CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 62/412,720, filed October 25, 2016 and U.S. Provisional Application Serial No. 62/396,734, filed September 19, 2016. The disclosure of each of the prior applications is considered part of, and is hereby incorporated by reference in its entirety, in the disclosure of this application.

FIELD

[0002] Provided herein are methods of treating diseases using a combination therapy for treatment of a proliferative disease, including a cancer, an autoimmune disease and an inflammatory disease. In certain embodiments, the methods comprise administering an effective amount of a phosphoinositide -3 -kinase (PI3K) inhibitor and an effective amount of a second agent selected from a Bruton tyrosine kinase (BTK) inhibitor, a Bcl-2 inhibitor, EZH2 inhibitor or a combination thereof to a patient.

BACKGROUND OF THE INVENTION

[0003] Phosphoinositide-3-kinases (PBKs) play a variety of roles in normal tissue physiology (Foukas & Shepherd, Biochem. Soc. Trans. 2004, 32, 330; Shepherd, Acta Physiol. Scand. 2005, 183, 3), with pi 10a having a specific role in cancer growth, pi 10β in thrombus formation mediated by integrin α _π β ₃ (Jackson et al. , Nat. Med. 2005, 11, 507), and pl lOy, in inflammation, rheumatoid arthritis, and other chronic inflammation states (Barber et al., Nat. Med. 2005, 11, 933; Camps et al. , Nat. Med. 2005, 11, 936; Rommel et al , Nat. Rev. 2007, 7, 191; and Ito, et al. , J. Pharm. Exp. Therap. 2007, 321, 1). Inhibitors of PI3K have therapeutic potential in the treatment of various proliferative diseases, including cancer.

[0004] The Bruton 's tyrosine kinase (BTK) inhibitors are a class of drugs that inhibit Bruton tyrosine kinase (BTK), a member of the Tec family of kinases with a very distinct role in B-cell antigen receptor (SCR) signaling.

[0005] There continues to be a need for development of effective dosages and dosing regimens for administering PI3K inhibitors and BTK inhibitors in combination with a second agent in treating, preventing and managing various proliferative diseases, including cancers, autoimmune diseases and/or inflammatory diseases.

SUMMARY OF THE DISCLOSURE INVENTION

[0006] Disclosed herein is a method for treating or preventing a disease, comprising administering to a patient in need thereof:

(i) an effective amount of a compound of Formula (I) :

Formula (I),

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

X, Y, and Z are each independently N or CR ^X , with the proviso that at least two of X, Y, and Z are nitrogen atoms; where R ^x is hydrogen or Ci_ ₆ alkyl;

R ¹ and R ² are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , - OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , - NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , - NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or - S(0) ₂ NR ^lb R ^lc ; wherein each R ^la , R ^lb , R ^lc , and R ^ld is independently (i) hydrogen; (ii) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R ^lb and R ^lc together with the N atom to which they are attached form heterocyclyl;

R ³ and R ⁴ are each independently hydrog en or Ci_6 alkyl; or R ³ and R ⁴ are linked together to form a bond, Ci_ ₆ alkylene, Ci_ ₆ heteroalkylene, C ₂ _ ₆ alkenylene, or

C ₂ _6 heteroalkenylene;

R ^5a is (a) hydro gen or halo; (b) Ci_ _¾ alkyl, C ₂ _ _¾ alkenyl, C ₂ _ _¾ alkynyl, C ₃ _io cycloalkyl, C¾_i4 aryl, C ₇ _ ₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , -C(0)NR ^lb R ^lc , - C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , -OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , - OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , -NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , - NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , -NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , - NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or -S(0) ₂ NR ^lb R ^lc ;

R ^5b is (a) halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , - OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , -OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , - OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , -NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , - NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , -NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , - S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or -S(0) ₂ NR ^lb R ^lc ; R ^5c is -(CR ^5f R ^5g )„-(C ₆ _ ₁₄ aryl) or -(CR ^5f R ^5g )„-heteroaryl;

R ^5d and R ^5e are each independently (a) hydrogen or halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , - OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , - NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , - NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or - S(0) ₂ NR ^lb R ^lc ;

R ^5f and R ^5g are each independently (a) hydrogen or halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , - OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , - NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , - NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc ; or - S(0) ₂ NR ^lb R ^lc ; or (d) when one occurrence of R ^5f and one occurrence of R ^5g are attached to the same carbon atom, the R ^5f and R ^5g together with the carbon atom to which they are attached form a C ₃ _i ₀ cycloalkyl or heterocyclyl;

R ⁶ is hydrogen, Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -S(0)-Ci_ ₆ alkyl, or -S0 ₂ -Ci_ ₆ alkyl;

m is 0 or 1 ; and

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

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^x , R ^la , R ^lb , R ^lc , R ^ld , R ^5a , R ^5b , R ^5c , R ^5d , R ^5e , R ^5f , and R ^5g is optionally substituted with one, two, three, four, or five substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one, two, three, or four, substituents Q ^a ; and (c) - C(0)R ^a , -C(0)OR ^a , -C(0)NR ^b R ^c , -C(NR ^a )NR ^b R ^c , -OR ^a , -OC(0)R ^a , -OC(0)OR ^a , -OC(0)NR ^b R ^c , - OC(=NR ^a )NR ^b R ^c , -OS(0)R ^a , -OS(0) ₂ R ^a , -OS(0)NR ^b R ^c , -OS(0) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C(0)R ^d , - NR ^a C(0)OR ^d , -NR ^a C(0)NR ^b R ^c , -NR ^a C(=NR ^d )NR ^b R ^c , -NR ^a S(0)R ^d , -NR ^a S(0) ₂ R ^d , -NR ^a S(0)NR ^b R ^c , - NR ^a S(0) ₂ NR ^b R ^c , -SR ^a , -S(0)R ^a , -S(0) ₂ R ^a , -S(0)NR ^b R ^c , and -S(0) ₂ NR ^b R ^c , wherein each R ^a , R ^b , R ^c , and R ^d is independently (i) hydrogen; (ii) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _ _i4 aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one, two, three, or four, substituents Q ^a ; or (iii) R ^b and R ^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one, two, three, or four, substituents Q ^a ;

wherein each Q ^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _ _i4 aryl, C ₇ _ _i5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)R ^e , -C(0)OR ^e , -C(0)NR ^f R ^g , -C(NR ^e )NR ^f R ^g , -OR ^e , - OC(0)R ^e , -OC(0)OR ^e , -OC(0)NR ^f R ^g , -OC(=NR ^e )NR ^f R ^g , -OS(0)R ^e , -OS(0) ₂ R ^e , -OS(0)NR ^f R ^g , - OS(0) ₂ NR ^f R ^g , -NR ^f R ^g , -NR ^e C(0)R ^h , -NR ^e C(0)OR ^h , -NR ^e C(0)NR ^f R ^g , -NR ^e C(=NR ^h )NR ^f R ^g , - NR ^e S(0)R ^h , -NR ^e S(0) ₂ R ^h , -NR ^e S(0)NR ^f R ^g , -NR ^e S(0) ₂ NR ^f R ^g , -SR ^e , -S(0)R ^e , -S(0) ₂ R ^e , -S(0)NR ^f R ^g , and -S(0) ₂ NR ^f R ^g ; wherein each R ^e , R ^f , R ^g , and R ^h is independently (i) hydrogen; (ii) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R ^f and R ^g together with the N atom to which they are attached form heterocyclyl;

wherein two substituents Q that are adjacent to each other optionally form a C3_io cycloalkenyl, C ₆ _i ₄ aryl, heteroaryl, or heterocyclyl, each optionally substituted with one, two, three, or four substituents Q ^a ; and

(ii) an effective amount of a second agent selected from a BTK inhibitor, a Bcl-2 inhibitor, an EZH2 inhibitor, or any combination thereof to a patient, wherein the disease is cancer, an autoimmune disease, or an inflammatory disease.

[0007] In some embodiments, R ^5b is (a) halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _ ₁₄ aryl, C ₇ _ ₁₅ aralkyl, or heteroaryl; or (c) -C(0)R ^la , -C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , - OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , -OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , - OS(0)NR ^lb R ^lc , -S(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , -NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , - NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , -NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , - S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or -S(0) ₂ NR ^lb R ^lc .

[0008] In some embodiments, R ^5a and R ^5b are each independently (a) halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ 6 alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , - C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , - OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , - NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , - NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or - S(0) ₂ NR ^lb R ^lc .

[0009] In some embodiments, R ^5a and R ^5b are each methyl, optionally substituted with one, two, or three halo(s). In some embodiments, n is 1. In some embodiments, n is 1 and R ^5f and R ^5g are each hydrogen. In some embodiments, n is 0. In some embodiments, m is 0.

[0010] Synthesis of compounds of Formula (I) is described in US Patent No. 9,056,852 B2, which is incorporated by reference for such disclosure.

[0011] In some embodiments, the compound of Formula (I) is of Formula (XI):

Formula (XI)

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R ^a , R , R ^c , R , and R ^e are each independently (a) hydrogen, cyano, halo, or nitro; (b)

Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ . _u aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; or (c) -C(0)R ^a , - C(0)OR ^a , -C(0)NR ^b R ^c , -C(NR ^a )NR ^b R ^c , -OR ^a , -OC(0)R ^a , -OC(0)OR ^a , -OC(0)NR ^b R ^c , - OC(=NR ^a )NR ^b R ^c , -OS(0)R ^a , -OS(0) ₂ R ^a , -OS(0)NR ^b R ^c , -OS(0) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C(0)R ^d , - NR ^a C(0)OR ^d , -NR ^a C(0)NR ^b R ^c , -NR ^a C(=NR ^d )NR ^b R ^c , -NR ^a S(0)R ^d , -NR ^a S(0) ₂ R ^d , -NR ^a S(0)NR ^b R ^c , - NR ^a S(0) ₂ NR ^b R ^c , -SR ^a , -S(0)R ^a , -S(0) ₂ R ^a , -S(0)NR ^b R ^c , or -S(0) ₂ NR ^b R ^c ; or

two of R ^a , R , R , R , and R ^e that are adjacent to each other form

C3-10 cycloalkenyl, C ₆ _i ₄ aryl, heteroaryl, or heterocyclyl, each optionally substituted with one, two, three, or four substituents Q ^a .

[0012] Synthesis of compounds of Formula (XI) is described in US Patent No. 9,056,852 B2, which is incorporated by reference for such disclosure

[0013] In some embodiments, the compound of Formula (I) is Compound I:

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0014] In some embodiments, the compound of Formula (I) is Compound II:

Compound II

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0015] In some embodiments, the compound of Formula (I) is Compound III:

Compound III

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0016] In some embodiments, the compound of Formula (I) is Compound IV:

Compound IV

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0017] In some embodiments, the compound of Formula (I) is Compound V:

Compound V

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0018] In some embodiments, the compound of Formula (I) is Compound VI:

Compound VI

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0019] In some embodiments, the compound of Formula (I) is Compound VII:

Compound VII

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0020] In some embodiments, the compound of Formula (I) is Compound VIII:

Compound VIII

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0021] In some embodiments, the c ound IX:

Compound IX

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0022] In some embodiments, the compound of Formula (I) is Compound X:

Compound X

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0023] In some embodiments, the second agent is a BTK inhibitor. In some embodiments, the second agent is a BTK inhibitor selected from ibrutinib, BGB3111, CC-292, ACP 196, CNX-774, CGI 1746, LFM-A13, CNX-774, ONO-4059, RN486 CPI-0610, DUAL946, GSK525762, 1-BET151, JQl, OTX015, PFI-1, RVX-208, RVX2135, TEN-010, and a combination thereof. In some embodiments, the second agent is a BTK inhibitor selected from ibrutinib and BGB3111. In another embodiment, the second agent is the BTK inhibitor, ibrutinib. In yet another embodiment, the second agent is the BTK inhibitor BGB3111. In some embodiments, the second agent is a Be 1 -2 inhibitor. In some embodiments, the second agent is a Be 1-2 inhibitor selected from venetoclax and PNT2258. In some embodiments, the second agent is an EZH2 inhibitor. In some embodiments, the second agent is the EZH2 inhibitor tazemetostat.

[0024] In some embodiments, the disease treated is cancer. In some embodiments, the cancer being treated is chronic lymphocytic leukemia or non-Hodgkin's lymphoma. In some embodiments, the cancer being treated is non-Hodgkin's lymphoma and the non-Hodgkin's lymphoma is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the diffuse large B-cell lymphoma is of the activated B-cell (ABC DLBCL) or Germinal center B-cell (GCB DLBCL).

INCORPORATION BY REFERENCE

[0025] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0027] FIG. 1 illustrates % growth inhibition vs. concentration of compound I in DB cells as measured in ATPLite assay.

[0028] FIG. 2 illustrates % growth inhibition vs. concentration of compound I in DOHH-2 cells as measured in ATPLite assay.

[0029] FIG. 3 illustrates % growth inhibition vs. concentration of compound I in HT cells as measured in ATPLite assay.

[0030] FIG. 4 illustrates % growth inhibition vs. concentration of compound I in NU-DHL-1 cells as measured in ATPLite assay.

[0031] FIG. 5 illustrates % growth inhibition vs. concentration of compound I in OCI-Lyl9 cells as measured in ATPLite assay.

[0032] FIG. 6 illustrates % growth inhibition vs. concentration of compound I in OCI- Ly3 cells as measured in ATPLite assay.

[0033] FIG. 7 illustrates % growth inhibition vs. concentration of compound I in Pfeiffer cells as measured in ATPLite assay.

[0034] FIG. 8 illustrates % growth inhibition vs. concentration of compound I in SU-DHL-10 cells as measured in ATPLite assay.

[0035] FIG. 9 illustrates growth inhibition (GI ₅₀ ) for compound I in the tested cell lines.

[0036] FIG. 10 illustrates % growth inhibition for compound I in the tested cell lines. DETAILED DESCRIPTION OF THE INVENTION

[0037] Described herein are pharmaceutical compositions comprising i) a PI3K inhibitor; and ii) a BTK inhibitor, a Bcl-2 inhibitor, an EZH2 inhibitor, or any combination thereof. In some instances, the pharmaceutical compositions described herein may be used for treating diseases or disorders such as cancer, an autoimmune disease, or an inflammatory disease. Also described herein are methods of treating the diseases and disorders such as cancer, an autoimmune disease, or an inflammatory disease with a combination of i) a PI3K inhibitor, and; ii) a BTK inhibitor, a Bcl-2 inhibitor, an EZH2 inhibitor, or any combination thereof.

[0038] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0039] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. DEFINITIONS

[0040] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in one embodiment, a human.

[0041] The terms "treat," "treating," and "treatment" are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.

[0042] The terms "prevent," "preventing," and "prevention" are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.

[0043] The terms "therapeutically effective amount" and "effective amount" are meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The terms "therapeutically effective amount" or "effective amount" also refer to the amount of a compound that is sufficient to elicit the biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0044] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," and "physiologically acceptable excipient" refer to a

pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al , Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and

Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009.

[0045] The terms "about" and "approximately" mean an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the terms "about" and "approximately" mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0046] The terms "active ingredient" and "active substance" refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition. As used herein, "active ingredient" and "active substance" may be an optically active isomer of a compound described herein.

[0047] The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition.

[0048] The terms "naturally occurring" and "native" when used in connection with biological materials such as nucleic acid molecules, polypeptides, host cells, and the like, refer to materials which are found in nature and are not manipulated by man. Similarly, "non-naturally occurring" or "non-native" refers to a material that is not found in nature or that has been structurally modified or synthesized by man.

[0049] The term "PI3K" refers to a phosphoinositide 3-kinase or variant thereof, which is capable of phosphorylating the inositol ring of PI in the D-3 position. The term "PI3K variant" is intended to include proteins substantially homologous to a native PI3K, i.e., proteins having one or more naturally or non- naturally occurring amino acid deletions, insertions, or substitutions (e.g., PI3K derivatives, homologs, and fragments), as compared to the amino acid sequence of a native PI3K. The amino acid sequence of a PI3K variant is at least about 80% identical, at least about 90% identical, or at least about 95% identical to a native PI3K. Examples of PI3K include, but are not limited to, p i 10a, p i 10β, p i 10δ, p i 10γ, PI3K-C2a, PI3K-C2P, PI3K-C2y, Vps34, mTOR, ATM, ATR, and DNA-PK. See, Fry, Biochem. Biophys. Acta 1994, 1226, 237-268; Vanhaesebroeck and Waterfield, Exp. Cell. Res. 1999, 253, 239-254; and Fry, Breast Cancer Res. 2001, 3, 304-312. PI3Ks are classified into at least four classes. Class I includes pi 10a, p l lOp, ρΐ ΐθδ, and p i 10γ. Class II includes PI3K-C2a, PI3K-C2P, and PI3K-C2y. Class III includes Vps34. Class IV includes mTOR, ATM, ATR, and DNA-PK. In certain embodiments, the PI3K is a Class I kinase. In certain embodiments, the PI3K is pi 10a, pi 10β, pi 10δ, or pi 10γ. In certain embodiments, the PI3K is a variant of a Class I kinase. In certain embodiments, the PI3K is a pi 10a mutant. Examples of pi 10a mutants include, but are not limited to, R38H, G106V, Kl 1 IN, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, E453Q, H710P, I800L, T1025S, M10431, M1043V, H1047L, H1047R, and H1047Y (Ikenoue et al , Cancer Res. 2005, 65, 4562-4567; Gymnopoulos et al , Proc. Natl. Acad Sci. , 2007, 104, 5569-5574). In certain embodiments, the PI3K is a Class II kinase. In certain embodiments, the PI3K is PI3K-C2a, PI3K- C2p, or PI3K-C2y. In certain embodiments, the PI3K is a Class III kinase. In certain embodiments, the PI3K is Vps34. In certain embodiments, the PI3K is a Class IV kinase. In certain embodiments, the PI3K is mTOR, ATM, ATR, or DNA-PK.

[0050] As used herein, "BTK" refers to Bruton's tyrosine kinase. BTK belongs to the Tec tyrosine kinase family (Vetrie et al , Nature 361 : 226-233, 1993; Bradshaw, Cell Signal. 22: 1175-84, 2010). BTK is primarily expressed in most hematopoietic cells such as B cells, mast cells and macrophages (Smith et al, J. Immunol. 152: 557-565, 1994) and is localized in bone marrow, spleen and lymph node tissue. BTK plays important roles in B-cell receptor (BCR) and FcR signaling pathways, which involve in B-cell development, differentiation (Khan, Immunol. Res. 23: 147, 2001. The BTK inhibitor may be selected from the compounds disclosed in US Patent Nos. 8,084,620B2; 7,514,444B2; 7,718,662B1; and

7,393,848B 1; US Publication Nos. 2016/0083392A1; 2015/0005277A1; 2015/0259354A1;

2012/053189A1; 2010/254905A1; 2008/0139582A1; 2012/0077832A1; 2012/0232054A1;

2012/082702A1; 2010/0160303A1, 2012/129852A1; 2006/0178367A1; 2006/0183746A1;

2012/040961A1; 2010/144705A1; 2012/0028981A1; 2012/058996A1; 2009/0318448A1;

2010/0016301A1; 2009/105209A1; 2010/0222325A1; and 2010/0004231 Al; International Publication Nos. WO 2011/153514; WO 2011/046964; WO 2010/009342; WO 2008/121742; WO 2008/054827; WO 2007/087068; WO 2011/090760; WO 2010/028236; WO 2009/158571; WO 2009/051822, WO

2010/123870; WO 2010/126960; WO 2011/162515; WO 2012/135801; WO 2011/152351; WO

2007/136790A2; WO 2002/050071; WO 2008/116064; WO 2010/011837; WO 2011/159857,. WO 2011/019780, WO 2011/029043; WO 2011/029046; WO 2005/005429; WO 2005/014599; WO

2005/047290; WO 2006/053121; WO 2008/033834; WO 2008/033858; WO 2006/099075; WO

2008/033854; WO 2008/033857; WO 2009/039397, WO 2009/137596; WO 2010/056875; WO

2010/068788; WO 2010/068806; WO 2010/068810, WO 2011/140488; WO 2012/030990; WO

2012/031004; WO 2005/011597; WO 2008/045627; WO 2008/144253, WO 2007/140222, WO

2013/008095, WO 2012/170976A2, WO 2012/135944A1; WO 2010/065898A2; WO 2012/158795A1; WO 2012/158764A1; WO 2012/158810A1; WO 2012156334A1; WO 2012020008; WO 2010122038; WO 2010006970; WO 2010006947; WO 2010000633; WO 2009077334; WO 2009098144, WO

2006065946; WO 2007027594; WO 2007027729 and EP2068849. The BTK inhibitor may also be selected from ibrutinib, BGB3111, CC-292 (AVL-292), ACP 196 (Acalabrutinib), CNX-774, CGI1746, LFM-A13, CNX-774, ONO-4059, RN486 CPI-0610, DUAL946, GSK525762, 1-BET151, JQ1, OTX015, PFI-1, RVX-208, RVX2135, TEN-010, and a combination thereof. In one embodiment, the BTK inhibitor is ibrutinib or BGB3111.

[0051] As used herein "Bcl-2" refers to B-cell lymphoma 2, an anti-apoptotic protein that has been implicated in numerous types of cancers including chronic lymphocytic leukemia, melanoma, breast, prostate and lung carcinomas. In one embodiment, the Bcl-2 inhibitor is ABT-199 (venetoclax), ABT- 737, ABT-263 (navitoclax), or PNT2258. In another embodiment, the Bcl-2 inhibitor is venetoclax or PNT2258.

[0052] As used herein "EZH2" refers to enhancer of zeste homolog 2, which is a histone-lysine N- methyltransferase enzyme (EC 2.1.1.43) encoded by EZH2 gene, that participates in DNA methylation and, ultimately, transcriptional repression. Mutation or over-expression of EZH2 has been linked to many to forms of cancer. In one embodiment, the EZH2 inhibitor is EPZ-6438 (tazemetostat, E7438), DNZeP (3-Deazaneplanocin), GSK2816126, EPZ005687 or Ell . In another embodiment, the EZH2 inhibitor is tazemetostat (EPZ-6438).

[0053] The terms "synergy," "synergism," and "synergistic" as used herein refer to a combination of therapies (e.g., use of a PI3K inhibitor of Formula (I) and a BTK inhibitor, a Bcl-2 inhibitor, an EZH2 inhibitor or any combination thereof) that is more effective than the expected additive effects of any two or more single therapies. For example, a synergistic effect of a combination of therapies permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject. The ability to utilize lower dosages of therapies and/or to administer the therapies less frequently reduces the toxicity associated with the administration of the therapies to a subject without reducing the efficacy of said therapies in the prevention, management, treatment, or amelioration of a given disease, such as an autoimmune disease, inflammatory disease, or cancer including, but not limited to, chronic lymphocytic leukemia or non-Hodgkin's lymphoma. In addition, a synergistic effect can result in improved efficacy of therapies in the prevention, management, treatment, or amelioration of a given disease, such an autoimmune disease, inflammatory disease, or cancer i, but not limited to, chronic lymphocytic leukemia or non-Hodgkin's lymphoma. Finally, synergistic effects of a combination of therapies may avoid or reduce adverse or unwanted side effects associated with the use of any single therapy. The "synergy," "synergism," or "synergistic" effect of a combination may be determined herein by the methods of Chou et al., and/or Clarke et al. See Ting-Chao Chou, Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies, Pharmacol Rev 58:621-681 (2006), and Clarke et al., Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models, Breast Cancer Research and Treatment 46:255-278 (1997), which are both incorporated by reference for the methods of determining the "synergy," synergism," or "synergistic" effect of a combination.

[0054] The term "isotopic variant" refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 2 3 11 12 13

H), deuterium ( H), tritium ( H), carbon-1 1 ( C), carbon-12 ( C), carbon-13 ( C), carbon-

14 ( ¹⁴ C), nitrogen-13 ( ¹ N), nitrogen-14 ( ¹⁴ N), nitrogen-15 ( ¹⁵ N), oxygen-14 ( ¹⁴ 0), oxygen-15 ( ¹⁵ 0), oxygen-16 ( ¹⁶ 0), oxygen-17 ( ¹⁷ 0), oxygen-18 ( ¹⁸ 0), fluorine-17 ( ¹⁷ F), fluorine-18 ( ¹⁸ F), phosphorus-31 ( ¹ P), phosphorus-32 ( ² P), phosphorus-33 ( P), sulfur-32 ( ² S), sulfur-33 ( S), sulfur-34 ( ⁴ S), sulfur-35 ( ⁵ S), sulfur-36 ( ⁶ S), chlorine-35 ( ⁵ C1), chlorine-36 ( ⁶ C1), chlorine-37 ( ⁷ C1), bromine-79 ( ⁷⁹ Br), bromine-81 ( ⁸¹ Br), iodine-123 ( ¹² I), iodine-125 ( ¹²⁵ I), iodine-127 ( ¹²⁷ I), iodine-129 ( ¹²⁹ I), and iodine-13 1 ( ^{1 1} I). In certain embodiments, an "isotopic variant" of a compound is in a stable form, that is, nonradioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (¾), deuterium ( ² H), carbon-12 ( ¹² C), carbon-13 ( ¹ C), nitrogen-14 ( ¹⁴ N), nitrogen-15 ( ¹⁵ N), oxygen-16 ( ¹⁶ 0), oxygen-17 ( ¹⁷ 0), oxygen-18 ( ¹⁸ 0), fluorine-17 ( ¹⁷ F), phosphorus-3 1 ( ¹ P), sulfur-32 ( ² S), sulfur-33 ( S), sulfur-34 ( ⁴ S), sulfur-36 ( ⁶ S), chlorine-35 ( ⁵ C1), chlorine-37 ( ⁷ C1), bromine-79 ( ⁷⁹ Br), bromine-81 ( ⁸¹ Br), and iodine-127 ( ¹²⁷ I). In certain embodiments, an "isotopic variant" of a compound is in an unstable form, that is, radioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium ( 3

H), carbon 11 14 13

-1 1 ( C), carbon-14 ( C), nitrogen-13 ( N), oxygen-14 ( ¹⁴ 0), oxygen-15 ( ¹⁵ 0), fluorine-18 ( ¹⁸ F), phosphorus-32 ( ² P), phosphorus-33 ( P), sulfur-35 ( ⁵ S), chlorine-36 ( ⁶ C1), iodine-123 ( ¹² I), iodine-125 ( ¹²⁵ I), iodine-129 ( ¹²⁹ I), and iodine-13 1 ( ^{1 1} I). It will be understood that, in a compound as provided herein, any hydrogen can be ² H, for example, or any carbon can be ¹ C, for example, or any nitrogen can be ¹⁵ N, for example, or any oxygen can be ¹⁸ 0, for example, where feasible according to the judgment of one of skill. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of deuterium (D).

[0055] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkylene may optionally be substituted with one or more substituents Q as described herein. The term "alkyl" also encompasses both linear and branched alkyl, unless otherwise specified. In certain embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (Ci_ ₂ o), 1 to

15 (Ci_i ₅ ), 1 to 10 (Ci_io), or 1 to 6 (Ci_ ₆ ) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C ₃ _ ₂ o), 3 to 15 (C ₃ _i ₅ ), 3 to 10 (C ₃ _i ₀ ), or 3 to 6 (C ₃ _ ₆ ) carbon atoms. As used herein, linear Ci_ ₆ and branched C ₃ _ ₆ alkyl groups are also referred as "lower alkyl." Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), ^-propyl, isopropyl, butyl (including all isomeric forms), «-butyl, isobutyl, sec-butyl, /-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms). For example, Ci_ ₆ alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.

[0056] The term "alkylene" refers to a linear or branched saturated divalent hydrocarbon radical, wherein the alkylene may optionally be substituted with one or more substituents Q as described herein. The term "alkylene" encompasses both linear and branched alkylene, unless otherwise specified. In certain embodiments, the alkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (Ci_ ₂ o), 1 to 15 (Ci-15), 1 to 10 (Ci-10), or 1 to 6 (Ci_ ₆ ) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C ₃ - ₂₀ ), 3 to 15 (C3-15), 3 to 10 (C ₃ _i ₀ ), or 3 to 6 (C ₃ _ ₆ ) carbon atoms. As used herein, linear Ci_ ₆ and branched C ₃ _ ₆ alkylene groups are also referred as "lower alkylene." Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene (including all isomeric forms), n- propylene, isopropylene, butylene (including all isomeric forms), «-butylene, isobutylene, 7-butylene, pentylene (including all isomeric forms), and hexylene (including all isomeric forms). For example, Ci_6 alkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms.

[0057] The term "heteroalkylene" refers to a linear or branched saturated divalent hydrocarbon radical that contains one or more heteroatoms each independently selected from O, S, and N in the hydrocarbon chain. For example, Ci_ ₆ heteroalkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (Ci_ ₂ o), 1 to 15 (Ci_i ₅ ), 1 to 10 (Ci_io), or 1 to 6 (Ci_ ₆ ) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C ₃ _ ₂ o), 3 to 15 (C ₃ _ _i5 ), 3 to 10 (C ₃ _i ₀ ), or 3 to 6 (C ₃ _ ₆ ) carbon atoms. As used herein, linear Ci_ ₆ and branched C ₃ _ ₆ heteroalkylene groups are also referred as "lower heteroalkylene." Examples of heteroalkylene groups include, but are not limited to, -CH ₂ 0-, -CH ₂ OCH ₂ -, -CH ₂ CH ₂ 0-, -CH ₂ NH-, -CH ₂ NHCH ₂ - -CH ₂ CH ₂ NH- -CH ₂ S- -CH ₂ SCH ₂ - and -CH ₂ CH ₂ S-. In certain embodiments, heteroalkylene may also be optionally substituted with one or more substituents Q as described herein.

[0058] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon- carbon double bond(s). The alkenyl may be optionally substituted with one or more substituents Q as described herein. The term "alkenyl" also embraces radicals having "cis" and "trans" configurations, or alternatively, "Z" and "E" configurations, as appreciated by those of ordinary skill in the art. As used herein, the term "alkenyl" encompasses both linear and branched alkenyl, unless otherwise specified. For example, C ₂ _ ₆ alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C ₂ _ ₂₀ ), 2 to 15 (C ₂ _ _i5 ), 2 to 10 (C ₂ _io), or 2 to 6 (C ₂ _ ₆ ) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C ₃ _ ₂₀ ), 3 to 15 (C ₃ _i ₅ ), 3 to 10 (C ₃ _io), or 3 to 6 (C ₃ _ ₆ ) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propen-l -yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.

[0059] The term "alkenylene" refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon- carbon double bond(s). The alkenylene may be optionally substituted with one or more substituents Q as described herein. Similarly, the term "alkenylene" also embraces radicals having "cz ^' s" and "trans" configurations, or alternatively, "E" and "Z" configurations. As used herein, the term "alkenylene" encompasses both linear and branched alkenylene, unless otherwise specified. For example, C ₂ _ ₆ alkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C ₂ - ₂₀ ), 2 to 15 (C ₂ - ₁₅ ), 2 to 10 (C ₂ -io), or 2 to 6 (C ₂ _ ₆ ) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C ₃ _ ₂₀ ), 3 to 15 (C ₃ _i ₅ ), 3 to 10 (C ₃ _i ₀ ), or 3 to 6 (C ₃ _ ₆ ) carbon atoms. Examples of alkenylene groups include, but are not limited to, ethenylene, allylene, propenylene, butenylene, and 4-methylbutenylene.

[0060] The term "heteroalkenylene" refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon-carbon double bond(s), and which contains one or more heteroatoms each independently selected from O, S, and N in the hydrocarbon chain. The heteroalkenylene may be optionally substituted with one or more substituents Q as described herein. The term "heteroalkenylene" embraces radicals having a "cz ^' s" or "tra s" configuration or a mixture thereof, or alternatively, a "Z" or "E" configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C ₂ _ ₆ heteroalkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C ₂ _ ₂₀ ), 2 to 15 (C ₂ _i ₅ ), 2 to 10 (C ₂ _i ₀ ), or 2 to 6 (C ₂ _ ₆ ) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C ₃ _ ₂₀ ), 3 to 15 (C ₃ _i ₅ ), 3 to 10 (C ₃ _i ₀ ), or 3 to 6 (C ₃ _ ₆ ) carbon atoms. Examples of heteroalkenylene groups include, but are not limited to, -CH=CHO-, - CH=CHOCH ₂ - -CH=CHCH ₂ 0- -CH=CHS- -CH=CHSCH ₂ - -CH=CHCH ₂ S- or -CH=CHCH ₂ NH-.

[0061] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon- carbon triple bond(s). The alkynyl may be optionally substituted with one or more substituents Q as described herein. The term "alkynyl" also encompasses both linear and branched alkynyl, unless otherwise specified. In certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C ₂ _ ₂₀ ), 2 to 15 (C ₂ _i ₅ ), 2 to 10 (C ₂ _i ₀ ), or 2 to 6 (C ₂ _ ₆ ) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C ₃ _ ₂₀ ), 3 to 15 (C ₃ _i ₅ ), 3 to 10 (C ₃ _i ₀ ), or 3 to 6 (C ₃ _ ₆ ) carbon atoms.

Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH) and propargyl (- CH ₂ C≡CH). For example, C ₂ _ ₆ alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.

[0062] The term "cycloalkyl" refers to a cyclic saturated bridged and/or non-bridged monovalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein. In certain embodiments, the cycloalkyl has from 3 to 20 (C ₃ _ ₂₀ ), from 3 to 15 (C ₃ _i ₅ ), from 3 to 10 (C ₃ _io), or from 3 to 7 (C ₃ _ ₇ ) carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.

[0063] The term "cycloalkenyl" refers to a cyclic unsaturated, nonaromatic bridged and/or non -bridged monovalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein. In certain embodiments, the cycloalkenyl has from 3 to 20 (C ₃ _ ₂ o), from 3 to 15 (C ₃ _i ₅ ), from 3 to 10 (C ₃ _i ₀ ), or from 3 to 7 (C ₃ _ ₇ ) carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl,

[0064] The term "aryl" refers to a monocyclic aromatic group and/or multicyclic monovalent aromatic group that contain at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 20 (C ₆ _2o), from 6 to 15 (C ₆ _i ₅ ), or from 6 to 10 (C ₆ _i ₀ ) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments, aryl may be optionally substituted with one or more substituents Q as described herein.

[0065] The terms "aralkyl" and "arylalkyl" refer to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl has from 7 to 30 (C ₇ _ ₃₀ ), from 7 to 20 (C ₇ _ ₂ o), or from 7 to 16 (C ₇ _i ₆ ) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, 2- phenylethyl, and 3-phenylpropyl. In certain embodiments, the aralkyl are optionally substituted with one or more substituents Q as described herein.

[0066] The term "heteroaryl" refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, N, and P in the ring. A heteroaryl group is bonded to the rest of a molecule through its aromatic ring. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, one to four N atoms, and/or one or two P atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, the heteroaryl may also be optionally substituted with one or more substituents Q as described herein as described herein.

[0067] The terms "heterocyclyl" and "heterocyclic" refer to a monovalent monocyclic non-aromatic ring system or monovalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, N, and P; and the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. A heterocyclyl group is bonded to the rest of a molecule through its non-aromatic ring. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be spiro, fused, or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl,

benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl,

dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,

octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4- piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl,

tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl may also be optionally substituted with one or more substituents Q as described herein.

[0068] The terms "halogen", "halide" and "halo" refer to fluorine, chlorine, bromine, and/or iodine.

[0069] The term "optionally substituted" is intended to mean that a group or substituent, such as an alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaryl-Ci_ ₆ alkyl, and heterocyclyl group, may be substituted with one or more substituents Q, each of which is independently selected from, e.g., (a) oxo (=0), halo, cyano (-CN), and nitro (-N0 ₂ ); (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, four, or five, substituents Q ^a ; and (c) -C(0)R ^a , -C(0)OR ^a , -C(0)NR ^b R ^c , -C(NR ^a )NR ^b R ^c , -OR ^a , -OC(0)R ^a , -OC(0)OR ^a , -OC(0)NR ^b R ^c , -OC(=NR ^a )NR ^b R ^c , -OS(0)R ^a , -OS(0) ₂ R ^a , - OS(0)NR ^b R ^c , -OS(0) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C(0)R ^d , -NR ^a C(0)OR ^d , -NR ^a C(0)NR ^b R ^c , - NR ^a C(=NR ^d )NR ^b R ^c , -NR ^a S(0)R ^d , -NR ^a S(0) ₂ R ^d , -NR ^a S(0)NR ^b R ^c , -NR ^a S(0) ₂ NR ^b R ^c , -P(0)R ^a R ^d , - P(0)(OR ^a )R ^d , -P(0)(OR ^a )(OR ^d ), -SR ^a , -S(0)R ^a , -S(0) ₂ R ^a , -S(0)NR ^b R ^c , and -S(0) ₂ NR ^b R ^c , wherein each R ^a , R ^b , R ^c , and R ^d is independently (i) hydrogen; (ii) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i4 aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four substituents Q ^a ; or (iii) R ^b and R ^c together with the N atom to which they are attached form heteroaryl or heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q ^a . As used herein, all groups that can be substituted are "optionally substituted," unless otherwise specified.

[0070] In one embodiment, each substituent Q ^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; and (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)R ^e , -C(0)OR ^e , -C(0)NR ^f R ^g , -C(NR ^e )NR ^f R ^g , -OR ^e , - OC(0)R ^e , -OC(0)OR ^e , -OC(0)NR ^f R ^g , -OC(=NR ^e )NR ^f R ^g , -OS(0)R ^e , -OS(0) ₂ R ^e , -OS(0)NR ^f R ^g , - OS(0) ₂ NR ^f R ^g , -NR ^f R ^g , -NR ^e C(0)R ^h , -NR ^e C(0)OR ^h , -NR ^e C(0)NR ^f R ^g , -NR ^e C(=NR ^h )NR ^f R ^g , - NR ^e S(0)R ^h , -NR ^e S(0) ₂ R ^h , -NR ^e S(0)NR ^f R ^g , -NR ^e S(0) ₂ NR ^f R ^g , -P(0)R ^e R ^h , -P(0)(OR ^e )R ^h , - P(0)(OR ^e )(OR ^h ), -SR ^e , -S(0)R ^e , -S(0) ₂ R ^e , -S(0)NR ^f R ^g , and -S(0) ₂ NR ^f R ^g ; wherein each R ^e , R ^f , R ^g , and R ^h is independently (i) hydrogen, Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (ii) R ^f and R ^g together with the N atom to which they are attached form heteroaryl or heterocyclyl.

[0071] In certain embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules, which has an enantiomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. In certain embodiments, the compound comprises about 95% or more of the desired enantiomer and about 5% or less of the less preferred enantiomer based on the total weight of the racemate in question.

[0072] In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation, (+) and (-), is not related to the absolute configuration of the molecule, R and S.

[0073] The phrase "an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof has the same meaning as the phrase "an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant of the compound referenced therein; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of the compound referenced therein; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant of the compound referenced therein."

[0074] The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which present in a stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, «-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

COMPOUNDS

[0075] Disclosed herein are PI3K inhibitors of Formula (I):

Formula (I)

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

X, Y, and Z are each independently N or CR ^X , with the proviso that at least two of X, Y, and Z are nitrogen atoms; where R ^x is hydrogen or Ci_ ₆ alkyl;

R ¹ and R ² are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ -6 alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , - C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , - OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , - NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , - NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or - S(0) ₂ NR ^lb R ^lc ; wherein each R ^la , R ^lb , R ^lc , and R ^ld is independently (i) hydrogen; (ii) d_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R ^lb and R ^lc together with the N atom to which they are attached form heterocyclyl;

R ³ and R ⁴ are each independently hydrog en or alkyl; or R ³ and R ⁴ are linked together to form a bond, Ci_ ₆ alkylene, Ci_ ₆ heteroalkylene, C ₂ _ ₆ alkenylene, or C ₂ _ ₆ heteroalkenylene;

R ^5a is (a) hydro gen or halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _ is aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , - OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -C(0)NR ^lb R ^lc , -OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , - OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , -NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , - NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , -NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , - S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or -S(0) ₂ NR ^lb R ^lc ;

R ^5b is (a) halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , - OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , -OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , - OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , -NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , - NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , -NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , - S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or -S(0) ₂ NR ^lb R ^lc ;

R ^5c is -(CR ^5f R ^5g ) _n -(C ₆ _ ₁₄ aryl) or -(CR ^5f R ^5g ) _n -heteroaryl;

R ^5d and R ^5e are each independently (a) hydrogen or halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _io cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , - C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , - OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , - NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , - NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or - S(0) ₂ NR ^lb R ^lc ;

R ^5f and R ^5g are each independently (a) hydrogen or halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3- ₁₀ cycloalkyl, C ₆ _i aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , - C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , - OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , - NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , - NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc ; or - S(0) ₂ NR ^lb R ^lc ; or (d) when one occurrence of R ^5f and one occurrence of R ^5g are attached to the same carbon atom, the R ^5f and R ^5g together with the carbon atom to which they are attached form a C ₃ _i ₀ cycloalkyl or heterocyclyl;

R ⁶ is hydrogen, Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -S(0)-Ci_ ₆ alkyl, or -S0 ₂ -Ci_ ₆ alkyl;

m is 0 or 1 ; and

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

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^x , R ^la , R ^lb , R ^lc , R ^ld , R ^5a , R ^5b , R ^5c , R ^5d , R ^5e , R ^5f , and R ^5g is optionally substituted with one or more, in one embodiment, one, two, three, four, or five substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _ _i4 aryl, C ₇ _i ₅ aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q ^a ; and (c) -C(0)R ^a , -C(0)OR ^a , -C(0)NR ^b R ^c , - C(NR ^a )NR ^b R ^c , -OR ^a , -OC(0)R ^a , -OC(0)OR ^a , -OC(0)NR ^b R ^c , -OC(=NR ^a )NR ^b R ^c , -OS(0)R ^a , - OS(0) ₂ R ^a , -OS(0)NR ^b R ^c , -OS(0) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C(0)R ^d , -NR ^a C(0)OR ^d , -NR ^a C(0)NR ^b R ^c , - NR ^a C(=NR ^d )NR ^b R ^c , -NR ^a S(0)R ^d , -NR ^a S(0) ₂ R ^d , -NR ^a S(0)NR ^b R ^c , -NR ^a S(0) ₂ NR ^b R ^c , -SR ^a , -S(0)R ^a , - S(0) ₂ R ^a , -S(0)NR ^b R ^c , and -S(0) ₂ NR ^b R ^c , wherein each R ^a , R ^b , R ^c , and R ^d is independently (i) hydrogen; (ii) Ci-6 alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q ^a ; or (iii) R ^b and R ^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four substituents Q ^a ;

wherein each Q ^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)R ^e , -C(0)OR ^e , -C(0)NR ^f R ^g , -C(NR ^e )NR ^f R ^g , -OR ^e , -OC(0)R ^e , -OC(0)OR ^e , -OC(0)NR ^f R ^g , -O C(=NR ^e )NR ^f R ^g , -OS(0)R ^e , -OS(0) ₂ R ^e , -OS(0)NR ^f R ^g , -OS(0) ₂ NR ^f R ^g , -NR ^f R ^g , - NR ^e C(0)R ^h , -NR ^e C(0)OR ^h , -NR ^e C(0)NR ^f R ^g , -NR ^e C(=NR ^h )NR ^f R ^g , -NR ^e S(0)R ^h , -NR ^e S(0) ₂ R ^h , - NR ^e S(0)NR ^f R ^g , -NR ^e S(0) ₂ NR ^f R ^g , -SR ^e , -S(0)R ^e , -S(0) ₂ R ^e , -S(0)NR ^f R ^g , and -S(0) ₂ NR ^f R ^g ; wherein each R ^e , R ^f , R ^g , and R ^h is independently (i) hydrogen; (ii) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R ^f and R ^g together with the N atom to which they are attached form heterocyclyl; or

wherein two substituents Q that are adjacent to each other optionally form a C ₃ _i ₀ cycloalkenyl, C ₆ _i4 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one, two, three, or four substituents Q ^a .

[0076] In one embodiment of a compound of Formula (I),

X, Y, and Z are each independently N or CR ^X ' with the proviso that at least two of X, Y, and Z are nitrogen atoms; where R ^x is hydrogen or Ci_ ₆ alkyl;

R ¹ and R ² are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _6 alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , - C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , - OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , - NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , - NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or - S(0) ₂ NR ^lb R ^lc ; wherein each R ^la , R ^lb , R ^lc , and R ^ld is independently (i) hydrogen; (ii) d_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _ _i5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R ^lb and R ^lc together with the N atom to which they are attached form heterocyclyl;

R ³ and R ⁴ are each independently hydrog en or alkyl; or R ³ and R ⁴ are linked together to form a bond, Ci_ ₆ alkylene, Ci_ ₆ heteroalkylene, C ₂ _ ₆ alkenylene, or C ₂ _ ₆ heteroalkenylene;

R ^5a is (a) hydro gen or halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _ is aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , - OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , -OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , - OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , -NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , - NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , -NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , - S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or -S(0) ₂ NR ^lb R ^lc ;

R ^5b is (a) halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , - OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , -OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , - OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , -NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , - NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , -NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , - S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or -S(0) ₂ NR ^lb R ^lc ;

R ^5c is -(CR ^5f R ^5g ) _n -(C ₆ _ ₁₄ aryl) or -(CR ^5f R ^5g ) _n -heteroaryl;

R ^5d and R ^5e are each independently (a) hydrogen or halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _io cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , - C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , - OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , - NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , - NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or - S(0) ₂ NR ^lb R ^lc ; R ^5f and R ^5g are each independently (a) hydro gen or halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , - OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , - NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , - NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc ; or - S(0) ₂ NR ^lb R ^lc ; or (d) when one occurrence of R ^5f and one occurrence of R ^5g are attached to the same carbon atom, the R ^5f and R ^5g together with the carbon atom to which they are attached form a C ₃ _i ₀ cycloalkyl or heterocyclyl;

R ⁶ is hydrogen, Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -S(0)-Ci_ ₆ alkyl, or -S0 ₂ -Ci_ ₆ alkyl;

m is 0 or 1 ; and

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

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, four, or five substituents Q as defined herein.

[0077] In another embodiment of a compound of Formula (I),

X, Y, and Z are each independently N or CR ^X , with the proviso that at least two of X, Y, and Z are nitrogen atoms; where R ^x is hydrogen or Ci_ ₆ alkyl;

R ¹ and R ² are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _6 alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , - C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , - OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , - NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , - NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or - S(0) ₂ NR ^lb R ^lc ; wherein each R ^la , R ^lb , R ^lc , and R ^ld is independently (i) hydrogen; (ii) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R ^lb and R ^lc together with the N atom to which they are attached form heterocyclyl;

R ³ and R ⁴ are each independently hydrog en or Ci_6 alkyl; or R ³ and R ⁴ are linked together to form a bond, Ci_ ₆ alkylene, Ci_ ₆ heteroalkylene, C ₂ _ ₆ alkenylene, or C ₂ _ ₆ heteroalkenylene;

R ^5a is (a) hydro gen or halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _ is aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , - OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , -OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , - OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , -NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , - NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , -NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , - S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or -S(0) ₂ NR ^lb R ^lc ;

R ^5b is (a) halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , - OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , -OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , - OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , -NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , - NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , -NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , - S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or -S(0) ₂ NR ^lb R ^lc ;

R ^5c is -(CR ^5f R ^5g )„-(C ₆ _ ₁₄ aryl) or -(CR ^5f R ^5g )„-heteroaryl;

R ^5d and R ^5e are each independently (a) hydrogen or halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3-10 cycloalkyl, C ₆ _i aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , - C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , - OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , - NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , - NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or - S(0) ₂ NR ^lb R ^lc ;

R ^5f and R ^5g are each independently (a) hydrogen or halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _io cycloalkyl, C ₆ _ _i4 aryl, C ₇ _ _i5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , - C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , - OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , - NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , - NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc ; or - S(0) ₂ NR ^lb R ^lc ; or (d) when one occurrence of R ^5f and one occurrence of R ^5g are attached to the same carbon atom, the R ^5f and R ^5g together with the carbon atom to which they are attached form a C ₃ _i ₀ cycloalkyl or heterocyclyl;

R ⁶ is hydrogen, Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -S(0)-Ci_ ₆ alkyl, or -S0 ₂ -Ci_ ₆ alkyl; m is 0 or 1 ; and

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

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, four, or five substituents Q as defined herein.

[0078] In yet another embodiment of a compound of Formula (I),

X, Y, and Z are each independently N or CR ^X , with the proviso that at least two of X, Y, and Z are nitrogen atoms; where R ^x is hydrogen or Ci_ ₆ alkyl;

R ¹ and R ² are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ -6 alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , - C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , - OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , - NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , - NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or - S(0) ₂ NR ^lb R ^lc ; wherein each R ^la , R ^lb , R ^lc , and R ^ld is independently (i) hydrogen; (ii) d_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R ^lb and R ^lc together with the N atom to which they are attached form heterocyclyl;

R ³ and R ⁴ are each independently hydrog en or Ci_6 alkyl; or R ³ and R ⁴ are linked together to form a bond, Ci_ ₆ alkylene, Ci_ ₆ heteroalkylene, C ₂ _ ₆ alkenylene, or C ₂ _ ₆ heteroalkenylene;

R ^5a is (a) halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , - OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , -OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , - OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , -NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , - NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , -NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , - S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or -S(0) ₂ NR ^lb R ^lc ;

R ^5b is (a) halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , - OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , -OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , - OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , -NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , - NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , -NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , - S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or -S(0) ₂ NR ^lb R ^lc ;

R ^5c is -(CR ^5f R ^5g ) _n -(C ₆ _ ₁₄ aryl) or -(CR ^5f R ^5g ) _n -heteroaryl;

R ^5d and R ^5e are each independently (a) hydrogen or halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _io cycloalkyl, C ₆ _i aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , - C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , - OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , - NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , - NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or - S(0) ₂ NR ^lb R ^lc ;

R ^5f and R ^5g are each independently (a) hydrogen or halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3-10 cycloalkyl, C ₆ _i aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , - C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , - OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , - NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , - NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc ; or - S(0) ₂ NR ^lb R ^lc ; or (d) when one occurrence of R ^5f and one occurrence of R ^5g are attached to the same carbon atom, the R ^5f and R ^5g together with the carbon atom to which they are attached form a C3_io cycloalkyl or heterocyclyl;

R ⁶ is hydrogen, Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -S(0)-Ci_ ₆ alkyl, or -S0 ₂ -Ci_ ₆ alkyl;

m is 0 or 1 ; and

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

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, four, or five substituents Q as defined herein.

[0079] In still another embodiment of a compound of Formula (I),

X, Y, and Z are N;

R ¹ and R ² are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ -6 alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , - C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , - OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , - NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , - NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or - S(0) ₂ NR ^lb R ^lc ; wherein each R ^la , R ^lb , R ^lc , and R ^ld is independently (i) hydrogen; (ii) d_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R ^lb and R ^lc together with the N atom to which they are attached form heterocyclyl;

R ³ and R ⁴ are each independently hydrog en or alkyl; or R ³ and R ⁴ are linked together to form a bond, Ci_ ₆ alkylene, Ci_ ₆ heteroalkylene, C ₂ _ ₆ alkenylene, or C ₂ _ ₆ heteroalkenylene;

R ^5a is (a) hydro gen or halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _ is aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , - OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , -OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , - OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , -NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , - NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , -NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , - S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or -S(0) ₂ NR ^lb R ^lc ; R is (a) halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i aryl, C ₇ _i ₅ aralkyl, or heteroaryl; or (c) -C(0)R ^la , -C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , - OC(0)OR ^la , -OC(0)NR ^lb R ^lc , -OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , - OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , -NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -

NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , -NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , - S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or -S(0) ₂ NR ^lb R ^lc ;

R ^5c is -(CR ^5f R ^5g ) _n -(C ₆ _ ₁₄ aryl) or -(CR ^5f R ^5g ) _n -heteroaryl;

R ^5d and R ^5e are each independently (a) hydrogen or halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _io cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , - C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , - OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , - NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , - NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or - S(0) ₂ NR ^lb R ^lc ;

R ^5f and R ^5g are each independently (a) hydrogen or halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C3- ₁₀ cycloalkyl, C ₆ _i aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , - C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , -OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , - OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , -OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , - NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , -NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , - NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , -S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc ; or - S(0) ₂ NR ^lb R ^lc ; or (d) when one occurrence of R ^5f and one occurrence of R ^5g are attached to the same carbon atom, the R ^5f and R ^5g together with the carbon atom to which they are attached form a C ₃ _i ₀ cycloalkyl or heterocyclyl;

R ⁶ is hydrogen, Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -S(0)-Ci_ ₆ alkyl, or -S0 ₂ -Ci_ ₆ alkyl;

m is 0 or 1 ; and

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

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, four, or five substituents Q as defined herein.

[0080] Synthesis of compounds of Formula (I) is described in US Patent No. 9,056,852 B2, which is incorporated by reference for such disclosure.

[0081] Also provided herein is a compound of Formula (IX):

Formula (IX),

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

_R 7a _R 7b _R 7c _R 7d ^ _R 7e are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_ _¾ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; or (c) -C(0)R ^a , -C(0)OR ^a , -C(0)NR ^b R ^c , -C(NR ^a )NR ^b R ^c , -OR ^a , -OC(0)R ^a , -OC(0)OR ^a , -OC(0)NR ^b R ^c , -OC(=NR ^a )NR ^b R ^c , - OS(0)R ^a , -OS(0) ₂ R ^a , -OS(0)NR ^b R ^c , -OS(0) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C(0)R ^d , -NR ^a C(0)OR ^d , - NR ^a C(0)NR ^b R ^c , -NR ^a C(=NR ^d )NR ^b R ^c , -NR ^a S(0)R ^d , -NR ^a S(0) ₂ R ^d , -NR ^a S(0)NR ^b R ^c , -NR ^a S(0) ₂ NR ^b R ^c , -SR ^a , -S(0)R ^a , -S(0) ₂ R ^a , -S(0)NR ^b R ^c , or -S(0) ₂ NR ^b R ^c ; or

two of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e that are adjacent to each other form C ₃ _i ₀ cycloalkenyl, C ₆ _i ₄ aryl, heteroaryl, or heterocyclyl, each optionally substituted with one, two, three, or four substituents Q ^a ; and

R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^la , R ^lb , R ^lc , R ^ld , R ^5a , R ^5b , R ^5d , R ^5e , X, Y, and Z are each as defined herein.

[0082] Synthesis of compounds Formula (IX) is described in US Patent No. 9,056,852 B2, which is incorporated by reference for such disclosure.

[0083] In one embodiment, the compound of Formula (IX) has the structure of Formula (IXa):

Formula (IXa),

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^5d , R ^5e , R ^7a , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0084] Synthesis of compounds of Formula (IXa) is described in US Patent No. 9,056,852 B2, which is incorporated by reference for such disclosure.

[0085] In another embodiment, the compound of Formula (IX) has the structure of Formula (IXb):

Formula (IXb),

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^5d , R ^5e , R ^7a , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0086] Synthesis of compounds of Formula (IXb) is described in US Patent No. 9,056,852 B2, which is incorporated by reference for such disclosure.

[0087] In certain embodiments of compounds of Formula (IX), (IXa), or (IXb), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is C¾_i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, one of R ^7a , R^, R ^7c , R ^7d , and R ^7e is C ₆ _i ₄ aryl, e.g., phenyl, optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, one of R ^7a , R^, R ^7c , R ^7d , and R ^7e is heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl, optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, one of R ^7a , R ^¾ , R ^7c , R ^7d , and R ^7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, one of R ^7a , R ^¾ , R ^7c , R ^7d , and R ^7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, one of R ^7a , R^, R ^7c , R ^7d , and R ^7e is phenyl, 2- fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3- chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l -yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, l -methylpiperidin-4-yl, or 4-methylpiperazin- 1-yl; and in certain embodiments, one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3- fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-moφholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl - pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2- methylpyridin-4-yl, 2-(4-methylpiperazin-l -yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l -methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, 1 - isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l -yl.

[0088] In certain embodiments of compounds of Formula (IX), (IXa), or (IXb), R ^7a is C ₆ _i ₄ aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, R ^7a is C ₆ _i ₄ aryl, e.g., phenyl, optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, R ^7a is heteroaryl, e.g., 5-membered or 6- membered heteroaryl, optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, R ^7a is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl, optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, R ^7a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, imidazol-l -yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3- yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1 - methylpiperidin-4-yl, or 4-methylpiperazin-l-yl; and in certain embodiments, R ^7a is phenyl, 2- fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2- methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4- chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l -yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2- fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin- 1 -yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l -methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, 1- ethylpiperidin-4-yl, l -isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin- 1 -yl .

[0089] In certain embodiments of compounds of Formula (IX), (IXa), or (IXb),

R ¹ is hydrogen or -OR ^la , where R ^la is Ci_ ₆ alkyl, optionally substituted with one, two, three, four, or five substituents Q;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is Ci_ ₆ alkyl, optionally substituted with one, two, three, four, or five substituents Q;

R ^5a and R ^5b are each independently hydrogen, halo, Ci_ ₆ alkyl, optionally substituted with one, two, three, four, or five substituents Q;

R ^5d and R ^5e are each independently Ci_ ₆ alkyl, optionally substituted with one, two, three, four, or five substituents Q;

_R 7a

is C¾_i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ;

R ⁷ ", R ^7c , R ^7d . and R ^7e are hydrogen; and

X, Y, and Z are each independently N or CR ^X , with the proviso that at least two of X, Y, and Z are N; where R ^x is a hydrogen or Ci_ ₆ alkyl, optionally substituted with one, two, three, or four substituents

Q ^a .

[0090] In certain embodiments of compounds of Fonnula (IX), (IXa), or (IXb),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is Ci_ ₆ alkyl, optionally substituted with one or more halo;

R ^5a and R ^5b are hydrogen;

R ^5d and R ^5e are each independently Ci_ ₆ alkyl;

R ^7a is C ₆ _i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ;

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen; and

X, Y, and Z are each independently N or CH.

[0091] In certain embodiments of compounds of Formula (IX), (IXa), or (IXb),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is difluoromethyl;

R ^5a and R ^5b are hydrogen;

R ^5d and R ^5e are methyl;

R ^7a is C ₆ _i4 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one. two, three, or four substituents Q ^a ;

R ^¾ , R ^7c , R ^7d . and R ^7e are hydrogen; and

X, Y, and Z are each independently N or CH.

[0092] In certain embodiments of compounds of Formula (IX), (IXa), or (IXb),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is difluoromethyl;

R ^5a and R ^5b are hydrogen;

R ^5d and R ^5e are methyl;

R ^7a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; R ⁷ \ R ^7c , R ^7d , and R ^7e are hydrogen; and

X, Y, and Z are each independently N or CH.

[0093] In certain embodiments of compound of Formula (IX), (IXa), or (IXb),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is difluoromethyl;

R ^a and R ^5b are hydrogen;

R ^5d and R ^5e are methyl:

R ^7a is phenyl, imidazoh l. pyrozolyl, pyridinyl, pyrimidin} !, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ;

R ⁷ ", R ^7c , R ^7d , and R ^7e are hydrogen; and

X, Y, and Z are each independently N or CH.

[0094] In certain embodiments of compound of Formula (IX), (IXa), or (IXb),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen:

R ⁶ is difluoromethyl;

R ^5a and R ^5b are hydrogen;

R ^5d and R ^5e are methyl;

R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ;

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen; and

X, Y, and Z are each independently N or CH.

[0095] Also provided herein is a compound of Formula (X):

Formula (X),

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R ¹ , R ² , R\ R ⁴ , R ⁶ , R ^5a , R ^5b , R ^5d , R ^5e , R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e are each as defined herein. [0096] Synthesis of compounds of Formula (X) is described in US Patent No. 9,056,852 B2, which is incorporated by reference for such disclosure.

[0097] In one embodiment, the compound of Formula (X) has the structure of Formula (Xa):

Formula (Xa),

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^5d , R ^5e , R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e are each as defined herein.

[0098] Synthesis of compounds of Formula (Xa) is described in US Patent No. 9,056,852 B2, which is incorporated by reference for such disclosure.

[0099] In another embodiment cture of Formula (Xb):

Formula (Xb),

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^5d , R ^5e , R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e are each as defined herein.

[0100] Synthesis of compounds of Formula (Xb) is described in US Patent No. 9,056,852 B2, which is incorporated by reference for such disclosure.

[0101] In certain embodiments of compound of Formula (X), (Xa), or (Xb), one of R ^7a , R ^7b , R ^7c , R ^7d , and

_R 7e is C¾_i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, one of R ^7a , R^, R ^7c , R ^7d , and R ^7e is C ₆ . _u aryl, e.g., phenyl, optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, one of R ^7a , R^, R ^7c , R ^7d , and R ^7e is heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl, optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, one of R ^7a , R ^¾ , R ^7c , R ^7d , and R ^7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, one of R ^7a , R ^¾ , R ^7c , R ^7d , and R ^7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, one of R ^7a , R^, R ^7c , R ^7d , and R ^7e is phenyl, 2- fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3- chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, l-methylpiperidin-4-yl, or 4-methylpiperazin- 1-yl; and in certain embodiments, one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3- fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl - pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2- methylpyridin-4-yl, 2-(4-methylpiperazin-l-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, 1- isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l-yl.

[0102] In certain embodiments of compound of Formula (X), (Xa), or (Xb), R ^7a is C ₆ _i ₄ aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q ^a ; in certain embodiments, R ^7a is C ₆ _i ₄ aryl, e.g., phenyl, optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, R ^7a is heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, R ^7a is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl, optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, R ^7a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3- yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1- methylpiperidin-4-yl, or 4-methylpiperazin-l-yl; and in certain embodiments, R ^7a is phenyl, 2- fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2- methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4- chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2- fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin- 1 -yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l -methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, 1- ethylpiperidin-4-yl, l -isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin- 1 -yl .

[0103] In certain embodiments of compound of Formula (X), (Xa), or (Xb),

R ¹ is hydrogen or -OR ^la , where R ^la is Ci_ ₆ alkyl, optionally substituted with one, two, three, four, or five substituents Q;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is Ci_ ₆ alkyl, optionally substituted with one, two, three, four, or five substituents Q;

R ^5a and R ^5b are each independently hydrogen, halo, Ci_ ₆ alkyl, optionally substituted with one, two, three, four, or five substituents Q;

R ^5d and R ^5e are each independently Ci_ ₆ alkyl, optionally substituted with one, two, three, four, or five substituents Q;

_R 7a

is C¾_i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen.

[0104] In certain embodiments of compound of Formula (X), (Xa), or (Xb),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is Ci-6 alkyl, optionally substituted with one or more halo;

R ^5a and R ^5b are hydrogen;

R ^5d and R ^5e are each independently Ci_ ₆ alkyl;

_R 7a

is C¾_i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen.

[0105] In certain embodiments of compound of Formula (X), (Xa), or (Xb),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is difluoromethyl;

R ^5a and R ^5b are hydrogen;

R ^5d and R ^5e are methyl;

_R 7a

is Οή-ΐ4 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen. [0106] In certain embodiments of compound of Formula (X), (Xa), or (Xb),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is difluoromethyl;

R ^5a and R ⁵ are hydrogen;

R ^5d and R ^5e are methyl;

R ^7a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen.

[0107] In certain embodiments of compound of Formula (X), (Xa), or (Xb),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is difluoromethyl;

R ^a and R ^5b are hydrogen;

R ^5d and R ^5e are methyl;

R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinvl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and

R ⁷ ", R ^7c , R ^7d , and R ^7e are hydrogen.

[0108] In certain embodiments of compound of Formula (X), (Xa), or (Xb),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ¹ and R ⁴ are hydrogen;

R ⁶ is difluoromethyl;

R ^5a and R ^5b are hydrogen;

R ^5d and R ^5e are methyl;

R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinvl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen.

[0109] Provide herein is a compound of Formula (XI):

Formula (XI),

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

_R 7a _R 7b _R 7c _R 7d ^ _R 7e are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_ _¾ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; or (c) -C(0)R ^a , -C(0)OR ^a , -C(0)NR ^b R ^c , -C(NR ^a )NR ^b R ^c , -OR ^a , -OC(0)R ^a , -OC(0)OR ^a , -OC(0)NR ^b R ^c , -OC(=NR ^a )NR ^b R ^c , - OS(0)R ^a , -OS(0) ₂ R ^a , -OS(0)NR ^b R ^c , -OS(0) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C(0)R ^d , -NR ^a C(0)OR ^d , - NR ^a C(0)NR ^b R ^c , -NR ^a C(=NR ^d )NR ^b R ^c , -NR ^a S(0)R ^d , -NR ^a S(0) ₂ R ^d , -NR ^a S(0)NR ^b R ^c , -NR ^a S(0) ₂ NR ^b R ^c , -SR ^a , -S(0)R ^a , -S(0) ₂ R ^a , -S(0)NR ^b R ^c , or -S(0) ₂ NR ^b R ^c ; or two of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e that are adjacent to each other form C ₃ _i ₀ cycloalkenyl, C ₆ _i ₄ aryl, heteroaryl, or heterocyclyl, each optionally substituted with one, two, three, or four substituents Q ^a ; and

R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^la , R ^lb , R ^lc , R ^ld , R ^5a , R ^5b , R ^5f , R ^5g , X, Y, and Z are each as defined herein.

[0110] Synthesis of compounds of Formula (XI) is described in US Patent No. 9,056,852 B2, which is incorporated by reference for such disclosure.

[0111] In one embodiment, the compound of Formula (XI) has the structure of Formula (XIa):

Formula (XIa),

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^5f , R ^5g , R ^7a , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0112] Synthesis of compounds of Formula (XIa) is described in US Patent No. 9,056,852 B2, which is incorporated by reference for such disclosure.

[0113] In another embodiment, the compound of Formula (XI) has the structure of Formula (Xlb):

Formula (Xlb),

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^5f , R ^5g , R ^7a , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0114] Synthesis of compounds of Formula (Xlb) is described in US Patent No. 9,056,852 B2, which is incorporated by reference for such disclosure.

[0115] In certain embodiments of compound of Formula (XI), (XIa), or (Xlb), R ^5a and R ^5b are each independently (a) halo; (b) Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _i ₀ cycloalkyl, C ₆ _i ₄ aryl, C ₇ _i ₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R ^la , -C(0)OR ^la , -C(0)NR ^lb R ^lc , -C(NR ^la )NR ^lb R ^lc , -OR ^la , - OC(0)R ^la , -OC(0)OR ^la , -OC(0)NR ^lb R ^lc , -OC(=NR ^la )NR ^lb R ^lc , -OS(0)R ^la , -OS(0) ₂ R ^la , - OS(0)NR ^lb R ^lc , -OS(0) ₂ NR ^lb R ^lc , -NR ^lb R ^lc , -NR ^la C(0)R ^ld , -NR ^la C(0)OR ^ld , -NR ^la C(0)NR ^lb R ^lc , - NR ^la C(=NR ^ld )NR ^lb R ^lc , -NR ^la S(0)R ^ld , -NR ^la S(0) ₂ R ^ld , -NR ^la S(0)NR ^lb R ^lc , -NR ^la S(0) ₂ NR ^lb R ^lc , -SR ^la , - S(0)R ^la , -S(0) ₂ R ^la , -S(0)NR ^lb R ^lc , or -S(0) ₂ NR ^lb R ^lc ; and R ¹ , R ² , R ³ , R ⁴ , R ^5f , R ^5g , R ⁶ , R ^7a , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, Z, R ^la , R ^lb , R ^lc , and R ^ld are defined herein elsewhere.

[0116] In certain embodiments of compound of Formula (XI), (XIa), or (Xlb), one of R ^7a , R ⁷ ", R ^7c , R ^7d , and R ^7e is C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, one of R ^7a , R^, R ^7c , R ^7d , and R ^7e is C ₆ _i ₄ aryl, e.g., phenyl, optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, one of R ^7a , R^, R ^7c , R ^7d , and R ^7e is heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl, optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, one of R ^7a , R ^¾ , R ^7c , R ^7d , and R ^7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, one of R ^7a , R ^¾ , R ^7c , R ^7d , and R ^7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q ^a ; in certain embodiments, one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3- methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2- methylpyridin-4-yl, 2-methoxypyridin-4-yl, l-methylpiperidin-4-yl, or 4-methylpiperazin-l-yl; and in certain embodiments, one of R ^a , R , R ^c , R , and R ^e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2- bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3- chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4- methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2- methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2- (4-methylpiperazin-l-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1- methylpyrrolidin-3-yl, piperidin-4-yl, 1 -methylpiperidin-4-yl, l-ethylpiperidin-4-yl, 1-isopropylpiperidin- 4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l-yl.

[0117] In certain embodiments of compound of Formula (XI), (XIa), or (Xlb), R ^7a is C ₆ _i ₄ aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, R ^7a is C ₆ _i ₄ aryl, e.g., phenyl, optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, R ^7a is heteroaryl, e.g., 5-membered or 6- membered heteroaryl, optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, R ^7a is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl, optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, R ^7a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, imidazol-l -yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3- yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1 - methylpiperidin-4-yl, or 4-methylpiperazin-l-yl; and in certain embodiments, R ^7a is phenyl, 2- fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2- methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4- chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-mo holin-4-ylmethylphenyl, imidazol-l -yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2- fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin- 1 -yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l -methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, 1- ethylpiperidin-4-yl, l -isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin- 1 -yl .

[0118] In certain embodiments of compound of Formula (XI), (XIa), or (Xlb),

R ¹ is hydrogen or -OR ^la , where R ^la is Ci_ ₆ alkyl, optionally substituted with one, two, three, four, or five substituents Q;

R ² is hydrogen; R ³ and R ⁴ are hydrogen;

R ⁶ is Ci-6 alkyl, optionally substituted with one, two, three, four, or five substituents Q;

R ^5a and R ^5b are each independently Ci_ ₆ alkyl, optionally substituted with one, two, three, four, or five substituents Q;

R ^5f and R ^5g are each independently hydrogen, halo, Ci_ ₆ alkyl, optionally substituted with one, two, three, four, or five substituents Q; or R ^5f and R ^5g together with the carbon atom to which they are attached form Ci_i ₀ cycloalkyl or heterocyclyl, each of which is optionally substituted with one, two, three, four, or five substituents Q;

_R 7a is C¾_i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ;

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen; and

X, Y, and Z are each independently N or CR ^X , with the proviso that at least two of X, Y, and Z are N; where R ^x is a hydrogen or Ci_ ₆ alkyl, optionally substituted with one, two, three, or four substituents

Q ^a .

[0119] In certain embodiments of compound of Formula (XI), (XIa), or (Xlb),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is Ci-6 alkyl, optionally substituted with one or more halo;

R ^5a and R ^5b are each independently Ci_ ₆ alkyl;

R ^5f and R ^5g are each independently hydrog en or Ci_6 alkyl; or R ^5f and R ^5g together with the carbon atom to which they are attached form Cm cycloalkyl;

_R 7a is Οή-ΐ4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ;

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen; and

X, Y, and Z are each independently N or CH.

[0120] In certain embodiments of compound of Formula (XI), (XIa), or (Xlb),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is difluoromethyl;

R ^5a and R ^5b are methyl;

R ^5f and R ^5g are hydrogen; or R ^5f and R ^5g together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

_R 7a is Οή-ΐ4 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; R ^b , R ^c , R ^Cl , and R ^e are hydrogen; and

X, Y, and Z are each independently N or CH.

[0121] In certain embodiments of compound of Formula (XI), (XIa), or (Xlb),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is difluoromethyl;

R ^5a and R ^5b are methyl;

R ^5f and R ^5g are hydrogen; or R ^5f and R ^5g together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

R ^7a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ;

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen; and

X, Y, and Z are each independently N or CH.

[0122] In certain embodiments of compound of Formula (XI), (XIa), or (Xlb),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is difluoromethyl;

R ^5a and R ^5b are methyl;

R ^5f and R ^5g are hydrogen; or R ^5f and R ^5g together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ;

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen; and

X, Y, and Z are each independently N or CH.

[0123] In certain embodiments of compound of Formula (XI), (XIa), or (Xlb),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is difluoromethyl;

R ^5a and R ^5b are methyl;

R ^5f and R ^5g are hydrogen; or R ^5f and R ^5g together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; R ^b , R ^c , R ^Cl , and R ^e are hydrogen; and

X, Y, and Z are each independently N or CH.

[0124] Provided herein is a compound of Formula (XVI):

Formula (XVI),

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e are each as defined herein.

[0125] Synthesis of compounds of Formula (XVI) is described in US Patent No. 9,056,852 B2, which is incorporated by reference for such disclosure.

[0126] In one embodiment of a compound of Formula (XVI), one of R ^7a , R ⁷ ", R ^7c , R ^7d , and R ^7e is C _6- i ₄ aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0127] In another embodiment of a compound of Formula (XVI), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is C ₆ -i ₄ aryl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ ,

R ^5a , R ^5b , the remaining of R ^7a , R ⁷ ", R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0128] In yet another embodiment of a compound of Formula (XVI), one of R ^7a , R ⁷ ", R ^7c , R ^7d , and R ^7e is heteroaryl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ ,

R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0129] In yet another embodiment of a compound of Formula (XVI), one of R ^7a , R ⁷ ", R ^7c , R ^7d , and R ^7e is

5-membered or 6-membered heteroaryl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0130] In yet another embodiment of a compound of Formula (XVI), one of R ^7a , R ⁷ ", R ^7c , R ^7d , and R ^7e is heterocyclyl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0131] In yet another embodiment of a compound of Formula (XVI), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is 5-membered or 6-membered heterocyclyl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0132] In yet another embodiment of a compound of Formula (XVI), one of R ^7a , R^, R ^7c , R ^7d , and R ^7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^¾ , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0133] In yet another embodiment of a compound of Formula (XVI), one of R ^7a , R^, R ^7c , R ^7d , and R ^7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0134] In yet another embodiment of a compound of Formula (XVI), one of R ^7a , R ⁷ ", R ^7c , R ^7d , and R ^7e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3- dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3- methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4- ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin-l -yl)pyridin- 4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, 1 - methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l -isopropylpiperidin-4-yl, 1 -acetylpiperidin-4-yl, 1 - methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l-yl.

[0135] In still another embodiment of a compound of Formula (XVI), one of R ^7a , R ⁷ ", R ^7c , R ^7d , and R ^7e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3- fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4- methoxyphenyl, imidazol-l -yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, l-methylpiperidin-4-yl, or 4- methylpiperazin-l -yl; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^¾ , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0136] In one embodiment of a compound of Formula (XVI), R ^7a is C ₆ _i ₄ aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0137] In another embodiment of a compound of Formula (XVI), R ^7a is C ₆ _i ₄ aryl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ⁷ ", R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0138] In yet another embodiment of a compound of Formula (XVI), R ^7a is heteroaryl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein. [0139] In yet another embodiment of a compound of Formula (XVI), R ^a is 5-membered or 6-membered heteroaryl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0140] In yet another embodiment of a compound of Formula (XVI), R ^7a is heterocyclyl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0141] In yet another embodiment of a compound of Formula (XVI), R ^7a is 5-membered or 6-membered heterocyclyl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0142] In yet another embodiment of a compound of Formula (XVI), R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0143] In yet another embodiment of a compound of Formula (XVI), R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^¾ , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0144] In yet another embodiment of a compound of Formula (XVI), R ^7a is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3- fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-moφholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl - pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2- methylpyridin-4-yl, 2-(4-methylpiperazin-l -yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l -methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, 1 - isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l -yl.

[0145] In yet another embodiment of a compound of Formula (XVI), R ^7a is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3- methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l -yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2- methylpyridin-4-yl, 2-methoxypyridin-4-yl, l-methylpiperidin-4-yl, or 4-methylpiperazin-l-yl; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0146] In one embodiment of a compound of Formula (XVI),

R ¹ is hydrogen or -OR ^la , where R ^la is Ci_ ₆ alkyl, optionally substituted with one, two, three, four, or five substituents Q;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is Ci_ ₆ alkyl, optionally substituted with one, two, three, four, or five substituents Q; R ^5a and R ^5b are each independently Ci- ₆ alkyl, optionally substituted with one, two, three, four, or five substituents Q;

R ^7a is C _6- i4 aryl, heteroaiyl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q ^a ; and

R ⁷ ", R ^7c , R ^7d , and R ^7e are hydrogen.

[0147] In one embodiment of a compound of Formula (XVI),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is Ci_ ₆ alkyl, optionally substituted with one or more halo;

R ^5a and R ^5b are each independently Ci_ ₆ alkyl;

R ^7a is C _6- i4 aryl, heteroaiyl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and

R ⁷ ", R ^7c , R ^7d , and R ^7e are hydrogen.

[0148] In one embodiment of a compound of Formula (XVI),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is difluoromethyl;

R ^5a and R ^5b are methyl;

R ^7a is Ce- aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen.

[0149] In one embodiment of a compound of Formula (XVI),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is difluoromethyl;

R ^5a and R ^5b are methyl;

R ^7a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl. each of which is optionally substituted with one. two, three, or four substituents Q ^a ; and

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen.

[0150] In one embodiment of a compound of Formula (XVI),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is difluoromethyl; R ^5a and R ^5b are methyl;

R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three, four, or five substituents Q; and

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen.

[0151] In one embodiment of a compound of Formula (XVI),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is difluoromethyl;

R ^5a and R ^5b are methyl;

R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen.

[0152] In one embodiment, the compound of Formula (XVI) has the structure of Formula (XVIa):

Formula (XVIa)

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7a , R ^¾ , R ^7c , R ^7d , and R ^7e are each as defined herein.

[0153] Synthesis of compounds of Formula (XVIa) is described in US Patent No. 9,056,852 B2, which is incorporated by reference for such disclosure.

[0154] In one embodiment of a compound of Formula (XVIa), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is C ₆ _ ₁₄ aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0155] In one embodiment of a compound of Formula (XVIa), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is C ₆ _i ₄ aryl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ⁷ ", R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0156] In one embodiment of a compound of Formula (XVIa), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is heteroaryl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein. [0157] In one embodiment of a compound of Formula (XVIa), one of R , R , R , R , and R ^e is 5- membered or 6-membered heteroaryl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0158] In one embodiment of a compound of Formula (XVIa), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is heterocyclyl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0159] In one embodiment of a compound of Formula (XVIa), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is 5- membered or 6-membered heterocyclyl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0160] In one embodiment of a compound of Formula (XVIa), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^¾ , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0161] In one embodiment of a compound of Formula (XVIa), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0162] In one embodiment of a compound of Formula (XVIa), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3- dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3- methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4- ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin-l-yl)pyridin- 4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, 1- methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, 1 -acetylpiperidin-4-yl, 1- methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l-yl.

[0163] In one embodiment of a compound of Formula (XVIa), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3- fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4- methoxyphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, l-methylpiperidin-4-yl, or 4- methylpiperazin-l-yl; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^¾ , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein. [0164] In one embodiment of a compound of Formula (XVIa), R ^a is C ₆ _i ₄ aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0165] In one embodiment of a compound of Formula (XVIa), R ^7a is C ₆ _i ₄ aryl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ⁷ ", R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0166] In one embodiment of a compound of Formula (XVIa), R ^7a is heteroaryl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ⁷ ", R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0167] In one embodiment of a compound of Formula (XVIa), R ^7a is 5-membered or 6-membered heteroaryl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0168] In one embodiment of a compound of Formula (XVIa), R ^7a is heterocyclyl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ⁷ ", R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0169] In one embodiment of a compound of Formula (XVIa), R ^7a is 5-membered or 6-membered heterocyclyl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0170] In one embodiment of a compound of Formula (XVIa), R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^¾ , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0171] In one embodiment of a compound of Formula (XVIa), R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^¾ , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0172] In one embodiment of a compound of Formula (XVIa), R ^7a is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3- fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl - pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2- methylpyridin-4-yl, 2-(4-methylpiperazin-l -yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l -methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, 1 - isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l -yl.

[0173] In one embodiment of a compound of Formula (XVIa), R ^7a is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3- methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l -yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2- methylpyridin-4-yl, 2-methoxypyridin-4-yl, l-methylpiperidin-4-yl, or 4-methylpiperazin-l-yl; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0174] In one embodiment of a compound of Formula (XVIa),

R ¹ is hydrogen or -OR ^la , where R ^la is Ci_ ₆ alkyl, optionally substituted with one, two, three, four, or five substituents Q;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is Ci_ ₆ alkyl, optionally substituted with one, two, three, four, or five substituents Q;

R ^5a and R ^5b are each independently hydrogen or Ci_ ₆ alkyl, optionally substituted with one, two, three, four, or five substituents Q;

_R 7a

is C¾_i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen.

[0175] In one embodiment of a compound of Formula (XVIa),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is Ci-6 alkyl, optionally substituted with one or more halo;

R ^5a and R ^5b are each independently hydrogen or Ci_ ₆ alkyl;

_R 7a

is Οή-ΐ4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen.

[0176] In one embodiment of a compound of Formula (XVIa),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is difluoromethyl;

R ^5a and R ^5b are each independently hydrogen or Ci_ ₆ alkyl;

_R 7a

is C¾_i4 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen.

[0177] In one embodiment of a compound of Formula (XVIa),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is difluoromethyl; R ^a and R are each independently hydrogen or Ci- ₆ alky 1;

R ^7a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen.

[0178] In one embodiment of a compound of Formula (XVIa),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ^J and R ⁴ are hy drogen;

R ⁶ is difluoromethyl;

R ^5a and R ^5b are each independently hydrog en or alkvl:

R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrrolidinyl, piperidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen.

[0179] In one embodiment of a compound of Formula (XVIa),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is difluoromethyl;

R ^5a and R ^5b are each independently hydrog en or Ci_6 alkyl;

R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and

R ^¾ R ^7c , R ^7d , and R ^7e are hydrogen.

[0180] Synthesis of compounds of Formula (XVIa) is described in US Patent No. 9,056.852 B2. which is incorporated by reference for such disclosure.

[0181] In another embodiment, the compound of Formula (XVI) has the structure of Formula (XVlb):

Formula (XVlb)

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7a , R ^¾ , R ^7c , R ^7d , and R ^7e are each as defined herein. [0182] In one embodiment of a compound of Formula (XVIb), one of R , R , R , R , and R ^e is C _6- i ₄ aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0183] In one embodiment of a compound of Formula (XVIb), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is C _6- i ₄ aryl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ⁷ ", R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0184] In one embodiment of a compound of Formula (XVIb), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is heteroaryl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0185] In one embodiment of a compound of Formula (XVIb), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is 5- membered or 6-membered heteroaryl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0186] In one embodiment of a compound of Formula (XVIb), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is heterocyclyl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0187] In one embodiment of a compound of Formula (XVIb), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is 5- membered or 6-membered heterocyclyl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0188] In one embodiment of a compound of Formula (XVIb), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^¾ , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0189] In one embodiment of a compound of Formula (XVIb), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0190] In one embodiment of a compound of Formula (XVIb), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3- dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3- methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4- ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin-l -yl)pyridin- 4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, 1 - methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l -isopropylpiperidin-4-yl, 1 -acetylpiperidin-4-yl, 1 - methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l-yl.

[0191] In one embodiment of a compound of Formula (XVIb), one of R ^7a , R ^7b , R ^7c , R ^7d , and R ^7e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3- fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4- methoxyphenyl, imidazol-l -yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, l-methylpiperidin-4-yl, or 4- methylpiperazin-l -yl; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , the remaining of R ^7a , R ^¾ , R ^7c , R ^7d , and R ^7e , X, Y, and Z are each as defined herein.

[0192] In one embodiment of a compound of Formula (XVIb), R ^7a is C ₆ _i ₄ aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, four, or five substituents Q; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^¾ , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0193] In one embodiment of a compound of Formula (XVIb), R ^7a is C ₆ _i ₄ aryl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ⁷ ", R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0194] In one embodiment of a compound of Formula (XVIb), R ^7a is heteroaryl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ⁷ ", R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0195] In one embodiment of a compound of Formula (XVIb), R ^7a is 5-membered or 6-membered heteroaryl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0196] In one embodiment of a compound of Formula (XVIb), R ^7a is heterocyclyl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ⁷ ", R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0197] In one embodiment of a compound of Formula (XVIb), R ^7a is 5-membered or

6-membered heterocyclyl, which is optionally substituted with one, two, three, or four substituents Q ^a ; and

R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^¾ , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0198] In one embodiment of a compound of Formula (XVIb), R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents

Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^¾ , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0199] In one embodiment of a compound of Formula (XVIb), R ^7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^¾ , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0200] In one embodiment of a compound of Formula (XVIb), R ^7a is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3- fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl - pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2- methylpyridin-4-yl, 2-(4-methylpiperazin-l-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, 1- isopropylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-l-yl.

[0201] In one embodiment of a compound of Formula (XVIb), R ^7a is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3- methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2- methylpyridin-4-yl, 2-methoxypyridin-4-yl, l-methylpiperidin-4-yl, or 4-methylpiperazin-l-yl; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

[0202] In one embodiment of a compound of Formula (XVIb),

R ¹ is hydrogen or -OR ^la , where R ^la is Ci_ ₆ alkyl, optionally substituted with one, two, three, four, or five substituents Q;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is Ci-6 alkyl, optionally substituted with one, two, three, four, or five substituents Q;

R ^5a and R ^5b are each independently hydrogen or Ci_ ₆ alkyl, optionally substituted with one, two, three, four, or five substituents Q;

_R 7a is Οή-ΐ4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen.

[0203] In one embodiment of a compound of Formula (XVIb),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is Ci_ ₆ alkyl, optionally substituted with one or more halo;

R ^5a and R ^5b are each independently hydrogen or Ci_ ₆ alkyl;

_R 7a is C¾_i4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q ^a ; and

R ^¾ , R ^7c , R ^7d , and R ^7e are hydrogen.

[0204] In one embodiment of a compound of Formula (XVIb),

R ¹ is hydrogen or methoxy;

R ² is hydrogen;

R ³ and R ⁴ are hydrogen;

R ⁶ is difluoromethyl; R ^a and R ^5b are each independently hydrogen or C ₆ alkyl;