰;

wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰, and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -OR²⁰;

f76

4824-4563-0480.1

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, acylamino, -NO₂, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF3, -OCH2CF3, -C(0)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with C1-4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO_2>-S(O)₂R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and R²⁶ and R²⁸ are in each instance independently selected from the group consisting of hydrogen, C1-4 alkyl, aryl and cycloalkyl; and wherein the Ci-4 alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkoxy, -CF₃ and -OCF3, or a pharmaceutically acceptable sait, ester, hydrate, solvaté, stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or prodrug thereof.

[0294] In some embodiments, R² is C1-15 alkyl;

wherein said alkyl is optionally substituted with heteroaryl; and wherein said heteroaryl is optionally further substituted with halo.

ΥγΎ • · r

[0295] In some embodiments, R² is selected from the group consisting of

[0296] In some embodiments, R¹⁰ is 4-trifluoromethyl.

177

4824-4563-0480.1

[0297] In some embodiments, the compound is selected from the group consisting of:

2-((pyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2Hbenzo[b][l,4,5]oxathiazepin-sulfone; and

2-((5-chloropyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2Hbenzo[b][l,4,5]oxathiazepin-sulfone;

[0298] In certain alternative embodiments, the disclosure provides compounds of

Formula X:

(R¹⁰)_n 4- I ^N'+'R⁴ wherein:

n is 0, 1, 2 or 3;

R¹⁰ is independently selected from the group consisting of halo, -NO₂, -CN, -SF₅, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -S(O)2-N(R²⁰)(R²²), C1-6 alkyl, C2-4 alkenyl, C₂-₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Ci-₆ alkyl, C₂m alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Ci-6 alkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is hydrogen, Ci.» alkyl, -C(O)-R²⁰, -C(O)-OR²⁶, -CIOJ-NIR^XR²⁸),

N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C1-15 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C₂-₄ alkynyl, halo, -NO₂,

178

4824-4563-0480.1 cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰,

-C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -O-R²⁰;

wherein said Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, -CF3, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -OR²⁰;

each R⁴ is independently hydrogen, C1-15 alkyl, Ci-₄ alkoxy, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁸), -N(R²⁰)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally fùrther substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO2, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

179

4824-4563-0480.1 or two R⁴ together with the carbon atom to which they are attached form an oxo;

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF₃, -OCF3, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with C1-4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with

180

4824-4563-0480.1 one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO₂,

-S(O)₂R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and

R²⁶ and R²⁸ are in each instance independently selected from the group consisting of hydrogen, Ci-4 alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkoxy, -CF3 and -OCF3;

[0299] In some embodiments, R² is C1-15 alkyl;

wherein the alkyl is optionally substituted with aryl or -O-R²⁰; and

R²⁰ is C1-C15 alkyl;

wherein the alkyl is optionally substituted with aryl.

₉ . N \\ z/ Y

[0300] In some embodiments, R² is —^z or

[0301] In some embodiments, R¹⁰ is 4-trifluoromethyl or 4-trifluoromethoxy.

[0302] In some embodiments, two R⁴ together with the carbon atom to which they are attached form an oxo.

[0303] In some embodiments, R⁶ is hydrogen or C1-15 alkyl.

[0304] In some embodiments, R⁶ is hydrogen or methyl.

[0305] In some embodiments, the compound is selected from the group consisting of

4-(2-(benzyloxy)ethyl)-l-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-lHbenzo[e][1,4]diazepine-2,5 -dione; and

4-benzyl-7-(4-(trifluoromethy l)phenyl)-3,4-dihydro-1 H-benzo[e] [ 1,4]diazepine-2,5 dione;

181

4824-4563-0480.1

[0306] In some embodiments of Formula I and each of the other formulas disclosed herein, R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Ci-₆ alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, -OCH2CF3, -C(O)NH2, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Ci-4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl.

[0307] In certain embodiments, R²⁰ is hydrogen or C1-6 alkyl; wherein the C1-6 alkyl is optionally substituted with one, two or three halo.

[0308] In certain embodiments, R²⁰ is hydrogen. In other embodiments, R²⁰ is -CF3.

4. Further Embodiments

[0309] In some embodiments, the compounds provided by the présent disclosure are effective in the treatment of conditions or diseases known to respond to administration of late sodium channel blockers, including but not limited to cardiovascular diseases such as atrial and ventricular arrhythmias, including atrial fibrillation, Prinzmetal s (variant) angina, stable angina, unstable angina, ischemia and reperfusion injury in cardiac, kidney, liver and the brain, exercise induced angina, pulmonary hypertension, congestive heart disease including diastolic and systolic heart failure, and myocardial infarction. In some embodiments, compounds provided by the présent disclosure which function as late sodium channel blockers may be used in the treatment of diseases affecting the neuromuscular system resulting in pain, itching, seizures, or paralysis, or in the treatment

182

4824-4563-048U.1 of diabètes or reduced insulin sensitivity, and disease states related to diabètes, such as diabetic peripheral neuropathy.

[0310] Certain compounds of the disclosure may also possess a suffîcient activity in modulating neuronal sodium channels, i.e., Na_v 1.1., 1.2, 1.3, 1.5, 1.7, and/or 1.8, and may hâve appropriate pharmacokinetic properties such that they may be active with regard to the central and/or peripheral nervous system. Consequently, some compounds ofthe disclosure may also be ofuse in the treatment of epilepsy or pain or itching or heachache of a neuropathie origin.

[0311] In one embodiment, this disclosure provides a method of treating a disease state in a mammal that is alleviable by treatment with an agent capable of reducing late sodium current, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I, IA, IB, Π, IIA, ΠΒ, ΠΙ, ΠΙΑ, IV, V, VI, VUI, VIIIA, IX, X, ΧΠ or ΧΠΙ or other formulas or compounds disclosed herein. In another embodiment, the disease state is a cardiovascular disease selected from one or more of atrial and ventricular arrhythmias, heart failure (including congestive heart failure, diastolic heart failure, systolic heart failure, acute heart failure), Prinzmetal s (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, ischemia, récurrent ischemia, reperfüsion injury, myocardial infarction, acute coronary syndrome, peripheral arterial disease, pulmonary hypertension, and intermittent claudication.

[0312] In another embodiment, the disease state is diabètes or diabetic peripheral neuropathy. In a further embodiment, the disease State results in one or more of neuropathie pain, epilepsy, heachache, seizures, or paralysis.

[0313] In one embodiment, this disclosure provides a method of treating diabètes in a mammal, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I, IA, IB, II, IIA, ΠΒ, III, ΠΙΑ, IV, V, VI, Vin, VIIIA, IX, X, ΧΠ or ΧΠΙ or other formulas or compounds disclosed herein. Diabètes mellitus is a disease characterized by hyperglycemia; altered metabolism of hpids, carbohydrates and proteins; and an increased risk of complications from vascular disease. Diabètes is an increasing public health problem, as it is associated with both increasing âge and obesity.

[0314] There are two major types of diabètes mellitus: 1) Type I, also known as insulin

183

4824-4563-0480.1 dépendent diabètes (IDDM) and 2) Type II, also known as insulin independent or noninsulin dépendent diabètes (NIDDM). Both types of diabètes mellitus are due to insufficient amounts of circulating insulin and/or a decrease in the response of peripheral tissue to insulin.

[0315] Type I diabètes results from the body’s failure to produce insulin, the hormone that unlocks the cells ofthe body, allowing glucose to enter and fuel them. The complications of Type I diabètes include heart disease and stroke; retinopathy (eye disease); kidney disease (nephropathy); neuropathy (nerve damage); as well as maintenance of good skin, foot and oral health.

[0316] Type II diabètes results from the body’s inability to either produce enough insulin or the cells inability to use the. insulin that is naturally produced by the body. The condition where the body is not able to optimally use insulin is called insulin résistance. Type II diabètes is often accompanied by high blood pressure and this may contribute to heart disease. In patients with type II diabètes mellitus, stress, infection, and médications (such as corticosteroids) can also lead to severely elevated blood sugar levels. Accompanied by déhydration, severe blood sugar élévation in patients with type II diabètes can lead to an increase in blood osmolality (hyperosmolar state). This condition can lead to coma.

[0317] It has been suggested that ranolazine (RANEXA®, a sélective inhibitor of INaL) may be an antidiabetic agent that causes β-cell préservation and enhances insulin sécrétion in a glucose-dependent manner in diabetic mice (see, Y. Ning et al. J Pharmacol Exp Ther. 2011, 337(1), 50-8). Therefore it is contemplated that the compounds of Formula I, IA, IB, II, ΠΑ, HB, III, ΙΠΑ, IV, V, VI, VIII, VHIA, IX, X, ΧΠ or ΧΠΙ or other formulas or compounds disclosed herein can be used as antidiabetic agents for the treatment of diabètes.

5. Pharmaceutical Compositions and Administration ]0318] Compounds provided in accordance with the présent disclosure are usually administered in the form of pharmaceutical compositions. This disclosure therefore provides pharmaceutical compositions that contain, as the active ingrédient, one or more ofthe compounds described, or a pharmaceutically acceptable sait or ester thereof, and

184

4824-4563-0480.1 one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including stérile aqueous solution and various organic solvents, perméation enhancers, solubilizers and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985); and Modem Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.)

[0319] The pharmaceutical compositions may be administered in either single or multiple doses by any ofthe accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.

[0320] One mode for administration is parentéral, particularly by injection. The forms in which the novel compositions of the présent disclosure may be incorporated for administration by injection include aqueous or oil suspensions, or émulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as élixirs, mannitol, dextrose, or a stérile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context ofthe présent disclosure. Ethanol, glyceroi, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin dérivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance ofthe required particle size in the case of dispersion and by the use of surfactants. The prévention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phénol, sorbic acid, thimerosal, and the like.

[0321] Stérile injectable solutions are prepared by incorporating a compound according to the présent disclosure in the required amount in the appropriate solvent with various other ingrédients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingrédients into a stérile vehicle which contains the basic dispersion medium and the

185

4824-4563-0480.1 required other ingrédients from those enumerated above. In the case of stérile powders for the préparation of stérile injectable solutions, the preferred methods of préparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingrédient plus any additional desired ingrédient from a previously sterile-filtered solution thereof. Preferably, for parentéral administration, stérile injectable solutions are prepared containing a therapeutically effective amount, e.g., 0.1 to 700 mg, of a compound described herein. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the âge, weight, and response of the individual patient, the severity of the patient s symptoms, and the like.

[0322] Oral administration is another route for administration of compounds in accordance with the disclosure. Administration may be via capsule or enteric coated tablets, or the like. In making the pharmaceutical compositions that include at least one compound described herein, the active ingrédient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semisolid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingrédient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, élixirs, suspensions, émulsions, solutions, syrups, aérosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, stérile injectable solutions, and stérile packaged powders.

[0323] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, stérile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnésium stéarate, and minerai oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates, sweetening agents; and flavoring agents.

[0324] The compositions of the disclosure can be formulated so as to provide quick, sustained or delayed release ofthe active ingrédient after administration to the patient by

186

4824-4563-0480.1 employing procedures known in the art. Controlled release drug delivery Systems for oral administration include osmotic pump Systems and dissolutional Systems containing polymer-coated réservoirs or drug-polymer matrix formulations. Examples of controlled release Systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the présent disclosure employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuons infusion of the compounds of the présent disclosure in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0325] The compositions are preferably formulated in a unit dosage form. The term “unit dosage forms” refers to physically discrète units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains from 1 mg to 2 g, or altematively, or 100 mg to 500 mg, of a compound described herein, and for parentéral administration, preferably from 0.1 mg to 700 mg, or altematively, 0.1 mg to 100 mg, of a compound a compound described herein. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the âge, weight, and response ofthe individual patient, the severity ofthe patient’s symptoms, and the like.

[0326] For preparing solid compositions such as tablets, the principal active ingrédient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound ofthe présent disclosure. When referring to these preformulation compositions as homogeneous, it is meant that the active ingrédient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

187

4824-4563-0480.1

[0327] The tablets or pills of the présent disclosure may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodénum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0328] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

Combination Therapy

[0329] Patients being treated by administration of the late sodium channel blockers of the disclosure often exhibit diseases or conditions that benefit from treatment with other therapeutic agents. These diseases or conditions can be of cardiovascular nature or can be related to pulmonary disorders, metabolic disorders, gastrointestinal disorders and the like. Additionally, some coronary patients being treated by administration ofthe late sodium channel blockers of the disclosure exhibit conditions that can benefit from treatment with therapeutic agents that are antibiotics, analgésies, and/or antidepressants and anti-anxiety agents.

188

4824-4563-0480.1

Cardiovascular Agent Combination Therapy

[0330] Cardiovascular related diseases or conditions that can benefit from a combination treatment of the late sodium channel blockers of the disclosure with other therapeutic agents include, without limitation, angina including stable angina, unstable angina (U A), exercised-induced angina, variant angina, arrhythmias, intermittent claudication, myocardial infarction including non-STE myocardial infarction (NSTEMI), pulmonary hypertension including pulmonary arterial hypertension, heart failure including congestive (or chronic) heart failure and diastolic heart failure and heart failure with preserved éjection fraction (diastolic dysfunction), acute heart failure, or récurrent ischemia.

[0331] Therapeutic agents suitable for treating cardiovascular related diseases or conditions include anti-anginals, heart failure agents, antithrombotic agents, antiarrhythmic agents, antihypertensive agents, and lipid lowering agents.

[0332] The co-administration ofthe late sodium channel blockers ofthe disclosure with therapeutic agents suitable for treating cardiovascular related conditions allows enhancement in the standard of care therapy the patient is currently receiving. In some embodiments, the late sodium channel blockers of the disclosure are co-administered with ranolazine (RANEXA®).

Anti-anginals

[0333] Anti-anginals include beta-blockers, calcium channel blockers, and nitrates. Beta blockers reduce the heart's need for oxygen by reducing its workload resulting in a decreased heart rate and less vigorous heart contraction. Examples of beta-blockers include acébutolol (Sectral®), atenolol (Tenormin®), betaxolol (Kerlone®), bisoprolol/hydrochlorothiazide (Ziac®), bisoprolol (Zebeta®), carteolol (Cartrol ), esmolol (Brevibloc®), labetalol (Normodyne®, Trandate®), metoprolol (Lopressor®, Toprol® XL), nadolol (Corgard®), propranolol (Inderal®), sotalol (Betapace®), and timolol (Blocadren®).

[0334] Nitrates dilate the arteries and veins thereby increasing coronary blood flow and decreasing blood pressure. Examples of nitrates include nitroglycenn, nitrate patches, isosorbide dinitrate, and isosorbide-5-mononitrate.

189

4824-4563-0480.1

[0335] Calcium channel blockers prevent the normal flow of calcium into the cells of the heart and blood vessels causing the blood vessels to relax thereby increasing the supply of blood and oxygen to the heart. Examples of calcium channel blockers include amlodipine (Norvasc®, Lotrel®), bepridil (Vascor®), diltiazem (Cardizem , Tiazac ), felodipine (Plendil®), nifedipine (Adalat®, Procardia®), nimodipine (Nimotop®), nisoldipine (Sular®), verapamil (Calan®, Isoptin®, Verelan®), and nicardipine.

Heart Failure Agents

[0336] Agents used to treat heart failure include diuretics, ACE inhibitors, vasodilators, and cardiac glycosides. Diuretics eliminate excess fluids in the tissues and circulation thereby relieving many of the symptoms of heart failure. Examples of diuretics include hydrochlorothiazîde, metolazone (Zaroxolyn®), furosemide (Lasix®), bumetamde (Bumex®), spironolactone (Aldactone®), and eplerenone (Inspra®).

[0337] Angiotensin converting enzyme (ACE) inhibitors reduce the workload on the heart by expanding the blood vessels and decreasing résistance to blood flow. Examples of ACE inhibitors include benazepril (Lotensin®), captopril (Capoten®), enalapril (Vasotec®), fosinopril (Monopril®), lisinopril (Prinivil®, Zestril®), moexipril (Univasc®), perindopril (Aceon®), quinapril (Accupril®), ramipril (Altace®), and trandolapril (Mavik®).

[0338] Vasodilators reduce pressure on the blood vessels by making them relax and expand. Examples of vasodilators include hydralazine, diazoxide, prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassium channel activators, and calcium channel blockers also act as vasodilators.

[0339] Cardiac glycosides are compounds that increase the force ofthe heart s contractions. These compounds strengthen the pumping capacity ofthe heart and improve irregular heartbeat activity. Examples of cardiac glycosides include digitalis, digoxin, and digitoxin.

Antithrombotic Agents

[0340] Antithrombotics inhibit the clotting ability of the blood. There are three main types of antithrombotics - platelet inhibitors, anticoagulants, and thrombolytic agents.

190

4824-4563-0480.1

[0341] Platelet inhibitors inhibit the clotting activity of platelets, thereby reducing clotting in the arteries. Examples of platelet inhibitors include acetylsalicylic acid (aspirin), ticlopidine, clopidogrel (Plavix®), prasugrel (Effient®), dipyridamole, cilostazol, persantine sulfinpyrazone, dipyridamole, indomethacin, and glycoprotein llb/llla inhibitors, such as abciximab, tirofiban, and eptifibatide (Integrelin®). Beta blockers and calcium channel blockers also hâve a platelet-inhibiting effect.

[0342] Anticoagulants prevent blood clots from growing larger and prevent the formation of new clots. Examples of anticoagulants include bivalirudin (Angiomax ), warfarin (Coumadin®), unfractionated heparin, low molecular weight heparin, danaparoid, lepirudin, and argatroban.

[0343] Thrombolytic agents act to break down an existing blood clôt. Examples of thrombolytic agents include streptokinase, urokinase, and tenecteplase (TNK), and tissue plasminogen activator (t-PA).

Antiarrhythmic agents

[0344] Antiarrhythmic agents are used to treat disorders ofthe heart rate and rhythm. Examples of antiarrhythmic agents include amiodarone, dronedarone, quinidine, procainamide, lidocaine, and propafenone. Cardiac glycosides and beta blockers are also used as antiarrhythmic agents.

[0345] Combinations with amiodarone and dronedarone are of particular interest (see U.S. Patent Application Publication No. 2010/0056536 and U.S. Patent Application Publication No. 2011/0183990, the entirety of which are incorporated herein).

Antihypertensive agents

[0346] Antihypertensive agents are used to treat hypertension, a condition in which the blood pressure is consistently higher than normal. Hypertension is associated with many aspects of cardiovascular disease, including congestive heart failure, atherosclerosis, and clôt formation. Examples of antihypertensive agents include alpha- 1-adrenergic antagonists, such as prazosin (Minipress®), doxazosin mesylate (Cardura®), prazosin hydrochloride (Minipress®), prazosin, polythiazide (Mimzide®), and terazosin hydrochloride (Hytrin®); beta-adrenergic antagonists, such as propranolol (Inderal®), nadolol (Corgard®), timolol (Blocadren®), metoprolol (Lopressor®), and pindolol (Visken®); central alpha-adrenoceptor agonists, such as clonidine hydrochloride

191

4824-4563-0480.1 (Catapres®), clonidine hydrochloride and chlorthalidone (Clorpres®, Combipres®), guanabenz Acetate (Wytensin®), guanfacine hydrochloride (Tenex®), methyldopa (Aldomet®), methyldopa and chlorothiazide (Aldoclor®), methyldopa and hydrochlorothiazide (Aldoril®); combined alpha/beta-adrenergic antagonists, such as labetalol (Normodyne®, Trandate®), carvedilol (Coreg®); adrenergic neuron blocking agents, such as guanethidine (Ismelin®), reserpine (Serpasil®); central nervous systemacting antihypertensives, such as clonidine (Catapres®), methyldopa (Aldomet®), guanabenz (Wytensin®); anti-angiotensin II agents; ACE inhibitors, such as perindopril (Aceon®) captopril (Capoten®), enalapril (Vasotec®), lisinopril (Prinivil®, Zestril®); angiotensin-II receptor antagonists, such as candesartan (Atacand®), eprosartan (Teveten®), irbesartan (Avapro®), losartan (Cozaar®), telmisartan (Micardis®), valsartan (Diovan®); calcium channel blockers, such as verapamil (Calan®, Isoptin®), diltiazem (Cardizem®), nifedipine (Adalat®, Procardia®); diuretics; direct vasodilators, such as nitroprusside (Nipride®), diazoxide (Hyperstat® IV), hydralazine (Apresoline®), minoxidil (Loniten®), verapamil; and potassium channel activators, such as aprikalim, bimakalim, cromakalim, emakalim, nicorandil, and pinacidil.

Lipid Lowering Agents

[0347] Lipid lowering agents are used to lower the amounts of cholestérol or fatty sugars présent in the blood. Examples of lipid lowering agents include bezafibrate (Bezalip®), ciprofibrate (Modalim®), and statins, such as atorvastatin (Lipitor®), fluvastatin (Lescol®), lovastatin (Mévacor®, Altocor®), mevastatin, pitavastatin (Livalo®, Pitava®) pravastatin (Lipostat®), rosuvastatin (Crestor®), and simvastatin (Zocor®).

[0348] In this disclosure, the patient presenting with an acute coronary disease event often suffers from secondary medical conditions such as one or more of a metabolic disorder, a pulmonary disorder, a peripheral vascular disorder, or a gastrointestmal disorder. Such patients can benefit from treatment of a combination therapy comprising administering to the patient a compound as disclosed herein (e.g., Formula I, IA, IB, Π, IIA, IIB, ΠΙ, ΠΙΑ, IV, V, VI, VIII, VIIIA, IX, X, XII or ΧΠΙ) in combination with at least one therapeutic agent.

192

4824-4563-0480.1

Pulmonary Disorders Combination Therapy

[0349] Pulmonary disorder refers to any disease or condition related to the lungs. Examples of pulmonary disorders include, without limitation, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and emphysema.

[0350] Examples of therapeutics agents used to treat pulmonary disorders include bronchodilators including beta2 agonists and anticholinergics, corticosteroids, and electrolyte suppléments. Spécifie examples of therapeutic agents used to treat pulmonary disorders include epinephrine, terbutaline (Brethaire®, Bricanyl®), albuterol (Proventil ), salmeterol (Serevent®, Serevent Diskus®), theophylline, ipratropium bromide (Atrovent®), tiotropium (Spiriva®), méthylprednisolone (Solu-Medrol®, Medrol®), magnésium, and potassium.

Metabolic Disorders Combination Therapy

[0351] Examples of metabolic disorders include, without limitation, diabètes, including type I and type II diabètes, metabolic syndrome, dyslipidemia, obesity, glucose intolérance, hypertension, elevated sérum cholestérol, and elevated triglycérides.

[0352] Examples of therapeutic agents used to treat metabolic disorders include antihypertensive agents and lipid lowering agents, as described in the section “Cardiovascular Agent Combination Therapy” above. Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretin mimetics.

Peripheral Vascular Disorders Combination Therapy

[0353] Peripheral vascular disorders are disorders related to the blood vessels (arteries and veins) located outside the heart and brain, including, for example peripheral arterial disease (PAD), a condition that develops when the arteries that supply blood to the internai organs, arms, and legs become completely or partially blocked as a resuit of atherosclerosis.

Gastrointestinal Disorders Combination Therapy

[0354] Gastrointestinal disorders refer to diseases and conditions associated with the gastrointestinal tract. Examples of gastrointestinal disorders include gastroesophageal

193

4824-4563-0480.1 reflux disease (GERD), inflammatory bowel disease (IBD), gastroenteritis, gastritis and peptic ulcer disease, and pancreatitis.

[0355] Examples of therapeutic agents used to treat gastrointestinal disorders include proton pump inhibitors, such as pantoprazole (Protonix®), lansoprazole (Prevacid ), esomeprazole (Nexium®), omeprazole (Prilosec®), rabeprazole; H2 blockers, such as cimetidine (Tagamet®), ranitidine (Zantac®), famotidine (Pepcid ), nizatidine (Axid ), prostaglandins, such as misoprostol (Cytotec®); sucralfate; and antacids.

Antibiotics, analgésies, antidepressants and anti-anxiety agents Combination Therapy

[0356] Patients presenting with an acute coronary disease event may exhibit conditions that benefït from administration of therapeutic agent or agents that are antibiotics, analgésies, antidepressant and anti-anxiety agents in combination with a compound as disclosed herein (e.g., Formula I, IA, IB, Π, IIA, HB, IH, ΠΙΑ, IV, V, VI, VHI, VHIA, IX, X, ΧΠ or XIII)

Antibiotics ]0357] Antibiotics are therapeutic agents that kill, or stop the growth of, microorganisms, including both bacteria and fungi. Example of antibiotic agents include β-Lactam antibiotics, including penicillins (amoxicillin), cephalosporins, such as cefazolin, cefuroxime, cefadroxil (Duricef®), cephalexin (Keflex®), cephradine (Velosef®), cefaclor (Ceclor®), cefuroxime axtel (Ceftin®), cefprozil (Cefzil®), loracarbef (Lorabid®), cefixime (Suprax®), cefpodoxime proxetil (Vantin®), ceftibuten (Cedax®), cefdinir (Omnicef®), ceftriaxone (Rocephin®), carbapenems, and monobactams; tetracyclines, such as tétracycline; macrolide antibiotics, such as erythromycin, aminoglycosides, such as gentamicin, tobramycin, amikacin; qumolones such as ciprofloxacin; cyclic peptides, such as vancomycin, streptogramins, polymyxins; lincosamides, such as clindamycin; oxazolidinoes, such as linezolid; and sulfa antibiotics, such as sulfisoxazole.

Analgésies

[0358] Analgésies are therapeutic agents that are used to relieve pain. Examples of analgésies include opiates and morphinomimetics, such as fentanyl and morphine; paracétamol; NSAIDs, and COX-2 inhibitors. Given the abilty ofthe late sodium channel blockers ofthe disclosure to treat neuropathie pain via inhibition ofthe Nav 1.7 and 1.8

194

4824-4563-048U.1 sodium channels, combination with analgésies are particularly invisioned. See U.S.

Patent Application Publication 20090203707.

Antidepressant and Anti-anxiety agents

[0359] Antidepressant and anti-anxiety agents include those agents used to treat anxiety disorders, dépréssion, and those used as sédatives and tranquillers. Examples of antidepressant and anti-anxiety agents include benzodiazépines, such as diazepam, lorazépam, and midazolam; enzodiazepines; barbiturates; glutethimide; chloral hydrate; meprobamate; sertraline (Zoloft®, Lustral®, Apo-Sertral®, Asentra®, Gladem®, Serlift , Stimuloton®); escitalopram (Lexapro®, Cipralex®); fluoxetine (Prozac®, Sarafem®, Fluctin®, Fontex®, Prodep®, Fludep®, Lovan®); venlafaxine (Effexor® XR, Efexor®); citalopram (Celexa®, Cipramil®, Talohexane®); paroxetine (Paxil®, Seroxat®, Aropax®); trazodone (Desyrel®); amitriptyline (Elavil®); and bupropion (Wellbutrin®, Zyban®).

[0360] Accordingly, one aspect of the disclosure provides for a composition comprising the late sodium channel blockers of the disclosure and at least one therapeutic agent. In an alternative embodiment, the composition comprises the late sodium channel blockers of the disclosure and at least two therapeutic agents. In further alternative embodiments, the composition comprises the late sodium channel blockers of the disclosure and at least three therapeutic agents, the late sodium channel blockers of the disclosure and at least four therapeutic agents, or the late sodium channel blockers of the disclosure and at least five therapeutic agents.

[0361] The methods of combination therapy include co-administration of a single formulation containing the the late sodium channel blockers of the disclosure and therapeutic agent or agents, essentially contemporaneous administration of more than one formulation comprising the late sodium channel blocker of the disclosure and therapeutic agent or agents, and consecutive administration of a late sodium channel blocker ofthe disclosure and therapeutic agent or agents, in any order, wherein preferably there is a time period where the late sodium channel blocker of the disclosure and therapeutic agent or agents simultaneously exert their therapeutic affect.

6. Synthesis of Example Compounds

195

4824-4563-0480.1

[0362] The compounds of the disclosure may be prepared using methods disclosed herein and routine modifications thereof which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein, e.g. compounds having structures described by one or more of Formula I, IA, IB, II, IIA, ΠΒ, III, ΠΙΑ, IV, V, VI, VIII, VÏÏIA, IX, X, XII or ΧΠΙ or other formulas or compounds disclosed herein, may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g. from Sigma Aldrich or other Chemical suppliers.

General Synthèses

[0363] Typical embodiments of compounds in accordance with the présent disclosure may be synthesized using the general reaction schemes described below. It will be apparent given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to resuit in products that are correspondingly different. Descriptions of synthèses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Given a desired product for which the substituent groups are defined, the necessary starting materials generally may be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For synthesizing compounds which are embodiments ofthe présent disclosure, inspection ofthe structure ofthe compound to be synthesized will provide the identity of each substituent group. The identity ofthe final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein.

Synthetic Reaction Parameters

[0364] The compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction températures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

196

4824-4563-0480.1

[0365] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain fùnctional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein.

[0366] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. Ail such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stéréo sélective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

[0367] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplémentais (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5^th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0368] The terms “solvent,” “inert organic solvent” or “inert solvent” refer to a solvent inert under the conditions ofthe reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ( THF ), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like). Unless specified to the contrary, the

197

4824-4563-0480.1 solvents used in the reactions of the présent disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.

[0369] The term “q.s.” means adding a quantity sufficient to achieve a stated function,

e.g., to bring a solution to the desired volume (i.e., 100%).

Synthesis of the Compounds of Formula I

[0370] The compounds of Formula I (and Formula IA, IB, II, IIA, ΠΒ, III, IIIA, IV, V, VI, VIII, VIIIA, IX, X ΧΠ or ΧΠΙ) are typically prepared by first providing the molecular core 1-1 and then attaching the desired -Q-R¹ substituents using suitable coupling conditions (e.g., Suzuki coupling) and the desired -R² substituents using suitable 10 substitution conditions. These processes are show below in Scheme 1 for the synthesis of a compound of Formula I, wherein -Q-R¹ is at either Z³ or Z⁴ in each of Formulas 1-1, 12, 1-3 and I shown in Scheme 1, wherein the bromo and/or -Q-R¹ is at either Z³ or Z⁴ in each of the Formulas shown in Scheme 1.

Scheme 1

Pd-cat, base, solvent heat or microwave irradiation

[0371] In general, a halogenated compound of formula 1-1, in this case a brominated compound, is reacted with an appropriately substituted boronic acid dérivative of formula Κ^-Β(ΟΗ)? or a boronic ester thereof, in an inert solvent, for example aqueous N,N20 dimethylformamide, in the presence of a mild base, for example potassium carbonate or sodium bicarbonate. The reaction is typically conducted in the presence of a métal

198

4824-4563-0480.1 catalyst with an appropriate ligand, for example dichlorobis(triphenylphosphine) palladium(II), at a température of about 120-170°C, for about 10 minutes to about 1 hour or at a lower température, i.e., 90-110°C for 2 to 5 days. When the reaction is substantially complété, the product of Formula I is isolated by conventional means.

[0372] It will be appreciated that the R² subsitutent can be modified or added either before (as shown in Scheme 1) or after the addition of the R¹ moiety. The R² moiety may be coupled to the core 1-1 under substitution reaction conditions with an appropriate reagent of formula LG-R² (where LG is a leaving group such as a halo, hydroxyl, alkoxy or the like) as shown in Scheme 1. Typical substitution reaction conditions include the presence of a base, such as ssium carbonate, sodium bicarbonate, triethylamine, and the like, in a polar aprotic solvent, such as Ν,Ν-dimethylformamide, and optionally an elevated température of about 100-150°C or in a microwave. Also, in the case where the R² substituent contains a heteroaryl ring, the heteroaryl ring may be synthesized and cyclized before or after addition of the -Q-R¹ portion.

Optional Core Synthesis

[0373] In certain embodiments, the core may be synthesized before or after addition of the -Q-R¹ subsitutent (Scheme 2). For example, such alternative routes for the synthesis of 3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one compounds of Formula 2-8 (i.e., Formula ΙΑ, II, ΠΑ, IIB, IV, V, VI VIH, X, XII and XIII) are shown in Scheme 2, below, wherein the bromo and/or -Q-R¹ is at either Z³ or Z⁴ in each of the Formulas shown in Scheme 2.

199

4824-4563-0480.1

Scheme 2

2-3

R¹Q

Pd-cat, base, heat or microwave irradiation

B(OH)₂

O r³ r³

2-4

NaH

R¹Q^

B(OH)₂

Pd-cat, base, heat or microwave irradiation deprotect

[0374] In one embodiment, compounds of Formula 2-3 can be provided from compounds of Formula 2-1 via amide formation with a suitably protected amino alcohol 2-2, where PG is a protecting group, such as benzyl. Compounds of Formula 2-3 are coupled with an appropriately substituted boronic acid dérivative of formula R¹Q-B(OH)₂or a boronic ester thereof, under typical coupling reaction conditions. Typical couphng reaction conditions an inert solvent, for example aqueous Ν,Ν-dimethylformamide, m the presence of a mild base, for example potassium carbonate or sodium bicarbonate. The reaction is typically conducted in the presence of a métal catalyst with an appropriate ligand, for example dichlorobis(triphenylphosphine) palladium(II), at a température of

200

4824-4563-0480.1

045710-5210 about 120-170°C, for about 10 minutes to about 1 hour or at a lower température, i.e., 90110°C for 2 to 5 days. When the reaction is substantially complété, the compounds of Formula 2-4 can be isolated by conventional means. Compounds of Formula 2-4 are cyclized to afford compounds of Formula 2-5 using sodium hydride, in a suitable solvent, such as dimethylformamide. Deprotection under suitable conditions provides compounds of Formula 2-6.

[0375] In another embodiment, compounds of Formula 2-8 are prepared from commercially available compounds of Formula 2-7 using sodium azide. Compounds of Formula 2-6 can be obtained from compounds of Formula 2-8 via reaction with an appropriately substituted boronic acid dérivative of formula iVQ-BiOHh or a boronic ester thereof, under typical coupling reaction conditions as described above.

[0376] The R² moiety may be coupled to compounds of Formula 2-6 under substitution reaction conditions with an appropriate reagent of formula LG-R² (where LG is a leaving group such as a halo, hydroxyl, alkoxy or the like) as shown in Scheme 1 to afford 3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one compounds of Formula 2-9. Typical substitution reaction conditions include the presence of a base, such as ssium carbonate, sodium bicarbonate, trîethylamine, and the like, in a polar aprotic solvent, such as N,Ν’dimethylformamide, and optionally an elevated température of about 100-150°C or in a micro wave.

[0377] 2,3,4,5-Tetrahydrobenzo[f][l,4]oxazepine compounds of Formula 3-2 (i.e., Formula ΠΙ and ΙΙΙΑ) are synthesized from compounds of Formula 2-6 as shown in Scheme 3, below, wherein -Q-R¹ is at either C7 or C8 in each ofthe Formulas shown in Scheme 2.

Scheme 3

[0378] In one embodiment, compounds of Formula 3-1 can be provided from the réduction of compounds of Formula 2-6 via amide formation with a suitably protected amino alcohol 2-2, where PG is a protecting group, such as benzyl. The R² moiety may

201

4824-4563-0480.1

045710-5210 be coupled to compounds of Formula 2-6 under substitution reaction conditions with an appropriate reagent of formula LG-R² (where LG is a leaving group such as a halo, hydroxyl, alkoxy or the like) as shown in Scheme 1 to afford compounds of Formula 3-2.

[0379] Compounds of Formula 4-3 (i.e., Formula IX) are synthesized as shown in Scheme 4, below, wherein -Q-R¹ is at either C7 or C8 in each of the Formulas shown in Scheme 2.

Scheme 4

Pd-cat, base, heat or microwave irradiation

R¹Q.

B(OH)₂

4-6 R⁴

NaH

LG-R²

[0380] In one embodiment, compounds of Formula 4-3 can be provided from compounds of Formula 4-1 via sulfonamide formation with an amino alcohol 4-2. Compounds of Formula 4-3 are coupled with an appropriately substituted boronic acid dérivative of formula R¹Q-B(OH)₂ or a boronic ester thereof, under typical coupling reaction conditions as discussed in Scheme 2. Compounds of Formula 4-4 are cyclized to afford compounds of Formula 5-5 using sodium hydride, in a suitable solvent, such as dimethylformamide.

[0381] The R² moiety may be coupled to compounds of Formula 4-5 under substitution reaction conditions with an appropriate reagent of formula LG-R² (where LG is a leaving group such as a halo, hydroxyl, alkoxy or the like) as shown in Scheme 1 to afford compounds of Formula 4-6. Typical substitution reaction conditions include the presence of a base, such as ssium carbonate, sodium bicarbonate, triethylamine, and the like, in a polar aprotic solvent, such as Ν,Ν-dimethylformamide, and optionally an elevated température of about 100-150 °C or in a microwave.

[0382] It will also be appreciated that the addition of any substituent may resuit in the

202

4824-4563-0480.1

045710-5210 production of a number of isomeric products any or ail of which may be isolated and purified using conventional techniques.

Examples

[0383] The following examples are included to demonstrate preferred embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the présent disclosure, appreciate that many changes can be made in the spécifie embodiments which are disclosed and still obtain a like or similar resuit without departing from the spirit and scope of the disclosure.

	List of abbreviations and acronyms.
Abbreviation	Meaning
°C	Degree Celcius
anal	Analytical
ATP	Adeno sine- 5 '-trip ho sphate
ATX II	Anemonia sulcata toxin
ACN	Acetonitrile
CHO	Chinese hamster ovary
conc.	Concentrated
d	Doublet
DABCO	1,4-Diazabicyclo[2.2.2]octane
dd	Doublet of doublets
DCM	Dichloromethane
DIPEA	N,N-diisopropylethylamine
DMF	Dimethylformamide
DMSO	Dimethylsulfoxide
dppf	1,1 '-Bis(diphenylphosphino)ferrocene
EA	Ethyl alcohol
ECF	Extracellular fluid
EDTA	Ethylenediaminetetraacetic acid
EGTA	Ethylene glycol tetraacetic acid
equiv/eq	Equivalents
ESI	Electrospray ionization
Ac	Acetate
Et	Ethyl
g	Grams
HEPES	(4-(2-Hydroxyethyl)-l-piperazineethanesulfonic acid )
HATU	2-(7-Aza-1 H-Benzotriazole -1 -yl)-1,1,3,3-
	tetramethyluronium hexafluorophosphate
hERG	human Ether-à-go-go Related Gene

203

4824-4563-0480.1

045710-5210

HPLC	High-performance liquid chromatography
h	Hours
Hz	Hertz
IC₅₀	The half maximal inhibitory concentration
IMR-32	Human neuroblastoma cell line
J	Coupling constant
Kg	Kilogram
kHz	Kilohertz
LCMS/LC-MS	Liquid chromatography-mass spectrometry
M	Molar
m	multiplet
m/z	mass-to-charge ratio
M+	Mass peak
M+H	Mass peak plus hydrogen
Me	Methyl
mg	Milligram
MHz	Mégahertz
min/m	Minute
ml/mL	Milliliter
mM	Millimolar
mmol	Millimole
nmol	Nanomole
mOsmol	Milliosmole
MRM	Magnetic Résonance Microscopy
MS	Mass spectroscopy
ms	Millisecond
mV	Millivolt
mw	Microwave
N	Normal
mol	Mole
NMR	Nuclear magnetic résonance
pA	Picoamps
Ph	Phenyl
prep	Préparative
q.s.	Quantity sufficient to achieve a stated fùnction
Rf	Rétention factor
RT/rt	Room température
s	Second
s	Singlet
SEM	Standard error of the mean
t	Triplet
TB	Tonie Block
TEA	Triethylamine
TFA	Trifluoroacetic acid
THF	T etrahydrofuran
TLC	Thin layer chromatography
TTX	Tetrodotoxin
UDB	Use Dépendent Block
WT	Wild type
δ	Chemical shift

204

4824-4563-0480.1

045710-5210 pL/ μΐ μΜ μιη pmol

Microgram Microliter Micromolar Micrometer Micromole

EXAMPLES

Example 1

7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one

[0384] Commercially available 6-bromochroman-4-one (1.0g, 3 mmol) was dissolved in 10 mL methanesulfonic acid. The solution was cooled using an ice bath and sodium azide (0.30 g, 4.5 mmol) was added over a period of 45 min. The mixture was stirred at RT for 16 h. The mixture was neutralized using conc. HCl. The resulting solid was filtered and washed with water to afford Comound 1-A as analytically pure sample.

[0385] For the Suzuki coupling reaction the following conditions were applied: To a suspension of Compound 1-A (1 eq), the substituted boronic acid or boronate ester (1.2 eq) and base sodium bicarbonate (3 eq) in solvent (DMF:water in the ratio of 4:1) was added palladium catalyst Pd(dppf)C12 (10 mol%) and heated at 80 °C for 2-4h. The reaction progress was followed by LC and after completion, the reaction mixture was filtered through celite, washed with ethyl acetate. The filtrate was concentrated the filtrate and purified by prep TLC/ prep HPLC or column chromatography to afford Compound 11-74

205

4824-4563-0480.1

045710-5210

4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethyl)phenyl)ethynyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound VIII-6)

Example 2

[0386] Compound 2-A was prepared from Compound 1-A according to Example 1 using l-ethynyl-4-(trifluoromethyl)benzene in place of the boronic acid.

[0387] To a solution of 2-A (1 eq) in DMF was added the corresponding halide (1.3 eq).

To the mixture was added sodium hydride (60% dispersion in oil, 2 mmol) and stirred at 10 room température for 10 min, followed by heating at 80 °C for 24h. The reaction mixture was quenched with water, extracted with ethyl acetate (100 mL). The organic layer was washed with water, brine and dried over sodium sulphate and concentrated And purified using prep TLC/ prep HPLC or column chromatography to afford Compound VIII-6.

[0388] 'H-NMR (CDCh) δ 8.71 (d, 2H, J= 4.4 Hz), 8.20 (d, 1H, J= 2.4 Hz), 7.55-7.59 15 (m, 5H), 7.20 (t, 1H, J= 4.8 Hz), 7.01 (d, 1H, J= 8.4 Hz), 5.08 (s, 2H), 4.58 (t, 2H, J=

4.6 Hz), 3.76 (t, 2H, J= 5.0 Hz); MS m/z 424.1 (M+H).

206

4824-4563-0480.1

045710-5210

Example 3

4-(pyridin-2-ylmethyI)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-72)

[0389] Compound Π-72 was prepared according to Example 1 using the appropriate starting materials. ¹ H-NMR (CDC1₃) δ 8.81 (d, IH, J = 5.6 Hz), 8.27 (t, IH, J= 7.8 Hz), 8.07 (d, IH, J= 8.4 Hz), 8.02 (d, IH, J= 2.4 Hz), 7.75 (t, IH, J= 6.4 Hz), 7.65 (dd, IH, J = 8.6, 2.6 Hz), 7.58 (dd, 2H, J = 4.8, 2.8 Hz ), 7.28 (d, 2H, J= 8.4 Hz), 7.12 (d, IH, J = 8.4 Hz), 5.24 (s, 2H), 4.39 (t, 2H, J= 5.0 Hz), 3.85 (t, 2H, J= 5.0 Hz); MS m/z 415.1 (M+H).

Example 4

4-(pyridin-3-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4 dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound 11-70)

[0390] Compound Π-70 was prepared according to Example 1 using the appropriate starting materials. ^XH-NMR (CDCI3) δ 9.00 (s, IH), 8.75 (d, IH, J = 5.2 Hz), 8.47 (d, IH, J= 7.6 Hz), 8.05 (d, IH, J= 2.4 Hz), 7.83 (dd, IH, J= 7.8, 5.4 Hz), 7.66 (dd, IH, J= 8.8, 2.4 Hz ), 7.60 (d, 2H, J= 8.4 Hz), 7.28 (d, 2H, J= 8.4 Hz), 7.13 (d, IH, J= 8.0 Hz), 4.99 (s, 2H), 4.37 (t, 2H, J= 5.0 Hz), 3.67 (t, 2H, J = 5.0 Hz); MS m/z 415.1 (M+H).

Example 5

4-(2-(pyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-69)

4824-4563-0480.1

[0391] Compound Π-69 was prepared according to Example 1 using the appropriate starting materials. 'H-NMR (CDC1₃) δ 8.53 (d, 2H, J = 4.8 Hz), 8.03 (d, IH, J = 2.4 Hz),

7.58-7.61 (m, 3H), 7.27 (d, 2H, J= 5.2 Hz), 7.07 (d, IH, J= 8.0 Hz), 6.97 (t, IH, J= 4.8

Hz), 4.66 (t, 2H, J= 4.8 Hz), 4.51 (t, 2H, J= 52 Hz), 4.07 (t, 2H, J= 5.0 Hz), 3.78 (t, 2H,

J= 5.0 Hz); MS m/z 468.0 (M+Na).

045710-5210

Example 6

4-(4-fluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (Compound Π-62)

[0392] Compound Π-62 was prepared according to Example 1 using the appropriate starting materials. 'H-NMR (CDCh) δ 8.10 (d, IH, J= 2.8 Hz), 7.60-7.63 (m, 3H), 7.35 (dd, 2H, J= 8.4, 1.2 Hz), 7.28 (d, 2H, J= 8.0 Hz), 7.03-7.09 (m, 3H), 4.82 (s, 2H), 4.22 (t, 2H, J= 5.2 Hz), 3.51 (t, 2H, J= 5.2 Hz); MS m/z 432.1 (M+H).

Example 7

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyI)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 11-61)

[0393] Compound Π-61 was prepared according to Example 1 using the appropriate starting materials. ¹ H-NMR (CDCh) δ 8.80 (d, 2H, J= 5.2 Hz), 8.19 (d, IH, J = 2.8 Hz), 7.66-7.71 (m, 5H), 7.33 (t, lH,J=5.0Hz), 7.13 (d, IH, J= 8.4 Hz), 5.14 (s, 2H), 4.59 (t, 2H, J= 4.8 Hz), 3.81 (t, 2H, J= 5.0 Hz); MS m/z 400.1 (M+H).

4824-4563-0480.1

045710-5210

Example 8

4-(2-fluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (Compound Π-57)

[0394] Compound Π-57 was prepared according to Example 1 using the appropriate starting materials. 'H-NMR (CDCh) δ 8.07 (d, IH, J= 2.4 Hz), 7.58-7.61 (m, 3H), 7.497.51 (m, IH), 7.26-7.31 (m, 3H), 7.16 (t, IH, J= 7.6 Hz), 7.07-7.18 (m, 2H), 4.92 (s, 2H), 4.29 (t, 2H, J= 4.8 Hz), 3.61 (t, 2H, J= 5.0 Hz); MS m/z 432.1 (M+H).

Example 9

4-(2-(pyridin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-54)

[0395] Compound Π-54 was prepared according to Example 1 using the appropriate starting materials. 'H-NMR (CDCI3) δ 8.57 (d, IH, J= 4.8 Hz), 8.03 (d, IH, J = 2.4 Hz), 7.67-7.69 (m, IH), 7.57-7.61 (m, 3H), 7.20-7.33 (m, 4H), 7.04 (d, IH, J= 8.8 Hz), 4.19 (t, 2H, J = 4.8 Hz), 4.06 (t, 2H, J= 7.4 Hz), 3.51 (t, 2H, J= 5.0 Hz), 3.24 (t, 2H, J= 6.8 Hz); MS m/z 429.1 (M+H).

Example 10

4-(2-(lH-pyrazol-l-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4 dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-50)

209

4824-4563-0480.1

045710-5210

[0396] Compound Π-50 was prepared according to Example 1 using the appropriate starting materials. 'H-NMJR. (CDCh) δ 8.02 (d, 1H, J = 2.4 Hz), 7.58-7.64 (m, 4H), 7.47 (d, 1H, J= 1.6 Hz), 7.28 (d, 2H, 8.8 Hz), 7.04 (d, 1H, J = 8.4 Hz), 6.30 (t, 1H, J =2.2

Hz), 4.55 (t, 2H, J= 5.8 Hz), 4.11 (t, 2H, J= 5.4 Hz), 3.96 (t, 2H, J= 5.0 Hz), 3.28 (t, 2H,

J = 5.0 Hz); MS m/z 418.1 (M+H).

Example 11

4-(2,6-difluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepm-5(2H)-one (Compound Π-49)

[0397] Compound 11-49 was prepared according to Example 1 using the appropriate starting materials. ’H-NMR (CDCh) δ 8.08 (d, 1H, J= 2.4 Hz), 7.57-7.61 (m, 3H), 7.267.33 (m, 3H), 7.05 (d, 1H, J= 8.4 Hz), 6.95 (t, 2H, J= 8.0 Hz), 4.98 (s, 2H), 4.23 (t, 2H, J = 4.8 Hz), 3.59 (t, 2H, J= 4.8 Hz); MS m/z 450.1 (M+H).

Example 12

4-(2,6-dichlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-48)

[0398] Compound Π-48 was prepared according to Example 1 using the appropriate starting materials. Ή-NMR (CDCh) δ 8.06 (d, 1H, J= 2.4 Hz), 7.59-7.62 (m, 3H), 7.40 (d, 2H, J= 8.0 Hz), 7.25-7.29 (m, 3H), 7.06 (d, 1H, J= 8.4 Hz), 5.24 (s, 2H), 4.07 (t, 2H, J= 5.0 Hz), 3.42 (t, 2H, J = 5.2 Hz); MS m/z 483.0 (M+H).

210

4824-4563-0480.1

045710-5210

4-(2-chlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-47)

Example 13

[0399] Compound Π-47 was prepared according to Example 1 using the appropriate starting materials. ‘H-NMR (CDCh) δ 8.10 (d, 1H, J= 2.4 Hz), 7.60-7.64 (m, 3H), 7.47 (dd, 1H, J= 7.0, 2.2 Hz), 7.41 (dd, 1H, J= 7.4, 1.8 Hz), 7.26-7.30 (m, 4H), 7.09 (d, 1H, J = 8.4 Hz), 5.01 (s, 2H), 4.28 (t, 2H, J= 5.0 Hz), 3.58 (t, 2H, J= 5.2 Hz); MS m/z 448.1 (M+H).

Example 14

7-(phenylethynyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one (Compound V111-5)

[0400] Compound VIII-5 was prepared according to Example 2 using the appropriate starting materials. *H-NMR (CD₃OD) δ 8.76 (d, 2H, J= 4.8 Hz), 7.92 (d, 1H, J= 2.4 Hz), 7.60 (dd, 1H, J= 8.6, 1.8 Hz), 7.48-7.51 (m, 2H), 7.35-7.39 (m, 4H), 7.07 (d, 1H, J= 8.8 Hz), 5.05 (s, 2H), 4.59 (t, 2H, J= 4.8 Hz), 3.83 (t, 2H, J= 4.8 Hz); MS m/z 356.1 (M+H).

Example 15

4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethoxy)phenyl)ethynyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound V111-4)

211

4824-4563-0480.1

045710-5210

[0401] Compound V111-4 was prepared according to Example 2 using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.76 (d, 2H, J = 7.2 Hz), 7.95 (d, 1H, J= 2.4 Hz),

7.59-7.63 (m, 3H), 7.38 (t, 1H, J= 5.0 Hz), 7.29 (d, 2H, J= 8.4 Hz), 7.08 (d, 1H, J= 8.8

Hz), 5.05 (s, 2H), 4.60 (t, 2H, J= 5.0 Hz), 3.83 (t, 2H, J= 4.8 Hz); MS m/z 440.1 (M+H).

Example 16

4-(2-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4 dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-44)

[0402] Compound Π-44 was prepared according to Example 1 using the appropriate starting materials. 'H-NMR (CDCI3) δ 8.70 (d, 2H, J = 5.2 Hz), 8.00 (d, 1H, 2.4 Hz),

7.56- 7.59 (m, 3H), 7.26(d, 2H, J= 8.4 Hz), 7.20 (t, 1H, J= 5.2 Hz), 7.04 (d, 1H, J= 8.8 Hz), 4.36 (t, 2H, J= 5.0 Hz), 4.16 (t, 2H, J= ΊΛ Hz), 3.59 (t, 2H, 5.0 Hz), 3.38 (t, 2H,

J= 6.0 Hz); MS m/z 430.1 (M+H).

Example 17

4-((4,6-dimethoxypyrimidin-2-yl)methyI)-7-(4-(trifluoromethoxy)phenyl)-3,4 dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-42)

[0403] Compound Π-42 was prepared according to Example 1 using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.00 (d, 1H, J= 2.4 Hz), 7.76 (dd, 1H, J= 8.2, 2.6 Hz), 7.69 (dd, 2H, J= 6.8, 2.0 Hz), 7.34 (d, 2H, J= 8.0 Hz), 7.16 (d, 1H, J= 8.8 Hz), 6.11 (s, 1H), 4.87 (s, 2H), 4.58 (t, 2H, J= 5.0 Hz), 3.93 (s, 6H), 3.84 (t, 2H, J= 5.2 Hz); MS m/z 476.1 (M+H).

212

4824-4563-0480.1

045710-5210

Example 18

4-((5-methyloxazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-33)

[0404] Compound Π-33 was prepared according to Example 1 using the appropriate starting materials. ¹ H-NMR (CD3OD) δ 8.00 (d, IH, J= 2.4 Hz), 7.77 (dd, IH, J= 8.4, 2.4 Hz), 7.71(d, 2H, J = 8.8 Hz), 7.34 (d, 2H, J= 8.0 Hz), 7.15 (d, IH, J= 8.4 Hz), 6.81 (d, IH, J= 0.8 Hz), 4.93 (s, 2H), 4.43 (t, 2H, J= 52 Hz), 3.76 (t, 2H, J= 52 Hz), 2.34 (d, 3H, J = 0.8 Hz); MS m/z 419.1 (M+H).

Example 19

4-(pyrazin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-31)

[0405] Compound Π-31 was prepared according to Example 1 using the appropriate starting materials. ’H-NMR (CD3OD) δ 8.71 (d, IH, J= 0.8 Hz), 8.60 (t, IH, J= 2.0 Hz), 8.53 (d, IH, J= 2.4 Hz), 7.99 (d, IH, J= 2.4 Hz), 7.77 (dd, IH, J= 8.4, 2.4 Hz), 7.72 (dd, 2H, J = 6.6, 2.2 Hz), 7.34 (d, 2H, J= 8.0 Hz), 7.15 (d, IH, J= 8.4 Hz), 5.01 (s, 2H), 4.47 (t, 2H, J= 52 Hz), 3.82 (t, 2H, J= 5.0 Hz); MS m/z 416.1 (M+H).

Example 20

4-((6-methylpyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-17)

[0406] Compound Π-17 was prepared according to Example 1 using the appropriate starting materials. ’Η-NMR (CD3OD) δ 8.28 (t, IH, J= 7.8 Hz), 8.00 (t, IH, J= 2.4 Hz),

213

4824-4563-0480.1

7.81 (dd, 1H, J= 8.2, 2.6 Hz), 7.68-7.73 (m, 4H), 7.35 (dd, 2H, J= 8.6, 1.0 Hz), 7.20 (d,

1H, J = 8.8 Hz), 5.09 (s, 2H), 4.50 (t, 2H, J= 5.0 Hz), 3.86 (t, 2H, J= 5.0 Hz), 2.77 (s,

3H); MS m/z 429.1 (M+H).

045710-5210

Example 21

7-(4-(trifluoromethoxy)phenyl)-4-((6-(trifluoromethyl)pyridin-2-yl)methyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound 11-15)

[0407] Compound II-15 was prepared according to Example 1 using the appropriate starting materials. ‘H-NMR (CD₃OD) δ 7.98-8.04 (m, 2H), 7.68-7.77 (m, 5H), 733 (d, 2H, J =8.0 Hz), 7.14 (d, 1H, J = 8.4 Hz), 5.01 (s, 2H), 4.48 (t, 2H, J = 5.2 Hz), 3.80 (t, 2H, J= 5.2 Hz); MS m/z 483.1 (M+H).

Example 22

6-((5-oxo-7-(4-(trifluoromethoxy)phenyI)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)methyl)picolinonitrile (Compound Π-14)

[0408] Compound Π-14 was prepared according to Example 1 using the appropriate starting materials. ‘H-NMR (CD3OD) δ 7.96-8.00 (m, 2H), 7.69-7.79 (m, 5H), 733 (d, 2H, J= 8.0 Hz), 7.15 (d, 1H, J= 8.4 Hz), 4.98 (s, 2H), 4.46 (t, 2H, J= 5.2 Hz), 3.79 (t, 2H, J = 5.0 Hz); MS m/z 440.1 (M+H).

Example 23

4-(cyclopropylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-10)

F₃CO

4824-4563-0480.1

045710-5210

[0409] Compound Π-10 was prepared according to Example 1 using the appropriate starting materials. ’H-NMR (CD₃OD) δ 7.92 (d, 1H, J= 2.8 Hz), 7.69-7.75 (m, 3H), 7.34 (d, 2H, J= 8.0 Hz), 7.13 (d, 1H, J= 8.4 Hz), 4.48 (t, 2H, J= 5.2 Hz), 3.70 (t, 2H, J= 5.2

Hz), 3.53 (d, 2H, J= 6.8 Hz), 1.13-1.18 (m, 1H), 0.57-0.61 (m, 2H), 0.35-0.40 (m, 2H);

MS m/z 378.1 (M+H).

Example 24

4-(quinolin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-7)

[0410] Compound Π-7 was prepared according to Example 1 using the appropriate starting materials. Ή-NMR (CD3OD) δ 8.35 (d, 1H, 8.8 Hz), 8.02-8.05 (m, 2H), 7.93 (d, 1H, J= 7.6 Hz), 7.72-7.79 (m, 4H), 7.60 (d, 2H, J= 8.4 Hz), 7.35 (d, 2H, J= 8.0 Hz), 7.16 (d, 1H, J= 8.8 Hz), 5.15 (s, 2H), 4.43 (t, 2H, J= 5.2 Hz), 3.79 (t, 2H, J= 5.0 Hz); MS m/z 465.1 (M+H).

Example 25

7-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-130)

[0411] 7-Bromo-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (1.0g, 4.13mmol) was dissolved in DMF (10 ml) cooled down in a ice/water bath and treated with sodium hydride (60% dispersion) (363mg, 9.08mmol) portion wise. After 10 min a solution of 2(chloromethyl)pyrimidine hydrochloride (813mg, 4.96mmol) in DMF (4ml) was added, the reaction mixture warmed up to room température and quenched with 12 mL of water after it was complété. The reaction mixture was extracted with EtOAc and water and the organic phase was dried, evaporated and purified by silica gel chromatography (95%

215

4824-4563-0480.1

045710-5210

DCM/MeOH) to afford 7-bromo-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one.

[0412] Similar procedure to Example 1 for the synthesis of 7-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)-3,4-dihydrobenzo[f|[l,4]oxazepin-5(2H)-one was followed to obtain the title compound using instead of 7-bromo-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one.

[0413] A mixture of 7-bromo-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (50mg, 0.15mmol), 2-(3-fluoro-4(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (52mg, 0.18mmol), césium carbonate (146mg, 0.45mmol), 1,1’bis(diphenylphosphino)ferrocene]dichloropalladium (lOmg, 0.015 mmol) was dissolved in a degassed mixture of DMF and water 3/1.5 (4.5 mL). The mixture was heated in microwave at 85 °C for 40 min. The mixture was poured into EtOAc and washed with water and brine. The organic layer was collected, dried over sodium sulfate and loaded onto silica gel. A flash column (5% MeOH in EtOAc) and reverse phase chromatography gave 7-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H)-one.

[0414] MS found for C21H15F4N3O2 as (M+H)⁺ 418.13. Ή NMR (400 MHz, DMSOd₆y δ: 8.78 (d, J=4.0Hz, 2H), 8.09 (d, J=2.0Hz, 1H), 7.91 (dd, J=2.4, 8.0Hz, 1H), 7.857.80 (m, 2H), 7.70 (d, J=8.4Hz, 1H), 7.41 (t, .7=4,8Hz, 1H), 7.17 (d, J=8.4Hz, 1H), 4.98 (s, 2H), 4.55 (t, .7=4.8 Hz, 2H), 3.79 (t, J=4.8Hz, 2H).

Example 26

7-(4-(difluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-124)

[0415] Compound Π-124 was prepared according to Example 25 using 4(difluoromethyl)phenylboronic acid. MS found for C21H17F2N3O2 as (M+H)⁺ 382.15. Ή NMR (400 MHz, DMSO -d₆y δ: 8.77 (d, J=4.8Hz, 2H), 8.00 (d, J=2.4HzO, 1H), 7.84-7.77

216

4824-4563-0480.1

045710-5210 (m, 4H), 7.63 (d, ,/=7.6 Hz, 2H), 7.40 (t, ,/=5 2Hz, IH), 7.15 (d, J=8.8Hz, IH), 7.06 (t,

J=56.4Hz, IH), 4.98 (s, 2H), 4.52 (t, J=4.4Hz, 2H), 3.77 (t, J=5.2Hz, 2H).

Example 27

7-(4-cyclopentylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f|[l,4]oxazepin5(2H)-one (Compound Π-120)

[0416] Compound Π-120 was prepared according to Example 25 using 4cyclopentylphenylboronic acid. MS found for C25H25N3O2 as (M+H)⁺ 400.2. 'H NMR (400 MHz, DMSO -def. δ: 8.77 (d, J=4.8Hz, 2H), 7.90 (d, J=2.4Hz, IH), 7.74 (dd, J=2.4, 8.8 Hz, IH), 7.52 (d, ,7=8.4 Hz, 2H), 7.40 (t, ,/=4.8Hz, IH), 7.30 (d, J=8.0Hz, 2H), 7.10 (d, J=8.8Hz, IH), 4.97 (s, 2H), 4.48 (t, ,7=4.4 Hz, 2H), 3.74 (t, J=5.2Hz, 2H), 3.00-2.96 (m, IH), 2.01-1.97 (m, 2H), 1.78-1.51 (m, 6H).

Example 28

7-(4-chloro-3-fluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-131)

[0417] Compound Π-131 was prepared according to Example 25 using 4-chloro-3fluorophenylboronic acid. MS found for C20H15C1FN3O2 as (M+H)⁺ 384.09. ’H NMR (400 MHz, DMSO-def. δ: 8.78 (d, J=5.2Hz, 2H), 7.99 (d, ,7=2.4HzO, IH), 7.83 (dd, J=2.08.0 Hz, IH), 7.72 (d, J=8.8Hz, IH), 7.62 (t, J=8.0Hz, IH), 7.51 (dd, J=1.2-8.4Hz, IH), 7.42 (t, J=4.8Hz, IH), 7.13 (d, J=8.0Hz, IH), 4.98 (s, 2H), 4.52 (t, J=4.8Hz, 2H), 3.77 (t, /=4.8Hz, 2H).

217

4824-4563-0480.1

045710-5210

7-(2-tert-butoxypyridin-4-yl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound VI-2)

Example 29

[0418] To a mixture of 4-bromo-2-tert-butoxypyridine (1.0 g, 4.34 mmol), bis(pinacolato)diboron (1.32 g, 5.22 mmol), potassium acetate (1.28 g, 13.0 mmol), [1,1bis(diphenylphosphino)ferrocene]dichloropalladium methylene choloride complex (310 mg, 0.43 mmol) was suspended with degassed dioxane (15 mL) and heated at 85 °C for 60 min. The reaction mixture was diluted with EtOAc, washed with water and brine, dried (MgS(O)₄), filtered and concentrated. The concentrate was purified by flash chromatography on silica gel eluding with 33% percent ethyl acetate/hexanes to afford the compound 2-tert-butoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine.

[0419] Similar procedure as in Example 25 was followed to obtain the title compound using 2-tert-butoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine that was previously prepared.

[0420] MS found for C23H24N4O3 as (M+H)⁺ 405.13. Ή NMR (400MHz, DMSOd₆): δ: 8.77 (d, J=4.8Hz, 2H), 8.14 (d, J=5.6Hz, IH), 8.03 (d, J=2.4Hz, IH), 7.88 (dd, J=2.4-8.4 Hz, IH), 7.40 (t, J=4.8Hz, IH), 7.18 (d, J=5.6Hz, IH), 7.12 (d, J=8.4Hz, IH), 6.89 (s, IH), 4.97 (s, 2H), 4.53 (t, J=4.8Hz, 2H), 3.77 (t, J=4.4Hz, 2H), 1.54 (s, 9H).

Example 30

7-(5-methylthiophen-2-yl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]o^xazepin-5(2H)-one (Compound VI-20)

[0421] A mixture of 4-(pyrimidin-2-yimethyl)-7-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (50mg, 0.13mmol), 2218

4824-4563-0480.1

045710-5210 bromo-5-methylthiophene (28mg, 0.156mmol), césium carbonate (128mg, 0.39mmol), l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium (9mg, 0.013 mmol) was dissolved in a degassed mixture of DMF and water 3/1.5 (4.5ml). The mixture was heated in microwave at 85°C for 40min. The mixture was poured into EtOAc and washed with water and brine. The organic layer was collected, dried over sodium sulfate and loaded onto silica gel. A flash column (5% MeOH in EtOAc) and reverse phase chromatography gave 7-(5-methylthiophen-2-yl)-4-(pyrimidin-2-ylmethy 1)-3,4dihy drobenzo [f] [ 1,4]oxazepin-5 (2H)-one.

[0422] MS found for C19H17N3O2S as (M+H)⁺ 352.09. ’H NMR (400 MHz, DMSOd₆y ’H-NMR (DMSO) δ: 8.70 (d, J=4.0Hz, 2H), 7.80 (d, J=2.0Hz, IH), 7.68 (dd, J=2.08.4 Hz, IH), 7.40 (t, J=4.8Hz, IH), 7.23 (d, J=3.2Hz, IH), 7.05 (d, J=8.4Hz, IH), 6.77 (d, J=2.8Hz, IH), 4.95 (s, 2H), 4.46 (t, J=4.8Hz, 2H), 3.73 (t, J=4.8Hz, 2H), 2.48 (s, 3H).

Example 31

-(4-(5-oxo-4-(py rimidin-2-ylmethyl)-2,3?4,5-tetrahyd robenzo [f] [ 1,4] oxazepin-7yl)phenyl)cyclopentanecarbonitrile (Compound Π-122)

[0423] To a solution of 2-(4-bromophenyl)acetonitrile (1.0 g, 5.10 mmol) and 1,4dibromobutane (0.67 ml, 5.6 mmol) in THF (10 ml) was added potassium bis (trimethylsilyl) amide(2.23 g, 11.2 mmol) and tetra-n-butylammonium bromide (164mg, 0.51 mmol). The mixture was stirred for 2 h and then quenched with IN HCl. Ethyl acetate was added, the layers separated and the organic layer was washed with water and brine. Drying, solvent évaporation and flash chromatography (silica gel, 20% EtOAc/hexanes) gave l-(4-bromophenyl)cyclopentanecarbonitrile.

[0424] Similar procedure as in Example 30 was followed to obtain the title compound using 1 -(4-bromophenyl)cyclopentanecarbonitrile.

[0425] MS found for C26H24N4O2 as (M+H)⁺ 425.21. ’H NMR (400MHz, DMSOd₆y ’H-NMR (DMSO) δ: 8.72 (d, .7=4,0Hz, 2H), 7.90 (d, .7=2,4Hz, IH), 7.74 (dd, J=2.48.8 Hz, IH), 7.63 (d, .7=8.4Hz, 2H), 7.50 (d, J=8.4Hz, 2H), 7.35 (t, J=4.8Hz, IH), 7.08 (d,

219

4824-4563-0480.1

J=8.8Hz, 1H), 4.92 (s, 2H), 4.45 (t, ./=4,4 Hz, 2H), 3.71 (t, J=4.8Hz, 2H), 2.37-2.34 (m,

2H), 2.05-2.02 (m, 2H), 1.85-1.83 (m, 4H).

Example 32

7-(4-ethoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (Compound Π-123)

[0426] Compound 11-123 was prepared according to Example 30 using l-bromo-4ethoxybenzene. MS found for C22H21N3O3 as (M+H)' 376.15. ‘H NMR (400MHz, DMSO-de): δ: 8.77 (d, J=5.2Hz, 2H), 7.86 (d, J=2.4HzO, 1H), 7.71 (dd, J=2.8-8.4 Hz, 1H), 7.54 (d, J=8.8Hz, 2H), 7.40 (t, J=4.8Hz, 1H), 7.08 (d, J=8.0Hz, 1H), 6.97 (d, J=8.4Hz, 2H), 4.96 (s, 2H), 4.47 (t, ,/=4.8 Hz, 2H), 4.06-4.01 (m, 2H), 3.74 (t, ./=4.4 Hz, 2H), 1.34-1.30 (m, 3H).

Example 33

7-(4-(difluoromethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 11-119)

[0427] Compound 11-119 was prepared according to Example 30 using l-bromo-4(difluoromethoxy)benzene. MS found for C21H17F2N3O3 as (M+H)⁺ 398.13. ‘H NMR (400MHz, DMSO-d₆y. ‘H-NMR (DMSO) δ: 8.77 (d, J=4.8Hz, 2H), 7.92 (d, J=2.0Hz0, 1H), 7.77 (dd, J=2.4-8.4 Hz, 1H), 7.68 (d, ./=8,4Hz, 2H), 7.40 (t, .7=4.8 Hz, 1H), 7.26 (t, .7=74,OHz, 2H), 7.23 (d, J=8.8Hz, 1H), 7.12 (d, J=8.4Hz, 1H), 4.97 (s, 2H), 4.50 (t, J=4.8Hz, 2H), 3.75 (t, .7=4.8 Hz, 2H).

220

30.1

Example 34

4-(4-fluorobenzyl)-7-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-3,4diliydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VI-22)

[0428] Compound VI-22 was prepared according to Example 30 using 1(chloromethyl)-4-fluorobenzene and 4-bromo-l-methylpyridin-2(lH)-one. MS found for C22H19FN2O3 as (M+H)⁺ 379.27 ¹H NMR (400MHz, DMSO-dfi: δ: 8.01 (d, J=2.4Hz, IH), 7.83 (dd, J=2.0-8.4 Hz, IH), 7.75 (d, .7=6.8Hz, IH), 7.42-7.38 (m, 2H), 7.17 (t, J=9.2Hz, 2H), 7.10 (d, J=8.0Hz, IH), 6.63 (s, IH), 6.56 (dd, 1=2.0-7.2 Hz, IH), 4.74 (s, 2H), 4.27 (t, J=4.8Hz, 2H), 3.56 (t, ,7=4.8 Hz, 2H), 3.42 (s, 3H).

Example 35

7-(l-isopropyl-2-methyl-lH-imidazol-5-yl)-4-(pyrimidin-2-ylmethyI)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VI-23)

[0429] Compound VI-23 was prepared according to Example 30 using 5-bromo-lisopropyl-2-methyl-lH-imidazole. MS found for C21H23N5O2 as (M+H)⁺ 378.14 'H NMR (400MHz, DMSO-de): δ: 8.77 (d, 7=4.8Hz, 2H), 8.15 (s, IH), 7.63 (d, .7=2.0 Hz. IH), 7.40 (t, J=4.8Hz, 2H), 7.10 (d, J=8.0Hz, IH), 6.68 (s, IH), 4.95 (s, 2H), 4.52 (t, .7=4.8Hz, IH), 4.32-4.29 (s, IH), 3.77 (t, J=4.8Hz, 2H), 2.41 (s, 3H), 1.34 (d, J=6.8Hz, 6H).

221

4824-4563-0480.1

Example 36

7-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-4-(pyrimidm-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VI-13)

[0430] A mixture of 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (200 mg, 0.69 mmol), 4-bromo-lmethylpyridin-2(lH)-one (156mg, 0.83mmol), césium carbonate (674mg, 2.07 mmol), l,l’-Bis(diphenylphosphino)fenOcene]dichloropalladium (49 mg, 0.069 mmol) was dissolved in a degassed mixture of DMF and water 3/1.5 (4.5mL). The mixture was heated in microwave at 85°C for 40min. The mixture was poured into EtOAc and washed with water and brine. The organic layer was collected, dried over sodium sulfate and loaded onto silica gel. A flash column (5% MeOH in EtOAc) and reverse phase chromatography gave 7-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-3,4dihy drobenzo [f] [ 1,4]oxazepin-5(2H)-one.

[0431] 7-( 1 -methyl-2-oxo-1,2-dihydropyridin-4-yl)-3,4-dihydrobenzo[f] [ 1,4]oxazepin5(2H)-one (50mg, 0.185mmol) was dissolved in DMF (3 mL) and cooled down in a ice/water bath and treated with sodium hydride (60% dispersion) (17mg, 0.41mmol) portion wise. After 10 min a solution of 2-(chloromethyl)pyrimidine hydrochloride (37mg, 0.22mmol) in DMF (2mL) was added and the reaction mixture was warmed up to room température and quenched with 6mL of water after it was complété. The reaction mixture was extracted with EtOAc and water and the organic phase was dried, evaporated and purified by silica gel chromatography (95% DCM/MeOH) and then purified by reverse phase chromatography to afford 7-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-4(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one.

[0432] MS found for C20H18N4O3 as (M+H)⁺ 363.19. 'H NMR (400MHz, DMS0-d₆) δ: 8.77 (d, J=5.2Hz, 2H), 7.99 (d, ,/=2.8HzO, 1H), 7.83 (dd, J=2.4-8.4 Hz, 1H), 7.73 (d, ,/=7.2Hz, 1H), 7.40 (t, .7=5.2Hz, 1H), 7.12 (d, J=8.8Hz, 1H), 6.60 (d, J=1.6Hz, 1H), 6.53 (dd, J=2.0-7.2 Hz, 1H), 4.97 (s, 2H), 4.54 (t, J=4.8Hz, 2H), 3.77 (t, J=4.4Hz, 2H), 3.42 (s, 3H).

222

4824-4563-0480.1

Example 37

7-(l-methyI-2-oxo-l,2-dihydropyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VI-12)

[0433] Compound VI-12 was prepared according to Example 36 using 2(chloromethyl)pyridine hydrochloride. MS found for C21H19N3O3 as (M+H)⁺ 362.18. Ή NMR (400MHz, DMSO-de): δ: 8.73 (s, 1H), 8.25 (s, 1H), 7.99 (s, 1H), 7.84-7.75 (m, 4H), 7.12 (d, J=8.0Hz, 1H), 6.60-6.53 (m, 2H), 5.02 (s, 2H), 4.44 (s, 2H), 3.79 (s, 2H), 3.41 (s, 3H).

Example 38

7-(2-tert-butoxypyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound VI-4)

[0434] Compound VI-4 was prepared according to Example 36 using 7-bromo-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one, 2-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyridine and 2-(chloromethyl)pyridine hydrochloride.

[0435] MS found for C24H25N3O3 as (M+H)⁺ 404.18. Ή NMR (400MHz, DMSOd₆f. δ: 8.52 (d, ,7=4.8Hz, 1H), 8.15 (d, ,/=5.2Hz, 1H), 8.03 (d, J=2.4Hz, 1H), 7.87 (dd, J=2.0-8.0 Hz, 1H), 7.79-7.75 (m, 1H), 7.35 (d, J=8.0Hz, 1H), 7.29 (dd, J=4.8-6.8 Hz, 1H), 7.21 (d, J=5.6Hz, 1H), 7.12 (d, J=8.4Hz, 1H), 6.91 (s, 1H), 4.85 (s, 2H), 4.39 (t, J=4.4Hz, 2H), 3.69 (t, J=4 8Hz, 2H), 1.54 (s, 9H).

223

4824-4563-0480.1

Example 39

7-(2-oxo-l,2-dihydropyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4 dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound VI-3)

[0436] Compound VI-3 was generated after the acidic hydrolysis of Compound VI-4 with formic acid. MS found for C20H17N3O3 as (M+H)⁺ 348.13 ‘H NMR (400MHz, DMSO-dèf. δ: 11.56 (s, 1H), 8.52 (d, J=4.8Hz, 1H), 7.98 (d, J=2.4Hz, 1H), 7.82-7.75 (m, 2H), 7.42 (d, J=6.8Hz, 1H), 7.35 (d, J=7.6Hz, 1H), 7.28 (dd, J=4.8-6.8 Hz, 1H), 7.11 (d, J=8.8Hz, 1H), 6.53 (s, 1H), 6.47 (dd, J=l.6-6.4 Hz, 1H), 4.85 (s, 2H), 4.39 (t, J=4.4Hz, 10 2H), 3.69 (t, J=4.4Hz, 2H).

Example 40

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 11-73)

224

4824-4563-0480.1

[0437] To a solution of Compound 1-A (20 g, 0.083 mol, 1 eq.) and Compound 40-A (25 g, 0.15 mol, 1.8 eq.) in DMF (150 mL), NaOH solution (20 mL, 10M, 5 eq.) was slowly added at room température (slightly exothermic) and stirred at r.t. for 10 min, followed by heating at 95 °C for 2h. After cooling the reaction mixture, ethyl acetate (200 mL) was added and the organic layer was separated. The organics was washed with water (20 mL), brine, dried over sodium sulphate and concentrated.

[0438] The residue was dissolved in 1,4-dioxane (50 mL) and to this 4N HCl in dioxane (50 mL) and conc. HCl ( 2mL) was added and stirred at room température for 4h, filtered the precipitate, washed with ethyl acetate and dried. Compound 40-B obtained (30 g) was a light yellow solid.

[0439] To the bromide (15 g, 0.04 mol, 1 eq), boronic acid (12.5 g, 0.06 mol, 1.5 eq) and potassium carbonate (22 g, 0.16 mol, 4 eq) in a round bottom flask, solvent (150 mL, toluene/isopropano/water : 2/1/1) was added and stirred under nitrogen for 10 min. To the above solution the palladium catalyst (1 g, 0.012 mol, 0.02 eq) was added and heated at 85 °C for 2h. The reaction mixture was diluted with ethyl acetate, separated the organic layer and filtered the organic layer through a plug of celite and silica gel and concentrated. Column purification on silica gel using ethyl acetate/hexane as eluent provided Compound Π-73 (13 g).

[0440] To a solution of Compound Π-73 (26 g) in 1,4-dioxane (25 mL), 4N HCl/dioxane (25 mL) was added followed by conc. HCl (2 mL) and stirred at room température for 4h. Solvent was distilled off, dichloromethane was added and distilled off and to the residue, ethyl acetate (150 mL) was added and stirred at room température overnight and filtered the precipitate, washed with ethyl acetate, hexane and dried under vacuum. Compound Π-73-HCl obtained (24.8 g) was a white solid.

[0441] Ή-NMR (CDC1₃) δ 8.72 (d, 2H, J= 5.2 Hz), 8.17 (d, IH, J= 2.4 Hz), 7.59-7.63 (m, 3H), 7.26 (d, 2H, J= 3.2 Hz), 7.22 (t, IH, J = 4.8 Hz), 7.10 (d, IH, J= 8.4 Hz), 5.10 (s, 2H), 4.56 (t, 2H, J= 5.0 Hz), 3.77 (t, 2H, J = 5.0 Hz); MS m/z 416.1 (M+H).

225

4824-4563-0480.1

Example 41

7-(4-(trifluoromethyI)phenyI)-3,4-dihydrobenzo[f|[l,4]oxazepin-5(2H)-one

(Compound Π-128)

[0442] 7-Bromo-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (2.0 g), 4trifluoromethoxyphenylboronic acid (2.2 g) and potassium carbonate (2.0 g) were combined in a mixture of toluene (20 mL), isopropanol (10 mL) and water (10 mL) and the resulting suspension was degassed with nitrogen. Palladium chloride dppf complex was added (0.42 g) and the reaction was heated overnight at 85 °C. After cooling aqueous layer was discarded and the organic layer was diluted 2-fold with ethyl acetate, dried over MgS(O)4 and concentrated. Recrystallization was conducted by dissolving in a minimum necessary amount of dichloromethane and crushing with excess hexane, resulting in 7-(4(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one as a grey solid (1.43 g).

[0443] ΉΝΜΚ. 8.42 (t, 1H); 8.12 (d, 1H); 7.86-7.76 (m, 5H); 7.13 (d, 1H); 4.38 (t, 2H); 3.37 (quartet, 2H).

Example 42

4-(imidazo[l,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 11-129)

226

4824-4563-0480.1

[0444] 7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[fj[l,4]oxazepin-5(2H)-one (50 mg) was dissolved in dry THF and the NaH suspension (6 mg, 60% in oil) was added, followed shortly by 2-(chloromethyl)imidazo[l,2-a]pyridine (29 mg) and stirred overnight at room température. Worked up with ethyl acetate and pH 7 buffer organic layer dried over MgS(O)₄and concentrated. Purification was conducted on normal phase (CH2CI2 / 10% EtOH in ethyl acetate gradient) followed by reverse-phase (ACN / H2O, 0.1% TFA). Resulting glassy solid was dissolved in dioxane, diluted 10-fold with 0. IN HCl and lyophilized resulting in 4-(imidazo[l,2-a]pyridin-2-ylmethyl)-7-(4(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one hydrochloride sait as a white solid (42.2 mg).

[0445] ’H NMR: 7.95 (s, IH); 7.53 (d, 2H); 7.36 (m, 2H); 7.31 (d, 2H); 7.20 (d, IH); 5.30 (s, 2H); 2.16 (s, 3H); ¹⁹F NMR: -58.36 (s); MS (ESI+): 391.0 (base peak, M+H⁺); 803.2 (2M+Na⁺).

Example 43

8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-suIfone (Compound IX-1 )

227

4824-4563-0480.1

[0446] To a cooled (0°C) solution of Compound 43-A (1.368 g, 5.0 mmol) in anhydrous THF (10 mL) was added dropwise 2-aminoethanol (1.833 g, 30.0 mmol) in THF (10 mL) with stir. After completion of addition, the reaction mixture was allowed to warm to room température overnight. The mixture was concentrated in vaccuo, taken up in EA-H2O (100-50 mL), transferred to séparation funnel, the aqueous layer was extracted with EA (50 mL x 3), combined organic phase was washed with 0.1 N HCl (100 mL x 2), dried, concentrated to give Compound 43-B (1.355 g). LCMS m/z 226.0 (M+H), 228.0 (M+H+2), anal HPLC > 98%. It was used directly in the next step without further purification.

[0447] To a solution of Compound 43-B (920 mg, 3.11 mmol) and 4trifluoromethylphenylboronic acid Compound 43-C (886 mg, 4.66 mmol) in DMF (6 mL) was added K2CO3 (1.932 g, 13.98 mmol), triethylamine (1 mL) and H2O (1 mL). The reaction mixture was stirred for 5 min under an atmosphère of dry N₂. PdC12(dppf) (68 mg, 0.09 mmol) was added and the resulting mixture was heated at 130°C for 30 min in a Biotage microwave. The reaction mixture was cooled, diluted with EtOAc (30 mL), filtered through a layer of celite, washed with 20% DMF in EtOAc (60 mL), combined filtrate concentrated in vaccuo. To the resulting slurry was added 1% MOH in CH2CI2 (10 mL), filtered and the filtrate was subjected to Yamazen chromatography, eluting with a gradient of EtOAc in CH2CI2 to afford the desired product Compound 43-D (823 mg, 2.26 mmol, 73%). LCMS m/z 364.1 (M+H), anal HPLC > 92% in purity.

[0448] To a cooled (0°C) solution of Compound 43-D (73 mg, 0.20 mmol) in anhydrous DMF (3 mL) was added 95% NaH (10 mg, 0.40 mmol) in 3 portions and the resulting mixture was allowed to warm to room température under an atmosphère of N₂for 3 h. The reaction was quenched with solid NH₄C1 (159 mg, 3.0 mmol), then EtOAcH₂O (30 mL and 10 mL) was added, transferred to a séparation fünnel. The aqueous layer was extracted with EtOAc (3x10 mL), combined organic phase dried (MgS(O)4), concentrated. The crude mixture was subjected to Yamazen chromatography, eluting with a gradient of EtOAc in CH₂C1₂ (0% to 25%) to afford Compound IX-1 (34 mg, 0.10 mmol, 50%).

[0449] LCMS m/z 344.0 (M+H), anal HPLC > 96% in purity. Ή NMR (400 MHz; DMSO-d6) δ 7.97 (d, J = 2.3 Hz, IH); 7.93 (dd, J= 8.3, 2.4 Hz, IH ); 7.90 (s, IH ); 7.85 (m, 4H ); 7.35 (d, J= 8.2 Hz, IH ); 4.14 (m, 2H ); 3.47 (m, 2H ). ¹⁹F NMR (400 MHz; DMSO-d6) δ-61.50 (s, 3F).

228

4824-4563-0480.1

Example 44

2-((5-chloropyrimidin-2-yl)methyl)-8-(4-(trifluoromethyI)phenyl)-3,4-dihydro-2Hbenzo[b][l,4,5]oxathiazepin-sulfone (Compound IX-3)

IX-1

IX-3

[0450] A mixture of chloromethyl-5-chloropyrimidine (82 mg, 0.50 mmol), Compound IX-1 (17 mg, 0.05 mmol), K2CO3 (169 mg, 1.22 mmol), triethylamine (0.5 mL) anhydrous DMF (3 mL) in a Biotage microwave vial was capped and irradiated at 130 °C for 30 min in a Biotage microwave. The reaction was cooled, taken up in EtOAc (30 mL), filtered through a silica gel plug and concentrated. The crude mixture was subjected to Gilson préparative HPLC, eluting with a gradient of ACN in H2O (5% to 95%) to afford Compound IX-3 (19 mg, 0.04 mmol, 80%).

[0451] LCMS m/z 470.0 (M+H), 472.0 (M+H+2), anal HPLC > 98% in purity, ’H NMR (400 MHz; acetone-d6) 8.77 (s, 2H); 8.04 (d, J = 2.3 Hz, IH ); 7.95 (m, 3H ); 7.84 (d, J= 8.4 Hz, 2H ); 7.37 (d, J = 8.4 Hz, IH ); 4.57 (s, 2H ); 4.41 (m, 2H ); 4.00 (m, 2H ). ¹⁹F NMR (400 MHz; acetone -d6) -63.62 (s, 3F).

Example 45

8-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-sulfone (Compound IX-5)

229

4824-4563-0480.1

[0452] Compound IX-5 was prepared according to Example 44 using the appropriate starting materials [m/z 360.1, M+H],

Example 46

2-(2,2,2-trifluoroeth-l-yl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2Hbenzo[b][l,4,5]oxathiazepin-sulfone (Compound IX-4)

[0453] Compound IX-4 was prepared according to Example 44 using the appropriate starting materials [m/z 426.1, M+H],

Example 47

2-(2,2,2-trifluoroeth-l-yl)-8-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-2Hbenzo[b][l,4,5]oxathiazepin-sulfone (Compound IX-7)

[0454] Compound IX-7 was prepared according to Example 44 using the appropriate starting materials.

Example 48

2-((pyrimidin-2-yI)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2Hbenzo[b][l,4,5]oxathiazepin-sulfone (Compound IX-2)

[0455] Compound IX-2 was prepared according to Example 44 using the appropriate starting materials [m/z 436.1, M+H],

230

4824-4563-0480.1

Example 49

2-((pyrimidin-2-yl)methyI)-8-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-2Hbenzo[b]]l,4,5]oxathiazepin-sulfone (Compound IX-6)

[0456] Compound IX-6 was prepared according to Example 44 using the appropriate starting materials.

Example 50

2-((5-cydobutyl-l,3,4-oxadiazol-2-yl)methyl)-8-(4-(trifluoromethoxy)phenyl)-3,4dihydro-2H-benzo[b][l,4,5]oxathiazepin-sulfone (Compound IX-8)

[0457] Compound IX-8 was prepared according to Example 44 using the appropriate starting materials.

Example 51

2-(cyclopropylmethyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H15 benzo[b][l,4,5]oxathiazepin-sulfone (Compound IX-9)

[0458] Compound IX-9 was prepared according to Example 44 using the appropriate starting materials.

231

4824-4563-0480.1

Example 52

2-(2-methoxyeth-l-yl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2Hbenzo[b][l,4,5]oxathiazepin-sulfone (Compound IX-10)

[0459] Compound IX-10 was prepared according to Example 44 using the appropriate starting materials [m/z 402.1, M+H],

Example 53

4-((5-cyclobutyl-l,3,4-oxadiazol-2-yI)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-4)

[0460] Compound Π-4 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.01 (d, 1H, J= 2.0 Hz), 7.78 (dd, 1H, J= 8.8, 2.4 Hz), 7.71 (d, 2H, J= 8.4 Hz), 7.35 (d, 2H, J= 8.0 Hz), 7.16 (d, 1H, J = 8.8 Hz), 5.07 (s, 2H), 4.49 (t, 2H, J= 5.0 Hz), 3.75-3.83 (m, 3H), 2.41-2.47 (m, 4H), 2.00-2.21 (m, 2H); MS m/z 460.1 (M+H).

Example 54

4-((3-methylpyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-75)

[0461] Compound Π-75 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.35 (d, 1H, J- 4.8 Hz), 8.00 (d, 1H, J= 2.4 Hz), 7.70-7.77 (m, 3H), 7.66 (d, 1H, J= 7.6 Hz), 7.35 (d, 1H, J= 8.0

232

4824-4563-0480.1

Hz), 7.26-7.29 (m, 2H), 7.13 (d, 1H, 8.0 Hz), 5.01 (s, 2H), 4.25 (t, 2H, J= 5.2 Hz),

3.68 (t, 2H, J= 5.2 Hz), 2.43 (s, 3H); MS m/z 429.1 (M+H).

Example 55

7-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-105)

[0462] Compound Π-105 was prepared according to the Examples disclosed herein using the appropriate starting materials. Ή-ΝΜβ. (CDsOD) δ 8.76 (d, 2H, J= 4.8 Hz), 8.02 (s, 1H), 7.71-7.75 (m, 2H), 7.54-7.59 (m, 2H), 7.38 (t, 1H, J= 4.8 Hz), 7.18 (d, 1H, J = 8.4 Hz), 5.07 (s, 2H), 4.62 (t, 2H, ./=4.8 Hz), 3.86 (t, 2H, J= 4.8 Hz); MS m/z 418.1 (M+H).

Example 56

7-(2-chloro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-110)

[0463] Compound Π-110 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.76 (d, 2H, J= 4.8 Hz), 7.88 (d, 1H, J= 2.4 Hz), 7.82 (s, 1H), 7.69 (d, 1H, J= 7.6 Hz), 7.60-7.63 (m, 2H), 7.38 (t, 1H, J= 5.0 Hz), 7.17 (d, 1H, J= 8.0 Hz), 5.07 (s, 2H), 4.62 (t, 2H, J= 4.8 Hz), 3.86 (t, 2H, J= 4.8 Hz); MS m/z 434.0 (M+H).

4824-4563-0480.1

Example 57

7-(4-(trifluoromethoxy)phenyl)-4-((4-(trifluoromethyl)pyrimidin-2-yl)methyI)-3,4dihydrobenzo[f][l,4]o^xazepin-5(2H)-one (Compound Π-113)

[0464] Compound Π-113 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 9.08 (d, IH, J = 5.2 Hz), 8.01 (d, IH, J= 2.0 Hz), 7.76-7.79 (m, 2H), 7.71 (d, 2H, J =9.2 Hz), 7.34 (d, 2H, J= 8.0 Hz), 7.17 (d, IH, J= 8.4 Hz), 5.16 (s, 2H), 4.63 (t, 2H, J= 5.0 Hz), 3.88 (t, 2H, J= 4.8 Hz); MS m/z 484.1 (M+H).

Example 58

7-(4-(trifluoromethoxy)phenyl)-4-((3-(trifluoromethyl)pyridin-2-yl)methyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-126)

[0465] Compound Π-126 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD₃OD) δ 8.74 (d, IH, J = 5.2 Hz), 8.13 (d, IH, J= 7.6 Hz), 8.01 (d, IH, J= 6.4 Hz), 7.77 (dd, IH, J= 8.2, 2.2Hz), 7.71 (d, 2H, J= 8.4 Hz), 7.48 (dd, IH, J= 7.4, 5.0 Hz), 7.34 (d, 2H, J= 8.4 Hz), 7.16 (d, IH, J = 8.8 Hz), 5.18 (s, 2H), 4.57 (t, 2H, J=4.8 Hz), 3.81 (t, 2H, J= 5.2 Hz), MS m/z 483.1 (M+H).

234

4824-4563-0480.1

Example 59

4-(oxazol-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-127)

[0466] Compound Π-127 was prepared according to the Examples disclosed herein using the appropriate starting materiais. ’H-NMR (CD3OD) δ 8.00 (d, IH, J = 2.4 Hz), 7.92 (s, IH), 7.77 (dd, IH, J= 8.6, 2.2 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.35 (d, 2H, J = 8.0 Hz), 7.14-7.17 (m, 2H), 4.99 (s, 2H), 4.44 (t, 2H, J= 5.0 Hz), 3.78 (t, 2H, J= 5.0 Hz); MS m/z 405.0 (M+H).

Example 60

4-(2-(benzyloxy)ethyl)-l-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-lHbenzo[e][l,4]diazepine-2,5-dione (Compound X-7)

Pd(dppfCI₂, K₂C0₃H₂O/toluene//-PrOH

F₃CO

B(OH)₂

[0467] 6-Bromo-lH-benzo[d][l,3]oxazine-2,4-dione (5.0 g, 20.66 mmol), iodomethane (1.94 mL, d = 2.28, 4.4 g, 31.0 mmol, 1.5 equiv.) and NazCCh (4.38 g, 41.3 mmol, 2 equiv.) were placed in a round bottomed flask. To the flask were added DMF (40 mL) at

235

4824-4563-0480.1 ambient température. The mixture was stirred overnight at room température and then filtered through a glass filter. Obtained filtrate was diluted with water to form précipitâtes. The précipitâtes were dissolved in EtOAc and the solution was dried over MgS(O)4. The solvent was removed under reduced pressure. At this point, since the conversion was ~50%, K2CO3 (14.3 g, 103.3 mmol, 5 equiv.) and iodomethane (2.58 mL, d = 2.28, 41.3 mmol, 2.0 equiv.) were added to the solution of the crude material in DMF. The mixture was heated at 30°C so that the reaction can go to completion and then filtered through a glass filter. Obtained filtrate was diluted with water to form précipitâtes. Formed précipitâtes were filtered through a glass filter to give the desired product (6-bromo-lmethyl-lH-benzo[d][l,3]oxazine-2,4-dione). This was used for the subséquent step without further purification.

[0468] 6-Bromo-l-methyl-lH-benzo[d][l,3]oxazine-2,4-dione (5.29 g, 20.66 mmol) and glycine (1.7 g, 22.73 mmol, 1.1 equiv.) were dissolved in AcOH (100 mL) in a round bottomed flask. The mixture was heated under reflux conditions for 2 hours. The mixture was purified by automated silica-gel column chromatography using EtOAc/hexane gradient as the eluent. The purification give the desired product (7-bromo-l-methyl-3,4dihydro-lH-benzo[e][l,4]diazepine-2,5-dione, colorless powder, 446.7 mg).

[0469] 7-Bromo-l-methyl-3,4-dihydro-lH-benzo[e][l,4]diazepine-2,5-dione (446.7 mg, 1.661 mmol), 4-trifluoromethoxyboronic acid (445.0 mg, 2.159 mmol, 1.3 equiv.) Pd(dppf)C12’CH₂Cl₂ (120.0 mg, 0.166 mmol, 10 mol%) and K₂CO₃ (482.0 mg, 3.49 mmol, 2.1 equiv.) were dissolved in a mixed solvents, H₂O/toluene/i-PrOH (2.5 mL: 5 mL: 2.5 mL) in a 10 mL round bottomed flask under a nitrogen atmosphère. The mixture was heated at 60°C for 64 h. The mixture was purified by automated silica-gel column chromatography using EtOAc/hexane gradient as the eluent. The purification give the desired product (1 -methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro- 1Hbenzo[e][l,4]diazepine-2,5-dione, 415.0 mg).

[0470] l-Methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-lHbenzo[e][l,4]diazepine-2,5-dione (50.0 mg, 0.143 mmol) and NaH (17 mg, 0.428 mmol, 3.0 equiv.) were placed in a 2-5 mL Smith process vial under a nitrogen atmosphère. To the vial was added DMF (5 mL) to observe hydrogen extlusion. And then ((2bromoethoxy)methyl)benzene (45 pL, 0.285 mmol, d = 0.135, 2 equiv.) was added at room température. After stirring for 50 min, the reaction was quenched with AcOH. Resulting mixture was directly injected to a préparative HPLC to give the desired product

236

4824-4563-0480.1 (4-(2-(benzyloxy)ethyl)-l-methyl-7-(4-(trifluoromethoxy)-phenyl)-3,4-dihydro-lHbenzo[e][l,4]diazepine-2,5-dione, 42.7 mg) as a light yellow film.

[0471] LCMS (El: 70 eV) 503 (M⁺+Na), 486 (M⁺+l).

Example 61

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-lHbenzo[e][l,4]diazepine-2,5-dione (Compound X-9)

[0472] Procedure to 61-B To a mixture of compound 61-A (4.380 g, 20.0 mmol), NBoc diamine (5.000 g, 31.2 mmol) and EDC (5.600 g, 38.74 mmol) in anhydrous CH2CI2 (80 mL) was added dropwise Hunig’s base (10 mL, 56.16 mmol) with stir. After completion of addition, the reaction mixture was concentrated in vaccuo, taken up in EAH₂O (200-100 mL), transferred to séparation fùnnel, the aqueous layer was extracted with EA (100 mL x 3), combined organic phase was washed with 0.1 N HCl (100 mL x 2), dried, concentrated, column chromatographed using Yamazen, eluting with EaOAc/whexane to give compound 61-B (6.386 g, 17.67 mmol, 88%). LCMS m/z 362.0 (M+H), anal HPLC > 90%. It was used directly in the next step without further purification.

[0473] Procedure to Compound 61-C Standard Suzuki coupling as described above, starting from compound 61-B (658 mg, 1.8 mmol), a pale yellow solid 61-D (610 mg, 1.4 mmol, 79%) was obtained using Yamazen chromatography eluting with EaOAc/n237

4824-4563-0480.1 hexane, LCMS m/z 327.1 (M-t-Butyl), 876.3 (2M+Na), it was used directly in the next step without further purification.

[0474] Procedure to Compound 61-D and 61-E To a anhydrous DMF (30 mL) solution of compound C (213 mg, 0.500 mmol) and chloromethyl pyrimidine HCl sait (248 mg, 1.50 mmol) was added slowly 95% NaH (65 mg, 2.7 mmol) and stirred 5 min. Another portion of 95% NaH (55 mg, 2.3 mmol) was added, stirred for 5 min. The crude mixture was quenched by 30% aqueous NH4CI (40 mL), extracted with EtOAc (3 x 100 mL), combined organic phase was washed with saturated NaHCOs (100 mL), brine (100 mL), dried, concentrated in vaccuo. Reverse-phase HPLC was used to obtain a yellow solid 61-D (75 mg, 0.14 mmol, 29%). LCMS m/z 519.2 (M+H). It was used directly in the next step without further purification.

[0475] To a solution of compound 61-D (70 mg, 0.13 mmol) in DCM (5.0 mL) was added TFA (2.0 mL) and stirred overnight. Then it was concentrated in vaccuo, only one single peak in LCMS as compound 61-E, m/z 419.1 (M+H), anal HPLC > 95 in purity.

[0476] Procedure to compound X-9 To a anhydrous DMF solution (15 mL) of the above compound 61-E (54 mg, 0.13 mmol) was added Hunig’s base (2 mL), capped in a Biotage microwave vial and subjected to microwave heating at 150°C for 40 min. The reaction mixture was filtered, concentrated in vaccuo and subjected to Gilson préparative HPLC, eluting with a gradient of ACN in H2O (5% to 95%) to afford X-9 (16 mg, 0.04 mmol, 31%). LCMS m/z 399.1 (M+H), anal HPLC > 98% in purity.

Example 62 l-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-lHbenzo[e][l,4]diazepin-5(2H)-one (Compound X-10)

238

4824-4563-0480.1

NaBH(OAc)₃, DCM

H₂O, rt

HO

X-10

Paraformaldéhyde

[0477] Procedure to compound X-10 To a anhydrous DCM solution (3 mL) of the compound X-9 (14 mg, 0.035 mmol) was added paraformaldéhyde (0.5 mL) and H₂O (1 mL), stirred for 5 min, THF (1 mL) was added to help solubility. After 5 min, borohydride (63 mg, 0.31 mmol) was added, stirred for 30 min until the starting material disappeared in LCMS. The crude mixture was quenched by 30% aqueous NH₄C1 (10 mL), extracted with EtOAc (3x30 mL), combined organic phase was washed with saturated NaHCO₃ (30 mL), brine (30 mL), dried, concentrated in vaccuo. Reverse-phase HPLC was used to obtain a yellow solid X-10 (6 mg, 0.015 mmol, 42%). LCMS m/z 412.1 (M+H), anal HPLC > 98%.

Example 63

4-((l-methyl-lH-imidazol-2-yI)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-186)

[0478] Compound Π-186 was prepared according to the Examples disclosed herein using the appropriate starting materials. The Suzuki coupling was performed under standard conditioned explained in the other procedures using Pd(dppf)Cl₂.

[0479] Alkylation of the amide was performed using sodium hydride following the standard procedure to provide the final products.

239

4824-4563-0480.1

[0485] Compound Π-189 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 454.1. ’H NMR (400 d₆) δ 6.80 - 8.50 (m, 12H ); 5.36 (s, 2H); 4.82 (m, 2H); 4.24 (m, 2H). ¹⁹F NMR (400

MHz; DMSO-d6) δ -57.38 (s, 3F).

241

4824-4563-0480.1

[0480] Mass (M+H)⁺418.1. ’HNMR (400 MHz; dmso-d₆) δ 7.93 (s, IH ); 7.75 (m, 3H ); 7.58 (m, 2H ); 7.42 (m, 2H ); 4.86 (m, 2H); 4.18 (m, 2H); 3.75 (s, 3H); 3.65 (m, 2H). ¹⁹F NMR (400 MHz; DMSO-d6) δ -57.26 (s, 3F).

Example 64

4-(2-morpholinoethyl)-7-(4-(trifluoromethoxy)phenyI)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-188)

[0481] Compound Π-188 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺437.1.

Example 65

4-((5-methylpyrazin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-172)

[0482] Compound Π-172 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 430.1. ’H NMR (400 MHz;

DMSO-d6) δ 8.50 (m, 2H ); 7.94 (s, IH ); 7.78 (m, 3H ); 7.41 (d, J = 8.5 Hz, 2H ); 7.13 (d, J = 8.1 Hz, IH); 4.86 (s, 2H); 4.38 (m, 2H); 3.71 (m, 2H); 2.48 (s, 3H). ¹⁹F NMR (400 MHz; DMSO-d6) δ -57.26 (s, 3F).

Example 66

4-((6-methylpyrazin-2-yl)methyI)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-175)

240

4824-4563-0480.1

Example 69 tert-butyl 2-(7-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f|[l,4]oxazepine4-carbonyl)-5,6-dihydroimidazo[l,2-a]pyrazine-7(8H)-carboxylate (Compound TTT40)

69-A

111-40

[0486] Décarboxylation of the amide was performed using IM BH₃ in THF for 1-5 days following the standard procedure to provide amine 69-A. This was followed by a standard HATU catalyzed condensation reaction to afford Compound ΠΙ-40. Mass (M+H)⁺ 543.2.

Example 70 (5,6,7,8-tetrahydroimidazo[l,2-a]pyrazin-2-yl)(7-(4-(trifluoromethyl)phenyl)-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (Compound III-42)

[0487] Compound ΙΠ-40 was deprotected using TFA in dichloromethane in a standard procedure to give Compound ΠΙ-42. Mass (M+H)¹ 443.1.

242

4824-4563-0480.1

Example 71 l-(2-(7-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f|[l,4]oxazepine-4carbonyl)-5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)ethanone (Compound ΠΙ-48)

Ac₂O

[0488] Standard acylation using acetic anhydride at room température of Compound

ΙΠ-42 afforded Compound ΙΠ-48. Mass (M+H)⁺485.1.

Example 72 (l-methyI-lH-imidazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-2,310 dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (Compound ΙΠ-32)

[0489] Compound ΙΠ-32 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺402.1.

Example 73 (lH-imidazol-2-yl)(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f| [l,4]oxazepin4(5H)-yl)methanone (Compound ΙΠ-33)

243

4824-4563-0480.1

[0490] Compound ΙΠ-33 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 388.1.

Example 74 (l-((lH-imidazol-l-yl)methyl)cyclopropyl)(7-(4-(trifluoromethyl)phenyl)-2,35 dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (Compound ΙΠ-34)

[0491] Compound ΠΙ-34 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺442.1.

Example 75 (l-methyl-lH-imidazol-2-yl)(7-(4-(trifluoromethyl)phenyl)-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (Compound ΙΠ-37)

[0492] Compound ΠΙ-37 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 402.1.

Example 76 (R)-tert-butyl 2-(7-(4-(trifluoromethyl)phenyl)-2,3,4,5tetrahydrobenzo[f][l,4]oxazepine-4-carbonyl)pyrrolidine-l-carboxylate (Compound HI-52)

244

4824-4563-0480.1

[0493] Compound ΙΠ-52 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺491.2.

Example 77 (lH-l,2,3-triazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-2,3dihydrobenzo[f|[l,4]oxazepin-4(5H)-yl)methanone (Compound ΠΙ-49)

[0494] Compound ΙΠ-49 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺389.1.

Example 78 (lH-l,2,4-triazol-3-yl)(7-(4-(trifluoromethyl)phenyl)-2,3dihydrobenzo[f] [l,4]oxazepin-4(5H)-yl)methanone (Compound III-50)

[0495] Compound III-50 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺389.1.

Example 79 (3-amino-lH-l,2,4-triazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (Compound ΙΠ-51)

[0496] Compound ΙΠ-51 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 404.1.

245

4824-4563-0480.1

Example 80 (R)-py^rrolidin-2-yl(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f|[l,4]oxazepin4(5H)-yl)methanone (Compound ΙΠ-53)

[0497] Compound ΙΠ-53 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺391.1.

Example 81 (l-phenyl-lH-l,2,3-triazol-5-yl)(7-(4-(trifluoromethyl)phenyl)-2,3dihydrobenzo[f][l,4]oxazepm-4(5H)-yl)methanone (Compound ΠΙ-54)

[0498] Compound ΙΠ-54 was prepared according to the Examples disclosed herein using the appropriate starting materials.

Example 82 (R)-l-(2-(7-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[fJ[l,4]oxazepine-415 carbonyl)pyrrolidin-l-yl)ethanone (Compound ΙΠ-55)

[0499] Compound ΙΠ-55 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 433.1.

246

4824-4563-0480.1

Example 83 (lH-imidazol-2-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (Compound ΠΙ-56)

[0500] Compound ΙΠ-56 was prepared according to the Examples disclosed herein using the appropriate starting materiais. Mass (M+H)⁺404.1.

Example 84 (S)-4-benzyl-3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 11-132)

3) NaH, DMF

[0501] A solution of 5-bromo-2-fluorobenzoic acid (1 mmol), benzyl (S)-valinol (1 mmol), HATU (1 mmol) and diisopropylethylamine (3 mmol) in DMF (3 mL) was stirred at room température for 30 minutes. The reaction mixture was poured into a 1:1 solution 15 of IM HCl and brine and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried and concentrated. The resided was taken up in a mixture of toluene, isopropanol and water (ImL each) and added to a flask containing 4-trifluoromethylphenyl boronic acid (3 mmol), K₂CO₃ (3

247

4824-4563-0480.1 mmol) and dppfPdCh (40 mg) under nitrogen. The reaction mixture was stirred at 90°C for 1 h. The organic layer was separated and concentrated before being purified by flash chromatography (rf = 0.28 in 2:1 hexanes/ethyl acetate) to give a viscous oil. The product was dissolved in DMF (5 mL) and sodium hydride was added (5 mmol). The reaction mixture was stirred at room température for 40 minutes and was poured into a 1:1 solution of IM HCl and brine and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried and concentrated before being purified by flash chromatography (rf = 0.59 in 2:1 hexanes/ethyl acetate) to give (S)-4-benzyl-3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one as an oil.

[0502] To a solution of the above product in chloroform was added NB S (2.5 equiv) and N-methylacetamide (10 mol%). The reaction was stirred for 18 hours at room température before being concentrated under vacuum. The residue was dissolved in ethyl acetate (10 mL) and IM NaOH solution was added (10 mL). The mixture was stirred vigorously for 5 minutes and the organic layer was separated, washed with brine and concentrated. Flash chromatography (rf = 0.10 in 2:1 hexanes/ethyl acetate) gave the debenzylated product.

[0503] To a solution of the above product (20 mg) and 2-chloromethylpyrimidine HCl sait (30 mg) in DMF was added sodium hydride (40 mg) and the reaction was stirred for 1 h at room température. The reaction mixture was quenched with IM HCl and purified by préparative HPLC to give (S)-3-methyl-4-(pyrimidin-2-ylmethyl)-7-(4(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one TFA sait as a white powder.

Example 85 (2S,1 laS)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,11,11atetrahydrobenzo[f]pyrrolo[2,l-c][l,4]oxazepin-5(lH)-one (Compound Π-51)

[0504] Compound Π-51 was prepared according to the Examples disclosed herein using the appropriate starting materials. C19H17F3N2O2 x TFA. 363.1 (M+l). ‘H NMR

248

4824-4563-0480.1 (DMSO) δ 8.34 (d, J = 2.8 Hz, 1H), 8.20 (br, 3H), 7.85 (m, 5H), 7.16 (d, J = 8.4 Hz, 1H),

4.61 (d, J = 12.0 Hz, 1H), 4.16 (m, 2H), 3.96 (m, 1H), 3.83 (br, 1H), 3.58 (m, 1H), 2.54 (m, 1H), 1.80 (m, 1H). ¹⁹F NMR (DMSO) δ -61.4 (s, 3F).

Example 86 (R)-2-(pyrimidin-2-ylmethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydrolH-benzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one (Compound Π-8)

[0505] Compound II-8 was prepared according to the Examples disclosed herein using the appropriate starting materials. C24H21F3N4O2X 2-TFA. 455.1 (M+l).

Example 87 (S)-2-(pyrimidin-2-ylmethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydrolH-benzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one (Compound Π-9)

[0506] Compound Π-9 was prepared according to the Examples disclosed herein using the appropriate starting materials. C24H21F3N4O2X 2-TFA. 455.1 (M+l).

Example 88 (S)-3-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 11-12)

[0507] Compound Π-12 was prepared according to the Examples disclosed herein using the appropriate starting materials. C22H18F3N3O2 x TFA. 414.1 (M+l). 'H NMK

249

4824-4563-0480.1 (DMSO) δ 8.77 (d, J = 5.2 Hz, 2H), 8.38 (d, J = 2.4 Hz, IH), 7.85 (m, 5H), 7.40 (t, J = 5.0

Hz, IH), 7.20 (d, J = 8.4 Hz, IH), 5.10(J= 17.0 Hz, IH), 4.79 (d, J =17.0 Hz, IH), 4.60 (m, 2H), 4.05 (m, IH). 1.22 (d, J = 6.8 Hz, 3H). ¹⁹F NMR (DMSO) δ -61.37 (s, 3F).

Example 89 (R)-3-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-13)

[0508] Compound 11-13 was prepared according to the Examples disclosed herein using the appropriate starting materials. C22H18F3N3O2X TFA. 414.1 (M+l). 'H NMR (DMSO) δ 8.77 (d, J = 5.2 Hz, 2H), 8.38 (d, J = 2.4 Hz, IH), 7.85 (m, 5H), 7.40 (t, J = 5.0 Hz, IH), 7.20 (d, J = 8.4 Hz, IH), 5.10 (J = 17.0 Hz, IH), 4.79 (d, J = 17.0 Hz, IH), 4.60 (m, 2H), 4.05 (m, IH). 1.22 (d, J = 6.8 Hz, 3H). ¹⁹F NMR (DMSO) δ -61.37 (s, 3F).

Example 90 (S)-3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f[[l,4]oxazepin-5(2H)one (Compound Π-18)

[0509] Compound Π-18 was prepared according to the Examples disclosed herein using the appropriate starting materials. C17H14F3NO2. 322.1 (M+l). ’HNMR (DMSO) δ 8.41 (d, J = 4.4 Hz, IH), 8.20 (d, J = 1.6 Hz, IH), 7.85 (m, 5H), 7.16 (d, J = 8.4 Hz, IH), 4.22 (m, 2 H), 3.68 (br, IH), 1.15 (d, J = 6.4 Hz, 3H).

4824-4563-0480.1

Example 91 (R)-3-methyl-7-(4-(trifluoromethyl)phenyI)-3,4-dihydrobenzo[f|]l,4]oxazepin5(2H)-one (Compound Π-19)

[0510] Compound Π-19 was prepared according to the Examples disclosed herein using the appropriate starting materials. C17H14F3NO2. 322.1 (M+l). ‘H NMR (DMSO) δ 8.41 (d, J = 4.4 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.85 (m, 5H), 7.16 (d, J = 8.4 Hz, 1H), 4.22 (m, 2 H), 3.68 (br, 1H), 1.15 (d, J = 6.4 Hz, 3H).

Example 92 (2R,llaS)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,ll,llatetrahydrobenzo[f]pyrrolo[2,l-c][l,4]oxazepin-5(lH)-one (Compound Π-21)

[0511] Compound Π-21 was prepared according to the Examples disclosed herein using the appropriate starting materials. C19H17F3N2O2X TFA. 363.1 (M+l).

Example 93 (R)-2-(2,2-difluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-lHbenzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one (Compound Π-22)

[0512] Compound 11-22 was prepared according to the Examples disclosed herein using the appropriate starting materials. C21H19F5N2O2X TFA. 427.1 (M+l). ‘H NMR (DMSO) δ 8.22 (d, J = 2.4 Hz, 1H), 7.84 (m, 5H), 7.18 (d, J = 8.4 Hz, 1H), 6.22 (tm, J =

251

4824-4563-0480.1

55.6 Hz, IH), 4.53 (m, IH), 4.27 (m, IH), 3.97 (br, 2H), 3.62 (m, IH), 2.90-2.60 (m, 6H).

¹⁹F NMR (DMSO) δ -61.4 (s, 3F), -119.4 (dt, 55.6, 16.2 Hz, 2F).

Example 94 (R)-2-ethyl-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-lHbenzo[f|pyrazino[2,l-c][l,4]oxazepin-6(2H)-one (Compound Π-23)

[0513] Compound Π-23 was prepared according to the Examples disclosed herein using the appropriate starting materials. C21H21F3N2O2 x TFA. 391.1 (M+l).

Example 95 (S)-2-(2,2-difluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-lHbenzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one (Compound Π-24)

[0514] Compound Π-24 was prepared according to the Examples disclosed herein using the appropriate starting materials. C21H19F5N2O2X TFA. 427.1 (M+l). Ή NMR (DMSO) δ 8.22 (d, J = 2.4 Hz, IH), 7.84 (m, 5H), 7.18 (d, J = 8.4 Hz, IH), 6.22 (tm, J = 55.6 Hz, IH), 4.53 (m, IH), 4.27 (m, IH), 3.97 (br, 2H), 3.62 (m, IH), 2.90-2.60 (m, 6H). ¹⁹F NMR (DMSO) δ -61.4 (s, 3F), -119.4 (dt, 55.6, 16.2 Hz, 2F).

Example 96 (S)-2-ethyl-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-lHbenzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one (Compound Π-25)

4824-4563-0480.1

[0515] Compound Π-25 was prepared according to the Examples disclosed herein using the appropriate starting materials. C21H21F3N2O2 x TFA. 391.1 (M+l).

Example 97 (S)-3-isopropyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f|[l,4]oxazepin5(2H)-one (Compound Π-77)

[0516] Compound Π-77 was prepared according to the Examples disclosed herein using the appropriate starting materials. C19H18F3NO2. 350.1 (M+l).

Example 98 (R)-3-methyl-4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-80)

[0517] Compound Π-80 was prepared according to the Examples disclosed herein using the appropriate starting materials. C23H19F3N2O2 x TFA. 413.1 (M+l).

Example 99 (S)-3-methyl-4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyI)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-81)

[0518] Compound Π-81 was prepared according to the Examples disclosed herein using the appropriate starting materials. C23H19F3N2O2 x TFA. 413.1 (M+l).

253

4824-4563-0480.1

Example 100

4-(l-(pyridin-2-yl)ethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-82)

F

[0519] Compound Π-82 was prepared according to the Examples disclosed herein using the appropriate starting materiais. C22H18F3N3O2 x TFA. 414.1 (M+l)

Example 101 (R)-2-(2,2,2-trifluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-lHbenzo[f|pyrazino[2,l-c][l,4]oxazepin-6(2H)-one (Compound Π-83)

[0520] Compound Π-83 was prepared according to the Examples disclosed herein using the appropriate starting materiais. C21H18F6N2O2X TFA. 445.1 (M+l)

Example 102 (R)-4-benzyl-2-methyI-7-(4-(trifluoromethyl)phenyl)-3,415 dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-85)

[0521] Compound Π-85 was prepared according to the Examples disclosed herein using the appropriate starting materiais. C24H20F3NO2.412.I (M+l).

254

4824-4563-0480.1

Example 103 (S)-4-benzyl-2-methyl-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-86)

[0522] Compound Π-86 was prepared according to the Examples disclosed herein using the appropriate starting materials. C24H20F3NO2.412.1 (M+l).

Example 104 (S)-2-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyI)phenyI)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-101)

[0523] Compound Π-101 was prepared according to the Examples disclosed herein using the appropriate starting materials. C22H18F3N3O2. 414.1 (M+l)

Example 105

2-(pyridin-2-yl)-l-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin15 4(5H)-yl)ethanone (Compound ΠΙ-29)

[0524] Compound ΙΠ-29 was prepared according to the Examples disclosed herein using the appropriate starting materials. C23H19F3N2O2. 413.1 (M+l).

255

482+4563-0480.1

Example 106

2-(pyrimidin-2-yl)-l-(7-(4-(trifluoromethyl)phenyl)-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)ethanone (Compound ΙΠ-30)

[0525] Compound ΠΙ-30 was prepared according to the Examples disclosed herein using the appropriate starting materials. C22H18F3N3O2. 414.1 (M+l).

Example 107

4-(5-oxo-4-(pyrimidin-2-ylmethyl)-2,3»4,5-tetrahydrobenzo[f|[l,4]o^xazepin-7yl)phenyl trifluoromethanesulfonate (Compound Π-171)

[0526] Compound Π-171 was prepared according to the Examples disclosed herein using the appropriate starting materials. C2iHi6F₃N₃O5S. 480.1 (M+l).

Example 108 (R)-(2-methyl-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin15 4(5H)-yI)(pyrimidin-2-yl)methanone (Compound ΠΙ-38)

[0527] Compound ΙΠ-38 was prepared according to the Examples disclosed herein using the appropriate starting materials. C22HisF₃N₃O₃. 430.1 (M+l).

256

4824-4563-0480.1

Example 109 (S)-(2-methyl-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f|[l,4]oxazepin4(5H)-yl)(pyrimidin-2-yl)methanone (Compound III-39)

[0528] Compound ΙΠ-39 was prepared according to the Examples disclosed herein using the appropriate starting materials. C22H18F3N3O3. 430.1 (M+l).

Example 110

Phenyl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f|[l,4]oxazepin-4(5H)yl)methanone (Compound ΙΠ-4)

[0529] Compound ΙΠ-4 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C23H18F3NO3 as (M+H)^: 414.1.

Example 111

4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethyl)phenyl)-3,415 dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 11-150)

[0530] Compound Π-150 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C23H18F3NO3 as (M+H) 414.2.

257

4824-4563-0480.1

Example 112

4-(pyridin-2-yhnetliyl)-7-(4-(2.2,2-tiifluoroethyl)phenyl)-3.4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-151)

[0531] Compound Π-151 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C23H19F3N2O2 as (M+H) 413.2 'H NMR (400MHz, dmso-d₆y. δ: 8.54 (d, J=5.6 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.80-7.76 (m, 2H); 7.67 (d, J = 8.0 Hz, 1H), 7.42-7.28 (m, 4H); 7.14 (d, J= 8.4 Hz, 1H); 4.86 (s, 2H), 4.38-4.36 (m, 2H), 3.72-3.64 (m, 4H).

Example 113 (l-methylcyclopropyl)(7-(4-(trifluoromethoxy)phenyI)-2,3-dihydrobenzo[f][l,4] oxazepin-4(5H)-yl)methanone (Compound ΙΠ-10)

[0532] Compound ΙΠ-10 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C21H20F3NO3 as (M+H)⁺ 392.0.

Example 114 (3,3-difluorocyclobutyl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4] oxazepin-4(5H)-yl)methanone (Compound ΙΠ-11)

[0533] Compound ΙΠ-11 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C21H18F5NO3 as (M+H)⁺ 428.1.

258

4824-4563-0480.1

Example 115 (l-methyl-lH-pyrazol-4-yl)(7-(4-(trifluorometlioxy)phenyl)-2,3-dihydrobenzo[f][l,4] oxazepin-4(5H)-yl)methanone (Compound ΙΠ-12)

[0534] Compound ΠΙ-12 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C21H18F3N3O3 as (M+H) 418.1. Ή NMR (400MHz, dmso-d₆): δ: 8.03 (s, IH), 7.73-7.41 (m, 7H); 7.03 (d, J= 8.0 Hz, IH), 4.82 (s, 2H), 4.26 (m, 2H); 4.00 (m, 2H); 383 (s, 3H).

Example 116 (lH-pyrazol-3-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4] oxazepin-4(5H)-yl)methanone (Compound ΠΙ-15)

[0535] Compound ΠΙ-15 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C20H16F3N3O3 as (M+H)⁺ 404.1.

Example 117 (l,5-dimethyl-lH-pyrazol-3-yl)(7-(4-(trifluoromethoxy)phenyI)-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (Compound ΠΙ-58)

[0536] Compound ΠΙ-58 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C22H20F3N3O3 as (M+H)⁺ 432.1

259

4824-4563-0480.1

Example 118

Pyrazin-2-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f|[l,4]oxazepin4(5H)-yl)methanone (Compound ΙΠ-23)

[0537] Compound ΙΠ-23 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C21H16F3N3O3 as (M+H)⁺ 416.1.

Example 119

Pyridazin-3-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f[[l,4]oxazepin4(5H)-yl)methanone (Compound ΠΙ-24)

[0538] Compound ΠΙ-24 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C16H14F3NO2 as (M+H)⁺ 310.1.MS found for C21H16F3N3O3 as (M+H)⁺ 416.1.

Example 120

4-(pyrimidin-2-ylmethyl)-7-p-toIyl-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-87)

[0539] Compound Π-87 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C21H19N3O2 as (M+H)⁺ 346.1 'H NMR (400MHz, dmso-d₆y δ: 8.77 (d, J=5.2Hz, 2H), 7.90 (d, J=2.4Hz, 1H), 7.75 (dd, J=2.4, 8.8 Hz, 1H), 7.52 (d, J=8.8Hz, 2H), 7.40 (t, J=5.2Hz, 1H), 7.25 (d, J=8.0Hz, 2H), 7.42 (d, J=8.4Hz, 1H), 4.96 (s, 2H), 4.49-4.47 (m, 2H), 3.75-3.73 (m, 2H), 2.31 (s, 3H).

260

4824-4563-0480.1

Example 121

7-(4-chlorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (Compound 11-88)

[0540] Compound Π-88 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C2oEIi6N302Cl as (M+H)⁺ 366.1 Ή NMR (400MHz, dmso-d₆y. δ: 8.77 (d, J=5.2Hz, 2H), 7.94 (d, J=2.4Hz, 1H), 7.79 (dd, J=2.4, 8.8 Hz, 1H), 7.67 (d, J=8.8Hz, 2H), 7.49 (d, J=8.0Hz, 2H), 7.40 (t, J=5.2Hz, 1H), 7.13 (d, J=8.4Hz, 1H), 4.97 (s, 2H), 4.51-4.49 (m, 2H), 3.77-3.74 (m, 2H).

Example 122

7-(4-isopropylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (Compound 11-89)

[0541] Compound Π-89 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C23H23N3O2 as (M+H)⁺ 374.1 Ή NMR (400MHz, dmso-d₆). δ: 8.77 (d, J=5.2Hz, 2H), 7.90 (d, J=2.4Hz, 1H), 7.75 (dd, >2.4, 8.8 Hz, 1H), 7.55 (d, J=8.8Hz, 2H), 7.41 (t, J=5.2Hz, 1H), 7.29 (d, J=8.0Hz, 2H), 7.11 (d, J=8.4Hz, 1H), 4.96 (s, 2H), 4.49-4.47 (m, 2H), 3.75-3.73 (m, 2H), 2.91 (m, 1H); 1.22 (d, J = 7.2 Hz, 6H).

Example 123

7-(4-ethylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f|[l,4]oxazepin-5(2H)one (Compound Π-91)

4824-4563-0480.1

[0542] Compound Π-91 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C22H21N3O2 as (M+H)⁺ 360.1 'H NMR (400MHz, dmso-d₆): δ: 8.77 (d, J=5.2Hz, 2H), 7.91 (d, J=2.4Hz, IH), 7.75 (dd, J=2.4, 8.8 Hz, IH), 7.54 (d, J=8.8Hz, 2H), 7.41 (t, J=5.2Hz, IH), 7.28 (d, J=8.0Hz, 2H), 7.12 (d, J=8.4Hz, IH), 4.97 (s, 2H), 4.49-4.47 (m, 2H), 3.75-3.73 (m, 2H), 2.64 (q, J = 7.6 Hz, 2H); 1.20 (d, J = 7.6 Hz, 3H).

Example 124

7-(4-cyclopropylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (Compound Π-92)

[0543] Compound Π-92 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C22H21N3O2 as (M+H)⁺ 372.1 'H NMR (400MHz, dmso-d₆): δ: 8.77 (d, J=5.2Hz, 2H), 7.88 (d, J=2.4Hz, IH), 7.74 (dd, J=2.4, 8.8 Hz, IH), 7.50 (d, J=8.8Hz, 2H), 7.41 (t, J=5.2Hz, IH), 7.14 (d, J=8.0Hz, 2H), 7.10 (d, .7=8.4Hz, IH), 4.96 (s, 2H), 4.49-4.47 (m, 2H), 3.75-3.73 (m, 2H), 1.94-1.89 (m, IH); 0.97-0.93 (m, 2H); 0.70-0.66 (m, 2H).

Example 125

7-(4-methoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (Compound Π-94)

[0544] Compound Π-94 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C21H19N3O3 as (M+H)⁺ 362.1 'H NMR (400MHz, dmso-de): δ: 8.78 (d, J=5.2Hz, 2H), 7.86 (d, J=2.4Hz, IH), 7.72 (dd, J=2.4, 8.8 Hz, IH), 7.56 (d, J=8.8Hz, 2H), 7.41 (t, J=5.2Hz, IH), 7.10 (d, J=8.0Hz, 2H), 7.00 (d, J=8.4Hz, IH), 4.97 (s, 2H), 4.48-4.45 (m, 2H), 3.76 (s, 3H); 3.74-3.72 (m, 2H).

262

4824-4563-0480.1

Example 126

7-(4-isobutoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f|[l,4]oxazepin5(2H)-one (Compound Π-97)

[0545] Compound Π-97 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C24H25N3O3 as (M+H)⁺ 404.1. ‘H NMR (400MHz, dmso-d₆y δ: 8.78 (d, J=5.2Hz, 2H), 7.85 (d, J=2.4Hz, 1H), 7.72 (dd, J=2.4, 8.8 Hz, 1H), 7.54 (d, J=8.8Hz, 2H), 7.41 (t, J=5.2Hz, 1H), 7.10 (d, J=8.0Hz, 2H), 6.99 (d, J=8.4Hz, 1H), 4.97 (s, 2H), 4.48-4.46 (m, 2H), 3.76-3.72 (m, 4H); 2.03-1.97 (m, 10 1H); 0.97 (d, J = 6.4 Hz, 6H).

Example 127

7-(4-tert-butylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (Compound Π-98)

[0546] Compound Π-98 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C24H25N3O3 as (M+H)⁺ 404.1 ‘H NMR (400MHz, dmso-d₆y δ: 8.78 (d, J=5.2Hz, 2H), 7.91 (d, J=2.4Hz, 1H), 7.75 (dd, J=2.4, 8.8 Hz, 1H), 7.55 (d, J=8.8Hz, 2H), 7.46 (d, J=8.0Hz, 2H); 7.41 (t, J=5.2Hz, 1H); 7.1 l(d, J=8.4Hz, 1H), 4.97 (s, 2H), 4.50-4.47 (m, 2H), 3.76-3.73 (m, 4H); 1.29 (s, 9H).

263

4824-4563-0480.1

Example 128

7-(4-cyclopropoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-102)

[0547] Compound Π-102 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C23H21N3O3 as (M+H)⁺ 388.1 ’H NMR (400MHz, dmso-d₆y δ: 8.78 (d, J=5.2Hz, 2H), 7.86 (d, J2.4FIz, IH), 7.72 (dd, J=2.4, 8.8 Hz, IH), 7.57 (d, J=8.8Hz, 2H), 7.41 (t, J=5.2Hz, IH); 7.46 (d, J=8.0Hz, 2H), 7.11 (m, 3H), 4.97 (s, 2H), 4.48-4.46 (m, 2H), 3.87-3.86 (m, IH); 3.84-3.74 (m, 2H); 0.80-0.75 (m, 2H); 0.67-0.65 (m, 2H).

Example 129

7-(4-chloro-2-fluorophenyl)-4-(pyrimidin-2-ylmethyI)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-117)

[0548] Compound Π-117 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C20H15N3O2FCI as (M+H)⁴ 384.1 ’H NMR (400MHz, dmso-d₆y Ô: 8.77 (d, J=5.2Hz, 2H), 7.87 (d, J=2.4Hz, IH), 7.66 (dd, J=2.4, 8.8 Hz, IH), 7.57-7.51 (m, 2H); 7.41-7.35 (m, 2H); 7.16 (d, J=8.0Hz, IH), 4.97 (s, 2H), 4.54-4.52 (m, 2H), 3.79-3.76 (m, 2H).

Example 130 pyrimidin-2-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin4(5H)-yl)methanone (Compound ΙΠ-1)

4824-4563-0480.1

[0549] To a solution of 7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (660 mgs, 2.0 mmol) in THF (6 mL), 1.0M Borane in THF (6.0 mL, 6.0 mmol) was added and the mixture was heated at 70 °C. After 16h, the mixture was cooled to rt and Methanol (22 mL) and 6.0M HCl (22 mL) was added and stirred at rt for 2h. The reaction mixture was then concentrated and the solids formed were filtered and washed with ether and dried to give 7-(4(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepine as HCl sait. The above compound (100 mgs, 0.29 mmol), pyrimidine-2-carboxylic acid (47 mgs, 0.38 mmol), HATU (143 mgs, 0.38 mmol), in DMF (1 mL) was added NMM (0.1 mL, 0.86 mmol) and stirred at 60 °C for 30min.The reaction mixture was then diluted with EtOAc and washed with NaHCO₃, brine and dried (MgS(O)₄). The mixture was the filtered, concentrated and chromatographed (SiO2, 50% EtOAc/DCM) to provide the title compound.

[0550] MS found for C21H16F3N3O3 as (M+H)⁺ 415.9. ’H NMR (400MHz, dmso-dey mixture of rotomers (~2:1): ’H-NMR (DMSO) of the major rotomer. δ 8.86 (d, J=5.2Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.75 (m, IH); 7.69-7.54 (m, 2H); 7.47-7.40 (m, 2H); 7.11 (d, J = 8.0 Hz, IH); 4.85 (s, 2H); 4.25-4.03 (m, 4H); 3.58-3.56 (m, 2H).

Example 131

7-cyclohexenyl-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one (Compound V-3)

[0551] Compound V-3 was prepared according to the Examples disclosed herein using the appropriate starting materiais. MS found for C2oH2iN₃Û2as (M+H)* 336.1.

Example 132

7-(4-methylcyclohex-l-enyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound V-5)

4824-4563-0480.1

[0552] Compound V-5 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C21H23N3O2 as (M+H)⁺ 350.1 'H NMR (400MHz, dmso-de): δ: 8.76 (d, J=5.2Hz, 2H), 7.65 (d, J=2.4Hz, 1H), 7.53 (dd, J=2.4, 8.4

Hz, 1H), 7.42-7.39 (m, 1H); 6.98 (d, J= 84Hz, 1H); 6.08 (m, 1H); 4.94 (s, 2H), 4.44-4.42 (m, 2H), 3.69-3.67 (m, 2H); 2.36-2.23 (m, 4H); 1.81-1.66 (m, 5H); 1.31-1.26 (m, 1H).

Example 133

7-(4-ethylcyclohex-l-enyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[fJ[l,4]oxazepin-5(2H)-one (Compound V-6)

[0553] Compound V-6 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C22H25N3O2 as (M+H)⁺ 364.1 'HNMR (400MHz, dmso-de): δ: 8.77 (d, J=5.2Hz, 2H), 7.65 (d, J=2.4Hz, 1H), 7.52 (dd, J=2.4, 8.4 Hz, 1H), 7.42-7.38 (m, 1H); 6.98 (d, J= 8.4Hz, 1H); 6.09 (m, 1H); 4.94 (s, 2H), 4.444.42 (m, 2H), 3.70-3.67 (m, 2H); 2.36-2.25 (m, 3H); 1.84-1.77 (m, 2H); 1.32-1.26 (m, 4H); 0.91-0.88 (m, 3H).

Example 134 (R)-7-(4-methylcyclohex-l-enyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound V-8)

[0554] The racemic 7-(4-methylcyclohex-1 -enyl)-4-(pyrimidin-2-ylmethy 1)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one was separted using chiral préparative HPLC to give pure enantiomers of Compound V-8 and Compound V-9.

[0555] R-enantiomer: MS found for C21H23N3O2 as (M+H)⁺ 350.1

266

482+4563-0480.1

Example 135 (S)-7-(4-methylcyclohex-l-enyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound V-9)

[0556] Compound V-9 was prepared according to the Example above. S-enantiomer:

MS found for C21H23N3O2 as (M+H)⁺ 350.1

Example 136

3-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-142)

[0557] Synthesis of 6-(4-(trifluoromethoxy)phenyl)chroman-4-one. See previous

Suzuki reaction conditions, m/z = 309.0

[0558] Synthesis of 3-(pyridin-2-ylmethylene)-6-(4-(trifluoromethoxy)phenyl)chroman4-one. A solution of 400mg 6-(4-(trifluoromethoxy)phenyl)chroman-4-one (1.3 mmol, 1.0 eq), 150 pL 2-pyridine carboxaldehyde ( 1.6 mmol, 1.2 eq) and 130 pL pyrrolidine ( 1.6 mmol, 1.2 eq) in 10 mL éthanol was refluxed 3h. The reaction was concentrated and

267

4824-4563-0480.1 purified on silica gel column eluting with EA:Hex. 160 mg of a yellow solid was collected. m/z = 398.0

[0559] Synthesis of 3-(pyridin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)chroman-4one. A solution of 150 mg 3-(pyridin-2-ylmethylene)-6-(4(trifluoromethoxy)phenyl)chroman-4-one (0.38 mmol) in 20 mL EtOH with catalytic Pd/C was stirred under 1 atm of hydrogen gas for 16 h. The reaction was filtered through celite and the filtrate concentrated. The filtrate was purified on silica gel column eluting with EA.Hex. 85 mg of an off-white solid was collected. m/z= 400.

[0560] Synthesis of 3-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one. To a solution of 72 mg 3-(pyridin-2-ylmethyl)6-(4-(trifluoromethoxy)phenyl)chroman-4-one (0.18 mmol) in ImL methylsulfonic acid 35 mg sodium azide (0.54 mmol) was added. After Ih, reaction was diluted with 5 mL water and neutralized with addition of IN NaOH solution. The precipitate was filter off to afford 65 mg off-white powder of product. m/z= 415.0

Example 137

7-(4-(cyclobutylmethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-144)

[0561] Compound 11-144 was prepared according to example 25 using 2-(4(cyclobutylmethoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane. MS found for

C25H25N3O3 as (M+H)⁺ 416.22 Ή NMR (400MHz, dmso-d₆y. ’H-NMR (DMSO) δ:

268

4824-4563-0480.1

8.78 (d, J= 5.2Hz, 2H), 7.86 (d, 7=2.0Hz, IH), 7.72 (dd, J=2.4-8.4Hz, IH), 7.54 (d,

7=8.4Hz, 2H), 7.41 (t, 7= 5.2Hz, IH), 7.09 (d, 7=8.4Hz, IH), 6.99 (d, 7=8.8Hz, 2H), 4.97 (s, 2H), 4.48 (t, 7=4.4Hz, 2H), 3.97 (d, 7=6.8Hz, 2H), 3.74 (t, 7=4.8Hz, 2H), 2.75-2.67 (m, IH), 2.09-2.03 (m, 2H), 1.94-1.79 (m, 4H).

Example 138

4-(pyrimidin-2-ylmethyl)-7-(6-(2,2,2-trifluoroethyl)pyridin-3-yl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VI-24)

[0562] Compound VI-24 was prepared according to example 25 using 5-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethyl)pyridine.

Example 139

7-(2-methyl-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-145)

[0563] Compound Π-145 was prepared according to example 25 using 2-methyl-4(trifluoromethyl)phenylboronic acid. MS found for C22H18F3N3O2 as (M+H)⁺ 414.32

Example 140

7-(2-methyl-4-(trifluoromethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 11-146)

[0564] Compound Π-146 was prepared according to example 25 using 2-methyl-4(trifluoromethoxy)phenylboronic acid. MS found for C22H18F3N3O3 as (M+H) 430.19

269

4824-4563-0480.1 ’H NMR (400MHz, dmso-d₆y 'H-NMR (DMSO) δ: 8.77 (d, J= 5.2Hz, 2H), 7.64 (d,

J=2.4Hz, 1H), 7.48 (dd, J=2.4-8.4Hz, 1H), 7.40 (t, J=4.8Hz, 1H), 7.31 (d, J= 8.4Hz, 2H),

7.23 (d, J=8.8Hz, 1H), 7.11 (d, J=8.4Hz, 1H), 4.96 (s, 2H), 4.52 (t, ./=4.4 Hz, 2H), 3.78 (t, .7=4.4 Hz, 2H), 2.25 (s, 3H).

Example 141

7-(4-(difluoromethyI)phenyl)-4-(pyridin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-157)

[0565] Compound Π-157 was prepared according to example 25 using 410 (difluoromethyl)phenylboronic acid. MS found for C22H18F2N2O2 as (M+H)⁺ 381.20 Ή NMR (400MHz, dmso-d₆y Ή-NMR (DMSO) 5: 8.54 (s, 1H), 8.02 (s, 1H), 7.85-7.80 (m, 4H), 7.65 (d, J=7 6 Hz, 2H), 7.38-7.31 (m, 2H), 7.16 (d, J= 8.0Hz, 1H), 7.08 (t, J=55.6Hz, 1H), 4.87 (s, 2H), 4.40 (s, 2H), 3.71 (s, 2H).

Example 142

4-(pyridin-2-ylmethyl)-7-(2-(trifluoromethyl)pyridin-4-yl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VI-25)

[0566] Compound VI-25 was prepared according to example 25 using 4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine.

270

4824-4563-0480.1

Example 143

7-(4-chloro-3-fluorophenyl)-4-(pyridin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-158)

[0567] Compound 11-158 was prepared according to example 25 using 4-chloro-3fluorophenylboronic acid. MS found for C21H16C1FN2O2 as (M+H)⁺ 383.17 Ή NMR (400MHz, dmso-d₆y Ή-NMR (DMSO) δ: 8.60 (d, J= 4.8Hz, 1H), 8.01 (d, .7=7,2 Hz, 1H), 7.94 (d, J=2.4Hz, 1H), 7.79 (dd, J=2.4-8.4Hz, 1H), 7.69 (dd, J= 2.0-10.8Hz, 1H), 7.617.47 (m, 4H), 7.09 (d, ./=8.4Hz, 1H), 4.90 (s, 2H), 4.36 (t, J=4.8Hz, 2H), 3.69 (t, J=4.8Hz, 2H).

Example 144

7-(4-(difluoromethoxy)phenyI)-4-(pyridin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-159)

[0568] Compound Π-159 was prepared according to example 25 using 2-(4(difluoromethoxy)phenyl)-4,4,5,5-tetramethyi-l,3,2-dioxaborolane. MS found for C22H18F2N2O3 as (M+H)⁺ 397.22.

Example 145

4-(pyridin-2-ylmethyl)-7-(5-(trifluoromethyl)pyridin-2-yl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VI-26)

271

4824-4563-0480.1

[0569] Compound VI-26 was prepared according to example 25 using 2-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine. MS found for

C21H16F3N3O2 as (M+H)⁺ 400.21.

Example 146

7-(l-methyl-lH-pyrazol-4-yl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VI-27)

[0570] Compound VI-27 was prepared according to example 25 using l-methyl-4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole.

Example 147

7-(l-isopropyl-lH-pyrazol-4-yl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2II)-one (Compound VI-28)

[0571] Compound VI-28 was prepared according to example 25 using l-isopropyl-4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyr azole.

Example 148

7-(l-methyl-lH-pyrazol-3-yl)-4-(pyridin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VI-29)

[0572] Compound VI-29 was prepared according to example 25 using l-methyl-3(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl)-lH-pyrazole.

272

4824-4563-0480.1

Example 149

7-(2-isopropylthiazol-4-yl)-4-(pyridin-2-ylmethyI)-3,4-dihydrobenzo[f|[l,4]oxazepin5(2H)-one (Compound VI-30)

[0573] Compound VI-30 was prepared according to example 25 using 2-isopropyl-4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiazole. MS found for C21H21N3O2S as (M+H)⁺ 380.20 ’H NMR (400MHz, dmso-d₆y. Ή-NMR (DMSO) δ: 8.53 (d, J= 4.8Hz, 1H), 8.26 (d, 7=2.0Hz, 1H), 8.01 (dd, 7=2.0-8.8Hz, 1H), 7.94 (s, 1H), 7.78 (t, J= 7,2Hz, 1H), 7.36-7.28 (m, 2H), 7.09 (d, 7=8.0Hz, 1H), 4.85 (s, 2H), 4.36 (t, 7=4.4Hz, 2H), 3.66 (t, 7=4.8Hz, 2H), 1.36 (d, 7=6.8Hz, 6H).

Example 150

4-(pyrimidin-2-ylmethyl)-7-(2,3,4-trifluorophenyl)-3,4dihydrobenzo[f][l,4]o^xazepin-5(2H)-one (Compound Π-162)

[0574] Compound Π-162 was prepared according to example 25 using 2,3,4trifluorophenylboronic acid. MS found for C20H14F3N3O2 as (M+H)⁺ 386.14.

Example 151

7-(3,4-difluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f|[l,4]oxazepin5(2H)-one (Compound Π-163)

[0575] Compound Π-163 was prepared according to example 25 using 3,4difluorophenylboronic acid. MS found for C20H15F2N3O2 as (M+H)^T 368.15.

273

4824-4563-0480.1

Example 152

4-(pyridin-2-ylmethyl)-7-(5-(trifluoromethyl)thiophen-2-yl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VI-31)

[0576] Compound VI-31 was prepared according to example 29 using 2-bromo-5- (trifluoromethyl)thiophene. MS found for C20H15F3N2O2S as (M+H)⁺ 405.16 ‘H NMR (400MHz, dmso-d₆y ‘H-NMR (DMSO) δ: 8.53 (d, J= 4.8Hz, 1H), 8.02 (d, J=2.0Hz, 1H), 7.87-7.71 (m, 3H), 7.59 (d, J= 3.2Hz, 1H), 7.37-7.28 (m, 2H), 7.13 (d, J= 8.4Hz, 1H), 4.85 (s, 2H), 4.40 (t, 7=4.8Hz, 2H), 3.70 (t, 7=4.8Hz, 2H).

Example 153

7-(5-cyclopropylthiophen-2-yl)-4-(pyridin-2-ylmethyl)-3,4dihydrobenzo]f][l,4]oxazepin-5(2H)-one (Compound VI-32)

[0577] Compound VI-32 was prepared according to example 29 using 2-bromo-515 cyclopropylthiophene. MS found for C22H20N2O2S as (M+H)⁺ 377.18 ‘H NMR (400MHz, dmso-d₆y ‘H-NMR (DMSO) δ: 8.53 (d, J= 4.8Hz, 1H), 7.81-7.76 (m, 2H), 7.68 (dd, 7=2.4-8.0Hz, 1H), 7.36-7.24 (m, 3H), 7.04 (d, J= 8.4Hz, 1H), 6.80 (d, J= 3.6Hz, 1H), 4.84 (s, 2H), 4.34 (t,7=5.2Hz, 2H), 3.66 (t,7=5.2Hz, 2H), 2.14-2.10 (m, 1H), 1.020.97 (m, 2H), 0.71-0.67 (m, 2H).

274

4824-4563-0480.1

Example 154

7-(2-methylthiazol-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (Compound VI-33)

[0578] Compound VI-33 was prepared according to example 29 using 4-bromo-2methylthiazole.

Example 155

4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-lH-benzo[e][l,4]diazepine-2,5dione (Compound X-8)

[0579] A mixture of 5-bromoisatoic anhydride (1g, 4.13mmol), N-benzylglycine (0.628g, 4.13mmol) and DMSO (3mL) was heated in the microwave at 200°C for one hour. After cooling, the mixture was diluted with water and the precipitate was filtered off, washed with water and dried, giving 4-benzyl-7-bromo-3,4-dihydro-lHbenzo[e][l,4]diazepine-2,5-dione (1.4g, 98%) as an off-white powder.

[0580] 4-Benzyl-7-bromo-3,4-dihydro-1 H-benzo[e] [1,4] diazepine-2,5 -dione ( 1.4g, 4.05mmol) was combined with 4-(trifluoromethyl)phenylboronic acid (0.77g, 4.05mmol), potassium carbonate (1g) and [1,1'Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (148 mg, 0.202 mmol) in 5mL DMF. Water (3mL) was added and the mixture was heated under nitrogen atmosphère at 80°C for three hours. After cooling the mixture was diluted with ethyl acetate, washed with water and brine, dried with magnésium sulfate and evaporated. Purification by silica275

4824-4563-0480.1 gel chromatography (20-100% ethyl acetate in hexane) followed by recrystallization gave

4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-lH-benzo[e][l,4]diazepine-2,5-dione (1.25g, 75%) as a white powder.

[0581] 'H-NMR (DMSO) δ: 10.61 (s, 1H), 8.13 (d, J=1.6Hz, 1H), 7.92 (d, J=8.4Hz, 3H), 7.11 (d, J=8.4Hz, 2H), 7.36-7.25 (m, 5H), 7.22 (d, J=8.4Hz, 1H), 4.79 (s, 2H), 3.92 (s, 2H). MS: 411 (MH⁺).

Example 156

4-benzyl-l-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-lHbenzo[e][l,4]diazepine-2,5-dione (Compound X-ll)

[0582] 4-Benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1 H-benzo [e] [ 1,4] diazepine2,5-dione (9.80 mg, 0.024 mmol) and K2CO3 (10 mg, 0.072 mmol, 3.0 equiv.) were placed in a 0.5-2 mL Smith process vial under a nitrogen atmosphère. To the vial were added DMF (0.5 mL) and iodomethane (2.25 pL, 0.036 mmol, d = 2.28 g/cm³, 1.5 equiv) at room température. After heating, stirred, at 60°C for 2 hours, the reaction mixture was concentrated en vacuo. The resulting crude mixture was diluted with acetonitrile (1 mL), filtered through a syringe filter and injected into a préparative HPLC to give desired product (4-benzyl-l-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-lHbenzo[e][l,4]diazepine-2,5-dione, 1.8 mg) as a yellow film.

[0583] 'H-NMR (400 MHz; CD3CN) δ 8.16 (d, 1H, J= 2 Hz), 7.93 (dd, 1H, J = 8.4 Hz, 2 Hz), 7.92 (d, 2H, J= 7.8 Hz), 7.82 (d, 2H, J= 7.8 Hz), 7.47 (d, 1H, J= 8.4 Hz), 4.98 (d, 1H, J= 15 Hz), 4.73 (d, 1H, 15 Hz), 4.10 (d, 1H, J= 15 Hz), 3.70 (d, 1H, J= 15 Hz),

276

482+4563-0480.1

3.37 (s, 3H). ¹⁹F-NMR (400 MHz; CD₃CN) δ -63.96 (s, 3F). LCMS (EL 70 eV) 447.1 (M++Na), 425.1 (M++1).

Example 157 (S)-3-(2-hydroxyethyI)-l-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-lHbenzo[e][l,4]diazepine-2,5-dione (Compound X-l)

L-Homoserine

AcOH

[0584] 2-Amino-5-iodobenzoic acid (1.327 g, 5.05 mmol), 4-trifluoromethoxyboronic acid (1.455 g, 7.07 mmol, 1.4 equiv.), Pd(dppf)Cl₂CH₂Cl₂ (183.0 mg, 0.252 mmol, 5 mol%) and K₂CO₃ (1.604 g, 11.61 mmol, 2.3 equiv.) were dissolved in a mixture of H2O/toluene/i-PrOH (2.5 mL: 5 mL: 2.5 mL) in a 10 mL Smith process vial equipped with a stir bar under a nitrogen atmosphère. The mixture was heated at 90°C for 1 hour. After aqueous workup and removal of volatile solvents en vacuo, the mixture was purified by automated silica-gel column chromatography using an EtOAc/hexane gradient as the eluent. The purification gave the desired product (4-amino-4'-(trifluoromethoxy)biphenyl3-carboxylic acid, 462.0 mg) as a colorless powder.

[0585] To a suspension of 4-amino-4'-(trifluoromethoxy)biphenyl-3-carboxylic acid (462.0 mg, 1.554 mmol) in CH₂C1₂ (10 mL) in a round bottomed flask was added triethylamine (210pL, 1.492 mmol, d = 0.726 g/cm³, 0.96 equiv.). Flask was charged with nitrogen, cooled to 0°C and a solution of triphosgene (148.0 mg, 0.497 mmol, 0.32 equiv.) in 2 mL DCM was added, followed by a solution of N,N-dimethyl-4-aminopyridine (30 mg, 0.246 mmol, 25 mol%) in CH₂C1₂ (2 mL). Reaction mixture was allowed to stir 2 hours, then quenched with a small portion of IN HCl. Reaction mixture with resulting precipitate was filtered through a disposable filter tunnel and air-dried to give desired

277

4824-4563-0480.1 product (6-(4-(trifluoromethoxy)phenyl)-lH-benzo[d][l,3]oxazine-2,4-dione, 348.6 mg) as a colorless solid.

[0586] 6-(4-(Trifluoromethoxy)phenyl)-lH-benzo[d][l,3]oxazine-2,4-dione (348.6 mg, 1.077 mmol) and K2CO3 (228 mg, 2.153 mmol, 2 equiv.) were placed in a 0.5-2 mL Smith process vial. To the vial was added DMF (3 mL) and iodomethane (101 pL, d = 2.28, 1.615 mmol, 1.5 equiv.) at ambient température. The mixture was stirred overnight at room température and then filtered through a disposable filter fùnnel. Obtained filtrate was diluted with water to form précipitâtes, which were collected on a disposable filter funnel and allowed to air-dry to give desired product (l-methyl-6-(4(trifluoromethoxy)phenyl)-lH-benzo[d][l,3]oxazine-2,4-dione, 357.2 mg) as a colorless solid.

[0587] 1 -Methyl-6-(4-(trifluoromethoxy)phenyl)-1 H-benzo [d] [ 1,3 ]oxazine-2,4-dione (60 mg, 0.178 mmol) and L-homoserine (23.3 mg, 0.196 mmol, 1.1 equiv.) were added to a magnetically stirred 0.5-2 mL Smith process vial containing 0.75 mL glacial acetic acid. Reaction mixture was then heated for 2 hours at 130°C. Excess acetic acid was then removed en vacuo, residue was dissolved into a minimal amount of acetonitrile and purified by reverse-phase préparative HPLC to give the title compound (7.6 mg) following removal of solvent as a clear yellow film.

[0588] LCMS (El: 70 eV) 459.1 (M++Na), 437.1 (M++1)

Example 158 l-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-lH-benzo[e][l,4]diazepine-2,5dione (Compound X-2)

[0589] 6-Bromo-lH-benzo[d][l,3]oxazine-2,4-dione (5.0 g, 20.66 mmol), iodomethane:

(1.94 mL, d = 2.28, 4.4 g, 31.0 mmol, 1.5 equiv.) and Na₂CO₃ (4.38 g, 41.3 mmol, 2

278

4824-4563-0480.1 equiv.) were placed in a round bottomed flask. To the flask were added DMF (40 mL) at ambient température. The mixture was stirred overnight at room température and then filtered through a glass filter. Obtained filtrate was diluted with water to form précipitâtes. The précipitâtes were dissolved in EtOAc and the solution was dried over MgS(O)₄. The solvent was removed under reduced pressure. At this point, since the conversion was -50%, K2CO3 (14.3 g, 103.3 mmol, 5 equiv.) and iodomethane (2.58 mL, d = 2.28, 41.3 mmol, 2.0 equiv.) were added to the solution of the crude material in DMF. The mixture was heated at 30°C so that the reaction can go to completion and then filtered through a glass filter. Obtained filtrate was diluted with water to form précipitâtes. Formed précipitâtes were filtered through a glass filter to give the desired product (6-bromo-lmethyl-lH-benzo[d][l,3]oxazine-2,4-dione). This was used for the subséquent step ¹without fùrther purification.

[0590] 6-Bromo-l-methyl-lH-benzo[d][l,3]oxazine-2,4-dione (5.29 g, 20.66 mmol) ¹and glycine (1.7 g, 22.73 mmol, 1.1 equiv.) were dissolved in AcOH (100 mL) in a round bottomed flask. The mixture was heated under reflux conditions for 2 hours. The mixture was purified by automated silica-gel column chromatography using EtOAc/hexane gradient as the eluent. The purification give the desired product (7-bromo-l-methyl-3,4 dihydro-lH-benzo[e][l,4]diazepine-2,5-dione, colorless powder, 446.7 mg).

[0591] 7-Bromo-l-methyl-3,4-dihydro-lH-benzo[e][l,4]diazepine-2,5-dione (446.7 mg, 1.661 mmol), 4-trifluoromethoxyboronic acid (445.0 mg, 2.159 mmol, 1.3 equiv.) Pd(dppf)C12 CH₂C12 (120.0 mg, 0.166 mmol, 10 mol%) and K2CO3 (482.0 mg, 3.49 mmol, 2.1 equiv.) were dissolved in a mixture of H2O/toluene/i-PrOH (2.5 mL: 5 mL: 2.5 mL) in a 10 mL round bottomed flask under a nitrogen atmosphère. The mixture was heated at 60°C for 64 hours. The mixture was purified by automated silica-gel column chromatography using EtOAc/hexane gradient as the eluent. Evaporation of solvent en vacuo gave the title compound (415.0 mg) as a white powder.

[0592] LCMS (EL 70 eV) 373.1 (M++Na), 351.1 (M++1 )

279

4824-4563-0480.1

Example 159 l-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-lHbenzo[e][l,4]diazepine-2,5-dione (Compound X-3)

[0593] l-Methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-lHbenzo[e][l,4]diazepine-2,5-dione (22.9 mg, 0.065 mmol) andNaH (15.6 mg, 0.650 mmol, 10.0 equiv.) were placed in a 0.5-2 mL Smith process vial. To the vial was added DMF (0.5 mL) followed by 2-(chloromethyl)pyrimidine hydrochloride (53.9 mg, 0.327 10 mmol, 5 equiv.) was added at room température. After stirring for 50 min, reaction was quenched with AcOH. Resulting mixture was filtered and purified via préparative reverse phase HPLC to give the title compound (2.2 mg) as a clear yellow film.

[0594] LCMS (El: 70 eV) 443.1 (M++1)

Example 160 l-methyl-4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-lH benzo[e][l,4]diazepine-2,5-dione (Compound X-4)

[0595] Compound X-4 was prepared according to the above example using the appropriate starting materials.

280

4824-4563-0480.1

Example 161

4-(4-(lH-pyrazol-l-yl)benzyl)-l-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrolH-benzo[e][l,4]diazepine-2,5-dione (Compound X-6)

[0596] Compound X-6 was prepared according to the above example using the appropriate starting materials.

Example 162 l-(4-methoxybenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-lHbenzo]e][l,4]diazepine-2,5-dione (Compound X-5)

[0597] 7-Bromo-3,4-dihydro-lH-benzo[e][l,4]diazepine-2,5-dione (510.0 mg, 2 mmol) and CS2CO3 (1.955 mg, 6 mmol, 3 equiv.) were placed in a round bottomed flask. To the reaction vessel was added DMF (10 mL) and 4-methoxybenzyl chloride (273 pL, 1.615 mmol, d = 1.15 g/mL, 1 equiv.) at ambient température. The mixture was stirred overnight at room température and then filtered through a disposable filter tunnel. Resulting filtrate was concentrated en vacuo and purified by automated silica-gel column chromatography using an EtOAc/hexane gradient as the eluent to give the desired product (7-bromo-l-(4-methoxybenzyl)-3,4-dihydro-lH-benzo[e][l,4]diazepine-2,5-dione, 378.j mg) as a colorless solid.

281

4824-4563-0480.1

[0598] 7-Bromo-l-methyl-3,4-dihydro-lH-benzo[e][l,4]diazepine-2,5-dione (375.0 mg, 1.007 mmol), 4-trifluoromethoxyboronic acid (270.0 mg, 1.31 mmol, 1.3 equiv.) Pd(dppf)Cl₂ CH₂Cl₂ (72.9.0 mg, 0.101 mmol, 10 mol%) and K2CO3 (292.0 mg, 2.116 mmol, 2.1 equiv.) were dissolved in a mixture of H₂O/toluene/i-PrOH (1.25 mL: 2.5 mL: 1.25 mL) in a 2-5 mL Smith process vial equipped with a stir bar under a nitrogen atmosphère. The mixture was heated at 50°C for 17 hours. After aqueous workup and removal of volatile solvents en vacuo, the mixture was purified by automated silica-gel column chromatography using an EtOAc/hexane gradient as the eluent. The purification gave the title compound (419 mg) as a colorless powder.

[0599] LCMS (El: 70 eV) 479.1 (M++Na), 457.1 (M++1)

Example 163

4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][l,4]oxazepin5(2H)-one (Compound ΧΠ-1)

Pd(dppf)CI2

T ol/isopropanol/H2O 85 C, 2h

[0600] To 2-bromo-5-fluoroisonicotinic acid (5 g, 22.72 mmol) benzyl amino éthanol (4.20 g, 27.27 mmol, 1.2 eq) was added in the presence of EDCI (5.2 g, 27.27 mmol, 1.2 eq) in dichloromethane (100 mL) and stirred at room température for 4h. The reaction mixture was diluted with dichloromethane, washed with water, brine, dried over sodium sulfate and concentrated (5.0 g). The residue (5.0g, 14.16 mmol) was cyclized by

282

4824-4563-0480.1 dissolving in DMF (20 mL), sodium hydride (1.2 g, 28 mmol) was added and stirred at room température for 2h. The reaction mixture was neutralized with dil. HCl and extracted with ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated. Purified by flash chromatography furnished 4.4 g of the cyclized product.

[0601] The Suzuki coupling was performed under standard conditioned explained in the other procedures using Pd(dppf)C12. Mass (M+H)⁺ 415.1. CDCfl. 8.46 (S, 1H), 8.28 (S, 1H), 8.05 (d, J = 8.8 Hz, 2H), 7.42-7.32 (m, 5H), 7.30 (d, J = 8.0 Hz, 2H), 4.86 (s, 2H), 4.31 (t, J = 4 Hz, 2H), 3.57 (t, J = 4 Hz, 2H)

Example 164

4-(cyclopropylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3f|[l,4]oxazepin-5(2H)-one (Compound ΧΠ-9)

[0602] Alkylation of the amide was performed using sodium hydride following the standard procedure to provide Compound ΧΠ-9. Mass (M+H) 379.0.

Example 165

4-(pyrimidin-2-ylmethyI)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3f|[l,4]oxazepin-5(2H)-one (Compound ΧΠ-5)

[0603] Compound ΧΠ-5 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 417.0.

283

4824-4563-0480.1

Example 166

4-((3~methoxypyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydropyrido[4,3-f|[l,4]oxazepin-5(2H)-one (Compound ΧΠ-10)

[0604] Compound ΧΠ-10 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 446.1. CDCh: 8.55 (s, IH), 8.41 (s, IH), 8.22 (s, IH), 7.97 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 2.8 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 5.12 (s, 2H), 4.55 (t, J = 4 Hz, 2H), 4.03 (s, 3H), 3.89 (t, J = 4 Hz, 2h).

Example 167

4_((4-methylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydropyrido[4,3-f][l,4]o^xazepin-5(2H)-one (Compound ΧΠ-8)

[0605] Compound ΧΠ-8 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 431.1. CDCh: 8.54 (d, J = 4.8 Hz, IH), 8.50 (s, IH), 8.32 (s, IH), 80.2 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 83.4 Hz, 2H), 7.08 (d, J = 5.2 Hz, IH), 5.05 (s, 2H), 4.72 (t, J = 4.4 Hz, 2H), 3.83 (t, J = 4.4 Hz, 2H), 2.52 (s, 3H).

Example 168

4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydropyrido[4,3-f][l,4]oxazepin-5(2H)-one (Compound ΧΠ-11)

4824-4563-0480.1

[0606] Compound XII-11 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 434.0. CDCh: 8.42 (s, 1H), 8.30 (d, J = 4.4 Hz, 1H), 8.23 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.37 (t, J = 8.4 Hz, 1H), 7.22 (d,

J = 8 Hz, 2H), 7.21 (d, J = 8.4 Hz, 1H), 4.99 (s, 2H), 4.53 (t, J = 4.4 Hz, 2H), 3.78 (t, J =

4Hz, 2H).

Example 169

4-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydropyrido[4,3-f][l,4]oxazepin-5(2H)-one (Compound ΧΠ-14)

[0607] Compound ΧΠ-14 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 447.1.

Example 170

4-benzyI-9-fluoro-7-(4-(trifluoromethoxy)phenyI)-3,4-dihydrobenzo[f[[l,4]oxazepin5(2H)-one (Compound Π-165)

Br

OH

F

11-165

285

4824-4563-0480.1

[0608] Compound Π-165 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 432.1. CDCh:?.80 (s, IH), 7.53 (d, J = 8.8 Hz, 2H), 7.37 (dd, J1 = 2.4 Hz, J2 = 11.2 Hz, IH), 7.31 (d, J = 4 Hz, 2H),

7.29-7.20 (m, 5H), 4.79 (s, 2H), 4.21 (t, J = 5.2 Hz, 2H), 3.47 (t, J = 5.2 Hz, 2H).

Example 171

4-benzyl-9-fluoro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (Compound Π-166)

[0609] Compound Π-166 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 416.1. CDCh:7.87 (s, IH), 7.63 (s, 4H), 7.42 (dd, J1 = 1.6 Hz, J2 = 10.8 Hz, IH), 7.32 - 7.24 (m, 5H), 4.79 (s, 2H), 4.22 (t, J = 5.2 Hz, 2H), 3.48 (t, J = 5.2 Hz, 2H).

Example 172

4-benzyl-8-fluoro-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f] [l,4]oxazepin5(2H)-one (Compound Π-167)

F

286

4824-4563-0480.1

11-167

[0610] Compound Π-167 was prepared according to the Examples disclosed herein using the appropriate starting materiais. Mass (M+H)⁺ 432. E CDC13:8.07 (d, J = 9.2 Hz, 5 IH), 7.58 (d, J = 7.6 Hz, 2h), 7.40 - 7.32 (m, 5H), 7.28 (d, J = 8.4 Hz, 2H), 6.81 (d, J =

11.2 Hz, IH), 4.84 (s, 2H), 4.24 (t, J = 4.8 Hz, 2H), 3.54 (t, J = 4.8 Hz, 2H).

Example 173

4-benzyI-8-fluoro-7-(4-(trifluoromethyl)phenyI)-3,4-dihydrobenzo[f][l,4]o^xa^zepin5(2H)-one (Compound Π-168)

[0611] Compound Π-168 was prepared according to the Examples disclosed herein using the appropriate starting materiais. Mass (M+H)⁺ 416.1. CDC1₃:8.11 (d, J = 9.2 Hz, IH), 7.74 - 7.64 (m, 4H), 7.40 - 7.30 (m, 5H), 6.83 (d, J = 11.6 Hz, IH), 4.85 (s, 2H), 15 4.26 (t, J = 4.8 Hz, 2H), 3.56 (t, J = 4.8 Hz, 2H).

287

4824-4563-0480.1

Example 174

4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[2,3-f][l,4]oxazepin5(2H)-one (Compound ΧΠ-2)

Br

OH

F

o

B+ Λ o

Br N

OH

[0612] Compound ΧΠ-2 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 415.1. CDCh. 8.09 (d, J - 8.4 Hz, 2H), 7.79 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.44-7.32 (m, 5H), 7.30 (d, J = 8 Hz, 2H), 4.91 (s, 2H), 4.18 (t, J = 5.2 Hz, 2H), (t, J = 5.2 Hz, 2H).

Example 175

4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrido[2,3-f][l,4]oxazepin-5(2H)one (Compound ΧΠ-3)

288

482+4563-0480.1

Ο

ο

ΟΗ

[0613] Compound ΧΠ-3 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)¹ 399.1. CDCb: 8.18 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, IH), 7.71 (d, J = 8Hz, 2H), 7.48 (d, J = 8 Hz, IH), 7.46 - 7.30 (m, 5H), 4.91 (s, 2H), 4.20(t, J = 5.2 Hz, 2H), 3.54 (t, J = 5.2 Hz, 2H).

Example 176

4-(pyrimidin-2-yImethyl)-7-(4-(trifluoromethoxy)phenyI)-3,4-dihydropyrido[2,3f][l,4]oxazepin-5(2H)-one (Compound ΧΠ-6)

[0614] Compound ΧΠ-6 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 417.0.

289

4824-4563-0480.1

Example 177

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrido[2,3f][l,4]oxazepin-5(2H)-one (Compound ΧΠ-7)

[0615] Compound ΧΠ-7 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)¹ 401.0.

Example 178

2,2,3,3-tetradeutero-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,410 dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound 11-174)

290

4824-4563-0480.1

Step 1

Step 2

[0616] Step 1 : To a solution of 2-aminoethanol (2.0 g, 30 mmol) in methanol (50 mL) at 0 °C, Boc₂O (6.0 g, 27 mmol) was added slowly and the reaction mixture was stirred at 5 r.t. for 2h. Concentrate the reaction mixture to remove methanol, the residue was dissolved in ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate and concentrated to get the Boc protected amino éthanol (5.0 g) and used directly for the next reaction.

[0617] Step 2: To a solution of DABCO (5 g, 45 mmol) in toluene (50 mL), N-Boc-210 aminoethanol (5 g, 30 mmol) in toluene was added at room température. The reaction mixture was cooled to 0 °C and benzenesulfonyl chloride (5.8 g, 33 mmol) was added slowly and stirred at room température for 2h. Water was added to the reaction mixture, adjust the pH ofthe mixture to 2~3 by adding 6N HCl. The organic layer was separated, washed with water, sodium bicarbonate, water and brine. Dried over sodium sulfate and 15 concentrated to get an oily product (6.0 g, 70% yield from two steps) which was used directly for the next step.

[0618] Step 3: To a solution of protected aminoethanol (6 g, 19.5 mmol) in DMF (20 mL) methyl 5-bromo-2-hydroxybenzoate (3 g, 13 mmol) was added followed by

291

4824-4563-0480.1 potassium carbonate (3.58 g, 26 mmol) and heated the mixture at 70 °C for 4 h. Solvent was distilled off, the residue was treated with ethyl acetate. The organic layer was washed with water, brine and concentrated to give an oily product (4 g, 81%) and is used for the next step.

[0619] Step 4: To the above oily product in methanol (10 mL) at room température HCl in methanol (2 ml in 10 mL) was added and heated at 70 °C for 2h. Solvent was distilled off, the residue was treated with ether, filtered the precipitate. The product obtained (2.5 g, 85%) is used for the cyclization step.

[0620] Step 5: To the above product (2.5 g, 9 mmol) in toluene (10 mL), triethylamine (4 ml, 36 mmol) was added and heated at 105 °C for 48 h, until the LC-MS no starting material. The reaction mixture was cooled, diluted with methylene chloride, separated the organic layer. Add water to the organic layer and treated with 6N HCl, to adjust the pH 2. The organics were washed with water, brine and dried and concentrated. The residue was treated with dichloromethane and hexane and filtered the product 178-A (2.0 g, 90% yield).

[0621] Suzuki: To the bromide 178-A (2 g, 8.16 mmol, 1 eq), boronic acid 178-B (2.5 g, 12.2 mmol, 1.5 eq) and potassium carbonate (3.4 g, 24.48 mol, 3 eq) in a round bottom flask, solvent (60 mL, toluene/isopropano/water :2/1/1) was added and stirred under nitrogen for 10 min. To the above solution the palladium catalyst Pd(dppf)Cl₂ (142 mg, 0.16 mmol, 0.02 eq) was added and heated at 85 °C for 2h. The reaction mixture was diluted with ethyl acetate, separated the organic layer and filtered the organic layer through a plug of celite and silica gel and concentrated. Column purification on silica gel using ethyl acetate/hexane as eluent provided 178-C (2 g, 75% yield).

292

4824-4563-0480.1

[0622] Alkylation: To a solution of 178-C (2 g, 6.12 mmol, 1 eq.) chloromethyl pyrimidine 178-D (1.5 g, 9.17 mmol, 1.5 eq.) in DMF (10 mL), NaH (60% dispersion in oil) (600 mg, 25 mmol, 4 eq.) was slowly added at room température (slightly exothermic) and stirred at r.t. for 30 min. The reaction mixture was treated with few drops of HCl, diluted the reaction mixture with ethyl acetate and treated with water. The organic layer was separated, washed with brine, dried and concentrated. Column purification on silica gel using ethyl acetate/hexane as eluent provided Compound Π-174 (1.8 g, 70% yield). Mass (M+H)⁺ 420.1. CDC13:8.65 (d, J = 5.2 Hz, 2H), 8.10 (s, 1H), 7.58 - 7.50 (m, 3H), 7.18 (d, J = 8 Hz, 2H), 7.14 (t, J = 5.2 Hz, 1H), 7.02 (d, J = 8.4 Hz, 10 1H), 5.02 (s, 2H).

Example 179

4-((3-methyloxetan-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-1)

[0623] 4-((3-Methyloxetan-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one was prepared according to Example 25 using 3(bromomethyl)-3 methyloxetane.

[0624] 'H-NMR (400 MHz, DMSO) 1.305 (s, 3H), 3.618-3.643 (m, 2H), 3.750 (s, 2H), 20 4.183-4.198 (d, 2H, J = 6 Hz), 4.346-4.322 (t, 2H, J, = 4.8 Hz), 4.563-4.577 (d, 2H, J, =

5.6 Hz), 7.109-7.131 (d, 1H, J= 8.8 Hz), 7.413-7.433 (s, 2H, J= 8 Hz), 7.752-7.786 (m, 3H), 7.878-7.883 (d, 1H, J= 2 Hz), MS m/z 407.1 (M⁺).

293

4824-4563-0480.1

Example 180

4-((3-((2-oxopyrrolidin-l-yl)methyl)oxetan-3-yl)methyl)-7-(4(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-108)

[0625] Compound 180-A and Compound Π-108 was prepared according to Example using (3-(bromomethyl)oxetan-3-yl)methyl methanesulfonate.

Example 181

4-(2-(2-oxopyrrolidin-l-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-116)

[0626] Compound 11-116 was prepared according to Example 25 using l-(2bromoethyl)pyrrolidin-2-one.

294

4824-4563-0480.1

Example 182

7-(2-methoxypyrimidin-5-yl)-4-(pyrimidin-2-ylmethyI)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound VI-7)

Pd(dppf)-CH₂CI₂

Toluene/iPrOH/H2O (3/1/1 mL)

Κ2θθ3> 70 C

VI-7

[0627] 40-B (0.405 mmol), potassium carbonate (111 mmol) and Palladium chloride dppf catalyst (0.05 mmol) were combined in a mixture of toluene (3 mL), isopropanol (1 mL) and water (1 mL). The resulting suspension was heated at 85 degrees for 2 hours.

The reaction mixture was concentrated down and diluted with ethyl acetate and filtered through celite. The filtrate was washed with water. The organic layer was purified by prep HPLC and prep TLC to afford Compound VI-7.

Example 183 l-(4-(5-oxo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepin-715 yl)phenyl)cyclopropanecarbonitrile (Compound Π-109)

[0628] Compound Π-109 was prepared according to the Examples disclosed herein using the appropriate starting materiais.

295

4824-4563-0480.1

Example 184

N-(2-(5-oxo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f|[l,4]oxazepin-7-yl)5-(trifluoromethoxy)phenyl)acetamide (Compound Π-111)

[0629] Compound Π-lll was prepared according to the Examples disclosed herein using the appropriate starting materials.

Example 185

7-(2-(4-methyIpiperazin-l-yl)pyrimidin-5-yl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VI-14)

[0630] Compound VI-14 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 432.2 (M⁺).

Example 186

4-(pyrimidin-2-ylmethyl)-7-(2-(2,2,2-trifluoroethylamino)pyrimidin-5-yl)-3,415 dihydrobenzo [f] [1,4] oxazepin-5(2H)-one (Compound VI-15)

[0631] Compound VI-15 was prepared according to the Examples disclosed herein using the appropriate starting materials.

296

4824-4563-0480.1

Example 187

7-(6-morpholinopyridm-3-yl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f|[l,4]oxuzepin-5(2H)-one (Compound VI-16)

[0632] Compound VI-16 was prepared according to the Examples disclosed herein using the appropriate starting materials.

Example 188

N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f|[l,4]oxazepin-4(5H)yl)ethyl)ethanesulfonamide (Compound 11-178)

[0633] 11-74 (1.04 mmol) and NaH (3.13 mmol) was stirred in THF (6mL) at 0 degrees under nitrogen. Bromoacetonitrile was added dropwise. The resulting reaction mixture 15 was allowed to slowly warm up to room température over the period of 2 hours after which time the reaction mixture was quenched with water and then extracted with dichloromethane. The organic layer was purified by prep HPLC to afford 188-A.

[0634] 188-A (0.635 mmol) was dissolved in a mixture ofTHF:MeOH (4:6 mL). To this was added cobalt chloride (2.49 mmol) and di-tert-butyldicarbonate (1.26 mmol)

297

4824-4563-0480.1 under nitrogen follow by addition of sodium borohydride (0.762 mmol). The resulting mixture was stirred at ambient température overnight. The mixture was filtered through celite and washed with 9:1 mixture of MeOHÆhO. The filtrate was washed with saturated NaHCO₃ and then extracted with ethyl acetate. The organic layer was dried over Na2S(O)4 and concentrated down to afford 188-B as an oil which was used without further purifications to make 188-C.

[0635] 188-B (200 mg) was combined with TFA (9 mL) and H2O (1 mL) and stirred under nitrogen for 2 hours. The reaction mixture was concentrated and used without further purifications to make Compound Π-178.

[0636] A solution of 188-C (25mg) in dicholoromethane (3 mL) was chilled in an ice bath. To this was added triethylamine (0.1 mL) followed by ethanesulfonyl chloride (0.05 mL). The reaction mixture was stirred under cold conditions for 2 hours after which it was quenched with water. The mixture was extracted with dichloromethane and purified by prep HPLC to afford Compound Π-178. MS m/z 459.1 (M⁺).

Example 189

N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo [f] [1,4] oxazepin-4(5H)yl)ethyl)cyclopropanesulfonamide (Compound Π-179)

O

II

[0637] Compound Π-179 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 471.1 (M⁺).

298

4824-4563-0480.1

Example 190

4-fluoro-N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)ethyl)benzenesulfonamide (Compound Π-

[0638] Compound Π-181 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 525.1 (M⁺).

Example 191

N-(2-(5-oxo-7-(4-(trifluo romethoxy)phenyl)-2,3-dihydrobenzo [f] [1,4] oxazepin-4(5H)yl)ethyl)cyclopentanesulfonamide (Compound Π-183)

[0639] Compound Π-183 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 499.1 (M⁺).

Example 192 l-methyl-N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,315 dihydrobenzo[f] [l,4]oxazepin-4(5H)-yI)ethyl)-lH-imidazole-2-sulfonamide (Compound Π-184)

[0640] Compound Π-184 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 511.1 (M⁺).

299

4824-4563-0480.1

Example 193

N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)ethyl)benzenesulfonamide (Compound Π-177)

[0641] Compound Π-177 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 507.1 (M⁺).

Example 194

N-methyl-N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyI)-2,3dihydrobenzo[f|[l,4]oxazepin-4(5H)-yl)ethyl)benzenesulfonamide (Compound Π-

[0642] Compound Π-182 was prepared according to Example 25 using iodomethane and Compound 11-177.

Example 195

N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyI)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)ethyl)-2-(pyrimidin-2-yl)acetamide (Compound Π-185)

300

4824-4563-0480.1

DMF

[0643] 188-C (0.054 mmol) was dissolved in DMF (3mL) follow by addition of HATU and DIPEA. The resulting mixture was stirred at room température for 3 hours after which water was added and extracted with dichloromethane. The organic was purified by prep HPLC to afford Compound Π-185.

Example 196

4-((5-cyclopropyl-l,3,4-oxadiazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 11-68)

[0644] Compound Π-68 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 446.1 (M+H).

Example 197

4-(pyridin-4-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,415 dihydrobenzo[f] [l,4]oxazepin-5(2H)-one (Compound Π-67)

[0645] Compound Π-67 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 415.1 (M+H).

301

482+4563-0480.1

045710-5210

Example 198

4-((5-chloropyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[fj[l,4]o^xsizepin-5(2H)-one (Compound Π-65)

[0646] Compound Π-65 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 450.0 (M+H).

Example 199

4-((l-methyl-lH-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-64)

[0647] Compound Π-64 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 418.1 (M+H).

Example 200

4-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)15 one (Compound Π-46)

[0648] Compound Π-46 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 338.1 (M+H).

302

482+4563-0480.1

045710-5210

Example 201

4-(3,4-difluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]o^xazepin-5(2H)-one (Compound Π-45)

[0649] Compound Π-45 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 450.1 (M+H).

Example 202

4-((5-(pyridin-2-yl)isoxazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 11-41)

[0650] Compound Π-41 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 482.1 (M+H).

Example 203

7-(4-(trifluoromethoxy)phenyl)-4-((6-(trifluoromethyl)pyridin-3-yI)methyl)-3,415 dihydrobenzo[f] [l,4]oxazepin-5(2H)-one (Compound Π-16)

[0651] Compound Π-16 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 483.1 (M+H).

303

4824-4563-0480.1

045710-5210

Example 204

4-(2-methoxyethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-11)

[0652] Compound Π-ll was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 382.1 (M+H).

Example 205

4-(2,2-difluoroethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-6)

[0653] Compound Π-6 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 388.1 (M+H).

Example 206

4-((2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methyI)-7-(4-(trifluoromethoxy)phenyl)-3,415 dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-5)

[0654] Compound Π-5 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 472.1 (M+H).

304

4824-4563-0480.1

045710-5210

Example 207

7-(4-fluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[fJ[l,4]oxazepin5(2H)-one (Compound Π-104)

[0655] Compound Π-104 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 350.1 (M+H).

Example 208

7-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-106)

[0656] Compound Π-106 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 448.1 (M+H).

Example 209

4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethoxy)phenyl)-3,415 dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-107)

[0657] Compound Π-107 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 430.1 (M+H).

305

4824-4563-0480.1

045710-5210

Example 210

7-(4-(trifluoromethoxy)phenyl)-4-((5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2yl)methyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-115)

[0658] Compound Π-115 was prepared according to the Examples disclosed herein using the appropriate starting materiais. MS m/z 561.1 (M+H).

Example 211

4_((4-(pyrrolidin-l-yl)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-125)

[0659] Compound Π-125 was prepared according to the Examples disclosed herein using the appropriate starting materiais. MS m/z 485.1 (M+H).

Example 212

4-((4-morpholinopyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,415 dihydrobenzo[f|[l,4]o^xazepin-5(2H)-one (Compound Π-133)

[0660] Compound Π-133 was prepared according to the Examples disclosed herein using the appropriate starting materiais. MS m/z 501.1 (M+H).

306

482+4563-0480.1

045710-5210

Example 213

4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f|[l,4]oxazepin-5(2H) one (Compound Π-134)

[0661] Compound Π-134 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.01 (d, 1H, J= 2.4 Hz), 7.72-7.78 (m, 3H), 7.31-7.42 (m, 7H), 7.14 (d, 1H, J= 8.0 Hz), 4.85 (s, 2H), 4.25 (t, 2H, J = 5.0 Hz), 3.60 (t, 2H, J= 5.4 Hz); MS m/z 414.1 (M+H).

Example 214

4-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-137)

[0662] Compound Π-137 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.41 (d, 1H, J= 6.0 Hz), 8.01 (d, 1H, J= 2.4 Hz), 7.77 (dd, 1H, J= 8.8, 2.4 Hz), 7.71 (d, 2H, J= 8.4 Hz), 7.35 (d, 2H, J= 8.0 Hz), 7.17 (d, 1H, J= 8.0 Hz), 6.75 (d, 1H, J= 6.0 Hz), 4.97 (s, 2H), 4.58 (t, 2H, J= 4.8 Hz), 3.95 (s, 3H), 3.84 (t, 2H, J= 5.2 Hz); MS m/z 446.1 (M+H).

Example 215

4-((4-methylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-138)

[0663] Compound Π-138 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.59 (d, 1H, J= 5.2 Hz),

307

4824-4563-0480.1

8.02 (d, 1H, J= 2.4 Hz), 7.76 (dd, 1H, J= 8.4, 2.4 Hz), 7.71 (d, 2H, J= 8.4 Hz), 7.34 (d,

2H, J = 8.0 Hz), 7.28 (d, 1H, J= 5.2 Hz), 7.16 (d, 1H, J= 8.4 Hz), 5.03 (s, 2H), 4.59 (t,

2H, J= 5.0 Hz), 3.83 (t, 2H, J= 5.0 Hz) ), 2.53 (s, 3H); MS m/z 430.1 (M+H).

045710-5210

Example 216

4-((4-(piperidin-l-yl)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f[[l,4]oxazepin-5(2H)-one (Compound Π-139)

[0664] Compound Π-139 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.10 (d, 1H, J= 7.2 Hz), 7.98 (d, 1H, J= 2.4 Hz), 7.81 (dd, 1H, J= 8.4, 2.4 Hz), 7.71 (d, 2H, J= 9.2 Hz), 7.35 (d, 2H, J = 8.0 Hz), 7.20 (d, 1H, J= 8.8 Hz), 7.01 (d, 1H, J= 7.6 Hz), 4.91 (s, 2H), 4.56 (t, 2H, J= 5.0 Hz), 4.01 (br, 2H), 3.88 (t, 2H, J= 4.8 Hz) ), 3.73 (br, 2H), 1.59-1.73 (m, 6H); MS m/z 499.2 (M+H).

Example 217

4_^4-(dimethylamino)pyrimidin-2-yI)methyI)-7-(4-(trifluoromethoxy)phenyl)-3,4 dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-140)

[0665] Compound Π-140 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.14 (d, 1H, J= 72 Hz), 7.99 (d, 1H, J = 2.4 Hz), 7.81 (dd, 1H, J= 8.0, 2.4 Hz), 7.70 (d, 2H, J= 92 Hz), 7.35 (d, 2H, 8.4 Hz), 7.19 (d, 1H, J = 8.4 Hz), 6.93 (d, 1H, J= 7.2 Hz), 4.93 (s, 2H), 4.59 (t,

2H, J= 5.0 Hz), 3.90 (t, 2H, J= 5.0 Hz) ), 3.30 (s, 6H); MS m/z 459.1 (M+H).

482+4563-0480.1

045710-5210

Example 218

4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 11-141)

[0666] Compound Π-141 was prepared according to the Examples disclosed herein using the appropriate starting materials. ‘H-NMR (CD3OD) δ 8.08 (d, 1H, J= 2.4 Hz), 7.79-7.84 (m, 3H), 7.74 (d, 2H, 8.4 Hz), 7.29-7.41 (m, 5H), 7.15 (d, 1H, J= 8.4 Hz),

4.86 (s, 2H), 4.26 (t, 2H, J= 5.2 Hz), 3.60 (t, 2H, J= 5.2 Hz); MS m/z 398.1 (M+H).

Example 219

4-((3-methoxypyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-143)

[0667] Compound Π-143 was prepared according to the Examples disclosed herein using the appropriate starting materials. ‘H-NMR (CD3OD) δ 8.23 (d, 1H, J= 5.6 Hz), 8.00 (d, 1H, 2.8 Hz), 7.92 (d, 1H, J= 8.4 Hz), 7.77 (dd, 1H, J= 8.4, 2.4 Hz), 7.68-

7.71 (m, 3H), 7.34 (d, 2H, J= 8.0 Hz), 7.15 (d, 1H, J= 8.8 Hz), 5.03 (s, 2H), 4.45 (t, 2H, J= 4.8 Hz), 4.05 (s, 3H), 3.82 (t, 2H, J= 5.0 Hz); MS m/z 445.1 (M+H).

Example 220

4-((l-(difluoromethyl)-lH-pyrazol-3-yI)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound 11-147)

F

309

4824-4563-0480.1

045710-5210

[0668] Compound Π-147 was prepared according to the Examples disclosed herein using the appropriate starting materials. ¹ H-NMR (CD3OD) δ 8.01 (dd, 2H, J= 9.4, 2.6

Hz), 7.76 (dd, IH, J= 8.2, 2.6 Hz), 7.72 (d, 2H, J= 8.8 Hz), 7.73-7.76 (m, 2H), 7.13 (d,

IH, J= 8.4 Hz), 6.54 (d, IH, J= 2.4 Hz), 4.88 (s, 2H), 4.35 (t, 2H, J= 5.0 Hz), 3.69 (t,

2H, J= 5.0 Hz); MS m/z 454.0 (M+H).

Example 221

7-(4-(trifluoromethoxy)phenyl)-4-((3-(trifluoromethyl)-lH-pyrazol-l-yl)methyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-148)

[0669] Compound Π-148 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 494.0 (M+Na).

Example 222

4-((l-cyclopentyl-lH-pyrazol-3-yI)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-152)

[0670] Compound Π-152 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 472.1 (M+H).

Example 223

4-((l-ethyl-lH-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 11-153)

4824-4563-0480.1

045710-5210

[0671] Compound Π-153 was prepared according to the Examples disclosed herein using the appropriate starting materials. Ή-ΝΜΚ (CD3OD) δ 7.99 (d, IH, J= 2.4 Hz),

7.71-7.76 (m, 3H), 7.61 (d, IH, J= 2.4 Hz), 7.35 (d, 2H, J= 8.0 Hz), 7.12 (d, 1H,7=8.4

Hz), 6.31 (d, IH, 7= 2.4 Hz), 4.82 (s, 2H), 4.29 (t, 2H, 7= 5.0 Hz), 4.17 (q, 2H, 7= 7.2

Hz), 3.64 (t, 2H, J= 7.4 Hz), 1.45 (t, 3H, J= 7.4 Hz); MS m/z 432.1 (M+H).

Example 224

4-((l-methyl-lH-imidazol-4-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 11-154)

[0672] Compound Π-154 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 418.1 (M+H).

Example 225

4-((4-methyl-lH-pyrazol-l-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound 11-155)

[0673] Compound Π-155 was prepared according to the Examples disclosed herein using the appropriate starting materials. ’H-NMR (CD3OD) δ 7.98 (d, IH, 7 = 2.4 Hz), 7.76 (dd, IH, J= 8.2, 2.6 Hz), 7.71 (d, 2H, 7= 8.4 Hz), 7.61 (s, IH), 7.34-7.37 (m, 3H), 7.11 (d, IH, 7= 8.8 Hz), 5.83 (s, 2H), 4.21 (t, 2H,7= 5.0 Hz), 3.76 (t, 2H, 7= 5.0 Hz), 2.09 (s, 3H); MS m/z 418.1 (M+H).

311

4824-4563-0480.1

045710-5210

Example 226

4-((4-chloro-lH-pyrazol-l-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-156)

[0674] Compound Π-156 was prepared according to the Examples disclosed herein using the appropriate starting materials. ¹ H-NMR (CD3OD) δ 7.99 (d, 1H, J= 2.4 Hz), 7.91 (s, 1H), 7.77 (dd, 1H, J= 8.4, 2.4 Hz), 7.71 (d, 2H, J= 8.8 Hz), 7.52 (s, 1H), 7.35 (d, 2H, J= 8.0 Hz), 7.13 (d, 1H, J= 8.8 Hz), 5.85 (s, 2H), 4.29 (t, 2H, J= 5.0 Hz), 3.81 (t, 2H, J = 5.2 Hz); MS m/z 438.0 (M+H).

Example 227

4-((l-methyl-lH-pyrazol-4-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 11-160)

[0675] Compound Π-160 was prepared according to the Examples disclosed herein using the appropriate starting materials. ¹ H-NMR (CD3OD) δ 7.98 (d, 1H, 7= 2.8 Hz), 7.67-7.76 (m, 4H), 7.53 (s, 1H), 7.35 (d, 2H, 7= 8.0 Hz), 7.12 (d, 1H,7= 8.0 Hz), 4.69 (s, 2H), 4.31 (t, 2H, 7= 5.2 Hz), 3.87 (s, 3H), 3.62 (t, 2H, 7= 5.0 Hz); MS m/z 418.1 (M+H).

Example 228

4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound 11-164)

312

482+4563-0480.1

045710-5210

[0676] Compound Π-164 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.37 (d, 1H, J= 4.8 Hz),

8.00 (d, 1H, J= 2.4 Hz), 7.76 (dd, 1H, J= 8.0, 2.4 Hz), 7.72 (d, 2H, J= 8.8 Hz), 7.61 (t,

1H, J= 9.2 Hz), 7.38-7.42 (m, 1H), 7.34 (d, 2H, J= 8.0 Hz), 7.14 (d, 1H, J= 8.0 Hz),

5.07 (s, 2H), 4.45 (t, 2H, J= 4.8 Hz), 3.78 (t, 2H, J= 4.8 Hz); MS m/z 433.1 (M+H).

Example 229

7-(4-chloro-3-fluorophenyl)-4-((3-fluoropyridin-2-yl)methyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-169)

[0677] Compound Π-169 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.35 (d, 1H, J= 5.2 Hz), 8.00 (s, 1H), 7.76 (d, 1H, J= 8.4 Hz), 7.61 (t, 1H, 7= 9.2 Hz), 7.51-7.55 (m, 2H), 7.387.46 (m, 2H), 7.14 (d, 1H, 7= 8.0 Hz), 5.07 (s, 2H), 4.46 (t, 2H, 7= 4.8 Hz), 3.78 (t, 2H, J = 4.8 Hz); MS m/z 401.1 (M+H).

Example 230

7-(2-fluoro-4-(trifluoromethyI)phenyl)-4-((3-fluoropyridin-2-yI)methyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-170)

[0678] Compound Π-170 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.37 (d, 1H, 7= 4.8 Hz), 7.99 (s, 1H), 7.70-7.74 (m, 2H), 7.53-7.63 (m, 3H), 7.38-7.42 (m, 1H), 7.17 (d, 1H, 7 = 8.4 Hz), 5.07 (s, 2H), 4.49 (t, 2H, 7= 5.0 Hz), 3.80 (t, 2H, 7= 4.8 Hz); MS m/z 435.1 (M+H).

313

4824-4563-0480.1

045710-5210

Example 231

4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-176)

[0679] Compound Π-176 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.36 (d, IH, J= 4.4 Hz), 8.06 (s, IH), 7.71-7.81 (m, 3H), 7.72 (d, 2H, J= 8.0 Hz), 7.60 (t, IH, J= 9.0 Hz), 7.377.41 (m, IH), 7.15 (d, IH, J= 8.4 Hz), 5.06 (s, 2H), 4.46 (t, 2H, J= 5.0 Hz), 3.78 (t, 2H, J = 4.8 Hz); MS m/z 417.1 (M+H).

Example 232

4-(pyrimidin-2-ylmethyI)-7-(4-(trifluoromethoxy)phenylamino)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound ΧΠΙ-1)

[0680] Compound ΧΙΠ-l was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 431.1 (M+H).

Example 233

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenoxy)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound ΧΠ1-2)

314

4824-4563-0480.1

045710-5210

[0681] 233-A (70 mg, 0.21 mmol), 4-(trifluoromethoxy)phenol (45 mg, 0.252 mmol), K3PO4 (134 mg, 0.63 mmol), Pd(0Ac)2 (3%) and di-tert-butyl(2’4’6’triisopropylbiphenyl-2-yl)phosphine (6%) in toluene (3.5 mL) were put onto microwave 5 at 140 °C for 20 min. The reaction mixture was diluted with EtOAC, filtered through ceilite and washed with EtOAc. The fïltrate was concentrated and purified by HPLC followed by prep-TLC (EtOAc) to afford Compound ΧΠΙ-2 (1.8 mg). MS m/z 432.1 (M+H).

Example 234

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenylamino)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound ΧΙΠ-3)

[0682] Compound XHI-3 was prepared accoruing to the Exampies disclosed herein using the appropriate starting materials. MS m/z 415.1 (M+H).

Example 235

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenylamino)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound ΧΙΠ-4)

O

-i.

235-A

Pd₂(dba)₃, (R)-BINAP

NaO‘Bu, toluene ^NHs 130°C, 10min, MW

XIII-4

315

4824-4563-0480.1

045710-5210

[0683] 235-A (70 mg, 0.21 mmol), 4-(trifluoromethoxy)aniline (45 mg, 0.252 mmol),

NaO’Bu (40mg, 0.42 mmol), Pd₂(dba)3 (3%) and (R)-BINAP (6%) in toluene (3.5 mL) were put onto microwave at 130 °C for 10 min. The reaction mixture was diluted with

EtOAC, filtered through ceilite and washed with EtOAc. The filtrate was concentrated and purified by HPLC to afford Compound ΧΠΙ-4 (22.8 mg).

[0684] ’H-NMR (CD₃OD) δ 8.66 (d, IH, J= 5.2 Hz), 8.23 (t, IH, J= 8.0 Hz), 7.78 (d, IH, J = 8.0 Hz), 7.68 (t, IH, J= 6.4 Hz), 7.41 (s, IH), 7.22-7.40 (m, IH), 7.06-7.13 (m, 4H), 7.01 (d, IH, J = 8.8 Hz), 5.04 (s, 2H), 4.33 (t, 2H, J= 5.0 Hz), 3.74 (t, 2H, J= 5.4 Hz); MS m/z 430.1 (M+H).

Example 236

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenylamino)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound ΧΙΠ-6)

[0685] Compound ΧΙΠ-6 was prepared according to the Examples disclosed herein using the appropriate starting materiais. ¹ H-NMR (CD3OD) δ 8.52 (d, IH, J= 5.2 Hz), 7.84 (t, IH, J= 7.6 Hz), 7.44-7.50 (m, 4H), 7.29-7.36 (m, 2H), 7.10 (d, 2H, J= 8.0 Hz), 7.03 (d, IH, J= 8.8 Hz), 4.94 (s, 2H), 4.29 (t, 2H, J= 5.2 Hz), 3.68 (t, 2H, J= 5.6 Hz); MS m/z 414.1 (M+H).

Example 237

7-(methyl(4-(trifluoromethoxy)phenyl)amino)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound ΧΙΠ-10)

[0686] Compound ΧΙΠ-10 was prepared according to the Examples disclosed herein using the appropriate starting materiais. MS m/z 445.1 (M+H).

4824-4563-0480.1

045710-5210

Example 238

7-(methyl(4-(trifluoromethoxy)phenyl)amino)-4-(pyridin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound ΧΠ1-12)

[0687] Compound ΧΙΠ-12 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 444.1 (M+H).

Example 239

5-benzyl-8-(4-(trifluoromethyl)phenyl)-4H-benzo[f|imidazo[l,2-a][l,4]diazepin6(5H)-one (Compound X-12)

[0688] 239-A (0.100g, 0.244mmol), 2, 2-dimethoxyethanamine (ImL, 9.3mmol) were mixed together, the resulting mixture was stirred at 100°C for 4 hours. When the reaction was cooled down, Water was added dropwise until précipitation was finished. The précipitâtes were collected by filtration and washed with water to afford 239-B (0.111g, 92%), MS m/z'. 498 (M + H)+

[0689] 239-B (0.104g, 0.209mmol), PPTS (0.525g, 2.09mmol) were added to Toluene (5mL). The resulting mixture was stirred at 120°C overnight, concentrated and purified by préparative HPLC to afford Compound X-12 (0.013g, 14%). MS m/z; 434 (MH⁺).

317

4824-4563-0480.1

045710-5210

Example 240

N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyI)-2,3-dihydrobenzo[f|[l,4]oxazepin-4(5H)yl)ethyl)pyrimidine-2-carboxamide (Compound Π-192)

[0690] Compound Π-192 was prepared according to Examples 188 and 195 disclosed herein using the appropriate starting materials. MS m/z 473.1 (M⁺).

Example 241

7-(5-cyclopropylthiophen-2-yl)-4-(pyrimidin-2-ylmethyl)-3,410 dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound VI-36)

[0691] Compound VI-36 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (DMSO) δ 8.77 (d, 2H, J= 5.2 Hz), 7.79 (d, 1H, J= 2.4 Hz), 7.68 (dd, 1H, J= 8.2, 2.6 Hz), 7.40 (t, 1H, J= 5.0 Hz), 7.22 (d, 15 1H, J = 3.2 Hz), 7.04 (d, 1H, J= 8.8 Hz), 6.78-6.79 (m, 1H), 4.95 (s, 2H), 4.47 (t, 2H, J =

5.0 Hz), 3.73 (t, 2H, J= 5.0 Hz), 2.07-2.13 (m, 1H), 0.96-1.00 (m, 2H), 0.66-0.70 (m, 2H); MS m/z 378 (M+H).

318

4824-4563-0480.1

045710-5210

Example 242

4-(pyrimidin-2-ylmethyl)-7-(5-(trifluoromethyl)thiophen-2-yl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VI-37)

[0692] Compound VI-37 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (DMSO) δ 8.70 (d, 2H, J= 5.2 Hz), 7.72 (d, IH, J=2.4Hz), 7.61 (dd, IH, J= 8.2, 2.6 Hz), 7.30 (t, IH, J = 5.0 Hz), 7.12 (d, IH, J= 3.2 Hz), 7.01 (d, IH, J= 8.8 Hz), 6.72-6.75 (m, IH), 4.91 (s, 2H), 4.42 (t, 2H, J= 5.0 Hz), 3.71 (t, 2H, J= 5.0 Hz), 2.07-2.11 (m, IH), 0.94-1.1 (m, 2H), 0.64-0.69 (m, 2H); MS m/z 406 (M+H).

Example 243

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VIII-8)

[0693] Compound VHI-8 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.74 (d, 2H, J= 4.8 Hz), 7.51-7.54 (m, 3H), 7.33-7.37 (m, 3H), 7.26 (dd, IH, J= 8.2, 2.2 Hz), 6.94 (d, IH, J= 8.0 Hz), 5.02 (s, 2H), 4.45 (t, 2H, J= 5.2 Hz), 3.72 (t, 2H, J = 52 Hz), 2.91-3.00 (m, 4H); MS m/z 428.1 (M+H).

Example 244

4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethyl)phenethyI)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VHI-9)

319

4824-4563-0480.1

[0694] Compound VTH-9 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.34 (d, 1H, J= 5.2 Hz),

7.50-7.60 (m, 4H), 7.33-7.40 (m, 3H), 7.25 (dd, 1H, J = 8.4, 2.4 Hz), 6.92 (d, 1H, J= 8.0

Hz), 5.01 (d, 2H, J= 1.6 Hz), 4.32 (t, 2H, J= 5.2 Hz), 3.66 (t, 2H, J=5.2Hz), 2.90-3.00 (m, 4H); MS m/z 445.1 (M+H).

045710-5210

Example 245

7-(4-(4-fluorophenoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 11-193)

[0695] Compound 11-193 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.77 (d, 2H, J= 5.2 Hz), 7.97 (d, 1H, J= 2.0 Hz), 7.73 (dd, 1H, J= 8.8, 2.4 Hz), 7.61 (dd, 2H, J= 6.8, 2.0 Hz), 7.38 (t, 1H, J= 4.8 Hz), 7.02-7.14 (m, 7H), 5.07 (s, 2H), 4.56 (t, 2H, ./ = 5.0 Hz), 3.82 (t, 2H, J= 5.0 Hz); MS m/z 442.1 (M+H).

Example 246

7-(4-phenoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (Compound Π-194)

[0696] Compound Π-194 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.77 (d, 2H, J= 5.2 Hz), 7.97 (d, 1H, J= 2.4 Hz), 7.74 (dd, 1H, J= 8.6, 2.6 Hz), 7.61 (dd, 2H, J= 6.8, 2.4 Hz), 7.35-7.39 (m, 3H), 7.10-7.15 (m, 2H), 7.01-7.06 (m, 4H), 5.07 (s, 2H), 4.56 (t, 2H, J = 5.2 Hz), 3.82 (t, 2H, J= 5.0 Hz); MS m/z 424.1 (M+H).

320

482+4563-0480.1

045710-5210

7-(3-phenoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f|[l,4]oxazepin5(2H)-one (Compound Π-195)

Example 247

[0697] Compound Π-195 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.76 (d, 2H, J= 5.2 Hz), 7.96 (d, IH, J= 2.4 Hz), 7.71 (dd, IH, J= 8.2, 2.6 Hz), 7.34-7.44 (m, 5H), 7.23 (t, IH, J = 2.0 Hz), 7.10-7.14 (m, 2H), 7.02-7.04 (m, 2H), 6.93-6.96 (m, IH), 5.06 (s, 2H), 4.56 (t, 2H, J= 5.0 Hz), 3.81 (t, 2H, J = 5.2 Hz); MS m/z 424.1 (M+H).

Example 248 (E)-4-benzyl-7-(4-(trifluoromethyl)styryl)-3,4-dihydrobenzo[f][l,4]o^xazepin-5(2H)one (Compound V111-10)

[0698] Compound VHI-10 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 424.1 (M+H).

Example 249

4-benzyl-7-(4-(trifluoromethyl)phenethyl)-3,4-dihydrobenzo[f][l,4]o^xazepin-5(2H)one (Compound VIH-ll)

[0699] Compound VIII-11 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 7.53-7.54 (m, 3H), 7.267.37 (m, 8H), 6.93 (d, IH, J= 8.0 Hz), 4.82 (s, 2H), 4.16 (t, 2H, J = 5.2 Hz), 3.49 (t, 2H, J = 5.2 Hz), 2.95-3.02 (m, 4H); MS m/z 426.1 (M+H).

321

4824-4563-0480.1

045710-5210

Example 250

4-(3-(azetidin-l-ylsulfonyl)propyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-191)

[0700] Compound 250-C was synthesized from Compound 250-A and sultone 250-B following general alkylation procedures. Compound 250-C (84 mg, 0.19 mmol) was treated with thionyl chloride at 60°C overnight. The resulting mixture was concentrated to afford crude Compound 250-D which was treated with a solution of azetidine (26pL, 2 eq) and triethylamine (250 pL) in DCM, the resulting mixture was stirred at room température for several hours, concentrated and purified with HPLC to afford Compound Π-191 (42 mg). MS m/z: 485 (MH ).

Example 251

N-cyclopropyl-3-(5-oxo-7-(4-(trifluoromethoxy)phenyI)-2,315 dihydrobenzo[f|[l,4]oxazepin-4(5H)-yI)propane-l-suIfonamide (Compound Π-190)

[0701] Compound Π-190 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z\ 485 (MH⁺)

322

4824-4563-0480.1

045710-5210

[0702] The following compounds were prepared according to the Examples disclosed herein using the appropriate starting materials:

4-(2,2,2-trifluoroethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-2) MS m/z 406.0 (M+H)

4-(2-(pyrrolidin-l-yl)ethyI)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-3) MS m/z 421.1 (M+H)

(2S, 11 aR)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a10 tetrahydrobenzo[f]pyrrolo[2,l-c][l,4]oxazepin-5(lH)-one (Compound Π-20) MS m/z\

363 (MH⁺)

(R)-8-(4-(trifluoromethyI)phenyl)-3,4,12,12a-tetrahydro-lH-benzo[f]pyrazino[2,Ιέ] [1,4] oxazepin-6(2H)-one (Compound Π-26) MS m/z\ 363 (MH )

323

4824-4563-0480.1

045710-5210 (R)-tert-butyl 6-oxo-8-(4-(trifluoromethyI)phenyl)-3,4,12,12a-tetrahydro-lHbenzo[f]pyrazino[2,l-c][l,4]oxazepine-2(6H)-carboxyIate (Compound Π-27) MS m/z:

463 (MH⁺)

(S)-8-(4-(trifluoromethyI)phenyl)-3,4,12,12a-tetrahydro-lH-benzo[f]pyrazino[2,lc][l,4]oxazepin-6(2H)-one (Compound Π-28) MS m/z: 363 (MH )

(S)-tert-butyl 6-oxo-8-(4-(trifluoromethyl)phenyI)-3,4,12,12a-tetrahydro-lHbenzo[f]pyrazino[2,l-c][l,4]oxazepine-2(6H)-carboxyIate (Compound Π-29) MS m/z: 463 (MH⁺)

(2R,llaR)-2-(pyrimidin-2-ylamino)-7-(4-(trifluoromethyl)phenyl)-2,3,ll,llatetrahydrobenzo[f|pyrrolo[2,l-c][l,4]oxazepin-5(lH)-one (Compound Π-30) MS m/z:

441 (MH¹)

324

4824-4563-0480.1

045710-5210

4-((l-phenyI-5-(trifluoromethyl)-lH-pyrazoI-4-yI)methyl)-7-(4(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound

11-32) MS m/z 548.1 (M+H)

(2S, 11 aS)-2-(py rimidin-2-ylamino)-7-(4-(trifluo romethyl)phenyl)-2,3,11,11atetrahydrobenzo[f|pyrrolo[2,l-c][l,4]oxazepin-5(lH)-one (Compound Π-34) MS m/z:

441 (MH⁺)

7-(4-(trifluoromethoxy)phenyl)-4-(2-(2,5,5-trimethyl-l,3-dioxan-2-yl)ethyl)-3,410 dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-35) m/z: 480 1 (MH⁺)

(2R, 11 aR)-2-(diethylamino)-7-(4-(trifluoromethyI)phenyl)-2,3,11,11atetrahydrobenzo[f|pyrrolo[2,l-c][l,4]oxazepin-5(lH)-one (Compound Π-36) MS m/z;

419 (MH j

325

482+4563-0480.1

045710-5210 (2S,llaS)-2-(diethylamino)-7-(4-(trifluoromethyI)phenyl)-2,3,ll,llatetrahydrobenzo[f]pyrrolo[2,l-c][l,4]oxazepin-5(lH)-one (Compound Π-37) MS me.

419 (MH⁺)

(2R,llaR)-2-amino-7-(4-(trifluoromethyI)phenyl)-2,3,ll,llatetrahydrobenzo[f]pyrroIo[2,l-c][l,4]oxazepin-5(lH)-one (Compound Π-38) MS me: 363 (MH⁺)

tert-butyl (2R, 11 aR)-5-oxo-7-(4-(trifluoromethyl)phenyl)-1,2,3,5,11,11 a10 hexahydrobenzo[f|pyrrolo[2,l-c][l,4]oxazepin-2-ylcarbamate (Compound Π-39) MS m/z; 463 (MH⁺)

326

4824-4563-0480.1

045710-5210

4-((5-(pyrimidin-2-yl)isoxazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound Π-40) MS m/z 483.1 (M+H)

ethyl 3-((5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f|[l,4]oxazepin5 4(5H)-yl)methyl)benzoate (Compound 11-43) m z. 486.1 (MH⁺)

tert-butyl (2S, 11 aS)-5-oxo-7-(4-(trifluoromethyl)phenyl)-1,2,3,5,11,11ahexahydrobenzo[f|pyrrolo[2,l-c][l,4]oxazepm-2-ylcarbamate (Compound 11-52) MS m/z\ 463 (MH⁺)

4-((3-cyclopropyl-l-methyl-lH-pyrazol-5-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)3,4-dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound H-53) MS m/z 458.1 (M+H)

4-(4-(trifluoromethoxy)benzyl)-7-(4-(trifluoromethoxy)phenyl)-3,415 dihydrobenzo[f] [l,4]oxazepin-5(2H)-one (Compound Π-55) MS m/z 498.1 (M+H)

327

4824-4563-0480.1

045710-5210

7-(4-(trifIuoromethoxy)phenyI)-4-(4-(trifluoromethyl)benzyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-56) MS m/z 482.1 (M+H)

(2R,llaS)-2-hydroxy-7-(4-(trifluoromethyl)phenyl)-2,3,11,11a5 tetrahydrobenzo[f|pyrrolo[2,l-c][l,4]oxazepin-5(lH)-one (Compound Π-58) MS m/r.

364 (MH⁺)

(R)-7-(4-(trifluoromethyl)phenyl)-2,3,11, lla-tetrahydrobenzo[f]pyrrolo[2,1c][l,4]oxazepin-5(lH)-one (Compound Π-59) MS m/z\ 348 (MH )

(S)-7-(4-(trifluoromethy l)phenyl)-2,3,l 1,11 a-tetrahyd robenzo [f] py rrolo [2,1c][l,4]oxazepin-5(lH)-one (Compound Π-60) MS m/z'. 348 (MH )

8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydrobenzo[f][l,4]oxazino[3,4c] [l,4]oxazepin-6(lH)-one (Compound Π-63) MS m/z. 364 (MH )

328

482+4563-0480.1

045710-5210

2-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyI)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)ethoxy)pyrimidine-4-carbonitrile (Compound Π-66) MS m/z 471.1 (M+H)

4-(2-hydroxyethyl)-7-(4-(trifluoromethoxy)phenyl)-3,45 dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-71) MS m/z 368 1 (M+H)

(R)-3-isopropyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (Compound Π-76) MS m/z. 349 (MH )

(R)-3-isopropyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 11-78) MS m/z. 442 (MH )

(S)_3_isopropyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-79) MS m/z. 442 (MH )

329

4824-4563-0480.1

045710-5210 (S)-2-(2,2,2-trifluoroethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-lHbenzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one (Compound Π-84) m/z. 445 (MH )

7-(4-morpholinophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5 5(2H)-one (Compound Π-90) m/z. 417.2 (MH⁺)

7-(4-(methylsulfonyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-93) m/z. 410 0 (MH )

(R)-4-(l-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-95) m/z. 414 (MH )

(S)-4-(l-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-96) m/z. 414 (MH )

F

330

4824-4563-0480.1

045710-5210

7-(4-tert-butoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f|[l,4]oxazepin5(2H)-one (Compound Π-99) m/z. 404.5 (MH )

(R)-2-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyI)-3,45 dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-100) m/z. 414 (MH )

tert-butyl 4-(5-oxo-4-(pyrimidin-2-ylmethyl)-2,3,4,5tetrahydrobenzo[i][l,4]oxazepin-7-yl)phenylcarbamate (Compound Π-103) m/z.

447.1 (MH⁺)

N_(4.(5__oxo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f|[l,4]oxazepin-7yl)phenyl)cyclopropanecarboxamide (Compound Π-112) m/z. 415.2 (MH )

4-((5-(pyridin-3-yI)pyrimidin-2-yI)methyl)-7-(4-(trifluoromethoxy)phenyI)-3,4dihydrobenzo[f][l,4]oxazepm-5(2H)-one (Compound Π-114) MS m/z 493.1 (M+H)

331

4824-4563-0480.1

045710-5210

7-(4-(2-hydroxypropan-2-yl)phenyl)-4-(pyrimidin-2-ylmethyI)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-118) 390.2 (MH⁺)

4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroacetyl)phenyl)-3,45 dihydrobenzo[f][l,4]o^xazepin-5(2H)-one (Compound Π-121) mz: 428.2 (MH⁺)

O

4-(pyrimidin-2-ylmethyl)-8-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound IV-1) MS m/z 416 0 (M+H)

o 4-(pyridin-2-ylmethyI)-8-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound IV-2) MS m/z 415 1 (M+H)

4-(pyridin-2-ylmethyl)-8-(3-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound IV-3) MS m/z 399 1 (M+H)

332

4824-4563-0480.1

045710-5210

4-(pyrimidin-2-ylmethyl)-8-(3-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound IV-4) MS m/z 400.1 (M+H)

4-(pyrimidin-2-ylmethyl)-8-(4-(trifluoromethyl)phenyl)-3,45 dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound IV-5) MS m/z 400.1 (M+H)

4-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[fHl,4]oxazepin-5(2H)-one (Compound IV-6) MS m/z 415.1 (M+H)

4-(pyrimidin-2-ylmethyl)-8-(3-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound IV-7) MS m/z 416 1 (M+H)

333

482+4563-0480.1

045710-5210

4-(pyridin-2-ylmethyl)-8-(4-(trifluoromethyl)phenyI)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound IV-8) MS m/z 399.1 (M+H)

7-(4-tert-butylcyclohex-l-enyl)-4-(pyrimidin-2-ylmethyI)-3,45 dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound V-l) m/z; 392 2 (MH )

7-cycIopentenyI-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one (Compound N-2)m/z; 322.1 (MH⁺)

o 7-(4,4-dimethylcycIohex- l-enyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound V-4) m/z: 364.2 (MH )

7-(bicyclo[3.1.1]hept-2-en-3-yl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound V-7) m z. 348.1 (MH )

334

4824-4563-0480.1

045710-5210

7-(2-oxo-l,2-dihydropyridin-4-yl)-4-(pyrimidin-2-ylmethyI)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VI-1) m/z. 349.1 (MH⁺)

O

tert-butyl 4-(5-oxo-4-(pyrimidin-2-yImethyl)-2,3,4,55 tetrahydrobeuzo[fHl,4]oxazepin-7-yI)-5,6-dihydropyridine-l(2H)-carboxylate (Compound VI-5) m/z. 436.9 (MH⁺)

4-(pyrimidin-2-ylmethyl)-7-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VI-6) MS m/z 431 1 (M+H)

F

4-(pyrimidin-2-ylmethyI)-7-(6-(trifluoromethyl)pyridin-3-yl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VI-8) MS m/z 401.1 (M+H)

7-(6-fluoropyridin-3-yI)-4-(pyrimidin-2-yImethyl)-3,4-dihydrobenzo[f|[l,4]oxazepin15 5(2H)-one (Compound VI-9) MS m/z 351.1 (M+H)

4824-4563-0480.1

045710-5210

4-(pyrimidin-2-ylmethyl)-7-(2-(pyrrolidin-l-yl)pyrimidin-5-yl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VI-10) MS m/z 403.1 (M+H)

7-(2-(piperidin-l-yl)pyrimidin-5-yl)-4-(pyrimidin-2-ylmethyl)-3,45 dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VI-11) MS m/z 417 1 (M+H)

7-(l-(cyclopropanecarbonyl)-l,2,3,6-tetrahydropyridin-4-yl)-4-(pyrimidin-2ylmethyI)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VI-17) m/z. 405.2 (MH⁺)

O

7-(pyrimidin-2-yI)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f|[l,4]oxazepin5(2H)-one (Compound VI-18) MS m/z 334.1 (M+H)

4-(pyrimidin-2-ylmethyl)-7-(5-(trifluoromethyl)pyrimidin-2-yI)-3,4

15 dihydrobenzo [f] [1,4] oxazepin-5(2H)-oi F F-J . 1 if

ie (Compound VI-19) MS m/z 402.1 (M+H) n N—_λ T /-+Λ 336

4824-4563-0480.1

045710-5210

7-(cyclopropylethynyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (Compound VIH-1) m/r. 320.2 (MH)

7-(3,3-dimethylbut-l-ynyl)-4-(pyrimidin-2-ylmethyl)-3,45 dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound VIII-2) m/z\ 336 1 (MH )

7-((l-methyl-lH-imidazol-5-yl)ethynyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound VIII-3) m/z: 360 2 (MH⁺)

4-(imidazo[l,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-135) m/z: 438 1 (MH )

7-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyI)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound Π-136) m/z: 418 1 (MH )

337

4824-4563-0480.1

045710-5210

4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 11-150) m/z. 459.2 (MH⁺)

4-(pyridin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethyl)phenyl)-3,45 dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound 11-151) m/z. 458 2 (MH )

cycIopropyl(7-(4-(trifluoromethoxy)phenyI)-2,3-dihydrobenzo[f][l,4]oxazepin4(5H)-yI)methanone (Compound ΙΠ-8) m/z. 378 (MH )

(lH-pyrazol-4-yl)(7-(4-(trifluoromethoxy)phenyI)-2,3-dihydrobenzo[f][l,4]oxazepin

4(5H)-yl)methanone (Compound ΙΠ-13) m/z. 404 (MH )

(3,5-dimethyI-lH-pyrazol-4-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (Compound ΠΙ-14) m/z. 4j2.2 (MH⁺)

4824-4563-0480.1

045710-5210 (l-methyl-3-(trifluoromethyl)-lH-pyrazol-4-yl)(7-(4-(trifluoromethoxy)phenyI)-2,3dihydrobenzo[f|[l,4]oxazepin-4(5H)-yl)methanone (Compound ΙΠ-16) m/z\ 486.1 (MH⁺)

(3-methyl-lH-pyrazoI-4-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (Compound ΙΠ-17) m/r. 418.2 (MH⁺)

l-morpholino-2-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f](l,4|oxazepin10 4(5H)-yl)ethanone (Compound ΙΠ-28) m/z\ 421 (MH )

4-(pyrimidin-2-ylmethyI)-7-(pyrrolidin-l-yl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (Compound VI-34) MS m/z 325.1 (M+H)

4-(pyridin-2-ylmethyl)-7-(pyrroIidin-l-yl)-3,4-dihydrobenzo[f| [l,4]oxazepin-5(2H)one (Compound VI-35) MS m/z 324.1 (M+H)

339

4824-4563-0480.1

045710-5210

4-benzyI-7-(4-(trifluoromethoxy)phenyI)-3,4-dihydropyrido[3,2-f|[l,4]oxazepin5(2H)-one (Compound ΧΠ-12) MS m/z 415.1 (M+H)

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[3,25 f][l,4]oxazepin-5(2H)-one (Compound ΧΠ-13) MS m/z 417.1 (M+H)

4-(pyridin-2-yImethyl)-7-(4-(trifluoromethoxy)phenoxy)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound ΧΙΠ-5) MS m/z 431.1 (M+H)

N-(5-oxo-4-(pyridin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepin-7yl)benzamide (Compound ΧΙΠ-7) MS m/z 374.1 (M+H)

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenoxy)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound ΧΙΠ-8) MS m/z 415 1 (M+H)

340

482+4563-0480.1

045710-5210

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)benzylamino)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (Compound ΧΙΠ-9) MS m/z 445 1 (M+H)

4-(pyridin-2-ylmethyI)-7-(4-(trifluoromethoxy)benzylamino)-3,45 dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound ΧΠΙ-11) MS m/z 444.1 (M+H)

N-(5-oxo-4-(pyridin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[fj[l,4]oxazepin-7-yl)-4(trifluoromethyl)benzamide (Compound ΧΠΙ-13) MS m/z 442.1 (M+H)

7a-(7-(4-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepine-4carbonyl)tetrahydro-lH-pyrrolizin-3(2H)-one (Compound III-59) MS m/z 461 4 (M+H)

N-(5-oxo-4-(pyridin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepin-7-yI)-415 (trifluoromethoxy)benzamide (Compound ΧΠΙ-14) MS m/z 458 1 (M+H)

341

482+4563-0480.1

045710-5210

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenethyI)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound V111-7) MS m/z 427.4 (M+H)

Example 252

[0703] Hard gelatin capsules containing the following ingrédients are prepared:

Quantity

Ingrédient (mg/capsule)

Active Ingredi ent30.0

Starch305.0

Magnésium stéarate3.0

[0704] The above ingrédients are mixed and filled into hard gelatin capsules.

Example 253

A tablet Formula Is prepared using the ingrédients below:

Quantity

Ingrédient (mg/tablet)

Active Ingrédient25.0

Cellulose, microcrystalline200.0

Colloïdal Silicon dioxide

Stearic acid

The components are blended and compressed to form tablets.

Example 254

[0705] A dry powder inhaler formulation is prepared containing the following components:

Ingrédient Weight /o

Active Ingrédient ⁵

Q5 Lactose

[0706] The active ingrédient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.

342

4824-4563-0480.1

045710-5210

Example 255

[0707] Tablets, each containing 30 mg of active ingrédient, are prepared as follows:

	Quantity
Ingrédient	(mg/tablet)
Active Ingrédient	30.0 mg
Starch	45.0 mg
Microcrystalline cellulose	35.0 mg
Polyvinylpyrrolidone
(as 10% solution in stérile water)	4.0 mg
Sodium carboxymethyl starch	4.5 mg
Magnésium stéarate	0.5 mg
Talc	1.0 mg
Total	120 mg

[0708] The active ingrédient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the résultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50 °C to 60 °C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnésium stéarate and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.

Example 256

107091 Cimnncitoripe parti rnntainino 25 mg of active ingrédient are made as follows.

Ingrédient Amount

Active Ingrédient 25 mg

Saturated fatty acid glycerides to 2,000 mg

[0710] The active ingrédient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.

343

4824-4563-0480.1

Example 257

[0711] Suspensions, each containing 50 mg of active ingrédient per 5.0 mL dose are made as follows:

045710-5210

Ingrédient Active Ingrédient Xanthan gum Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%)	Amount 50.0 mg 4.0 mg 50.0 mg
Sucrose	1.75 g
Sodium benzoate	10.0 mg
Flavor and Color	q.v.
Purified water to	5.0 mL

[0712] The active ingrédient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.

[0713]

[0714]

Example 258

A subcutaneous formulation may be prepared as follows:

Ingrédient

Active Ingrédient

Quantity 5.0 mg 1.0 mL

Example 259

An injectable préparation is prepared having the following composition:

Ingrédients

Active ingrédient Mannitol, USP Gluconic acid, USP water (distilled, stérile) Nitrogen Gas, NF

Amount

2.0 mg/mL mg/mL q.s. (pH 5-6) q.s. to 1.0 mL

q.s.

344

482+4563-0480.1

045710-5210

Example 260

[0715] A topical préparation is prepared having the following composition:

Ingrédients grams

Active ingrédient 0.2-10

Span 60 2.0

Tween 602.0

Minerai oil3.0

Petrolatumθ

Methyl paraben0.15

Propyl paraben θ·θ3

BHA (butylated hydroxy anisole) θ θ¹

Water fl·⁸· ί°1θθ

[0716] Ail ofthe above ingrédients, except water, are combined and heated to 60°C with stirring. A sufficient quantity of water at 60°C is then added with vigorous stirring to emulsify the ingrédients and water then added q.s. 100 g.

Example 261

[0717] Sustained Release Composition

Ingrédient Weight Range%

Active ingrédient50-95

Microcrystalline cellulose (filler)1-35

Methacrylic acid copolymer1-35

Sodium hydroxide 0.1 -1.0

Hydroxypropyl methylcellulose 0.5-5.0

Magnésium stéarate 0.5-5.0

[0718] The sustained release formulations ofthis disclosure are prepared as follows. compound and pH-dependent binder and any optional excipients are intimately mixed(dry-blended). The dry-blended mixture is then granulated in the presence of an aqueous solution of a strong base which is sprayed into the blended powder. The granulate is dried, screened, mixed with optional lubricants (such as talc or magnésium stéarate) and compressed into tablets. Preferred aqueous solutions of strong bases are solutions of alkali métal hydroxides, such as sodium or potassium hydroxide, preferably sodium hydroxide, in water (optionally containing up to 25% of water-miscible solvents such as lower alcohols).

345

4824-4563-0480.1

045710-5210

[0719] The resulting tablets may be coated with an optional film-forming agent, for identification, taste-masking purposes and to improve ease of swallowing. The film forming agent will typically be présent in an amount ranging from between 2% and 4% of the tablet weight. Suitable film-forming agents are well known to the art and include hydroxypropyl methylcellulose, cationic méthacrylate copolymers (dimethylaminoethyl méthacrylate/ methyl-butyl méthacrylate copolymers - Eudragit® E - Rohm. Pharma) and the like. These film-forming agents may optionally contain colorants, plasticizers and other supplémentai ingrédients.

[0720] The compressed tablets preferably hâve a hardness sufficient to withstand 8 Kp compression. The tablet size will dépend primarily upon the amount of compound in the tablet. The tablets will include from 300 to 1100 mg of compound free base. Preferably, the tablets will include amounts of compound free base ranging from 400-600 mg, 650-850 mg and 900-1100 mg.

[0721] In order to influence the dissolution rate, the time during which the compound containing powder is wet mixed is controlled. Preferably the total powder mix time, i.e. the time during which the powder is exposed to sodium hydroxide solution, will range from 1 to 10 minutes and preferably from 2 to 5 minutes. Following granulation, the particles are removed from the granulator and placed in a fluid bed dryer for drying at about 60°C.

Example 262

[0722] Activity testing is conducted in the Examples below using methods described herein and those well known in the art.

Sodium current screening assays:

[0723] The late sodium current (Late INa) and peak sodium current (Peak INa) assays are performed on an automated electrophysiology platform, QPatch 16X (Sophion Bioscience, Copenhagen, Denmark), which uses the whole cell patch clamp technique to measure currents through the cell membrane of up to 16 cells at a time. The assay uses an HEK293 (human embryonic kidney) cell line heterologously expressing the wild-type human cardiac sodium channel, hNa_v1.5, purchased from Millipore (Billerica, MA). No beta subunits were coexpressed with the Na channel alpha subunit. Cells are maintained with standard tissue culture procedures and stable channel expression is maintained with 400 pg/mL Geneticin in the culture medium. Cells isolated for use on QPatch are

346

4824-4563-0480.1

045710-5210 incubated for 5 minutes in Detachin IX (Genlantis, San Diego, USA) at 37 °C to ensure that 80-90% ofthe cells are single and not part of a cell cluster. Experiments are carried out at 23-25 °C.

[0724] For both the Late INa and Peak INa assays, sériés résistance compensation is set to 100% and sériés résistance and whole-cell compensation are performed automatically. Currents are digitized at 25 kHz and low-pass filtered at 12 kHz and 10 kHz for the late and peak INa assays, respectively. Currents through open sodium channels are automatically recorded and stored in the Sophion Bioscience Oracle database (Sophion Bioscience, Copenhagen, Denmark). Analysis is performed using QPatch Assay and database software and data are compiled in Excel.

[0725] Compound stocks are routinely made by the Gilead Sample Bank in plastic vials to 10 mM in dimethyl sulfoxide (DMSO). In some cases, when compounds are not soluble in DMSO, they are made in 100% éthanol. Stocks are sonicated as necessary. The extracellular solution for screening Late INa is composed of: 140 mM NaCl, 4 mM KC1, 1.8 mM CaCl₂, 0.75 mM MgCh and 5 mM HEPES with pH adjusted to 7.4 using NaOH. The intracellular solution used to perfuse the inside ofthe cells for both the Late INa and Peak INa assays contains: 120 mM CsF, 20 mM CsCl, 5 mM EGTA, 5 mM HEPES and pH adjusted to 7.4 with CsOH. Compounds are diluted in extracellular solution to 1 μΜ in glass vials and then transferred to glass well plates before robotic addition to the cells. The 0 mM Na extracellular solution (ONa-ECF) used at the end of each experiment for the Late INa and Peak INa assays to measure baseline current contains: 140 mM N-methyl-D-glucamine; 4 mM KC1; 1.8 mM CaCl₂; 0.75 mM MgCh; 5 mM HEPES and pH was adjusted to 7.4 with HCl.

Late INa Screening Assay:

[0726] For the Late INa assay, sodium channels are activated every 10 seconds (0.1 Hz) by depolarizing the cell membrane to -20 mV for 250 milliseconds (ms) from a holding potential of-120 mV. In response to a -20 mV voltage step, typical hNa_vL5 sodium currents activate rapidly to a peak négative current and then inactivate nearly completely within 3-4 ms.

[0727] Compounds were tested to détermine their activity in blocking the late sodium current. Late INa was generated by adding 10 μΜ Tefluthrin (pyrethroid) to the extracellular solution while recording Na currents. To confîrm the block of late I_Na

347

4824-4563-0480.1

045710-5210 observed using the automated screening method, a second late iNa enhancer (ATX-II) and the manual patch clamp method were used. ATX-II and tefluthrin occupy distinct, nonoverlapping binding sites and modify Na⁺ channel function differently to increase late I_Na. Compounds tested hâve been found generally to inhibit the enhanced late I\a caused by either late INa enhancer. For the purposes of the screening, late INa is defined as the mean current between 225 ms and 250 ms after stepping to -20 mV to activate Na channels. After establishing the whole cell recording configuration, late INa activator is added to each well 4 times over a 16-17 minute period so that the late component ofthe Na current reaches a stable value. Compounds were then added (typically at 1 μΜ), in the presence ofthe late INa activator, with 3 additions over the course of 7 or 8 minutes. Measurements were made at the end of exposure to the third compound addition and values were normalized to the current level when ail Na⁺ was removed from the extracellular solution after two additions of ONa-ECF.

[0728] Results are reported as percent block of late INa. When tested in the assay disclosed above with 10 μΜ Tefluthrin activating late INa, for example Compounds II105 inhibited (or reduced) the late sodium current by 45% (see Table 1 for additional compound data). The inhibition of Late INa ofthe cardiac isoform hNa_v 1.5 support the use ofthe compounds of this disclosure to treat atrial arrhythmias, ventricular arrhythmias, heart failure (including congestive heart failure, diastolic heart failure, systolic heart failure, acute heart failure), Prinzmetal’s (variant) angina, stable angina, unstable angina, exercise induced angina, congestive heart disease, ischemia, récurrent ischemia, reperfusion injury, myocardial infarction, acute coronary syndrome, peripheral arterial disease, pulmonary hypertension and intermittent claudication.

Peak INa Screening Assay:

[0729] Compounds were also evaluated for their effect in several other assays, including their effect on Peak INa. Good séparation between the concentrations of test compound to reduce late and peak I_Na is bénéficiai to enable séparation ofthe desired effect to reduce late Na-induced electrical and mechanical dysfonction from the undesired effect to reduce peak foa, which can lead to slowing or block of conduction of electrical excitation in the heart. It is contemplated that the compounds of Formula I avoid significant block of peak INa. Since the peak INa in the cells used herein can be very large, introducing artifacts m the recording, the concentration of Na⁺ in the bath can be reduced to 20 mM and a nonpermeant cation added to compensate for the Na⁺ that was removed to maintain the

348

4324=4563=0480.1

045710-5210 osmolarity and ionic strength ofthe solution (see solution details below). Analysis of peak INa generally requires correction for rundown before determining the % block of peak current by the tested compound.

[0730] A separate Peak INa screening assay was developed to allow assessment of the effect of compounds on peak INa at both low and high stimulation frequencies in order to identify compounds that are highly sélective for block of late INa but do not block peak INa. A low stimulation frequency of 0. f Hz was used to détermine the effect ofthe test compound when the channel spent most ofthe time in the resting (closed) State and provides information about Tonie Block (TB). A higher stimulation frequency (3Hz) was used to measure block ofthe channel when it spent more time in the activated and inactivated States and provided a measure of Use-Dependent Block (UDB). Usedependent block refers to the accumulation of block with increased frequency of channel activation. Block of cardiac peak INa by compounds of this disclosure is increased with an increase in the frequency of stimulation from 0.1 to 1-5 Hz (frequencies encountered either in the normal heart or during tachycardia). It is therefore expected that réduction of peak Ua by compounds of this disclosure will be greater at high heart rates, such as those during tachyarrhythmias, than at normal heart rates. As a conséquence, compounds of this disclosure may reduce Na⁺ and Ca²⁺ overload due to late INa and abnormal electrical activity and electrical conduction in myocardium that is arrhythmic, especially during ischemia.

[0731] The -100 mV holding potential and the 3 Hz stimulation frequency were chosen so that the benchmark compound would hâve a small but détectable effect under experimental conditions, allowing for direct comparison of new compounds with the benchmark. The extracellular solution for screening Peak INa is composed of: 20 mM NaCl, 120 mM N-methyl-D glucamine, 4 mM KC1, 1.8 mM CaCl₂, 0.75 mM MgCl₂ and 5 mM HEPES with pH adjusted to 7.4 using HCl. The intracellular solution used for the Peak INa assay is the same as outlined for the Late INa assay (see above).

[0732] For the peak INa assay, Na⁺ channels were activated by depolarizing the cell membrane to 0 mV for 20 ms from a holding potential of-100 mV. After estabhshing the whole cell recording configuration, channels were stimulated to open with low frequency stimulation (0.1 Hz) for 7 minutes so that the recording can be monotered and the extent to which the recording has stabilized can be assessed. After this stabilization period the stimulation frequency was increased to 3 Hz for 2 minutes and then returned to 0.1 Hz.

349

4824-4563-0480.1

045710-5210

Since 3 Hz stimulation causes a small decrease in the peak current even in the absence of compound, this internai control was used for each cell, when no compound is présent, to correct the results from 3 Hz stimulation when compound is présent. Following 3 Hz stimulation under control conditions, the cell is allowed to recover for 200 seconds before compound is added. The test compound tested at 1 or 3 μΜ (depending on the % block of late INa at 1 μΜ) was added 3 times at 60 second intervals, while stimulating the channels to open at 0.1 Hz to monitor the progression of TB. After the third compound addition, a 320 second wait period was imposed to allow for équilibration before the second period of 3 Hz stimulation begins. TB was measured before the second period of 3 Hz stimulation. Both TB and UDB were analyzed by incorporating rundown correction for the peak INa and UDB as calculated by compensating for the small use-dependent effect ofthe stimulation protocol on peak INa in the absence of compound. Compound 11-105 exhibited peak INa TB of 9% and peak INa UDB of 11%, both measured at 1 μΜ. [0733] The above data demonstrates the selectivity of Compound 11-105 to block late INa compared to peak INa (45% versus 9% for peak INa TB; and 45% versus 11% for peak INa UDB) and suggests that Compound 11-105 should show minimal to no effects on conduction through the heart (which is driven by peak INa) at concentrations that effectively block late INa.

hERG Screening Assay:

[0734] Compounds were also tested for their effect to block the hERG K channel. At least a 3-5-fold séparation, preferably 10 fold séparation, of IC₅o values for compounds to inhibit late I_Na (more potent) and hERG (less potent) indicates that a compound is unlikely to cause QT prolongation and/or proarrhythmic effects at concentrations needed to reduce late INa.

[0735] Compounds were screened to test their activity in blocking the hERG potassium channel at AVIVA Biosciences (San Deigo, CA, USA). The hERG channel is heterologously expressed in a CHO (Chinese Hamster Ovary) cell line. Cells were maintained with standard tissue culture procedures and stable channel expression was maintained with 500 ug/mL G418 in the culture medium. Cells were harvested for testing on the PatchXpress 7000A automated patch clamp with Accumax (Innovative Cell Technologies, San Diego, CA) to isolate single cells.

350

4824-4563-0480.1

045710-5210

[0736] The following solutions were used for electrophysiological recordings. The external solution contained: 2 mM CaCh; 2 mM MgCh; 4 mM KC1; 150 mMNaCl; 10 mM Glucose; 10 mM HEPES (pH 7.4 with IM NaOH; osmolarity, -310 mOsm). The internai solution contained: 140 mM KO, 10 mM MgCh, 6 mM EGTA, 5 mM HEPES, 5 mM ATP (pH adjusted to 7.25 with KOH; osmolarity, -295 mOsm).

[0737] hERG channels were activated when the voltage was first stepped to -50 mV for 300 ms from the -80 mV holding potential and then stepped to +20 mV for 5 seconds. At +20 mV the channels open and then largely inactivate, so the currents are relatively small. Upon returning to -50 mV from +20 mV, hERG currents transiently become much larger as inactivation is rapidly removed and then the channel closes. The first step to -50 mV for 300 ms was used as a baseline for measuring the peak amplitude during the step to -50 mV after channel activation. The peak tail current at -50 mV was measured both under control conditions and after addition of compound, each cell serving as its own control.

[0738] Ail compounds were prepared as 10 mM DMSO stocks in glass vials. Stock solutions were mixed by vigorous vortexing and sonication for about 2 minutes at room température. For testing, compounds were diluted in glass vials using an intermediate dilution step in pure DMSO and then further diluted to working concentrations in external solution. Dilutions were prepared no longer than 20 minutes before use.

[0739] For the electrophysiological recordings, after achieving the whole-cell configuration, cells were monitored for 90 seconds to assess stability and washed with external solution for 66 seconds. The voltage protocol described above was then applied to the cells every 12 seconds and throughout the whole procedure. Only cells with stable recording parameters and meeting specified health criteria were allowed to enter the compound addition procedure.

[0740] External solution containing 0.1% DMSO (vehicle) was applied to the cells first to establish the control peak current amplitude. After allowing the current to stabilize for 3 to 5 minutes, 1 μΜ and then 10 μΜ test compounds were applied. Each compound concentration was added 4 times and cells were kept in test solution until the effect ofthe compound reached steady State or for a maximum of 12 minutes. After addition of test compound, a positive control (1 μΜ Cisapride) was added and must block >95 % ofthe current for the experiment to be considered valid. Washout in the external solution compartment was performed until the recovery of the current reached steady state. Data

351

4824-4563-0480.1

045710-5210 were analyzed using DataXpress software and its associated SQL server database,

Clampfit (Molecular Devices, Inc., Sunnyvale, USA) and Origin 7 (Originlab Corp.)

When tested in the assay disclosed above, Compound 11-105 inhibited (or reduced) the activity of the hERG potassium channel by <10% at 1 μΜ (see Table 1 for additional compound data).

[0741] Compounds were tested using the above described assay methods. Data are obtained by testing the listed compounds at 1 μΜ concentration in the late and peak INa assays (and other concentrations as needed) and at 1 μΜ and 10 μΜ for the hERG channel assay.

Table 1 : Late ÏN_a Assay results

No.	Late INa ΙμΜ	Peak TB ΙμΜ	Peak UDB ΙμΜ
Π-1	25
Π-3	15
Π-4	30
II-5	26
Π-6	16
II-7	34
Π-8	21
Π-10	43	9	2
Π-11	23
Π-12	21
Π-13	18
Π-14	47	7	6
11-15	48	8	8
Π-16	19
Π-17	59	47	46
Π-19	21

352

4824-4563-0480.1

045710-5210

No.	Late ÏNa ΙμΜ	Peak TB ΙμΜ	Peak UDB ΙμΜ
Π-21	18
Π-22	30
Π-23	25
Π-24	23
Π-25	25
Π-31	51	9	8
Π-33	46	10	13
Π-35	25
Π-39	16
Π-41	17
Π-42	34
Π-43	23
Π-44	39
Π-45	27
Π-46	25
Π-47	60	13	45
Π-48	47	13	53
Π-49	63	28	44
Π-50	48	5	19
Π-51	20
Π-54	51	13	20
Π-57	55	50	41
Π-59	15
Π-61	41
Π-62	49	10	¹⁴

353

4824-4563-0480.1

045710-5210

No.	Late ÏNa ΙμΜ	Peak TB ΙμΜ	Peak UDB ΙμΜ
Π-64	55	12	19
Π-65	19
Π-67	22
Π-68	17
Π-69	33
Π-70	37
Π-71	12
11-72	60	22	34
Π-73	42
Π-74	12
Π-75	68	45	59
Π-77	21
Π-83	31
Π-87	22
Π-88	41
Π-89	28
Π-91	54	8	11
Π-92	34
Π-95	19
Π-97	36
Π-98	39
Π-102	21
Π-104	21
Π-105	45	9	11
Π-106	18

354

4824-4563-0480.1

045710-5210

No.	Late iNa ΙμΜ	Peak TB ΙμΜ	Peak UDB ΙμΜ
Π-107	18
Π-110	35
Π-113	27
Π-115	21
Π-117	37
Π-122	19
Π-123	21
Π-124	17
Π-129	33
Π-133	23
Π-134	69	38	34
Π-135	32
Π-136	30
Π-137	54	28	26
Π-138	47	16	23
Π-139	31
Π-140	32
Π-141	73	40	40
Π-142	19
Π-143	65
Π-144	68	34	41
Π-145	19
Π-146	36
Π-147	54	13	6
Π-148	17

355

4824-4563-0480.1

045710-5210

No.	Lâtc Ιν» ΙμΜ	Peak ΤΒ ΙμΜ	Peak UDB ΙμΜ
Π-150	27
Π-151	51	13	14
Π-152	23
Π-153	56	15	13
Π-154	25
Π-155	38	13	11
Π-156	48	23	13
Π-157	43	13	16
Π-158	58	34	26
Π-159	28
Π-160	48
Π-162	20
Π-163	28
Π-164	75
Π-165	56	15	30
Π-166	53	20	34
Π-167	56	20	25
Π-168	44	36	47
Π-169	65	23	23
Π-170	66	36	31
Π-171	24
Π-172	33
Π-174	48	7	18
Π-175	53	21	16
Π-176	68	45	44

356

4824-4563-0480.1

045710-5210

No.	Late I_Na ΙμΜ	Peak TB ΙμΜ	Peak UDB ΙμΜ
Π-177	22
Π-178	19
Π-179	21
Π-186	55	20	30
Π-187	62	9	21
11-189	53	23	28
Π-190	18
Π-191	25
Π-192	15
Π-193	70
Π-194	63
Π-195	66
ΙΠ-1	33
ΙΠ-4	35
ΠΙ-10	29
ΠΙ-11	20
ΠΙ-12	39	10	17
ΠΙ-15	50	19	18
ΙΠ-23	26
ΠΙ-24	17
ΠΙ-29	48	11	14
ΠΙ-30	16
ΠΙ-32	22
ΠΙ-33	37
ΠΙ-37	41

357

482+4563-0480.1

045710-5210

No.	Late In₃ΙμΜ	Peak TB ΙμΜ	Peak UDB ΙμΜ
ΙΠ-38	28
ΙΠ-40	22
ΙΠ-50	24
ΙΠ-58	26
IV-4	14
V-l	24
V-3	23
V-5	49	5	5
VI-4	36
VI-11	19
VI-26	28
VI-30	40
VI-31	61	50	42
VI-32	66	28	26
VI-36	47
VI-37	48
VHI-4	61	12	19
VIII-5	32
VIII-6	38
VUI-7	59
VTII-8	47
VIII-9	50
vm-io	25
vm-ii	42
IX-2	22

358

482+4563-0480.1

045710-5210

No.	Late La ΙμΜ	Peak TB ΙμΜ	Peak UDB ΙμΜ
IX-3	27
X-8	50	6	10
X-ll	48	17	20
X-12	26
XII-1	53	25	21
ΧΠ-2	57	45	64
ΧΠ-3	44	51	79
ΧΠ-5	25
ΧΠ-8	36
XII-9	22
XII-10	45	13	20
XII-11	55	25	24
ΧΠ-14	26
XIII-1	16
ΧΠΙ-2	19
xm-3	17
ΧΙΠ-4	51	8	9
ΧΙΠ-6	60	8	8
ΧΠΙ-10	22

[0742] The assay results shown in the above table establishes that compounds tested showed activity as modulators of late sodium current, for example by inhibiting (or reducing) the late sodium current.

[0743] In some embodiments the effects of a compound of Formula I are spécifie for the late sodium current and show little or no activity with respect to one or more other ion channels. Thus, in some embodiments, a compound having an activity of reducing late

359

482+4563-0480.1

045710-5210 sodium current will also exhibit little or no activity with regard to the peak sodium current. In particular embodiments, a compound having an activity of reducing late sodium current will also exhibit little or no activity with regard to the hERG potassium channel.

[0744] Table 2 is a summary comparing compound 11-73 and ranolazine ability to block late and peak hNa_v 1.5 Na⁺ current and hERG K⁺ current. The data in Table 2 were obtained in similar but not necessarly contemporaneous experiments.

Table 2

	ICso μΜ	ICso Ratio (fold)
Late INa	Peak INa	hERG	Peak INa/Late INa	hERG/Late INa
Π-73	0.6 ±0.1	52 ± 5	5.7 ±0.6	87	10
Ranolazine	6.7 ± 1.4	428 ± 33	13.4 ±0.5	64	2

[0745] The above data suggests that the compound of Example 11-73 exhibits comparable or improved properties with respect to the tested paramaters.

L-type Ca2+ Channel Assay - ChanTest:

[0746] Selected compounds were screened for block of the cardiac L-type Ca² channel (hCavl.2, encoded by the human CACNA1C gene and coexpressed with the beta 2 subunit, encoded by the human CACNB2 gene and alpha2deltal, encoded by the CACNA2D1 gene). The Ca²⁺ channel is heterologously expressed in a CHO (Chinese Hamster Ovary) cell line. Cells are maintained following standard tissue culture procedures and stable channel expression is maintained with appropriate sélection antibiotics in the culture medium. Cells are harvested for testing on the PatchXpress automated patch clamp (Model 7000A, Molecular Devices, Sunnyvale, CA) by washing twice with Hank’s Balanced Sait Solution, treating the cells with trypsin and resuspending cells in culture medium (4-6 xlO⁶ cells in 20 mL). Cells in suspension are allowed to recover for 10 minutes in a tissue culture incubator set at 37°C in a humidified 95% air, 5% CO₂ atmosphère.

360

4824-4563-0480.1

045710-5210

[0747] The following solutions are used for electrophysiological recordings. The external solution contains (mM): 137 NaCl, 4 KC1, 1.8 CaCh, 1 MgCh, 10 Glucose, 10

HEPES (pEl 7.4 with NaOEI). The internai solution contains (mM): 130 Cs Aspartate, 5

MgCh, 10 EGTA, 4 ATP, 0.5 GTP, 10 HEPES, (pH adjusted to 7.2 with N-methyl-Dglucamine).

[0748] Vehicle is applied to naïve cells (n > 2, where n = the number cells), for a 5-10 minute exposure interval. Each solution exchange is performed in quadruplicate. At the end of each experiment, a saturating concentration of nifedipine (10 μΜ) is added to block hCavl.2 current. Leak current is digitally subtracted from the total membrane current record.

[0749] Test compound stock solutions are prepared by addition of dimethyl sulfoxide (DMSO) and stored frozen. Each test compound DMSO stock is sonicated (Model 2510/5510, Branson Ultrasonics, Danbury, CT), at ambient room température for at least 20 minutes to facilitate dissolution. Test compound concentrations are prepared fresh daily by diluting stock solutions into the standard extracellular physiological saline solution (see above). The maximum percent of DMSO added with compound is 0.1%. Ail test compound and control solutions are placed in a glass-lined 96-well compound plate before loading on PatchXpress.

[0750] Two concentrations (1,10 μΜ) of each test compound are applied at five (5) minute intervals via disposable polyethylene micropipette tips to naïve cells (n > 2, where n = the number cells/concentration). Each test compound concentration is added to the cell in quadruplicate. Total duration of exposure to each test compound concentration is 5 minutes.

[0751] Onset and steady state block of hCavl.2 (αΉ/β2/α2δΠ channels is measured using a stimulus voltage pattern consisting of a depolarizing test puise (duration, 200 ms; amplitude, 10 mV) at 10 s intervals from a -80 mV holding potential. Peak current is measured during a step to 10 mV.

[0752] When tested in the assay disclosed above, Compound 11-73 blocked the hCav 1.2 late current by 14% and peak current by 32% at 1 μΜ concentration. At 10 μΜ concentration the compound Π-73 blocked the hCavl.2 late current by 47% and the peak current by 79%.

361

4824-4563-0480.1

045710-5210

Example 263

[0753] Compounds of this disclosure that block cardiac late foa may also médiate UDB of other Na⁺ channel isoforms including the major Na⁺ channel isoforms in peripheral nervous system pain libers, Navl.7 and 1.8. Compounds of this disclosure that block these channels may also be useful to decrease neuropathie pain.

[0754] In particular embodiments, a compound will exhibit a high selectivity for the late sodium current modulatory activity as compared to the activity in one or more other ion channels. The selectivity of a compound may be determined by determining the percentage réduction in late sodium current due to the compound, as measured by the assay described above. The percentage réduction in one other ion channel activity, such as the hERG potassium channel, due to the compound is determined as described above. The selectivity is determined by taking the ratio of (percentage réduction in late sodium current) to (percentage réduction in one other ion channel activity). The assays conducted to measure activities in this regard should be performed as described above, with the compound at a concentration of 10 μΜ (or at the upper limit of solubility, if less). In particular embodiments, the selectivity of a compound of the disclosure will be at least 5:1, e.g. at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 12:1, at least 15:1, at least 20:1, or at least 25:1, when comparing the percentage réduction in late sodium current versus percentage réduction of one of the peak sodium current, the hERG potassium channel current. Selectivity data can be calculated based on the values provided in the Examples above.

[0755] Evidence supports a rôle for the tetrodotoxin-sensitive Na_vl .7 in the pathogenesis of pain. In this assay, using whole-cell patch-clamp technique, the effects of compounds ofthe disclosure on hNa_v1.7 (hNa_v1.7+pl subunits) peak Na⁺ current (I_Na) are tested as described previously (Rajamani et al, 2009). Cells are continuously maintained using MEM (Gibco-Invitrogen, Carlsbad, CA) supplemented with 10% heat inactivated fêtai bovine sérum, 1% penicillin-streptomycin, 600 pg/mL geneticin (Gibco-Invitrogen), 2 pg/mL blastocydin (Calbiochem, NJ, USA), and are incubated at 37°C in an atmosphère of 5% CO₂ in air. For recording hNavl.7 I\_a, HEK293 cells are superfused with an extracellular solution containing (in mM): 140 NaCl, 3KC1, 10 HEPES, 10 glucose, 1 MgCl₂, 1 CaCl₂, pH 7.4 (with NaOH). Patch pipettes are filled with an internai solution containing (in mM): 140 CsF, 10 NaCl, 1 EGTA, 10 HEPES, pH 7.3 (with CsOH).

362

4824-4563-0480.1

045710-5210

[0756] Whole-cell INa are recorded as described previously (Rajamani et al, 2009) using an Axopatch 200B amplifier (Molecular Devices, Sunnyvale, USA). Signais are filtered at 5 kHz and sampled at 20 kHz. Patch pipettes are formed using borosilicate glass (World Précision Instruments, Sarasota, USA) using a micropipette puller (Dagan Corporation, Minneapolis, USA). The offset potential is zeroed before the pipette is attached to the cell and the voltages are not corrected for the liquid junction potential. In ail recordings, 7580% ofthe sériés résistance compensation will be achieved, thus yielding a maximum voltage error of ~5 mV and leak currents are cancelled by P/4 subtraction. pCLAMP 10.0 software (Molecular Devices) will be used to generate voltage clamp protocols and acquire data. The membrane potential is held at -100 or -120 mV and the cell dialyzed with the pipette solution for 5-7 minutes before current is recorded, to avoid timedependent shifts in Na⁺ channel gating within the first several minutes after patch rupture. In ail experiments, the température of experimental solutions will be maintained at 20±l°C using a CL-100 bipolar température controller (Warner Instruments, Hamden, USA).

[0757] Data are analyzed using Clampfit and Microcal Origin (MicroCal, Northampton, USA) software.

[0758] When tested in the assay disclosed above, Compound 11-73 blocked the hNa_v 1.7 sodium channel isoform with IC50 of 5.2 μΜ at a frequency of 10 Hz. Compound 11-73 blocked the hNa_v 1.8 sodium channel isoform with a IC50 of >10 μΜ at a 10 Hz frequency. At higher frequency of 25 Hz, compound 11-73 blocked both hNa_v 1.7 and hNa_v 1.8 isoforms with IC50 of 1.1 and 1.5 μΜ respectively. The inhibition of either hNa_v 1.7 and hNa_v 1.8 isoforms or the inhibition of both channels when stimulated at these frequencies support the use of compounds of this disclosure to decrease neuropathie pain.

Example 264

Expression of human Navl.l cDNA

[0759] Ail experiments with human Navl. 1 are conducted as described (Kahlig, et al., PNAS, 105: 9799-9804). Briefly, expression of hNavl.l is achieved by transient transfection using Qiagen Superfect reagent (5.5 pg of DNA is transfected at a plasmid mass ratio of 10:1:1 for αι:βι:β₂). The human βι and β₂ cDNAs are cloned into plasmids

363

482+4563-0480.1

045710-5210 containing the marker genes DsRed (DsRed-lRES2-hpi) or eGFP (eGFP-IRES2-hp2) flanking an internai ribosome entry site (IRES).

Electrophysiology

[0760] Whole-cell voltage-clamp recordings are used to measure the biophysical properties of WT and mutant Navl.l channels, as described previously (Kahlig, 2008). For recording hNavl.l I\_a, HEK293 cells are superfiised with solution containing (in mM): 145 NaCl, 4 KC1, 1.8 CaCh, 1 MgCh, 10 dextrose, 10 HEPES, with a pH of 7.35 and osmolarity of 310 mOsmol/kg. The pipette solution contains (in mM): 110 CsF, 10 NaF, 20 CsCl, 2 EGTA, 10 HEPES, with a pH of 7.35 with an osmolarity of 300 mOsmol/kg. Cells are allowed to stabilize for 10 min after establishment of the whole-cell configuration before current is measured. Sériés résistance is compensated 90% to assure that the command potential is reached within microseconds with a voltage error <2 mV. Leak currents are subtracted by using an online P/4 procedure and ail currents are lowpass Bessel filtered at 5 kHz and digitized at 50 kHz.

[0761] For use-dependent studies, cells are stimulated with depolarizing puise trains (-10 mV, 5 ms, 300 puises, 10 and 25Hz) from a holding potential of-120 mV. Currents are then normalized to the peak current recorded in response to the first puise in each frequency train. For tonie block studies, peak and persistent (late) currents are evaluated in response to a 200 ms depolarization to -10 mV (0.2 Hz) following digital subtraction of currents recorded in the presence and absence of 0.5 μΜ tetrodotoxin (TTX). The sodium current termed Late INa in the periphery is commonly called persistent INa in the CNS. Persistent current is calculated during the final 10 ms ofthe 200 ms step. Data analysis is performed using Clampfit 9.2 (Axon Instruments, Union City, CA, U.S.A), Excel 2002 (Microsoft, Seattle, WA, U.S.A.), and OriginPro 7.0 (OriginLab, Northampton, MA, U. S. A) software. Results are presented as mean ± SEM.

In vitro Pharmacology

[0762] A stock solution of lOmM compound of Formula I is prepared in 0.1 M HCl or DMSO. A fresh dilution of the compound of Formula I in the bath solution is prepared every experimental day and the pH is readjusted to 7.35 as necessary. The final DMSO concentration was kept at 0.1% in ail solutions. Direct application ofthe perfusion

364

4824-4563-0480.1

045710-5210 solution to the clamped cell is achieved using the Perfüsion Pencil System (Automate, Berkeley, CA). Direct cell perfusion is driven by gravity at a flow rate of 350 pL/min using a 250 micron tip. This System sequesters the clamped cell within a perfusion stream and enables complété solution exchange within 1 second. The clamped cell is perfused continuously starting immediately after establishing the whole-cell configuration. Control currents are measured during control solution perfusion. Where appropriate, concentration inhibition curves are fit with the Hill équation: I/Imax ⁼ l/[l+10^A(logIC5o-I)*k], where IC50 is the concentration that produces half inhibition and k is the Hill slope factor.

[0763] Solutions containing the compounds of the disclosure are perfused for three minutes prior to current recordings to allow equilibrium (tonie) drug block. Tonie block of peak current is measured from this steady-state condition. Use-dependent block of peak current is measured during puise number 300 ofthe puise train, (-10 mV, 5 ms, 3 00 puises, 10Hz) from a holding potential of-120 mV. Two sequential puise train stimulations are averaged to obtain mean current traces for each recording condition.

In vivo pharmacology

[0764] Jugular vein cannulated male Sprague Dawley rats (250 - 350g, Charles River Laboratories, Hollister, CA) are used to study brain pénétration ofthe compounds ofthe disclosure in vivo. Animal use is approved by the Institutional Animal Care and Use Committee, Giiead Sciences. Three rats per group are infused intravenously with the compound of the disclosure in saline at 85.5 pg/kg/min. After 1, 2.5 or 5 h the animais are sacrificed for plasma and brain collection, and concentrations ofthe compound ofthe disclosure are measured by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Brain tissue is homogenated in 1% 2N HCl acidified 5% sodium fluoride (final homogenate is diluted 3-fold). Plasma and brain homogenate samples (50 pl) are precipitated along with deuterated D3-Formula I as an internai standard, vortexed and centrifuged. The supernatant (50 pL) is transferred and diluted with water (450 pl) prior to injection (10 pl). High performance liquid chromatography was performed using a Shimadzu LC-1 OAD liquid chromatograph and a Luna Cl8(2), 3 pm, 20 x 2.0 mm column with a mobile phase consisting of water containing 0.1% formic acid (solution A) and acetonitrile (solution B) carried out under isocratic conditions (75% solution A, 25% solution B; flow rate 0.300 ml/min). Mass spectrométrie analyses are performed using an API3000 mass spectrometer (Applied Biosystems, Foster City, CA)

365

4824-4563-0480.1 operating in positive ion mode with MRM transition 428.1 > 98. Brain-to-plasma ratios are calculated for each sample as ng compound/g brain divided by ng compound/ml plasma.

045710-5210

Example 265

Expression of human NavE2 cDNA

[0765] Wild-type (WT) cDNA stably transfected in Chinese hamster ovary (CHO) cells is used to record INa. Unless otherwise noted, ail reagents are purchased from SigmaAldrich ( St Louis, MO, U.S. A.).

Electrophysiology

[0766] Whole-cell voltage-clamp recordings are used to measure the biophysical properties of WT. Briefly, the pipette solution consists of (in mM) 110 CsF, 10 NaF, 20 CsCl, 2 EGTA, 10 HEPES, with a pH of 7.35 and osmolarity of 300 mOsmol/kg. The bath (control) solution contains in (mM): 145 NaCl, 4 KC1, 1.8 CaCh, 1 MgCh, 10 dextrose, 10 HEPES, with a pH of 7.35 and osmolarity of 310 mOsmol/kg. Cells are allowed to stabilize for 10 min after establishment of the whole-cell configuration before current is measured. Sériés résistance is compensated 90% to assure that the command potential is reached within microseconds with a voltage error <2 mV. Leak currents are subtracted by using an online P/4 procedure and ail currents are low-pass Bessel filtered at 5 kHz and digitized at 50 kHz.

[0767] For clarity, représentative ramp currents are low pass filtered off-line at 50 Hz. Spécifie voltage-clamp protocols assessing channel activation, fast inactivation and availability during répétitive stimulation are used. Results are presented as mean ± SEM.,.

[0768] Tonie block of peak current is measured using a step to -lOmV (20ms) from a holding potential of -120mV (0.2Hz). Use-dependent block of peak current is measured during puise number 300 of a puise train (-10 mV, 5 ms, 300 puises, 10Hz or 25Hz) from a holding potential of-120 mV. Two sequential puise train stimulations are averaged to obtain mean current traces for each recording condition, which are then used for offline subtraction and analysis.

[0769] For use-dependent studies, cells are stimulated with depolarizing puise trains (10 mV, 5 ms, 300 puises, 10 and 25Hz) from a holding potential of-120 mV. Currents

366

4824-4563-0480.1

045710-5210 are then normalized to the peak current recorded in response to the first puise in each frequency train. For tonie block studies, peak current is evaluated in response to a 20 ms depolarization to -10 mV (0.2 Hz). Data analysis is performed using Clampfit 9.2 (Axon Instruments, Union City, CA, U.S.A), Excel 2002 (Microsoft, Seattle, WA, U.S.A.), and OriginPro 7.0 (OriginLab, Northampton, MA, U. S.A) software. Results are presented as mean ± SEM.

In vitro Pharmacology

[0770] A stock solution of lOmM compound of Formula I is prepared in 0.1 M HCl or DMSO. A fresh dilution of the compound of Formula I in the bath solution is prepared every experimental day and the pH is readjusted to 7.35 as necessary. The final DMSO concentration was kept at 0.1% in ail solutions. Direct application of the perfusion solution to the clamped cell is achieved using the Perfusion Pencil System (Automate, Berkeley, CA). Direct cell perfusion is driven by gravity at a flow rate of 350 pL/min using a 250 micron tip. This System sequesters the clamped cell within a perfusion stream and enables complété solution exchange within 1 second. The clamped cell is perfüsed continuously starting immediately after establishing the whole-cell configuration. Control currents are measured during control solution perfusion.

[0771] Solutions are perfüsed for three minutes prior to current recordings to allow equilibrium (tonie) drug block. Tonie block of peak currents is measured from this steady-state condition. Three sequential current traces are averaged to obtain a mean current for each recording. The mean current traces are utilized for offline analysis. Usedependent block of peak current is measured during puise number 300 of the puise train, (-10 mV, 5 ms, 300 puises, 10Hz) from a holding potential of-120 mV. Two sequential puise train stimulations are averaged to obtain mean current traces for each recording condition, which are then used for offline subtraction and analysis Where appropriate, concentration inhibition curves are fit with the Hill équation: I/Imax = l/[l+10^A(logICjoI)*k], where IC50 is the concentration that produces half inhibition and k is the Hill slope factor.

Results

[0772] Using the above methods it may be demonstrated that the compounds of the disclosure are sélective for inhibiting cardiac Late Ina current without inhibiting peak and low frequency currents of brain isoforms NaV 1.1 and 1.2. The compounds of the

367

482+4563-0480.1

045710-5210 disclosure may inhibit the very high frequency firing of Na_vl. 1 and Na_vl .2 or demonstrate voltage dépendent block of mutant Navl.l and Navl.2 observed with epilepsy patients.

In addition compounds of this disclosure may show activity for inhibition of a panel of

Navl.l mutant channels associated with the epilepsy and headache (migraine) syndromes

GEFS+, SMEI and FHM3 suggesting the ability of the compounds of the disclosure to preferentially block the abnormal increased persistent current carried by these mutant channels. disclosure

[0773] When tested in the assay disclosed above for hNa_v 1.1 and hNa_v 1.2 sodium channel isoforms, Compound 11-73 blocked the hNa_v 1.1 sodium channel isoform peak

INa with IC50 value of >100 μΜ at a frequency of 10 Hz and the hNa_v 1.2 sodium channel isoform peak INa with IC50 value of > 30 μΜ at the same frequency. At higher frequency of 25 Hz the compound 11-73 blocked both hNa_v 1.1 and hNa_v 1.2 isoforms with IC50 of 3.4 μΜ and 10.1 μΜ respectively. The inhibition of either hNa_v 1.1 and hNa_v 1.2 isoforms or the inhibition of both channels when stimulated at these frequencies support the use of compounds of this disclosure to treat patients with epilepsy.

Table 3: Late INa Assay results

No.	Late INa*	NAV1.1* UDB-10HZ	NAV1.2* UDB-10HZ	hERG	RHEART MAPD90 ΛΤΧ
II-7	34	0	13		-10
11-10	43	-4	9
11-14	47	16	19
Π-17	59			<10
11-22	30	3	15	16
11-42	34	2	12		-27
11-46	25	2	16
Π-61	41	9	25	<10	-62
11-73	42	10	19	18	-56
11-75	68	35	52
11-83	31	-2	10	21

368

4824-4563-0480.1

045710-5210

No.	Late Ka*	NAV1.1* UDB-10HZ	NAV1.2* UDB-10HZ	hERG	RHEART MAPD90 ATX*
11-88	41	-10	-1	26	-69
11-91	54	-9	-3
Π-98	39	-1	-8	<10	-50
Π-105	45	-17	1	<10
11-110	35	-4	-2	26
Π-117	37	-11	-18	<10
11-129	33	8	7	17	-49
11-138	47	21	40
11-143	65	29	44
11-156	48				-23
ΠΙ-1	33	-1	-3	<10	-47
V-5	49	-18	3
VIII-4	61	5	18	30	-25
VUI-6	38	6	20	<10	-49
X-8	50	-12	-14	<10
XII-1	53	-1	-4
ΧΠ-8	36	11	11		-34

* %Inhibition at 1 uM

Example 266

Ischemia-induced ST segment élévation in anesthetized rabbits

[0774] This study was undertaken to détermine the anti-ischemic effects of compounds of the présent disclosure in an in vivo rabbit model.

Methods:

[0775] Female New Zealand rabbits (3.0-4.0 kg) were purchased from Western Oregon

Rabbitry. Animais were housed on a 12-h light and dark cycle and received standard

369

4824-4563-0480.1

045710-5210 laboratory chow and water. Ail experiments were performed in accordance with the

Guide for the Care and Use of Laboratory Animais published by The National Research

Council and with the experimental protocol approved by the Institutional Animal Care

Committee of Gilead Sciences, Inc.

[0776] Rabbits were anesthetized with ketamine (35 mg/kg) and xylazine (5 mg/kg) intramuscular injection (im). A tracheotomy was performed and the trachea was intubated with an endotrachéal tube. The animal was ventilated with room air supplemented with oxygen using a pressure control animal ventilator (Kent Scientific Corp., Torrington, CT) at a respiratory rate of 40 strokes/min and peak inspiration pressure of 10 mmlfO, which was adjusted to keep blood gases and pH within the physiological range (iSTAT clinic analyzer, Heska Corp.; Waukesha, WI). The left fémoral artery was cannulated for the measurement of blood pressure (BP). Blood samples were also withdrawn from fémoral artery. The right external jugular vein was cannulated for drug/vehicle administration. Needle électrodes were inserted subcutaneously into the limbs for recording of the surface electrocardiogram (ECG). The heart was exposed via an incision in the 4^th intercostal space (4^th and /or 5^th ribs were eut for a clear surgical vision). The chest was opened and a pericardial cradle was formed using 4 retractors. A coronary artery occluder, comprised of a snare made of 5 cm PE-10 tubing with a 6-0 Prolene polypropylene suture in it, was placed loosely around the left anterior descending artery (LAD) at its origin. Two unipolar électrodes, made with teflon coated silver wire attached to a small patch of filter paper, were attached on the surface ofthe ischémie and normal régions ofthe left ventricle to record epicardial electrocardiogram. Reference électrodes were placed in the open incision of the neck. The body température of the animal was monitored via a rectal thermometer and maintained at 37-40°C by adjusting the surface température of the surgical table. Régional ischemia (15 min) was induced by ligating the LAD followed by 15 min of reperfusion caused by releasing the ligation. The heart was excised at the end of the experiment and the LAD was re-ligated. The ischémie area was visualized by perfusing the heart with 1% Evans blue in saline and calculated as a percentage of total ventricular weight. Rabbits with ischémie area less than 10% or larger than 25% were excluded from the analysis. Animais were randomly assigned to vehicle and test compound groups. Test compounds was dissolved in 5% NMP, 30% PG, 45% PEG 400 and 20% de-ionized water (dH₂O). Test compound was given as an iv bolus at 0.1, 0.2

370

482+4563-0480.1

045710-5210 and 0.4 mg/kg. After 30 min of dosing, the heart was subjected to 15 min of ischemia followed by 15 min of reperfusion.

Results:

[0777] The compound of Example Π-61 dose-dependently prevented the ischemia- induced ST élévation. The area under curve (AUC) for the ST segment height was reduced (vs. control) by 38% and 88% at 0.28 and 0.52 μΜ plasma concentration of compound of Example Π-61. At the plasma concentration levels studied, compound of Example 11-61 had no significant effect on blood pressure (BP), heart rate (HR) and ECG intervals prior to the ischemia. The data suggests the compound of Example 11-61 prevents ischemia-induced myocardial electrical dysfunction in a dose-dependent manner.

[0778] Similarly, compound of Example 11-73 dose-dependently prevented the ischemiainduced ST élévation. The area under curve (AUC) for the ST segment height was reduced (vs. control) by 55% and 93% at 0.25 and 0.5 μΜ respective plasma concentration of compound of Example Π-73. At the plasma concentration levels studied, compound of

Example 11-73 had no signifîcant effect on blood pressure (BP), heart rate (HR) and ECG intervals prior to the ischemia. The data suggests the compound of Example 11-73 prevents ischemia-induced myocardial electrical dysfunction in a dose-dependent manner.

371

4824-4563-0480.1

Claims

CLAIMS:

1. A compound of Formula 11:

II wherein:

m is 0, 1 or 2;

n is 0, 1,2 or 3;

R² is -Cm alkylene-R', -Cm alkylene-L-R³ or -C« alkylene-L-C m alkylene-R³;

L is -O-, -C(O)-, -NHSlOh-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-;

each R³ is independently hydrogen, deuterium or Cm alkyl;

each R* is independently hydrogen, deuterium or Cm alkyl;

R^s is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyL aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, halo, cycloalkyl, heterocyclyl, heteroaryl, -N(R²⁰)(R”), -C(O)-OR“ -CN, and -O-R²⁰;

wherein said Cm alkyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo. Cm alkyl and aryl; and wherein said Cm alkyl is optionally further substituted with one, two or three halo.;

each R¹⁰ is independently selected from the group consisting of halo, -NO?, CN, -SF_s, -SMCH₃)3. -O-R²⁰. -S-R²⁰, -CiOLR³⁰. -C(O)-OR²® -NiR^CR²²), -C(O>

372

N(R^2O)(R-), -N(R²⁰)-C(0)-R²², -N(R²⁰)-C(O)-OR“, -NtR^-SfOh-R²⁶, -SiOb-R²⁰, -OSfOfe-R²⁰, -S(O),-N(R^2üMR²²)_f C_m alkyl, alkenyl, C?.₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;

wherein said Cm alkyl, C₂m alkenyl, Cu alkynyl, cycloalkyl. aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, aryl, heterocyclyl, heteroaryl, Cu alkyl, Cu haloalkyl, cycloalkyl, -N(R^2t’)(R²²), -C(O)-R²⁰, -CfOi-OR²⁰, -CiOJ-NfR^XR²²), -CN and -O-R“°;

R¹⁷ is halo, or Cu alkyl;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C« alkyl. C₂^ alkenyl, C₂^ alkynyl. cycloalkyl, heterocyclyl. aryl and heteroaryl;

wherein the C« alkyl, C₂^ alkenyl, C?^ alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cu alkyl, acylamino. oxo, -NOi -S(O)₂R“, -CN, C1.3 alkoxy, CF3, -OCF3, -OCFhCFj, -C(O>-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cu alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R‘° and R^-2 may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cu alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO?. -S(O)?R“⁵, -CN, Ch alkoxy, CF3, -OCF3, aryl, heteroaryl and cycloalkyl: and each R²⁶ is independently selected from the group consisting of hydrogen. Ch alkyl, aryl and cycloalkyl;

373 wherein the Ch alkyl, aryl and cycloalkyl may be further substituted with front 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo. Ch alkoxy, -CF₃ and -OCF₃;

wherein in each instance independently a cycloalkyl group is from 3 to 20 carbon atoms; an aryl group is from 6 to 20 carbon atoms; a heteroaryl group comprises single or multiple rings comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen. nitrogen and sulfur within at least one ring; and a heterocyclyl group is a monoradical saturated group having a single ring or multiple condensed rings, having from 1 to 40 carbon atoms and from 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphores, and/or oxygen within the ring;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.

The compound of claim 1, wherein R² is -C_w alkylene-R³ or -Ci^, alkylene-L-R³.

374

4. The compound of claim 1, wherein n is 1,2 or 3; and each R¹⁰ is independently selected from the group consisting of halo, -O-R²⁰, -O-S(OhR²⁰, C_[Jt alkyl and cycloalkyl; and

375 wherein said alkyl and cycloalkyl are optionally substituted with one. two or three halo or -CN; and

R³⁰ is independently selected from the group consisting of Ci.₆ alkyl, cycloalkyl and aryl; and wherein the alkyl and ary l are optionally substituted with one. two or three halo or cycloalkyl.

5. The compound of claim 1, wherein n is 1,2 or 3; and each R¹⁰ is independently 2-fhioro, 3-fluoro. 4-fluoro, 2-chloro, 4-chloro, 2-methyl, 4-methyl, 4-ethyl, 4-isopropyk 4-iertbutyl, 4-difluoromethyl, 4-trifluoromethyl, 4-cyclopropyl. 4-isobutoxy, 4difluoromethoxy, 4-trifluoromethoxy, 4-(2,2,2-trifluoroethoxy), 4-trifluoromethylsulfoxyL 4-(2,2,2-trifluoroethyl), 4-cyclopropôxy, 4-cyclobutylmethoxy, 4-fluorophenoxy, 4-phenoxy or 3-phenoxy.

6. The compound of claim 1, wherein R²⁰ and R“ are in each instance independently selected from the group consisting of hydrogen, alkyl and heteroaryl.

7. The compound of claim 1, wherein each R^a is independently hydrogen. deuterium, methyl, or isopropyl;

m is 0 or 1 ; and

R¹⁷ is halo.

8. The compound of claim 1, wherein the compound is represented by Formula ΠΒ:

ΠΒ wherein: n is 0, 1, 2 or 3:

R² is -Ci-6 alkylene-R⁵;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl

376 wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one. two or three substituents independently selected froin the group consisting of Cj^ alkyl,, halo, -NCR^XIU²), -CfOj-OR²⁰, -CNand -O-R²⁰; and wherein said Ci^ alkyl is optionally further substituted with one, two or three halo;

each R¹⁰ is independently selected from the group consisting of halo, -NO?, CN, -SF5, -SitCHsh, -O-R²⁰, -S-R²⁰, -C(Ol-R²⁰ -C(O)-OR²⁰, -NfR^JiR²²), -C(O> NfR^XR²²), -NtR^J-CiOi-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -SfO^R²⁰, -OS(O>?-R°, -SfOh-NfR^XR²²), Cj^ alkyl, Cm alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;

wherein said C^ alkyl, alkenyl, Czm alkynyl, cycloalkyl· aryl, heteroaryl or heterocyclyl are optionally substituted with one. two or three substituents independently selected from the group consisting of halo, -NO?, aryl, heterocyclyl, heteroaryl, Cr, alkyl. G.? haloalkyl, cycloalkyl, -NfR^XR²²), =C(O)-R²⁰, -C(O)-OR®, -CfO^NfR^XR²²), -CN and -O-R²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen. Cj^ alkyl, C?^ alkenyl, C₂^ alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and wherein the Cj^ alkyl· C?^ alkenyl. C₂^ alkynyl· cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo. Cm alkyl, acylamino, oxo, -NO?. -S(O)?R²⁶, -CN, C_M alkoxy, -CF₃, -OCF,, -OCH?CF₃and -C(O)-NH₂; or when R° and R“ are attached to a common nitrogen atom R^-0 and R~ may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo. Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO?. — SfOhR⁶, -CN, C1-3 alkoxy, -CF3 and -OCF3; and

377 each R⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl:

wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo. Cm alkoxy, -CFj and -OCF»;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.

9. The compound of claim 1, wherein the compound is selected from the group consisting of:

4-((3-methyloxetan-3-yl)methyl)-7-(4-(tiifluorœiiethoxy)phenyl)-3,4dihydrobenzo[fj[ 1,4Joxazepin-5(2H i-one (Π-1 );

4-(2-(pyrrolidin-l-yl)e thyl )-7-(4-( trifluoromethoxy )phenyl)-3.4dihydrobenzo|f|[ 1,4]oxazepin-5(2H)-one (113):

4-((5-cyclobulyl-l ,3,4-oxadiazoi-2-yl)methyl)-744-(trifluoromethoxy)phenyl )-3,4dihydrobenzô[f][ 1,4]oxazepin-5(2H)-one (Π-4):

4-i(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methyl )-7-(4-( trinuoromethûxy)phenyl)-3.4dihydrobenzo[f|[l,4joxazepin-5(2H)-one (Π-5)·

4-fquinolin-2-ylmethyl)-7-(4-( trifluoromethoxy (phenyl )-3,4dihydrobenzo(f][ 1.4|oxazepin-5(2H)-one (II-7);

4-(cyclopropylme1hyl)-7-(4-(trifluorômethoxy)phenyl)-3,4dihydrobenzô[fj( 1,4]oxazepin-5(2H)-one (Π-10);

(S>3-methyl-4-(pyrimidin-2-yÎmeüiyl)-7-(4Ttrifluoromethyl)phenyl>3,4dihydrobenzo(fJ[l,4]oxazepin-5(2H)-one (11-12);

(Rj-3-methyl-4-(pyrimidin-2-ylmethyi)-7-(4-(trifluorometliyl)phenyl)-3,4dihydrobenzoff][ i ,4] oxazepin-5( 2 H )-one ( Π- i 3 );

6-((5-oxo-7-(4-(trifluoromelhoxy)phenyl)-2,3-dihydrobenzo[f|[l,4]oxazepin-4(5H)yl)methyl)picolinonitrile (11-14);

378

7-(4-( trifiuoromethoxy)phenyl)-4-((6-( tri nuoromethyi)pyridm-2-yl)methyl)-3,4dihydrobenzo(f][l _}4]oxazepin-5(2H)-one (II-15);

7-(4-(trifluoromethoxy)phenyl)-4-((6-(trifliioroinethyl)pyridin-3-yl)methyl)-3,4dihydrobenzoff][ 1.4 Joxazepm-5( 2 H)-one (II-16);

4-((6-methylpyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l ,4]oxazepin-5(2H)-one (II-17j;

(2R,1 laS)-2-amino-7-(4-(trifluoromelhyl)phenyl)-2,3,l 1,11atelrahydrobenzo[f]pyrrolo[2,1 -c][ 1,4]oxazepm-5( lH)-one ( Π-21);

4-(pyrazin-2-ylmethyl)-7-(4-(trifluoromethaxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (II-31 );

4-((5-methyloxazol-2-yI)methyl)-7-(4-( trifluûrômethoxyjphenyl)-3,4dihydrobenzo|i|[ 1 -4]oxazepm-5(2H)-one (11-33);

7-(4-(trifluoromethoxy )phenyl)-4-(2-(2,54-trünethyl-13-dioxan-2-yl)ethyl)-3,4dihydrobeiizo[f][ 1,4]oxazepin-5(2H)-one (11-35);

4-((5-(pyTidin-2-yI)isoxazoi-3-yr)methyl)-7-(4-(trifluoromethoxylphenyI)-3,4dihydrobenzo[f|[ 1,4]oxazepin-5(2H)-one (II-41 );

4-((4,6-dimethoxypyrimidin-2-yl)methyl )-7-(4-( tri fluoromethoxy)phenyl)-3,4dihydrobenzoff] [ 1,41oxazepin-5(2H)-one ( 11-42);

ethyl 3-((5-üxo-7-(4-(trifluoromethoxy)p3ienyl)-2,3-dihydrobenzo[f][l,4}oxazepiri-4(5H)yl)methyl)benzoate (11-43);

4-(2-(pyTimidin-2-yl)ethyl)-7-(4-(trifluoroniethoxy)phenyl)-3_!4dihydrobenzo[f|[l,4Joxazepin-5(2H)-one (11-44);

4-(3.4-difluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobettzo[f|[ 1.4]oxazepm-5(2H)-one (11-45);

4-(2-chlorobenzyl)-7-(4-(trifluoromelhoxy)phenyr)-3,4-iühydrobenzü[fj[l,4]oxazepin5(2H)-one (Π-47);

379

4-(2,6-dichlorobenzyI)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-48);

4-(2,6-difluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3.4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (Π-49);

4-(2-( 1 H-pyrazol-1 -yl)elhyl)-7-(4-(trifluoromethoxy)phenyr)-3_s4dihydrobenzo(fj[ l,4]oxazepin-5(2H)-one (11-50);

(2S,1 laS)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,i 1,1 latetrahydrobenzo[f]pyTroIo[2,1 -c] [ 1,4]oxazepin-5( 1 H)-one (Π-51 );

4-(2-(pjTidin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ L4]oxazepïn-5(2H)-one (11-54);

4-(2-fluorobenzyi)-7-(4-(trifluoromethoxy)phenyl)-3_J4-dihydrobenzo[f)[l,4]oxazepin5(2H)-one (Π-57);

4-(pyrimidin-2-ylmeÜiyl)-7-(4-(trifluorômethyl)phenyl)-3,4dihydrobenzo[f|( 1,4}oxazepin-5(2H)-one (11-61 );

4-(4-fluorobenzyl )-7-(4-( trifluoromethoxy)phenyl)-3,4-dihydrobenzo|f[[l,4]oxazepin5(2H)-one (11-62);

4-(( 1-meihyl-I H-pyrazoI-3-yl)methyl)-7-(4-( trifluoromeÜioxy)phenyl)-3,4dihydrobenzo[f][ 1,4Joxazepin-5( 2H)-one (11-64);

4-((5-chloropyri nùdin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl )-3,4dîhydrobenzo[fH l,4Joxazepin-5(2H)-one (11-65);

4-(pyridin-4-y!merhyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dïhydrobenzo[f][ 1,4]oxazepin-5(2H)-one (11-67);

4-((5-cyclopropyl-l,3,4-oxadiazol-2-yi)niethyl)-744-(trifIuoromethoxy)phenyl)-3,4dihydrobenzo[f] [ 1,4 Jôx azepin-5( 2H)-one (11-68 );

4-(2-(pyrimidin-2-yloxy)ethyl)-7-(4-(trifIiioromelhoxy)phenyl )-3,4dihydrobenzo[f] [ 1,4]oxazepîn-5(2H)-one (11-69);

380

4-(pyridm-3-yimethyi)-7-(4-(trifluoromethoxy)phenyl)-3.4dihydrobenzo[f](l ,4]oxazepin-5(2H)-one (11-70);

4-( pyridin-2-ylmethy 1)-7-(4-(tri fl uorome thoxy lphenyl )-3,4dîhydrobenzo[f][ î .4]oxazepîn-5(2H)-one (11-72);

4-(pyrimidîn-2-ylmethyI)-7-(4-(trifluoromethoxy)phenyI)-3,4dihydrobenzo[fJ[l,4]oxazepin-5(2H)-one (11-73);

4-((3-methylpjridin-2-yl)melhyl)-7-(4-(lrifluorômethoxy)phenyi)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (11-75);

4-{pyiiniidin-2-ylniethyl)-7-p-tolyl-3,4-dil»ydrobenzo[f}[l,4]<»iazepin-5(2H)-one (11-87);

7-(4-ch!orophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f|[i,4]oxazepin-5(2H)one (11-88);

7-(4-isopropylphenyl)-4-(pyTinûdin-2-ylmeihyl>3_}4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-89);

7-(4-ethylphenyl )-4-( pyrimidin-2-ylinethyl)-3,4-dihydrobenzo[f| [ 1,4]oxazepin-5(2H)-one ( 11-91);

7-(4-cydopropylphenyl)-4-(pyrimidin-2-ylmelhyl)-3,4-dihydrobeiizo[f][l,4]oxazepiii5(2H)-one (11-92);

( R)-4-( 1 -( pyrimidin-2-yl)ethyl)-7-(4-Îtrifluoromethyl (phenyl )-3,4dihydrobenzo[f][l ,4]oxazepin-5(2H)-one (11-95);

7-(4-isobutoxyplienyl)-4-(pyrimidin-2-ylinethyl)-3,4-dihydrc)benzo[f|[l,4]oxazepin5(2H)-one (11-97);

7-(4-tert-butylphenyD-4-(p5Tiniidin-2-ylmethyl)-3,4-dih¥drobenzolf|[I_f4]oxazepin5(2H)-one (11-98);

7-(4-€yclopropoxj'phenyl)-4-(pyriniidÎn-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-102);

7-(4-fluorophenyl }-4-(pyriniidin-2-ylmethyl)-3,4-dihydrobenzo[f|[ 1,4]oxazepin-5(2H)one (11-104);

381

7-(2-iluoro-4-(trifluorümethyl)phenylM-(pyrinüdin-2-ylmethyl)-3,4dihydrobenzô[f][l,4]oxazepin-5(2H)-one (Π-105);

7-(3-nuoro-4-(2,2,2-trifluoroethoxy)phenyl)-4-(pjTimidin-2-ylmethyr)-3,4dihydrobenzo[f][l ,4]oxazepïn-5(2H)-one (11-106);

4-(pTOmidin-2-yIniethyr)-7-(4-(2,2,2-trïfluoroeth0xy)phenyI)-3,4dihydrobenzoffj [ 1,4]oxazepîn-5( 2H)-one (Π-107) ;

7-(2-chloro-4-(trinuoromethyl)phenyb-4-(pyrimidÎn-2-ylme!hv!i-3,4dîhydrobenzo[f][ 1,4]oxazepin-5(2H)-one (II-110);

7-(4-( trifluoromethoxy (phenyl )A-((4-(trifluoromethyl)pyrimidin-2-yl)methyl)-3,4dihydrobenzo(fJ[l,4joxazepin-5(2H)-one (Π-113);

7-(4-( trifluoromethoxy)phenyl)Y((5-(6-(trifluoromethyl)pyridm-3-yT)pyrirnidin-2yl)melhyl)-3,4-dihydrobenzo[fj( 1,4joxazepîn-5(2H)-one (II-115);

7-(4-chloro-2-fluorophenyl)-4-(pyriniidin-2-yimethyI)-3,4-dihydrobenzo[f][l,4]oxàzepin5(2H)-one (Π-117);

1 -(4-(5-oxo-4-( pyriinidin-2-ylmethyI)-2,3,4,5-tetrahydrobenzo[f|[ 1,4]oxazepin-7yi)phenyl)cyclopentanecarbonïtrile ( 11-122);

7-(4-ethoxyphenyr)-4-(pyrinüdin-2-ylinethyl )-3,4-dihydrobenzo[f][ 1,4]oxazepin-5(2H)one (11-123);

7-(4-(difluorômethyl)phenyl)-4-(pyrimïdin-2-ylmethyl)-3,4dihydrobenzo[f][l,4Joxazepin-5(2H)-one (H-124);

4-((4-morpholinopyTÎmidin-2-yr)methyl)-7-(4-(trifluOTomethoxy)phenyl)-3,4dihydrobenzo[fJ [1,4] oxazepin-5( 2H )-one (II-133) ;

4-benzyl-7-(4-(trifluoromethoxy)pheQyl)-3,4-dihydrôbenzo|f][l,4]oxazepni-5(2H)-one (11-134);

4-(imidazo[ 1,2-a]pyridin-2-ylmethyl)-7-(4-( trifluoroniethyl (phenyl)-3,4dihydrobenzo[f][ 1,4]uxazepin-5(2H)-one (H-135);

382

7-(3-fluoro-4-(trifluoromethyl Iphenyl )-4-(p yrimidin-2-ylme thyl )-3,4dihydrobenzo[f][ i ,4]oxazepin-5(2H)-one (11-136);

4-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifIuoronlethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4joxazepin-5(2H)-one (11-137);

4-((4-methylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1.4]oxazepin-5(2H)-one (11-138);

4-((4-(piperidin-1-yl)py'rimidin-2-yl)methyl)-7-(4-(trifluoromethoxy Jphenyl)-3,4dihydrobenzo[f](l ,4]oxazepin-5(2H)-one (11-139);

4-((4-(dimethyIâmino)pyrimidin-2-yl)methyl)-7-(4-(tiifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]o.xazepin-5(2H)-one (Π-140);

4-benzyl-7-(4-<trifluoromeihyl)ptenyl)-3,4-dihydrobenzo(f][l,4]oxazepin-5(2H)-one (11-141);

4-((3-methoxypyridin-2-yl)methyI)-7-(4-(trifluoromeÜioxy)phenyl)-3,4dihydrobenzo[f][ 1,4Jo.xazepin-5(2H)-one (11-143);

7-(4-(cyclobulylmethoxy)phenyl}-4-(pyrirnidin-2-ylmethyl)-3,4dihydrobenzo[f][ 1,41oxazepin-5(2H)-one (II-144);

7-(2-methyi-4-(tiîfloorûn»ediyl)phenyl)-4-(pyrimidm-2-ylmethyi )-3,4dïhydrobenzo[f][ 1,4]oxazepin-5(2H)-one (II-145);

7-(2-methyl-4-(ttifluoromeîhoxy)phenyl)-4-(pyrimidin-2-ylmethyl )-3,4dihydrobenzo[f][ 1,4]oxazépïn-5(2H)-one (11-146);

4-( ( 1-(di lluoromethyl )-1 H-pyrazol-3-yl)methyl)-7 44-( trifluoromethoxy (phenyl )-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-147);

7-(4-(trifluoromethoxy )phenyl)-4-((3-(trifluoromelhyl)-1 H-pyrazol-1 -yl)methyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (H-148);

4-(pyrïmidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroethyl)phenyl)-3,4dihydrobenzo[f] [ 1,4]oxazepin-5(2H )-one (II-150) ;

383

4-(pyridin-2-yImethyl)-7-( 4-(2.2»2-trifluoroethyl)phen¥l )-3,4dihydrobenzo[fj[ 1,4]ôxazepin-5(2H)-one (II-151);

4-(( 1 -cyclopentyl-1 H-pyrazol-3-yl)methyl>7-(4-(trifluoromelhoxy (phenyl )-3,4dïhydrobenzo[fj[ 1,4]oxazepin-5(2H)-one ( 11-152);

4-(( 1 -ethyl-1 H-pyrazol-3-yl )methy!)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo(f][ 1,4]oxazepin-5(2H)-one (II-153);

4-(( 1-methyl-1 H-imidazol-4-yl)methyI)-7-(4-(trifluoroniethoxy )phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-ône (11-154);

4-(I4-methyI-lH-p>Tazôl-l-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo(n[l,4]oxazepin-5(2H)-one (11-155);

4-((4-chloro-1 H-pyrazol-1 -yi)methyl )-7-(4-(trifluoromethoxy)phenyi)-3,4dihydrobenzo[f|| 1,4]oxazepîn-5(2H)-one (Π-156);

7-(4-(difluoromethyl )phenyl)-4-(pyridin-2-ylinethyl)-3,4-dihydrobenzo[f][ 1,4]oxazepin5(2H)-one (11-157);

7-44^hlonH3-fluorophenyl)-44pyridm-2-yiinethyl>3,4-dihydrobenzo[fl[l,4]oxazepin5(2H)-one (11-158);

7-(4-( difluoromethoxy)phenyl)-4-(pyridin-2-ylmethyl)-3,4dihydrobenzo[f][ k4|oxazepin-5(2H)-one (11-159);

4-(( 1 -methyl-1 H-pyrazol-4-yi)methyl>7-(4-(trifluOTûmethoxy)phenjd>3,4dihydrobenzo[f][ 1 _T4]oxazepin-5(2H)-one ( 11-160);

4-(pyrimidin-2-ylmethyl)-7-(23,4-trifliioroplienyl)-3,4-dihydrobenzo[f|[l,4]oxazepin5(2H)-one (11-162);

7-(3,4-difluorophenyl)-4-(pyrimidin-2-ylniethyl)-3,4-iiihj^rdrobenzo[f](l_ï4]oxazepin5(2H)-one (11-163);

4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3_t4dihydrobenzo[f][ 1,4]oxazepin-5(2H i-one (11-164);

384

4-benzyl-9-fl uoro-7 -(4-(trifluoromethoxy )phenyï)-3.4-dihydrobenzo [f] [ 1,4]oxazepin5(2H)-one ( Π-165);

4-benzyl-9-fluoro-7-(4-(trifluoromethyr)phenyl)-3_s4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (Π-166);

4-benzyl-8-fluoro-7-(4-( trifluoromethoxy )phenyl)-3₅4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-167);

4-benzy 1- 8-fl uoro-7 -(4-( irifluoromethy 1 )phenyl)-3 A-dihydrobenzof f] [ 1,4] oxazepin5(2H)-one (H-168);

7-(4-chloro-3-fluorophenyl)-4-((3-fluorop}ridin-2-yl)methyI)-3,4dihydrobenzo[f| [ 1,4]oxazepin-5( 2H )-one (II-169) ;

7-(2-fluoro-4-(trifluoromethyl)phenj4)-4-((3-fluoropyridin-2-yl)methyI)-3,4dihydrobenzo[f)[ 1,4joxazepin-5(2H)-one (U-170);

4-(5-oxo-4-(pyrimidin-2-ylmethyl)-2_t3.4J-tetrdhydrobenzo[f][l,4]oxazepin-7-ynphenyl tri Huoromethanesulfonate (Ή-171);

4-((5-methylpyrarin-2-yl)niethyl)-7~(Ή( trifluoromethoxy )phenyl)-3,4dihydrobenzo[f]( 1,4]oxazepin-5(2H j-one (II-172);
2,2.
3,3-tetradeutero-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1.4]oxazepin-5(2H)-one (II-174);
4-( ( 6-methylpyrazin-2-yl) methyl )-7-(4-(trïfluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-175);

4-((3-fluoropyridin-2-yl)methyl)-7-(4-( trifluoromethyl)phenyl)-3,4dihydrobenzo[f][L4]oxazepin-5(2H)-one (Π-176);

N-(2-(5-oxo-7-(4-(trifluôromethoxy (phenyl )-2_s3-dihydrôbenzo[fj[ 1,4]Dxazepin-4(5H)yl)ethyl)benzenesulfonamide (11-177);

N-(2-(5-oxo-7-(4-( trifluoromethoxy (phenyl )-2,3-dîhydrobenzo[f][l,4]oxazepin-4(5H)yl)ethyl)cyclopropanesulfonamide (11-179);

385

4-(( l-methyl-lH-imidazol-2-yl)methyl)-7-(4-(trifluôromethoxy)phenyr}-3,4dihydrobenzo[f][ 1,4|oxazepin-5(2H)-one (II-186) ;

4-« 1 -benzyl-1 H-imidazol-2-yl)methy!)-7-(4-( trifluoromethoxy)phenyl)-3,4dihydrobenzo(fj[l ,4]oxazepm-5(2H)-one (II-187);

4-(imidazo[ 1,2-a]pyridm-2-ylmethyl)-7-(4-( trifluoromethoxy)phenyD-3,4dihydrobenzo[f][l,4]oxazepm-5(2H)-one (H-189);

N-cyciopropyl-3-(5-oxo-7-(4-(trifluôKMnethoxy)phenyl)-23dihydrobenzo[f][i,4]oxazepm4(5H)-yl)propane-l-sulfonamide (11-190);

N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyI)-2,3-dihydrobenzo[f][ 1,4]oxazepin-4(5H)yl)ethyl)pyrimîdine-2-carboxamide (Π-192);
7-(4-(4-fluorophenoxy)phenyl)-4-(pyrimidin-2-ylniethyl )-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (II-193);

7-(4-phenoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f) [ 1,4]oxazepin-5(2H)one (11-194); and

7-(3-phenoxyphenyl>Mpyriinidin-2-ylmethyl>3,4-dihydrobeiizo[f)[l,4}oxazepin-5(2H)one (H-195);

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
10. The compound of claim 1 having the structure.

or a pharmaceutically acceptable sait thereof;

a compound having the structure:

386

or a pharmaceutically acceptable sait thereof;

a compound having the structure:

or a pharmaceutically acceptable sait thereof;

a compound having the structure:

or a pharmaceutically acceptable sait thereof;

a compound having the structuré:

or a pharmaceutically acceptable sait thereof;

a compound having the structure;

a compound having the structure:

387

IL The compoundof claim 1 having the structure:
12. The compound of claim 1 having the structure:
13. A phannaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of any one of claims 1-12 or a pharmaceutically acceptable sait thereof.
14. A compound of any one of claims 1-12 or a pharmaceutically acceptable sait thereof for use in therapy; preferably for use in treating a disease State in a human that is alleviable by treatment with an agent capable of reducing late sodium current.
15. The compound for use according to claim 14, wherein the disease state is selected from the group consisting of atrial arrhythmias, ventricular arrhythmias, heart failure. diastolic heart failure, systolic heart failure, acute heart failure, stable angina, unstable angina, exercise induced angina. congestive heart disease, ischemia, récurrent ischemia, reperfusion injury. myocardial infarction, acute coronary syndrome, peripheral arterial disease, pulmonary hypertension and intermittent claudication; or wherein the disease state is diabètes or diabetic peripheral neuropathy; or wherein the disease state results in one or more of neuropathie pain, epilepsy, migraine, seizures or paralysïs.

388
16. A composition comprising a compound of any of claims 1 to 12 in combination with at least one therapeutic agent.
17. The composition according to claim 16 for use in therapy, preferably for use in treating cardiovascuiar related diseases or conditions, preferably angina including stable angina, unstable angina, exercise induced angina, variant angina, arrhythmias, intermittent claudication, myocardial infarction including non-STE myocardial infarction, pulmonary hypertension including pulmonary artërial hypertension, heart failure including congestive heart failure and diastolic heat failure and heart failure with preserved éjection fraction, acute heart failure or récurrent ischemia.
18. The composition according to daim 16 or the composition for use according to daim 17, wherein the other therapeutic agent is selected from the group consisting of anti-anginals. heart failure agents, antithrombotic agents, antiarrhythniic agents, antihypertensive agents and lipid lowering agents.

389