INHIBITORS OF RAF KINASES

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims benefit of U.S. Patent Application No. 62/822,733, filed on March 22, 2019, which is hereby incorporated by reference in its entirety.

BACKGROUND

[0002] RAF kinase functions in the Ras-Raf-MEK-ERK mitogen activated protein kinase (MAPK)

pathway (also known as MAPK/ERK pathway) by phosphorylating and activating MEK. By altering the levels and activities of transcription factors, MAPK leads to altered transcription of genes that are important for the cell cycle. Deregulation of MAPK activity occurs frequently in tumors. Accordingly, therapies that target RAF kinase activity are desired for use in the treatment of cancer and other disorders characterized by aberrant MAPK/ERK pathway signaling.

BRIEF SUMMARY OF THE INVENTION

[0003] Provided herein are inhibitors of the receptor tyrosine kinase effector Raf (RAF), pharmaceutical compositions comprising said compounds, and methods for using said compounds for the treatment of diseases.

[0004] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):

wherein,

G is C=0 or S0 ₂ ;

R is C1-C8 optionally substituted alkyl, -(C1-C8 optionally substituted alkyl ene)- OPO(OH) ₂ , -(C1-C8 optionally substituted alkylene)-S(0)NHMe, C3-C6 optionally substituted cycloalkyl, -(C3-C6 optionally substituted cycloalkylene)-OPO(OH) ₂ , C4-C6 optionally substituted cycloalkylalkyl, -(C3-C6 optionally substituted cycloalkylalkylene)-OPO(OH) ₂ , C3-C6 optionally substituted heterocyclyl, -(C3-C6 optionally substituted heterocyclyl)-OPO(OH) ₂ , C3-C6 optionally substituted heterocyclylalkyl, -(C3-C6 optionally substituted heterocyclylalkyl)- OPO(OH) ₂ ;

X is N, C-H, C-D, C-F, or C-C¾;

R ¹ is C1-C3 optionally substituted alkyl, and q is 0, 1, or 2; or optionally, if q is 2, then two R ¹ groups join to form a fused ring;

R ² is H, D or F;

R ⁴ is halogen, optionally substituted C1-C3 alkyl, -CD3, or optionally substituted

C1-C3 alkoxy;

R ⁶ is H, D, Cl or F;

R ^c is H or D;

Z is selected from:

(a) -NR ^a R ^b , wherein R ^a is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and

R ^b is selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted

heterocyclylalkyl;

(b) wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R ¹¹ groups together form an oxo;

(c) wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4;

W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl); and

each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SC alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 0, 1, or 2; nl is

0, 1, or 2 provided both ml and nl are not both 0; p is 0, 1, or 2; and q is 0, 1 or 2;

W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

0, 1, or 2; n is 0, 1, or 2; ml is 1, or 2; p is

0, 1, 2, or 3; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , - CH2-CH2-, -CH2-CHR ¹¹ -, -CH ₂ -C(R ¹¹ ) ₂ -, -CHR ¹¹ -CH ₂ -, -C(R ¹¹ )2-CH ₂ -, -NH-CH2-, -NH-CHR ¹¹ -, - NH-C(R ¹¹ ) ₂ -, -CH2-NH-, - CHR ¹¹ -NH-, -C(R ¹¹ ) ₂ -NH-, -N(R ¹¹ )-CH ₂ -, -N(R ¹¹ )-CHR ¹¹ -, -N(R ¹¹ )- C(R ¹¹ ) ₂ -, -CH ₂ -N(R ¹¹ )-, -CHR ¹¹ -N(R ¹¹ )-, -C(R ¹¹ )2-N(R ¹¹ )-, -O-CH2-, or -CH2-O-; each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3- C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo; and R ¹² and R ¹³ are each independently selected from H, or optionally substituted C1-C6 alkyl; or

(f)

wherein m is 0, 1, or 2; n is 0,

1, or 2; ml is 0, 1, or 2; p is 0, 1, or 2;

W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2;

each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

and R ¹² and R ¹³ are each independently selected from H, or optionally substituted C1-C6 alkyl;

(g) wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3 provided both m and n are not both 0; p is 0, 1, 2, 3, or 4; and

each R ¹¹ is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

(h) wherein m is 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, or 2; and

each R ¹³ or R ¹⁴ is independently selected from hydrogen, halogen, -CN, optionally substituted Cl- C6 alkyl, or optionally substituted C3-C6 cycloalkyl; each R ¹¹ is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; (i) wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 0, 1, or 2; p is

0, 1, or 2; and q is 0, 1 or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two geminal R ¹¹ groups together form an oxo.

[0005] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II):

wherein,

G is C=O or SO ₂ ;

R is C1-C8 optionally substituted alkyl, -(C1-C8 optionally substituted alkyl ene)- OPO(OH)2, -(C1-C8 optionally substituted alkylene)-S(O)NHMe, C3-C6 optionally substituted cycloalkyl, -(C3-C6 optionally substituted cycloalkylene)-OPO(OH)2, C4-C6 optionally substituted cycloalkylalkyl, -(C3-C6 optionally substituted cycloalkylalkylene)-OPO(OH)2, C3-C6 optionally substituted heterocyclyl, -(C3-C6 optionally substituted heterocyclyl)-OPO(OH)2, C3-C6 optionally substituted heterocyclylalkyl, -(C3-C6 optionally substituted heterocyclylalkyl)- OPO(OH) ₂ ;

X is N, C-H, C-D, C-F, or C-CH ₃ ;

R ¹ is C1-C3 optionally substituted alkyl, and q is 0, 1, or 2; or optionally, if q is 2, then two R ¹ groups join to form a fused ring; R ² is H, D or F;

R ⁴ is halogen, optionally substituted C1-C3 alkyl, -CD3, or optionally substituted

C1-C3 alkoxy;

R ⁶ is H, D, Cl or F;

R ^c is H or D;

Z is selected from:

(a) -NR ^a R ^b , wherein R ^a is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and

R ^b is selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted

heterocyclylalkyl;

wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R ¹¹ groups together form an oxo;

(c) wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4;

W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl); and

each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo; (d) wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 0, 1, or 2; nl is

0, 1, or 2 provided both ml and nl are not both 0; p is 0, 1, or 2; and q is 0, 1 or 2;

W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

0, 1, or 2; n is 0, 1, or 2; ml is 1, or 2; p is

0, 1, 2, or 3; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , - CH2-CH2-, -CH2-CHR ¹¹ -, -CH ₂ -C(R ¹¹ ) ₂ -, -CHR ¹¹ -CH ₂ -, -C(R ¹¹ )2-CH ₂ -, -NH-CH2-, -NH-CHR ¹¹ -, - NH-C(R ¹¹ ) ₂ -, -CH2-NH-, -CHR ¹¹ -NH-, -C(R ¹¹ ) ₂ -NH-, -N(R ¹¹ )-CH ₂ -, -N(R ¹¹ )-CHR ¹¹ -, -N(R ¹¹ )- C(R ¹¹ ) ₂ -, -CH ₂ -N(R ¹¹ )-, -CHR ¹¹ -N(R ¹¹ )-, -C(R ¹¹ )2-N(R ¹¹ )-, -O-CH2-, or -CH2-O-; each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3- C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo; and R ¹² and R ¹³ are each independently selected from H, or optionally substituted C1-C6 alkyl;

(f) m is 0, 1, or 2; n is 0 ,

1, or 2; m1 is 0, 1, or 2; p is 0, 1, or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2;

each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

and R ¹² and R ¹³ are each independently selected from H, or optionally substituted C1-C6 alkyl;

(g) wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3 provided both m

and n are not both 0; p is 0, 1, 2, 3, or 4; and

each R ¹¹ is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

(h) wherein m is 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, or 2; and each R ¹³ or R ¹⁴ is independently selected from hydrogen, halogen, -CN, optionally substituted Cl- C6 alkyl, or optionally substituted C3-C6 cycloalkyl; each R ¹¹ is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SCbalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; (i) wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 0, 1, or 2; p is

0, 1, or 2; and q is 0, 1 or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two geminal R ¹¹ groups together form an oxo.

[0006] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0007] One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the disease or disorder is cancer.

[0008] One embodiment provides a pharmaceutical composition comprising a compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0009] One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the disease or disorder is cancer.

INCORPORATION BY REFERENCE

[0010] All publications, patents, and patent applications mentioned in this specification are herein

incorporated by reference for the specific purposes identified herein.

DETAILED DESCRIPTION OF THE INVENTION

[0011] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of or "consist essentially of the described features.

Definitions

[0012] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0013] "Amino" refers to the -NH ₂ radical.

[0014] "Cyano" refers to the -CN radical.

[0015] "Nitro" refers to the -NO2 radical.

[0016] "Oxa" refers to the -O- radical.

[0017] "Oxo" refers to the =O radical.

[0018] "Thioxo" refers to the =S radical.

[0019] "Imino" refers to the =N-H radical.

[0020] "Oximo" refers to the =N-OH radical.

[0021] "Hydrazino" refers to the =N-NH ₂ radical.

[0022] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms ( e.g ., C ₁ -C ₁₅ alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C ₁ -C ₁₃ alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-Cx alkyl).

In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C ₁ -C ₅ alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C ₁ -C ₄ alkyl). In other

embodiments, an alkyl comprises one to three carbon atoms (e.g., C ₁ -C ₃ alkyl). In other

embodiments, an alkyl comprises one to two carbon atoms (e.g., C ₁ -C ₂ alkyl). In other

embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C ₅ -C ₁₅ alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms ( e.g ., C ₅ -C ₈ alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C ₂ -C ₅ alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C ₃ -C ₅ alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (n -propyl), 1 -methyl ethyl (iso-propyl), 1 -butyl (//-butyl), 1-methylpropyl (.sec- butyl), 2-methylpropyl (iso-butyl), 1,1 -dimethyl ethyl (tert-butyl), 1 -pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethyl silanyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a )2, - C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -OC(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^a , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t R ^a (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0023] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0024] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , - OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -OC(O)-N(R ^a ) ₂ , - N(R ^a )C(O)R ^a , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t R ^a (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),

carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0025] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,

trimethylsilanyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a ) ₂ , - N(R ^a )C(O)OR ^a , -OC(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^a , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t R ^a (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0026] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, «-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms ( e.g ., C ₁ -C ₈ alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C ₁ -C ₅ alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C ₁ -C ₄ alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C ₁ -C ₃ alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C ₁ -C ₂ alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C ₅ -C ₈ alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C ₂ -C ₅ alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C ₃ -C ₅ alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -0C(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , - C(O)OR ^a , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -0C(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^a , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t R ^a (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0027] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C ₂ -C ₈ alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C ₂ -C ₅ alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C ₂ -C ₄ alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C ₂ -C ₃ alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C ₂ alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms ( e.g ., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon

atoms (e.g., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a )2, -C(O)R ^a , - C(O)OR ^a , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -0C(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^a , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t R ^a (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0028] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms.

The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C ₂ -C ₈ alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C ₂ -C ₅ alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C ₂ -C ₃ alkynylene). In other embodiments, an alkynylene comprises two carbon atoms

(e.g., C ₂ alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C ₅ -C ₈ alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , - C(O)OR ^a , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -OC(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^a , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t R ^a (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,

hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0029] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted

heteroarylalkyl, -R ^b -OR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b - C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -O-R ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b - N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t OR ^a (where t is 1 or 2) and -R ^b -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0030] "Aralkyl" refers to a radical of the formula -R ^c -aryl where R ^c is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0031] "Aralkenyl" refers to a radical of the formula -R ^d -aryl where R ^d is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0032] "Aralkynyl" refers to a radical of the formula -R ^e -aryl, where R ^e is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0033] " Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -0-R ^c -aryl where R ^c is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0034] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical

consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbomyl (i.e., bicyclo[2.2.1]heptanyl), norbomenyl, decalinyl, 7, 7-dimethyl -bicyclo[2.2. l]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b -OR ^a , -R ^b -0C(0)-R ^a , -R ^b -0C(0)-0R ^a , -R ^b - 0C(0)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(0)R ^a , -R ^b -C(0)0R ^a , -R ^b -C(0)N(R ^a ) ₂ , -R ^b -0-R ^c -C(0)N(R ^a ) ₂ , - R ^b -N(R ^a )C(0)0R ^a , -R ^b -N(R ^a )C(0)R ^a , -R ^b -N(R ^a )S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t OR ^a (where t is 1 or 2) and -R ^b -S(0) _t N(R ^a ) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0035] "Carbocyclylalkyl" refers to a radical of the formula -R ^c -carbocyclyl where R ^c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0036] "Carbocyclylalkynyl" refers to a radical of the formula -R ^c -carbocyclyl where R ^c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0037] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- R ^c -carbocyclyl where R ^c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0038] As used herein,“carboxylic acid bioisostere” refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to,

[0039] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0040] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl,

2,2,2-trifluoroethyl, 1 -fluoromethyl -2 -fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0041] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted

heteroarylalkyl, -R ^b -OR ^a , -R ^b -OC(0)-R ^a , -R ^b -OC(0)-OR ^a , -R ^b -OC(0)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b - C(0)R ^a , -R ^b -C(0)OR ^a , -R ^b -C(0)N(R ^a ) ₂ , -R ^b -0-R ^c -C(0)N(R ^a ) ₂ , -R ^b -N(R ^a )C(0)OR ^a , -R ^b - N(R ^a )C(0)R ^a , -R ^b -N(R ^a )S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t OR ^a (where t is 1 or 2) and -R ^b -S(0) _t N(R ^a ) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0042] "/V-heterocyclyl" or“N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An A -heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N- heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1- pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0043] "C-heterocyclyl" or“C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C- heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2- piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0044] "Heterocyclylalkyl" refers to a radical of the formula -R ^c -heterocyclyl where R ^c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the

heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0045] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- R ^c -heterocyclyl where R ^c is an alkylene chain as defined above. If the heterocyclyl is a

nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group. [0046] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that

comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,

benzo[£][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl,

6.7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,

5.6.7.8.9.10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,

5.6.7.8.9.10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl,

5.8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl,

1 -phenyl- 1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl,

pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7, 8-tetrahydroquinazolinyl,

5.6.7.8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,

6.7.8.9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidiny l,

5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl,

optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b -OR ^a , -R ^b -0C(0)-R ^a , -R ^b -0C(0)-0R ^a , -R ^b -0C(0)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(0)R ^a , -R ^b -C(0)0R ^a , -R ^b - C(0)N(R ^a ) ₂ , -R ^b -0-R ^c -C(0)N(R ^a ) ₂ , -R ^b -N(R ^a )C(0)0R ^a , -R ^b -N(R ^a )C(0)R ^a , -R ^b -N(R ^a )S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t OR ^a (where t is 1 or 2) and -R ^b - S(0) _t N(R ^a ) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a straight or branched alkylene or alkenyl ene chain, and R ^c is a straight or branched alkylene or alkenyl ene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0047] "/V-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An A-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0048] "C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0049] "Heteroarylalkyl" refers to a radical of the formula -R ^c -heteroaryl, where R ^c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0050] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- R ^c -heteroaryl, where R ^c is an alkylene chain as defined above. If the heteroaryl is a

nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is

optionally substituted as defined above for a heteroaryl group.

[0051] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as ( R )- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers ( e.g cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term“geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term“positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0052] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0053] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of ² H, ³ H, ¹¹ C, ¹³ C and/or ¹⁴ C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0054] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³ C- or ¹⁴ C-enriched carbon are within the scope of the present disclosure.

[0055] The compounds of the present disclosure optionally contain unnatural proportions of atomic

isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium ( ² H), tritium (¾), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C). Isotopic substitution with ² H, ^U C, ¹³ C, ¹⁴ C, ¹⁵ C, ¹² N, ¹³ N, ¹⁵ N, ¹⁶ N, ¹⁶ 0, ¹⁷ 0, ¹⁴ F, 1 ⁵ F, ¹⁶ F, ¹⁷ F, ¹⁸ F, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ³⁵ C1, ³⁷ C1, ⁷⁹ Br, ⁸¹ Br, ¹²⁵ I are all contemplated. In some embodiments, isotopic substitution with ¹⁸ F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0056] In certain embodiments, the compounds disclosed herein have some or all of the ¾ atoms replaced with ² H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0057] Deuterium substituted compounds are synthesized using various methods such as described in:

Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0058] Deuterated starting materials are readily available and are subjected to the synthetic methods

described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0059] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as

iodomethane-d ₃ (CD ₃ I), are readily available and may be employed to transfer a deuterium- substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD ₃ I is illustrated, by way of example only, in the reaction schemes below.

[0060] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAID ₄ ), are employed to

transfer deuterium under reducing conditions to the reaction substrate. The use of L1AID ₄ is illustrated, by way of example only, in the reaction schemes below.

[0061] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.

[0062] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another

embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another

embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable ¹ H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0063] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the heteroaromatic RAF inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically

acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0064] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bi sulfates, sulfites, bi sulfites, nitrates, phosphates,

monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al.,

"Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0065] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological

effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N/N-dibenzyl ethyl enedi ami ne, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N- methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0066] "Pharmaceutically acceptable solvate" refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in either unsolvated as well as solvated forms.

The term“subject” or“patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as

chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0067] As used herein,“treatment” or“treating,” or“palliating” or“ameliorating” are used

interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. The RAF Family of Kinases

[0068] The RAF kinases are a family of serine/thronine protein kinases constitute core components of the RAS-RAF-MEK-ERK mitogen activated protein kinase (MAPK) signalling cascade (also known as the MAPK/ERK pathway), a pathway that mediates signals from cell surface receptors to the nucleus to regulate cell growth, differentiation and survival. The RAF proteins are related to retroviral oncogenes and are structurally conserved from metazoans to mammals, as is the

MAPK/ERK pathway. Their dysregulation leads to uncontrolled cellular proliferation, survival and dedifferentiation. Consequently, RAF kinases are altered or inappropriately activated in a majority of cancers.

[0069] The MAPK/ERK signalling pathway is a network of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a signaling molecule binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a protein and produces some change in the cell, such as cell division. The pathway includes many proteins, which communicate by adding phosphate groups to a neighboring protein, which acts as a molecular "on" or "off switch, and overall the pathway can be divided into 3 steps: (i) Ras activation, (ii) a kinase signal transduction cascade, and (iii) regulation of translation and transcription. Briefly, an extracellular mitogen or a signaling molecule binds to the membrane receptor. This allows Ras (a small GTPase) to swap its GDP for a GTP and become active. Activated Ras activates the protein kinase activity of RAF kinase. RAF kinase

phosphorylates and activates MEK (MEK1 and MEK2). MEK then phosphorylates and activates a MAPK (also known as ERK). MAPK activation regulates activities of several transcription factors and also alters the translation of mRNA to proteins. By altering the levels and activities of transcription factors, MAPK leads to altered transcription of genes that are important for the cell cycle.

[0070] There are three known mammalian RAF isoforms: C-RAF (also known as RAF-1, or c-RAF-1), B- RAF, and A-RAF. All RAF kinases share a common modular structure consisting of 3 conserved regions (CR1, CR2, and CR3) with distinct functions. CR1 contains (i) a Ras-binding domain (RBD), which is necessary for the interaction with Ras and with membrane phospholipids required for membrane recruitment, and (ii) a cysteine-rich domain (CRD), which is a secondary Ras- binding site and also necessary for the interaction of CR1 with the kinase domain for RAF autoinhibition. CR2 contains important inhibitory phosphorylation sites participating in the negative regulation of Ras binding and RAF activation. CR3 features the kinase domain, including the activation segment, whose phosphorylation is crucial for kinase activation.

[0071] Functionally, the RAF structure can be split into a regulatory N-terminal region, containing the

RBD, which is critical for activation as well as inhibitory phosphorylation sites, and a catalytic C- terminal region, which includes phosphorylation sites necessary for the kinase activation. The regulatory domain restrains the activity of the kinase domain, and its removal results in constitutive oncogenic activation. However, the activity of the isolated C-RAF kinase domain is subjected to further regulation and can be stimulated by phorbol esters, v-Src, and phosphorylation.

[0072] The common and key step in the activation of all 3 RAF kinase isoforms is membrane recruitment by a Ras family protein. The RAF kinases are located in the cytosol in their inactive state when bound to 14-3-3 proteins. In the presence of active Ras, they translocate to the plasma membrane.

Membrane translocation triggers further activation events, such as the binding of PP2A to dephosphorylate the inhibitory pS259 site in RAF-1 (and presumably the corresponding sites in A- RAF and B-RAF) and the co-localization with the kinases responsible for the multiple activating phosphorylations. The sequences forming the binding interface are well conserved in the RAF as well as Ras family indicating that several members of the Ras family have the ability to bind RAF kinases. H-Ras, N-Ras, and K-Ras stimulate all 3 RAF isoforms and are the only Ras proteins that activate B-RAF. In contrast, A-RAF is also activated by R-Ras3, while C-RAF responds weakly to R-Ras3, Rit, and TC21as well. But, all RAF kinases share MEK1/2 kinases as substrates. MEK1/2 in turn activate ERK1/2, and this pathway regulates many cellular functions such as cell proliferation, differentiation, migration, or apoptosis.

C-RAF

[0073] C-RAF was first to be identified and is a ubiquitously expressed isoform. In humans, C-RAF is encoded by the RAF1 gene. C-RAF also has a known splice variant preferentially expressed in the muscle and brain. C-RAF plays a critical role in mediating the cellular effects of growth factor signals. In the inactive state, C-RAF exists in a closed conformation in which the N-terminal regulatory region folds over and occludes the catalytic region. This conformation is stabilized by a 14-3-3 dimer binding to an N-terminal site, phospho-S259 (pS259), and a C-terminal site, pS621. Dephosphorylation of pS259 at the cell membrane by specific phosphatases (PP2A, PP1) releases 14-3-3 from its N-terminal binding site in C-RAF, thereby allowing conformational changes to occur that unmask the RBD and CRD domains in the CR1 region to enable Ras binding and membrane recruitment.

B-RAF

[0074] B-RAF is encoded in humans by the BRAF gene, also known as proto-oncogene B-RAF and v-RAF murine sarcoma viral oncogene homolog B. Alternative splicing gives rise to multiple B-RAF isoforms which are differentially expressed in various tissues. Whereas activation of A-RAF and C- RAF requires both phosphorylation and dephosphorylation of certain residues, as well as binding to other proteins, B-RAF becomes activated immediately upon translocation to the plasma membrane. B-RAF exhibits higher basal kinase activity than A-RAF and C-RAF. B-RAF requires Ras and 14- 3-3 binding for its activation, and is inhibited or activated by PKA depending on the levels of 14-3- 3 expression, which need to be high for permitting activation. B-RAF activity is also regulated by splicing. B-RAF isoforms containing exon 8b are more phosphorylated on the inhibitory S365 site, leading to an increased interaction with 14-3-3 and strengthening the inhibitory interaction between N-terminal regulatory domain and kinase domain, altogether resulting in lower kinase activity. A-RAF

[0075] Serine/threonine-protein kinase A-RAF or A-RAF is an enzyme encoded by the ARAF gene in humans. There are 2 known splice isoforms of A-RAF - DA-RAFl and D-RAF2. They lack the kinase domain and act as dominant inhibitory mutants of Ras and ARF GTPases. DA-RAFl is a positive regulator of myogenic differentiation by mediating the inhibition of the ERK pathway required for differentiation. There are several ways A-RAF is different from the other RAF kinases. A-RAF is the only steroid hormone-regulated Raf isoform. In addition, the A-RAFprotein has amino acid substitutions in a negatively charged region upstream of the kinase domain (N-region), which contributes to its low basal activity. A-RAF is also only weakly activated by oncogenic H- Ras and Src and also displays low kinase activity towards MEK (the lowest kinase activity towards MEK proteins in the Raf kinase family). In addition to phosphorylating MEK, A-RAF also inhibits MST2, a tumor suppressor and pro-apoptotic kinase not found in the MAPK pathway. By inhibiting MST2, A-RAF prevents apoptosis from occurring. However, this inhibition is only occurs when the splice factor heterogenous nuclear ribonucleoprotein H (hnRNP H) maintains the expression of a full-length A-RAF protein. Tumorous cells often overexpress hnRNP H which leads to full-length expression of A-Raf which then inhibits apoptosis, allowing cancerous cells that should be destroyed to stay alive. A-RAF also binds to pyruvate kinase M2 (PKM2), again outside the MAPK pathway. PKM2 is an isozyme of pyruvate kinase that is responsible for the Warburg effect in cancer cells. A-RAF upregulates the activity of PKM2 by promoting a conformational change in PKM2. This causes PKM2 to transition from its low-activity dimeric form to a highly active tetrameric form. This causes more glucose carbons to be converted to pyruvate and lactate, producing energy for the cell, linking A-Raf to energy metabolism regulation and cell

transformation, both of which are very important in turn ori genesis.

RAF Kinase Inhibitors

[0076] Aberrant activation of the MAPK/ERK pathway is frequently found in various cancers and is a target for cancer therapeutics. In particular, B-RAF has emerged as one of the most attractive molecular targets for cancer therapeutics because somatic mutations of B-RAF have frequently been found in human tumors. Approximately 20% of all cancer samples tested to date harbor mutations in B-RAF. B-RAF-V600E, a missense mutation in the kinase domain generated by the substitution of glutamic acid with valine at position 600 is the most common B-RAF mutation. C- RAF is mutated in ~ 1% of the various tumor types tested and the rate of mutations in A-RAF is even lower. B-RAF and C-RAF form both homo- and heterodimers as part of their activation mechanism and A-RAF stabilizes the B-RAF:C-RAF complexes to sustain signaling efficiency. Also, it is C-RAF, not B-RAF, that transmits signals from oncogenic RAS to MEK. Therefore, in different contexts, each of the RAF isoforms act as a potential therapeutic target.

[0077] Sorafenib was the first RAF inhibitor to enter clinical trials. Sorafenib is a broad specificity drug that inhibits additional kinases, including vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3), platelet-derived growth factor receptor family (PDGFR-b and KIT) and FLT3. Clinical trials showed no correlation between the clinical responses with B-RAF mutation status, indicating it is a poor inhibitor of B-RAF. This led to the development of a new generation of B-RAF inhibitors, including, but not limited to vemurafenib, SB-590885, and dabrafenib (GSK2118436). Although the initial results of the clinical studies in B-RAF-mutant melanoma were encouraging, as clinical testing began in other B-RAF-mutated cancers (such as thyroid and colorectal cancers) it became apparent that tumors of different cell types harboring B-RAF mutations responded differently to selective B-RAF inhibition. Moreover, the existence of both primary and secondary resistance to RAF inhibition poses as one of the greatest challenges to the progress of RAF kinase inhibitor therapy. The mechanisms of resistance fall into two broad categories. Intrinsic/primary resistance is displayed by approximately 50% of patients. The other 50% of the patients initially respond (>30% tumor shrinkage) to RAF inhibitor but subsequently develop progressive disease associated with acquired/secondary resistance to RAF inhibitor. These two categories are not mutually exclusive because nearly all responders have remaining disease and, thus, may display intrinsic resistance. The determinants of primary RAF inhibitor resistance seem to vary with tumor type, with alteration in RTK signaling also being involved. Potential mechanisms of secondary B-RAF inhibitor resistance include, but are not limited to, reactivation of ERK1/2 pathways, upregulation of RTK signaling, the upregulation of receptor tyrosine kinases, mutations in RAS, and upregulation of COT. B-Raf alternative splicing and amplification of B- RAF-V600E have also been implicated in ~ 30 and 20% of patients, respectively. Moreover, RAF kinase inhibitors cause paradoxical activation of the MAPK pathway, which, in some instances, leads to the development of secondary RAS mutation-driven malignancies. As such, there is a need in the field for new RAF kinase inhibitors that overcome the existing pitfalls and challenges posed by the current inhibitors.

Heteroaromatic RAF Inhibitory Compounds

[0078] In one aspect, provided herein is a heteroaromatic RAF inhibitory compound.

[0079] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):

wherein,

G is C=0 or S0 ₂ ;

R is C1-C8 optionally substituted alkyl, -(C1-C8 optionally substituted alkyl ene)- OPO(OH)2, -(C1-C8 optionally substituted alkylene)-S(0)NHMe, C3-C6 optionally substituted cycloalkyl, -(C3-C6 optionally substituted cycloalkylene)-OPO(OH)2, C4-C6 optionally substituted cycloalkylalkyl, -(C3-C6 optionally substituted cycloalkylalkylene)-OPO(OH)2, C3-C6 optionally substituted heterocyclyl, -(C3-C6 optionally substituted heterocyclyl)-OPO(OH)2, C3-C6 optionally substituted heterocyclylalkyl, -(C3-C6 optionally substituted heterocyclylalkyl)- OPO(OH) ₂ ;

X is N, C-H, C-D, C-F, or C-CH ₃ ;

R ¹ is C1-C3 optionally substituted alkyl, and q is 0, 1, or 2; or optionally, if q is 2, then two R ¹ groups join to form a fused ring;

R ² is H, D or F;

R ⁴ is halogen, optionally substituted C1-C3 alkyl, -CD3, or optionally substituted

C1-C3 alkoxy;

R ⁶ is H, D, Cl or F;

R ^c is H or D;

Z is selected from:

(a) -NR ^a R ^b , wherein R ^a is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and

R ^b is selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted

heterocyclylalkyl; wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R ¹¹ groups together form an oxo;

wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4;

W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl); and

each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 0, 1, or 2; nl is

0, 1, or 2 provided both ml and nl are not both 0; p is 0, 1, or 2; and q is 0, 1 or 2;

W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo; (e) wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 1, or 2; p is

0, 1, 2, or 3; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , - CH2-CH2-, -CH2-CHR ¹¹ -, -CH ₂ -C(R ¹¹ ) ₂ -, -CHR ¹¹ -CH ₂ -, -C(R ^{1 1} )2-CH ₂ -, -NH-CH2-, -NH-CHR ¹¹ -, - NH-C(R ¹¹ ) ₂ -, -CH2-NH-, -CHR ^{1 1} -NH-, -C(R ^{1 1} ) ₂ -NH-, -N(R ^{1 1} )-CH ₂ -, -N(R ^{1 1} )-CHR ¹¹ -, -N(R ¹¹ )- C(R ¹¹ ) ₂ -, -CH ₂ -N(R ¹¹ )-, -CHR ^{1 1} -N(R ¹¹ )-, -C(R ^{1 1} )2-N(R ¹¹ )-, -O-CH2-, or -CH2-O-; each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO ₂ alkyl, optionally substituted C3- C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo; and R ¹² and R ¹³ are each independently selected from H, or optionally substituted C1-C6 alkyl;

(f) m is (0, 1, or 2; n is (0,

1, or 2; ml is 0, 1, or 2; p is 0, 1, or 2;

W is O, S, S(O), SO ₂ , NH or N(optionally substituted C1-C6 alkyl), CH ₂ , CHR ¹¹ , or C(R ¹¹ )2;

each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

and R ¹² and R ¹³ are each independently selected from H, or optionally substituted C1-C6 alkyl;

(g) wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3 provided both m

and n are not both 0; p is 0, 1, 2, 3, or 4; and each R ¹¹ is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl,

optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

(h) wherein m is 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, or 2; and

each R ¹³ or R ¹⁴ is independently selected from hydrogen, halogen, -CN, optionally substituted Cl- C6 alkyl, or optionally substituted C3-C6 cycloalkyl; each R ¹¹ is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SCbalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;

(i) wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 0, 1, or 2; p is

0, 1, or 2; and q is 0, 1 or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two geminal R ¹¹ groups together form an oxo.

[0080] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II):

wherein,

G is C=O or SO ₂ ;

R is C1-C8 optionally substituted alkyl, -(C1-C8 optionally substituted alkyl ene)- OPO(OH)2, -(C1-C8 optionally substituted alkylene)-S(0)NHMe, C3-C6 optionally substituted cycloalkyl, -(C3-C6 optionally substituted cycloalkylene)-OPO(OH)2, C4-C6 optionally substituted cycloalkylalkyl, -(C3-C6 optionally substituted cycloalkylalkylene)-OPO(OH)2, C3-C6 optionally substituted heterocyclyl, -(C3-C6 optionally substituted heterocyclyl)-OPO(OH)2, C3-C6 optionally substituted heterocyclylalkyl, -(C3-C6 optionally substituted heterocyclylalkyl)- OPO(OH) ₂ ;

X is N, C-H, C-D, C-F, or C-C¾;

R ¹ is C1-C3 optionally substituted alkyl, and q is 0, 1, or 2; or optionally, if q is 2, then two R ¹ groups join to form a fused ring;

R ² is H, D or F;

R ⁴ is halogen, optionally substituted C1-C3 alkyl, -CD3, or optionally substituted

C1-C3 alkoxy;

R ⁶ is H, D, Cl or F;

R ^c is H or D;

Z is selected from:

(a) -NR ^a R ^b , wherein R ^a is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and

R ^b is selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted

heterocyclylalkyl; (b) wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R ¹¹ groups together form an oxo;

wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4;

W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl); and

each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 0, 1, or 2; nl is

0, 1, or 2 provided both ml and nl are not both 0; p is 0, 1, or 2; and q is 0, 1 or 2;

W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo; (e) wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 1, or 2; p is

0, 1, 2, or 3; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , - CH2-CH2-, -CH2-CHR ¹¹ -, -CH ₂ -C(R ¹¹ ) ₂ -, -CHR ¹¹ -CH ₂ -, -C(R ¹¹ )2-CH ₂ -, -NH-CH2-, -NH-CHR ¹¹ -, - NH-C(R ¹¹ ) ₂ -, -CH2-NH-, -CHR ¹¹ -NH-, -C(R ¹¹ ) ₂ -NH-, -N(R ¹¹ )-CH ₂ -, -N(R ¹¹ )-CHR ¹¹ -, -N(R ¹¹ )- C(R ¹¹ ) ₂ -, -CH ₂ -N(R ¹¹ )-, -CHR ¹¹ -N(R ¹¹ )-, -C(R ¹¹ )2-N(R ¹¹ )-, -0-CH2-, or -CH2-O-; each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3- C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo; and R ¹² and R ¹³ are each independently selected from H, or optionally substituted C1-C6 alkyl;

(f) m is 0 , 1, or 2; n is 0 ,

1, or 2; ml is 0, 1, or 2; p is 0, 1, or 2;

W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ ) ₂ ;

each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

and R ¹² and R ¹³ are each independently selected from H, or optionally substituted C1-C6 alkyl;

(g) wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3 provided both m and n are not both 0; p is 0, 1, 2, 3, or 4; and each R ¹¹ is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl,

optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

wherein m is 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, or 2; and each R ¹³ or R ¹⁴ is independently selected from hydrogen, halogen, -CN, optionally substituted Cl- C6 alkyl, or optionally substituted C3-C6 cycloalkyl; each R ¹¹ is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SCbalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;

wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 0, 1, or 2; p is 0, 1, or 2; and q is 0, 1 or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two geminal R ¹¹ groups together form an oxo.

[0081] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein G is C=0.

[0082] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R ^c is hydrogen. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R ^c is deuterium. [0083] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R ² is hydrogen or deuterium. One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R ² is F.

[0084] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is hydrogen or deuterium. One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is F.

[0085] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein X is N. One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein X is C-H or C-D. One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein X is C-F.

[0086] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted Cl alkyl. One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein q is 0. One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein q is 1. One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is CFF, q is 1, and R ¹ is positioned to provide a 3-methylmorpholino.

[0087] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R is C1-C8 optionally substituted alkyl, C3-C6 optionally substituted cycloalkyl, C4-C6 optionally substituted cycloalkylalkyl, C3-C6 optionally substituted

heterocyclyl, or C3-C6 optionally substituted heterocyclylalkyl.

[0088] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R is C1-C8 optionally substituted alkyl. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein the C1-C8 optionally substituted alkyl is a C2 optionally substituted alkyl.

[0089] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R is -(C1-C8 optionally substituted alkyl ene)-OPO(OH)2. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein the -(C1-C8 optionally substituted alkyl ene)-OPO(OH)2 is a C2 optionally substituted alkylene.

[0090] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R is C3-C6 optionally substituted cycloalkyl. One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R is C4-C6 optionally substituted cycloalkylalkyl. One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R is C3-C6 optionally substituted heterocyclyl. One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R is C3-C6 optionally substituted heterocyclyl alkyl.

[0091] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is halogen. One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is optionally substituted C1-C3 alkyl. One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is methyl.

[0092] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein Z is -NR ^a R ^b , wherein R ^a is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted

heterocyclyl, or optionally substituted heterocyclylalkyl; and R ^b is selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R ^a is H. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R ^a is optionally substituted alkyl. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R ^b is optionally substituted alkyl.

[0093] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt

wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SOialkyk optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocy cl yl alkyl; or two R ¹¹ groups together form an oxo. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein m is 0. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein m is 2. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein m is 3. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein p is 0. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein p is 1. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein p is 2. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein p is 1. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ is optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl. Another embodiment provides the compound of Formula (I) or (II) or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl is substituted with at least a halogen.

[0094] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt

or solvate thereof, wherein wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or

4;

W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl); and

each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SOialkyf optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein W is O. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein W is S. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1, and n is 1. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1, and n is 2. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ is optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl is substituted with at least a halogen.

[0095] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt

wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 0,

1, or 2; nl is 0, 1, or 2 provided both ml and nl are not both 0; p is 0, 1, or 2; and q is 0, 1 or 2;

W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1, and n is 1. Another embodiment provides the compound of Formula (I) or (II), or

pharmaceutically acceptable salt or solvate thereof, wherein m is 0, and n is 2. Another

embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein ml is 0, and nl is 2. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein ml is 1, and nl is 1. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein W is O. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein W is CH2.

Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein W is CHR ¹¹ . Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein W is C(R ¹¹ )2. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ is halogen and q is 1. [0096] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt

or solvate thereof, wherein wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is

1, or 2; p is 0, 1, 2, or 3; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2,

CHR ¹¹ , -CH2-CH2-, -CH2-CHR ¹¹ -, -CH ₂ -C(R ¹¹ ) ₂ -, -CHR ¹¹ -CH ₂ -, -C(R ¹¹ )2-CH ₂ -, -NH-CH2-, -NH- CHR ¹¹ -, -NH-C(R ¹¹ ) ₂ -, -CH2-NH-, -CHR ¹¹ -NH-, -C(R ¹¹ ) ₂ -NH-, -N(R ¹¹ )-CH ₂ -, -N(R ¹¹ )-CHR ¹¹ -, - N(R ¹¹ )-C(R ¹¹ ) ₂ -, -CH ₂ -N(R ¹¹ )-, -CHR ¹¹ -N(R ¹¹ )-, -C(R ¹¹ )2-N(R ¹¹ )-; each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo; and R ¹² and R ¹³ are each independently selected from H, or optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein m is 0, n is 1, and ml is 1; and

W is -O-CH2-, or -CH2-O-.

[0097] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt

or solvate thereof, wherein Z is wherein m is 0,

1, or 2; n is 0, 1, or 2; ml is 0, 1, or 2; p is 0, 1, or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2; each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo; and R ¹² and R ¹³ are each independently selected from H, or optionally substituted Cl- C6 alkyl. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein W is O. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein W is C¾, or CHR ¹¹ . Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein ml is 0. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein ml is 1. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 1. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 0. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein m is 0 and n is 1.

[0098] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt

or solvate thereof, wherein wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3 provided both m and n are not both 0; p is 0, 1, 2, 3, or 4; and

each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SOialkyf optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocy cl yl alkyl. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1, and n is 1. Another

embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1, and n is 2. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein p is 1. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein p is 2. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein at least one R ¹¹ is attached to an alkene carbon. Another embodiment provides the compound of Formula (I) or (II), or

pharmaceutically acceptable salt or solvate thereof, wherein at least one R ¹¹ is not attached to an alkene carbon. Another embodiment provides the compound of Formula (I) or (II), or

pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ is optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein p is 0. [0099] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt

or solvate thereof, wherein wherein m is 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, or 2; and each R ¹³ or R ¹⁴ is independently selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocy cl yl alkyl. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein m is 2, and n is 1. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein p is 0. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein p is 1. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein one of R ¹³ or R ¹⁴ is not hydrogen. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein one of R ¹³ or R ¹⁴ is optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁴ is optionally substituted C1-C6 alkyl.

[00100] One embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt

or solvate thereof, wherein wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is

0, 1, or 2; p is 0, 1, or 2; and q is 0, 1 or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SCbalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally

substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two geminal R ¹¹ groups together form an oxo. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein W is O. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein m is 2, and n is 1. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein ml is 1 or 2. Another embodiment provides the compound of Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, wherein p is 0 or 1, and q is 0 or 1.

[00101] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, of Formula (I) having the structure of Formula (la):

wherein,

G is C=0 or S0 ₂ ;

R is C1-C8 optionally substituted alkyl, -(C1-C8 optionally substituted alkyl ene)- OPO(OH)2, C3-C6 optionally substituted cycloalkyl, -(C3-C6 optionally substituted

cycloalkylene)-OPO(OH)2, C4-C6 optionally substituted cycloalkylalkyl, -(C3-C6 optionally substituted cycloalkylalkylene)-OPO(OH)2, C3-C6 optionally substituted heterocyclyl, -(C3-C6 optionally substituted heterocyclyl)-OPO(OH)2, C3-C6 optionally substituted heterocyclylalkyl, - (C3-C6 optionally substituted heterocyclylalkyl)-OPO(OH)2;

X is N, C-H, C-D, C-F, or C-CH ₃ ;

R ¹ is C1-C3 optionally substituted alkyl, and q is 0, 1, or 2;

R ² is H, D or F;

R ⁴ is halogen, optionally substituted C1-C3 alkyl, -CD ₃ , or optionally substituted

C1-C3 alkoxy;

R ⁶ is H, D, Cl or F;

R ^c is H or D;

Z is selected from: (a) -NR ^a R ^b , wherein R ^a is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and

R ^b is selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted

heterocyclylalkyl;

wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SCbalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R ¹¹ groups together form an oxo;

wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4;

W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl); and

each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 0, 1, or 2; nl is

0, 1, or 2 provided both ml and nl are not both 0; p is 0, 1, or 2; and q is 0, 1 or 2;

W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 1, or 2; p is

0, 1, 2, or 3; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , - CH2-CH2-, -CH2-CHR ¹¹ -, -CH ₂ -C(R ¹¹ ) ₂ -, -CHR ¹¹ -CH ₂ -, -C(R ¹¹ )2-CH ₂ -, -NH-CH2-, -NH-CHR ¹¹ -, - NH-C(R ¹¹ ) ₂ -, -CH2-NH-, -CHR ¹¹ -NH-, -C(R ¹¹ ) ₂ -NH-, -N(R ¹¹ )-CH ₂ -, -N(R ¹¹ )-CHR ¹¹ -, -N(R ¹¹ )- C(R ¹¹ ) ₂ -, -CH2-N(R ¹¹ )-, -CHR ¹¹ -N(R ¹¹ )-, -C(R ¹¹ )2-N(R ¹¹ )-; each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo; and R ¹² and R ¹³ are each independently selected from H, or optionally substituted Cl- C6 alkyl;

wherein m is 0, 1, or 2; n is 0,

1, or 2; ml is 0, 1, or 2; p is 0, 1, or 2;

W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2;

each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

and R ¹² and R ¹³ are each independently selected from H, or optionally substituted C1-C6 alkyl; wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3 provided both m and n are not both 0; p is 0, 1, 2, 3, or 4; and

each R ¹¹ is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C 1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

wherein m is 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, or 2; and each R ¹³ or R ¹⁴ is independently selected from hydrogen, halogen, -CN, optionally substituted C l- C6 alkyl, or optionally substituted C3-C6 cycloalkyl; each R ¹¹ is independently selected from -OH, halogen, optionally substituted C 1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SCbalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or

wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 0, 1, or 2; p is 0, 1, or 2; and q is 0, 1 or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C 1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C 1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two geminal R ¹¹ groups together form an oxo. [00102] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, of Formula (II) having the structure of Formula (Ha):

wherein,

G is C=0 or S0 ₂ ;

R is C1-C8 optionally substituted alkyl, -(C1-C8 optionally substituted alkyl ene)- OPO(OH)2, C3-C6 optionally substituted cycloalkyl, -(C3-C6 optionally substituted

cycloalkylene)-OPO(OH)2, C4-C6 optionally substituted cycloalkylalkyl, -(C3-C6 optionally substituted cycloalkylalkylene)-OPO(OH)2, C3-C6 optionally substituted heterocyclyl, -(C3-C6 optionally substituted heterocyclyl)-OPO(OH)2, C3-C6 optionally substituted heterocyclylalkyl, - (C3-C6 optionally substituted heterocyclylalkyl)-OPO(OH)2;

X is N, C-H, C-D, C-F, or C-CH ₃ ;

R ¹ is C1-C3 optionally substituted alkyl, and q is 0, 1, or 2;

R ² is H, D or F;

R ⁴ is halogen, optionally substituted C1-C3 alkyl, -CD3, or optionally substituted

C1-C3 alkoxy;

R ⁶ is H, D, Cl or F;

R ^c is H or D;

Z is selected from:

(a) -NR ^a R ^b , wherein R ^a is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and

R ^b is selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted

heterocyclylalkyl; wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SCbalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocy cl yl alkyl; or two R ¹¹ groups together form an oxo;

wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4;

W is O, S, S(O), S02, NH or N(optionally substituted C1-C6 alkyl); and

each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SCbalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 0, 1, or 2; nl is

0, 1, or 2 provided both ml and nl are not both 0; p is 0, 1, or 2; and q is 0, 1 or 2;

W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo; wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 1, or 2; p is

0, 1, 2, or 3; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , - CH2-CH2-, -CH2-CHR ¹¹ -, -CH ₂ -C(R ¹¹ ) ₂ -, -CHR ¹¹ -CH ₂ -, -C(R ¹¹ )2-CH ₂ -, -NH-CH2-, -NH-CHR ¹¹ -, - NH-C(R ¹¹ ) ₂ -, -CH2-NH-, -CHR ¹¹ -NH-, -C(R ¹¹ ) ₂ -NH-, -N(R ¹¹ )-CH ₂ -, -N(R ¹¹ )-CHR ¹¹ -, -N(R ¹¹ )- C(R ¹¹ ) ₂ -, -CH2-N(R ¹¹ )-, -CHR ¹¹ -N(R ¹¹ )-, -C(R ¹¹ )2-N(R ¹¹ )-; each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo; and R ¹² and R ¹³ are each independently selected from H, or optionally substituted Cl- C6 alkyl;

1, or 2; ml is 0, 1, or 2; p is 0, 1, or 2;

W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2;

each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

and R ¹² and R ¹³ are each independently selected from H, or optionally substituted C1-C6 alkyl;

wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3 provided both m and n are not both 0; p is 0, 1, 2, 3, or 4; and each R ¹¹ is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl,

optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo;

wherein m is 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, or 2; and each R ¹³ or R ¹⁴ is independently selected from hydrogen, halogen, -CN, optionally substituted Cl- C6 alkyl, or optionally substituted C3-C6 cycloalkyl; each R ¹¹ is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SCbalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or

wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 0, 1, or 2; p is 0, 1, or 2; and q is 0, 1 or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two geminal R ¹¹ groups together form an oxo.

[00103] One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein G is C=0.

[00104] One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R ^c is hydrogen. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R ^c is deuterium. [00105] One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R ² is hydrogen or deuterium. One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R ² is F.

[00106] One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is hydrogen or deuterium. One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is F.

[00107] One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein X is N. One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein X is C-H or C-D. One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein X is C-F.

[00108] One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted Cl alkyl. One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein q is 0. One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein q is 1. One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is CFF, q is 1, and R ¹ is positioned to provide a 3-methylmorpholino.

[00109] One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R is C1-C8 optionally substituted alkyl, C3-C6 optionally substituted cycloalkyl, C4-C6 optionally substituted cycloalkylalkyl, C3-C6 optionally substituted heterocyclyl, or C3-C6 optionally substituted heterocyclylalkyl.

[00110] One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R is C1-C8 optionally substituted alkyl. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein the C1-C8 optionally substituted alkyl is a C2 optionally substituted alkyl.

[00111] One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R is -(C1-C8 optionally substituted alkyl ene)-OPO(OH)2. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein the -(C1-C8 optionally substituted alkyl ene)-OPO(OH)2 is a C2 optionally substituted alkylene. [00112] One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R is C3-C6 optionally substituted cycloalkyl. One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R is C4-C6 optionally substituted cycloalkylalkyl. One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R is C3-C6 optionally substituted heterocyclyl. One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R is C3-C6 optionally substituted heterocyclylalkyl.

[00113] One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is halogen. One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is optionally substituted C1-C3 alkyl. One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is methyl.

[00114] One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein Z is -NR ^a R ^b , wherein R ^a is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and R ^b is selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R ^a is H. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R ^a is optionally substituted alkyl. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R ^b is optionally substituted alkyl.

[00115] One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable

salt or solvate thereof, wherein Z is wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or

4; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SOialkyk optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R ¹¹ groups together form an oxo. Another embodiment provides the

compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein m is 0. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein m is 2.

Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein m is 3. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein p is 0. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein p is 1. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein p is 2. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein p is 1. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ is optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl. Another embodiment provides the compound of Formula (la) or (Ila) or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl is substituted with at least a halogen.

[00116] One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable

salt or solvate thereof, wherein wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl); and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SOialkyf optionally substituted C3- C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo. Another embodiment provides the compound of Formula (la) or (Ha), or pharmaceutically acceptable salt or solvate thereof, wherein W is O. Another embodiment provides the compound of Formula (la) or (Ha), or pharmaceutically acceptable salt or solvate thereof, wherein W is S. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1, and n is 1. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1, and n is 2. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ is

optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl is substituted with at least a halogen.

[00117] One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable

wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 0, 1, or 2; nl is 0, 1, or 2 provided both ml and nl are not both 0; p is 0, 1, or 2; and q is 0, 1 or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo. Another embodiment provides the compound of Formula (la) or (Ha), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1, and n is 1. Another embodiment provides the compound of Formula (la) or (Ha), or pharmaceutically acceptable salt or solvate thereof, wherein m is 0, and n is 2. Another

embodiment provides the compound of Formula (la) or (Ha), or pharmaceutically acceptable salt or solvate thereof, wherein ml is 0, and nl is 2. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein ml is 1, and nl is 1. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein W is O. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein W is CH2. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein W is CHR ¹¹ . Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein W is C(R ¹¹ ) ₂ . Another embodiment provides the compound of Formula (la) or (Ila), or

pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ is halogen and q is 1. [00118] One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable

« 13 salt or solvate thereof, wherein Z is wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 1, or 2; p is 0, 1, 2, or 3; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH 2, CHR ¹¹ , -CH2-CH2-, -CH2-CHR ¹¹ -, -CH ₂ -C(R ¹¹ ) ₂ -, -CHR ¹¹ -CH ₂ -, -C(R ¹¹ )2-CH ₂ -, -NH-CH2-, - NH-CHR ¹¹ -, -NH-C(R ¹¹ ) ₂ -, -CH2-NH-, -CHR ¹¹ -NH-, -C(R ¹¹ ) ₂ -NH-, -N(R ¹¹ )-CH ₂ -, -N(R ¹¹ )-CHR ¹¹ - , -N(R ¹¹ )-C(R ¹¹ )2-, -CH ₂ -N(R ¹¹ )-, -CHR ¹¹ -N(R ¹¹ )-, -C(R ¹¹ )2-N(R ¹¹ )-; each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo; and R ¹² and R ¹³ are each independently selected from H, or optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein m is 0, n is 1, and ml is 1; and W is -O-CH2-, or -CH2-O-.

[00119] One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable

salt or solvate thereof, wherein Z is wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 0, 1, or 2; p is 0, 1, or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2; each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S0 ₂ alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R ¹¹ groups together form an oxo; and R ¹² and R ¹³ are each independently selected from H, or optionally substituted Cl- C6 alkyl. Another embodiment provides the compound of Formula (la) or (Ila), or

pharmaceutically acceptable salt or solvate thereof, wherein W is O. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein W is C¾, or CHR ¹¹ . Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein ml is 0. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein ml is 1. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 1. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 0. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein m is 0 and n is 1.

[00120] One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable

salt or solvate thereof, wherein wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3 provided both m and n are not both 0; p is 0, 1, 2, 3, or 4; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SOialkyf optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocy cl yl alkyl. Another embodiment provides the compound of Formula (la) or (Ha), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1, and n is 1. Another embodiment provides the compound of Formula (la) or (Ha), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1, and n is 2. Another embodiment provides the compound of Formula (la) or (Ha), or pharmaceutically acceptable salt or solvate thereof, wherein p is 1. Another embodiment provides the compound of Formula (la) or (Ha), or pharmaceutically acceptable salt or solvate thereof, wherein p is 2. Another embodiment provides the compound of Formula (la) or (Ha), or pharmaceutically acceptable salt or solvate thereof, wherein at least one R ¹¹ is attached to an alkene carbon. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein at least one R ¹¹ is not attached to an alkene carbon. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ is optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein p is 0. [00121] Another embodiment provides the compound of Formula (la) or (Ha), or pharmaceutically

acceptable salt or solvate thereof, wherein wherein m is 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, or 2; and each R ¹³ or R ¹⁴ is independently selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SOialkyf optionally substituted C3- C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocy cl yl alkyl. Another embodiment provides the compound of Formula (la) or (Ha), or pharmaceutically acceptable salt or solvate thereof, wherein m is 2, and n is 1. Another embodiment provides the compound of Formula (la) or (Ha), or pharmaceutically acceptable salt or solvate thereof, wherein p is 0. Another embodiment provides the compound of Formula (la) or (Ha), or pharmaceutically acceptable salt or solvate thereof, wherein p is 1. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein one of R ¹³ or R ¹⁴ is not hydrogen. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein one of R ¹³ or R ¹⁴ is optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁴ is optionally substituted C1-C6 alkyl.

[00122] One embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable

salt or solvate thereof, wherein wherein m is 0, 1, or 2; n is 0, 1, or 2; ml is 0, 1, or 2; p is 0, 1, or 2; and q is 0, 1 or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR ¹¹ , or C(R ¹¹ )2; and each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SCbalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two geminal R ¹¹ groups together form an oxo. Another embodiment provides the compound of Formula (la) or (Ha), or pharmaceutically acceptable salt or solvate thereof, wherein W is O. Another embodiment provides the compound of Formula (la) or (Ha), or pharmaceutically acceptable salt or solvate thereof, wherein m is 2, and n is 1. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein ml is 1 or 2. Another embodiment provides the compound of Formula (la) or (Ila), or pharmaceutically acceptable salt or solvate thereof, wherein p is 0 or 1, and q is 0 or 1.

[00123] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (III):

wherein,

G is C=0 or S0 ₂ ;

R is C1-C8 optionally substituted alkyl, -(C1-C8 optionally substituted alkyl ene)- OPO(OH)2, C3-C6 optionally substituted cycloalkyl, -(C3-C6 optionally substituted

cycloalkylene)-OPO(OH)2, C4-C6 optionally substituted cycloalkylalkyl, -(C3-C6 optionally substituted cycloalkylalkylene)-OPO(OH)2, C3-C6 optionally substituted heterocyclyl, -(C3-C6 optionally substituted heterocyclyl)-OPO(OH)2, C3-C6 optionally substituted heterocyclylalkyl, - (C3-C6 optionally substituted heterocyclylalkyl)-OPO(OH)2;

X is N, C-H, C-D, C-F, or C-CH ₃ ;

R ¹ is C1-C3 optionally substituted alkyl, and q is 0, 1, or 2;

R ² is H, D or F;

R ⁴ is halogen, optionally substituted C1-C3 alkyl, -CD ₃ , or optionally substituted

C1-C3 alkoxy;

R ⁶ is H, D, Cl or F;

R ^c is H or D;

Z is selected from: (a) wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and W is

O, NH or N(optionally substituted C1-C6 alkyl); each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -SOialkyk optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocy cl yl alkyl; or two R ¹¹ groups together form an oxo;

wherein m is 1, 2, or 3; n is 1, 2, or 3; ml is 0, 1, 2, or

3; p is 0, 1, or 2; q is 0, 1, or 2; each R ¹¹ is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SOialkyf optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclyl alkyl; or two R ¹¹ groups together form an oxo; and each R ¹² is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted - SOialkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R ¹² groups together form an oxo.

[00124] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IV):

wherein,

G is C=0 or S0 ₂ ;

R is C1-C8 optionally substituted alkyl, -(C1-C8 optionally substituted alkyl ene)- OPO(OH)2, C3-C6 optionally substituted cycloalkyl, -(C3-C6 optionally substituted

cycloalkylene)-OPO(OH)2, C4-C6 optionally substituted cycloalkylalkyl, -(C3-C6 optionally substituted cycloalkylalkylene)-OPO(OH)2, C3-C6 optionally substituted heterocyclyl, -(C3-C6 optionally substituted heterocyclyl)-OPO(OH)2, C3-C6 optionally substituted heterocyclylalkyl, - (C3-C6 optionally substituted heterocyclylalkyl)-OPO(OH)2;

X is N, C-H, C-D, C-F, or C-C¾;

R ¹ is C1-C3 optionally substituted alkyl, and q is 0, 1, or 2;

R ² is H, D or F;

R ⁴ is halogen, optionally substituted C1-C3 alkyl, -CD3, or optionally substituted

C1-C3 alkoxy;

R ⁶ is H, D, Cl or F;

R ^c is H or D;

Z is selected from:

(a) wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and W is

O, NH or N(optionally substituted C1-C6 alkyl); each R ¹¹ is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -SCbalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocy cl yl alkyl; or two R ¹¹ groups together form an oxo;

wherein m is 1, 2, or 3; n is 1, 2, or 3; ml is 0, 1, 2, or 3; p is 0, 1, or 2; q is 0, 1, or 2; each R ¹¹ is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SCbalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocy cl yl alkyl; or two R ¹¹ groups together form an oxo; and each R ¹² is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted - SOialkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R ¹² groups together form an oxo.

[00125] One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein G is C=0.

[00126] One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein R ^c is hydrogen. Another embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein R ^c is deuterium.

[00127] One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein R ² is hydrogen or deuterium. One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein R ² is F.

[00128] One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is hydrogen or deuterium. One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is F.

[00129] One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein X is N. One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein X is C-H or C-D. One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein X is C-F.

[00130] One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted Cl alkyl. One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein q is 0. One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein q is 1. One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is C¾, q is 1, and R ¹ is positioned to provide a 3-methylmorpholino.

[00131] One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein R is C1-C8 optionally substituted alkyl, C3-C6 optionally substituted cycloalkyl, C4-C6 optionally substituted cycloalkylalkyl, C3-C6 optionally substituted heterocyclyl, or C3-C6 optionally substituted heterocyclylalkyl.

[00132] One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein R is C1-C8 optionally substituted alkyl. Another embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein the C1-C8 optionally substituted alkyl is a C2 optionally substituted alkyl.

[00133] One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein R is -(C1-C8 optionally substituted alkyl ene)-OPO(OH)2. Another embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein the -(C1-C8 optionally substituted alkyl ene)-OPO(OH)2 is a C2 optionally substituted alkylene.

[00134] One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein R is C3-C6 optionally substituted cycloalkyl. One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein R is C4-C6 optionally substituted cycloalkylalkyl. One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein R is C3-C6 optionally substituted heterocyclyl. One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein R is C3-C6 optionally substituted heterocyclylalkyl.

[00135] One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is halogen. One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is optionally substituted C1-C3 alkyl. One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is methyl.

[00136] One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein Z is

wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and W is O, NH or N(optionally substituted C1-C6 alkyl); each R ¹¹ is independently selected from amino, alkylamino,

dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -SOialkyk optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R ¹¹ groups together form an oxo. Another embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1 or 2. Another embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1. Another embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein W is O. Another embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein W is NH. Another embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein W is N(optionally substituted C1-C6 alkyl). Another embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein p is 0. Another embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein p is 1.

Another embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein two R ¹¹ groups together form an oxo.

[00137] One embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein Z is

wherein m is 1, 2, or 3; n is 1, 2, or 3; ml is 0, 1, 2, or 3; p is 0, 1, or 2; q is 0, 1, or 2; each R ¹¹ is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SOialkyk optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocy cl yl alkyl; or two R ¹¹ groups together form an oxo; and each R ¹² is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SCkalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclyl alkyl; or two R ¹² groups together form an oxo. Another embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 2. Another embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein ml is 0, 1, or 2. Another embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1, n is 2, and ml is 0, 1, or 2. Another embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein m is 1, n is 2, and ml is 0. Another embodiment provides the compound of Formula (III) or (IV), or

pharmaceutically acceptable salt or solvate thereof, wherein p is 0 or 1. Another embodiment provides the compound of Formula (III) or (IV), or pharmaceutically acceptable salt or solvate thereof, wherein q is 0 or 1.

[00138] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (V):

wherein,

G is C=0 or S0 ₂ ;

R is C1-C8 optionally substituted alkyl, -(C1-C8 optionally substituted alkyl ene)- OPO(OH)2, C3-C6 optionally substituted cycloalkyl, -(C3-C6 optionally substituted

cycloalkylene)-OPO(OH)2, C4-C6 optionally substituted cycloalkylalkyl, -(C3-C6 optionally substituted cycloalkylalkylene)-OPO(OH)2, C3-C6 optionally substituted heterocyclyl, -(C3-C6 optionally substituted heterocyclyl)-OPO(OH)2, C3-C6 optionally substituted heterocyclylalkyl, - (C3-C6 optionally substituted heterocyclylalkyl)-OPO(OH)2;

X is N, C-H, C-D, C-F, or C-CH ₃ ;

R ¹ is C1-C3 optionally substituted alkyl, and q is 0, 1, or 2;

R ² is H, D or F;

R ⁴ is halogen, optionally substituted C1-C3 alkyl, -CD ₃ , or optionally substituted

C1-C3 alkoxy;

R ⁶ is H, D, Cl or F;

R ^c is H or D;

Z is an optionally substituted N-linked pyrrole, optionally substituted-NH-pyrazole, or optionally substituted -N(optionally substituted C1-C6 alkyl)-pyrazole.

[00139] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (VI):

wherein,

G is C=0 or S0 ₂ ;

R is C1-C8 optionally substituted alkyl, -(C1-C8 optionally substituted alkyl ene)- OPO(OH)2, C3-C6 optionally substituted cycloalkyl, -(C3-C6 optionally substituted

cycloalkylene)-OPO(OH)2, C4-C6 optionally substituted cycloalkylalkyl, -(C3-C6 optionally substituted cycloalkylalkylene)-OPO(OH)2, C3-C6 optionally substituted heterocyclyl, -(C3-C6 optionally substituted heterocyclyl)-OPO(OH)2, C3-C6 optionally substituted heterocyclylalkyl, - (C3-C6 optionally substituted heterocyclylalkyl)-OPO(OH)2;

X is N, C-H, C-D, C-F, or C-C¾;

R ¹ is C1-C3 optionally substituted alkyl, and q is 0, 1, or 2;

R ² is H, D or F;

R ⁴ is halogen, optionally substituted C1-C3 alkyl, -CD3, or optionally substituted

C1-C3 alkoxy;

R ⁶ is H, D, Cl or F;

R ^c is H or D;

Z is an optionally substituted N-linked pyrrole, optionally substituted-NH-pyrazole, or optionally substituted -N(optionally substituted C1-C6 alkyl)-pyrazole.

[00140] One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein G is C=0.

[00141] One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein R ^c is hydrogen. Another embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein R ^c is deuterium.

[00142] One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein R ² is hydrogen or deuterium. One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein R ² is F. [00143] One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is hydrogen or deuterium. One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is F.

[00144] One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein X is N. One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein X is C-H or C-D. One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein X is C-F.

[00145] One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is optionally substituted Cl alkyl. One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein q is 0. One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein q is 1. One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is CFF, q is 1, and R ¹ is positioned to provide a 3-methylmorpholino.

[00146] One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein R is C1-C8 optionally substituted alkyl, C3-C6 optionally substituted cycloalkyl, C4-C6 optionally substituted cycloalkylalkyl, C3-C6 optionally substituted heterocyclyl, or C3-C6 optionally substituted heterocyclylalkyl.

[00147] One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein R is C1-C8 optionally substituted alkyl. Another embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein the C1-C8 optionally substituted alkyl is a C2 optionally substituted alkyl.

[00148] One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein R is -(C1-C8 optionally substituted alkyl ene)-OPO(OH)2. Another embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein the -(C1-C8 optionally substituted alkyl ene)-OPO(OH)2 is a C2 optionally substituted alkylene.

[00149] One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein R is C3-C6 optionally substituted cycloalkyl. One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein R is C4-C6 optionally substituted cycloalkylalkyl. One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein R is C3-C6 optionally substituted heterocyclyl. One embodiment provides the compound of

Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein R is C3-C6 optionally substituted heterocyclylalkyl.

[00150] One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is halogen. One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is optionally substituted C1-C3 alkyl. One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is methyl.

[00151] One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein Z is an optionally substituted N-linked pyrrole.

[00152] One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein Z is an optionally substituted -NH-pyrazole.

[00153] One embodiment provides the compound of Formula (V) or (VI), or pharmaceutically acceptable salt or solvate thereof, wherein Z is an optionally substituted -N(optionally substituted C1-C6 alkyl)-pyrazole.

[00154] In some embodiments, the heteroaromatic RAF kinase inhibitory compound as described herein has a structure provided in Table 1.

Table 1

[00155] In some embodiments, the heteroaromatic RAF kinase inhibitory compound as described herein has a structure provided below.

Preparation of Compounds

[00156] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc.

(Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[00157] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et ak, "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York,

1983; H. O. House, "Modem Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An

Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C.

"Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471- 60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871- 1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley- Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and

"Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[00158] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses ( e.g ., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

Pharmaceutical Compositions

[00159] In certain embodiments, the heteroaromatic RAF kinase inhibitory compound described herein is administered as a pure chemical. In other embodiments, the heteroaromatic RAF kinase inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 ^st Ed. Mack Pub. Co., Easton, PA (2005)).

[00160] Provided herein is a pharmaceutical composition comprising at least one heteroaromatic RAF

kinase inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers.

The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

[00161] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I)-(VI), or a pharmaceutically acceptable salt or solvate thereof. [00162] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I)-(VI), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[00163] In certain embodiments, the heteroaromatic RAF kinase inhibitory compound as described by

Formula (I)-(VI), or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[00164] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21 ^st Ed. Mack Pub. Co., Easton, PA (2005)).

[00165] In some embodiments, the heteroaromatic RAF kinase inhibitory compound as described by

Formula (I)-(VI), or pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[00166] The dose of the composition comprising at least one heteroaromatic RAF kinase inhibitory

compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.

[00167] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[00168] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day. Methods of Treatment

[00169] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[00170] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

[00171] One embodiment provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[00172] In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the cancer is breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, or lung cancer.

[00173] One embodiment provides a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[00174] One embodiment provides a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

[00175] One embodiment provides a use of a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[00176] In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the cancer is breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, or lung cancer.

[00177] One embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[00178] One embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease. [00179] One embodiment provides a use of a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[00180] In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the cancer is breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, or lung cancer.

[00181] One embodiment provides a compound of Formula (Ha), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[00182] One embodiment provides a compound of Formula (Ha), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

[00183] One embodiment provides a use of a compound of Formula (Ha), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[00184] In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (Ha), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the cancer is breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, or lung cancer.

[00185] One embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[00186] One embodiment provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

[00187] One embodiment provides a use of a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[00188] In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical

composition comprising a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the cancer is breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, or lung cancer.

[00189] One embodiment provides a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[00190] One embodiment provides a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

[00191] One embodiment provides a use of a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[00192] In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the cancer is breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, or lung cancer.

[00193] One embodiment provides a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[00194] One embodiment provides a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

[00195] One embodiment provides a use of a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[00196] In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the cancer is breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, or lung cancer.

[00197] One embodiment provides a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. [00198] One embodiment provides a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

[00199] One embodiment provides a use of a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[00200] In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the cancer is breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, or lung cancer.

[00201] Provided herein is the method wherein the pharmaceutical composition is administered orally.

Provided herein is the method wherein the pharmaceutical composition is administered by injection.

[00202] Other embodiments and uses will be apparent to one skilled in the art in light of the present

disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.

EXAMPLES

I. Chemical Synthesis

[00203] In some embodiments, the heteroaromatic RAF kinase inhibitory compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:

°C degrees Celsius

5H chemical shift in parts per million downfield from tetramethylsilane

DCM dichloromethane (CH2CI2)

DMF dimethylformamide

DMSO dimethylsulfoxide

EA ethyl acetate

ESI electrospray ionization

Et ethyl

g gram(s)

h hour(s) HPLC high performance liquid chromatography

Hz hertz

J coupling constant (in NMR spectrometry)

LCMS liquid chromatography mass spectrometry

m micro

m multiplet (spectral); meter(s); milli

M molar

M ⁺ parent molecular ion

Me methyl

MHz megahertz

min minute(s)

mol mole(s); molecular (as in mol wt)

mL milliliter

MS mass spectrometry

nm nanometer(s)

NMR nuclear magnetic resonance

pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solution

PE petroleum ether

RT room temperature

s singlet (spectral)

t triplet (spectral)

T temperature

TFA trifluoroacetic acid

THF tetrahydrofuran

: 2-fluoro-4-methyl-5-(5-morpholino-6-(2-((tetrahydro-2H-pyran -2- yl)oxy)ethoxy)pyridin-3-yl)aniline

Step 1 : 4-(5-bromo-2-fluoropyridin-3-vDmorpholine step 1

NaH (3 eq.), DMF, rt, 15 min

[00204] To a solution of 5-bromo-2-fluoropyri din-3 -amine (6.00 g, 31.41 mmol) in DMF (60.00 mL) was added NaH (3.77 g, 94.24 mmol, 60%) at 0 °C. The reaction mixture was stirred for 15 min. To the above mixture l-bromo-2-(2-bromoethoxy)ethane (10.93 g, 47.12 mmol) was added. The reaction mixture was allowed to heat to 85 °C and stirred for 0.5 h. The resulting mixture was poured into water (250 mL). The resulting precipitate was collected by vacuum filtration. The filter cake was rinsed twice with water and heptanes. The solid was dried under high vacuum to give 4-(5-bromo- 2-fluoropyri din-3 -yl)morpholine (5.6 g, 68%) as a yellow solid. MS ESI calculated for

C ₉ Hi ₀ FBrN ₂ O [M + H] ⁺ , 261.00, 262.99, found 261.05, 263.00. ¹ H-NMR (400 MHz, -DMSO) d 7.86 (d, J= 2.0 Hz, 1H), 7.64 (dd, J= 9.2, 2.4 Hz, 1H), 3.82 - 3.64 (m, 4H), 3.10 - 3.05 (m, 4H). Step 2: 4-r5-bromo-2-r2-(oxan-2-yloxy)ethoxy1pyridin-3-yl1morpholine

step 2

,0.

[00205] To a solution of 2-(oxan-2-yloxy)ethanol (4.62 g, 31.60 mmol) in 1,4-dioxane (60.00 mL) was added NaH (1.26 g, 31.60 mmol, 60%) at 0 °C. The reaction mixture was stirred for 20 min at room temperature. To the above mixture 4-(5-bromo-2-fluoropyridin-3-yl)morpholine (1.65 g, 6.32 mmol) was added and the reaction mixture was allowed to heat to 105 °C and stirred for 3 h. The resulting mixture was cooled to room temperature and quenched with water (30 mL). The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers was washed with water (2 x 10 mL), dried over anhydrous NaiSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EtOAc: EtOH = 3: 1)/PE (10-50%). The fractions contained desired product were combined and concentrated to afford 4-[5-bromo-2-[2-(oxan-2-yloxy)ethoxy]pyridin-3-yl]morpholine (1.8 g,

73%) as a yellow oil. MS ESI calculated for Ci ₆ H ₂₃ BrN ₂ 0 ₂ [M + H] ⁺ , 387.08, 389.08; found 387.10, 389.10. ¹ H-NMR (400 MHz, -DMSO) d 7.82 (d, J= 2.0 Hz, 1H), 7.29 (d, J= 2.4 Hz, 1H), 4.65 (d, J= 3.6 Hz, 1H), 4.48 - 4.28 (m, 2H), 3.93 - 3.90 (m, 1H), 3.78 - 3.65 (m, 6H), 3.47 - 3.42 (m, 1H), 3.09 - 3.03 (m, 4H), 1.64 - 1.60 (m, 2H), 1.49 - 1.45 (m, 4H).

Step 3 : 2-fluoro-4-methyl-5-r5-(morpholin-4-vD-6-r2-( ^' oxan-2-yloxy)ethoxy1pyridin-3-yl1aniline

step 3

[00206] To a solution of 4-[5-bromo-2-[2-(oxan-2-yloxy)ethoxy]pyridin-3-yl]morpholine (550.00 mg, 1.42 mmol) and 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)aniline (534.93 mg, 2.13 mmol) in 1,4-dioxane (0.5 mL) and ThO (0.1 mL) were added NaiCCb (301.05 mg, 2.84 mmol) and l, l-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (463.91 mg, 0.57 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 16 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (1-10%). The fractions contained desired product were combined and concentrated to afford 2-fluoro-4- methyl-5-[5-(morpholin-4-yl)-6-[2-(oxan-2-yloxy)ethoxy]pyrid in-3-yl]aniline (580 mg, 95%) as a yellow solid. MS ESI calculated for C ₂₃ H ₃₀ FN ₃ O ₄ [M + H] ⁺ , 432.22; found 432.30. ¹ H-NMR (400 MHz, -DMSO) d 7.63 (d, J= 2.0 Hz, 1H), 7.05 (d, J= 2.0 Hz, 1H), 6.93 (d, J= 12.4 Hz, 1H), 6.65 (d, J= 9.6 Hz, 1H), 4.96 (s, 2H), 4.48 - 4.44 (m, 2H), 3.92 (s, 1H), 3.82 - 3.68 (m, 6H), 3.50 - 3.46 (m, 1H), 3.10 - 3.06 (m, 4H), 2.08 (s, 3H), 1.73 - 1.58 (m, 2H), 1.57 - 1.45 (m, 5H).

Intermediate 2: 2-fluoro-4-methyl-5-(5-morpholino-6- (tetrahvdro-2H-pyran-4-

v0oxy)pyridin-3-v0aniline

Step 1 : 4-r5-bromo-2-(oxan-4-yloxy)pyridin-3-yllmorpholine step 1

1

[00207] To a solution of oxan-4-ol (1.96 g, 19.15 mmol) in dioxane (40.0 mL) was added NaH (0.77 g,

19.15 mmol, 60%) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. To the above mixture was added 4-(5-bromo-2-fluoropyridin-3-yl)morpholine (1.00 g, 3.83 mmol) and the reaction mixture was allowed to warm to 105 °C and stirred for 2 h. The resulting mixture was quenched by water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous NaiSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column

chromatography, eluted with 20-50% EtO Ac/PE. The fractions contained desired product were combined and concentrated to afford 4-[5-bromo-2-(oxan-4-yloxy)pyridin-3-yl]morpholine (0.95 g, 72%) as an off-white solid. MS ESI calculated for CwHigBrNiCL [M + H] ⁺ , 343.06, 345.06, found 343.05, 345.05. ¹ H-NMR (300 MHz, ί/6-DMSO) d 7.83 (d, J= 2.1 Hz, 1H), 7.30 (d, J = 2.1 Hz, 1H), 5.24 (t, J= 8.1Hz, 1H), 3.90 - 3.68 (m, 6H), 3.58 - 3.51 (m, 2H), 3.14 - 2.96 (m, 4H), 2.02 - 1.97 (m, 2H), 1.72 - 1.62 (m, 2H).

Step 2: 2-fluoro-4-methyl-5-r5-(morpholin-4-vn-6-(oxan-4-yloxy)pyrid in-3-yl1aniline

[00208] To a solution of 4-[5-bromo-2-(oxan-4-yloxy)pyridin-3-yl]morpholine (940.00 mg, 2.74 mmol) and 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)aniline (894.05 mg, 3.56 mmol) in dioxane (15.00 mL) and H2O (3.00 mL) were added NaiCCL (580.55 mg, 5.48 mmol) and 1, 1- bis(diphenylphosphino)ferrocene-palladium(II)di chloride dichloromethane complex (223.66 mg, 0.27 mmol). The reaction mixture was degassed with nitrogen for three times and stirred at 80 °C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 - 10% MeOH in CH ₂ CI ₂ . The fractions

contained desired product were combined and concentrated to afford 2-fluoro-4-methyl-5-[5- (morpholin-4-yl)-6-(oxan-4-yloxy)pyridin-3-yl]aniline (0.86 g, 81%) as an off-white solid. MS ESI calculated for C ₂₁ H ₂₆ FN ₃ O ₃ [M + H] ⁺ , 388.20; found 388.20. ¹ H-NMR (400 MHz, ί/6-DMSO) d 7.62 (d, J= 2.0 Hz, 1H), 7.04 (d, J= 2.0 Hz, 1H), 6.91 (d, J= 12.4 Hz, 1H), 6.63 (d, J= 9.2 Hz, 1H), 5.31- 5.30 (m, 1H), 4.96 (brs, 2H), 3.89 - 3.79 (m, 2H), 3.75 - 3.73 (m, 4H), 3.58 - 3.53 (m, 2H), 3.07 - 3.05 (m, 4H), 2.11 - 1.95 (m, 5H), 1.72 - 1.65 (m, 2H).

Intermediate 3 : 4-methyl-3-i5-mornholino-6-(Ttetrahydro-2H-nyran-4-yl)oxy)ny ridin-3- yllaniline

[00209] The title compound was prepared using procedures similar to those described in Intermediate 2 using 4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)anil ine instead of 2-fluoro-4- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)anilin e to afford the title compound as a solid.

Intermediate 4 : 2-fluoro-4-methyl-5-t2-mornholino-6-i2-(Ttetrahydro-2H-nyran -2- yl)oxy)ethoxy)nyridin-4-yl)aniline

Step 1 : 4-(6-fluoro-4-iodopyridin-2-vDmorpholine

step 1

[00210] To a stirred solution of 2,6-difluoro-4-iodopyridine (16.00 g, 66.40 mmol) in DMSO (240.00 mL) were added morpholine (5.49 mL, 63.04 mmol) and DIEA (12.07 mL, 93.40 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 3 h at 70 °C. The resulting mixture was diluted with water (150 mL) and extracted with EA (3 x 300 mL). The combined organic layers was washed with brine (4 x 100 mL), dried over anhydrous NaiSCL and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 30% EA in PE. The fractions contained desired product were combined and concentrated to afford 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (17.6 g,

86%) as an off-white solid. MS ESI calculated for C9H10FIN2O [M + H] ⁺ , 308.98, found 309.10. H- NMR (300 MHz, CDCh) d 6.77 - 6.76 (m, 1H), 6.60 - 6.59 (m, 1H), 3.78 (t, J= 4.8 Hz, 4H), 3.49 (t, J = 5.0 Hz, 4H).

Step 2: 4-r4-iodo-6-r2-(oxan-2-yloxy)ethoxy1pyridin-2-yl1morpholine

[00211] To a stirred solution of 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (5.00 g, 16.23 mmol) and 2- (oxan-2-yloxy)ethanol (9.49 g, 64.92 mmol) in dioxane (100 mL) was added NaH (2.60 g, 64.92 mmol, 60%) in portions at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at 100 °C. The resulting mixture was quenched with water (500 mL) at 0 °C and extracted with EA (3 x 300 mL). The combined organic layers was washed with brine (3 x 200 mL), dried over anhydrous NaiSCL and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 30% EA in PE. The fractions contained desired product were combined and concentrated to afford 4-[4-iodo-6-[2-(oxan-2- yloxy)ethoxy]pyridin-2-yl]morpholine (5.85 g, 83%) as a yellow oil. MS ESI calculated for C ₁₆ H ₂₃ IN ₂ O ₄ [M + H] ⁺ , 434.07, found 435.10. H-NMR (400 MHz, CDCh) d 6.56 (s, 1H), 6.50 (s, 1H), 4.67 (t, J= 3.6 Hz, 1H), 4.50 - 4.36 (m, 2H), 4.03 - 3.98 (m, 1H), 3.91 - 3.85 (m, 1H), 3.80 - 3.70 (m, 5H), 3.53 - 3.49 (m, 1H), 3.45 (t, J= 4.9 Hz, 4H), 1.87 - 1.51 (m, 6H).

Step 3 : 2-fluoro-4-methyl-5-r2-(morpholin-4-vn-6-r2-(oxan-2-yloxy)et hoxy1pyridin-4-yl1aniline

[00212] To a solution of 4-[4-iodo-6-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]morpholine (5.75 g, 13.24

mmol) and 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)aniline (3.66 g, 14.56 mmol) in dioxane (170 mL) and water (40 mL) were added NaiCCb (4.21 g, 39.72 mmol) and 1,1- bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.08 g, 1.32 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 80 °C. The resulting mixture was diluted with water (100 mL) and extracted with EA (3 x 150 mL). The combined organic layers was washed with brine (3 x 100 mL), dried over anhydrous NaiSCL and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 - 40% EA in PE. The fractions contained desired product were combined and concentrated to afford 2-fluoro-4-methyl-5-[2-(morpholin-4-yl)-6-[2- (oxan-2-yloxy)ethoxy]pyridin-4-yl]aniline (4.4 g, 77%) as a yellow oil. MS ESI calculated for C ₂₃ H ₃₀ FN ₃ O ₄ [M + H] ⁺ , 432.22; found 432.25. H-NMR (300 MHz, CDCb) d 6.87 (d, 7= 11.7 Hz, 1H), 6.65 (d, J= 9.0 Hz, 1H), 6.11 - 6.07 (m, 2H), 4.70 (t, J= 3.6 Hz, 1H), 4.54 - 4.41 (m, 2H),

4.11 - 4.02 (m, 1H), 3.94 - 3.77 (m, 6H), 3.54 - 3.47 (m, 5H), 2.14 (s, 3H), 1.89 - 1.43 (m, 6H).

Intermediate 5: 4-methyl-3-(2-morpholino-6-(2-(Ytetrahydro-2H-pyran-2- yPoxy)ethoxy)pyridin-4-yPaniline

[00213] The title compound was prepared using procedures similar to those described in Intermediate 4 using 4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)anil ine and 4-(4-iodo-6-(2- ((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)morpholin e to afford the title compound as an oil.

Intermediate 6 : 2-fluoro-4-methyl-5-t2-(YR)-3-methylmorpholino)-6-i2-(Ytetra hydro-2H- pyran-2-yPoxy)ethoxy)pyridin-4-yPaniline

[00214] The title compound was prepared using procedures similar to those described in Intermediate 4 using (7i)-3 -methyl morpholine instead of morpholine to afford the title compound as a solid.

Intermediate 7: 3-[2-[[ 2,2-dimethyl-l,3-dioxolan-4-yl]methoxy]-6-[morpholin-4-

yl)nyridin-4-yl)-4-methylaniline

[00215] The title compound was prepared using procedures similar to those described in Intermediate 4 using [(4S)-2, 2-dimethyl- 1, 3 -dioxolan-4-yl]methanol instead of 2-(oxan-2-yloxy)ethanol to afford the title compound as a solid.

Intermediate 8: 3-i2-[ -2,2-dimethyl-l,3-dioxolan-4-yllmethoxy|-6-(mornholin-4-

yl)nyridin-4-yl)-4-methylaniline

[00216] The title compound was prepared using procedures similar to those described in Intermediate 4 using [(4/^)-2, 2-dim ethyl - 1 ,3-dioxolan-4-yl]methanol instead of 2-(oxan-2-yloxy)ethanol to afford the title compound as a solid.

Intermediate 9 and 10: -l-[[4-iodo-6-(mornholin-4-yl)nyridin-2-ylloxy|nronan-2-ol and

-2-[[4-iodo-6-(mornholin-4-yl)nyridin-2-ylloxy|nronan-l-ol

[00217] The title compound was prepared using procedures similar to those described in Intermediate 4 using (S)- 1,2-propanediol instead of 2-(oxan-2-yloxy)ethanol to afford the title compound as a solid.

Intermediate 11 and 12: -l-[[4-iodo-6-(morpholin-4-yDpyridin-2- 2-ol and

-2-[[4-iodo-6-(morpholin-4-yDpyridin-2- l-ol

[00218] The title compound was prepared using procedures similar to those described in Intermediate 4 using (R)- 1,2-propanediol instead of 2-(oxan-2-yloxy)ethanol to afford the title compound as a solid.

Intermediate 13: 4-i4-iodo-6-[[2-methyl-l-(oxan-2-yloxy)propan-2-ylloxy|pyrid in-2- yllmorpholine

1

Step 1 : methyl 2-(oxan-2- acetate

Step 1

DHP (1.4 eq.), Py-TsOH (cat.) O

THPc l _0/

DCM, rt, 16 h

1

[00219] To a stirred solution of methyl 2-hydroxyacetate (6.30 g, 69.94 mmol) in DCM (100 mL) was added dihydropyran (8.93 mL, 97.88 mmol) and 4-m ethylbenzene- 1 -sulfonate; pyridin-l-ium (175.76 mg, 0.70 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with NaHCCh (sat., 2 x 200 mL) and brine (300 mL), dried over anhydrous NaiSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc in PE (0-50%) to afford methyl 2-(oxan-2-yloxy)acetate (8.6 g, 70%) as colorless oil. H- NMR (400 MHz, CDCh) d 4.76-4.74 (m, 1H), 4.24 (s, 2H), 3.90-3.76 (m, 1H), 3.75 (s, 3H), 3.56- 3.51 (m, 1H), 1.91-1.71 (m, 3H), 1.66-1.52 (m, 3H).

Step 2: 2 -methyl- l-(oxan-2-yloxy)propan-2-ol

Step 2

[00220] To a stirred solution of methyl 2-(oxan-2-yloxy)acetate (1.00 g, 5.74 mmol) in Et ₂ 0 (14 mL) was added C¾MgBr (5.74 mL, 17.220 mmol, 1 M) dropwise at -70 °C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of MLCl (sat., 20 mL). The resulting mixture was extracted with Et ₂ 0 (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SC> _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-100%) to afford 2-methyl- l-(oxan-2-yloxy)propan-2-ol (860 mg, 86%) as colorless oil. H-NMR (400 MHz, CDCh) d 4.62-4.60 (m, 1H), 3.94-3.88 (m, 1H), 3.61-3.53 (m, 2H), 3.36-3.34 (m, 1H), 2.70 (brs, 1H), 1.93-1.74 (m, 3H), 1.68-1.53 (m, 3H), 1.22 (s, 6H).

Step 3 : 4-(4-iodo-6- methyl-l-(oxan-2-yloxy)propan-2-vnoxy1pyridin-2-vDmorpholine

Step 3

OH (0.2 eq)

THPO^<

NaH (1 eq), DMF, 100 °C, 2 h

2

[00221] To a stirred mixture of 2-methyl- l-(oxan-2-yloxy)propan-2-ol (848.31 mg, 4.87 mmol) in DMF (1.50 mL) was added NaH (38.95 mg, 0.97 mmol, 60%) in portions at 0 °C under nitrogen atmosphere. To the above mixture was added 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (300.00 mg, 0.97 mmol) at room temperature. The resulting mixture was stirred for additional 2 h at 100 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous NaiSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 25% EA in PE to afford 4-(4-iodo-6-[[2-methyl-l-(oxan-2- yloxy)propan-2-yl]oxy]pyridin-2-yl)morpholine (190 mg, 42%) as light yellow oil. MS ESI calculated for C18H27IN2O4 [M + H] ⁺ , 463.10, found 463.10. H-NMR (400 MHz, CDCh) d 6.52-

6.51 (m, 2H), 4.64-4.63 (m, 1H), 3.96-3.94 (m, 1H), 3.85-3.79 (m, 5H), 3.72-3.70 (m, 1H), 3.53- 3.42 (m, 5H), 1.83-1.47 (m, 12H).

Intermediate 14: l-[[4-iodo-6-(mornholin-4-yl)nyridin-2-ylloxyl-2-methylnrona n-2-ol

[00222] The title compound was prepared using procedures similar to those described in Intermediate 4 step 2 using 2-methyl-propan e-l,2-diol instead of 2-(oxan-2-yloxy)ethanol to afford the title compound as a solid.

Intermediate 15: l- iodo-6-mornholinonyridin-2-yl)oxy)-3-methoxynronan-2-ol

[00223] The title compound was prepared using procedures similar to those described in Intermediate 4 step 2 using 3-methoxypropane-l,2-diol instead of 2-(oxan-2-yloxy)ethanol to afford the title compound as a solid.

Intermediate 16: [3R]-N-[4-methyl-3-[4,4,5,5-tetramethyl-l,3.,2-dioxaborolan- 2-vnphenyl]-3- itrifluoromethoxv)Dvrrolidine-l-carboxamide

Step 1 : -A ^f -r4-methyl-3-(4.4.5.5-tetramethyl- l .3.2-dioxaborolan-2-yl )phenyll-3- (trifluoromethoxy)pyrrolidine- 1 -carboxamide

[00224] To a stirred solution of (3R)-3 -(tri fl uoro ethoxy )pyrrol i di ne hydrochloride (150 mg, 0.64 mmol) and DIEA (415.80 mg, 3.22 mmol) in THF (5 mL) was added triphosgene (76.38 mg, 0.26 mmol,) at room temperature. The resulting mixture was stirred for 0.5 h at room temperature. To this was added (3i?)-3-(trifluoromethoxy)pyrrolidine hydrochloride (135.60 mg, 0.708 mmol) at room temperature. The solution was stirred for 1 h at room temperature. The resulting mixture was

concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA/PE (0 to 60%) to afford (3f?)-/V-[4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan -2- yl)phenyl]-3-(trifluoromethoxy)pyrrolidine-l-carboxamide (250 mg, 94%) as an off-white solid.

MS ESI calculated for C19H26BF3N2O4 [M + H] ⁺ , 415.19, found 415.25. H-NMR (400 MHz, CDCb) d 7.73-7.71 (m, 1H), 7.46-7.45 (m, 1H), 7.16-7.14 (m, 1H), 6.14 (s, 1H), 4.95-4.92 (m, 1H), 3.80-3.71 (m, 2H), 3.64-3.61 (m, 2H), 2.51 (s, 3H), 2.37-2.20 (m, 2H), 1.37 (s, 12H). F-NMR (376 MHz, CDCb) d -58.70 (3F).

Intermediate 17: -N-[4-methyl-3-i4,4,5,5-tetramethyl-l,3.,2-dioxaborolan-2-yl )nhenyll-3-

itrifluoromethoxy)nyrrolidine-l-carboxamide

[00225] The title compound was prepared using procedures similar to those described in Intermediate 16 using (3ri)-3-(trifluoromethoxy)pyrrolidine hydrochloride instead of (3R)-3- (trifluoromethoxy)pyrrolidine hydrochloride to afford the title compound as a solid.

Intermediate 18: 3-methyl-l-[4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborol an-2- yl)nhenyll-3- [l-itrifluoromethyl)nyrazol-4-yll urea

[00226] The title compound was prepared using procedures similar to those described in Intermediate 16 using /V-m ethyl- l-(trifluorom ethyl )pyrazol -4-amine instead of (3R)-3- (trifluoromethoxy)pyrrolidine hydrochloride to afford the title compound as a solid. Intermediate 19: N-[4-methyl-3-[4,4,5,5-tetramethyl-l,3.,2-dioxaborolan-2-vBp henvB-3-[2,2,2- trifluoroethyl)Dyrrolidine-l-carboxamide

[00227] The title compound was prepared using procedures similar to those described in Intermediate 16 using 3-(2,2,2-trifluoroethyl)pyrrolidine instead of (3i?)-3-(trifluoromethoxy)pyrrolidine hydrochloride to afford the title compound as a solid.

Intermediate 20: 3-11.,1-difluoroethvDpyrrolidine hydrochloride

Step 1 : /^/V -butyl 3-P J -difluoroethyl Ipyrrolidine- 1 -carboxyl ate

1

[00228] To a stirred solution of tert- butyl 3-acetylpyrrolidine-l-carboxylate (600.00 mg, 2.81 mmol) in CHCh (12.00 mL) was added BAST (2.49 g, 11.26 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred overnight at 60 °C. The resulting mixture was quenched with NaHCCb (sal. ) at 0 °C and extracted with EA (3 x 40 mL). The combined organic layers was washed with brine (3 x 30 mL), dried over anhydrous NaiSCE, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column

chromatography, eluted with PE/EA (3 : 1). The fractions contained desired product were combined and concentrated to afford /cvV-butyl 3-(l, l-difluoroethyl)pyrrolidine-l-carboxylate (360 mg, 54%) as a yellow oil. H-NMR (400 MHz, CDCh) d 3.57 (s, 2H), 3.33 - 3. 28 (m, 2H), 2.64-2.60 (m, 1H), 2.04 - 1.92 (m, 2H), 1.61 (t, J= 18.8 Hz, 3H), 1.46 (s, 9H).

Step 2: 3-P .1 -difluoroethyl ipyrrolidine hydrochloride

[00229] To a stirred solution of /er/-butyl 3-(l,l-difluoroethyl)pyrrolidine-l-carboxylate (360 mg, 1.53 mmol) in EA (1.00 mL) was added HC1 (10 mL, 2 M in EA) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 3 -(1,1 -difluoroethyl )pyrrolidine hydrochloride (320 mg) as a yellow oil. It was used to next step without further purification. H-NMR (400 MHz, CDCh) d 3.65 - 3.32 (m, 4H), 2.91 - 2.87 (m, 1H), 2.25 - 2.09 (m, 2H), 1.63 (t, J= 18.0 Hz, 3H).

Intermediate 21: 2-(l.,l-difluoroethvPmorpholine hydrochloride

[00230] The title compound was prepared using procedures similar to those described in Intermediate 20 using /er/-butyl 2-acetylmorpholine-4-carboxylate instead of /er/-butyl 3-acetylpyrrolidine-l- carboxylate to afford the title compound as a yellow oil.

Intermediate 22: 3-(trifluoromethyl)-2,5-dihydro-lH-nyrrole hydrochloride

Step 1 : 3-(trifluoromethvD-2.5-dihvdro- pyrrole hydrochloride

step 1

Boc dioxane HCI

1

[00231] A solution of tert- butyl 3-(trifluoromethyl)-2,5-dihydropyrrole-l-carboxylate (100 mg, 0.42 mmol) and HCI (gas) in 1,4-dioxane (2 mL, 65.82 mmol, 2 N) was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford 3 -(tri fl uoro ethyl )-2, 5 -di hydro- 1 //-pyrrol e hydrochloride (80 mg, crude) as a yellow solid.

It was used directly to next step without further purification. MS ESI calculated for C5H7CIF3N [M + H - HC1] ⁺ , 138.05, found 138.20.

Intermediate 23: 3-fl,l,2,2,2-pentafluoroethvnpyrrolidine hydrochloride

Step 1 butyl 3 -hydroxy-3 -P J .2.2.2-pentafluoroethyl (pyrrolidine-! -carboxyl ate

[00232] To a stirred solution of /er/-butyl 3-oxopyrrolidine-l-carboxylate (2.00 g, 10.80 mmol) and

trimethyl(l,l,2,2,2-pentafluoroethyl)silane (3.11 g, 16.20 mmol) in THF (20 mL) was added TBAF (14.58 mL, 14.58 mmol) dropwise at -40 °C under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with EA (100 mL). The resulting solution was washed with water (3 x 100 mL) and brine (100 mL), dried over anhydrous NaiSCL. After filtration, the filtrate was concentrated under reduced pressure to afford /tvV-butyl 3-hydroxy-3-(l, l,2,2,2-pentafluoroethyl)pyrrolidine-l-carboxylate (3.3 g, 80%) as a light brown oil. MS ESI calculated for C11H16F5NO3 [M - Boc + H] ⁺ , 206.11, found 206.05.

Step 2: fc/V-butyl 3-P . 1.2.2.2-pentafluoroethyl )-2.5-dihvdropyrrole-l -carboxyl ate step 2

Boc Boc

[00233] To a stirred solution of /er/-butyl 3 -hydroxy-3 -(1,1, 2,2, 2-pentafluoroethyl)pyrrolidine-l- carboxylate (2.10 g, 6.88 mmol) in pyridine (20 mL) was added SOCI2 (4.09 g, 34.40 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0- 30%). The fractions contained desired product were combined and concentrated to afford /er/-butyl 3-(l,l,2,2,2-pentafluoroethyl)-2,5-dihydropyrrole-l-carboxyl ate (1.25 g, 63%) as yellow oil. MS ESI calculated for C ₁₁ H ₁₄ F ₅ NO ₂ [M - Boc + H] ⁺ , 188.04, found 187.85. H-NMR (400 MHz, CDCb) d 6.43-6.38 (m, 1H), 4.35-4.30 (m, 4H), 1.51 (s, 9H). F-NMR (376 MHz, i¾-DMSO) d - 83.57 (3F), -113.39 (2F).

Step 3 : fer/-butyl 3-P J .2.2.2-pentafluoroethyl )pyrrolidine- l -carboxyl ate step 3

[00234] A mixture of /er/-butyl 3-(l,l,2,2,2-pentafluoroethyl)-2,5-dihydropyrrole-l-carboxyl ate (1.25 g, 4.35 mmol) and Pd/C (Wet) (0.50 g, 4.70 mmol) in MeOH (15 mL) was stirred for 2 h at room temperature under hydrogen (2 atm) atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure to afford /c77-butyl 3-(l,l,2,2,2-pentafluoroethyl)pyrrolidine-l-carboxylate (1.2 g, 95%) as a light yellow oil. MS ESI calculated for CnHieFsNOi [M - Boc + H] ⁺ , 190.06, found 189.90. H-NMR (400 MHz, i/g-DMSO) d 3.59-3.44 (m, 2H), 3.28-3.25 (m, 3H), 2.10-1.95 (m, 2H), 1.41 (s, 9H). F- NMR (376 MHz, i¾-DMSO) d -83.29 (3F), -119.74-122.14 (2F).

Step 4: 3-P J .2.2.2-pentafluoroethyl Ipyrrolidine hydrochloride

[00235] To a stirred solution of /t'/7 -butyl 3-(l,l,2,2,2-pentafluoroethyl)pyrrolidine-l-carboxylate (1.20 g, 4.15 mmol) in dioxane (10.00 mL) was added HC1 (gas) in 1,4-dioxane (10.00 mL) dropwise at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 3-(l,l,2,2,2-pentafluoroethyl)pyrrolidine

hydrochloride (930 mg, crude) as a yellow solid. It was used directly to next step without further purification. MS ESI calculated for C ₆ H ₉ C1F ₅ N [M - HC1 + H] ⁺ , 190.06, found 190.10. H-NMR (400 MHz, i¾-DMSO) d 9.72 (brs, 2H), 3.55-3.50 (m, 1H), 3.43-3.30 (m, 2H), 3.24-3.15 (m, 2H), 2.30-2.22 (m, 1H), 2.02-1.92 (m, 1H). F-NMR (376 MHz, ^-DMSO) d -83.30 (3F), -118.90, - 121.75 (2F).

Intermediate 24: 3-(trifluoromethyl)-l,2,5,6-tetrahydronyridine hydrochloride

Step 1 : tert- butyl 3 -(tri fl uorom ethyl )-5.6-dihvdro-2//-pyridine-l -carboxyl ate

Boc step 1 Boc

[00236] To a stirred solution of /v/V-butyl 4-hydroxy-3-(trifluoromethyl)piperidine-l-carboxylate (0.50 g, 1.86 mmol) in pyridine (10 mL) was added SOCh (1.35 mL, 18.61 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at 80 °C. The resulting mixture was quenched with water (50 mL) and extracted with EA (3 x 40 mL). The combined organic layers was washed with 1 M HCI (3 x 30 mL) and brine (30 mL), dried over anhydrous NaiSCh and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC (PE/EA=3/1) to afford tert- butyl 3 -(tri fl uoro ethyl )-5 , 6-di hydro-2//-pyri di ne- 1 -carboxyl ate (0.30 g, 64%) as a yellow oil. H-NMR (400 MHz, CDCh) d 6.47 (d, J= 3.6 Hz, 1H), 4.02 (s, 2H), 3.50 (t, J= 5.6 Hz, 2H), 2.27 - 2.24 (m, 2H), 1.48 (s, 9H). F-NMR (376 MHz, CDCh) d -68.27. Step 2: 3 -(tri fl uorom ethyl )- l .2.5.6-tetrahvdropyridine hydrochloride

[00237] To a stirred solution of /er/-butyl 3 -(tri fl uorom ethyl )-5,6-di hydro-2// -pyridine-1 -carboxyl ate (0.17 g, 0.68 mmol) in EA (1 mL) was added 2 M HCI in EA (5 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 3-(trifluoromethyl)-l,2,5,6-tetrahydropyridine hydrochloride (0.13 g, 100%) which was directly used to next step without further purification. H- NMR (400 MHz, CDCh) d 6.60 (s, 1H), 3.88 (s, 2H), 3.42 - 3.38 (m, 2H), 2.69 - 2.65 (m, 2H); F- NMR (376 MHz, CDCh) d -68.58.

Intermediate 25: 3-t2,2,2-trifluoroethyl)-2,5-dihydro-lH-nyrrole hydrochloride

Step 1 : tert- butyl 3-(2.2.2-trifluoroethyl )-2.5-dihydropyrrole- l -carboxyl ate

[00238] To a solution of /er/-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5-dihydrop yrrole-l- carboxylate (0.50 g, 1.69 mmol) and l,l,l-trifluoro-2-iodoethane (1.07 g, 5.08 mmol) in 1,4- dioxane (10 mL) were added CS ₂ CO ₃ (2.21 g, 6.77 mmol) and XantPhos (0.196 g, 0.34 mmol) and Pd2(dba)3.CHCh (0.35 g, 0.34 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred overnight at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1 :2). The fractions contained desired product were combined and concentrated to afford /tvV-butyl 3-(2,2,2-trifluoroethyl)-2,5-dihydropyrrole-l-carboxylate (0.12 g, 25%) as a colorless oil. MS ESI calculated for C ₁₁ H ₁₆ F ₃ NO ₂ [M + H - /-Bu] ⁺ , 196.11, found 196.10.

Step 2: 3-(2.2.2-trifluoroethyl )-2.5-dihydro- l //-pyrrole hydrochloride step 2

[00239] To a stirred solution of /tvV-butyl 3-(2,2,2-trifluoroethyl)-2,5-dihydropyrrole-l-carboxylate (0.12 g, 0.48 mmol) in DCM (2.00 mL) was added HCI (gas) in 1,4-dioxane (4 M, 2.00 mL, 0.05 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 0.5 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 3-(2,2,2- trifluoroethyl)-2, 5 -dihydro- liT-pyrrole hydrochloride (85 mg, 100%) as a yellow solid. It was used in the next step directly without further purification. MS ESI calculated for C6H9CIF3N [M + H] ⁺ , 152.06; found 152.10. ¾ NMR (400 MHz, CDCb) d 10.43 (brs, 2H), 5.84 (s, 1H), 4.24-4.20 (m, 2H), 4.18-4.10 (m, 2H), 3.05 (q, J= 10.4 Hz, 2H).

Intermediate 26: 3-(l,l,2,2,2-Dentafluoroethyl)-2,5-dihvdro-lH-Dyrrole hydrochloride

Step 1 : 3-P J .2.2.2-pentafluoroethyl )-2.5-dihydro- l //-pyrrole hydrochloride

[00240] To a stirred solution of /er/-butyl 3-(l,l,2,2,2-pentafluoroethyl)-2,5-dihydropyrrole-l-carboxyl ate (0.1 g, 0.35 mmol) in dioxane (1 mL, 11.80 mmol) was added HCI (gas) in 1,4-dioxane (4 M) (1 mL, 32.91 mmol) dropwise at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 3-(l,l,2,2,2- pentafluoroethyl)-2, 5-dihydro- liT-pyrrole hydrochloride (79 mg, 91%) as a yellow solid. It was used directly to next step without further purification. MS ESI calculated for C ₆ H ₇ CIF ₅ N [M - HCI + H] ⁺ , 188.11, found 187.90. H-NMR (400 MHz, CDCh) d 10.19 (brs, 2H), 6.82 (s, 1H), 4.21-4.17 (m, 4H).

Intermediate 27: l,l-difluoro-6-azaspiro[3.41octane

1

[00241] To a stirred solution of benzyl l-oxo-6-azaspiro[3.4]octane-6-carboxylate (2.00 g, 7.71 mmol) in CHCb (20.00 mL) was added BAST (6.83 g, 30.852 mmol) dropwise at 0 °C under argon atmosphere. The reaction mixture was stirred for 20 h at 60 °C under argon atmosphere. The resulting mixture was neutralized to pH 7 with saturated NaHCCh. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column

chromatography, eluted with PE/EtOAc (3: 1). The fractions contained desired product were combined and concentrated to afford benzyl l,l-difluoro-6-azaspiro[3.4]octane-6- carboxylate(lg,46.09%) as a yellow oil. MS ESI calculated for C15H17F2NO2 [M + H] ⁺ , 282.1, found 282.3.

Step 2: Ll-difluoro-6-azaspiror3.41octane

step 2

Cbz H

TFA, rt, 16 h N. VP

1 2

[00242] A solution of benzyl l,l-difluoro-6-azaspiro[3.4]octane-6-carboxylate (75.00 mg, 0.267 mmol) in CF ₃ COOH (5.00 mL) was stirred for 2 h at 70 °C under argon atmosphere. The solution was concentrated under reduced pressure. The residue was diluted with EA (10 mL). The resulting mixture was washed with sat. aqueous NaHCCb (10 mL x 2). The organic layer was dried over anhydrous Na ₂ SC> ₄ and filtered. The filtrate was concentrated under reduced pressure to afford 1,1- difluoro-6-azaspiro[3.4]octane (35 mg, 90%) as an off-white semi-solid. The crude product was used directly to next step without further purification. 'H NMR (400 MHz, DMSO-6/6) 5 3.12 - 2.99 (m, 2H), 3.02 - 2.90 (m, 2H), 2.10 - 1.83 (m, 3H), 1.82 - 1.67 (m, 4H).

Intermediate 28: tZ)-3-i2,2,2-trifluoroethylidene)Dyrrolidine hydrochloride

Step 1 : tert- butyl (3Z)-3-(bromomethylidene)pyrrolidine-l-carboxylate and fer/-butyl (3E)-3-

(bromomethylidene)pyrrolidine- 1 -carboxylate

step 1

B CH PPh B 1 3 Boc

[00243] To a solution of (bromomethyl)triphenylphosphanium bromide (30.61 g, 70.18 mmol) in THF (220 mL) was added /-BuOK (1 M in THF) (64.78 mL, 64.78 mmol) dropwise at -78 °C. The reaction mixture was stirred for 1.5 h at -78 °C. To the above solution was added te/7-butyl 3- oxopyrrolidine-l-carboxylate (10 g, 53.99 mmol) in THF (40 mL). The reaction mixture was allowed to gradually warm to room temperature and stirred overnight. The resulting mixture was quenched by the addition of water (500 mL) at room temperature and extracted with DCM (2 x 500 mL). The combined organic layers was washed with brine (2 x 300 mL), dried over anhydrous NaiSCri and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (0 to 20%). The fractions

contained desired product were combined and concentrated to afford /c/V-butyl (3Z)-3- (bromomethylidene)pyrrolidine-l-carboxylate (1.5 g, 11%) as a yellow oil and tert- butyl (3E)-3- (bromomethylidene)pyrrolidine-l-carboxylate (1.8 g, 13%) as a yellow oil. /b/V-butyl (3Z)-3- (bromomethylidene)pyrrolidine-l-carboxylate, MS ESI calculated for CioHieBrNCh [M - /-Bu] ⁺ , 205.97, 207.97, found 205.85, 207.85. ¹ H-NMR (400 MHz, i&-DMSO) d 6.43-6.40 (m, 1H), 3.93-

3.91 (m, 2H), 3.45-3.42 (m, 2H), 2.58-2.55 (m, 2H), 1.41 (s, 9H). Tert- butyl (3£)-3- (bromomethylidene)pyrrolidine-l-carboxylate, MS ESI calculated for CioHieBrNCh [M - /-Bu] ⁺ , 205.97, 207.97, found 205.85, 207.85. ¹ H-NMR (400 MHz, i&-DMSO) d 6.37-6.34 (m, 1H), 3.87- 3.84 (m, 2H), 3.47-3.44 (m, 2H), 2.60-2.57 (m, 2H), 1.42 (s, 9H).

Step 2: -butyl (3Z)-3-(2.2.2-trifluoroethylidene)pyrrolidine- l -carboxyl ate

Br— J ft

, ,

1

2

[00244] To a mixture of /ert-butyl (3Z)-3-(bromomethylidene)pyrrolidine-l-carboxylate (0.39 g, 1.49

mmol) and Cul (0.68 g, 3.571 mmol) in HMPA (2.50 mL, 14.29 mmol) and DMF (2.50 mL, 32.30 mmol) was added a solution of methyl 2,2-difluoro-2-sulfoacetate (2.86 g, 14.88 mmol) and DMF (2.50 mL, 0.034 mmol) dropwise over 1 h at 75 °C. The reaction mixture was degassed with nitrogen and stirred for 3 days at 75 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (4: 1). The fractions contained desired product were combined and concentrated to afford /c/V-butyl (3Z)-3-(2,2,2-trifluoroethylidene)pyrrolidine-l-carboxylate (66 mg, 18%) as a colorless oil. MS ESI calculated for C11H16F3NO2 [M - /Bu] ⁺ , 195.11, found 195.90.

Step -(2.2.2-trifluoroethyli dene (pyrrolidine hydrochloride

[00245] To a mixture of /c/7-butyl (3Z)-3-(2,2,2-trifluoroethylidene)pyrrolidine-l-carboxylate (66.00 mg, 0.263 mmol) in 1,4-dioxane (2.00 mL, 23.608 mmol) was HC1 (gas) in 1,4-dioxane (1.00 mL, 32.912 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum to afford (3Z)-3 -(2,2,2- trifluoroethylidene) pyrrolidine hydrochloride (48 mg, 97.41%) as a light yellow solid. The crude product was used in the next step directly without further purification. MS ESI calculated for C6H9CIF3N [M + H - HC1] ⁺ , 152.06; found 151.90.

Intermediate 29: t3E)-3-i2,2,2-trifluoroethylidene)nyrrolidine hydrochloride

[00246] The title compound was prepared using procedures similar to those described in Intermediate 28 using (3A)-3-(bromomethylidene)pyrrolidine- i -carboxyl ate instead of (3Z)-3- (bromomethylidene)pyrrolidine-l-carboxylate to afford the title compound as a yellow solid.

Intermediate 30: iZ)-3-(l,l,l-trifluoronronan-2-ylidene)nyrrolidine hydrochloride

[00247] To a stirred mixture of pyrrolidine-3 -carboxylic acid (4.00 g, 34.74 mmol) in Toluene (60.00 mL) were added TFAA (26.58 mL, 126.55 mmol) dropwise and Pyridine (22.37 mL, 282.835 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 48 h at 50 °C. The resulting mixture was quenched with water (50 mL) at 0 °C and stirred for additional 2 h at 45 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers was washed with brine (100 mL), dried over anhydrous NaiSCL and filtered. The filtrate was concentrated under vacuum to afford 2,2,2-trifluoro-l-[3-(2,2,2-trifluoroacetyl)pyrrolidin-l- yljethanone (lOg, crude) as brown oil. The crude product was used directly to next step without further purification. MS ESI calculated for CsFLFeNCh [M + H + H ₂ 0] ⁺ , 282.04, found 282.00. Step 2: fert-butyl 3-(2.2.2-trif1uoroacetyl )pyrrolidine- l -carboxyl ate

[00248] To a stirred mixture of 2,2,2-trifluoro-l-[3-(2,2,2-trifluoroacetyl)pyrrolidin-l-yl] ethanone (2.30 g, 8.74 mmol), MeOH (15.00 mL) and H ₂ 0 (0.47 mL, 26.222 mmol) was added K ₂ C0 ₃ (2.42 g,

17.481 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 2 h at room temperature. To the above mixture was added (Boc) ₂ 0 (2.29 g, 10.493 mmol) dropwise at room temperature. The resulting mixture was stirred for additional 16 h at room temperature. The resulting mixture was concentrated and extracted with EtOAc (3 x 100 mL). The combined organic layers was washed with brine (100 mL), dried over anhydrous Na ₂ SC> ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column

chromatography, eluted with EA/PE (0 to 70%). The fractions contained desired product were combined and concentrated to afford /tvV-butyl 3-(2,2,2-trifluoroacetyl)pyrrolidine-l-carboxylate (1.87 g, 80%) as a brown oil. MS ESI calculated for C11H16F3NO3 [M - /-Bu + H] ⁺ , 212.05, found 212.05

Step 3: fc/V-butyl 3-(T.El-trifluoro-2-hvdroxypropan-2-vDpynOlidine-l-carboxyla te

Boc step 3 Boc

[00249] To a stirred solution of /tvV-butyl 3-(2,2,2-trifluoroacetyl)pyrrolidine-l-carboxylate (5.8 g, 21.70 mmol) in THF (60.00 mL) was added MeMgBr (21.70 mL, 65.109 mmol) dropwise at -70 °C under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of NH ₄ CI (aq.) (sat., 200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers was washed with brine (1 x 500 mL), dried over anhydrous Na ₂ S0 ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column

chromatography, eluted with EtO Ac/PE (0-100%). The fractions contained desired product were combined and concentrated to afford /tvV-butyl 3-(l,l,l-trifluoro-2-hydroxypropan-2- yl)pyrrolidine-l-carboxylate (0.87g, 14%) as a light yellow solid. MS ESI calculated for

CiiH FsNOs [M - /-Bu + H] ⁺ , 228.14, found 228.05. H-NMR (400 MHz, ^-DMSO) d 6.02-5.99 (m, 1H), 3.43-3.40 (m, 2H), 3.18-3.01 (m, 2H), 2.45-2.41 (m, 1H), 1.92-1.80 (m, 2H), 1.40 (s, 9H), 1.27 (s, 3H).

Step 4: tert- butyl (3Z)-3-( l J . 1 -trifluoropropan-2-ylidene)pyrrolidine- l -carboxyl ate and tert- butyl (3E)-3 -(1.1.1 -trifluoropropan-2-ylidene)pyrrolidine- 1 -carboxylate

Boc ^ste P ^ Boc Boc

[00250] To a stirred solution of /er -butyl 3-(l,l, l-trifluoro-2-hydroxypropan-2-yl)pyrrolidine-l- carboxylate (1.13 g, 3.99 mmol) in Pyridine (11.00 mL) was added SOCb (2372.76 mg, 19.944 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The resulting mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-30%). The fractions contained desired product were combined and concentrated to afford /er -butyl (3Z)-3-(l,l, l-trifluoropropan-2- ylidene)pyrrolidine-l -carboxylate (0.20 g, 19%) as a yellow oil and /er -butyl (3£)-3-( 1,1, 1- trifluoropropan-2-ylidene)pyrrolidine-l -carboxylate (0.70 g, 66%) as a yellow oil. Zb/V-butyl (3 Z)- 3 -(l,l, l-trifluoropropan-2-ylidene)pyrrolidine-l -carboxylate: MS ESI calculated for C12H18F3NO2 [M - /-Bu + H] ⁺ , 210.13, found 209.95. H-NMR (400 MHz, ^-DMSO) d 4.23-4.19 (m, 2H), 3.56- 3.54 (m, 2H), 2.68-2.66 (m, 2H), 1.82 (s, 3H), 1.56 (s, 9H).

[00251] Tert- butyl (3//)-3-( l , 1 , 1 -trifluoropropan-2-ylidene)pyrrolidine- l -carboxylate: MS ESI calculated for C12H18F3NO2 [M - /-Bu + H] ⁺ , 210.13, found 209.95. H-NMR (400 MHz, ^-DMSO) d 4.08- 4.06 (m, 2H), 3.59-3.57 (m, 2H), 2.84-2.82 (m, 2H), 1.80 (s, 3H), 1.53 (s, 9H).

Step 5: (3Z)-3-( \ J J -trifluoropropan-2-ylidene)pyrrolidine hydrochloride

4 5

[00252] To a stirred solution of /e/7-butyl (3 Z)-3-(l,l, l-trifluoropropan-2-ylidene)pyrrolidine-l -carboxylate (80.00 mg, 0.302 mmol) in dioxane (1.50 mL) was added HC1 (gas) in 1,4-dioxane (1.50 mL) dropwise at 0 °C. The reaction solution was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (3Z)-3-(l, l,l-trifluoropropan-2- ylidene)pyrrolidine hydrochloride (58 mg) as a yellow solid. The crude product was used directly to next step without further purification. MS ESI calculated for C7H11CIF3N [M - HCI + H] ⁺ , 166.08, found 166.10. H-NMR (400 MHz, ^-DMSO) d 9.57 (brs, 2H), 4.02-3.99 (m, 2H), 3.58- 3.40 (m, 2H), 2.74-2.72 (m, 2H), 1.85 (s, 3H).

Intermediate 31: fE)-3-n,l,l-trifluoronronan-2-ylidene)nyrrolidine hydrochloride

[00253] The title compound was prepared using procedures similar to those described in Intermediate 30 step 5 using /tvV-butyl (3//)-3-( l , 1 , 1 -trifluoropropan-2-ylidene)pyrrolidine- l -carboxyl ate instead of /tvV-butyl (3Z)-3-(l,l,l-trifluoropropan-2-ylidene)pyrrolidine-l-carbox ylate to afford the title compound as a light yellow solid.

Intermediate 32: 3-i2,2,2-trifluoroethyl)-2,5-dihydro-lH-nyrrole hydrochloride

Step 1 : Tert- butyl 3-(2.2.2-trifluoroethyl )-2.5-dihydropyrrole- l -carboxyl ate

1

[00254] To a solution of /er/-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5-dihydrop yrrole-l- carboxylate (0.50 g, 1.69 mmol) and l,l,l-trifluoro-2-iodoethane (1.07 g, 5.08 mmol) in 1,4- dioxane (lOmL) were added CS2CO3 (2.21 g, 6.78 mmol), XantPhos (0.196 g, 0.339 mmol) and Pd ₂ (dba) _3. CHCh (0.35 g, 0.339 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred overnight at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica

el column chromatography, eluted with PE/EtOAc (1 :2). The fractions contained desired product were combined and concentrated to afford /er/-butyl 3-(2,2,2-trifluoroethyl)-2,5-dihydropyrrole-l- carboxylate (0.12 g, 25%) as a white oil. MS ESI calculated for C ₁₁ H ₁₆ F ₃ NO ₂ [M + H - /Bu] , 196.05, found 196.10.

Step 2: 3-(2.2.2-trifluoroethyl )-2.5-dihydro- l H-pyrrole hydrochloride step 2

Boc HCI H

1 2

[00255] To a stirred solution of tert-butyl 3-(2,2,2-trifluoroethyl)-2,5-dihydropyrrole-l-carboxylate (0.12 g, 0.48 mmol) in DCM (2.00 mL) was added HCI (gas) in 1,4-dioxane (4 M)

(2.00 mL, 0.055 mmol) at 0

oC under nitrogen atmosphere. The reaction mixture was stirred for 0.5h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 3-(2,2,2-trifluoroethyl)-2,5- dihydro-lH-pyrrole hydrochloride (90 mg, 100%) as a yellow solid. The crude product was used directly in next step without further purification. MS ESI calculated for C ₆ H ₉ CIF ₃ N [M + H - HC1] ⁺ , 152.06; found 152.10.

Intermediate 33: (pyrrolidin-3-ylidene)propanenitrile hydrochloride

Step 1 : -3-(T-cvanoethylidene)pyrrolidine-l-carboxylate/ -3-(T-

cvanoethylideneipyrrolidine- 1 -carboxylate

[00256] To a solution of diethyl 1 -cyanoethylphosphonate (1.15 g, 5.99 mmol) in THF (30 mL) was added /-BuOK (0.81 g, 7.19 mmol) at 0 °C. The reaction mixture was stirred for 10 min. After which time, a solution of tert- butyl 3 -oxopyrrolidine-1 -carboxylate (1.11 g, 5.99 mmol) in THF (6 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 20-35% EA in PE. The fractions contained desired product were combined and concentrated to afford /er/-butyl (3£)-3-(l- cyanoethylidene)pyrrolidine-l -carboxylate (0.50 g, 38%) as a colorless oil and tert- butyl (3Z)-3-(l- cyanoethylidene)pyrrolidine-l-carboxylate (0.48 g, 36%) as a colorless oil. /b/V-butyl (3£)-3-(l- cyanoethylidene)pyrrolidine-l-carboxylate: MS ESI calculated for C12H18N2O2 [M + H]+, 223.14; found 223.05. ¹ H-NMR (400 MHz, ί/6-DMSO) d 4.03 (m, 2H), 3.46 (t, J= 7.2 Hz, 2H), 2.79 (s, 2H), 1.84-1.78 (m, 3H), 1.41 (s, 9H). 7er/-butyl (3Z)-3-(l-cyanoethylidene)pyrrolidine-l- carboxylate: MS ESI calculated for C12H18N2O2 [M + H]+, 223.14; found 223.05. ¹ H-NMR (400 MHz, <76-DMSO)5 4.02 (s, 2H), 3.40 (t, J= 7.2 Hz, 2H), 2.64 (s, 2H), 1.78 (s, 3H), 1.34 (s, 9H). Step 2: (Z)-2-(pyrrolidin-3-ylidene)propanenitrile hydrochloride

step 2

[00257] To a stirred solution of /c/7-butyl (3Z)-3-(l-cyanoethylidene)pyrrolidine-l-carboxylate (0.23 g, 1.03 mmol) in dioxane (5.75 mL, 65.26 mmol) was added HC1 (4M in 1,4-dioxane) (5.75 mL) dropwise at 25 °C .The reaction mixture was stirred for 16 h. The resulting mixture was concentrated under vacuum to afford (Z)-2-(pyrrolidin-3-ylidene)propanenitrile hydrochloride (165 mg, 100%) as a yellow solid. The crude product was used in the next step directly without further purification. MS ESI calculated for C ₇ H ₁₁ CIN ₂ [M + H - HC1] ⁺ , 123.08; found 123.20.

Intermediate 34: (pyrrolidin-3-ylidene)propanenitrile hydrochloride

[00258] The title compound was prepared using procedures similar to those described in Intermediate 33 step 2 using /c/V-butyl (3//)-3-( l -cyanoethylidene)pyrrolidine- 1 -carboxyl ate instead of /c/7-butyl (3Z)-3-(l-cyanoethylidene)pyrrolidine-l-carboxylate to afford the title compound as a light yellow solid.

Intermediate 35: 2-methyl-2-(pyrrolidin-3-v0propanenitrile hydrochloride

Step 1 : Tert- butyl 3-P -cvano- 1 -methylethyl )pyrrolidine- l -carboxyl ate Boc Step 1 Boc

M

3N

1

[00259] To a stirred solution of /ert-butyl 3-(cyanomethyl)pyrrolidine-l-carboxylate (0.5 g, 2.38 mmol) in THF (4 mL) was added KHMDS (1.43 mL, 1.43 mmol) dropwise at -5 °C under nitrogen atmosphere. The reaction mixture was stirred for 10 minutes, after which time a solution of C¾I (0.776 g, 5.47 mmol) in THF (0.70 mL) was added slowly over a period of 10 minutes. The reaction mixture was stirred for another 1 h. The resulting mixture was quenched with MLCl (sal. ) at 0 °C and extracted with EA (3 x 30 mL). The combined organic layers was washed with brine (2 x 30 mL), dried over anhydrous NaiSCL and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 30% EA in PE. The fractions contained desired product were combined and concentrated to afford /ert-butyl 3- (1-cyano-l -methyl ethyl)pyrrolidine-l-carboxylate (0.23 g, 41%) as a colorless oil. H-NMR (400 MHz, CDCh) d 3.60 (s, 2H), 3.31 - 3.15 (m, 2H), 2.20 - 1.85 (m, 3H), 1.47 (s, 9H), 1.40 (s, 3H), 1.37 (s, 3H).

Step 2: 2-Methyl-2-(pynOlidin-3-v0propanenitrile hydrochloride

1 2

[00260] To a stirred solution of /cvV-butyl 3-(l-cyano-l-methylethyl)pyrrolidine-l-carboxylate (0.23 g, 0.98 mmol) in EA (1.00 mL, 10.22 mmol) was added 4 M HCI in 1,4-dioxane dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 3 h at ambient temperature. The resulting mixture was concentrated under reduced pressure to afford 2-methyl-2-(pyrrolidin-3- yl)propanenitrile hydrochloride (0.16 g, 94%) as an off-white solid. H-NMR (400 MHz, CDCh) d 3.66-3.62 (m, 1H), 3.54-3.50 (m, 1H), 3.44-3.40 (m, 1H), 3.12-3.08 (m, 1H), 2.26-2.24 (m, 1H), 2.01-1.93 (m, 2H), 1.43-1.42 (m, 6H).

Intermediate 36: 3-(l,l,l-trifluoroDroDan-2-vnDyrrolidine hydrochloride

Step 1 : 7er/-butyl 3 - 1 -trifluoropropan-2-yl (pyrrol idine- 1 -carboxyl ate

step 1

Boc Boc

1

[00261] To a solution of /er/-butyl (3/', ^’ )-3-( 1 , 1 , 1 -trifluoropropan-2-ylidene)pyrrolidine- l -carboxyl ate (0.35 g, 1.32 mmol) in MeOH (5.00 mL) was added Pd/C (10%) (0.15 g, 1.41 mmol). The reaction mixture was degassed with hydrogen and stirred for 1 h at room temperature under (1 atm) hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (4 x 5 mL). The filtrate was concentrated under reduced pressure. This resulted in /er/-butyl 3-(l, 1,1- trifluoropropan-2-yl)pyrrolidine-l-carboxylate (320 mg) as colorless oil. The crude product was used directly to next step without further purification. MS ESI calculated for C12H20F3NO2 [M - Boc + H] ⁺ , 168.09, found 167.95. ¹ H-NMR (400 MHz, CDCh) d 3.68-3.51 (m, 2H), 3.32-3.18 (m, 1H), 3.04-2.94 (m, 1H), 2.35-2.03 (m, 3H), 1.74-1.52 (m, 1H), 1.51 (s, 9H), 1.22-1.08 (m, 3H).

Step 2: 3-(LL l-Trifluoropropan-2-vDpyrrolidine hydrochloride

[00262] To a stirred solution of /y/V-butyl 3-(l,l, l-trifluoropropan-2-yl)pyrrolidine-l-carboxylate (0.32 g, 1.20 mmol) in dioxane (3.00 mL) was added HC1 (gas, 2 M) in 1,4-dioxane (3.00 mL) dropwise at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 3-(l,l, l-trifluoropropan-2-yl)pyrrolidine

hydrochloride (280 mg) as colorless oil. The crude product was used directly to next step without further purification. MS ESI calculated for C7H13CIF3N [M - HC1 + H] ⁺ , 168.09, found 168.15. H- NMR (400 MHz, i¾-DMSO) d 9.44-9.37 (m, 2H), 3.52-3.40 (m, 2H), 3.14-3.03 (m, 1H), 2.90-2.81 (m, 1H), 2.68-2.57 (m, 1H), 2.39-2.25 (m, 1H), 2.09-2.04 (m, 1H), 1.75-1.61 (m, 1H), 1.12-1.08 (m, 3H).

Intermediate 37: 3-i2,2-difluorocycloDroDyl)Dyrrolidine hydrochloride

Step 1 : Tert- butyl 3-(2.2-difluorocvclopropyl (pyrrol idine- 1 -carboxyl ate

step 1

Boc

1

[00263] To a mixture of /er/-butyl 3-ethenylpyrrolidine-l-carboxylate (0.20 g, 1.01 mmol), and Nal (30.39 mg, 0.20 mmol) in THF (1.00 mL) was added trifluoromethyltrimethylsilane (0.36 g, 2.53 mmol). The reaction mixture was stirred overnight at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column

chromatography, eluted with EA/PE (0 to 55%). The fractions contained desired product were combined and concentrated to afford /tvV-butyl 3-(2,2-difluorocyclopropyl)pyrrolidine-l- carboxylate (74 mg, 50% purity, 30% yield) as a yellow oil. It was used directly for next step without further purification. MS ESI calculated for C ₁₂ H ₁₉ F ₂ NO ₂ [M - /Bu + CEBCN + H] ⁺ , 233.14, found 233.05.

Step 2: 3-(2.2-difluorocvclopropyl (pyrrolidine hydrochloride

1 2

[00264] To a stirred solution of /tvV-butyl 3-(2,2-difluorocyclopropyl)pyrrolidine-l-carboxylate (74.00 mg, 0.299 mmol) in dioxane (1.00 mL) was added 4 M HC1 in 1,4-dioxane (1.00 mL) dropwise at 0 °C. The reaction solution was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 3-(2,2-difluorocyclopropyl)pyrrolidine hydrochloride (55 mg, 100%) as yellow oil. MS ESI calculated for C ₇ H ₁₂ CIF ₂ N [M - HC1 + H] ⁺ , 148.09, found 148.10.

Intermediate 38: 3- [itrifluoromethyl)sulfanyll pyrrolidine hydrochloride

Step 1 : Tert- butyl 3-r(trifluoromethv0sulfanvnpyrrolidine-l-carboxylate

[00265] To a mixture of /er/-butyl 3-hydroxypyrrolidine-l-carboxylate (0.60 g, 3.20 mmol),

tetrabutylammonium iodide (14.2 g, 38.45 mmol, 12.00 equiv), KI (4.2 g, 25.64 mmol) in toluene (30 mL) was added [(trifluoromethyl)sulfanyl]silver (0.89 g, 4.27 mmol). The reaction mixture was stirred for 16 h at 120 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (0 to 15%). The fractions contained desired product were combined and concentrated to afford te/7-butyl 3- [(trifluoromethyl)sulfanyl]pyrrolidine-l-carboxylate (1 g, crude) as brown oil. MS ESI calculated for C ₁₀ H ₁₆ F ₃ NO ₂ S [M + H - /-Bu] ⁺ , 216.09, found 215.95.

Step 2: 3-r(trifluoromethvDsulfanyl1pynOlidine hydrochloride ste 2

HCI

CF ₃

1 2

[00266] To a mixture of /er/-butyl 3-[(trifluoromethyl)sulfanyl]pyrrolidine-l-carboxylate (1.00 g, 3.69 mmol) in MeOH (4.00 mL) was added 4 M HCI in 1,4-dioxane (4.00 mL). The reaction mixture was stirred for additional 16 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 3-[(trifluoromethyl)sulfanyl]pyrrolidine hydrochloride (1 g, crude) as a brown oil. The crude product was used directly to next step without further purification. MS ESI calculated for C ₅ H ₉ CIF ₃ NS [M + H - HC1] ⁺ , 172.03, found 172.05.

Intermediate 39: t3R)-3-i2,2,2-trifluoroethoxy)Dyrrolidine

Step 1 : Tert- butyl 3-r(trifluoromethvnsulfanyl1pyrrolidine-l-carboxylate Step 1

1

[00267] A mixture of (3f?)-pyrrolidin-3-ol hydrochloride (5.00 g, 40.46 mmol), 4-methoxybenzyl chloride (6336.38 mg, 40.46 mmol) and K2CO3 (16775.23 mg, 121.38 mmol) in acetone (50 mL) was stirred for 16 h at 60 degrees C under nitrogen atmosphere. The solid was filtered out. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with MeOH with 10% NH3.H2O/DCM (0 to 8%) to afford (3f?)-l-[(4- methoxyphenyl)methyl]pyrrolidin-3-ol (6.4g, 76%) as brown oil. MS ESI calculated for C12H17NO2 [M + H - /-Bu] ⁺ , 208.13, found 208.00.

Step 2: (3/% ! -r(4-methoxyphenyl ) ethyll-3-(2.2.2-trifluoroethoxy)pyrrolidine

Step 2 PMB

F

P _I MB

Tfo

1 2

[00268] To a stirred solution of (3f?)-l-[(4-methoxyphenyl)methyl]pyrrolidin-3-ol (4.80 g, 23.16 mmol) and THF (50 mL) was added NaH (926 mg, 23.16 mmol, 60%) in portions at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at room temperature under nitrogen atmosphere. To the above mixture was added 2,2,2-trifluoroethyl

trifluoromethanesulfonate (88.06 g, 34.74 mmol) dropwise over 5 min at 0 degrees C. The resulting mixture was stirred for additional 4 h at 60 degrees C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with

MeOH/DCM (0 to 8%) to afford (3f?)-l-[(4-methoxyphenyl)methyl]-3-(2,2,2- trifluoroethoxy)pynOlidine (4 g, 60%) as brown oil. MS ESI calculated for C14H18F3NO2 [M + H] ⁺ , 290.13, found 290.00.

Step 3: -3-(2.2.2-trifluoroethoxy)pyrrolidine

[00269] A mixture of (3f?)-l-[(4-methoxyphenyl)methyl]-3-(2,2,2-trifluoroethoxy)p yrrolidine (1.00 g, 3.46 mmol), ammonium formate (1089.81 mg, 17.28 mmol), Pd(OH)2/C (24 mg, 0.03 mmol, 20%) and MeOH (1.00 mL) was stirred for 16 h at 60 degrees C. The solid was filtered out and washed with MeOH (3 x 10 mL). The resulting mixture was concentrated under vacuum to afford (3R)-3 -(2,2,2- trifluoroethoxy)pyrrolidine (580 mg, crude) as brown oil. MS ESI calculated for C6H10F3NO [M + H] ⁺ , 170.07, found 169.90.

Intermediate 40: [2,2,2-trifluoroethoxylpyrrolidine

[00270] The Intermediate 27 was prepared using procedures similar to that described in Intermediate 39 using appropriate starting materials.

Intermediate 41: 3-trifluoromethanesulfonylpyrrolidine hydrochloride

Step 1 : fe/V-butyl 3-trifluoromethanesulfonylpyrrolidine-l-carboxylate

^ Stem

°Y° mCP ^S B ^t A ^p (1 ^l .5 eq.) o _Y G o

DCM, rt, 16 h

S-CF 0

3 q ^' § ^“CF 3

O

1

[00271] A solution of tert- butyl 3-[(trifluoromethyl)sulfanyl]pyrrolidine-l-carboxylate (200.00 mg, 0.74 mmol) and MCPBA (299.33 mg, 1.47 mmol, 85%) in DCM (2.00 mL) was stirred for 16 h at 25 degrees C. The resulting mixture was concentrated under vacuum. To the reside was added MCPBA (299.33 mg, 1.47 mmol, 2.00 equiv, 85%) in DCM (2.00 mL ), the resulting mixture was stirred for 16 h at 25 degrees C. The resulting mixture was diluted with CH2CI2 (20 mL), washed with sat. NaHCCh, dried over anhydrous Na ₂ SC> _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (4: 1) to afford /er/-butyl 3-trifluoromethanesulfonyl pyrrolidine- 1-carboxylate (120 mg, 54%) as an off-white solid. MS ESI calculated for: C10H16F3NO4S [M + H] ⁺ , 304.08; found 304.10. 1H-NMR (400 MHz, i&-DMSO) d 4.69 (s, 1H), 3.76-3.67 (m, 2H), 3.48 (t, J= 10.4 Hz, 1H), 2.41

(s, 3H), 1.41 (s, 9H).

Step 2: (3/% ! -r(4-methoxyphenyl ) ethyll-3-(2.2.2-trifluoroethoxy)pyrrolidine " Step 2 H HCI

°Y° HCI in dioxane N,

rt, 16 h

O-S-CFs

0'§ ^'CF 3 O

O

1 2

[00272] A mixture of tert- butyl 3 -trifluoromethanesulfonylpyrrolidine- 1-carboxylate (120.00 mg, 0.40

mmol), HCI (4 N in 1,4-dioxane, 4.00 mL) and MeOH (4.00 mL) was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. MS ESI calculated for :

C ₅ H ₉ CIF ₃ NO ₂ S [M + H - Cl] ⁺ , 204.02; found 204.10.

Intermediate 42: t3S)-3-isoDroDoxyDyrrolidine

Step 1 : benzyl -3-isopropoxypynOlidine-l-carboxylate

Step 1

I Cbz

C _I bz I

N. A as solvent

Q Ag ₂ 0 (2 eq ), 40 °C, 3 d

OH

[00273] To a stirred mixture of benzyl (3,V)-3-hydroxypyrrolidine- l -carboxyl ate (3.00 g, 13.56 mmol),

Ag ₂ 0 (6284.19 mg, 27.12 mmol) and 2-iodopropane (30 mL) was stirred for 48 h at 40 degrees C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA/PE (0 to 30%) to afford benzyl (3,V)- 3-isopropoxypyrrolidine-l-carboxylate (2 g, 56%) as a light yellow oil. MS ESI calculated for:

C15H21NO3 [M + H] ⁺ , 264.15; found 264.00. ¹ H-NMR (400 MHz, r/e-DMSO) d 7.40-7.32 (m, 5H), 5.16-5.15 (m, 2H), 4.15-4.14 (m, 1H), 3.66-3.64 (m, 1H), 3.57-3.46 (m, 4H), 1.98-1.95 (m, 2H), 1.18-1.15 (m, 6H).

Step 2: (3L')-3-ί sopropoxypyrrol i dine

Step 2

[00274] A mixture of benzyl (3A)-3-isopropoxypyrrolidine- l -carboxyl ate (500.00 mg, 1.90 mmol),

ammonium formate (598.62 mg, 9.49 mmol), Pd(OH)2/C (266.64 mg, 0.38 mmol, 20%) and MeOH (5.00 mL) was stirred for 1 h at 60 degrees C. The solid was filtered out. The resulting filtrate was concentrated under vacuum to afford (3ri)-3 -i sopropoxypyrrol i di ne (320mg, crude) as light yellow oil. MS ESI calculated for: C7H15NO [M + H] ⁺ , 130.12; found 129.95.

Intermediate 43: [l,l-difluoroethoxy)pyrrolidine

Step 1 : (4-methoxyphenyl )methyllpyrrolidin-3-ol

Step 1

1

[00275] A mixture of (3A)-pyrrolidin-3-ol hydrochloride (20 g, 161.84 mmol), 4-methoxybenzyl chloride (25345.53 mg, 161.84 mmol) and K2CO3 (67100.91 mg, 485.51 mmol) in acetone (200 mL) was stirred for 3 h at 60 degrees C under nitrogen atmosphere. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure to afford (3ri)-l-[(4- methoxyphenyl)methyl]pyrrolidin-3-ol (35 g, crude) as brown oil. MS ESI calculated for:

C12H17NO2 [M + H] ⁺ , 208.13; found 208.00.

Step 2: (3L')- 1 -r(4-methoxyphenyl )methyllpyrrolidin-3-yl acetate

[00276] To a solution of (3ri)-l-[(4-methoxyphenyl)methyl]pyrrolidin-3-ol(35 g, crude) in Pyridine (350 mL) was added AC2O (34477.24 mg, 337.72 mmol) dropwise at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure. The residue was diluted with EA (500 mL) and washed with sat. Na2CCh (3 x 250 mL). The organic layer was dried over anhydrous NaiSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10: 1) to afford (3ri)-l-[(4-methoxyphenyl)methyl]pyrrolidin-3-yl acetate (17 g, 40%) as brown oil. MS ESI calculated for: C ₁₄ H ₁₉ NO ₃ [M + H] ⁺ , 250.14; found 250.00. ¾-NMR (400 MHz, CDCh) d 7.27- 7.23 (m, 2H), 6.89-6.86 (m, 2H), 5.20-5.16 (m, 1H), 3.82 (s, 3H), 3.82-3.52 (m, 2H), 2.81-2.83 (m, 2H), 2.66-2.63 (m, 1H), 2.43-2.41 (m, 1H), 2.30-2.25 (m, 1H), 2.05 (s, 3H), 1.88-1.84 (m, 1H).

Step 3 : (3L')- I -r(4-methoxyphenyl )methyllpyrrolidin-3-yl ethanethioate

[00277] A mixture of (3ri)-l-[(4-methoxyphenyl)methyl]pyrrolidin-3-yl acetate (1 g, 4.01 mmol),

hexamethyldisiloxane (3907.88 mg, 24.07 mmol), P ₂ S ₅ (1069.86 mg, 4.81 mmol) and Toluene (20 mL) was stirred for 16 h at 120 degrees C under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0 to 7%) to afford (3ri)-l-[(4- methoxyphenyl)methyl]pyrrolidin-3-yl ethanethioate (120 mg, 11%) as yellow oil. MS ESI calculated for: C ₁₄ H ₁₉ NO ₂ S [M + H] ⁺ , 266.11; found 266.05. ¾-NMR (400 MHz, CDCh) d 7.35- 7.33 (m, 2H), 6.92-6.90 (m, 2H), 5.73-5.71 (m, 1H), 3.83 (s, 3H), 3.76-3.73 (m, 3H), 3.05-2.95 (m, 3H), 2.57 (s, 3H), 2.48-2.42 (m, 1H), 2.15-2.05 (m, 1H).

Step 4: (3L')-3-P J -difluoroethoxy)- ! -r(4-methoxyphenyl ) ethyl lpyrroli dine

[00278] To a stirred solution of (3L')- 1 -[(4-methoxyphenyl)methyl]pyrrolidin-3-yl ethanethioate (120.00 mg, 0.45 mmol) and tetrabutylammonium ion dihydrofluoride fluoride (408.99 mg, 1.36 mmol) in DCM (4.00 mL) was added NBS (32.19 mg, 0.18 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of sat. NaHC03 (50 mL) at 0 degrees C. The resulting mixture was extracted with DCM (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0 to 5%) to afford (3L')-3-( 1 , 1 -difluoroethoxy)-! -[(4-methoxyphenyl)methyl]pyrrolidine (50 mg, 41%) as a brown oil. MS ESI calculated for: C ₁₄ H ₁₉ F ₂ NO ₂ [M + H] ⁺ , 272.14; found 272.20. ¹ H-NMR (400 MHz, CDCb) d 7.28-7.25 (m, 2H), 6.90-6.87 (m, 2H), 4.85-4.83 (m, 1H), 3.83 (s, 3H), 2.86-2.22 (m, 5H), 1.95-1.75 (m, 1H), 1.73 (t, J= 13.2 Hz, 1H). F-NMR (376 MHz, CDCb) d -66.52 (2F). Step 5: (3L')-3-( 1 J -difluoroethoxyipyrrolidine

[00279] A mixture of (3L')-3-( 1 , 1 -difluoroethoxy)-! -[(4-methoxyphenyl)methyl]pyrrolidine (50.00 mg, 0.18 mmol), ammonium formate (116.21 mg, 1.84 mmol), Pd(OH)2/C (25.88 mg, 0.04 mmol, 20%) and MeOH (2.00 mL) was stirred for 1 h at 60 degrees C. The solid was filtered out. The filtrate was concentrated under reduced pressure to afford (3S)-3 -( 1 , 1 -di fl uoroethoxy )pyrrol i di ne (40 mg, crude) as yellow oil. MS ESI calculated for: C6H11F2NO [M + H] ⁺ , 152.08; found 152.05.

Intermediate 44: [3SV3-[l,l-difluoroethoxylpyrrolidine

Step 1 : fer/-butyl A-ri-(trifluoromethvDpyrazol-4-yllcarbamate Step 1

BOC ₂ 0 (1.5 eq.),

1

[00280] To a stirred solution of l-(trifluoromethyl)pyrazol-4-amine (0.30 g, 1.99 mmol) and di-/er/-butyl dicarbonate (0.69 g, 3.18 mmol) in THF (9 mL) was added NaHCCb (417.0 mg, 4.96 mmol) in water (3 mL) at room temperature. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The mixture was diluted with water (25 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over anhydrous NaiSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (9: 1) to afford /tvV-butyl /V-[l-(trifluoromethyl)pyrazol-4-yl]carbamate (0.46 g, 92%) as a yellow solid. MS ESI calculated for C9H12F3N3O2 [M + H] ⁺ , 252.09, found 252.10. H-NMR (400 MHz, Chloroform -if) d 8.11 (s, 1H), 7.63 (s, 1H), 6.42 (s, 1H), 1.54 (s, 9H). F-NMR (376 MHz, CDCb) d -60.69 (3F). Step 2: fe/V-butyl A-methyl-A'-fl -(trifluoromethyl )pyrazol-4-yllcarba ate

Step 2 N

1 2

[00281] To a stirred solution of NaH (99.35 mg, 4.14 mmol, 60%) in THF (5.00 mL) was added tert- butyl N- [ 1 -(tri fl uoro ethyl )py razol -4-yl ] carbarn ate (0.52 g, 2.07 mmol) in THF(2.0 mL) dropwise at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. To the above mixture was added Mel (0.59 g, 4.14 mmol) at 0 °C. The resulting mixture was stirred for additional 1 h at room temperature. The resulting mixture was quenched with water (20 mL) and extracted with EA (3 x 60 mL). The combined organic layers were dried over anhydrous Na ₂ SC> _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column

chromatography, eluted with PE/EA (5: 1) to afford tert- butyl /V-methyl-/V-[l- (trifluoromethyl)pyrazol-4-yl]carbamate (0.50 g, 91%) as a yellow solid. MS ESI calculated for C10H14F3N3O2 [M + H] ⁺ , 266.10, found 266.20. H-NMR (400 MHz, Chloroform-i7) d 8.10 (s, 1H), 7.83 (s, 1H), 3.27 (s, 3H), 1.54 (s, 9H).

Step 3: (3 AVI -r(4-methoxyphenyl )methyllpyrrolidin-3-yl ethanethioate

[00282] To a solution of /er/-butyl /V-methyl-/V-[l-(trifluoromethyl)pyrazol-4-yl]carbamate (0.60 g, 2.26 mmol) in dioxane (1.0 mL) was added HCI (4 M in dioxane, 5.00 mL) at room temperature. The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford A-m ethyl- l-(trifluorom ethyl )pyrazol -4-amine hydrochloride (0.40 g, crude) as a yellow solid. MS ESI calculated for C5H7CIF3N3 [M + H - HC1] ⁺ , 166.05, found 166.00. H-NMR (400 MHz, ^-DMSO) d 8.77 (s, 2H), 8.38 (s, 1H), 7.98 (s, 1H), 2.81 (s, 3H).

Intermediate 45: 4-[2,2,2-trifluoroethvnpyrrolidin-3-yl benzoate

Step 1 : Tert- butyl 3-hydroxy-4-methylidenepyrrolidine-l-carboxylate

„ step 1

Boc ^K Boc

[00283] To a stirred mixture of (CH3)3Si (24.46 g, 119.86 mmol) in THF (225.00 mL) was added «-BuLi

(44.35 mL, 110.88 mmol) dropwise at -10 °C under nitrogen atmosphere. The reaction mixture was stirred for 30 min at -10 °C under nitrogen atmosphere. To the above mixture was added a solution of /er/-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (5.55 g, 29.96 mmol) in THF (45.00 mL) dropwise at -10 °C. The reaction mixture was slowly allowed to warm to room temperature over 1 h and then was stirred for 3 h at room temperature under nitrogen atmosphere. The resulting mixture was quenched by the addition of water (300 mL). The resulting mixture was extracted with EA (3 x 200 mL). The combined organic layers was washed with brine (300 mL), dried over anhydrous NaiSCL and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-100%). The fractions contained desired product were combined and concentrated to afford /tvV-butyl 3-hydroxy-4- methylidenepyrrolidine-l-carboxylate (2.5 g, 42%) as light brown oil. MS ESI calculated for C10H17NO3 [M - /-Bu + H] ⁺ , 144.06, found 144.10.

Step 2 butyl 3-hvdroxy-4-(2.2.2-trifluoroethyl (pyrrolidine- 1 -carboxyl ate

step 2

Boc

I Tfo ( ¹ - ^{2 e}

Ru(bpy) ₃ CI ₂ (0.05 eq.), Py (1.2 e

HO R visible light, MeOH, rt, 16 h

[00284] To a solution of / /7-butyl 3-hydroxy-4-methylidenepyrrolidine-l-carboxylate (1.00 g, 5.02 mmol), tris(2,2-bipyridine)ruthenium dichloride (0.16 g, 0.25 mmol) and 8-(trifluoromethyl)-8- thiatricyclo[7.4.0.0 ^A [2,7]]trideca-l(13),2,4,6,9,l l-hexaen-8-ium; trifluoromethanesulfonic acid (2.43 g, 6.02 mmol) in MeOH (15.00 mL) was added pyridine (0.48 g, 6.02 mmol). The reaction mixture was irradiated with a fluorescent lamp and stirred for 16 h at room temperature under argon atmosphere. The resulting mixture was quenched by the addition of aqueous NaHC0 ₃ (sat., 100 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (1 x 50 mL), dried over anhydrous Na ₂ S0 ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (0 - 100%). The fractions contained desired product were combined and concentrated to afford /tvV-butyl 3-hydroxy-4-(2,2,2-trifluoroethyl)pyrrolidine-l- carboxylate (480 mg, 36%) as a yellow oil. MS ESI calculated for C11H18F3NO3 [M - /-Bu + H] ⁺ , 214.06, found 214.05.

Step 3: butyl 3-(benzoyloxy)-4-(2.2.2-trifluoroethyl (pyrrol idine- l -carboxyl ate

Boc step 3 Boc

[00285] To a stirred solution of /tvV-butyl 3-hydroxy-4-(2,2,2-trifluoroethyl)pyrrolidine-l-carboxylate

(65.00 mg, 0.24 mmol) in DCM (3.50 mL) were added TEA (122.14 mg, 1.207 mmol), DMAP (32.44 mg, 0.266 mmol) and benzoyl chloride (67.87 mg, 0.483 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixtuer was quenched by the addition of water (20 mL). The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers was washed with brine (20 mL), dried over anhydrous NaiSCL and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0- 50%). The fractions contained desired product were combined and concentrated to afford /tvv-butyl 3-(benzoyloxy)-4-(2,2,2-trifluoroethyl)pynOlidine-l-carboxyl ate (60 mg, 67%) as a light yellow solid. MS ESI calculated for C18H22F3NO4 [M - /-Bu + H] ⁺ , 318.09, found 318.05. Step 4: 4- trifluoroethyl )pyrrolidin-3-yl benzoate; trifluoroacetic acid

TFA ^N — CF ₃

[00286] To a stirred solution of tert- butyl 3-(benzoyloxy)-4-(2,2,2-trifluoroethyl)pyrrolidine-l-carboxy late (60.00 mg, 0.161 mmol) in DCM (2.50 mL) was added TFA (0.50 mL) dropwise at room temperature. The reaction solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 4-(2,2,2-trifluoroethyl)pyrrolidin-3-yl benzoate; trifluoroacetic acid (65mg) as a brown oil. The product was used directly to next step without further purification. MS ESI calculated for C15H15F6NO4 [M - TFA + H] ⁺ , 274.10, found 274.05.

Intermediate 46: (3R)-3-(trifluoromethoxy)pyrrolidine hydrochloride

H HCI

,N,

O

¾CF ₃

[00287] Step 1 : benzyl -3-(trifluoromethoxy)pyrrolidine-l-carboxylate

Step 1

Cbz Cbz

I I

N. N.

O

Selectfluor (1.5 eq ), KF (4 eq.) O

bH AgOTf (3 eq.), AcOEt, 12 h, rt ^' bCF ₃

1

[00288] To a stirred mixture of AgOTf (34.84 g, 135.59 mmol) and KF (10.50 g, 180.79 mmol), Selectfluor (24.02 g, 67.79 mmol), benzyl (3i?)-3-hydroxypyrrolidine-l-carboxylate (10.00 g, 45.20 mmol) in EtOAc (270 mL) were added 2-fluoropyridine (13.16 g, 135.54 mmol) and TMSCF3 (19.28 g, 135.59 mmol) dropwise at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 12 h at room temperature under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5: 1) to afford benzyl (3 f?)-3-(trifluorom ethoxy) pyrrolidine- 1-carboxylate (2.6 g, 15%) as colorless oil. MS ESI calculated for C13H14F3NO3 [M + H] ⁺ , 290.09, found 290.10. ¹ H-NMR (400 MHz, d _e - DMSO): d 7.38-7.30 (m, 5H), 5.13-5.03(m, 3H), 3.66-3.22 (m, 4H), 2.20-2.13 (m, 2H). ¹⁹ F-NMR (376 MHz, i/e-DMSO): -56.83. Step 2: (3i?)-3-(trifluoromethoxy)pyrrolidine hydrochloride

Step 2

Cbz

I H HCI

l\f H ₂ (1 atm), Pd(OH) ₂ /C (0.2 eq.), ,I\F

o MeOH, rt, 1 h O

bcF ₃ ¾CF ₃

1 2

[00289] To a stirred solution of benzyl (3f?)-3-(trifluoromethoxy)pyrrolidine-l-carboxylate (1.00 g, 3.28 mmol) in MeOH (10 mL) was added Pd(OH)2/C (46.12 mg, 0.33 mmol, 20%) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for lh at room temperature under hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (5 x 10 mL). The filtrate was treated with HCI (2 mL, 4 M in dioxane) and concentrated under reduced pressure to afforded (3f?)-3-(trifluoromethoxy)pyrrolidine hydrochloride (600 mg, crude) as a light yellow solid. MS ESI calculated for C5H9CIF3NO [M + H - HC1] ⁺ , 156.12, found 156.10. H-NMR (400 MHz, DMSO-^e) d 9.97-9.77 (m, 2H), 5.25-5.22 (m, 1H), 3.50-3.18 (m, 4H), 2.26-2.15 (m, 2H).

Intermediate 47: -3-itrifluoromethoxy)nyrrolidine hydrochloride

[00290] The title compound was prepared using procedures similar to those described in Intermediate 35 using benzyl (3k)-3-hydroxypyrrolidine- l -carboxyl ate instead of benzyl (3f?)-3- hydroxypyrrolidine-l-carboxylate to afford the title compound as a solid.

Intermediate 48: 3-cvclopropylidenepyrrolidine hydrochloride

[00291] Step 1 : tert-butyl 3-cvclopropylidenepyrrolidine-l-carboxylate

step 1

[00292] To a mixture of (3-bromopropyl)triphenylphosphanium bromide (10.02 g, 21.60 mmol) and in DME (23.00 mL) was added NaH(1.73 g, 43.25 mmol, 60%) at 0 °C. The reaction mixture was stirred for 6 h at 65 °C. To the above mixture was added /er/-butyl 3-oxopyrrolidine-l-carboxylate (1.00 g, 5.40 mmol) at 65 °C. The resulting mixture was stirred for additional 22 h at 65 °C. The reaction was quenched by the addition of Water/Ice (30 mL) at 0 °C. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers was washed with brine (10 mL), dried over anhydrous Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5: 1). The fractions contained desired product were combined and concentrated to afford fe/7-butyl 3- cyclopropylidenepyrrolidine-l-carboxylate (0.49 g, 39%) as a light yellow oil. MS ESI calculated for C ₁₂ H ₁₉ NO ₂ [M+H-56] ⁺ , 154.14, found 153.90.

Step 2: 3-cvclopropylidenepyrrolidine hydrochloride

step 2

1 2

[00293] To a stirred mixture of tert- butyl 3-cyclopropylidenepyrrolidine-l-carboxylate (0.49 g, 2.34 mmol) in 1,4-dioxane (2.00 mL) was added HCI (gas) in 1,4-dioxane (2.00 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. This resulted in 3- cyclopropylidenepyrrolidine hydrochloride (0.46 g, 67%) as a brown oil. MS ESI calculated for C ₇ H ₁₂ CIN [M + H - HC1] ⁺ , 110.09; found 110.20.

Intermediate 49: benzyl 4-ltrifluoromethoxylpyrazolidine-l-carboxylate 2,2,2-trifluoroacetate

Cbz

Step 1 : A- b utox vcarb on yl )b enz yl ox vcarb oh vdrazi de

Step 1

_H (BOC) ₂ 0 (1 .2 eq.), TEA (1 .2 eq.)

N -

H ₂ N" "Cbz THF, rt, 16 h

[00294] To a stirred solution of benzyl oxycarbohydrazide (5.00 g, 30.09 mmol) and TEA (3.65 g, 36.11 mmol) in THF (15.00 mL) was added a solution of (Boc) ₂ 0 (7.88 g, 36.11 mmol) in THF (10.00 mL) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by trituration with hexane (100 mL) to afford N-(tert- butoxycarbonyl)benzyloxycarbohydrazide (7.1 g, 89%) as an off-white solid. MS ESI calculated for C13H18N2O4 [M - Boc + H] ⁺ , 167.07, found 167.10.

Step 2 butyim .3-dibromopropan-2-yl loxyldi methyl si lane

Step 2

TBSCI (1.05 eq.), imidazole (1.05 eq.)

[00295] To a stirred solution of l,3-dibromo-2-propanol (10.00 g, 45.90 mmol) in DCM (50.00 mL) were added liT-imidazole (3.28 g, 48.19 mmol), TBS-C1 (7.26 g, 48.19 mmol) and DMAP (0.56 g, 4.59 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers was washed with water (100 mL) and brine (100 mL), dried over anhydrous NaiSCL and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-20%). The fractions contained desired product were combined and concentrated to afford /e/7-butyl[(l,3- dibromopropan-2-yl)oxy]dimethylsilane (14.3 g, 94%) as a light yellow oil. H-NMR (400 MHz, CDCb) d 4.08-4.01 (m, 1H), 3.55-3.48 (m, 4H), 0.94 (s, 9H), 0.17 (s, 6H).

Step 3: 1-Benzyl 2-fer/-butyl 4-hydroxypyrazolidine-L2-dicarboxylate

Step 3

H Cbz

[00296] To a stirred mixture of NaH (3.61 g, 90.32 mmol) in DMF (30.00 mL) was added a solution of N- (/ _<3/7 -butoxycarbonyl)benzyloxycarbohydrazide (10.58 g, 39.74 mmol) in DMF (48.00 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 45 min at room temperature under nitrogen atmosphere. To the above mixture was added /e/7-butyl[(l,3- dibromopropan-2-yl)oxy]dimethylsilane (12.00 g, 36.13 mmol) dropwise at room temperature. The reaction mixture was stirred for additional 36 h at room temperature. The reaction was quenched with aqueous NH ₄ CI (sat., 500 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers was washed with brine (300 mL), dried over anhydrous NaiSCL and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-50%). The fractions contained desired product were combined and concentrated to afford 1 -benzyl 2-/er/-butyl 4- hydroxypyrazolidine-l,2-dicarboxylate (2.3 g, 20%) as a light brown oil. MS ESI calculated for C22H36N2O5 S1 [M - Boc + H] ⁺ , 337.20, found 337.10.

Step 4: 1 -Benzyl 2-fer/-butyl 4-hydroxypyrazolidine-E2-dicarboxylate

Cbz Step 4 Cbz

[00297] To a stirred solution of 1-benzyl 2-/er/-butyl 4-[(/er/-butyldimethylsilyl)oxy]pyrazolidine-l,2- dicarboxylate (2.2 g, 5.04 mmol) in THF (30.00 mL) was added TBAF (6.05 mL, 6.05 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction solution was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-100%). The fractions contained desired product were combined and concentrated to afford 1 -benzyl 2-tert- butyl 4-hydroxypyrazolidine-l,2-dicarboxylate (1.55 g, 95%) as a yellow oil. MS ESI calculated for C 16H22N2O5 [M + H] ⁺ , 323.15, found 323.10.

Step 5: 1 -Benzyl 2-fer/-butyl 4-(trifluoromethoxy)pyrazolidine-E2-dicarboxylate

Step 5

[00298] To a stirred solution of argentio trifluoromethanesulfonate (3.71 g, 14.44 mmol) and KF (1.12 g, 19.28 mmol), 4-(chloromethyl)-l-fluoro-l,4-diazabicyclo[2.2.2]octane-l,4- diium;

bis(tetrafluoroboranuide) (2.56 g, 7.23 mmol), 1-benzyl 2-/er/-butyl 4-hydroxypyrazolidine-l,2- dicarboxylate (1.55 g, 4.81 mmol) in EA (25.00 mL) were added 2-fluoropyridine (1.40 g, 14.42 mmol) and TMSCF3 (2.05 g, 14.42 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 12 h at room temperature under nitrogen atmosphere. The resulting mixture was filtered. The filter cake was washed with EtOAc (3 x 25 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-40%). The fractions contained desired product were combined and concentrated to afford 1 -benzyl 2-/er/-butyl 4-(trifluoromethoxy)pyrazolidine- 1,2-dicarboxylate (0.35 g, 19%) as a colorless oil. MS ESI calculated for C17H21F3N2O5 [M -Boc + H] ⁺ , 291.09, found 291.05.

Step 6: benzyl 4-(trifluoromethoxy)pyrazolidine-l-carboxylate 2.2.2-trifluoroacetate Cbz Step 6

[00299] To a stirred solution of 1-benzyl 2-tert-butyl 4-(trifluoromethoxy)pyrazolidine-l,2-dicarboxylate (70.00 mg, 0.18 mmol) in DCM (2.50 mL) was added TFA (0.50 mL) dropwise at room

temperature. The reaction solution was stirred for 2 h at room temperature. The resulting solution was concentrated under reduced pressure to afford benzyl 4-(trifluorom ethoxy )pyrazolidine-l- carboxylate 2,2,2-trifluoroacetate (65 mg, 93%) as light brown oil. MS ESI calculated for

C14H14F6N2O5 [M -TFA+ H] ⁺ , 291.09, found 290.95.

Intermediate 50: 2-fluoro-4-methyl-5-[4,4,5,5-tetramethyl-l,3.,2-dioxaborolan -2-vnaniline

[00300] To a solution of 5 -bromo-2-fluoro-4-methyl aniline (2.0 g, 9.8 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (2.7 g, 10.8 mmol) and KOAc (2.9 g, 29.4 mmol) in dioxane (20 mL) was added Pd(dppf)Cl2 (359 mg, 0.49 mmol) under N2, and the mixture was stirred at 100 °C for 16 h. The reaction was cooled down to rt and the mixture was filtered. The filtrate was concentrated to give 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)aniline (crude), which was used in the next step without any further purification. MS Calcd.: 251, MS Found: 252 ([M+H] ⁺ ). Intermediate 51 : 4-i6-i3-ibenzvloxv)cvclobutoxv)-4-iodopvridin-2-vl)morpholin e

[00301] The title compound was prepared using procedures similar to those described in Intermediate 54 step 2 using 3-(benzyloxy)cyclobutan-l-ol instead of 2-(oxan-2-yloxy)ethanol to afford the title compound as a solid.

Intermediate 52: 3- (4-iodo-6-morpholinopyridin-2- cvclopentan-l-ol

[00302] The title compound was prepared using procedures similar to those described in Intermediate 54 step 2 using cyclopentane-l,3-diol instead of 2-(oxan-2-yloxy)ethanol to afford the title compound as a solid.

Intermediates 53 and 54: -4-[[4-iodo-6-[morpholin-4-vnpyridin-2-yl]oxy]-l-

methylcvclohexan-l-ol (cis) and (l/?.,4/?)-4-[[4-iodo-6-(morpholin-4-yBpyridin-2-ylloxy|-l- methylcyclohexan-l-ol (trans)

[00303] To a stirred solution of 4-(benzyloxy)cyclohexan-l-one (2.50 g, 12.24 mmol) in THF (25.00 mL) was added 1 M CTHMgBr in THF (3.18 mL, 3.18 mmol) dropwise at -70 °C under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was quenched with aqueous MLCl (sat., 100 ml) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers was washed with brine (50 mL), dried over anhydrous NaiSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (50%). The fractions contained desired product were combined and concentrated to afford 4-(benzyloxy)-l-methylcyclohexan-l-ol (1.05 g, 39%) as light yellow oil. H-NMR (400 MHz, CDCh) d 7.40-7.33 (m, 5H), 4.59-4.52 (m, 2H), 3.61-3.55 (m, 1H), 1.90-1.69 (m, 6H), 1.50- 1.40 (m, 2H), 1.29-1.25 (m, 3H).

Step 2: 1-m ethyl cyclohexane- L4-diol

[00304] A mixture of 4-(benzyloxy)-l -methyl cy cl ohexan-l-ol (1.05 g, 4.77 mmol), Pd/C (0.50 g, 0.47 mmol, 10%), HCOOH (0.75 mL) and MeOH (5.00 mL) was stirred for 16 h at room temperature under hydrogen (2 atm) atmosphere. The resulting mixture was filtered. The filter cake was washed with MeOH (4 x 10 mL). The combined filtrate was concentrated under reduced pressure to afford 1-m ethyl cy cl ohexane-l,4-diol (0.60 g, 97%) as light yellow oil. H-NMR (400 MHz, CDCh) d 3.93-3.62 (m, 1H), 2.50-1.43 (m, 8H), 1.30-1.25 (m, 3H).

Step 3 : iodo-6-(morpholin-4-yl )pyridin-2-ylloxyl- l -m ethyl cvcl oh exan-1 -ol (c/s)

iodo-6-(morpholin-4-vnpyridin-2-yl1oxy1-l-methylcvclohexan-l -ol (trans)

[00305] To a stirred mixture of NaH (0.16 g, 3.90 mmol) in DMF (4.00 mL) was added a solution of 1- methylcyclohexane-l,4-diol (0.51 g, 3.90 mmol) in DMF (4.00 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature under nitrogen atmosphere. To the above mixture was added a solution of 4-(6-fluoro-4-iodopyridin-2- yl)morpholine (0.40 g, 1.30 mmol) in DMF (2.00 mL) at room temperature. The reaction mixture was stirred for additional 2 h at 100 °C. The resulting mixture was allowed to cool down to room temperature and quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers was washed with Brine (100 mL), dried over anhydrous Na ₂ SC> ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-70%). The fractions contained desired product were combined and concentrated to afford (IS, 4,V)-4-[[4-iodo-6- (morpholin-4-yl)pyridin-2-yl]oxy]-l-methylcyclohexan-l-ol (0.13 g, 46%) (cis) as an off-white solid. MS ESI calculated for C16H23IN2O3 [M + H] ⁺ , 419.08, found 419.05. H-NMR (400 MHz, d ₆ - DMSO) d 6.68-6.65 (m, 1H), 6.44-6.39 (m, 1H), 4.84-4.75 (m, 1H), 4.14 (s, 1H), 3.72-3.66 (m,

4H), 3.42-3.37 (m, 4H), 1.77-1.67 (m, 4H), 1.62-1.58 (m, 2H), 1.45-1.33 (m, 2H), 1.12 (s, 3H).

And also to afford (1A, 4/^)-4-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]oxy]- l -methyl cyclohexan-1 - ol (0.10 g, 37%) trans) as an off-white solid. MS ESI calculated for C 16H23IN2O3 [M + H] ⁺ ,

419.08, found 419.10. H-NMR (400 MHz, ^-DMSO) d 6.66-6.65 (m, 1H), 6.44-6.43 (m, 1H), 4.98-4.92 (m, 1H), 4.10 (s, 1H), 3.72-3.66 (m, 4H), 3.42-3.39 (m, 4H), 1.94-1.84 (m, 2H), 1.62- 1.52 (m, 4H), 1.45-1.39 (m, 2H), 1.15 (s, 3H).

Intermediate 55: i4-fi4-iodo-6-imornholin-4-yl)Dyridin-2-ylloxyl-l-methylcycl ohexan-l-ol

Step 1 : G3 -(benzyl ox y)- l -methylcvclobutoxyl(7c/V-butyl )di phenyl si lane

step 1

[00306] To a stirred solution of 3 -(benzyl oxy)-l -methyl cy cl obutan-l-ol (1.00 g, 5.20 mmol) and imidazole (0.71 g, 10.40 mmol) in DMF (10.00 mL) was added /c/V-butyl (chi oro)di phenyl si 1 an e (2.02 mL, 7.79 mmol) at 0 °C. The reaction mixture was stirred for 18 h at 20 °C. The resulting mixture was diluted with water (100 mL) and extracted with EA (4 x 100 mL). The combined organic layers was washed with brine (100 mL), dried over anhydrous Na ₂ SC> ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column

chromatography, eluted with EA / PE (0-12%). The fractions contained desired product were combined and concentrated to afford [3-(benzyloxy)-l-methylcyclobutoxy](/er/- butyl)diphenylsilane (1.25 g, 56%) as a colorless crude oil. H-NMR (400 MHz, DMSO-i¾) d 7.76- 7.27 (m, 15H), 4.33-4.31 (m, 2H), 3.60-3.53 (m, 1H), 2.27-2.16 (m, 4H), 1.19-1.18 (m, 3H), 1.06- 1.05(m, 9H).

Step 2: 3 - butyl diphenyl si lyl )oxyl -3 -methyl cyclobutan-1 -ol step 2

[00307] To a mixture of [3 -(benzyl oxy)- l -methyl cyclobutoxy](/ _<2/7 -butyl)di phenyl si lane (1.25 g, 2.90

mmol) and Pd/C (0.31 g, 0.29 mmol, 10%) in MeOH (20.00 mL) was added HCO2H (1.00 mL).

The reaction mixture was degassed with ¾ for three times and stirred for 2 days at room

temperature. The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (4: 1). The fractions contained desired product were combined and concentrated to afford 3 -[(/tW-butyl diphenyl si lyl)oxy]-3 -methyl cyclobutan- 1 _ ol (0.60 g, 61%) as a colorless oil. H-NMR (400 MHz, CDCh) d 7.76-7.71 (m, 4H), 7.47-7.38 (m, 6H), 3.81-3.74 (m, 1H), 2.31-2.25 (m, 2H), 2.13-2.07 (m, 2H), 1.21 (m, 3H), 1.06-1.04 (m, 9H). Step 3: 4-(6- butyl diphenyl si lyl )oxyl-3 - ethyl cvclobutoxyl-4-iodopyridin-2-yl Imorpholine

and 3- iodo-6-(morpholin-4-vnpyridin-2-yl1oxy1-l-methylcvclobutan-l -ol

[00308] To a stirred solution of 3-[(/er/-butyldiphenylsilyl)oxy]-3-methylcyclobutan-l-ol (0.35 g, 1.03

mmol) in DMF (3.00 mL) was added NaH (41.11 mg, 1.03 mmol, 60%) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature. To the above mixture was added 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (0.10 g, 0.34 mmol) at room temperature.

The reaction mixture was stirred for additional 16 h at room temperature. The resulting mixture was quenched by the addition of saturated aqueous NaHCCb (100 mL) at room temperature. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers was washed with brine (3 x 50 mL), dried over anhydrous NaiSCL and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2: 1). The fractions contained desired product were combined and concentrated to afford 4-(6-[3-[(/er/-butyl diphenyl silyl)oxy] -3 -m ethyl cyclobutoxy]-4-iodopyridin-2-yl)morpholine (0.13 g, 18%) as an off-white solid. MS ESI calculated for CsoILvINiChSi [M + H] ⁺ , 629.16, found 629.00. Step 4: 3- iodo-6-(morpholin-4-vnpyridin-2-yl1oxy1-l-methylcvclobutan-l -ol and 3- ΐoάo-6-

(morpholin-4-vPpyridin-2- 1 -m ethyl cvclobutan- 1 -ol

[00309] To a stirred solution of 4-(6-[3-[(/tv7-butyl diphenyl si lyl )oxy]-3 - ethyl cyclobutoxy]-4-iodopyri din- 2-yl)morpholine (0.15 g, 0.24 mmol) in THF (2.00 mL) was added TBAF (0.36 mL, 0.36 mmol, 1 M) at °C under nitrogen atmosphere. The reaction mixture was stirred for 3 h at 80 °C under nitrogen atmosphere. The resulting mixture was quenched by the addition of water (100 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers was washed with brine (3 x 50 mL), dried over anhydrous NaiSCL and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / (EA / EtOH = 3 : 1) (2: 1). The fractions contained desired product were combined and concentrated to afford 3-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]oxy]-l-methylcyclo butan-l-ol (30 mg, 32%) as an off-white solid. MS ESI calculated for C ₁₄ H ₁₉ IN ₂ O ₃ [M + H] ⁺ , 391.04, found 390.90. ¾-NMR (400 MHz, DMSO-^e) d 6.67 (s, 1H), 6.42 (s, 1H), 5.08 (s, 1H), 4.68-4.61 (m, 1H), 3.68-3.65 (m, 4H), 3.41-3.39 (m, 4H), 2.48-2.43 (m, 2H), 2.09-2.04 (m, 2H), 1.25 (s, 3H). Intermediate 56: l-(T[4-iodo-6-(morDholin-4-vl)Dvridin-2-vlloxvlmethvl)cvcloD roDan-l-ol

Step 1 : l-nivdroxymethvDcvclopropan-l-ol

ste 1

[00310] To a stirred solution of 1-hydroxycyclopropane-l -carboxylic acid (0.6 g, 5.88 mmol) in THF

(10.00 mL) was added L1AIH4 (0.33 g, 8.82 mmol) in portions at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was quenched with water (0.66 mL), NaOH (aq. 10%, 1.32 mL) and water (1.98 mL) in sequence at 0 °C. The resulting mixture was filtered and the filter cake was washed with THF (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column

chromatography, eluted with EA / EtOH (3 / 1) in PE (60%). The fractions contained desired product were combined and concentrated to afford l-(hydroxymethyl)cyclopropan-l-ol (0.62 g, 60%) as a colorless oil. H-NMR (400 MHz, ^-DMSO) d 5.14 (s, 1H), 4.53 (t, J= 5.6 Hz, 1H), 3.40 (d, J= 5.6 Hz, 2H), 0.51-0.42 (m, 4H).

Step 2: l-ri(6-fluoro-4-iodopyri din-2 -vDoxylmethyllcvclopropan-l-ol

step 2

[00311] To a stirred solution of l-(hydroxymethyl)cyclopropan-l-ol (0.62 g, 7.05 mmol) in DMF (8.00 mL) was added /-BuOK (1 M in THF, 7.03 mL, 7.03 mmol) dropwise at 0 °C under nitrogen

atmosphere. The reaction mixture was stirred fori h at room temperature. To the above mixture was added a solution of 2,6-difluoro-4-iodopyridine (1.70 g, 7.03 mmol) in DMF (5.00 mL) at room temperature. The reaction mixture was stirred for additional 16 h at room temperature. The resulting mixture was quenched with water (150 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers was washed with brine (100 mL), dried over anhydrous Na ₂ SC> ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 32% EA in PE. The fractions contained desired product were combined and concentrated to afford l-[[(6-fluoro-4-iodopyridin-2- yl)oxy]methyl]cyclopropan-l-ol (0.32 g, 13%) as a yellow oil. MS ESI calculated for C ₉ H ₉ INO ₂ [M + H] ⁺ , 309.97, found 309.90.

Step 3 : iodo-6-(morpholin-4-vnpyridin-2-ylloxylmethvncvclopropan-l-o l

step 3

[00312] To a stirred solution of l-[[(6-fluoro-4-iodopyridin-2-yl)oxy]methyl]cyclopropan-l-ol (0.32 g, 1.02 mmol) in DMSO (6.00 mL) were added morpholine (97.67 mg, 1.12 mmol) and DIEA (0.16 g,

1.22 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 70 °C. The resulting mixture was diluted with water (60 mL) and extracted with EA (3 x 30 mL). The combined organic layers was washed with brine (50 mL), dried over anhydrous NaiSCL and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA (50%) in PE. The fractions contained desired product were combined and concentrated to afford l-([[4-iodo-6-(morpholin-4-yl)pyridin-2- yl]oxy]methyl)cyclopropan-l-ol (0.28 g, 73%) as a light yellow solid. MS ESI calculated for C ₁₃ H ₁₇ IN ₂ O ₃ [M + H] ⁺ , 377.03, found 377.00. H-NMR (400 MHz, ^-DMSO) d 6.67 (s, 1H), 6.48 (s, 1H), 5.49 (s, 1H), 4.18 (s, 2H), 3.67-3.65 (m, 4H), 3.42-3.39 (m, 4H), 0.66-0.57 (m, 4H).

Intermediate 57: oline

[00313] To a stirred solution of 3,3-difluorocyclopentan-l-ol (0.24 g, 1.95 mmol) in NMP (2.00 mL) was added NaH (46.73 mg, 1.95 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at 25 °C. To the above mixture was added 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (0.20 g, 0.65 mmol) at 25 °C. The reaction mixture was stirred for additional 3 h at 100 °C. The reaction was quenched by the addition of saturated aqueous NaHCCb (100 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers was washed with saturated brine (3 x 50 mL), dried over anhydrous NaiSCL and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2: 1). The fractions contained desired product were

combined and concentrated to afford 4-[6-[(3,3-difluorocyclopentyl)oxy]-4-iodopyridin-2- yljmorpholine (0.14 g, 52%) as an off-white solid. MS ESI calculated for C14H17F2IN2O2 [M + H] ⁺ , 411.03, found 411.05. ¾-NMR (400 MHz, DMSO-i¾) 5 6.71 (m, 1H), 6.45 (m, 1H), 5.36-5.31 (m,

1H), 3.69-3.65 (m, 4H), 3.46-3.41 (m, 4H), 2.70-2.56 (m, 1H), 2.31-2.12 (m, 3H), 1.96-1.85 (m, 2H).

Intermediate 58: Imino 4-iodo-6-(morpholin-4-vDpyridin-2-ylloxylethvDmethyl- ⁶ -

sulfanone

Step 1 : 4-r4-iodo-6-r2-(methylsulfanvnethoxylpyridin-2-yllmorpholine

s ep

[00314] To a stirred solution of 2-(methylthio)ethanol (1 g, 11.04 mmol) in dioxane (20 mL) was added NaH (0.44 g, 11.04 mmol, 60%) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 0.5 h at room temperature. To the above mixture was added 4-(6-fluoro-4-iodopyridin-2- yl)morpholine (0.85 g, 2.76 mmol) at room temperature. The reaction mixture was stirred for additional 16 h at 100 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (0 to 100%). The fractions contained desired product were combined and concentrated to afford 4-[4-iodo-6-[2- (methylsulfanyl)ethoxy]pyridin-2-yl]morpholine (1 g, 95%) as a grey solid. MS ESI calculated for C ₁₂ H ₁₇ IN ₂ O ₂ S [M + H] ⁺ , 381.01, found 380.95.

Step 2: 4-r4-iodo-6-(2-methanesulfmylethoxy)pyri din-2 -yllmorpholine

[00315] To a stirred solution of 4-[4-iodo-6-[2-(methylsulfanyl)ethoxy]pyridin-2-yl]morpholin e (1 g, 2.63 mmol) in DCM (20 mL) was added w-CPBA (0.59 g, 2.89 mmol, 85%) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA: EtOH = 3: 1 / PE (0 to 100%). The fractions contained desired product were combined and concentrated to afford 4-[4-iodo-6-(2-methanesulfinylethoxy)pyridin- 2-yl]morpholine (0.90 g, 86%) as a grey solid. MS ESI calculated for C ₁₂ H ₁₇ IN ₂ O ₃ S [M + H] ⁺ , 397.00, found 396.90.

Step 3 : imino iodo-6-(morpholin-4-yl )pyridin-2-ylloxylethyl)methyl- -sulfanone

step 3

[00316] To a solution of 4-[4-iodo-6-(2-methanesulfmylethoxy)pyridin-2-yl]morpholine (0.5 g, 1.26 mmol) and ammonium acetate (0.39 g, 5.05 mmol) in MeOH (2.5 mL) was added PhI(OAc) ₂ (1.2 g, 3.79 mmol). The reaction mixture was stirred for 0.5 h at room temperature under nitrogen atmosphere. The resulting mixture was purified by reverse flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, ACN in water, 20% to 50% gradient in 20 min; detector, UV 254/220 nm. The fractions contained desired product were combined and concentrated to afford i mi no(2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]oxy]ethyl (methyl -/’-sulfanone ] 5%) _{as a} brown solid. MS ESI calculated for C ₁₂ H ₁₈ IN ₃ O ₃ S [M + H] ⁺ , 412.01; found 411.95.

Intermediate 59: 3- iodo-6-mornholinonyridin-2-yl)oxy)-l-methylcvclonentan-l-ol

[00317] The title compound was prepared using procedures similar to those described in Intermediate 4 step 2 using l-methylcyclopentane-l,3-diol instead of 2-(oxan-2-yloxy)ethanol to afford the title compound as a solid.

Intermediate 60 : iodo-6-mornholinonyridin-2-yl)oxy)methyl)oxetan-3-ol

[00318] The title compound was prepared using procedures similar to those described in Intermediate 54 step 2 using 3-(hydroxymethyl)oxetan-3-ol instead of 2-(oxan-2-yloxy)ethanol to afford the title compound as a solid.

Intermediate 61 : 3- iodo-6-morpholinopyridin-2- ethyDoxetan-3-ol

[00319] The title compound was prepared using procedures similar to those described in Intermediate 54 step 2 using 3-(2-hydroxyethyl)oxetan-3-ol instead of 2-(oxan-2-yloxy)ethanol to afford the title compound as a solid.

Intermediates 12 and 13: 4-[6-chloro-2-[(3,3-difluorocyclopentyl)oxy|pyrimidin-4- yllmorpholine

Step 1 : (2R)- \ -r(6-f1uoro-4-iodopyridin-2-yl )oxy1propan-2-ol and (2R)-2-\ (6-fl uoro-4-i odop yri di n- 2-vnoxylpropan- 1 -ol

step 1

[00320] To a solution of R- 1,2-propanediol (5.00 g, 65.707 mmol, 1.10 equiv) in DMF (120 mL) was added NaH (2.63 g, 65.756 mmol, 1.10 equiv, 60%) at 0 degrees C. The mixture was stirred for 45 min. 2,6-difluoro-4-iodopyridine (14.40 g, 59.756 mmol, 1.00 equiv) was added and the mixture was allowed to warm to RT and stirred for 3 h. The reaction was quenched by the addition of sat. NH4CI (aq.) (100 mL) at 0 degrees C. The resulting mixture was extracted with DCM (4 x 80 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous NaiSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 30% EtOAc in PE to afford a mixture of (2R)- \ -[(6- fluoro-4-iodopyridin-2-yl)oxy]propan-2-ol (4.8 g, 27%) and (2f?)-2-[(6-fluoro-4-iodopyridin-2- yl)oxy]propan-l-ol (7.0 g, 40%, ratio ~2: 1) as a light yellow oil. MS ESI calculated for CsFLFINCh [M + H] ⁺ , 297.97; found 298.00.

Step 2: (2/0- 1 -r(6-f1uoro-4-iodopyridin-2-yl ) 2- G (6-fl uoro-4-i odop yri di n-

2-vDoxylpropan- 1 -ol

[00321] To a mixture of (2f?)-l-[(6-fluoro-4-iodopyridin-2-yl)oxy]propan-2-ol and (2f?)-2-[(6-fluoro-4- iodopyridin-2-yl)oxy]propan-l-ol (1.00 g, 3.366 mmol, 1.00 equiv) in DMSO (10 mL) were added (2ri)-2-methylmorpholine (340.49 mg, 3.366 mmol, 1.00 equiv) and DIEA (522.08 mg, 4.039 mmol, 1.20 equiv). The resulting mixture was stirred for 2 h at 70 degrees C. The resulting mixture was quenched with EhO (100 mL), then extracted with and EtOAc (4 x 50 mL). The combined organic layers were washed with brine (5 x 50 mL), dried over anhydrous Na ₂ S0 _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (4: 1) to afford a mixture of (2f?)-2-([4-iodo-6-[(2ri)-2- methylmorpholin-4-yl]pyridin-2-yl]oxy)propan-l-ol and (2f?)-l-([4-iodo-6-[(2ri)-2- methylmorpholin-4-yl]pyridin-2-yl]oxy)propan-2-ol (1.2 g, 93%) as an oyster white oil. MS ESI calculated for C13H19IN2O3 [M + H] ⁺ , 379.04; found 378.95.

Intermediate 64: (/?)-l-(Y4-iodo-6-(ti?V2-methylmorpholino)pyridin-2- propan-2-ol

[00322] The title compound was prepared using procedures similar to those described in Intermediate 63 and 2 using (2/^)-2-m ethyl morpholine instead of (2,V)-2-methyl morpholine to afford the title compound as a solid.

Intermediate 65: 2-oxa-5-azabicvclo[4.1.0]heptan-5-vD-4-iodopyridin-2-

vPoxylpropan-2-ol

[00323] The title compound was prepared using procedures similar to those described in Intermediate 63 and 2 using 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride instead of (2,V)-2-methyl morpholine to afford the title compound as a solid.

Intermediate 66: ( _> y)-/V-(3-(2-chloro-6-(Y/?y2-hvdroxypropoxy]pyridin-4-v n-4-methylphenvn-

3-12,2.,2-trifluoroethvOpyrrolidine-l-carboxamide

StepJ _^ _(R)-l-((6-chloro-4-iodopyri din-2 -yl)oxy)propan-2-ol and (R)-2-((6-chloro-4-iodopyri din-2 - yl)oxy)propan-l -ol

[00324] To a solution of R- 1,2-propanediol (1.53 g, 20.082 mmol, 1.10 equiv) in DMF (50 mL) was added NaH (0.80 g, 20.082 mmol, 1.10 equiv, 60%) at 0 °C. The mixture was stirred for 1 h at 25 °C. 2,6- dichloro-4-iodopyridine (5.00 g, 18.256 mmol, 1.00 equiv) was added and the mixture was stirred for 2 h at 25 °C. The resulting mixture was diluted water and extracted with EtOAc. The combined organic layers were washed with brine, and dried over anhydrous NaiSCE. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1 : 1) to afford a mixture of (R)-l-((6-chloro-4- iodopyridin-2-yl)oxy)propan-2-ol and (R)-2-((6-chloro-4-iodopyridin-2-yl)oxy)propan-l-ol (1.2 g, 21%) as an off-white oil. MS ESI calculated for C8H9CIINO2 [M + H] ⁺ , 313.94, found 313.95. H- NMR (300 MHz, Chloroform-7) d 7.33 - 7.27 (m, 1H), 7.12 (dd, 7 = 12.6, 1.1 Hz, 1H), 6.82 (d, 7 = 5.4 Hz, 1H), 4.25 - 4.09 (m, 2H), 1.49 (d, 7= 6.4 Hz, 1H), 1.36 - 1.26 (m, 3H).

Step 2: (3 V)-A ^f -(3-r2-chloro-6-r(27)-2-hvdroxypropoxylpyridin-4-yll-4 - phenyl ) -3 -(2 2 2-

trifluoroethvDpynOlidine- 1 -carboxamide

[00325] A mixture of (2f?)-l-[(6-chloro-4-iodopyridin-2-yl)oxy]propan-2-ol and (2f?)-2-[(6-fluoro-4- iodopyridin-2-yl)oxy]propan-l-ol (1.20 g, 3.828 mmol, 1.00 equiv), (3A)-/V-[4-methyl-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluo roethyl)pyrrolidine-l-carboxamide (1.58 g, 3.828 mmol, 1 equiv), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (0.31 g, 0.383 mmol, 0.1 equiv) and NaiCCb (1.22 g, 11.483 mmol, 3 equiv) in dioxane (12.00 mL) and H2O (1.20 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The compound was separated by Prep-Chiral HPLC with the following conditions: (Column:

CHIRALPAK IG, 5*25cm,10um; Mobile Phase A:C0 ₂ , Mobile Phase B: MeOH (0.1% 2M MB- MeOH); Flow rate: 180 mL/min; Gradient:45% B; 220 nm; RTF5.32; RT2:6.85; Injection

Volumn:2.5 ml; Number Of Runs: 16;). The collected fractions were combined and concentrated under reduced pressure to afford (3.V)-A ^f -(3-[2-chloro-6-[(2/^)-2-hydroxypropoxy]pyridin-4-yl]- 4- methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-l -carboxamide (650 mg, 36%) as a light yellow solid. MS ESI calculated for C22H25CIF3N3O3 [M + H] ⁺ , 472.15, found 472.15. H-NMR (300 MHz, Chloroform -if) d 7.37 - 7.28 (m, 2H), 7.20 (d, 7 = 8.3 Hz, 1H), 6.92 (d, 7= 1.1 Hz, 1H), 6.67 (d, 7 = 1.1 Hz, 1H), 6.27 (s, 1H), 4.38 (t, 7= 7.5 Hz, 1H), 4.30 - 4.15 (m, 2H), 3.82 (t, 7 = 8.6 Hz, 1H),

3.65 (t, 7 = 9.0 Hz, 1H), 3.45 (q, 7 = 9.2 Hz, 1H), 3.13 (t, 7 = 9.4 Hz, 1H), 2.56 (d, 7 = 9.5 Hz, 2H), 2.34 - 2.23 (m, 1H), 2.24 (s, 3H), 1.74 (q, 7 = 10.0, 9.6 Hz, 1H), 1.30 (t, 7 = 6.0 Hz, 3H).

Intermediate 67 : i2R,3R)-3-(Y4-iodo-6-morDholinoDvridin-2-vl)oxv)butan-2-ol

Step 1 : 4-(6-fluoro-4-iodopyridin-2-vDmorpholine

[00326] To a stirred solution of 2,6-difluoro-4-iodopyridine (16.00 g, 66.40 mmol) in DMSO (240 mL) were added morpholine (5.49 mL, 63.04 mmol) and DIEA (12.07 mL, 93.40 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 70 °C for 3h. The resulting mixture was cooled to rt, diluted with water (150 mL) and extracted with EA (300 mL x 3). The combined organic layers was washed with brine (100 mL x 4), dried over anhydrous Na ₂ SC> ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 30% EA in PE to afford 4-(6-fluoro-4-iodopyridin-2- yl)morpholine (17.60 g, 86%) as an off-white solid. MS ESI calculated for C9H10FIN2O [M + H] ⁺ , 308.98, found 309.10.

Step 2: (2R.3R)-3-(Y4-iodo-6-morpholinopyridin-2-yl )oxy)butan-2-ol

[00327] To a solution of (2R,3R)-butane-2,3-diol (1.40 g, 16.31 mmol) in DMF (20 mL) was added NaH (260 mg, 60%, 6.50 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Then 4-(6- fluoro-4-iodopyridin-2-yl)morpholine (1.00 g, 3.20 mmol) was added to the reaction mixture. The mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water (30 mL) and extracted with DCM (30 mL x 2). The combined organic layers were dried over Na ₂ SC> ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel column

chromatography eluting with 20% EA in PE to give (2R,3R)-3-((4-iodo-6-morpholinopyridin-2- yl)oxy)butan-2-ol (1.20 g, 80%) as yellow oil. MS ESI calculated for C19H19IN2O3 [M + H] ⁺ , 379.04, found 379.10.

Intermediate 68: lSV3-ldifluoromethoxy)-N-14-methyl-3-14,4,5,5-tetramethyl-l, 3.,2- dioxaborolan-2-vPphenvPpyrrolidine-l-carboxamide

Step 1 : (S)-3-(difluoromethoxy)pyrrolidine

Step 1

Cbz

[00328] To a solution of (S)-benzyl 3 -(difluorom ethoxy )pyrrolidine-l-carboxylate (7.00 g, 25.80 mmol) in DCM (100 mL) was added TFA (20 mL). The reaction mixture was stirred at room temperature overnight. The solution was concentrated in vacuum to afford the TFA salt of (S)-3- (difluoromethoxy)pyrrolidine (7.01 g, crude) as yellow oil.

Step 2: (S )-3 -(difluorom ethoxy )-N-(4- -3 -(4.4.5.5-tetram ethyl - 1.3.2-dioxaborolan-2-

vDphenvDpyrrolidine-l -carboxamide

[00329] To a solution of 4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)anil ine (1.01 g, 4.29 mmol) and DIEA (2.80 g, 21.50 mmol) in THF (50 mL) was added BTC (510 mg, 1.72 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 30 min. Then the TFA salt of (S)- 3-(difluoromethoxy)pyrrolidine (2.10 g, 8.33 mmol) was added to the mixture. The mixture was stirred at 0 °C for another lh. The mixture was concentrated and purified by silica gel column chromatography eluting with 50% EA in PE to afford (S)-3-(difluoromethoxy)-N-(4-methyl-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyrrolid ine-l-carboxamide (300 mg, 17%) as a white solid. MS ESI calculated for C16H23IN2O4 [M + H] ⁺ , 397.20, found 397.30

Intermediate 69 : N-i3-bromo-4-methylnhenyl)-3-itert-butyl)-lH-nyrrole-l-carbo xamide

N-(3-bromo-4-methylphenyl)-3-(tert-butyl)-lH-pyrrole-l-carbo xamide

[00330] To a solution of 3 -(tert-butyl)-l El-pyrrole (300 mg, 2.44 mmol) in THF (20 mL) was added n-BuLi (1.07 mL, 2.68 mmol) at 0 °C. Then the reaction mixture was stirred at rt for 30 min. To another flask was added BTC (288 mg, 1.04 mmol), DIEA (1.26 g, 9.76 mmol) and THF (20 mL). Then the mixture was stirred for 5 min at -78 °C. After stirring, the mixture was added to the previous solution and stirred for 30 min at -78 °C. Then the mixture was stirred at rt for another 30 min. The resulting mixture was quenched with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SC> ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column

chromatography eluting with EA in PE (0-50%) to afford N-(3-bromo-4-methylphenyl)-3-(tert- butyl)-lH-pyrrole-l-carboxamide (117 mg, 14%) as a yellow solid. MS ESI calculated for

Ci ₆ Hi ₉ BrN ₂ 0 [M + H] ⁺ , 335.07, found 335.10. Intermediate 70: (RV4- dimethyl-l.,3-dioxolan-4-yOmethoxy)-4-iodopyridin-2-

yDmornholine

[00331] The title compound was prepared using procedures similar to those described in Intermediate 67 step 2 using (R)-(2, 2-dimethyl- 1, 3 -dioxolan-4-yl)m ethanol to afford the title compound as a solid.

Intermediate 71: (SV4-(6-((2.,2-dimethyl-l.,3-dioxolan-4-y0methoxyV4-iodopyri din-2- vDmornholine

[00332] The title compound was prepared using procedures similar to those described in Intermediate 67 step 2 using (S)-(2, 2-dimethyl- 1, 3 -dioxolan-4-yl)methanol to afford the title compound as a solid.

Intermediate 72: N-t4-methyl-3-t4,4,5,5-tetramethyl-l,3.,2-dioxaborolan-2-vnp henvn-3-t2,2,2- trifluoroethyl)pyrrolidine-l-carboxamide

[00333] The title compound was prepared using procedures similar to those described in Intermediate 68 step 2 using 3-(2,2,2-trifluoroethyl)pyrrolidine to afford the title compound as a solid. Intermediate 73: 4-(4-iodo-6-(Y(2S -((tetrahydro-2H-pyran-2-yQoxy)propan-2-

[00334] The title compound was prepared using procedures similar to those described in Intermediate 67 step 2 using (2S)-l-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-ol to afford the title compound as a solid.

Intermediate 74: (R)-tert-butyl 3- iodo-6-morpholinopyridin-2- pyrrolidine-l-

carboxylate

[00335] The title compound was prepared using procedures similar to those described in Intermediate 67 step 2 using (R)-tert-butyl 3-hydroxypyrrolidine-l-carboxylate to afford the title compound as a solid.

Intermediate 75: tert-butyl 3- iodo-6-morpholinopyridin-2-yl)oxy)azetidine-l-carboxylate

Boc

[00336] The title compound was prepared using procedures similar to those described in Intermediate 67 using tert-butyl 3-hydroxyazetidine-l-carboxylate to afford the title compound as a solid. Example 1 and Example 2: Synthesis of (2-fluoro-5-(2-(2-hvdroxyethoxyV6-

morpholinopyridin-4-vP-4-methylphenvP-3-(trifluoromethvPpyrr olidine-l-carboxamide; tSl- N-(2-fluoro-5-(2-(2-hvdroxyethoxyV6-morpholinopyridin-4-vP-4 -methylphenvP-3- ttrifluoromethyPpyrrolidine-l-carboxamide

Step 1

[00337] To a solution of 2,6-difluoro-4-iodopyridine (10.0 g, 41.5 mmol) and morpholine (3.6 g, 41.5

mmol) in DMSO (100 mL) was added DIEA (10.7 g, 83.0 mmol) at rt. The mixture was stirred at 130 °C for 16 h in a sealed tube. The reaction was cooled down to rt, diluted with water (200 mL) and extracted with DCM (200 mL*3). The combined organic layers were washed with FLO (200 mL*2) and brine (200 mL), dried over NaiSCL, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA=20: 1 to PE:EA=10: 1) to afford 4-(6-fluoro-4- iodopyridin-2-yl)morpholine (10.4 g, 81.7%). MS Calcd.: 308, MS Found: 309 ([M+H] ⁺ ).

Step 2:

[00338] To a solution of 2-((tetrahydro-2H-pyran-2-yl)oxy)ethanol (24.8 g, 169.5 mmol) in dioxane (150 mL) was added NaH (6.8 g, 169.5 mmol, 60% in mineral oil) at 0 °C, and the mixture was stirred at rt for 15 min, 4-(6-fluoro-4-iodopyridin-2-yl)morpholine (10.4 g, 33.9 mmol) was added and the mixture was stirred at 100 °C for 2 h. The reaction was cooled down to rt, diluted with water (200 mL) and extracted with DCM (200 mL*3). The combined organic layers were washed with FLO (200 mL*2) and brine (200 mL), dried over NaiSCL, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA=20: 1 to PE:EA=5: 1) to afford 4-(4-iodo-6- (2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)morpho line (10.7 g, 72.8%). MS Calcd.: 434, MS Found: 435 ([M+H] ⁺ ).

Step 3: [00339] To a solution of 4-(4-iodo-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin -2-yl)morpholine (3.9 g, 8.9 mmol), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)aniline (crude, 9.8 mmol) and CS2CO3 (8.7 g, 26.7 mmol) in dioxane (100 mL) and water (10 mL) was added Pd(dppf)Cl2 (652 mg, 0.89 mmol) at rt under N2. The mixture was stirred at 100 °C for 16 h. The reaction was cooled down to rt, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA=5: 1 to PE:EA=2: 1) to afford 2-fluoro-4-methyl-5-(2- morpholino-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridi n-4-yl)aniline (2.7 g, 69.3%). MS Calcd. : 431 Found: 432 ([M+H] ⁺ ).

Step 4:

[00340] To a solution of 2-fluoro-4-m ethyl-5 -(2 -morpholino-6-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)pyridin-4-yl)aniline (492 mg, 1.14 mmol) in THF (20 mL) was added DIEA (221 mg, 1.71 mmol) and 4-nitrophenyl carbonochloridate (230 mg, 1.14 mmol) at 0 °C, and the mixture was stirred at rt for 1 h. The reaction was cooled down to 0 °C, DIEA (442 mg, 3.42 mmol) and 3- (trifluoromethyl)pyrrolidine hydrochloride (200 mg, 1.14 mmol) were added. The reaction mixture was stirred at rt for 1 h and then concentrated. The residue was purified by flash chromatography on silica gel (PE:EA=5: 1 to PE:EA=2: 1) to give N-(2-fluoro-4-methyl-5-(2-morpholino-6-(2- ((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)phenyl)-3 -(trifluorom ethyl )pyrrolidine-l- carboxamide (480 mg, 70.6%). MS Calcd.: 596 MS Found: 597 ([M+H] ⁺ ).

Step 5:

[00341] To a solution of N-(2-fluoro-4-methyl-5-(2-morpholino-6-(2-((tetrahydro-2H-py ran-2- yl)oxy)ethoxy)pyridin-4-yl)phenyl)-3-(trifluoromethyl)pyrrol idine-l -carboxamide (280 mg, 0.47 mmol) in EtOAc (15 mL) was added HCl/EtOAc (10 mL, 2 M) at rt, and the reaction was stirred for 30 min. The mixture was concentrated and the residue was purified by flash chromatography on silica gel (PE:EA=2: 1 to PE:EA=1 : 1) to yield the racemate mixture (120 mg, 49.8%). The mixture was then separated by chiral HPLC (Daicel Chiralpak IH: 20*250 mm L, 5 pm; CChMeOH = 75:25, 50 g/min, 230 nm) to give the two enantiomers: 50.8 mg (21.1%) of the first isomer eluted at

7.18 min (ee > 98%) and 51.6 mg (21.5%) of the second isomer eluted at 9.03 min (ee > 98%). ¾ NMR (400 MHz, DMSO-^e) of first eluted isomer: d 1.98-2.03 (m, 1H), 2.17-2.20 (m, 4H), 3.43- 3.53 (m, 8H), 3.64-3.72 (m, 7H), 4.24 (t, J= 5.6 Hz, 2H), 4.78 (t, J= 5.6 Hz, 1H), 5.98 (s, 1H),

6.19 (s, 1H), 7.13 (d, 7= 11.6 Hz, 1H), 7.32 (d, J= 8.4 Hz, 1H), 8.04 (s, 1H). MS Calcd.: 512 Found: 513 ([M+H] ⁺ ). ¾ NMR (400 MHz, DMSO-i¾) of the of the second eluted isomer: d 1.98- 2.03 (m, 1H), 2.17-2.20 (m, 4H), 3.43-3.53 (m, 8H), 3.68-3.72 (m, 7H), 4.24 (t, J= 5.6 Hz, 2H), 5.98 (s, 1H), 6.02 (brs, 1H), 6.19 (s, 1H), 7.13 (d, J= 11.6 Hz, 1H), 7.32 (d, J= 8.0 Hz, 1H), 8.04 (s, 1H). MS Calcd. : 512 Found: 513 ([M+H] ⁺ ). Example 3: fl? _> y)-N-(2-fluoro-5-(2-(2-hvdroxyethoxy)-6-morpholinopyri din-4-vD-4- methylphenyl)-3-(trifluoromethyl)pyrrolidine-l-carboxamide

[00342] To a solution of N-(2-fluoro-4-methyl-5-(2-morpholino-6-(2-((tetrahydro-2H-py ran-2- yl)oxy)ethoxy)pyridin-4-yl)phenyl)-3-(trifluoromethyl)pyrrol idine-l -carboxamide (280 mg, 0.47 mmol) in EtOAc (15 mL) was added HCl/EtOAc (10 mL, 2 M) at it, and the mixture was stirred for 30 min. The mixture was concentrated and the residue was purified by Prep- HPLC (Gilson-5 Xbridge, C8 5 pm 19*150 mm 30-70% B, A: H ₂ 0 (0.1% NH4HCO3), B: ACN, UV:214 nm, Flowrate 15 mL/min, GT=8 min) to give N-(2-fluoro-5-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-3-(trifluoromethyl)p yrrolidine-l -carboxamide (106.6 mg, 45.9%). ¾ NMR (400 MHz, DMSO-^e): d 1.98-2.04 (m, 1H), 2.17-2.20 (m, 4H), 3.43-3.54 (m, 8H), 3.64-3.72 (m, 7H), 4.24 (t, J= 5.6 Hz, 2H), 4.78 (t, J= 5.6 Hz, 1H), 5.98 (s, 1H), 6.19 (s, 1H), 7.14 (d, J = 11.6 Hz, 1H), 7.32 (d, J= 8.4 Hz, 1H), 8.04 (s, 1H). MS Calcd.: 512 Found: 513 ([M+H] ⁺ ).

Example 4: -[2-fluoro-5-[2-[2-hydroxyethoxy)-6-morpholinopyridin-4-yB-4 -

methylphenyl)-3-(trifluoromethyl)piperidine-l-carboxamide

Step 1:

[00343] A solution of 2-fluoro-4-methyl-5-{2-morpholin-4-yl-6-[2-(tetrahydro-pyran -2-yloxy)-ethoxy]- pyridin-4-yl}-phenylamine (150 mg, 0.34 mmol), CDI (74 mg, 0.45 mmol) and DIEA (147 mg, 1.14 mmol) in DMF (10 mL) was stirred at 50 °C for 2 h. 3-Trifluoromethyl-piperidine (59 mg, 0.38 mmol) was added and the reaction was stirred at 50 °C overnight. The mixture was

concentrated and the residue was purified by flash chromatography on silica gel (PE:EA = 5: 1 to PE:EA = 2: 1) to afford 3 -trifluoromethyl-piperidine-1 -carboxylic acid (2-fluoro-4-methyl-5-{2- morpholin-4-yl-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-pyrid in-4-yl}-phenyl)-amide (101 mg, 47.6%). MS Calcd.: 610 Found: 611 ([M+H] ⁺ ).

Step 2:

[00344] To a solution of N-(2-fluoro-4-methyl-5-(2-morpholino-6-(2-((tetrahydro-2H-py ran-2- yl)oxy)ethoxy)pyridin-4-yl)phenyl)-3-(trifluoromethyl)piperi dine-l -carboxamide (101 mg, 0.16 mmol) in dioxane (10 mL) was added HCl/dioxane (3 mL, 2 M) at rt, and the mixture was stirred for 30 min. The mixture was concentrated and the residue was purified by Prep- HPLC (Waters-2 Sunfire, C8 5 pm 19*150 mm 35-70% B, A: H ₂ 0 (0.1% HCOOH), B: ACN, UV:214 nm, Flowrate 15 mL/min, GT=10 min) to give N-(2-fluoro-5-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl) -4- methylphenyl)-3 -(trifluorom ethyl )piperi dine- 1 -carboxamide (38.3 mg, 44.5%). ¹ H NMR (400 MHz, DMSO-7,): d 1.44-1.52 (m, 2H), 1.70-1.73 (m, 1H), 1.94-1.96 (m, 1H), 2.20 (s, 3H), 2.79- 2.87 (m, 2H), 3.43-3.45 (m, 5H), 3.67-3.70 (m, 7H), 3.97-4.01 (m, 1H), 4.20-4.25 (m, 2H), 4.76- 4.79 (m, 1H), 5.97 (s, 1H), 6.18 (s, 1H), 7.12 (d, 7= 11.6 Hz, 1H), 7.22 (d, 7= 8.4 Hz, 1H), 8.41 (s, 1H). MS Calcd.: 526; MS Found: 527([M+H] ⁺ )

Example 5: -ftert-butvB-N-f2-fluoro-5-f2-f2-hvdroxyethoxyl-6-morpholino pyridin-4-

vl)-4-methvlphenvl)pyrrolidine-l-carboxamide

[00345] The title compound was prepared using general procedure of N-(2-fluoro-5-(2-(2-hydroxyethoxy)- 6-morpholinopyridin-4-yl)-4-methylphenyl)-3 -(trifluorom ethyl )pyrrolidine-l -carboxamide. 'H NMR (400 MHz, DMSO-7,): d 0.90 (s, 9H), 1.54-1.65 (m, 1H), 1.80-1.86 (m, 1H), 1.99-2.07 (m, 1H), 2.20 (s, 3H), 3.05 (t, J= 10.2 Hz, 1H), 3.20-3.27 (m, 1H), 3.43-3.47 (m, 5H), 3.54 (t, J= 9.2 Hz, 1H), 3.68-3.72 (m, 6H), 4.24 (t, J= 5.6 Hz, 2H), 4.78 (t, J= 5.6 Hz, 1H), 5.98 (s, 1H), 6.19 (s, 1H), 7.12 (d, J= 12.0 Hz, 1H), 7.36 (d, J= 8.4 Hz, 1H), 7.79 (s, 1H). MS Calcd.: 500; MS Found: 501 ([M+H] ⁺ ). Example 6: l-(3.,3-dimethylbutyP-3-(2-fluoro-5-(2-(2-hydroxyethoxy)-6-m orpholinopyridin-4- yP-4-methylphenyPurea

[00346] The title compound was prepared using general procedure of N-(2-fluoro-5-(2-(2-hydroxyethoxy)- 6-morpholinopyridin-4-yl)-4-methylphenyl)-3 -(trifluorom ethyl )pyrrolidine-l -carboxamide. 'H NMR (400 MHz, DMSO-7 ₆ ): d 0.89 (s, 9H), 1.32-1.36 (m, 2H), 2.15 (s, 3H), 3.05-3.10 (m, 2H), 3.44 (t, 7 = 4.8 Hz, 4H), 3.68-3.72 (m, 6H), 4.24 (t, 7 = 5.2 Hz, 2H), 4.78 (t, 7 = 5.6 Hz, 1H), 5.95 (s, 1H), 6.17 (s, 1H), 6.46 (t, 7= 5.4 Hz, 1H), 7.10 (d, 7 = 12.4 Hz, 1H), 7.97 (d, 7= 8.8 Hz, 1H), 8.20 (s, 1H). MS Calcd.: 474; MS Found: 475 ([M+H] ⁺ ).

Example 7 : fl? _> y)-N-(2-fluoro-5-(2-(2-hvdroxyethoxy)-6-morpholinopyri din-4-vP-4- methylphenyP-3-itrifluoromethyPpiperazine-l-carboxamide

[00347] The title compound was using general procedure of N-(2-fluoro-5-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-3 -(trifluorom ethyl)piperi dine- 1 -carboxamide. 'H NMR (400 MHz, DMSO-7 ₆ ): d 2.20 (s, 3H), 2.64-2.67 (m, 1H), 2.90-2.99 (m, 4H), 3.43-3.46 (m, 4H), 3.68-3.70 (m, 6H), 3.77-3.81 (m, 1H), 4.03 (dd, 7 = 2.8, 12.4 Hz, 1H), 4.24 (t, 7 = 5.2 Hz, 2H), 4.78 (t, 7= 5.6 Hz, 1H), 5.98 (s, 1H), 6.19 (s, 1H), 7.13 (d, 7= 11.6 Hz, 1H), 7.23 (d, 7= 8.0 Hz, 1H), 8.41 (s, 1H). MS Calcd.: 527; MS Found: 528 ([M+H] ⁺ ).

Example 8: -[tert-butyP-N-[2-fluoro-5-[2-[2-hydroxyethoxy)-6-morpholino pyridin-4-

yP-4-methylphenyPpiperidine-l-carboxamide

[00348] The title compound was prepared using general procedure of N-(2-fluoro-5-(2-(2-hydroxyethoxy)- 6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(trifluoromethyl )piperi dine- 1 -carboxamide. 'H NMR (400 MHz, DMSO-^e): d 0.87 (s, 9H), 1.11-1.18 (m, 2H), 1.40-1.43 (m, 1H), 1.66-1.69 (m, 1H), 1.79-1.82 (m, 1H), 2.19 (s, 3H), 2.42-2.50 (m, 1H), 2.62-2.66 (m, 1H), 3.43-3.46 (m, 4H), 3.68-3.69 (m, 6H), 4.03 (d, J= 13.2 Hz, 1H), 4.16 (d, J= 12.8 Hz, 1H), 4.24 (d, J= 5.6 Hz, 2H), 4.77 (brs, 1H), 5.97 (s, 1H), 6.19 (s, 1H), 7.11 (d, = 11.6 Hz, 1H), 7.24 (d, J= 8.4 Hz, 1H), 8.16 (s, 1H). MS Calcd.: 514; MS Found: 515 ([M+H] ⁺ ).

Example 9: 2-(tert- N-(2-fluoro-5-(2-(2-hvdroxyethoxyV6-morpholinopyridin-4-vO-4 -

methylphenyOmorpholine-4-carboxamide

[00349] The title compound was prepared using general procedure of N-(2-fluoro-5-(2-(2-hydroxyethoxy)- 6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(trifluoromethyl )piperi dine- 1 -carboxamide. 'H NMR (400 MHz, DMSO-^e): d 0.91 (s, 9H), 2.20 (s, 3H), 2.57-2.68 (m, 1H), 2.81-2.88 (m, 1H), 2.96-2.99 (m, 1H), 3.39-3.46 (m, 5H), 3.68-3.72 (m, 6H), 3.83-3.92 (m, 2H), 3.96 (d, J= 12.8 Hz, 1H), 4.24 (t, J= 5.6 Hz, 2H), 4.78 (t, J= 5.6 Hz, 1H), 5.98 (s, 1H), 6.19 (s, 1H), 7.13 (d, J= 12.0 Hz, 1H), 7.24 (d, J= 8.4 Hz, 1H), 8.33 (s, 1H). MS Calcd.: 516; MS Found: 517 ([M+H] ⁺ ).

Example 10: f&y)-N-(2-fluoro-5-(2-(2-hydroxyethoxyV6-morpholinopyrid in-4-yO-4- methylphenyO-2-(trifluoromethyQmorpholine-4-carboxamide

[00350] The title compound was prepared using general procedure of N-(2-fluoro-5-(2-(2-hydroxyethoxy)- 6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(trifluoromethyl )piperi dine- 1 -carboxamide. 'H NMR (400 MHz, DMSO-7 ₆ ): d 2.21 (s, 3H), 2.93-3.07 (m, 2H), 3.44 (t, 7 = 4.8 Hz, 4H), 3.58-3.64 (m, 1H), 3.68-3.72 (m, 6H), 3.93 (d, 7= 13.6 Hz, 1H), 4.00 (d, 7 = 10.4 Hz, 1H), 4.15-4.24 (m, 4H), 4.78 (t, 7 = 5.6 Hz, 1H), 5.98 (s, 1H), 6.19 (s, 1H), 7.15 (d, 7 = 12.0 Hz, 1H), 7.25 (d, 7= 8.4 Hz, 1H), 8.54 (s, 1H). MS Calcd.: 528; MS Found: 529 ([M+H] ⁺ ).

Example 11 : -[tert-butvn-N-[2-fluoro-5-[2-[2-hvdroxyethoxyV6-morpholinop yridin-4-

yD-4-methylphenyDpiperazine-l-carboxamide

[00351] The title compound was prepared using general procedure of N-(2-fluoro-5-(2-(2-hydroxyethoxy)- 6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(trifluoromethyl )piperi dine- 1 -carboxamide. 'H NMR (400 MHz, DMSO-T,): d 0.90 (s, 9H), 2.14-2.20 (m, 4H), 2.44 (t, 7= 11.8 Hz, 1H), 2.54-2.60 (m, 1H), 2.67-2.73 (m, 1H), 2.93 (d, 7= 11.6 Hz, 1H), 3.44 (t, 7= 4.8 Hz, 4H), 3.68-3.72 (m, 6H), 3.90 (d, 7= 12.4 Hz, 1H), 4.02 (d, 7= 12.0 Hz, 1H), 4.24 (t, 7= 5.6 Hz, 2H), 4.78 (t, 7= 5.6 Hz, 1H), 5.98 (s, 1H), 6.19 (s, 1H), 7.12 (d, 7= 12.0 Hz, 1H), 7.23 (d, 7= 8.4 Hz, 1H), 8.19 (s, 1H). MS Calcd.: 515; MS Found: 516 ([M+H] ⁺ ).

Example 12 and 13: -N-[2-fluoro-5-[6-(2-hydroxyethoxy)-5-(morpholin-4-yDpyridin -3-

yll-4-methylphenyll-3-(trifluoromethyDpyrrolidine-l-carboxam ide and -N-[2-fluoro-5-[6-

(2-hydroxyethoxy)-5-(morpholin-4-yDpyridin-3-yll-4-methylphe nyll-3- (trifluoromethyllpyrrolidine-l-carboxamide

Step 1 : A ^f -r2-fluoro-4- ethyl-5-r5-(morpholin-4-yl )-6-r2-(oxan-2-yloxy)ethoxylpyridin-3- yl1phenyl1-3-(trifluoromethvnpyrrolidine-l-carboxamide

[00352] To a solution of 2-fluoro-4-methyl-5-[5-(morpholin-4-yl)-6-[2-(oxan-2-yloxy)e thoxy]pyridin-3- yljaniline (560.00 mg, 1.30 mmol) in THF (25.00 mL) were added triphosgene (154.04 mg, 0.52 mmol) and DIEA (838.64 mg, 6.49 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 0.5 h. To the above mixture 3-(trifluoromethyl)pyrrolidine hydrochloride (227.86 mg, 1.30 mmol) was added and the reaction mixture was stirred for 4 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with water (20 mL) and extracted with EA (3 x 10 mL). The combined organic layers was washed with brine (20 mL), dried over anhydrous NaiSCL and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (1-10%). The fractions contained desired product were combined and concentrated to afford /V-[2-fluoro-4-methyl-5-[5-(morpholin-4-yl)-6-[2-(oxan-2-ylo xy)ethoxy]pyri din-3- yl]phenyl]-3-(trifluoromethyl)pyrrolidine-l-carboxamide (550 mg, 71%) as a yellow solid. MS ESI calculated for C29H36F4N4O5 [M + H] ⁺ , 597.26, found 597.25. ¾-NMR (300 MHz, 76-DMSO) d 8.07 (s, 1H), 7.68 (d, 7= 2.0 Hz, 1H), 7.33 (d, 7= 8.4 Hz, 1H), 7.17 (d, 7= 11.2 Hz, 1H), 7.10 (d, 7 = 2.0 Hz, 1H), 4.70 (d, 7= 3.6 Hz, 1H), 4.50 - 4.46 (m, 2H), 4.02 - 3.90 (m, 1H), 3.83 - 3.63 (m, 7H), 3.48 (m, 5H), 3.13-3.08 (m, 4H), 2.25-2.20 (m, 4H), 2.07 - 2.02 (m, 1H), 1.82 - 1.56 (m, 2H), 1.52-1.46 (m, 4H). Step 2: A ^f -r2-f1uoro-5-r6-(2-hvdroxyethoxy)-5-(morpholin-4-yl )pyri din-3 -nP-4-m ethyl phenyll-3 - (trifluoromethvnpyrrolidine-l-carboxamide

[00353] To a solution of A ^f -[2-fluoro-4-methyl-5-[5-(morpholin-4-yl)-6-[2-(oxan-2 -yloxy)ethoxy]pyri din-3- yl]phenyl]-3-(trifluoromethyl)pyrrolidine-l-carboxamide (300.00 mg, 0.50 mmol) in MeOH (4.50 mL) was added HC1 (4 M in 1,4-dioxane) (1.50 mL). The reaction solution was stirred for 30 min at 25 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CTbCN in water, 0% to 100% gradient in 25 min; detector, UV 254 nm. The fractions contained desired product were combined and concentrated to afford to give A ^f -[2-fluoro-5-[6-(2- hydroxyethoxy)-5-(morpholin-4-yl)pyridin-3-yl]-4-methylpheny l]-3-(trifluoromethyl)pyrrolidine- 1 -carboxamide (210 mg, 90%) as an off-white solid. MS ESI calculated for C24H28F4N4O4 [M + H] ⁺ , 513.20; found 513.35.

Step 3 : -A ^f -r2-fluoro-5-r6-(2-hvdroxyethoxy)-5-(morpholin-4-yl jpyri din-3 -yl 1-4- methylphenyl1-3-(trifluoromethvnpyrrolidine-l-carboxamide and -A ^f -r2-fluoro-5-r6-(2-

hvdroxyethoxy)-5-(morpholin-4-vnpyridin-3-vn-4-methylphenyl1 -3-(trifluoromethvnpyrrolidine- 1 -carboxamide

[00354] /V-[2-fluoro-5-[6-(2-hydroxyethoxy)-5-(morpholin-4-yl)pyri din-3-yl]-4-methylphenyl]-3-

(trifluoromethyl)pyrrolidine-l-carboxamide (210mg) was separated by Prep-Chiral HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 um; Mobile Phase A: Hex:DCM = 5: 1 (10 mM NH3-MEOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: lO B to lO B in 11 min; 254/220 nm. The fractions contained desired product were concentrated to give the two enantiomers: (71.8 mg) of the first isomer eluted at 8.296 min (ee > 98%) and

(75.9mg) of the second isomer eluted at 9.553 min (ee > 98%). ¹ H-NMR (400 MHz, -DMSO) of the first eluted isomer: d 8.04 (s, 1H), 7.65 (d, 7 = 1.6 Hz, 1H), 7.32 (d, 7 = 8.0 Hz, 1H), 7.16 (d, 7 = 11.6 Hz, 1H), 7.06 (d, 7 = 1.6 Hz, 1H), 4.79 (t, 7 = 4.2 Hz, 1H), 4.36 (t, 7 = 4.2 Hz, 2H), 3.77 - 3.74 (m, 7H), 3.69 - 3.57 (m, 3H), 3.34 - 3.28 (m, 1H), 3.09 - 3.07 (m, 4H), 2.33 - 2.15 (m, 4H), 2.05 - 1.98 (m, 1H). MS ESI calculated for C24H28F4N4O4 [M + H] ⁺ , 513.20, found 513.15. ¹ H-NMR (400 MHz, -DMSO) of the first eluted isomer: d 8.04 (s, 1H), 7.65 (d, 7 = 1.6 Hz, 1H), 7.32 (d, 7 = 8.0 Hz, 1H), 7.16 (d, 7= 11.6 Hz, 1H), 7.06 (d, 7= 1.6 Hz, 1H), 4.79 (t, 7= 4.2 Hz, 1H), 4.36 (t, 7 =

4.2 Hz, 2H), 3.77 - 3.74 (m, 7H), 3.69-3.57 (m, 3H), 3.34 - 3.28 (m, 1H), 3.09 - 3.07 (m, 4H), 2.33 - 2.15 (m, 4H), 2.05-1.98 (m, 1H). MS ESI calculated for C24H28F4N4O4 [M + H] ⁺ , 513.20, found 513.15.

[00355] The following compounds in Table 3 were prepared using procedures similar to those described in Example 12 and 13 using appropriate starting materials. Racemic products were separated using chiral columns specified in Table 3.

TABLE 3

Example 149: (3R)-N-[3-[2-(2-hvdroxy-2-methylpropoxyV6-(morpholin-4-vDpyr idin-4-yll-4- methylphenyll-3-(trifluoromethoxy)pyrrolidine-l-carboxamide

-A ^f -r3-r2-(2-hvdroxy-2-methylpropoxy)-6-(morpholin-4-yl ipyri din-4-yl 1-4-methyl phenyl 1-3-

(trifluoromethoxy)pyrrolidine- 1 -carboxamide

[00356] A mixture of l-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]oxy]-2-methylpropa n-2-ol (100.00 mg, 0.26 mmol), (3f?)-/V-[4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan -2-yl)phenyl]-3- (trifluoromethoxy)pyrrolidine-l -carboxamide (120.48 mg, 0.29 mmol), Pd(dppf)Cl2.CH2Cl2 (21.59 mg, 0.03 mmol), INfeCCh (84.07 mg, 0.79 mmol), 1,4-dioxane (4 mL) and water (1 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column

chromatography, eluted with EA:EtOH (3: 1)/PE (0 to 100%). The crude product was purified by Prep-HPLC with following conditions: Column: XBridge BEH C18 OBD Prep Column, , 5 um, 19 mm x 250 mm ; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: acetonitrile; Flow rate: 20 mL/min; Gradient: 35 B to 65 B in 5 min; 254 nm; RT1 : 4.5 min to afford (3R)-N-[3- [2-(2-hydroxy-2-methylpropoxy)-6-(morpholin-4-yl)pyridin-4-y l]-4-methylphenyl]-3- (trifluoromethoxy)pyrrolidine-l -carboxamide (66.7 mg, 47%) as an off-white solid. MS ESI

calculated for C26H33F3N4O6 [M + H] ⁺ , 539.24, found 539.20. H-NMR (400 MHz, r¾-DMSO) d 8.25 (s, 1H), 7.46-7.43 (m, 1H), 7.38-7.37 (m, 1H), 7.15 (d, J= 8.4 Hz, 1H), 6.21 (s, 1H), 5.99 (s, 1H), 5.15-5.14 (m, 1H), 4.57 (s, 1H), 4.01 (s, 2H), 3.71-3.55 (m, 7H), 3.45-3.40 (m, 5H), 2.24-2.17 (m, 5H), 1.18 (s, 6H). F-NMR (376 MHz, r¾-DMSO) d -56.71 (3F).

[00357] The following compounds in Table 4 were prepared using procedures similar to those described in Example 149 using appropriate starting materials. Racemic products were separated using chiral columns specified in Table 4.

TABLE 4

Example 170: (3S)-N-(3-i2-i(l-hvdroxy-2-methylpropan-2-yl)oxyl-6-(morphol in-4-yl)pyridin-

4-yll-4-methylphenvD-3-(trifluoromethoxy)pyrrolidine-l-ca rboxamide

Step 1 : (3 V)-A ^f -r4-methyl-3-(2- methyl- l -(oxan-2-yloxy)propan-2-yl]oxy1-6-(morpholin-4-

vOpyridin-4-vOphenyl1-3-(trifluorc>methoxy)pyrrc>li dine-l-carboxamide

[00358] A mixture of 4-(4-iodo-6-[[2-methyl-l-(oxan-2-yloxy)propan-2-yl]oxy]pyri din-2 -yl)morpholine

(100.00 mg, 0.22 mmol), (3A)-/V-[4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl]- 3 -(trifluorom ethoxy )pyrrolidine-l -carboxamide (98.56 mg, 0.24 mmol), Pd(dppf)Cl2.CH2Ch (17.66 mg, 0.02 mmol), INfeCCb (68.77 mg, 0.65 mmol), 1,4-dioxane (4.00 mL) and water (1.00 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (0 to 100%) to afford (3A')-A ^f -[4-methyl-3-(2-[[2- methyl-l-(oxan-2-yloxy)propan-2-yl]oxy]-6-(morpholin-4-yl)py ridin-4-yl)phenyl]-3- (trifluoromethoxy)pyrrolidine-l -carboxamide (100 mg, 74.25%) as a light yellow solid. MS ESI calculated for C31H41F3N4O6 [M + H] ⁺ , 623.30, found 623.20.

Step 2 : (3S)-N-( 3 - G2- \( 1 -hvdroxy-2-methylpropan-2-vPoxyl -6-(morpholin-4-vnpyri din-4-yll-4- methylphenvn-3-(trifluoromethoxy)pyrrolidine-l -carboxamide

[00359] To a stirred solution of (3A)-/V-[4-methyl-3-(2-[[2-methyl-l-(oxan-2-yloxy)propan-2-y l]oxy]-6-

(morpholin-4-yl)pyridin-4-yl)phenyl]-3-(trifluoromethoxy) pyrrolidine-l -carboxamide (100.00 mg, 0.16 mmol) in MeOH (3 mL) was added HC1 (gas) in 1,4-dioxane (1.00 mL, 4 M) dropwise at room temperature. The resulting solution was stirred for 0.5 h at room temperature. The reaction solution was basified to pH ~8 with saturated NaHCCb (aq.). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers was washed with brine (100 mL), dried over anhydrous NaiSCri. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with following conditions: Column: XBridge C18 OBD Prep Column, 100 A, 10 pm, 19 mm x 250 mm; Mobile Phase A: water (10 mmoL/L NH4HCO3), Mobile Phase B:ACN; Flow rate:20 mL/min; Gradient: 50 B to 80 B in 5.8 min; 254/210 nm; RT1 : 5.75 min to afford (3ri)-/V-(3-[2-[(l-hydroxy-2-methylpropan-2-yl)oxy]-6-(morph olin-4- yl)pyridin-4-yl]-4-methylphenyl)-3-(trifluoromethoxy)pyrroli dine-l-carboxamide (35.3 mg, 41%) as an off-white solid. MS ESI calculated for C26H33F3N4O5 [M + H] ⁺ , 539.24, found 539.20. H- NMR (400 MHz, i¾-DMSO) d 8.25 (s, 1H), 7.46-7.43 (m, 1H), 7.39-7.38 (m, 1H), 7.15 (d, J= 8.4 Hz, 1H), 6.22 (s, 1H), 5.93 (s, 1H), 5.15-5.14 (m, 1H), 4.86 (t, J= 6.0 Hz, 1H), 3.74-3.56 (m, 9H), 3.48-3.40 (m, 5H), 2.25-2.19 (m, 5H), 1.51 (s, 6H). F-NMR (376 MHz, i¾-DMSO) d -56.71 (3F).

[00360] The following compounds in Table 5 were prepared using procedures similar to those described in Example 149 and related examples using appropriate starting materials. Racemic products were separated using chiral columns specified in Table 5.

TABLE 5

Example 227: (3S)-N-(3-[2-[(2R)-2-hvdroxypropoxyl-6-[Y2S)-2-methylmorphol in-4-yllpyridin-

4-yll-4-methylphenvD-3-(2 ,2 ,2-trifluoroethyl)pyrrolidine-l-carboxamide

Step 1 : (3 S)-N-(3-[2-[(2R)-2-hvdroxypropoxy]-6-[(2 S)-2-methylmorpholin-4-yl]pyridin-4-yl]-4- methylphenvn-3-(2.2.2-trifluoroethvnpyrrolidine-1-carboxamid e

[00361] A mixture of (2R)-1-([4-iodo-6-[(2S)-2-methylmorpholin-4-yl]pyridin-2-yl] oxy)propan-2-ol (240 mg, 0.635 mmol, 1.00 equiv) and (3ri)-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2- yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (261.61 mg, 0.635 mmol, 1.00 equiv), 1,4-dioxane (4.00 mL), H2O (1.00 mL), Na ₂ CO ₃ (201.77 mg, 1.904 mmol, 3.00 equiv) and

Pd(dppf)Cl2.DCM (51.82 mg, 0.063 mmol, 0.10 equiv) stirred for 2 h at 80 degrees C under N ₂ atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 60% EtOAc in PE. The crude was purified under following conditions: Column: GreenSep Basic, 30* 150mm 5um; Mobile Phase A:C02, Mobile Phase B:IPA(0.5% 2M NH3-MeOH); Flow rate:50 mL/min; Gradient:35% B; 254 nm; RTE5.08; RT2:5.45; Injection Volumn:0.6 ml; Number Of Runs:20; to afford (3S)-N-(3-[2- [(2R)-2-hydroxypropoxy]-6-[(2S)-2-methylmorpholin-4-yl]pyrid in-4-yl]-4-methylphenyl)-3-(2,2,2- trifluoroethyl)pynOlidine-l -carboxamide (39.9 mg, 12%) as a white solid. MS ESI calculated for C ₂₇ H ₃₅ F ₃ N ₄ O ₄ [M + H] ⁺ , 537.26, found 537.30.

[00362] The following compounds in Table 6 were prepared using procedures similar to those described in Example 227 using appropriate starting materials. Racemic products were separated using chiral columns specified in the table.

TABLE 6

II. Biological Evaluation

Example 1: Kinase assay protocol

[00363] Protein kinase assay: Assay platform was used to measure kinase/inhibitor interactions as

described previously (Anastassiadis et al., 2011). In brief, for each reaction, kinase and substrate were mixed in a buffer containing 20 mM HEPES (pH 7.5), 10 mM MgC12, 1 mM EGTA, 0.02% Brij 35, 0.02 mg/mL BSA, 0.1 mM Na3 V04, 2 mM DTT, and 1% DMSO. All compounds were solubilized in DMSO. Compounds were then added to each reaction mixture via acoustic dispense using an ECHO 550 nanoliter dispenser. For human RAF1 testing, human MEK1 (K97R) was used as a substrate at a concentration of 3 micromolar, with a final ATP concentration of 10 micromolar. For human BRAF testing, human MEKl (K97R) was used as a substrate at 1 micromolar concentration, with a final ATP concentration of 25 micromolar. Compounds were tested in 10- dose IC50 mode with a 3 -fold serial dilution starting at 10 micromolar. After a 20-min incubation, ATP (Sigma-Aldrich, St. Louis, MO 63178) and [g33P] ATP (specific activity 10

microCi/microliter) purchased at PerkinElmer (Boston, MA, 02118 Cat # BLU 003H250UC) were added at a final total concentration of 10 mM. Reactions were carried out at room temperature for 2 hr and spotted onto P81 ion exchange cellulose chromatography paper (Reaction Biology). Filter paper was washed in 0.75% phosphoric acid to remove unincorporated ATP. The percent remaining kinase activity relative to a vehicle-containing (DMSO) kinase reaction was calculated for each kinase/inhibitor pair. IC50 values were calculated using Prism 5 (GraphPad).

[00364] Representative data for exemplary compounds are presented in Table 5.

Table 5

Note: Biochemical assay IC50 data are designated within the following ranges:

A: < 0.010 mM C: > 0.10 pM to < 1.0 pM

B: > 0.010 pM to < 0.10 pM D: > 1.0 pM to < 10 pM

III. Preparation of Pharmaceutical Dosage Forms

Example 1: Oral capsule

[00365] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. A capsule for oral administration is prepared by mixing 1-1000 mg of active ingredient with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.

Example 2: Solution for injection

[00366] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt thereof, and is formulated as a solution in sesame oil at a concentration of 50 mg-eq/mL.

[00367] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.