THIENO[3,2-B]PYRIDINE DERIVATIVES AS UDP

GLYCOSYLTRANSFERASE INHIBITORS AND METHODS OF USE

This application is an international application claiming priority to and the benefit of U.S. Provisional Application No. 62/739,405, filed on October 1, 2018, the contents of which are hereby incorporated by reference in its entirety.

BACKGROUND

[0001] UDP Glycosyltransferase 8 (UGT8) is an enzyme within the UDP-glycosyltransferase enzyme family. UGT8 catalyzes the transfer of galactose to ceramide, a key enzymatic step in the biosynthesis of galactoyslceramides. These molecules are abundant sphingolipids of the myelin membrane of the central and peripheral nervous systems. Galactocerebrosides also serve as precursors in the glycosphingolipid biosynthetic pathway and are further modified by cerebroside sulfotransferase, an enzyme which converts Galactocerebrosides to sulfatides.

Sulfatides are also important components of the central nervous system (CNS) and peripheral nervous system (PNS) as a component of myelin, which is a crucial insulator sheath that surrounds axons as a bilayer membrane. The inappropriate recycling of sulfatides can result in the alteration of the myelin structure, affecting the physiological transmission of electrical impulse between nerve cells.

[0002] Krabbe’s disease (KD) is a lysosomal storage disorder in which galactosylceramide (a specific galactocerebroside) and psychosine cannot be adequately degraded because of a deficiency in the galactosylceramidase enzyme. To allow for the correction of the balance between formation and degradation of galactosylceramide and psychosine, a reduced

biosynthesis of glycosphingolipids by the inhibition of UGT8 is considered a validated therapeutic approach.

[0003] Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder caused by the deficiency of arylsulfatase A (ASA), a lysosomal sulfatase that hydrolyzes the 3-0 ester bond from sulfatides including 3-O-sulfogalactosylceramide and 3-0- sulfolactosylceramide. The deficiency expressed in MLD causes a buildup of sulfatides within the CNS and PNS. To allow for correction of the resulting sulfatide buildup, a therapeutic approach similar to Krabbe’s via the inhibition of UGT8 (and the resulting production of sulfatides) has been proposed.

[0004] Despite the awareness and research conducted on both Krabbe’s and MLD, there are no cures for these fatal and debilitating diseases. Thus, identification of new compounds and new methods of therapy are needed as well as new methods for treating or lessening the severity of Krabbe’s, MLD and other conditions and disease related to UGT8 in a patient.

SUMMARY

[0005] In one aspect, the present application is directed to a compound of Formula (I):

(D

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

(a) X ² is CR ² or N;

(b) X ⁵ is CR ⁷ or N;

(c) X ⁶ is CR ¹ or N;

(d) Y is -CN, Ci- ₄ alkyl, -C(0)NR ^a R ^b , -NR ^a -C(0)-R ^b , -C(0)0R ^a , -C(0)R ^a , heteroaryl or -S(0) ₂ NR ^a R ^b , wherein the C _M alkyl or heteroaryl may be substituted with 0-3 occurrences of R ^z ;

(e) each R ^a is independently H, Ci- ₄ alkyl, Ci- ₄ haloalkyl, Ci- ₄ alkyl-C ₃ -9 cycloalkyl or C3-9 cycloalkyl;

(f) each R ^b is independently Ci- ₄ alkyl, Ci- ₄ alkoxy, C3-9 cycloalkyl or Ci- ₄ alkyl-Ci- ₄ alkoxy; or

when Y is -C(0)NR ^a R ^b , R ^a and R ^b can be taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl ring substituted with 0-3 occurrences of R ^x ;

(g) R ⁷ is hydrogen, Ci- ₄ alkyl, C _{1 -4} alkoxy, -S(0) ₂ -NR ^a R ^b - or heteroaryl;

(h) R ¹ is hydrogen, halo, -OH, Ci- ₄ alkyl, Ci- ₄ alkoxy, Ci- ₄ haloalkyl, Ci- ₄ haloalkoxy, - NH _3, -NH(C _I-4 alkyl) or -N(C _I-4 alkyl) ₂ , C _3-9 cycloalkyl or heterocycloalkyl, wherein each -NH(C _I -4 alkyl), cycloalkyl or heterocycloalkyl is substituted with 0-5 occurrences of R ^x ;

(i) R ² is hydrogen, halo, -OH, C _M alkyl, C _M alkoxy or C _3-9 cycloalkyl;

(j) A ¹ is a bond, C _1-4 alkylene, -0-, -O-C _1-4 alkylene, -C _2-4 alkenylene, -C _2-4

alkynylene, -NR ^a , -NR ^a -Ci_ ₄ alkylene-, -S-, -S(O)-, -S(0) ₂ -, -C(O)-, -C(0)-0- or -O- C(O)-;

(k) L is aryl, heteroaryl, C3-12 cycloalkyl, a 3-12 membered heterocycloalkyl or a 3-12 membered heterocycloalkenyl each of which may be substituted with 0-3 occurrences of R ^x ;

(l) A ² is a bond, -0-, -NR ^a -, -Ci_ ₄ -alkyl-NR ^a -, -C(O)-, -CM alkyl-C(O)-, -O-C(O)-, -CM alkyl-O-C(O)-, -C(0)-0-, -CM alkyl-C(0)-0-, -0-C(0)-0-, -S(0) ₂ -, -NR ^a -S(0)-, -Ci- 4-alkyl-NR ^a -S(0)-, -NR ^a -S(0) ₂ -, -Ci- ₄ -alkyl-NR ^a -S(0) ₂ -, -C(0)-NR ^a -, -CM alkyl- C(0)-NR ^a -, -NR ^a -C(0)-, -Ci- ₄ -alkyl-NR ^a -C(0)-, -0-C(0)-NR ^a -, -Ci_ ₄ -alkyl-0-C(0)- NR ^a -, -NR ^a -C(0)-0- or -NR ^a -C(0)-NR ^a -, -NR ^a -CH ₂ -C(0)-NR ^a -, -0-CH ₂ -C(0)-NR ^a -, -C(0)-0-CH ₂ -C(0)-, -C(0)-NR ^a -CH ₂ -C(0)-;

(m)R ⁴ is hydrogen, -OH, Ci _-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-9 cycloalkyl,

heterocycloalkyl, aryl or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R ⁴ is substituted with 0-5 occurrences of R ⁵ ;

(n) R ⁵ is OH, halo, CO2H, CM alkyl, C2-6 alkynyl, CM alkoxy, CM haloalkyl, -O-C1-4 haloalkyl, -CM alkyl-O-Ci-4 alkyl, -S-CM alkyl, -S(0) ₂ -CM alkyl, -S(0)-CM alkyl, - N(R ^a ) ₂ , -CH ₂ N(R ^a ) ₂ , -N(R ^a )-S(0)-Ci- ₄ alkyl, -A-(R ^a )-S(0) ₂ -Ci- ₄ alkyl, -NO2, -CN, - CH2CN, C3-9 cycloalkyl, -O-C3-9 cycloalkyl, -CM alkyl-C3-9 cycloalkyl, -O-C1-4 alkyl- C3-9 cycloalkyl, -CM alkyl-O-Ci-4 haloalkyl, heterocycloalkyl, -CM alkyl- heterocycloalkyl, aryl, -O-aryl, heteroaryl, -O-heteroaryl, C 1-4-alkyl-heteroaryl, aralkyl or -O-aralkyl, wherein each alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of R ^w ;

(o) each R ^w is independently halo, -OH, CM alkyl, CM haloalkyl or -CM alkoxy;

(p) each R ^x is independently halo, -OH, CM alkyl, -CM alkoxy, -CM alkyl-O-Ci- ₄ alkyl, - C(0)-N(R ^a ) ₂ , -0-C(0)-N(R ^a ) ₂ , -N(R ^a ) ₂ , -CH ₂ N(R ^a ) ₂ , heterocycloalkyl, -O- heterocycloalkyl, -O-aryl or -O-heteroaryl; and (q) each R ^z is independently hydrogen, halo, -OH, C _M alkyl, C _1-4 alkoxy or C _3-9 cycloalkyl.

[0006] Various embodiments of the application are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments.

[0007] In some embodiments of the present disclosure, the compound of Formula I may be a compound of Formula la, as shown below:

[0008] In some embodiments of the present disclosure, the compound of Formula I may be a compound of Formula lb, as shown below:

[0009] In some embodiments of the present disclosure, the compound of Formula I may be a compound of Formula Ic, as shown below:

[0010] In some embodiments of the present disclosure, the compound of Formula I may be a compound of Formula Id, as shown below:

[0011] In some embodiments of the present disclosure, the compound of Formula I may be a compound of Formula Ie, as shown below:

[0012] In some embodiments of the present disclosure, the compound of Formula I may be a compound of Formula If, as shown below:

[0013] In some embodiments of the present disclosure, the compound of Formula I may be a compound of Formula II, Ila, lib, or lie, as shown below:

[0014] In some embodiments of the present disclosure, the compound of Formula I may be a compound of Formula III, Ilia, Illb, or IIIc, as shown below:

DETAILED DESCRIPTION

[0015] A description of embodiments of the application follows.

[0016] In one aspect, the present application is directed to a compound (Compound 1) of Formula (I):

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

(a) X ² is CR ² or N;

(b) X ⁵ is CR ⁷ or N;

(c) X ⁶ is CR ¹ or N;

(d) Y is -CN, Ci- ₄ alkyl, -C(0)NR ^a R ^b , -NR ^a -C(0)-R ^b , -C(0)OR ^a , -C(0)R ^a , heteroaryl or -S(0) ₂ NR ^a R ^b , wherein the C _M alkyl or heteroaryl may be substituted with 0-3 occurrences of R ^z ;

(e) each R ^a is independently H, Ci- ₄ alkyl, Ci- ₄ haloalkyl, -Ci- ₄ alkyl-C ₃ -9 cycloalkyl or C _3- 9 cycloalkyl; (f) Each R ^b is independently C1-4 alkyl, CM alkoxy, C3-9 cycloalkyl or -Ci- ₄ alkyl-Ci- ₄ alkoxy; or when Y is -C(0)NR ^a R ^b , R ^a and R ^b can be taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl ring substituted with 0-3 occurrences of R ^x ;

(g) R ⁷ is hydrogen, Ci- ₄ alkyl, C alkoxy, -S(0) ₂ -NR ^a R ^b - or heteroaryl;

(h) R ¹ is hydrogen, halo, -OH, C _M alkyl, Ci- ₄ alkoxy, Ci- ₄ haloalkyl, Ci- ₄ haloalkoxy, - NH _3, -NH(C _I-4 alkyl) or -N(C _I-4 alkyl) ₂ , C3-9 cycloalkyl or heterocycloalkyl, wherein each -NH(C _I-4 alkyl), cycloalkyl or heterocycloalkyl is substituted with 0-5

occurrences of R ^x ;

(i) R ² is hydrogen, halo, -OH, Ci- ₄ alkyl, Ci- ₄ alkoxy or C3-9 cycloalkyl;

(j) A ¹ is a bond, Ci- ₄ alkylene, -0-, -0-Ci- ₄ alkylene, -C2-4 alkenylene, -C2-4

alkynylene, -NR ^a , -NR ^a -Ci_ ₄ alkylene-, -S-, -S(O)-, -S(0) ₂ -, -C(O)-, -C(0)-0- or -O- C(O)-;

(k) L is aryl, heteroaryl, C _3-i2 cycloalkyl, a 3-12 membered heterocycloalkyl or a 3-12 membered heterocycloalkenyl each of which may be substituted with 0-3 occurrences of R ^x ;

(l) A ² is a bond, -0-, -NR ^a -, -Ci_ ₄ -alkyl-NR ^a -, -C(O)-, -CM alkyl-C(O)-, -O-C(O)-, -C _M alkyl-O-C(O)-, -C(0)-0-, -C _M alkyl-C(0)-0-, -0-C(0)-0-, -S(0) ₂ -, -NR ^a -S(0)-, -Ci- 4-alkyl-NR ^a -S(0)-, -NR ^a -S(0) ₂ -, -Ci_ ₄ -alkyl-NR ^a -S(0) ₂ -, -C(0)-NR ^a -, -C _M alkyl- C(0)-NR ^a -, -NR ^a -C(0)-, -Ci_ ₄ -alkyl-NR ^a -C(0)-, -0-C(0)-NR ^a -, -Ci- ₄ -alkyl-0-C(0)- NR ^a -, -NR ^a -C(0)-0- or -NR ^a -C(0)-NR ^a -, -NR ^a -CH ₂ -C(0)-NR ^a -, -0-CH ₂ -C(0)-NR ^a -, -C(0)-0-CH ₂ -C(0)-, -C(0)-NR ^a -CH ₂ -C(0)-;

(m)R ⁴ is hydrogen, -OH, C1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C3-9 cycloalkyl,

heterocycloalkyl, aryl or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R ⁴ is substituted with 0-5 occurrences of R ⁵ ;

(n) R ⁵ is OH, halo, C0 ₂ H, CM alkyl, C _2-6 alkynyl, Ci _-4 alkoxy, CM haloalkyl, -0-Ci- ₄ haloalkyl, -CM alkyl-0-Ci_ ₄ alkyl, -S-CM alkyl, -S(0) ₂ -CM alkyl, -S(0)-CM alkyl, - N(R ^a ) ₂ , -CH ₂ N(R ^a ) ₂ , -N(R ^a )-S(0)-Ci- ₄ alkyl, -A-(R ^a )-S(0) ₂ -Ci_ ₄ alkyl, -N0 ₂ , -CN, - CH ₂ CN, C3-9 cycloalkyl, -O-C3-9 cycloalkyl, -CM alkyl-C3-9 cycloalkyl, -0-Ci- ₄ alkyl- C _3-9 cycloalkyl, -CM alkyl-0-Ci- ₄ haloalkyl, heterocycloalkyl, -CM alkyl- heterocycloalkyl, aryl, -O-aryl, heteroaryl, -O-heteroaryl, Ci- ₄ -alkyl-heteroaryl, aralkyl or -O-aralkyl, wherein each alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of R ^w ;

(o) each R ^w is independently halo, -OH, CM alkyl, C1-4 haloalkyl or -Ci- ₄ alkoxy;

(p) each R ^x is independently halo, -OH, Ci- ₄ alkyl, -Ci- ₄ alkoxy, -Ci- ₄ alkyl-0-Ci- ₄ alkyl, - C(0)-N(R ^a ) ₂ , -0-C(0)-N(R ^a ) ₂ , -N(R ^a ) ₂ , -CH ₂ N(R ^a ) ₂ , heterocycloalkyl, -O- heterocycloalkyl, -O-aryl or -O-heteroaryl; and

(q) each R ^z is independently hydrogen, halo, -OH, Ci- ₄ alkyl, Ci- ₄ alkoxy or C3-9

cycloalkyl.

[0017] In particular embodiments of the first aspect, the present application further provides:

1.1 Compound 1, wherein X ⁶ is N.

1.2 Compound 1, wherein X ⁶ is CR ¹ .

1.3 Compound 1, 1.1 or 1.2, wherein X ² is N.

1.4 Compound 1, 1.1 or 1.2, wherein X ² is CR ² .

1.5 Any of Compound 1, or 1.1 et seq., wherein X ² is CR ² and X ⁶ is N (formula la).

1.6 Any of Compound 1, or 1.1 et seq., wherein X ² is N and X ⁶ is CR ¹ (formula lb).

1.7 Any of Compound 1, or 1.1 et seq., wherein X ² is CR ² and X ⁶ is CR ¹ (formula Ic).

1.8 Any of Compound 1, or 1.1 et seq., wherein X ² is CR ² and X ⁶ is N and X ⁵ is

CR ⁷ (formula Id).

1.9 Any of Compound 1, or 1.1 et seq., wherein X ² is N and X ⁶ is CR ¹ and X ⁵ is

CR ⁷ (formula Ie).

1.10 Any of Compound 1, or 1.1 et seq., wherein X ² is CR ² and X ⁶ is CR ¹ and X ⁵ is CR ⁷ (forumula If).

1.11 Any of Compound 1, or 1.1 et seq., wherein R ² is hydrogen, Ci- ₄ alkyl (e.g.,

methyl) or halo (e.g., fluoro, chloro or bromo).

1.12 Any of Compound 1, or 1.1-1.11, wherein R ² is hydrogen.

1.13 Any of Compound 1 , or 1.1-1.11, wherein R ² is halo, optionally wherein R ² is selected from fluoro, chloro and bromo.

1.14 Any of Compound 1, or 1.1-1.11, wherein R ² is Ci- ₄ alkyl, optionally wherein R ² is methyl.

1.15 Any of Compound 1 , or 1.1-1.11, wherein R ² is C i- ₄ alkoxy, optionally wherein R ² is methoxy. Any of Compound l, or 1.1-1.11, wherein R ² is C3-9 cycloalkyl, optionally wherein R ² is cyclopropyl.

Any of Compound l, or 1.1-1.11, wherein R ² is hydroxyl.

Any of Compound 1, or 1.1 et seq., wherein R ⁷ is C _M alkyl, optionally wherein R ⁷ is methyl.

Any of Compound 1, or 1.1-1.17, wherein R ⁷ is hydrogen.

Any of Compound 1, or 1.1 et seq., wherein Y is CN.

Any of Compound 1, or 1.1 et seq., wherein Y is -C(0)R ^a .

Compound 1.21, wherein R ^a is hydrogen.

Compound 1.21, wherein R ^a is C1-4 alkyl, optionally wherein R ^a is methyl or R ^a is ethyl.

Any of Compound 1, or 1.1 et seq., wherein Y is -NR ^a -C(0)-R ^b .

Compound 1.24, wherein R ^a is hydrogen and R ^b is C1-4 alkyl or C1-4 alkoxy.

Compound 1.24, wherein R ^a is hydrogen and R ^b is C1-4 alkyl, optionally wherein R ^b is methyl.

Compound 1.24, wherein R ^a is hydrogen and R ^b is C1-4 alkoxy, optionally wherein R ^b is methoxy or R ^b is i-butoxy.

Any of Compound 1, or 1.1 et seq., wherein Y is heteroaryl substituted with 0-3 occurrences of R ² , e.g., wherein Y is heteroaryl substituted with 0 occurrences of R ² , or Y is heteroaryl substituted with 1 occurrence of R ² , optionally wherein any one or more of the R ² are the same or different.

Compound 1.28, wherein Y is oxazolyl (e.g., 2-oxazolyl) substituted with 1 occurrence of R ² , optionally wherein Y is 4-methyl-2-oxazolyl or 5-methyl-2- oxazolyl.

Any of Compound 1, or 1.1 et seq., wherein Y is -C(0)OR ^a .

Compound 1.30, wherein R ^a is hydrogen

Compound 1.30, wherein R ^a is C1-4 alkyl (e.g., methyl or /-butyl), optionally wherein Y is -C(0)OMe.

Any of Compound 1, or 1.1 et seq., wherein Y is C1-4 alkyl substituted with 0-3 occurrences of R ² , optionally wherein any one or more of the R ² are the same or different. Compound 1.33, wherein Y is Ci- ₄ alkyl (e.g., methyl or propyl) substituted with 0 occurrences of R ² or with 1 occurrence of R ² , optionally wherein Y is methyl or propyl substituted with 0 occurrences of R ² or with 1 occurrence of R ² .

Compound 1.34, wherein R ² is -OH, optionally wherein Y is l-hydroxypropyl. Any of Compound 1, or 1.1 et seq., wherein Y is -C(0)NR ^a R ^b .

Compound 1.36, wherein R ^a is Ci- ₄ alkyl (e.g., methyl) and R ^b is C _M alkyl (e.g., methyl).

Compound 1.36, wherein R ^a and R ^b are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl ring substituted with 0-3 occurrences of R ^x , optionally 0 or 1 occurrences of R ^x .

Compound 1.38, wherein R ^a and R ^b are taken together with the nitrogen atom to which they are attached to form an azetidine ring substituted with 0 or 1 occurrences of R ^x , or to form a morpholine ring substituted with 0 or 1 occurrences of R ^x .

Compound 1.38 or 1.39, wherein R ^x is halo (e.g., chloro).

Compound 1.38 or 1.39, wherein R ^x is Ci- ₄ alkoxy (e.g., methoxy).

Compound 1.38 or 1.39, wherein R ^x is -O-heteroaryl (e.g., -O-2-pyridyl).

Compound 1.36, wherein R ^a is hydrogen and R ^b is Ci- ₄ alkyl, Ci- ₄ alkoxy, C3-9 cycloalkyl, or Ci- ₄ alkyl-Ci- ₄ alkoxy.

Compound 1.43, wherein R ^a is hydrogen and R ^b is Ci- ₄ alkoxy (e.g., methoxy). Compound 1.43, wherein R ^a is hydrogen and R ^b is C3-9 cycloalkyl (e.g., cyclopropyl).

Compound 1.43, wherein R ^a is hydrogen and R ^b is Ci- ₄ alkyl-Ci- ₄ alkoxy (e.g., 2- methoxyethyl).

Compound 1.43, wherein R ^a is hydrogen and R ^b is Ci- ₄ alkyl (e.g., methyl, ethyl, propyl, isopropyl or n-butyl), optionally wherein R ^a is hydrogen and R ^b is ethyl, or R ^a is hydrogen and R ^b is isopropyl, or R ^a is hydrogen and R ^b is «-butyl, or R ^a is hydrogen and R ^b is methyl.

Any of Compound 1, or 1.1 et seq., wherein X ² is CR ² , X ⁶ is CR ¹ , X ⁵ is CR ⁷ and R ⁷ is hydrogen, and Y is -C(0)NR ^a R ^b and R ^a is hydrogen and R ^b is methyl (formula II). Compound 1.48, wherein R ² is hydrogen (formula Ila).

Any of Compound 1, or 1.1 et seq., wherein X ² is CR ² , X ⁶ is CR ¹ , X ⁵ is CR ⁷ and R ⁷ is hydrogen, and Y is -C(0)OR ^a and R ^a is methyl (formula lib).

Compound 1.50, wherein R ² is hydrogen (formula lie).

Any of Compound 1, or 1.1 et seq., wherein R ¹ is hydrogen, halo, (e.g., chloro), Ci-4 haloalkyl (e.g., difluoromethyl or trifluoromethyl).

Compound 1.52, wherein R ¹ is hydrogen.

Compound 1.52, wherein R ¹ is halo, optionally, wherein R ¹ is chloro.

Any of Compound 1, or 1.1 et seq., wherein R ¹ is -OH.

Any of Compound 1, or 1.1 et seq., wherein R ¹ is -NH(C _I-4 alkyl) (e.g., -NHMe). Any of Compound 1, or 1.1 et seq., wherein R ¹ is -N(C _I-4 alkyl) ₂ (e.g., -N(Me) ₂ ). Any of Compound 1, or 1.1 et seq., wherein R ¹ is C3-9 cycloalkyl substituted with

0-3 occurrences of R ^x , optionally wherein R ¹ is C3-9 cycloalkyl substituted with 0 occurrences of R ^x .

Compound 1.58, wherein R ¹ is cyclopropyl or cyclopentyl substituted with 0 occurrences of R ^x .

Any of Compound 1, or 1.1 et seq., wherein R ¹ is heterocycloalkyl (e.g., azetidinyl) substituted with 0-3 occurrences of R ^x .

Compound 1.60, wherein R ¹ is azetidinyl substituted with 0-3 occurrences of R ^x , optionally wherein R ¹ is azetidinyl substituted with 0 or 2 occurrences of R ^x .

Any of compounds 1.58-1.61, wherein each R ^x is independently halo (e.g., fluoro), for example, wherein R ¹ is 2,2-difluoroazetidinyl.

Any of Compound 1, or 1.1 et seq., wherein R ¹ is C _M alkyl (e.g., methyl, isopropyl or /-butyl), optionally wherein R ¹ is methyl, or R ¹ is isopropyl, or R ¹ is t- butyl.

Any of Compound 1, or 1.1 et seq., wherein R ¹ is Ci- ₄ alkoxy, optionally wherein R ¹ is methoxy.

Any of Compound 1, or 1.1 et seq., wherein R ¹ is Ci- ₄ haloalkoxy (e.g., difluoromethoxy or 2,2,2-trifluoroethoxy), optionally wherein R ¹ is

difluoromethoxy or wherein R ¹ is 2,2,2-trifluoroethoxy. Any of Compound 1, or 1.1 et seq., wherein R ¹ is C _M haloalkyl, optionally wherein R ¹ is trifluoromethyl or difluoromethyl or l,l-difluoroethyl.

Any of Compound 1, or 1.1 et seq., wherein X ² is CR ² , X ⁶ is CR ¹ and R ¹ is trifluoromethyl, X ⁵ is CR ⁷ and R ⁷ is hydrogen, and Y is -C(0)NR ^a R ^b and R ^a is hydrogen and R ^b is methyl (formula III).

Compound 1.67, wherein R ² is hydrogen (formula Ilia).

Any of Compound 1, or 1.1 et seq., wherein X ² is CR ² , X ⁶ is CR ¹ and R ¹ is trifluoromethyl, X ⁵ is CR ⁷ and R ⁷ is hydrogen, and Y is -C(0)OR ^a and R ^a is methyl (formula Illb).

Compound 1.69, wherein R ² is hydrogen (formula IIIc).

Any of Compound 1, or 1.1 et seq., wherein A ¹ is -0-, Ci- ₄ alkylene, -O-Ci-4 alkylene, a bond, -O-C(O)-, -C(O)-, -S-, -S(O)-, -S(0) ₂ -, C2-4 alkynylene, -NR ^a - or -NR ^a -Ci-4 alkylene.

Compound 1.71, wherein A ¹ is a bond, -0-, -O-C _1-4 alkylene or C _1-4 alkylene. Compound 1.72, wherein A ¹ is a bond or -0-.

Compound 1.73, wherein A ¹ is a bond.

Compound 1.73, wherein A ¹ is -0-.

Compound 1.72, wherein A ¹ is C1-4 alkylene, optionally wherein A ¹ is -CH ₂ - or - CH(CH ₃ )-.

Any of Compound 1, or 1.1 et seq., wherein A ¹ is -O-C(O)-.

Any of Compound 1, or 1.1 et seq., wherein A ¹ is -S-, or A ¹ is -S(0) ₂ -, or A ¹ is - S(O)-.

Any of Compound 1, or 1.1 et seq., wherein A ¹ is C ₂ -4 alkynylene, optionally wherein A ¹ is -CºC- or -CºC-CH ₂ -.

Any of Compound 1, or 1.1 et seq., wherein A ¹ is -NR ^a -.

Any of Compound 1, or 1.1 et seq., wherein A ¹ is -NR ^a -Ci-4 alkylene-.

Any of Compound 1, or 1.1 et seq., wherein A ¹ is -NR ^a -CH ₂ -.

Any of Compound 1, or 1.1 et seq., wherein L is aryl or heteroaryl, each optionally substituted with 0-3 occurrences of R ^x .

Any of Compound 1, or 1.1 et seq., wherein L is C _3-i2 cycloalkyl, optionally substituted with 0-3 occurrences of R ^x . Any of Compound 1, or 1.1 et seq., wherein L is a 3-12 membered

heterocycloalkyl or a 3-12 membered heterocycloalkenyl, optionally substituted with 0-3 occurrences of R ^x .

Any of Compound 1, or 1.1 et seq., wherein L is selected from:

, and wherein each of which L moiety is substituted with 0-5 occurrences of R ^:

Any of Compound 1, or 1.1 et seq., wherein L is substituted with 1 occurrence of R ^x , or with 2 occurrences of R ^x , or with 3 occurrences of R ^x , or with 4 occurrences of R ^x .

Any of Compound 1, or 1.1 et seq., wherein L is selected from any one of:

1.89 Any of Compound 1, or 1.1 et seq., wherein L is selected from any one of: is selected from any one of:

is selected from any one of: is selected from any one of:

Any of Compound 1, or 1.1 et seq., wherein L is F

Any of Compound 1, or 1.1 et seq., wherein

Any of Compound 1, or 1.1 et seq., wherein L

Any of Compound 1, or 1.1 et seq., wherein

Any of Compound 1, or 1.1 et seq., wherein

Any of Compound 1, or 1.1 et seq., wherein L is

Any of Compound 1, or 1.1 et seq., wherein

Any of Compound 1, or 1.1 et seq., wherein

Any of Compound 1, or 1.1 et seq., wherein L is

Any of Compound 1, or 1.1 et seq., wherein X

Any of Compound 1, or et seq., wherein L is X

□ X

Any of Compound 1, or 1.1 et seq., wherein L is

Any of Compound 1, or 1.1 et seq., wherein

Any of Compound 1, or 1.1 et seq., wherein L is

Any of Compound 1, or 1 1 et seq., wherein L is

Any of Compound 1, or 1 1 et seq., wherein L is

Any of Compound 1, or 1.1 et seq., wherein

Any of Compound 1, or 1.1 et seq., wherein L is

Any of Compound 1, or 1.1 et seq., wherein

Any of Compound 1, or 1.1 et seq., wherein

Any of Compound 1, or 1.1 et seq., wherein A ² is a bond, -C(0)-0-, -OC(0)-NR ^a -, -OC(O)-, -0-, -C(O)-, -NR ^a -C(0)-0-, -NR ^a -C(0)-NR ^a -, -C(0)-NR ^a -, -CM alkyl- C(0)-NR ^a -, -C1-4 alkyl-0-C(0)-NR ^a -, -0-C(0)-0-, -NR ^a -C(0)-, -NR ^a -, -S(0) ₂ -, - CM alkyl-C(O)-, -CM alkyl-NR ^a -, -CM alkyl-NR ^a -S(0)- or -CM alkyl-C(0)-0-. Compound 1.113, wherein A ² is a bond, -C(0)-0-, -0C(0)-NR ^a -, -OC(O)-, -0-, - NR ^a -C(0)-0-, -CM alkyl-C(0)-NR ^a -, -CM alkyl-0-C(0)-NR ^a - or -NR ^a -.

Compound 1.113, wherein A ² is -0-C(0)-0.

Compound 1.113, wherein A ² is -NR ^a -C(0)-, optionally wherein R ^a is H.

Compound 1.113, wherein A ² is -NR ^a -, optionally wherein R ^a is H.

Compound 1.113, wherein A ² is -S(0) ₂ -.

Compound 1.113, wherein A ² is -C(0)-NR ^a -, optionally wherein R ^a is H, or optionally wherein R ^a is C _M alkyl (e.g., methyl or ethyl).

Compound 1.119, wherein A ² is -C(0)-NH-, -C(0)-N(Me)-, or -C(0)-N(Et)-. Compound 1.113, wherein A ² is -NR ^a -C(0)-NR ^a -, optionally wherein both R ^a are

H.

Compound 1.113, wherein A ² is -C _M alkyl-C(O)-, optionally wherein A ² is -CH ₂ - C(O)- or A ² is -CH(CH ₃ )-C(0)-.

Compound 1.113, wherein A ² is -C _M alkyl-NR ^a -.

Compound 1.123, wherein R ^a is H, for example wherein A ² is -CH ₂ -NH-.

Compound 1.123, wherein R ^a is CM alkyl, optionally wherein R ^a is methyl, for example, wherein A ² is -C _M alkyl-N(Me)-, e.g., A ² is -CH ₂ -N(Me)-.

Compound 1.113, wherein A ² is -C _M alkyl-NR ^a -S(0)-, optionally wherein R ^a is H, for example, wherein A ² is -CH ₂ -NH-S(0)-.

Compound 1.113, wherein A ² is -C _M alkyl-C(0)-0-, optionally wherein A ² is - CH ₂ -C(0)-0- or -CH(CH ₃ )-C(0)-0-.

Compound 1.113, wherein A ² is -C _M alkyl-0-C(0)-NR ^a -, optionally wherein R ^a is H, for example, wherein A ² is -CH ₂ -0-C(0)-NH-.

Compound 1.113, wherein A ² is -C _M alkyl-C(0)-NR ^a -.

Compound 1.129, wherein R ^a is H, for example, wherein A ² is -CH ₂ -C(0)-NH- or A ² is -CH(CH ₃ )-C(0)-NH- or A ² is -C(CH ) ₂ -C(0)-NH- or A ² is -CH(CH ₂ CH )- C(0)-NH-.

Compound 1.129, wherein R ^a is C _M alkyl (e.g., methyl), for example, wherein A ² is -CH ₂ -C(0)-N(Me)-,

Compound 1.113, wherein or A ² is -C(O)-.

Compound 1.113, wherein A ² is -0-. Compound 1.113, wherein A ² is -NR ^a -C(0)-0-, optionally wherein R ^a is H, or wherein R ^a is C _M alkyl, for example, wherein A ² is -N(Me)-C(0)-0-.

Compound 1.113, wherein A ² is a bond.

Compound 1.113, wherein A ² is -O-C(O)-.

Compound 1.113, wherein A ² is -0-C(0)-NR ^a -, optionally wherein R ^a is H, or wherein R ^a is Ci- ₄ alkyl (e.g., methyl, ethyl or isopropyl), for example, wherein A ² is -0-C(0)-N(Me)-, or A ² is -0-C(0)-N(Et)-, or A ² is -0-C(0)-N(zPr)-.

Compound 1.113, wherein A ² is -C(0)-0-.

Any of Compound 1, or 1.1 et seq., wherein R ⁴ is hydrogen.

Any of Compound 1, or 1.1 et seq., wherein R ⁴ is -OH.

Any of Compound 1, or 1.1 et seq., wherein R ⁴ is Ci- ₆ alkyl, C _2-6 alkynyl, heterocycloalkyl, C3-9 cycloalkyl or heteroaryl, each optionally substituted with 0-5 occurrences of R ⁵ , optionally wherein any one or more of the R ⁵ are the same or different.

Compound 1.141, wherein R ⁴ is C1-6 alkyl substituted with 0-5 occurrences of R ⁵ . Compound 1.142, wherein R ⁴ is C1-6 alkyl substituted with 0 occurrences of R ⁵ , or with 1 occurrence of R ⁵ , or with 2 occurrences of R ⁵ , or with 3 occurrences of R ⁵ , or with 4 occurrences of R ⁵ , or with 5 occurrences of R ⁵ .

Compound 1.142 or 1.143, wherein the C1-6 alkyl of R ⁴ is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, 3,3-dimethylbutyl or 4-methylpentan-2-yl.

Compound 1.142 or 1.143, wherein the C1-6 alkyl of R ⁴ is methyl.

Compound 1.142 or 1.143, wherein the C1-6 alkyl of R ⁴ is ethyl.

Compound 1.142 or 1.143, wherein the C1-6 alkyl of R ⁴ is n-propyl.

Compound 1.142 or 1.143, wherein the C1-6 alkyl of R ⁴ is isopropyl.

Compound 1.142 or 1.143, wherein the C1-6 alkyl of R ⁴ is isobutyl.

Compound 1.142 or 1.143, wherein the C1-6 alkyl of R ⁴ is sec -butyl.

Compound 1.142 or 1.143, wherein the C1-6 alkyl of R ⁴ is t-butyl.

Compound 1.142 or 1.143, wherein the C1-6 alkyl of R ⁴ is isopentyl.

Compound 1.142 or 1.143, wherein the C1-6 alkyl of R ⁴ is n-pentyl.

Compound 1.142 or 1.143, wherein the C1-6 alkyl of R ⁴ is neopentyl. Compound 1.142 or 1.143, wherein the Ci _-6 alkyl of R ⁴ is 4-methylpentan-2-yl. Compound 1.142 or 1.143, wherein the Ci _-6 alkyl of R ⁴ is 3,3-dimethylbutyl.

Any of Compounds 1.144-1.156, wherein said Ci _-6 alkyl of R ⁴ is substituted with 0 occurrences of R ⁵ .

Any of Compounds 1.144-1.156, wherein said Ci _-6 alkyl of R ⁴ is substituted with 1 occurrence of R ⁵ .

Any of Compounds 1.144-1.156, wherein said Ci _-6 alkyl of R ⁴ is substituted with 2 occurrences of R ⁵ .

Any of Compounds 1.144-1.156, wherein said Ci _-6 alkyl of R ⁴ is substituted with 3 occurrences of R ⁵ .

Compound 1.141, wherein R ⁴ is C _2-6 alkynyl substituted with 0-5 occurrences of

R ⁵ .

Compound 1.161, wherein R ⁴ is C2-6 alkynyl substituted with 0 occurrences of R ⁵ , or with 1 occurrence of R ⁵ , or with 2 occurrences of R ⁵ , or with 3 occurrences of R ⁵ , or with 4 occurrences of R ⁵ , or with 5 occurrences of R ⁵ .

Compound 1.161 or 1.162, wherein the C2-6 alkynyl of R ⁴ is selected from ethynyl, 2-propynyl, l-butynyl, 2-butynyl, 2-pentynyl, and l-hexa-l,3-diynyl.

Compound 1.161 or 1.162, wherein the C2-6 alkynyl of R ⁴ is ethynyl.

Compound 1.161 or 1.162, wherein the C2-6 alkynyl of R ⁴ is 2-propynyl.

Compound 1.161 or 1.162, wherein the C2-6 alkynyl of R ⁴ is l-butynyl.

Compound 1.161 or 1.162, wherein the C2-6 alkynyl of R ⁴ is 2-butynyl

Compound 1.161 or 1.162, wherein the C2-6 alkynyl of R ⁴ is 2-pentynyl.

Compound 1.161 or 1.162, wherein the C2-6 alkynyl of R ⁴ is l-hexa-l,3-diynyl. Any of Compounds 1.163-1.169, wherein said C2-6 alkynyl of R ⁴ is substituted with 0 occurrences of R ⁵ .

Any of Compounds 1.163-1.169, wherein said C2-6 alkynyl of R ⁴ is substituted with 1 occurrence of R ⁵ .

Any of Compounds 1.163-1.169, wherein said C2-6 alkynyl of R ⁴ is substituted with 2 occurrences of R ⁵ .

Any of Compounds 1.163-1.169, wherein said C2-6 alkynyl of R ⁴ is substituted with 3 occurrences of R ⁵ . Compound 1.141, wherein R ⁴ is C3-9 cycloalkyl substituted with 0-5 occurrences of

R ⁵ .

Compound 1.174, wherein R ⁴ is C3-9 cycloalkyl substituted with 0 occurrences of R ⁵ , or with 1 occurrence of R ⁵ , or with 2 occurrences of R ⁵ , or with 3 occurrences of R ⁵ , or with 4 occurrences of R ⁵ , or with 5 occurrences of R ⁵ .

Compound 1.174 or 1.175, wherein the C3-9 cycloalkyl of R ⁴ is selected from cyclopropyl, cyclobutyl and cyclohexyl.

Compound 1.174 or 1.175, wherein the C3-9 cycloalkyl of R ⁴ is cyclopropyl.

Compound 1.174 or 1.175, wherein the C3-9 cycloalkyl of R ⁴ is cyclobutyl.

Compound 1.174 or 1.175, wherein the C3-9 cycloalkyl of R ⁴ is cyclohexyl.

Any of Compounds 1.176-1.179, wherein said C3-9 cycloalkyl of R ⁴ is substituted with 0 occurrences of R ⁵ .

Any of Compounds 1.176-1.179, wherein said C3-9 cycloalkyl of R ⁴ is substituted with 1 occurrence of R ⁵ .

Any of Compounds 1.176-1.179, wherein said C3-9 cycloalkyl of R ⁴ is substituted with 2 occurrences of R ⁵ .

Compound 1.141, wherein R ⁴ is aryl substituted with 0-5 occurrences of R ⁵ .

Compound 1.183, wherein R ⁴ is aryl substituted with 0 occurrences of R ⁵ , or with 1 occurrence of R ⁵ , or with 2 occurrences of R ⁵ , or with 3 occurrences of R ⁵ , or with 4 occurrences of R ⁵ , or with 5 occurrences of R ⁵ .

Compound 1.183 or 1.184, wherein the aryl of R ⁴ is phenyl.

Compound 1.185, wherein said aryl is aryl substituted with 0 occurrences of R ⁵ . Compound 1.185, wherein said aryl is aryl substituted with 1 occurrence of R ⁵ . Compound 1.185, wherein said aryl is aryl substituted with 2 occurrences of R ⁵ . Compound 1.141, wherein R ⁴ is heteroaryl substituted with 0-5 occurrences of R ⁵ . Compound 1.189, wherein R ⁴ is heteroaryl substituted with 0 occurrences of R ⁵ , or with 1 occurrence of R ⁵ , or with 2 occurrences of R ⁵ , or with 3 occurrences of R ⁵ , or with 4 occurrences of R ⁵ , or with 5 occurrences of R ⁵ .

Compound 1.189 or 1.190, wherein the heteroaryl of R ⁴ is selected from

imidazolyl, pyrimidinyl, pyridinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, thiazolyl, and thiophenyl. Compound 1.189 or 1.190, wherein the heteroaryl of R ⁴ is imidazolyl, e.g., 2- imidazolyl.

Compound 1.189 or 1.190, wherein the heteroaryl of R ⁴ is pyrimidinyl, e.g., 2- pyrimidinyl, 2-pyrimidinyl, 4-pyrimidinyl, or 5 -pyrimidinyl.

Compound 1.189 or 1.190, wherein the heteroaryl of R ⁴ is pyridinyl, e.g., 2- pyridinyl, 3-pyridinyl, or 4-pyridinyl.

Compound 1.189 or 1.190, wherein the heteroaryl of R ⁴ is pyrazinyl, e.g., 2- pyrazinyl.

Compound 1.189 or 1.190, wherein the heteroaryl of R ⁴ is oxadiazolyl, e.g., 2- ( 1 ,3 ,4-oxadiazolyl) .

Compound 1.189 or 1.190, wherein the heteroaryl of R ⁴ is thiadiazolyl, e.g., 5- ( 1 ,2,4-thiadiazolyl) .

Compound 1.189 or 1.190, wherein the heteroaryl of R ⁴ is thiazolyl, e.g., 2- thiazolyl, or 4-thiazolyl.

Compound 1.189 or 1.190, wherein the heteroaryl of R ⁴ is thiophenyl, e.g., 2- thiophenyl.

Any of Compounds 1.191-1.199, wherein said heteroaryl of R ⁴ is substituted with 0 occurrences of R ⁵ .

Any of Compounds 1.191-1.199, wherein said heteroaryl of R ⁴ is substituted with

1 occurrence of R ⁵ .

Any of Compounds 1.191-1.199, wherein said heteroaryl of R ⁴ is substituted with

2 occurrences of R ⁵ .

Compound 1.141, wherein R ⁴ is heterocycloalkyl substituted with 0-5 occurrences of R ⁵ .

Compound 1.203, wherein R ⁴ is heterocycloalkyl substituted with 0 occurrences of R ⁵ , or with 1 occurrence of R ⁵ , or with 2 occurrences of R ⁵ , or with 3 occurrences of R ⁵ , or with 4 occurrences of R ⁵ , or with 5 occurrences of R ⁵ .

Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, dioxanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, azaspiro[2.3]hexanyl, diazaspiro[3.3]heptanyl, oxaazaspiro[3.3]heptanyl, oxaspiro[3.3]heptanyl, oxaazaspiro[3.4]octanyl, dioxaazaspiro[3.4]octanyl, oxaazaspiro[3.5]nonanyl, diazabicyclo[4.1.0]heptanyl, 3-(tetrahydrothiophene- 1 , l-dioxide), 2- (octahydropyrrolo[3,4-c]pyrrolyl), 7-(5,6,7,8- tetrahydro[l,2,4]triazolo[l,5]pyrazinyl), 5-(4, 5,6,7- tetrahydropyrazolo[l,5]pyrazinyl, 7-(5,6,7,8-tetrahydroimidazo[l,5]pyrazinyl, 7- (5,6,7,8-tetrahydroimidazo[l,2]pyrazinyl, 3-pyrrolindin-2-onyl, and 3- (oxazolidine-2-onyl) .

Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is azetidinyl, e.g., 2- azetidinyl or 3 -azetidinyl.

Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is oxetanyl, e.g., 2- oxetanyl or 3-oxetanyl.

Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is pyranyl, e.g., 4- pyranyl.

Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is pyrrolidinyl, e.g.,

1-pyrrolidinyl, 2-pyrrolidinyl, or 3-pyrrolidinyl.

Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is 3-pyrrolidin-2- onyl.

Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is piperidinyl, e.g., 3-piperidinyl or 4-piperidinyl.

Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is piperazinyl, e.g., piperazin-3-onyl.

Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is

tetrahydrofuranyl, e.g., 2-tetrahydrofuranyl or 3-tetrahydrofuranyl.

Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is dioxanyl, e.g., 5- (l,3-dioxanyl).

Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is morpholinyl, e.g.,

2-morpholinyl.

Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is

azaspiro[2.3]hexanyl, e.g., 5-(5-azaspiro[2.3]hexanyl).

Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is

oxaspiro[3.3]heptanyl, e.g., 6-(2-oxaspiro[3.3]heptanyl). Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is

diazaspiro[3.3]heptanyl, e.g., 6-(l,6-diazaspiro[3.3]heptanyl), or l-(l,6- diazaspiro[3.3]heptanyl), or 2-(2,6-diazaspiro[3.3]heptanyl).

Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is

oxaazaspiro[3.3]heptanyl, e.g., 6-(l-oxa-6-azaspiro[3.3]heptanyl), or l-(6-oxa-l- azaspiro[3.3]heptanyl), or 6-(2-oxa-6-azaspiro[3.3]heptanyl).

Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is

diazabicyclo[4.1.0]heptanyl, e.g., 2-(2,5-diazabicyclo[4.1.0]heptanyl).

Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is

oxaazaspiro [3.4] octanyl, e.g . , 2-(5-oxa-2-azaspiro [3.4] octanyl) .

Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is

dioxaazaspiro[3.4]octanyl, e.g., 2-(5,8-dioxa-2-azaspiro[3.4]octanyl).

Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is

oxaazaspiro[3.5]nonanyl, e.g., 7-(l-oxa-7-azaspiro[3.5]nonanyl).

Compound 1.203 or 1.204, wherein the heterocycloalkyl of R ⁴ is thiomorpholinyl, e.g., thiomorpholinyl- 1 -oxide or thiomorpholinyl- l,l-dioxide.

Any of Compounds 1.205-1.224, wherein said heterocycloalkyl of R ⁴ is substituted with 0 occurrences of R ⁵ .

Any of Compounds 1.205-1.224, wherein said heterocycloalkyl of R ⁴ is substituted with 1 occurrence of R ⁵ .

Any of Compounds 1.205-1.224, wherein said heterocycloalkyl of R ⁴ is substituted with 2 occurrences of R ⁵ .

Any of Compound 1, or 1.1 et seq., wherein each R ⁵ is independently selected from OH, halo, C0 ₂ H, C _M alkyl, Ci- ₄ alkoxy, C _M haloalkyl, -0-Ci- ₄ haloalkyl, - CM alkyl-O-CM alkyl, -S-CM alkyl, -S(0) ₂ -CM alkyl, -S(0)-CM alkyl, -N(R ^a ) ₂ , - CH ₂ N(R ^a ) ₂ , -N(R ^a )-S(0)-Ci- ₄ alkyl, -N0 ₂ , -CN, -CH ₂ CN, C3-9 cycloalkyl, -C _M alkyl-C ₃ -9 cycloalkyl, -O-CM alkyl-C ₃ -9 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -O-heteroaryl, and -O-aralkyl, wherein each alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of R ^w , optionally wherein any one or more of the R ^w are the same or different. Compound 1.228, wherein R ⁵ is halo, Ci- ₄ alkyl, C _M alkoxy, Ci- ₄ haloalkyl, 0-Ci- ₄ haloalkyl, -CN, C3-9 cycloalkyl, Ci- ₄ alkyl-C _3-9 cycloalkyl, -0-Ci- ₄ alkyl-C _3-9 cycloalkyl, -Ci- ₄ alkyl-0-Ci- ₄ haloalkyl, or heterocycloalkyl, and wherein each of said cycloalkyl, aryl, heteroaryl or heterocycloalkyl is substituted with 0-3 occurrences of R ^w .

Compound 1.228, wherein each R ⁵ is independently selected from halo, C _M alkyl, CM alkoxy, CM haloalkyl, -0-C _M haloalkyl, N(R ^a ) ₂ , -N(R ^a )-S(0)-Ci- ₄ alkyl, -CN, C ₃ -9 cycloalkyl, -CM alkyl-C ₃ -9 cycloalkyl, -0-Ci- ₄ alkyl-C ₃ -9 cycloalkyl, and heterocycloalkyl, wherein each alkyl, aryl, heteroaryl, cycloalkyl or

heterocycloalkyl is substituted with 0-3 occurrences of R ^w .

Compound 1.228, wherein each R ⁵ is independently selected from halo, OH, CM alkoxy, -0-Ci- ₄ haloalkyl, N(R ^a ) ₂ , -CH ₂ -N(R ^a ) ₂ , -CN, C ₃ -9 cycloalkyl, -CM alkyl- C _3- 9 cycloalkyl, heteroaryl, and heterocycloalkyl, wherein each alkyl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of R ^w .

Compound 1.228, wherein each R ⁵ is independently selected from OH, C0 ₂ H, C _M alkoxy, C _M haloalkyl, -0-Ci- ₄ haloalkyl, -S(0) ₂ -Ci- ₄ alkyl, -N(R ^a ) ₂ , C ₃ -9 cycloalkyl, heterocycloalkyl, heteroaryl, wherein each alkyl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of R ^w .

Compound 1.228, wherein R ⁵ is independently selected from OH, halo, -CN, C _M alkoxy, S-CM alkyl, -S(0) ₂ -CM alkyl, -S(0)-CM alkyl, C ₃ -9 cycloalkyl, heterocycloalkyl, and heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is substituted with 0-3 occurrences of R ^w .

Compound 1.228, wherein each R ⁵ is independently selected from halo, OH, CM alkoxy, -O-CM haloalkyl, N(R ^a ) ₂ , -S(0) ₂ -CM alkyl, -CN, and O-aralkyl, wherein each alkyl or aryl is substituted with 0-3 occurrences of R ^w .

Compound 1.228, wherein each R ⁵ is independently selected from OH, halo, C _M alkyl, C _M alkoxy, C _M haloalkyl, N(R ^a ) ₂ , and O-heterocycloalkyl, wherein each alkyl or heterocycloalkyl is substituted with 0-3 occurrences of R ^w .

Compound 1.228, wherein R ⁵ is independently selected from C _M alkyl, C _M haloalkyl, S-CM alkyl, -S(0) ₂ -CM alkyl, -S(0)-CM alkyl, C ₃ -9 cycloalkyl, and heteroaryl, wherein each alkyl, cycloalkyl or heteroaryl is substituted with 0-3 occurrences of R ^w .

Compound 1.228, wherein R ⁵ is independently selected from C _M alkyl, Ci- ₄ alkoxy, -CH ₂ CN, and -S(0) ₂ -Ci- ₄ alkyl, wherein each alkyl, cycloalkyl or heteroaryl is substituted with 0-3 occurrences of R ^w .

Compound 1.228, wherein R ⁵ is independently selected from OH, halo, Ci- ₄ alkyl, -CN, -CH ₂ CN, and heteroaryl, wherein each alkyl or heteroaryl is substituted with 0-3 occurrences of R ^w .

Compound 1.228, wherein R ⁵ is independently selected from Ci- ₄ alkyl, Ci- ₄ haloalkyl, and C3-9 cycloalkyl, wherein each alkyl or cycloalkyl is substituted with 0-3 occurrences of R ^w .

Compound 1.228, wherein R ⁵ is independently selected from Ci- ₄ haloalkyl, C3-9 cycloalkyl, aryl, heteroaryl and heterocycloalkyl, wherein each alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of

R ^w .

Compound 1.228, wherein R ⁵ is independently selected from C3-9 cycloalkyl, aryl, heteroaryl and heterocycloalkyl, wherein each alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of R ^w .

Compound 1.228, wherein each R ⁵ is independently selected from halo, Ci- ₄ alkoxy, and -0-Ci- ₄ haloalkyl, wherein each alkyl is substituted with 0-3 occurrences of R ^w .

Compound 1.228, wherein each R ⁵ is independently selected from OH, Ci- ₄ alkyl, and C3-9 cycloalkyl, wherein each alkyl is substituted with 0-3 occurrences of R ^w . Compound 1.228, wherein each R ⁵ is independently selected from Ci- ₄ haloalkyl and -0-Ci- ₄ alkoxy, wherein each alkyl is substituted with 0-3 occurrences of R ^w . Compound 1.228, wherein R ⁵ is independently selected from C3-9 cycloalkyl and heteroaryl, wherein each cycloalkyl or heteroaryl is substituted with 0-3 occurrences of R ^w .

Compound 1.228, wherein each R ⁵ is independently selected from OH and Ci- ₄ alkyl, wherein each alkyl is substituted with 0-3 occurrences of R ^w . Compound 1.228, wherein each R ⁵ is independently selected from C _M alkyl, C _3-9 cycloalkyl, and C1-4 alkyl-C _3-9 cycloalkyl, wherein each alkyl is substituted with 0- 3 occurrences of R ^w .

Compound 1.228, wherein each R ⁵ is independently selected from C1-4 alkyl and C1-4 alkyl-O-Ci-4 alkyl, wherein each alkyl is substituted with 0-3 occurrences of

R ^w .

Compound 1.228, wherein R ⁵ is independently OH.

Compound 1.228, wherein R ⁵ is independently halo, optionally selected from fluoro, chloro or bromo.

Compound 1.228, wherein R ⁵ is independently C0 ₂ H.

Compound 1.228, wherein R ⁵ is independently C1-4 alkyl substituted with 0, 1, 2 or 3 occurrences of R ^w , optionally wherein said C1-4 alkyl is selected from methyl, ethyl, and isopropyl.

Compound 1.228, wherein R ⁵ is independently C1-4 alkoxy substituted with 0, 1, 2 or 3 occurrences of R ^w , optionally wherein said C1-4 alkoxy is selected from methoxy, ethoxy, isopropoxy and i-butoxy.

Compound 1.228, wherein R ⁵ is independently C1-4 haloalkyl substituted with 0, 1, 2 or 3 occurrences of R ^w , optionally wherein said C1-4 haloalkyl is selected from trifluoromethyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2,- trifluoroethyl, 3-fluoropropyl, l,l,l-trifluoroisopropyl, and l,3-difluoroisopropyl. Compound 1.228, wherein R ⁵ is independently -O-C1-4 haloalkyl substituted with 0, 1, 2 or 3 occurrences of R ^w , optionally wherein said -O-C1-4 haloalkyl is selected from fluoromethoxy, difluoromethoxy, 2,2-difluoroethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

Compound 1.228, wherein R ⁵ is independently -C1-4 alkyl-O-Ci-4 alkyl substituted with 0, 1, 2 or 3 occurrences of R ^w , optionally wherein said -C1-4 alkyl-O-Ci-4 alkyl is CH2-O-CH3.

Compound 1.228, wherein R ⁵ is independently -C1-4 alkyl-O-Ci-4 haloalkyl substituted with 0, 1, 2 or 3 occurrences of R ^w , optionally wherein said -C1-4 alkyl - O-C1-4 haloalkyl is CH2-O-CF3. Compound 1.228, wherein R ⁵ is independently -S-Ci-4 alkyl substituted with 0, 1,

2 or 3 occurrences of R ^w , optionally wherein said -S-Ci-4 alkyl is -S-CH ₃ .

Compound 1.228, wherein R ⁵ is independently -S(0) ₂ -Ci- ₄ alkyl substituted with 0, 1, 2 or 3 occurrences of R ^w , optionally wherein said -S(0) ₂ -Ci- ₄ alkyl is -S(0) ₂ -

CH ₃ .

Compound 1.228, wherein R ⁵ is independently -S(0)-Ci- ₄ alkyl substituted with 0, 1, 2 or 3 occurrences of R ^w , optionally wherein said -S(0)-Ci- ₄ alkyl is -S(0)-CH ₃ . Compound 1.228, wherein R ⁵ is independently -N(R ^a ) ₂ .

Compound 1.261, wherein each R ^a is independently H, Ci-4alkyl, or C ₃ -9 cycloalkyl, optionally wherein said R ^a is methyl or cyclopropyl, and further optionally wherein each R ^a is the same or each R ^a is different.

Compound 1.228, wherein R ⁵ is independently -CH ₂ N(R ^a ) ₂ .

Compound 1.263, wherein each R ^a is independently H, Ci-4alkyl, or C ₃ -9 cycloalkyl, optionally wherein said R ^a is methyl or cyclopropyl, and further optionally wherein each R ^a is the same or each R ^a is different.

Compound 1.228, wherein R ⁵ is independently -N(R ^a )-S(0)-Ci- ₄ alkyl substituted with 0, 1, 2 or 3 occurrences of R ^w , optionally wherein said -N(R ^a )-S(0)-Ci- ₄ alkyl is -N (R ^a )-S (O)-t-butyl.

Compound 1.228, wherein R ⁵ is independently -N0 ₂ .

Compound 1.228, wherein R ⁵ is independently -CN.

Compound 1.228, wherein R ⁵ is independently -CH ₂ CN.

Compound 1.228, wherein R ⁵ is independently C ₃ -9 cycloalkyl substituted with 0,

1, 2 or 3 occurrences of R ^w , optionally wherein said C ₃ -9 cycloalkyl is selected from cyclopropyl, cyclobutyl, and cyclohexyl.

Compound 1.228, wherein R ⁵ is independently -Ci-4 alkyl-C ₃ -9 cycloalkyl substituted with 0, 1, 2 or 3 occurrences of R ^w , optionally wherein said -Ci-4 alkyl - C ₃ -9 cycloalkyl is methylcyclopropyl.

Compound 1.228, wherein R ⁵ is independently -O-Ci-4 alkyl-C ₃ -9 cycloalkyl substituted with 0, 1, 2 or 3 occurrences of R ^w , optionally wherein said -O-Ci-4 alkyl-C ₃ -9 cycloalkyl is O-methyl-cyclopropyl. Compound 1.228, wherein R ⁵ is independently heterocycloalkyl substituted with 0, 1, 2 or 3 occurrences of R ^w , optionally wherein said heterocycloalkyl is selected from azetidinyl (e.g., 2-azetidinyl or 3-azetidinyl), oxetanyl (e.g., 2-oxetanyl or 3- oxetanyl), tetrahydrofuranyl (e.g., 2-tetrahydrofuranyl), pyrrolidinyl, dioxanyl (e.g., l,4-dioxanyl), morpholinyl (e.g., 2-morpholinyl), piperidinyl, and

dihydrooxazolyl (e.g., 2-(4,5-dihydrooxazolyl).

Compound 1.228, wherein R ⁵ is independently aryl substituted with 0, 1, 2 or 3 occurrences of R ^w , optionally wherein said aryl is phenyl.

Compound 1.228, wherein R ⁵ is independently heteroaryl substituted with 0, 1, 2 or 3 occurrences of R ^w , optionally wherein said heteroaryl is selected from imidazolyl (e.g., 2-imidazolyl), oxazolyl (e.g., 2-oxazolyl, or 4-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl), thiazolyl (e.g., 2-thiazolyl or 4-thiazolyl), pyrazolyl (e.g., l-pyrazolyl, 2-pyrazolyl), triazolyl (e.g., l,2,3-triazolyl or l,2,4-triazolyl), thiophenyl (e.g., 2-thiophenyl), oxadiazolyl (e.g., 2-(l,3,4-oxadiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrazinyl (e.g., 2-pyrazinyl), and pyrimidinyl (e.g., 2-pyrimidyl, or 4-pyrimidyl).

Compound 1.228, wherein R ⁵ is independently -O-heteroaryl substituted with 0, 1, 2 or 3 occurrences of R ^w , optionally wherein said O-heteroaryl is O-pyridiyl (e.g., 0-3 -pyridyl).

Compound 1.228, wherein R ⁵ is independently -O-aralkyl substituted with 0, 1, 2 or 3 occurrences of R ^w , optionally wherein said -O-aralkyl is O-benzyl (benzoxy). Compound 1, or any of 1.1 et seq., wherein R ⁴ is substituted with 2 occurrences of R ⁵ , and both occurrences of R ⁵ are the same.

Compound 1, or any of 1.1 et seq., wherein R ⁴ is substituted with 2 occurrences of R ⁵ , and the two occurrences of R ⁵ are different.

Compound 1, or any of 1.1 et seq., wherein R ⁴ is substituted with 3 occurrences of R ⁵ , and all three occurrences of R ⁵ are the same.

Compound 1, or any of 1.1 et seq., wherein R ⁴ is substituted with 3 occurrences of R ⁵ , and all two of the three occurrences of R ⁵ are the same.

Compound 1, or any of 1.1 et seq., wherein R ⁴ is substituted with 3 occurrences of R ⁵ , and all three occurrences of R ⁵ are different from each other. Compound 1, or any of 1.1 et seq., wherein the alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl of any R ⁵ is independently substituted with 0 R ^w , or with 1 R ^w , or with 2 R ^w , or with 3 R ^w .

Compound 1.282, wherein each R ^w is independently halo, optionally selected from fluoro, chloro and bromo.

Compound 1.282, wherein each R ^w is independently -OH.

Compound 1.282, wherein each R ^w is independently C _M alkyl, optionally selected from methyl, ethyl, and isopropyl.

Compound 1.282, wherein each R ^w is independently Ci- ₄ alkoxy, optionally selected from methoxy and isopropoxy.

Compound 1.282, wherein each R ^w is independently Ci- ₄ haloalkyl, optionally selected from trifluoromethyl and 2,2-difluoroethyl.

Any of Compounds 1.282-1.287, wherein any one or more R ⁵ is substituted with 2 occurrences of R ^w , and the two occurrences of R ^w on the R ⁵ are the same.

Any of Compounds 1.282-1.287, wherein any one or more R ⁵ is substituted with 2 occurrences of R ^w , and the two occurrences of R ^w on the R ⁵ are different from each other.

Any of Compounds 1.282-1.287, wherein any one or more R ⁵ is substituted with 3 occurrences of R ^w , and the three occurrences of R ^w on the R ⁵ are the same.

Any of Compounds 1.282-1.287, wherein any one or more R ⁵ is substituted with 3 occurrences of R ^w , and the two of the three occurrences of R ^w on the R ⁵ are the same.

Any of Compounds 1.282-1.287, wherein any one or more R ⁵ is substituted with 3 occurrences of R ^w , and the all three occurrences of R ^w on the R ⁵ are different from each other.

Compound 1 or any of 1.1-1.292, wherein: X ² is CR ² and R ² is hydrogen, halo (e.g., fluoro) or Ci- ₄ alkyl (e.g., methyl); X ⁵ is CR ⁷ and R ⁷ is hydrogen; X ⁶ is CR ¹ and R ¹ is Ci- ₄ haloalkyl (e.g., trifluoromethyl); Y is -C(0)NR ^a R ^b , and R ^a is H, and R ^b is Ci- ₄ alkyl (e.g., methyl), or R ^a and R ^b are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl ring substituted with 0 occurrences of R ^x (e.g., R ^a and R ^b form l-azetidinyl); A ¹ is a bond, Ci- ₄ alkyene (e.g., CH ₂ ) or -0-; L is a 3-12 membered heterocycloalkyl substituted with 0, 1 or 2 occurrences of R ^x , and R ^x is halo (e.g., fluoro) or C1-4 alkyl (e.g., methyl); A ² is selected from -0-, -NR ^a -, -O-C(O)-, -C(0)-0-, CH ₂ -C(0)-NR ^a , -0-C(0)-NR ^a , and NR ^a -C(0)-0-, and R ^a is hydrogen; R ⁴ is C1-4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), C3-9 cycloalkyl (e.g., cyclopropyl or cyclohexyl),

heterocycloalkyl (e.g., azetidinyl), or heteroaryl (e.g., 2-pyridyl), each substituted with 0 or 1 occurrences of R ⁵ , and each R ⁵ is independently selected from halo (e.g., fluoro), C1-4 alkyl (e.g., methyl or isopropyl), C1-4 alkoxy (e.g., methoxy), Ci- 4haloalkyl (e.g., trifluoromethyl), -OCi-4haloalkyl (e.g., trifluoromethoxy), CN, C3-9 cycloalkyl (e.g., cyclopropyl), heteroaryl (e.g., 2-thiazolyl), or

heterocycloalkyl (e.g., l-pyrrolidinyl) and said heteroaryl or heterocycloalkyl is substituted with 0, 1, or 2 halo (e.g., fluoro) or C1-4 alkyl (e.g., isopropyl).

Compound 1.293, wherein L is selected from one of the following moieties, each substituted with 0, 1 or 2 occurrences of R ^x , and wherein R ^x is halo (e.g., fluoro) or C1-4 alkyl (e.g., methyl):

Compound 1.294, wherein L is the following moiety substituted with 0

occurrences

Compound 1.295, wherein X ² is CR ² and R ² is hydrogen; X ⁵ is CR ⁷ and R ⁷ is hydrogen; X ⁶ is CR ¹ and R ¹ is trifluoromethyl; Y is -C(0)NR ^a R ^b , and R ^a is H, and R ^b is methyl; A ¹ is a bond; A ² is selected from -O-C(O)-, -C(0)-0-, CH ₂ -C(0)- NR ^a , -0-C(0)-NR ^a , and NR ^a -C(0)-0-, and R ^a is hydrogen; R ⁴ is C _M alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), C3-9 cycloalkyl (e.g., cyclopropyl or cyclohexyl), or heterocycloalkyl (e.g., azetidinyl), each substituted with 0 or 1 occurrences of R ⁵ , and each R ⁵ is independently selected from halo (e.g., fluoro), C1-4 alkyl (e.g., methyl or isopropyl), C1-4 alkoxy (e.g., methoxy), Ci-4haloalkyl (e.g., trifluoromethyl), -OCi-4haloalkyl (e.g., trifluoromethoxy), and C3-9 cycloalkyl (e.g., cyclopropyl). 1.297 Compound 1.296, wherein A ² is selected from -0-C(0)-NR ^a , and NR ^a -C(0)-0-, and R ^a is hydrogen;

1.298 Compound 1.296 or 1.297, wherein R ⁴ is Ci alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), C3-9 cycloalkyl (e.g., cyclopropyl or cyclohexyl), each substituted with 0 or 1 occurrences of R ⁵ , and each R ⁵ is independently selected from halo (e.g., fluoro), C _M alkyl (e.g., methyl or isopropyl), C1-4 alkoxy (e.g., methoxy), Ci- ₄ haloalkyl (e.g., trifluoromethyl), -OCi- ₄ haloalkyl (e.g., trifluoromethoxy), and C3-9 cycloalkyl (e.g., cyclopropyl).

1.299 Compound 1.298, wherein R ⁴ is substituted with 0 occurrences of R ⁵ .

1.300 Compound 1 or any of 1.1-1.298, or any group of such compounds, comprising any one of, any two of, any three of, any four of, any five of, any six of, any seven of, any eight of, any nine of, or any ten of, the compounds of Example 1 to Example 870.

[0018] In further embodiments, the present application provides Compound 1 or any of Compounds 1.1 to 1.300, wherein the compound is selected from one or more of the following compounds represented in Table 1 below:

Table 1



[0019] In further embodiments, the present application provides Compound 1 or any of Compounds 1.1 to 1.300, wherein the compound is selected from one or more of the following compounds represented in Table 2 below:

Table 2

[0020] In further embodiments, the present application provides Compound 1 or any of Compounds 1.1 to 1.300, wherein the compound is selected from the following named compounds below:

A/-Methyl-5-(4-((5-methylpyridin-2-yl)methyl)piperazin-l-yl) -7-(trifluoromethyl)thieno[3,2- h]pyridine-3-carboxamide;

5-(4-Benzylpiperazin-l-yl)-/V-methyl-7-(trifluoromethyl)thie no[3,2-h]pyridine-3- carboxamide;

/V-Mcthy 1-5 -(4-((2-mcthylpyri midi n-4-yl)mcthyl)pipcrazin- 1 -yl)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

5-(4-((6-Ethylpyridin-2-yl)methyl)piperazin-l-yl)-/V-methyl- 7-(trifluoromethyl)thieno[3,2- h]pyridine-3-carboxamide;

5-(4-((6-(Methoxymethyl)pyridin-2-yl)methyl)piperazin-l-yl)- /V-methyl-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

/V-Methyl-5-(4-((4-methylpyridin-2-yl)methyl)piperazin- 1 -yl)-7-(trifluoromethyl)thieno[3 ,2- h]pyridine-3-carboxamide;

/V-Methyl-5-(4-((3-methylpyridin-2-yl)methyl)piperazin-l-yl) -7-(trifluoromethyl)thieno[3,2- h]pyridine-3-carboxamide;

5-(4-((6-Methoxypyridin-2-yl)methyl)piperazin-l-yl)-/V-methy l-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide; /V-Methyl-5-(4-((6-methylpyridin-2-yl)methyl)piperazin-l-yl) -7-(trifluoromethyl)thieno[3,2-

/?Jpyridinc-3-carhoxamidc;

Methyl 5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-l-yl)-7-(trifl uoromethyl)thieno[3,2- h]pyridine-3 -carboxylate ;

5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-l-yl)-/V-methy l-7-(trifluoromethyl)thieno[3,2- h]pyridine-3-carboxamide;

5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-l-yl)-A/,A/-di methyl-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

Methyl 5-(4-(2-(benzylamino)-2-oxoethyl)piperazin-l-yl)-7-(trifluor omethyl)thieno[3,2- h]pyridine-3-carboxylate;

Methyl 5-(4-(2-oxo-2-(phenylamino)ethyl)piperazin-l-yl)-7-(trifluor omethyl)thieno[3,2- h]pyridine-3-carboxylate;

Methyl 5-(4-(2-(cyclohexylamino)-2-oxoethyl)piperazin-l-yl)-7-(trif luoromethyl)thieno[3,2- h]pyridine-3-carboxylate;

Methyl 5-(4-(2-oxo-2-(piperidin-l-yl)ethyl)piperazin-l-yl)-7-(trifl uoromethyl)thieno[3,2- h]pyridine-3-carboxylate;

Methyl 5-(4-(2-oxo-2-(pyrrolidin-l-yl)ethyl)piperazin-l-yl)-7-(trif luoromethyl)thieno[3,2- h]pyridine-3-carboxylate;

Methyl 5-(4-(2-(methylamino)-2-oxoethyl)piperazin-l-yl)-7-(trifluor omethyl)thieno[3,2- h]pyridine-3-carboxylate;

Methyl 5-(4-(4-methylpentanoyl)piperazin-l-yl)-7-(trifluoromethyl)t hieno[3,2-h]pyridine-3- carboxylate;

Methyl 5-(4-(4-methylpentyl)piperazin-l-yl)-7-(trifluoromethyl)thie no[3,2-h]pyridine-3- carboxylate;

Isobutyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperazine-l- carboxylate;

V-Mcthy 1-5 -(4-(pyridi n-2-y 1 mcthy 1 jpipcrazi n- 1 -yl)-7-(tnfl uoromcthyl)thicno[ 3, 2-/?J pyridine- 3-carboxamide;

/V-Methyl-5-(4-(pyridin-3-ylmethyl)piperazin-l-yl)-7-(triflu oromethyl)thieno[3,2-h]pyridine-

3-carboxamide; /V-Mcthyl-5-(4-(pyridin-4-yl methyl jpipcrazin- 1 -yl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyridinc- 3-carboxamide;

5-(4-(2-(Ethylamino)-2-oxoethyl)piperazin-l-yl)-A/-methyl-7- (trifluoromethyl)thieno[3,2-

/?]pyridinc-3-carboxamidc;

5-(4-(2-(Cyclopropylamino)-2-oxoethyl)piperazin-l-yl)-/V-met hyl-7- (tririuoromcthyl jthicno[3,2-/?]pyridinc-3-carboxamidc;

5-(4-(2-(Isobutylamino)-2-oxoethyl)piperazin-l-yl)-/V-methyl -7-(trifluoromethyl)thieno[3,2-

/?Jpyridinc-3-carboxamidc;

(+/-)-5 -(4-( 1 -(Isopropylamino)- 1 -oxobutan-2-yl)piperazin- 1 -ylj-/V-mcthyl-7- (trifluoromethyl)thieno[3,2-Z?]pyridine-3-carboxamide;

5-(4-(l-(Isopropylamino)-2-methyl-l-oxopropan-2-yl)piperazin -l-yl)- V-methyl-7-

(trifluoromethyl)thieno[3,2-//]pyridine-3-carboxamide;

tert- Butyl 2-(4-(3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[ 3, 2-/?Jpyridin-5-yl jpipcrazin- l-yl)acetate;

(+/-)-/ e/ - B utyl 2-(4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-//]p yridin-5- yljpiperazin- l-yl)propanoate;

(+/-)-Isopropyl 2-(4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-//]p yridin-5- yljpiperazin- l-yl)propanoate;

(+/-j-5-(4-( 1 -(Isopropylaminoj- l -oxopropan-2-yl jpipcrazin- 1 -ylj-/V-mcthyl-7- (trifluoromcthyl jthicno[3,2-/?Jpyridinc-3-carboxamidc;

Isopropyl 2-(4-(3-(mcthylcarbamoylj-7-(trinuoromcthyljthicno[3,2-/?Jpy ridin-5-yl jpipcrazin- l-yl)acetate;

5-(4-(2-(/e/7-butylaminoj-2-oxocthyljpipcrazin- l -yl j-A ^/ -mcthyl-7-(tnfluoiOmcthyljthicno[3,2- /?Jpyridinc-3-carboxamidc;

(Sj-5-(4-( 1 -(Isopropylaminoj- l -oxopropan-2-yl jpipcrazin- l -yl -/V-mcthyl-7- (trifluoromcthyl jthicno[3,2-/?Jpyridinc-3-carboxamidc;

(/^j-5-(4-( l -(Isopropylamino j- 1 -oxopropan-2-yljpipcrazin- l -ylj-/V-mcthyl-7- (trifluoromcthyl jthicno[3,2-/?Jpyridinc-3-carboxamidc;

A/-Methyl-5-(4-((6-methylpyrazin-2-yl)methyl)piperazin-l-yl) -7-(trifluoromethyl)thieno[3,2-

/?Jpyridinc-3-carboxamidc; (+/-)-5-(4-(2-(Cyclopropylmethoxy)propyl)piperazin-l-yl)-/V- methyl-7-

(trifluoromethyl)thieno[3,2-/?]pyridine-3-carboxamide;

(+/-)-5-(4-(l-(Cyclopropylmethoxy)propan-2-yl)piperazin-l-yl )-/V-methyl-7-

(trinuoromcthyl)thicno[3,2-/?Jpyndinc-3-carboxamidc;

5-(4-(2-(Cyclopropylmethoxy)ethyl)piperazin-l-yl)-/V-methyl- 7-(trifluoromethyl)thieno[3,2-

/?]pyridinc-3-carboxamidc;

5-(4-(2-Cyclopropoxyethyl)piperazin-l-yl)-/V-methyl-7-(trifl uoromethyl)thieno[3,2-

/?Jpyridinc-3-carboxamidc;

5-(4-(2-Isopropoxycthyl)pipcrazin- l -ylj- V-mcthy l-7-(tnfluoiOmcthyl)thicno[ 3, 2-/?J pyridine- 3-carboxamide;

5-(4-(2-Isopropoxyacctyl)pipcrazin- 1 -y lj- - methyl -7-(trinuoromcthyl)thicno[ 3, 2-/?Jpyridinc- 3-carboxamide;

5-(4-(2-(Isopropyl(methyl)amino)-2-oxoethyl)piperazin-l-yl)- /V-methyl-7-

(tnfluoiOmcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-( 1 -isoprop yl-2-oxopyrrolidin-3 -yl)piperazin- 1 -yl)-/V-methyl-7- (trifluoiOmcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-l-yl)-/V,6- dimethyl-7- (tnfluoiOmcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-(2-( Isopropyl ami no)-2-oxocthyl)pipcrazin- 1 -yl)-A ^/ ,7-di methyl thicnoj 3, 2-/?Jpyridinc-3- carboxamide;

5-(4-(2-(IsopiOpylamino)-2-oxocthyl)-3,3-dimcthylpipcrazin- l -ylj- V- methyl -7- (tnfluoiOmcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

(+/-)-5-(3-Isopropyl-4-(2-(isopropylamino)-2-oxoethyl)pipera zin-l-yl)-/V-methyl-7-

(tnfluoiOmcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

(+/-)-5-(3-Ethyl-4-(2-(isopropylamino)-2-oxoethyl)piperazin- l-yl)-/V-methyl-7-

(tnfluoiOmcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

(+/-)-5-(4-(2-( Isopropylamino)-2-oxocthyl)-2-mcthylpipcrazin- 1 -ylj- V- methy 1-7- (tnfluoiOmcthyl)thicno[ 3, 2-/?Jpyridinc-3 -carboxamide;

5-(8-(2-(Isopropylamino)-2-oxoethyl)-3,8-diazabicyclo[3.2.l] octan-3-yl)-/V-methyl-7- (tnriuoromcthyl)thicno[ 3, 2-/?] pyridinc-3 -carboxamide; 5-(4-(2-(isopropylamino)-2-oxoethyl)-4,7-diazaspiro[2.5]octa n-7-yl)-/V-methyl-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

(+/-)-5-(4-(2-(Isopropylamino)-2-oxoethyl)-3-methylpiperazin -l-yl)-/V-methyl-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

5-(4-(2-(Isopropylamino)-2-oxoethyl)-l,4-diazepan-l-yl)-/V-m ethyl-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

A/- Isopropyl -2-(4-(3-isopropyl-7-(trinuoromcthyl)thicno[ 3, 2-/?Jpyridin-5-yl)pipcrazin-l - yl)acetamide;

2-(4-(3 -(Hydroxy mcthy l)-7-(tnfluoiOmcthyl)thicno[ 3, 2-/?Jpyridin-5-yl)pipcrazin- 1 -y\)-N- isopropylacetamide;

5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-l-yl)-7-(trifl uoromethyl)thieno[3,2- /?Jpyridinc-3-carboxylic acid;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyridi n-5-yl)pipcridin-4-yl azetidine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidin-4-yl (S)- pentan-2-ylcarbamate;

l-(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndi n-5-yl)pipcndin-4-yl (S)-( 3- methylbutan-2-yl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidin-4-yl (SJ-sec- butylcarbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidin-4-yl cyclobutylcarbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidin-4-yl (2- (trifluoromethoxy)ethyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidin-4-yl 5- azaspiro[2.3]hexane-5-carboxylate;

l-(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndi n-5-yl)pipcndin-4-yl 1,1- difluoro-5 - azaspiro [2.3 ] hexane- 5 -c arboxylate ;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidin-4-yl 3- (methoxymethyl) azetidine- 1 -carboxylate; l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl 3- (dimethylamino)-3-methylazetidine-l-carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcndin-4-yl 3- ((dimethylamino)methyl)azetidine- 1 -carboxylate;

l -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcndin-4-yl 3- (oxetan-3 -yl)azetidine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl 3- hydroxy-3-(trifluoromethyl)azetidine-l-carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl (17?, 65/- 5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl ( 15,6/?/- 5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl 3- cyclopropylazetidine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl isopropylcarbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl

(cyclobutylmethyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (5/-but- 3-yn-2-ylcarbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (35,55/- 3,5-dimethylmorpholine-4-carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (5/-2- methylpiperidine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (5/-2- methylpyrrolidine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl (5/-(l- cy anoethyl)c arb amate ;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl 5,6,7,8- tetrahydro-[ 1 ,2,4]triazolo[ 1 ,5-a]pyrazine-7-carboxylate; l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidin-4-yl 6-oxa-l- azaspiro[3.3]heptane- l-carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidin-4-yl isopropyl(methyl)carbamate;

( 1 a,5a,6a)-3-(3-(Mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3, 2-/?Jpyridin-5-yl)-3- azabicyclo[3.1.0]hexan-6-yl (cyclopropylmethyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidin-4-yl 3- (difluoromethoxy)azetidine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidin-4-yl 3- (trifluoromethoxy)azetidine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidin-4-yl 3- ((trifluoromethoxy)methyl)azetidine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidin-4-yl (S)-(l- (trifluoromethoxy)propan-2-yl)carbamate;

3,3-Difluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thien o[3,2-h]pyridin-5-yl)piperidin- 4-yl isopropylcarbamate;

3,3-Difluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thien o[3,2-h]pyridin-5-yl)piperidin- 4-yl 4-cyclopropylpiperazine- l-carboxylate;

3.3-Difluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thien o[3,2-h]pyridin-5-yl)piperidin- 4-yl (2S)-2,4-dimethylpiperazine- l-carboxylate;

3.3-Dimethyl- l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5- yl)piperidin-4-yl 4-methylpiperazine- l-carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidin-4-yl 6,7- dihydropyrazolo[ 1 ,5-a]pyrazine-5(47 )-carboxylate;

l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidin-4-yl 5,6- dihydroimidazo [1,5 -a\ pyrazine-7 (87 ) -carboxylate ;

l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidin-4-yl 5,6- dihydroimidazo [ 1 , 5 -a] pyrazine-7 (8/7) -carboxylate ;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidin-4-yl

(3a7?,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrole-2(l77)-car boxylate; l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl 3- (dimethylamino)azetidine- 1 -carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl (S)-(l- (thiazol-2-yl)ethyl)carbamate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcndin-4-yl (S)-2- ethyl-4-methylpiperazine- 1 -carboxylate;

(+/-)-lrans- 1 -(3-(Mcthylcarbamoyl)-7-(trinuoiOmcthyl)thicno[3,2- ?Jpyridin-5-yl)pipcridin-4- yl 4-methoxy- l-methylpyrrolidin-3-yl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (R)- 2,4- dimethylpiperazine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (S)- 2,4- dimethylpiperazine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-Z?]pyri din-5-yl)piperidin-4-yl (2- (pyrrolidin- 1 -yl)ethyl)carbamate;

(+/-)- l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (2- (3-fluoropyrrolidin-l-yl)ethyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (2-(3,3- difluoropyrrolidin- 1 -yl)ethyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (/^/-( l - cyclopropylethyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (SJ-(l- cyclopropylethyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl pyrrolidin- 1 - ylcarb amate ;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-Z?]pyri din-5-yl)piperidin-4-yl

(cyclopropylmethyl)(methyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl 4- (cyclopropylmethyl)piperazine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (2- isopropoxyethyl)carbamate; l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl 4- methylpiperazine- 1 -carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcndin-4-yl ((4- methylmorpholin-2-yl)methyl)carbamate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl ( ?J-3,4- dimethylpiperazine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (SJ-3,4- dimethylpiperazine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (R)- 2- (hydroxymethyl)-4-methylpiperazine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl

((2S,3 ?J-3-hydroxybutan-2-yl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (S)-3- methylmorpholine-4-carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-Z?]pyri din-5-yl)piperidin-4-yl cis- 3- hydroxycyclobutyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl trans- 3- hydroxycyclobutyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (SJ-(l- cyanopropan-2-yl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (5/-( 1 - hydroxypropan-2-yl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl 3- hydroxyazetidine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (SJ-(l- methoxypropan-2-yl)carbamate;

(+/-)- l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl /raH.s-4-hydroxy- 1 -mcthylpym lidin-3-yl)carbamatc;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (2- hydroxy-2-methylpropyl)carbamate; l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (S)-2- methylpiperazine- 1 -carboxylate;

4-((Dimethylamino)methyl)-l-(3-(methylcarbamoyl)-7-(trifluor omethyl)thieno[3,2- /?]pyndin-5-yl)pipendin-4-yl (SJ-2-methylpyrrolidine-l -carboxylate;

4-((Dimethylamino)methyl)-l-(3-(methylcarbamoyl)-7-(trifl uoromethyl)thieno[3,2- /?Jpyridin-5-yl)pipcridin-4-yl isopropylcarbamate;

4-(Mcthoxy methyl)- 1 -(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2-/?Jpyrid in-5- yl)piperidin-4-yl isopropylcarbamate;

l-(3-(Dimethylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]py ridin-5-yl)piperidin-4-yl (S)-(l- cyanopropan-2-yl)carbamate;

1 -(3-(Azctidinc-l -carbonyl )-7-(trifl uoiOmcthyl)thicno[ 3,2-/?] pyridin-5-yl)pipcridin-4-yl (S)- ( 1 -cyanopropan-2-yl)carbamate;

(+/-)-iran5-3-(Dimethylamino)-l-(3-(methylcarbamoyl)-7-(trif luoromethyl)thieno[3,2- /?Jpyridin-5-yl)pipcridin-4-yl (cyclopropylmethyl)carbamate;

(+/-)- .s-3-Mcthyl-l -(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2-/?Jpyrid in-5- yl)piperidin-4-yl 4-methylpiperazine- 1 -carboxylate;

l-(3-(Methoxycarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5-yl)piperidin-4-yl (cycloprop ylmethyl)c arb amate ;

(+/-)-lrans- 1 -(3-(Mcthylcarbamoyl)-7-(trinuoiOmcthyl)thicno[3,2-/?Jpyridi n-5-yl)pipcridin-4- yl 4-fluoro-l-methylpyrrolidin-3-yl)carbamate;

(+/-)-cis- 1 -(3-(Mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2-/?Jpyrid in-5-yl)pipcridin-4-yl

4-fluoro-l-methylpyrrolidin-3-yl)carbamate;

5-(3-Isopropyl-2-oxo-l-oxa-3,8-diazaspiro[4.5]decan-8-yl)-/V -methyl-7- (trifluoromethyl)thieno[3,2-/?]pyridine-3-carboxamide;

5-(2-Isopropyl-2,8-diazaspiro[4.5]decan-8-yl)-/V-methyl-7-(t rifluoromethyl)thieno[3,2-

/?]pyridinc-3-carboxamidc;

1 -(3-(Mcthylcarbamoyl)thicno[3,2-/?Jpyndin-5-yl)pipcridin-4-y l (S)-( l - (trifluoromethoxy)propan-2-yl)carbamate;

1 -(7-Mcthyl-3-(mcthylcarbamoyl)thicno[3,2-/?]pyndin-5-yl)pipc ridin-4-yl

isopropylcarbamate; 1 -(7-Mcthyl-3-(mcthylcarbamoyl)thicno[3,2- ?Jpyridin-5-yl)pipcridin-4-yl (5/-( 1 - (trifluoromethoxy)propan-2-yl)carbamate;

/V-Methyl-5-(4-((6-methylpyridin-2-yl)oxy)piperidin-l-yl)-7- (trifluoromethyl)thieno[3,2-

/?]pyndinc-3-carboxamidc;

5-(4-((6-Ethylpyridin-2-yl)oxy)piperidin-l-yl)-/V-methyl-7-( trifluoromethyl)thieno[3,2-

/?]pyndinc-3-carboxamidc;

A/-Methyl-5-(4-((2-methylpyrimidin-4-yl)oxy)piperidin-l-yl)- 7-(trifluoromethyl)thieno[3,2-

/?Jpyridinc-3-carboxamidc;

(+/-)-A ^/ -Mcthyl-5-( .S-3-mcthyl-4-((2-mcthylpyn midin-4-yl)oxy)piperidin- 1 -yl)-7- (trifluoiOmcthyl)thicno[3,2- ?Jpyridinc-3-carboxamidc;

(+/-)-/V-Mcthyl-5-(/raH.S-3-mcthyl-4-((2-mcthylpyrimidin-4-y l)oxy)pipcridin- l-yl)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

5-(4-((3-Cyclopropyl-l,2,4-thiadiazol-5-yl)oxy)piperidin- l-yl)-/V-methyl-7- (trinuoromcthyl)thicno[3,2-/?Jpyndinc-3-carboxamidc;

l-(6-Methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno [3,2-h]pyridin-5-yl)piperidin-4-yl

(SJ-(l-cyclopropylethyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidin-4-yl (5/-( 1 - cy anopropan-2- yl) (methyl)c arb amate ;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcndin-4-yl ((l-(2,2- difluoroethyl)azetidin-3-yl)methyl)carbamate;

Methyl 5-(4-(2-(isopropylamino)-2-oxoethyl)piperidin-l-yl)-7-(trifl uoromethyl)thieno[3,2- h]pyridine-3 -carboxylate ;

5-(4-(2-(Isopropylamino)-2-oxoethyl)piperidin-l-yl)-/V-methy l-7-(trifluoromethyl)thieno[3,2- h]pyridine-3-carboxamide;

5-(4-(2-((l-Methoxypropan-2-yl)amino)-2-oxoethyl)piperidin-l -yl)-/V-methyl-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

5-(4-(2-((l,3-Dimethoxypropan-2-yl)amino)-2-oxoethyl)piperid in-l-yl)-/V-methyl-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

(S)- 1 -Mcthoxypropan-2-yl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din- 5-yl)piperidin-4-yl) carbonate;

Isopropyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din- 5-yl)piperidin-4-yl) carbonate;

(R )-\ -Cycloprop ylethyl 4-((3-(mcthylcarbamoyl)-7-(trifluoromcthyl)thicno[3,2-/?Jpyn din-5- yl)oxy)piperidine- l-carboxylate;

(5/-1 -Cyclopropylcthyl 4-((3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyri din-5- yl)oxy)piperidine- l-carboxylate;

Isopropyl 4-((3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyri din-5- yl)oxy)piperidine- l-carboxylate;

tert- Butyl 3,3-difluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thie no[3,2-Z?]pyridin-5- yl)oxy)piperidine- l-carboxylate;

/V-Methyl-5-((l-(6-methylpyridin-2-yl)piperidin-4-yl)oxy)-7- (trifluoromethyl)thieno[3,2-

/?Jpyridinc-3-carboxamidc;

2-Cyanoethyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5- yl)oxy)piperidine- l-carboxylate;

2-Isopropoxyethyl 4-((3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2-/?Jpyr idin-5- yl)oxy)piperidine- l-carboxylate;

2-(/er/-Butoxy)ethyl 4-((3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyri din-5- yl)oxy)piperidine- l-carboxylate;

(3-Fluoroazetidin-3-yl)methyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- Z?]pyridin-5-yl)oxy)piperidine- l-carboxylate;

l-(Prop-2-yn-l-yl)azetidin-3-yl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?]pyridin-5-yl)oxy)piperidine- l-carboxylate;

1-(Cyanomethyl)azetidin-3-yl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?]pyridin-5-yl)oxy)piperidine- l-carboxylate;

2-(Trifluoromethoxy)ethyl 4-((3-(mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyri din- 5-yl)oxy)piperidine- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl 4-((6-chloro-3-(mcthylcarbamoyl)thicno[3,2-/?Jpyndin-5- yl)oxy)piperidine- l-carboxylate;

2-(Trifluoromethoxy)ethyl 4-((6-bromo-3-(mcthylcarbamoyl)thicno[3,2-/?Jpyndin-5- yl)oxy)piperidine- l-carboxylate;

2-(Trifluoromethoxy)ethyl 4-((6-cyclopropyl-3-(methylcarbamoyl)thieno[3,2-/?]pyridin-5 - yl)oxy)piperidine- l-carboxylate; (SJ-l-(Trifluoromethoxy)propan-2-yl (27?,47?)-2-methyl-4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)piperidine-l- carboxylate;

(S)-l-(Trifluoromethoxy)propan-2-yl (2 ?,4 ?J-2-methyl-4-((6-methyl-3-(methylcarbamoyl)- 7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyridin-5-yl)oxy)pipcndinc- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl (2 ?,4 ?J-2-methyl-4-((6-methyl-3-(methylcarbamoyl)-7- (trinuoromcthyl)thicno[3,2-/?]pyridin-5-yl)oxy)pipcridinc- 1 -carboxylate;

(SJ-l-(Trifluoromethoxy)propan-2-yl 4-((6-methyl-3-(methylcarbamoyl)-7- (tnfluoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl (2/?,4S)-2-methyl-4-((6-methyl-3-(methylcarbamoyl)-7- (tnfluoromcthyl)thicno[3,2-/?Jpyridin-5-yl)oxy)pipcndinc- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl (3S,4/?)-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7- (tnfluoromcthyl)thicno[3,2-/?Jpyridin-5-yl)oxy)pipcndinc- 1 -carboxylate;

(S)-l-(Trifluoromethoxy)propan-2-yl (3S,4/?)-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7- (tnfluoromcthyl)thicno[3,2-/?Jpyridin-5-yl)oxy)pipcndinc- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl (3/?,4S)-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7- (tnfluoromcthyl)thicno[3,2-/?Jpyridin-5-yl)oxy)pipcndinc- 1 -carboxylate;

(S)-l-(Trifluoromethoxy)propan-2-yl (3/?,4S)-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7- (tnfluoromcthyl)thicno[3,2-/?Jpyridin-5-yl)oxy)pipcndinc- 1 -carboxylate;

(S)-l-(Trifluoromethoxy)propan-2-yl (2 ?,4SJ-2-methyl-4-((6-methyl-3-(methylcarbamoyl)-7- (tnfluoromcthyl)thicno[3,2-/?Jpyridin-5-yl)oxy)pipcndinc- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)isothiazolo[4,5-h] pyridin-5-yl)piperidin-4-yl (cycloprop ylmethyl)c arb amate ;

l-(7-(Methylcarbamoyl)-4-(trifluoromethyl)thieno[3,2- _< i]pyrimidin-2-yl)piperidin-4-yl (S)- ( 1 -methoxypropan-2-yl)carbamate;

l-(7-(Methylcarbamoyl)-4-(trifluoromethyl)thieno[3,2- _< i]pyrimidin-2-yl)piperidin-4-yl (S)-( 1 -cyclopropylethyl)carbamate;

l-(7-(Methylcarbamoyl)-4-(trifluoromethyl)thieno[3,2- _< i]pyrimidin-2-yl)piperidin-4-yl (SJ-2,4-dimethylpiperazine-l -carboxylate;

l-(3-Propionyl-7-(trifluoromethyl)thieno[3,2-h]pyridin-5-yl) piperidin-4-yl 4- methylpiperazine- 1 -carboxylate dihydrochloride; 5-(3-((5-Fluoropyridin-3-yl)oxy)azetidin-l-yl)-/V-methyl-7-( trifluoromethyl)thieno[3,2-

/?]pyndinc-3-carboxamidc;

A/-Methyl-5-(3-((3-methylpyridin-2-yl)oxy)azetidin-l-yl)-7-( trifluoromethyl)thieno[3,2-

/?]pyndinc-3-carboxamidc;

5-(3-((3-Fluoropyridin-2-yl)oxy)azetidin-l-yl)-/V-methyl-7-( trifluoromethyl)thieno

[3, 2b]pyridine-3 -carboxamide;

A/-Methyl-5-(3-((2-methylpyridin-3-yl)oxy)azetidin-l-yl)-7-( trifluoromethyl)thieno[3,2-

/?Jpyridinc-3-carboxamidc;

Isopentyl 3-(3-(mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndi n-5-yl)azctidinc- l - carboxylate;

Cyclopropylmethyl 3-(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- ?Jpyridin-5 yl)azetidine- 1 -carboxylate;

Isopropyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5- yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

l-Fluoropropan-2-yl 6-((3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyri din-5- yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

l-Methoxy-2-methylpropan-2-yl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

2,2-Difluoroethyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5- yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

Oxetan-3-ylmethyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5- yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

Cyclopropyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-Z?]pyr idin-5-yl)oxy)-2- azaspiro[3.3]heptane-2-carboxylate;

Oxetan-3-yl 6-((3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyri din-5-yl)oxy)-2- azaspiro[3.3]heptane-2-carboxylate;

2-(Trifluoromethoxy)ethyl 6-((3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- ?Jpyridin- 5-yl)oxy)-2-azaspiro [3.3 ]heptane-2-carboxylate;

(K)-l -Cycloprop ylethyl 6-((3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- ?Jpyridin-5- yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate; (5/-1 -Cyclopropylcthyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5- yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

5-((2-(3-Fluoro-2,2-dimethylpropanoyl)-2-azaspiro[3.3]heptan -6-yl)oxy)-/V-methyl-7-

(trifluoromethyl)thieno[3,2-//]pyridine-3-carboxamide;

5-((2-(2,2-Dimethyl-3-(trifluoromethoxy)propanoyl)-2-azaspir o[3.3]heptan-6-yl)oxy)-/V- mcthyl-7-(trifluoiOmcthyl)thicno[ 3, 2- /J pyridinc-3 -carboxamide;

5-((2-Isobutyryl-2-azaspiro[3.3]heptan-6-yl)oxy)-/V-methyl-7 -(trifluoromethyl)thieno[3,2-

/?Jpyridine-3-carboxamide;

5-((2-(5-Fluoropyridin-3-yl)-2-azaspiro[3.3]heptan-6-yl)oxy) -/V-methyl-7-

(trifluoromethyl)thieno[3,2-//]pyridine-3-carboxamide;

5-((2-(6-Fluoropyridin-2-yl)-2-azaspiro[3.3]heptan-6-yl)oxy) -/V-methyl-

7(trifluoiOmcthyl)thicno[3,2- ?Jpyridinc-3-carboxamidc;

/V-Methyl-5-((2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan -6-yl)oxy)-7-

(trifluoiOmcthyl)thicno[3,2- ?Jpyridinc-3-carboxamidc;

2-(Trifluoromethoxy)ethyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin- 5-yl)oxy)- 1 -azaspiro [3.3 ]heptane- 1 -carboxylate;

/c/7- Butyl 2-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-//]pyr idin-5-yl)oxy)-7- azaspiro [3.5] nonane-7 -carboxylate;

2-(Trifluoromethoxy)ethyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-//]pyr idin- 5-yl)oxy)-3-azabicyclo[3.l.l]heptane-3-carboxylate;

2-(Trifluoromethoxy)ethyl 3-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2- b ] pyridin-5 - yl)oxy ) azetidine- 1 -carboxylate ;

2-(Trifluoromethoxy)ethyl 6-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2- //]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

(S)- 1 -Cyclopropylcthyl 6-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2- //]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

Cyclopropylmethyl (( 1.s,3.s)-3-((6-mcthyl-3-(mcthylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-&]pyridin-5-yl)oxy)cyclobuty l)carbamate;

Isopropyl (( 1.s,3.s)-3-((6-mcthyl-3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl )thicno[3,2- /?]pyndin-5-yl)oxy)cyclobutyl)carbamatc; (5/-1 -Cyclopropylcthyl ((ls,3 ?)-3-((6-methyl-3-(methylcarbamoyl)-7

(trifluoiOmcthyl)thicno[3,2- ?Jpyridin-5-yl)oxy)cyclobutyl)carbamatc;

(K)-l -Cycloprop ylethyl (( l.s,35 ₎ -3-((6-mcthyl-3-(mcthylcarbamoyl)-7

(trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)cyclobutyl )carbamate;

Cyclopropylmethyl ((lr,3r)-3-((6-methyl-3-(methylcarbamoyl)-7(trifluoromethyl) thieno[3,2- /?]pyridin-5-yl)oxy)cyclobutyl)carbamatc;

2-(Trifluoromethoxy)ethyl (2 ?,4 ?)-4-((6-chloro-3-(methylcarbamoyl)-7- (tnfluoromcthyl)thicno[3,2-/?Jpyridin-5-yl)oxy)-2-mcthylpipc ndinc-l -carboxylatc;

2-(Trifluoromethoxy)ethyl (2S,4SJ-4-((6-chloro-3-(methylcarbamoyl)-7- (tnfluoromcthyl)thicno[3,2-/?Jpyridin-5-yl)oxy)-2-mcthylpipc ndinc-l -carboxylatc;

2-(Trifluoromethoxy)ethyl 4-((6-chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2- /?Jpyridin-5-yl)oxy)pipcridinc-l -carboxylatc;

/c/7- Butyl (2 ?,4 ?J-4-((6-fluoro-3-(methylcarbamoyl)-7-(trifluoromethyl)thien o[3,2- /?Jpyridin-5-yl)oxy)-2-mcthylpipcridinc- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl 6-((6-chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2- h]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

(SJ-l -Cycloprop ylethyl 6-((6-chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2- h]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

2-(Trifluoromethoxy)ethyl 6-((2-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2- h]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

5-( /.s-3-(3-(Cyclopropyl methyl )urcido)cyclobutoxy)-A ^/ ,2-dimcthyl-7

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

(S)- 1 -cyclopropylethyl ((ls,3 ?)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?]pyridin-5-yl)oxy)cyclobutyl)carbamatc;

( ?J-l -cyclopropylethyl ((ls,3S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2- h]pyridin-5-yl)oxy)cyclobutyl)carbamate;

Oxetan-3-yl (c/5-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h ]pyridin-5- yl)oxy)cyclobutyl)carbamate;

(S)- 1 -Methoxypropan-2-yl (c/5-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- h]pyridin-5-yl)oxy)cyclobutyl)carbamate; (R )- 1 -Methoxypropan-2-yl (cz5-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?]pyndin-5-yl)oxy)cyclobutyl)carbamatc;

2-(Trifluoromethoxy)ethyl (czs-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?Jpyridin-5-yl)oxy)cyclobutyl)carbamatc;

2,2-Difluoroethyl (cz5-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/ z]pyridin-5- yl)oxy)cyclobutyl)carbamate;

2-(4-Chloro- l /7-pyrazol- 1 -yljcthyl (cz5-3-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-/?]pyridin-5-yl)oxy)cyclobutyl)c arbamate;

Thiazol-2-ylmethyl (cz5-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/ z]pyridin-5- yl)oxy)cyclobutyl)carbamate;

Cyclopropylmethyl (cz5-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/ z]pyridin-5- yl)oxy)cyclobutyl)carbamate;

Isopropyl ( /.s-3-((3-(mcthylcarbamoyl)-7-(tnfluoromcthyl)thicno[3,2-/?J pyndin-5- yl)oxy)cyclobutyl)carbamate;

(+/-)-/ra/7.s-4-Fluoro- 1 -methylpym lidin-3-yl (c / .v - 3 - ((3 - (m c t h y 1 c a r b a m o y 1 ) - 7 - (t r i

fluoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)cyclobutyl)car bamatc;

2-Chloroethyl (cz4 ^, -3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2 -/?]pyridin

-5-yl)oxy)cyclobutyl)carbamate;

cz5-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2 -/z]pyridin-5-yl)oxy)cyclobutyl 3 , 3 -difluoroazetidine- 1 -c arboxylate ;

cz5-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2 -/z]pyridin-5-yl)oxy)cyclobutyl (2- (trifluoromethoxy)ethyl)carbamate;

cz5-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2 -/z]pyridin-5-yl)oxy)cyclobutyl 1- oxa-7-azaspiro[3.5]nonane-7-carboxylate;

;cz5-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/ z]pyridin-5-yl)oxy)cyclobutyl (5 ₎ -2,4-dimcthylpipcrazinc- l -carboxylatc;

cz5-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2 -/z]pyridin-5-yl)oxy)cyclobutyl ((5 )- 1 -cyclopropylethyl)carbamate;

cz5-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2 -/z]pyridin-5-yl)oxy)cyclobutyl

5,6-dihydro-[l,2,4]triazolo[l,5-a]pyrazine-7(87/)-carboxy late; .s-3-((3-(Mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jp yridin-5-yl)oxy)cyclohutyl 3- chloroazetidine- 1 -carboxylate;

.s-3-((3-(Mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jp yridin-5-yl)oxy)cyclobutyl (S)- 3-methylmorpholine-4-carboxylate;

.s-3-((3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jp yndin-5-yl)oxy)cyclobutyl (cycloprop ylmethyl)c arb amate ;

d- Mcthy l-5-( .s-3 -(pyridi n-2-y loxy jcyclobutoxy )-7-(tnfluoiOmcthyl)thicno[ 3, 2-/?J pyridine- 3-carboxamide;

2-(Trifluoromethoxy)ethyl 3-methyl-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2- b ] pyridin-5 - yl)oxy ) azetidine- 1 -carboxylate ;

3-(Trifluoromethoxy)propyl 3-methyl-3-((3-(methylcarbamoyl)-7- (trinuoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)azctidinc- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl 3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin- 5-yl)oxy)azetidine- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl 2-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?Jpyridin-5-yl)oxy) methyl jazctidinc- 1 -carboxylate;

(l-(Trifluoromethyl)cyclopropyl)methyl 4-((3-(methylcarbamoyl)-7- (trinuoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxylate;

Cyclopropylmethyl (/raH.s-3-((3-(mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2 -/?Jpyridin- 5-yl)oxy)cyclobutyl)carbamate;

/raH.s-3-((3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2- /?Jpyndin-5-yl)oxy)cyclobutyl (cycloprop ylmethyl)c arb amate ;

3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5-yl)oxy)cyclobutyl (cycloprop ylmethyl)c arb amate ;

3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-Z?]pyridin -5-yl 4-(3,3,3- trifluoropropoxy)piperidine- 1 -carboxylate;

1 -t/c/7- Butyl) 4-(3-(mcthylcarbamoyl)-7-(tnfluoromcthyl)thicno[3,2-/?Jpyrid in-5-yl) piperazine- 1 ,4-dicarboxylate;

ie/ -Butyl (2 ?,4 ?J-4-((6-chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thien o[3,2- /?Jpyridin-5-yl)oxy)-2-mcthylpipcridinc- 1 -carboxylate; tert- Butyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl)oxy)-2- azaspiro[3.3]heptane-2-carboxylate;

tert- Butyl 6-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2-h]pyridin -5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

tert- Butyl 6-((2-mcthyl-3-(mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3, 2-/?Jpyndin-5- yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

tert- Butyl 6-((6-ch loro-3 -(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[ 3, 2-/?Jpyridin-5- yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

tert- Butyl 3-mcthyl-3-((3-(mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3, 2-/?Jpyndin-5- yl)oxy)azetidine- l-carboxylate;

tert- Butyl 4-((6-ch loro-3 -(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[ 3, 2-/?Jpyridin-5- yl)oxy)piperidine- l-carboxylate;

2-(Trifluoromethoxy)ethyl 4-((5-chloro-3-(methylcarbamoyl)-7 (trifluoromethyl)thieno[3,2- h]pyridin-6-yl)oxy)piperidine- l-carboxylate;

Methyl 6-fluoro-5-((l-((2-(trifluoromethoxy)ethoxy)carbonyl)piperid in-4-yl)oxy)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate;

2-(Trifluoromethoxy)ethyl 4-((6-fluoro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2- h]pyridin-5-yl)oxy)piperidine- l-carboxylate;

Methyl 5-(l-(/eri-butoxycarbonyl)piperidin-4-yl)-7-(trifluoromethyl )thieno[3,2-h]pyridine-3- carboxylate;

Isobutyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidine-l- carboxylate;

5-(l-(4-Fluorophenethyl)piperidin-4-yl)-/V-methyl-7-(trifluo romethyl)thieno[3,2-h]pyridine-

3-carboxamide hydrochloride;

Benzyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidine-l- carboxylate;

/V-Methyl-5-(l-(4-methylpentyl)piperidin-4-yl)-7-(trifluorom ethyl)thieno[3,2-h]pyridine-3- carboxamide;

5-( l -(2-(Bcnzyloxy)cthyl)pipcridin-4-yl)-A ^/ - methyl -7-(tnfluoiOmcthyl)thicno[ 3, 2-/?J pyridine- 3-carboxamide hydrochloride; Isopentyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)piperidine-l- carboxylate;

Isopropoxyethyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5- yl)piperidine- 1 -carboxylate;

/ _/77 -Butyl 2,6-dimethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thie no[3,2-h]pyridin-5- yl)oxy)piperidine- 1 -carboxylate;

//77-Butyl (2S,4r,6 ?J-2,6-dimethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)t hieno[3,2- /?Jpyridin-5-yl)oxy)pipcridinc-l -carboxylate;

2-(Trifluoromethoxy)ethyl (2S,4r,6/?)-2,6-dimethyl-4-((3-(methylcarbamoyl)-7- (trinuoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxylate;

(+/-)-/z77- Butyl (2 ?,6 ?J-2,6-dimethyl-4-((3-(methylcarbamoyl)-7- (trinuoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxylate;

(+/-)-2-Trifluoromethoxy)ethyl (2 R, 6 R )-2,6-dimethyl-4-((3-(methylcarbamoyl)-7- (trinuoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl (2 R, 6 R )-2,6-dimethyl-4-((3-(methylcarbamoyl)-7- (trifluoromcthyl)thicno[3,2-/?Jpyridin-5-yl)oxy)pipcndinc- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl (2S,6SJ-2,6-dimethyl-4-((3-(methylcarbamoyl)-7- (trifluoromcthyl)thicno[3,2-/?Jpyridin-5-yl)oxy)pipcndinc- 1 -carboxylate;

4-Nitrophenyl (2S,4r,6/?)-2,6-dimethyl-4-((3-(methylcarbamoyl)-7- (trifluoromcthyl)thicno[3,2-/?Jpyridin-5-yl)oxy)pipcndinc- 1 -carboxylate;

/Z77- Butyl 4-((7-mcthoxy-3-(mcthylcarbamoyl)thicno[3,2- ?Jpyridin-5-yl)oxy)pipcridinc- 1 - carboxylate;

Methyl 5-(4-(((cyclopropylmethyl)carbamoyl)oxy)piperidin-l-yl)-7-me thoxythieno[3,2- h]pyridine-3 -carboxylate ;

Methyl 5-(4-((cyclopropylcarbamoyl)oxy)piperidin-l-yl)-7-methoxythi eno[3,2-h]pyridine-3- carboxylate;

Isobutyl 4-((7-methoxy-3-(methylcarbamoyl)thieno[3,2-h]pyridin-5-yl)o xy)piperidine-l- carboxylate;

2-(Trifluoromethoxy)ethyl 4-((7-hydroxy-3-(methylcarbamoyl)thieno[3,2-h]pyridin-5- yl)oxy)piperidine- 1 -carboxylate; 2-(Trifluoromethoxy)ethyl 4-((7-(difluoromethoxy)-3-(methylcarbamoyl)thieno[3,2- /?]pyndin-5-yl)oxy)pipcndinc-l -carboxylatc;

tert- Butyl (1 -(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2-/?Jpyrid in-5-yl)pipcridin-4- yl)carbamate;

Isobutyl ( 1 -(3-(mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4- yl) carbamate;

Cyclopropylmethyl ( l -(3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyridi n-5- yl)piperidin-4-yl)carbamate ;

Neopentyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl)piperidin-4- yl)carbamate;

tert- Butyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl) thicno[3,2-/?]pyndin-5-yl)azctidin-3- yl)carbamate;

Isobutyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl)azetidin-3-yl) carbamate ;

Cyclopropylmethyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5- yl)azetidin-3-yl)carbamate;

Neopentyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl)azetidin-3- yl)carbamate;

/c/7- Butyl methyl(l-(3-(methylcarbamoyl)-7-(trifluoromethyl) thicno[3,2-/?J pyridin-5-yl) piperidin-4-yl)carbamate;

Isobutyl methyl(l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- h]pyridin-5-yl) piperidin-4-yl) carbamate;

l-(7-Cyclopentyl-3-(methylcarbamoyl)thieno[3,2-h]pyridin-5-y l)piperidin-4-yl

(cycloprop ylmethyl)c arb amate ;

/c 7- Butyl (l-(7-cyclopentyl-3-(methylcarbamoyl)thieno[3,2-h]pyridin-5- yl)azetidin-3- yl)carbamate;

l-(7-(/er/-Butyl)-3-(methylcarbamoyl)thieno[3,2-h]pyridin-5- yl)piperidin-4-yl

(cycloprop ylmethyl)c arb amate ;

l-(7-Isopropyl-3-(methylcarbamoyl)thieno[3,2-h]pyridin-5-yl) piperidin-4-yl

(cyclopropylmethyl)carbamate ; tert- Butyl 4-fluoro-4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[ 3,2-Z?]pyridin-5- yl)oxy)methyl)piperidine- 1 -carboxylate;

Isobutyl 4-fluoro-4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[ 3,2-Z?]pyridin-5- yl)oxy)methyl)piperidine- 1 -carboxylate;

2.2.2-trifluoroethyl 4-fluoro-4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[ 3,2- /?Jpyridin-5-yl)oxy) methyl jpipcridinc- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl 4-fluoro-4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[ 3,2- /?Jpyridin-5-yl)oxy) methyl jpipcridinc- 1 -carboxylate;

tert- Butyl 3-fluoro-3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[ 3,2-/7]pyridin-5- yl)oxy)methyl)azetidine-l -carboxylate;

Isobutyl 3-fluoro-3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[ 3,2-Z?]pyridin-5- yl)oxy)methyl)azetidine-l -carboxylate;

2.2.2-Trifluoroethyl 3-fluoro-3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[ 3,2- /?Jpyridin-5-yl)oxy) methyl jazctidinc- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl 3-fluoro-3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[ 3,2- /?Jpyridin-5-yl)oxy) methyl jazctidinc- 1 -carboxylate;

ie/t-Butyl 3-methyl-3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[ 3,2-/?]pyridin-5- yl)oxy)methyl)azetidine-l -carboxylate;

Isobutyl 3-mcthyl-3-(((3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[ 3,2- ?Jpyridin-5- yl)oxy)methyl)azetidine-l -carboxylate;

2,2,2-Trifluoroethyl 3-methyl-3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[ 3,2- /?Jpyridin-5-yl)oxy) methyl jazctidinc- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl 3-methyl-3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[ 3,2- /?Jpyridin-5-yl)oxy) methyl jazctidinc- 1 -carboxylate;

//77-Butyl 4-(((3-(mcthylcarbamoyl)-7-(tnfluoromcthyl)thicno[3,2-/?Jpyr idin-5- yl)oxy)methyl)piperidine- 1 -carboxylate;

2,2,2-Trifluoroethyl 4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-//]py ridin-5- yl)oxy)methyl)piperidine- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl 4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-//]py ridin- 5-yl)oxy)methyl)piperidine- 1 -carboxylate; tert- Butyl 4-mcthyl-4-(((3-( mcthylcarbamoyl)-7-(tnfluoromcthyl)thicno[3,2-/?Jpyridin-5- yl)oxy)methyl)piperidine- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl 4-methyl-4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[ 3,2- /?Jpyridin-5-yl)oxy) methyl jpipcridinc- 1 -carboxylate;

tert- Butyl (2r,4.s)-2-((3-( mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2-/?Jpyridin-5- yl)oxy)-6-azaspiro[3.4]octane-6-carboxylate;

tert- Butyl (2s,4r)-2-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3, 2-/?]pyridin-5- yl)oxy)-6-azaspiro[3.4]octane-6-carboxylate;

2-(Trifluoromethoxy)ethyl (2,s,4r)-2-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2- Z?]pyridin-5-yl)oxy)-6-azaspiro[3.4]octane-6-carboxylate;

2-(Trifluoromethoxy)ethyl (2r,4,s)-2-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2- /7]pyridin-5-yl)oxy)-6-azaspiro[3.4]octane-6-carboxylate;

/e/7- Butyl (3a ?,5r,6aSJ- 5-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-//]pyr idin-5- yl)oxy)hexahydrocyclopenta[c]pyrrole-2(l//)-carboxylate;

2-(Trifluoromethoxy)ethyl (3a ?,5r,6aSJ-5-((3-(methylcarbamoyl)-7-

(trifluoromethyl)thieno[3,2-//]pyridin-5-yl)oxy)hexahydro cyclopenta[c]pyrrole-2(l7/)- carboxylate;

/ra/7.s-3-(TrifluoiOmcthoxy)cyclobutyl (2 ?,4 ?)-4-((6-chloro-3-(methylcarbamoyl)-7- (tri fluoromcthyljthicnol 3, 2-/?Jpyridin-5-yl)oxy)-2-mcthylpipcridinc- l -carboxylate;

/ra/7.s-3-((TrinuoiOmcthoxy) methyl jcyclobutyl 4-((3-(methylcarbamoyl)-7- (tnfluoiOmcthyl)thicno[3,2-/?Jpyridin-5-yl)oxy)pipcndinc- 1 -carboxylate;

/ ran s - 3 - (T ri fl uo ro m c t h o x y ) c y c 1 o b u t y 1 (2 ?,4 ?J-2-methyl-4-((3-(methylcarbamoyl)-7- (tnfluoiOmcthyl)thicno[3,2-/?Jpyridin-5-yl)oxy)pipcndinc- 1 -carboxylate;

cis-3 - H ydro x yc yc 1 o b u t y 1 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/7]pyr idin-5- yl)oxy)piperidine- 1 -carboxylate;

/ ran s - 3 - (T ri fl uo ro m c t h o x y ) c y c 1 o b u t y 1 4-((3-(methylcarbamoyl)-7- (trifluoiOmcthyl)thicno[3,2-/?Jpyridin-5-yl)oxy)pipcndinc- 1 -carboxylate;

c / .v - 3 - (T r i fl u o ro m c t h o x y ) c y c 1 o b u t y 1 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?Jpyridin-5-yl)oxy)pipcridinc- l -carboxylate;

Oxetan-3-yl 6-(3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyndi n-5-yl)-2,6- diazaspiro[3.3]heptane-2-carboxylate; /V-Methyl-5-(6-(2-morpholinoacetyl)-2,6-diazaspiro[3.3]hepta n-2-yl)-7-

(trifluoromethyl)thieno[3,2-/?]pyridine-3-carboxamide;

3-Methyloxetan-3-yl 6-(3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyrid in-5-yl)-

2,6-diazaspiro[3.3]heptane-2-carboxylate;

1 -Cycloprop ylethyl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)-

2,6-diazaspiro[3.3]heptane-2-carboxylate;

(K)-5-(6-(2-Methoxypropanoyl)-2,6-diazaspiro[3.3]heptan-2-yl )-/V-methyl-7-

(trifluoiOmcthyl)thicno[3,2- ?Jpyridinc-3-carboxamidc;

(SJ-5-(6-(2-Methoxypropanoyl)-2,6-diazaspiro[3.3]heptan-2-yl )-A/-methyl-7-

(trifluoromethyl)thieno[3,2-/?]pyridine-3-carboxamide;

l-Methoxypropan-2-yl 6-(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- ?Jpyridin-5- yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate;

Oxetan-3-ylmethyl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-Z?]pyri din-5-yl)-

2,6-diazaspiro[3.3]heptane-2-carboxylate;

l-Methylpiperidin-3-yl 6-(3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyrid in-5- yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate;

l-(l-Methylazetidin-3-yl)ethyl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?Jpyridin-5-yl)-2,6-diazaspiro[3.3Jhcptanc-2-carboxylatc;

l-Methylazetidin-3-yl 6-(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- ?Jpyridin-5-yl)-

2,6-diazaspiro[3.3]heptane-2-carboxylate;

l-Cyanopropan-2-yl 6-(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- ?Jpyridin-5-yl)-

2,6-diazaspiro[3.3]heptane-2-carboxylate;

l-(2-Fluoroethyl)azetidin-3-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?Jpyridin-5-yl)-2,6-diazaspiro[3.3Jhcptanc-2-carboxylatc;

l-(Cyanomethyl)azetidin-3-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?Jpyridin-5-yl)-2,6-diazaspiro[3.3Jhcptanc-2-carboxylatc;

2-(Trifluoromethoxy)ethyl 6-(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- ?Jpyridin-5- yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate;

5-(4-((l-Isopropylpyrrolidin-3-yl)oxy)piperidin-l-yl)-/V- methyl-7- (trifluoiOmcthyl)thicno[3,2- ?Jpyridinc-3-carboxamidc; 5-(4-(( l -(2,2-Din uoroethyl jpyrrolidi n-3-yl)oxy)pi peridin- 1 -ylj- V-methy 1-7- (trifluoromethyl)thieno[3,2-/?]pyridine-3-carboxamide;

5-(4-((l-(2-Fluoroethyl)pyrrolidin-3-yl)oxy)piperidin-l-y l)-/V-methyl-7- (tnnuoromcthyl)thicno[3,2-/?Jpyndinc-3-carboxamidc;

5-(4-((l-(l,3-Difluoropropan-2-yl)pyrrolidin-3-yl)oxy)piperi din-l-yl)-/V-methyl-7-

(tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-(( 1 -(2,2-Difluoroethyl)azetidin-3-yl)oxy)piperidin- 1 -yl)-/V-mcthyl-7 - (tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-(( l -(2-Fluorocthyl)azctidin-3-yl)oxy)pipcndin- l -yl)-A ^/ -mcthyl-7- (tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-((l-(l,3-Difluoropropan-2-yl)azetidin-3-yl)oxy)piperidi n-l-yl)-/V-methyl-7-

(tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-(2-(3 ,3 -Difluoropyrrolidin- 1 -yl)ethoxy)piperidin- 1 -yl)-/V-methyl-7 - (tnfluoiOmcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-(2-(3-Fluoropyrrolidin- 1 -yljcthoxyjpipcridin- 1 -yl)-/V-mcthyl-7- (tnfluoiOmcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-(2-(4,4-Difluoropiperidin-l-yl)ethoxy)piperidin-l-yl )-/V-methyl-7- (tnfluoiOmcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-(2-(3-Hydroxypyrrolidin-l-yl)ethoxy)piperidin-l-yl)- /V-methyl-7- (tnfluoiOmcthyl)thicno[ 3, 2-/?Jpyridinc-3 -carboxamide;

5-(4-(2-(/raH.s-3-Fluoro-4-hydiOxypynOlidin- 1 -yl)cthoxy)pipcridin- l -yl)-/V-mcthyl-7- (tnfluoiOmethyl)thieno[3,2-/?Jpyridine-3-carboxamide;

A/- Methyl-5 -(4-(2-morpholinoethoxy)pipendin- 1 -yl)-7-(tnfluoromethyl)thieno[3,2- b] pyridine- 3 -carboxamide ;

5-(4-((6-Isopropylpyridin-2-yl)oxy)piperidin-l-yl)-/V-methyl -7-(trifluoromethyl)thieno[3,2-

/?]pyridinc-3-carboxamidc;

(+/-)-tert- Butyl irans-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)th ieno[3,2- /?Jpyridin-5-yl)oxy)pipcridinc- l -carboxylatc;

(+/-)-iran5-2-(Trifluoromethoxy)ethyl-2-methyl-4-((3-(methyl carbamoyl)-7- (tnfluoiOmcthyl)thicno[3,2-/?Jpyridin-5-yl)oxy)pipcndinc- 1 -carboxyl ate; (+/-)-/ _{<? /} 7-Butyl cz ^' s-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl) thieno[3,2- /?]pyndin-5-yl)oxy)pipcndinc- l -carboxylatc;

(+/-)-cz5-2-(Trifluoromethoxy)ethyl-2-methyl-4-((3-(methylca rbamoyl)-7- (trinuoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxyl ate;

(S)- 1 -Cyclopropylcthyl (2/?,4/?)-2-methyl-4-((3-(methylcarbamoyl)-7- (trifluoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxyl ate;

(S)- 1 -Cyclopropylcthyl (2S,4S/-2-methyl-4-((3-(methylcarbamoyl)-7- (trifluoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxyl ate;

/ _<?/ 7- Butyl (2 ?,4 ?)-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thien o[3,2- /?Jpyridin-5-yl)oxy)pipcridinc- l -carboxylatc;

/ _{<? /} 7-Butyl (2S,4S)-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl) thieno[3,2- /?]pyndin-5-yl)oxy)piperidine- l -carboxylate;

2-(Trifluoromethoxy)ethyl f2 ?,4 ?J-2-methyl-4-((3-(methylcarbamoyl)-7- (trifluoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxyl ate;

2-(Trifluoromethoxy)ethyl (2S,4SJ-2-methyl-4-((3-(methylcarbamoyl)-7- (trifluoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxyl ate;

(+/-)-/i77-Butyl /ra/7.s-3-fluoro-4-((3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)t hicno[3,2- /?Jpyridin-5-yl)oxy)pipcridinc- l -carboxylatc;

(+/-)-2-(Trifluoromethoxy)ethyl iran5-3-fluoro-4-((3-(methylcarbamoyl)-7- (tnfluoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxyl ate;

(SJ-l -Cyclopropylcthyl (3 ?,4 ?)-3-fluoro-4-((3-(methylcarbamoyl)-7- (trifluoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxyl ate;

(SJ-l -Cyclopropylethyl (3S,4SJ-3-fluoro-4-((3-(methylcarbamoyl)-7- (trifluoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxyl ate;

(+/-)-/t77-Butyl czs-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thie no[3,2-h]pyridin- 5-yl)oxy)piperidine- 1 -carboxylate;

(+/-)-cz5-2-(Trifluoromethoxy)ethyl-3-fluoro-4-((3-(methylca rbamoyl)-7-

(trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)piperidine -l-carboxylate;

(S)- 1 -cyclopropylcthyl (3 ?,4SJ-3-fluoro-4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)piperidine-l- carboxylate; (S)- 1 -cyclopropylethyl (3S,4/?)-3-fluoro-4-((3-(methylcarbamoyl)-7- (trinuoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxyl ate;

Butyl (3S,4 ? ₎ -3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)t hieno[3,2-/7]pyridin- 5-yl)oxy)piperidine- 1 -carboxylate;

/c 7- Butyl (3/^,45 ₎ -3-fluoro-4-((3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)th icno[3,2-/?Jpyridin- 5-yl)oxy)piperidine- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl (3S,4/?)-3-fluoro-4-((3-(methylcarbamoyl)-7- (trifluoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl f3 ?,4SJ-3-fluoro-4-((3-(methylcarbamoyl)-7- (trinuoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxylate;

(+/-)-/ _{<? /7} - Butyl c 5-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7- (trinuoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxylate;

(+/-)-c 5-2-(Trifluoromethoxy)ethyl-3-fluoro-4-((6-methyl-3-(methylc arbamoyl)-7- (trinuoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxylate;

/<? /7-Butyl 4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2-//]pyridin-5- yl)oxy)piperidine- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl 4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2- /?Jpyridin-5-yl)oxy)pipcridinc-l -carboxylate;

ie/t-Butyl (2 ?,4 ?J-2-ethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno [3,2-//]pyridin- 5-yl)oxy)piperidine- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl (2/?,4/?)-2-ethyl-4-((3-(methylcarbamoyl)-7- (trifluoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxylate;

/c 7- Butyl (2 ?,4SJ-2-ethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thi eno[3,2-//]pyridin- 5-yl)oxy)piperidine- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl-(2 ?,4SJ-2-ethyl-4-((3-(methylcarbamoyl)-7- (trinuoromcthyl)thicno[3,2-/?Jpyridin-5-yl)oxy)pipcridinc- 1 -carboxylate;

2-Hydroxyethyl 4-((3-(mcthylcarbamoyl)-7-(trifluoromcthyl)thicno[3,2-/?Jpyr idin-5- yl)oxy)piperidine- 1 -carboxylate;

t7 - Butyl 7-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-//]pyr idin-5-yl)oxy)-2- azaspiro [3.5] nonane-2-carboxylate; (K)-5-(4-(2-Cyclopropoxyethyl)-3-methylpiperazin-l-yl)-/V-me thyl-7- (trifluoromethyl)thieno[3,2-Z?]pyridine-3-carboxamide;

(S)-5-(4-(2-Cyclopropoxyethyl)-3-methylpiperazin-l-yl)-/V -methyl-7- (trifluoromethyl)thieno[3,2-/?]pyridine-3-carboxamide;

5-(cz ^' 5-4-(2-Cyclopropoxyethyl)-3,5-dimethylpiperazin-l-yl)- A/-methyl-7- (trifluoromethyl)thieno[3,2-/?]pyridine-3-carboxamide;

5-(4-((4-Methoxy-6-methylpyndin-2-yl)methyl)piperazin-l -yl)-V- methyl-7- (tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-(3-((Dimethylamino)methyl)benzyl)piperazin-l-yl)-/V- methyl-7- (tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-(l-((4-Methoxycyclohexyl)amino)-l-oxopropan-2-yl)pipera zin-l-yl)-A/-methyl-7-

(tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

A ^/ -Mcthyl-5-(4-( l -oxo-1 -((tctrahydiO-2/7-pyran-4-yl)amino)propan-2-yl)pipcrazin- 1 -yl)-7- (trifluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

A/-Methyl-5-(4-((2-morpholinoethyl)sulfonyl)piperazin-l-yl)- 7-(trifluoromethyl)thieno[3,2-

/?]pyndinc-3-carboxamidc;

A/-Methyl-5-(4-((3-morpholinopropyl)sulfonyl)piperazin-l-yl) -7-(trifluoromethyl)thieno[3,2-

/?]pyndinc-3-carboxamidc;

( ?)-/V-(Cyclopropylmethyl)-2-(2-methyl-4-(3-propionyl-7-(trif luoromethyl)thieno[3,2- /?Jpyridin-5-yl)pipcrazin-l -yljacctamidc;

(SJ-A/-(Cyclopropylmethyl)-2-(2-methyl-4-(3-propionyl-7-(tri fluoromethyl)thieno[3,2- /?Jpyridin-5-yl)pipcrazin-l -yljacctamidc;

5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-l-yl)-/V,2-dim ethyl-7-

(tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-(2-(3 -Fluoropyrrolidin- 1 -yl)- 1 -hydroxyethyl)piperidin- 1 -yl)-/V-mcthyl-7 - (tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-(2-(4,4-Difluoropiperidin-l-yl)-l-hydroxyethyl)piperidi n-l-yl)-/V-methyl-7-

(tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-(l-Hydroxy-2-morpholinoethyl)piperidin-l-yl)-A/-methyl- 7-(trifluoromethyl)thieno[3,2-

/?]pyndinc-3-carboxamidc; 5-(4-(3-(4,4-Difluoropiperidin-l-yl)-2-hydroxypropyl)piperid in-l-yl)-/V-methyl-7-

(trifluoromethyl)thieno[3,2-/?]pyridine-3-carboxamide;

5-(4-(3-(3,3-Difluoropyrrolidin-l-yl)-2-hydroxypropyl)piperi din-l-yl)-/V- methyl-7- (trinuoromcthyl)thicno[3,2-/?Jpyndinc-3-carboxamidc;

5-(4-(2-(l-(2,2-Difluoroethyl)pyrrolidin-3-yl)-2-hydroxyethy l)piperazin-l-yl)-/V-methyl-7-

(tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

l-(2-Methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno [3,2-/?]pyridin-5-yl)piperidin-4-yl (cycloprop ylmethyl)c arb amate ;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (R)- 2- (methoxymethyl)pyrrolidine- 1 -carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyridi n-5-yl)pipcndin-4-yl (S)-(l- (2,2-difluoroethoxy)propan-2-yl)carbamate;

(+/-)-/raH.s-3-FluoiO- l -(3-(mcthylcarbamoyl)-7-(tnriuoiOmcthyl)thicno[3,2-/?]pyndin -5- yl)piperidin-4-yl ((SJ-l-(trifluoromethoxy)propan-2-yl)carbamate;

/V-Isopropyl-7-(trifluoromethyl)-5-(3-((4-(trifluoromethyl)c yclohexyl)amino)pyrrolidin-l- yl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

7-Cyclopropyl-/V-ethyl-5-(4-(2-(isopropylamino)-2-oxoethyl)p iperazin-l-yl)thieno[3,2-

/?Jpyridinc-3-carboxamidc;

/V-Butyl-7-cyclopropyl-5-(4-(2-(isopropylamino)-2-oxoethyl)p iperazin-l-yl)thieno[3,2-

/?Jpyridinc-3-carboxamidc;

l-(3-(Azetidine-l-carbonyl)-7-(trifluoromethyl)thieno[3,2 -/?]pyridin-5-yl)piperidin-4-yl tert- butylcarbamate;

1 -(3-(3-Mcthoxyazctidinc- l -carbonyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyridin-5-yl)pipc ridin- 4-yl tert- butylcarbamate;

1-(3-((3-Chloropropyl)carbamoyl)-7-(trifluoromethyl)thieno[3 ,2-/?]pyridin-5-yl)piperidin-4-yl ie/ -butylcarbamate hydrochloride;

2-(4-(3-Acctamido-7-(tnnuoromcthyl)thicno[3,2-/?Jpyridin-5-y l)pipcrazin- 1 -y\)-N- isopropylacetamide;

1 -(3-Acctamido-7-(tnriuoromcthyl)thicno[3,2-/?Jpyridin-5-yl)p ipcndin-4-yl

(cycloprop ylmethyl)c arb amate ; l-(3-Acetyl-7-(trifluoromethyl)thieno[3,2-h]pyridin-5-yl)pip eridin-4-yl

(cycloprop ylmethyl)c arb amate ;

Methyl 5-(4-(((cyclopropylmethyl)carbamoyl)oxy)piperidin-l-yl)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate;

l-(3-(Ethylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyr idin-5-yl)piperidin-4-yl

(cycloprop ylmethyl)c arb amate ;

1-(3-(Cyclopropylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h] pyridin-5-yl)piperidin-4-yl (cycloprop ylmethyl)c arb amate ;

2-(4-(3-Acctyl-7-(tnfluoromcthyl)thicno[3,2-/?Jpyridin-5-yl) pipcrazin- l -ylj- V- isopropylacetamide;

l-(3-(Azetidine-l-carbonyl)-7-(trifluoromethyl)thieno[3,2 -h]pyridin-5-yl)piperidin-4-yl (cycloprop ylmethyl)c arb amate ;

l-(3-((2-Methoxyethyl)carbamoyl)-7-(trifluoromethyl)thien o[3,2-h]pyridin-5-yl)piperidin-4- yl (cyclopropylmethyl)carbamate;

l-(3-Propionyl-7-(trifluoromethyl)thieno[3,2-h]pyridin-5- yl)piperidin-4-yl (SJ-(l- cyclopropylethyl)carbamate;

l-(3-(l-Hydroxypropyl)-7-(trifluoromethyl)thieno[3,2-h]py ridin-5-yl)piperidin-4-yl <( J- 1 - cyclopropylethyl)carbamate;

tert- Butyl 7-(3-acetyl-7-(trifluoromethyl)thieno[3,2-h]pyridin-5-yl)-2, 7- diazaspiro [3.5] nonane-2-carboxylate;

l-(7-(3-Acetyl-7-(trifluoromethyl)thieno[3,2-h]pyridin-5- yl)-2,7-diazaspiro[3.5]nonan-2-yl)- 3 -methylbutan- 1 -one ;

1 -(3 -( Azetidine- 1 -carbonyl)-7-(trifluoromethyl)thieno [3 ,2-/?J pyridi n-5-y 1 )pi peridi n-4-y 1 3 - fluoroazetidine- 1 -carboxylate;

1 -(3 -(Azetidine- 1 -carbonyl)-7-(trifluoromethyl)thieno [3 ,2-/?J pyridi n-5-yl)pi peridi n-4-yl 3 - chloroazetidine- 1 -carboxylate;

l-(3-(3-Chloroazetidine-l-carbonyl)-7-(trifluoromethyl)th ieno[3,2-h]pyridin-5-yl)piperidin-4- yl 3 -chloroazetidine- 1 -carboxylate;

(+/-)-lrans- 1 -(3-( Azetidine- 1 -carbonyl)-7-(trifluoromcthyl)thicno[ 3, 2-/?J pyridi n-5-yl)-3- fluoropiperidin-4-yl isopropylcarbamate; 7-Cyclopropyl-5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin- l-yl)-/V-methylthieno[3,2-

/?]pyridinc-3-carboxamidc;

7-Ethy l-5-(4-(2-(isopropyl ami no)-2-oxocthy 1 jpipcrazi n- 1 -ylj- V- methyl thicnoj 3, 2-/?Jpyridinc- 3-carboxamide;

7-Chloro-5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-l-yl) -/V-methylthieno[3,2-

/?]pyridinc-3-carboxamidc;

5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-l-yl)-7-methox y-/V-methylthieno[3,2-

/?]pyridinc-3-carboxamidc;

7-(Difluoromethyl)-5-(4-(2-(isopropylamino)-2-oxoethyl)piper azin-l-yl)-A/-methylthieno[3,2-

/?]pyridinc-3-carboxamidc;

7-(Di methyl ami no)-5-(4-(2-(i sopropy lami no)-2-oxocthyl jpiperazi n- 1 -yl)-/V- methyl thicno[ 3, 2- /?]pyndinc-3-carboxamidc;

5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-l-yl)-/V-methy l-7-(2,2,2- tnfluoiOcthoxy)thicno[ 3, 2-/?Jpyridinc-3 -carboxamide;

1 -(7-ChloiO-3-(mcthylcarbamoyl)thicno[3,2-/?Jpyridin-5-yl)pip cridin-4-yl

(cycloprop ylmethyl)c arb amate ;

1 -(7-(Dimcthylamino)-3-(mcthylcarbamoyl)thicno[3,2-/?Jpyridin -5-yl)pipcridin-4-yl

(cycloprop ylmethyl)c arb amate ;

l-(7-(Difluoromethyl)-3-(methylcarbamoyl)thieno[3,2-/?]py ridin-5-yl)piperidin-4-yl

(cycloprop ylmethyl)c arb amate ;

l-(7-(Difluoromethyl)-3-(methylcarbamoyl)thieno[3,2-/?]py ridin-5-yl)piperidin-4-yl isopropylcarbamate;

1 -(7-(DifluoiOmcthyl)-3-(mcthylcarbamoyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl cyclopropylcarbamate;

1 -(7-Mcthoxy-3-(mcthylcarbamoyl)thicno[3,2-/?Jpyridin-5-yl)pi pcridin-4-yl

isopropylcarbamate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyridi n-5-yl)azctidin-3-yl

(cyclopropylmethyl)carbamate trifluoroacetate;

5-(3-(2,2-Dicthoxycthoxy)azctidin- 1 -yl)-/V-mcthyl-7-(trifluoiOmcthyl)thicno[3,2-/?Jpyridinc- 3-carboxamide; 5-(3-(2-Hydroxy-2-methylpropoxy)azetidin-l-yl)-A/-methyl-7-( trifluoromethyl)thieno[3,2- /?] pyridine-3 -carboxamide trifluoroacetate;

5-(3-(2-(Cyclopropylmethoxy)ethoxy)azetidin-l-yl)-/V-methyl- 7-(trifluoromethyl)thieno[3,2-

/?Jpyridinc-3-carboxamidc;

( 1 -(3-(Mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2-/?Jpyndi n-5-yl)azctidin-3-yl)mcthyl (cycloprop ylmethyl)c arb amate ;

( 1 -(3-(Mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2-/?Jpyndi n-5-yl)azctidin-3-yl)mcthyl ( 1 -cyanopropan-2-yl)carbamate;

5-(3-((2-(Isopropylamino)-2-oxoethyl)amino)pyrrolidin-l-yl)- /V-methyl-7- (trinuoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(3-(2-(Isopropylamino)-2-oxoethoxy)pyrrolidin-l -yl)-V- methyl -7- (trinuoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(3-((2-(Isopropylamino)-2-oxoethyl)(methyl)amino)pyrrolidi n-l-yl)-/V-methyl-7-

(trinuoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(3-(3-(ieri-Butyl)ureido)pyrrolidin-l-yl)- V-methyl-7-(trifluoromethyl)thieno[3,2-

/?Jpyridinc-3-carboxamidc;

5-(3-(((5-Isopropyloxazol-2-yl)mcthyl)amino)pyrrolidin- 1 -yl)-/V-mcthyl-7- (trinuoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

/V-Mcthy 1-5 -(3-(((4-mcthylthiazol-2-yl) methyl jam inojpyrrolidin- 1 -ylj-7- (tririuoromcthyl jthicno[3,2-/?]pyridinc-3-carboxamidc;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]py ridin-5-yl)pyrrolidin-3-yl (cycloprop ylmethyljc arb amate ;

5-(4-(2-(Cyclopropylamino)-2-oxoethyl)piperazin-l-yl)- V-methyl-7- (trifluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc hydrogen chloride;

5-(4-(3-(ieri-Butyl)ureido)piperidin-l-yl)- V-methyl-7-(trifluoromethyl)thieno[3,2-h]pyridine- 3-carboxamide;

5-(4-(3,3-Dimethyl-2-oxobutyl)piperazin-l-yl)- V-methyl-7-(trifluoromethyl)thieno[3,2- h]pyridine-3-carboxamide;

5-(4-(l-(Cyclopropylamino)-l-oxopropan-2-yl)piperazin-l-yl)- V-methyl-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide; l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl tert- butylcarbamate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl cyclopropylcarbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl

(cycloprop ylmethyl)c arb amate ;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl

(cyclopropylmethyl)carbamate trifluoroacetate;

-(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridinc- 3 ,4-diyl bis((cyclopropylmethyl)carbamate) ;

(+/-)- .s-4-Hydroxy- l -(3-(mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5- yl)piperidin-3-yl (cyclopropylmethyl)carbamate;

(+/-)- .s-3-Hydroxy- l -(3-(mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5- yl)piperidin-4-yl (cyclopropylmethyl)carbamate;

3-Fluoro- 1 -(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2-/?Jpyrid in-5-yl)pipcridin-4-yl (cycloprop ylmethyl)c arb amate ;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl

((tetrahydrofuran-2-yl)methyl)carbamate;

(+/-)- .s-3-mcthoxy- 1 -(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2-/?Jpyrid in-5- yl)piperidin-4-yl (cyclopropylmethyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl (2- hydroxy- 3 -methoxypropyl)c arb amate ;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-Z?]p yridin-5-yl)piperidin-4-yl 3- cyanoazetidine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl 3- cyanomorpholine-4-carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl ((1,4- dioxan-2-yl)methyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl (5- fluoropyridin-3-yl)carbamate trifluoroacetate; l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl 3- chloroazetidine- 1 -carboxylate;

(+/-)-/raH.s-3-Fluoro- 1 -(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- ?Jpyridin-5- yl)piperidin-4-yl diisopropylcarbamate;

(+/-)-/raH.s-3-Fluoro- 1 -(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- ?Jpyridin-5- yl)piperidin-4- yl oxetan-3 -ylc arb amate ;

(+/-)-tran-3-Fluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethy l)thieno[3,2-/?]pyridin-5- yl)piperidin-4-yl isopropylcarbamate;

(+/-)-trans— 3-Fluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3, 2-/?]pyridin-5- yl)piperidin-4-yl 3-methoxyazetidine- 1 -carboxylate;

(+/-)-trans— 3-Fluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3, 2-/?]pyridin-5- yl)piperidin-4-yl cyclopropylcarbamate;

(+/-)-trans— 3-Fluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3, 2-/?]pyridin-5- yl)piperidin-4-yl 4-methylpiperazine- 1 -carboxylate;

(+/-)-/raH.s-3-Fluoro- 1 -(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- ?Jpyridin-5- yl)piperidin-4-yl ((S )- 1 -cyclopropylcthyljcarbamatc;

(3 ?,4 ?)-3-Fluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno [3,2-/?]pyridin-5- yl)piperidin-4-yl isopropylcarbamate;

(3S,4SJ-3-Fluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)t hieno[3,2-/7]pyridin-5- yl)piperidin-4-yl isopropylcarbamate;

(+/-)-/raH.s-3-FluoiO- l -(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2-/?Jpyrid in-5- yl)piperidin-4-yl (3-fluorocyclobutyl)carbamate;

(+/-)- .s-3-Fluoro- l -(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2-/?Jpyrid in-5- yl)piperidin-4-yl isopropylcarbamate;

(+/-)-trans— 3-Fluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3, 2-/?]pyridin-5- yl)piperidin-4-yl cyclopropylcarbamate;

(+/-)-trans— 3-Fluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3, 2-/?]pyridin-5- yl)piperidin-4-yl (2-(trifluoromethoxy)ethyl)carbamate;

(3 ?,4 ?)-3-Fluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno [3,2-/?]pyridin-5- yl)piperidin-4-yl cyclopropylcarbamate; (3S,4S)-3-Fluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)t hieno[3,2-Z?]pyridin-5- yl)piperidin-4-yl cyclopropylcarbamate;

(+/-)-/raH.s-3-Fluoro- 1 -(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- ?Jpyridin-5- yl)piperidin-4-yl (2-(trifluoromethoxy)ethyl)carbamate;

(+/-)-/raH.s-3-Fluoro- 1 -(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- ?Jpyridin-5- yl)piperidin-4-yl 3-(trifluoromethoxy)azetidine- l-carboxylate;

2-Cyanoethyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5- yl)piperidin-4- yl)c arbamate ;

3-Cyanocyclobutyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5- yl)piperidin-4- yl)c arbamate ;

l-Cyanopropan-2-yl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5- yl)piperidin-4- yl)c arbamate ;

4-Methyl -N-( l-(3-(methylcarbamo yl)-7-(trifluoromethyl)thieno[3,2-h]pyridin-5-yl)piperidin-

4-yl)morpholine-2-carboxamide;

l-Methoxypropan-2-yl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5- yl)piperidin-4- yl)c arbamate ;

l,3-Dimethoxypropan-2-yl ( 1 -(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- ?Jpyridin-

5-yl)piperidin-4-yl)carbamate;

(l,4-Dioxan-2-yl)methyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5- yl)piperidin-4- yl)c arbamate ;

Oetan-3-ylmethyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5- yl)piperidin-4- yl)c arbamate ;

(4-Methylmorpholin-3-yl)methyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?Jpyridin-5-yl)pipcridin-4-yl)carbamatc;

l-Methylpyrrolidin-3-yl ( 1 -(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- ?Jpyridin-5- yl)piperidin-4-yl)carbamate trifluoroacetate;

Oxetan-3-yl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl)piperidin- 4-yl)carbamate;

4-Methylpentan-2-yl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5- yl)piperidin-4- yl)c arbamate ; (S/-1 -Cyclopropylcthyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5- yl)piperidin-4- yl)c arbamate ;

(K)-l -Cycloprop ylethyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5- yl)piperidin-4-yl)carbamate trifluoroacetate;

1 -Cycloprop ylpropan-2-yl ( l -(3-(mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyridi n- 5-yl)piperidin-4-yl)carbamate;

2-(Trifluoromethoxy)ethyl ( l -(3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyndin - 5-yl)piperidin-4-yl)carbamate;

A/-Methyl-5-(4-((4-methylthiazol-2-yl)methyl)piperazin-l-yl) -7-(trifluoromethyl)thieno[3,2-

/?]pyridinc-3-carboxamidc;

5-(4-((4,5-Dimethyloxazol-2-yl)methyl)piperazin-l-yl)-A/-met hyl-7-

(trifluoromethyl)thieno[3,2-/?]pyridine-3-carboxamide;

5-(4-((5-Isopropyloxazol-2-yl)methyl)piperazin-l-yl)-/V-meth yl-7-(trifluoromethyl)thieno[3,2-

/?]pyridinc-3-carboxamidc;

5-(4-((5-Isopropyl-l,3,4-oxadiazol-2-yl)methyl)piperazin-l-y l)-/V-methyl-7-

(tnfluoromcthyl)thicno[3,2-/?Jpyndinc-3-carboxamidc;

5-(4-( (4, 5-Di mcthy 1- 1 //-imidazol-2-yl) methyl )pipcrazin- l -yl)-/V-mcthy 1-7- (tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-((l-((4, 5-dimethyl- IH- imidazol-2-yl)methyl)-4, 5-dimethyl- IH- imidazol-2- yl)mcthyl)pipcrazin- l -ylj- V-mcthy l-7-(trifluoiOmcthyl)thicno[ 3, 2-/?Jpyridinc-3-carboxamidc; /V-Methyl-5 -(4-((5-methyl- 1 ,3 ,4-oxadiazol-2-yl)methyl)piperazin- 1 -yl)-7- (tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-((4-Isopropylthiazol-2-yl)methyl)piperazin-l-yl)-A/- methyl-7- (tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

/V-Methyl-5-(4-(l-(4-methylthiazol-2-yl)ethyl)piperazin-l-yl )-7-(trifluoromethyl)thieno[3,2-

/?]pyridinc-3-carboxamidc;

/V-Methyl-5-(4-(l-(5-methylthiazol-2-yl)ethyl)piperazin-l-yl )-7-(trifluoromethyl)thieno[3,2-

/?]pyridinc-3-carboxamidc;

A/-Methyl-5-(l-((4-methylthiazol-2-yl)methyl)piperidin-4-yl) -7-(trifluoromethyl)thieno[3,2-

/?]pyndine-3-carboxamide; /V-Methyl-5-(4-((5-methyl-l,3,4-oxadiazol-2-yl)methoxy)piper idin-l-yl)-7-

(trifluoromethyl)thieno[3,2-/?]pyridine-3-carboxamide;

/V-Methyl-5-(4-(l-(6-methylpyridin-2-yl)ethyl)piperazin-l-yl )-7-(trifluoromethyl)thieno[3,2-

/?]pyndinc-3-carboxamidc;

/V-Methyl-5-(4-(2-methylthiazole-4-carbonyl)piperazin-l-yl)- 7-(trifluoromethyl)thieno[3,2-

/?]pyndinc-3-carboxamidc;

5-(4-(5-Cyclopropyl-l,3,4-oxadiazol-2-yl)piperidin-l-yl)-/V- methyl-7-

(trifluoromethyl)thieno[3,2-/?]pyridine-3-carboxamide;

5-(4-((2-(Cyclopropylamino)ethyl) sulfonyl)piperazin- 1 -yl)-/V-methyl-7 - (tnfluoromcthyl)thicno[3,2-/?Jpyndinc-3-carboxamidc trifluoroacetate;

5-(4-((2-Isopropoxyethyl)sulfonyl)piperazin-l-yl)-/V-meth yl-7-(trifluoromethyl)thieno[3,2- /?Jpyridinc-3-carboxamidc;

5-(4-((2-(Cyclopropylmethoxy)ethyl)sulfonyl)piperazin-l-yl)- /V-methyl-7-

(tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-((2-(Cyclopropyl(methyl)amino)ethyl)sulfonyl)piperazin- l-yl)-/V-methyl-7-

(tnfluoiOmcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-((2-(3-Mcthoxyazctidin- l -yljcthyljsulfonyljpipcrazin- 1 -yl)-/V-mcthyl-7- (tnfluoiOmcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-((2-(Isopropylamino)-2-oxoethyl)amino)piperidin-l-yl )-/V-methyl-7- (trifluoromethyl)thieno[3,2-/?]pyridine-3-carboxamide trifluoroacetate;

5-(4-(((/£ /7- Butyl sul finyljami no) methyl jpipcridin- 1 -yl)-/V-mcthyl-7- (tnriuoiOmcthyl)thicno[ 3, 2-/?] pyridinc-3 -carboxamide;

5-(4-(((Cyclopropylmethyl)amino)methyl)piperidin-l-yl)-A/ -methyl-7- (tnfluoiOmcthyl)thicno[ 3, 2-/?] pyridinc-3 -carboxamide trifluoroacetate;

5-(4-(2-Isopropoxycthoxy)pipcridin- l -ylj- V-mcthy l-7-(trinuoiOmcthyl)thicno[ 3, 2-/?J pyridine- 3-carboxamide;

5-(4-( l -(Cyclopropyl met hoxy)-3-hydroxypropan-2-yl)pipcrazin- 1 -yl)-/V-mcthyl-7- (trifluoiOmcthyl)thicno[ 3, 2- ?Jpyridinc-3 -carboxamide;

5-(4-(3-Formamidopropyl)piperazin-l-yl)-/V-methyl-7-(trifluo romethyl)thieno[3,2-/?]pyridine-

3-carboxamide; 5-(4-(2-(Bis(cyclopiOpylmethyl)amino)ethyl)piperazin-l -yl)-V- methyl-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

5-(4-(3-(Cyclopropanecarboxamido)propyl)piperazin-l-yl)-/V-m ethyl-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide trifluoroacetate;

5-(4-(2-(Cyclopropylmethoxy)ethoxy)piperidin-l-yl)-/V-methyl -7-(trifluoromethyl)thieno[3,2-

/?]pyridinc-3-carboxamidc;

5-(4-(2-(Isopropylsulfonyl)ethyl)piperazin-l-yl)-/V-methyl-7 -(trifluoromethyl)thieno[3,2-

/?]pyridinc-3-carboxamidc;

5-(4-(2-Hydroxy-3 -morpholinopropoxy)piperidin- 1 -yl) -/V-mcthyl-7 - (tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5-(4-((4-Isopropylmorpholin-2-yl)methyl)piperazin-l-yl)-A /-methyl-7- (tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc trifluoroacetate;

Methyl 5-(4-((3-isopropoxyazetidin-l-yl)methyl)piperidin-l-yl)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate;

5-(4-((3-Isopropoxyazetidin- l-yl)methyl)piperidin- 1 -yl)-/V-mcthyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

5-(4-(3-(3,3-Difluoropyrrolidin-l-yl)-2-hydroxypropoxy)piper idin-l-yl)-/V-methyl-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

5-(4-(2-hydroxy-3-isopropoxypropoxy)piperidin-l-yl)-/V-methy l-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

5-(4-((5-Isopropyl-l,3,4-oxadiazol-2-yl)methoxy)piperidin-l- yl)-/V-methyl-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

(S)- 1 -Cyclopropylcthyl 7-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5- yl)-2,7 -diazaspiro [3.5] nonane-2-carboxylate;

Cyclopropyl 7-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)-2,7- diazaspiro [3.5] nonane-2-carboxylate;

Oxetan-3-yl 7-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)-2,7- diazaspiro [3.5] nonane-2-carboxylate;

Isopropyl 7-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)-2,7- diazaspiro[3.5]nonane-2-carboxylate; 5-(2-(Ethyl(isopropyl)carbamoyl)-2,7-diazaspiro [3.5] nonan-7-yl)-/V-methyl-7 - (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

tert- Butyl 4-(3-(mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndi n-5-yl)pipcridinc-l - carboxylate;

5-( 1 -( 1 -(Cyclopropylamino)- 1 -oxopropan-2-yl)piperidin-4-yl)-/V-methyl-7 - (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

/V-Methyl-5-(l-((4-methylthiazol-2-yl)methyl)piperidin-4-yl) -7-(trifluoromethyl)thieno[3,2- /?]pyndinc-3-carboxamidc hydrogen chloride;

(SJ-l -Cycloprop ylethyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5- yl)piperidine- 1 -carboxylate;

4-Methylpentan-2-yl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5- yl)piperidine- 1 -carboxylate;

4-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)cyclohex-3-en-l-yl (cycloprop ylmethyl)c arb amate ;

2-Cyclopropylethyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5- yl)piperidine- 1 -carboxylate;

tert- Butyl (3S,4SJ-3,4-dihydroxy-4-(3-(methylcarbamoyl)-7-(trifluoromet hyl)thieno[3,2- /?Jpyridin-5-yl)pipcridinc- 1 -carboxylate;

2-Cyclopropyl-2-oxoethyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5- yl)piperidine- 1 -carboxylate;

4-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)cyclohexyl

(cycloprop ylmethyl)c arb amate ;

2-(Trifluoromethoxy)ethyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5- yl)piperidine- 1 -carboxylate;

tert- Butyl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)-2- azaspiro[3.3]heptane-2-carboxylate;

tert- Butyl 2-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl)-7- azaspiro [3.5] nonane-7 -carboxylate;

2-(Trifluoromethoxy)ethyl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5- yl)-2-azaspiro[3.3]heptane-2-carboxylate; 2-(Trifluoromethoxy)ethyl 2-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5- yl)-7-azaspiro[3.5]nonane-7-carboxylate;

tert- Butyl 4-((3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyri din-5- yl)thio)piperidine- 1 -carboxylate;

tert- Butyl 4-((3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyri din-5- yl) sulfinyl)piperidine- 1 -c arboxylate ;

tert- butyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5- yl) sulfonyl)piperidine- 1 -carboxylate;

5-(4-(2-(Cyclopropylamino)-2-oxoethoxy)phenyl)-/V-methyl-7-( trifluoromethyl)thieno[3,2-

/?]pyndinc-3-carboxamidc;

( 1 -(3-(Mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyndin -5-yl)- 1 H-imidazol-4- yl)methyl (cyclopropylmethyl)carbamate;

tert- Butyl 3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-Z?]py ridin-5- yl)oxy)methyl)pyrrolidine- 1 -carboxylate;

tert- Butyl 3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]py ridin-5- yl)oxy)methyl)azetidine-l -carboxylate;

5-((6-Mcthoxypyridin-3-yl)mcthoxy)-A ^/ -mcthyl-7-(trinuoromcthyl)thicno[ 3, 2-/?J pyridinc-3- carboxamide trifluoroacetate;

5-((l-(Cyclopropylcarbamoyl)azetidin-3-yl)methoxy)-/V-methyl -7-

(trinuoromcthyl)thicno[3,2-/?Jpyndinc-3-carboxamidc;

tert- Butyl 3-((3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyri din-5- yl)oxy)azetidine- 1 -carboxylate;

tert- Butyl 3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5- yl)oxy)pyrrolidine-l -carboxylate;

5-((l-((Cyclopropylmethyl)carbamoyl)pyrrolidin-3-yl)oxy)-/V- methyl-7-

(trinuoromcthyl)thicno[3,2-/?Jpyndinc-3-carboxamidc;

tert- Butyl (K)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/? ]pyridin-5- yl)oxy)pyrrolidine-l -carboxylate;

( ?J-5-((l-((Cyclopropylmethyl)carbamoyl)pyrrolidin-3-yl)oxy)- A/-methyl-7-

(trinuoromcthyl)thicno[3,2-/?Jpyndinc-3-carboxamidc; tert- Butyl (5 ₎ -3-((3-(mcthylcarbamoyl)-7-(tnfluoromcthyl)thicno[3,2- /?Jpyridin-5- yl)oxy)pyrrolidine-l-carboxylate;

(5/-5-(( 1 -((Cyclopropyl methyl jcarbamoyljpyrrolidin-S-yljoxyj- V-mcthy 1-7- (trifluoromcthyl)thicno[3,2-/?Jpyndinc-3-carboxamidc;

Cyclopropylmethyl (5 ₎ -3-((3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2- /?Jpyridin-5- yl)oxy)pyrrolidine-l-carboxylate;

l-Methoxypropan-2-yl (35 ₎ -3-((3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2- /?Jpyridin- 5-yl)oxy)pyrrolidine-l-carboxylate;

1-Cyanoethyl (3/^ ₎ -3-((3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2 -/?Jpyridin-5- yl)oxy)pyrrolidine-l-carboxylate;

l,3-Difluoropropan-2-yl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?Jpyridin-5-yl)oxy)pym lidinc- l -carboxyl ate;

/e/7- Butyl 3-hydroxy-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[ 3,2-h]pyridin-5- yl)oxy)pyrrolidine-l-carboxylate;

2-(Trifluoromethoxy)ethyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?]pyndin-5-yl)oxy)pym lidinc- l -carboxyl ate;

Isopropyl (SJ-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-// ]pyridin-5- yl)oxy)pyrrolidine-l-carboxylate;

(SJ-l -Cycloprop ylethyl (SJ-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-// ]pyridin- 5-yl)oxy)pyrrolidine-l-carboxylate;

3-(Trifluoromethoxy)propyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?]pyndin-5-yl)oxy)pym lidinc- l -carboxyl ate;

2,2,2-Trifluoroethyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h] pyridin-5- yl)oxy)pyrrolidine-l-carboxylate;

/erZ-Butyl (+/-)-/rara-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromet hyl)thieno[3,2- /?]pyndin-5-yl)oxy)pyrrolidinc- l -carboxyl ate;

2-(Trifluoromethoxy)ethyl (+/-)-iran5-3-fluoro-4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)pyrrolidine-l -carboxylate;

Cyclopropylmethyl (+/-)-/raH.s-3-fluoiO-4-((3-(mcthylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)pyrrolidine-l -carboxylate; 2-Cyclopropylethyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/? ]pyridin-5- yl)oxy)pyrrolidine-l-carboxylate;

/c/7- Butyl (+/-)-c 5-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno [3,2-/7]pyridin- 5-yl)oxy)pyrrolidine-l-carboxylate;

Cyclopropylmethyl (+/-)-c 5-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno [3,2- /?Jpyridin-5-yljoxy)pym lidinc-l -carboxyl ate;

2-(Trifluoromethoxy)ethyl (+/-)-c 5-3-fluoro-4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-Z?]pyridin-5-yl)oxy)pyrrolidine- l-carboxylate;

3.3.3-Trifluoropropyl (5 ₎ -3-((3-(methylcarbamoyl)-7-(trinuoromethyl)thieno[3,2- /?Jpyridin-5- yl)oxy)pyrrolidine-l-carboxylate;

(2,2-Difluorocyclopropyl)methyl (3S)-3-((3-(methylcarbamoyl)-7- (tnfluoromethyl)thieno[3,2-/?Jpyndin-5-yl)oxy)pynOlidine- 1 -carboxylate;

4.4.4-Trifluorobutyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-Z? ]pyridin-5- yl)oxy)pyrrolidine-l -carboxylate;

/c/7- Butyl (+/-)-/ra/7.s-3-((3-(mcthylcarbamoyl)-7-(trinuoromcthyl)thic no[3,2-/?Jpyndin-5- yl)oxy)-4-morpholinopyrrolidine-l -carboxylate;

(5-(Trifluoromethyl)isoxazol-3-yl)methyl (SJ-3-((3-(methylcarbamoyl)-7- (tnfluoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pynOlidinc- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl ( ?J-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?Jpyridin-5-yl)oxy)pym lidinc-l -carboxylate;

/c/7- Butyl ((+/-)-/ra/7.s-3-(dimcthylamino)-4-((3-(mcthylcarbamoyl)-7- (trifluoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pynOlidinc- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl (+/-)-/ra/7.s-3-(dimcthylamino)-4-((3-(mcthylcarbamoyl)-7- (tnfluoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pynOlidinc- 1 -carboxylate;

/c _/7 -Butyl (SJ-3-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thie no[3,2-/7]pyridin-5- yl)oxy)pyrrolidine-l -carboxylate;

ie _/ -Butyl (+/-)-ira775-3-methoxy-4-((3-(methylcarbamoyl)-7-(trifluorom ethyl)thieno[3,2- /?]pyridin-5-yl)oxy)pym lidinc-l -carboxylate;

2-(Trifluoromethoxy)ethyl ((+/-)-/ra/7.s-3-mcthoxy-4-((3-(mcthylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-/7]pyridin-5-yl)oxy)pyrrolidine- l-carboxylate; 2-(Trifluoromethoxy)ethyl (S)-3-((6-methyl-3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-/?]pyridin-5-yl)oxy)pyrrolidine- l-carboxylate;

Butyl 4-((3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyri din-5- yl)oxy)piperidine- l-carboxylate;

5-((l-(2-(Isopropylamino)-2-oxoethyl)piperidin-4-yl)oxy)-/V- methyl-7-

(trifluoiOmcthyl)thicno[3,2- ?Jpyridinc-3-carboxamidc;

Butyl (+/-)- ₍₇ ^' .s-4-((3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3 ,2-/?Jpyridin-5- yl)oxy)cyclohexyl)carbamate;

Isopropyl (+/-)-cz,s'-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thien o[3,2-/?]pyridin-5- yl)oxy)cyclohexyl)carbamate;

Butyl (+/-)-endo7-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[ 3,2-/?]pyridin-5- yl)oxy)-3-oxa-9-azabicyclo[3.3.l]nonane-9-carboxylate;

2-(Trifluoromethoxy)ethyl (+/-)-en _< 7o7-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3, 2- /?]pyridin-5-yl)oxy)-3-oxa-9-azabicyclo[3.3.l]nonane-9-carbo xylate;

Butyl (+/-)-£Ao-3-((3-(mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[ 3,2-/?Jpyndin-5- yl)oxy)-8-azabicyclo[3.2. l]octane-8-carboxylate;

Butyl (+/-)-£H£/o3-((3-(mcthylcarbamoyl)-7-(trinuoromcthyl)thicn o[3,2-/?Jpyndin-5- yl)oxy)-8-azabicyclo[3.2.l]octane-8-carboxylate;

2-(Trifluoromethoxy)ethyl 4-((3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- ?Jpyridin- 5-yl)methyl)piperidine- 1 -carboxylate;

5-(4-((Cyclopropylmethyl)carbamoyl)piperazin-l-yl)-/V- methyl-7 -(trifluoromethyl)thieno [3, 2- /?]pyndinc-3-carboxamidc trifluoroacetate;

Butyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5- yl)methyl)piperidine- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl (+/-)-ero-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[ 3,2- /?]pyridin-5-yl)oxy)-8-azabicyclo[3.2.l]octane-8-carboxylate ;

6-Chloro-5-[4-[2-(isopropylamino)-2-oxo-ethyl]piperazin-l-yl ]-/V-methyl-7- (trifluoromcthyl)thicno[3,2-/?Jpyndinc-3-carboxamidc;

6-Chloro-5-[4-[2-(isopropylamino)-2-oxo-ethyl]piperazin-l-yl ]-2-methoxy-/V-methyl-7-

(trifluoromcthyl)thicno[3,2-/?Jpyndinc-3-carboxamidc; [l-[6-Chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2-/?]pyridin-5-yl]-4-piperidyl]V-icyclopropyl methyl jcarbamatc;

[l-[6-Fluoro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2-/7]pyridin-5-yl]-4-piperidyl] N- [( 1 S)- 1 -cyclopropylethyl]carbamate;

[l-[6-Chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2-/7]pyridin-5-yl]-4-piperidyl]V-cyclopropylcarbamatc;

[l-[6-fluoro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2-Z?]pyridin-5-yl]-4-piperidyl]V-cyclopropylcarbamatc;

/e/7- Butyl N-[ 1 -[3-(isopropylcarbamoyl)-7-(tnfluoromcthyl)thicno[3,2-/?Jpyr idin-5- yl]pyrrolidin-3-yl]carbamate;

N- Isopropyl-2- [4- [3 -(5-methyloxazol-2-yl)-7-(trifluoromethyl)thieno [3 ,2-/?]pyridin-5- yl]piperazin- l-yl] acetamide;

N- [(4-Fluorophenyl)methyl] -5 - [4- [2-(isopropylamino)-2-oxo-ethyl]piperazin- 1 -yl] -7 - (tririuoromcthyl)thicno[3,2-/?Jpyndinc-3-carboxamidc;

5- [4- [2-(Isopropylamino)-2-oxo-ethyl]piperazin- 1 -yl] -7 -(trifluoromethyl)thieno [3 ,2- /?]pyridinc-3-carboxamidc;

A ^/ -IsopiOpyl-2-[4-[3-(4-mcthyloxazol-2-yl)-7-(trifluorom cthyl)thicno[3,2-/?]pyridin-5- yl]piperazin- l-yl] acetamide;

2- [4- [3 -( 1 -Hydroxypropyl)-7-(trifluoromethyl)thieno [ 3,2-/z] pyridi n-5-y 1 J piperazi n- l-yl] -N- isopropyl- acetamide ;

A/-Isopropyl-2-[4-[3-propanoyl-7-(trifluoromethyl)thieno[3,2 -//]pyridin-5-yl]piperazin-l- yl] acetamide;

2- [4- [3 -( Azetidine- 1 -carbonyl)-7-(trifluoromethyl)thieno [3 ,2-/?]pyndin-5-yl]pipcrazin- 1 -yl] - A/- i so p ro p y 1 - ace t a m i dc ;

A/-Isopropyl-2-[4-[3-(methoxymethyl)-7-(trifluoromethyl)thie no[3,2-//]pyridin-5-yl]piperazin- l-yl] acetamide;

A/-Isopropyl-2-[4-[3-methyl-7-(trifluoromethyl)thieno[3,2-// ]pyridin-5-yl]piperazin-l- yl] acetamide;

[l-[3-Propanoyl-7-(trifluoromethyl)thieno[3,2-//]pyridin-5-y l]-4-piperidyl] N- (cyclopropylmethyl)c arb amate ; [l-[3-(Trideuteriomethylcarbamoyl)-7-(trifluoromethyl)thieno [3,2-h]pyridin-5-yl]-4- piperidyl] /V-cyclopropylcarbamate;

7-(l,l-Difluoroethyl)-5-[4-[2-(isopropylamino)-2-oxo-ethyl]p iperazin-l-yl]-/V-methyl- thicno[3,2-/?]pyridinc-3-carboxamidc;

[ 1 - [7-( 1 , 1 -Difluoroethyl)-3 -(methylcarbamoyl)thieno [3 ,2-/?J pyridi n-5-y 1 J -4-piperidyl] N- (cyclopropylmethyl)c arb amate hydrochloride ;

[l-[3-(Methylcarbamoyl)-7-(2,2,2-trifluoroethoxy)thieno[3,2- h]pyridin-5-yl]-4-piperidyl] N- isopropylcarbamate;

5-[3-(4-Hydroxy-4- methyl -pcnt-2-ynoxy)azctidin- 1 -ylJ-/V-mcthyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

5 - [3- [3 -(Cycloprop ylmethoxy)azetidin- 1 -yl] azetidin- 1 -yl] -/V-methyl-7 - (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

Methyl 5-[3-(ieri-butoxycarbonylamino)pyrrolidin-l-yl]-7-(trifluoro methyl)thieno[3,2- h]pyridine-3-carboxylate;

5- [3 - [ [( 1 ?, 2R J-2-Hydroxycyclohexyl] amino]pyrrolidin- 1 -yl] -/V-methyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

5-[3-(2-Isopropoxyethylamino)pyrrolidin-l-yl]-/V-methyl-7-(t rifluoromethyl)thieno[3,2- h]pyridine-3-carboxamide;

5-[3-(3-Hydroxy-3-methyl-but-l-ynyl)pyrrolidin-l-yl]-/V-meth yl-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

5-[3-(Cyclopropylmethoxy)pyrrolidin-l-yl]-/V-methyl-7-(trifl uoromethyl)thieno[3,2- h]pyridine-3-carboxamide;

Methyl 5- [4-(/er/-butoxycarbonylamino)-l -piperidyl] -7-(trifluoromethyl)thieno [3,2- h]pyridine-3-carboxylate;

5 - [4- [2- [(2-Hydroxy- 1 , 1 -dimethyl-ethyl) amino] - 1 -methyl-2-oxo-ethyl]piperazin- 1 -yl] -N- mcthyl-7-(trinuoromcthyl)thicno[ 3, 2-/?] pyridinc-3 -carboxamide;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] N-(2- methoxy-2-methyl-propyl)carbamate;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] N-( - methoxy-2,2-dimethyl-propyl)carbamate; [l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] 3,3- dimethylpiperazine- 1 -carboxylate;

[ 1 -[3-(Mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyndin -5-ylJ-4-pipcndylJ N- (cyclopropylmethyl)c arb amate hydrochloride ;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] N-(2,2- difluoro- 1 -methyl-ethyl)carbamate;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] N-(2- fluoro- 1 -methyl-ethyl)carbamate;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] N-\2- hydroxy-l-(hydroxymethyl)ethyl]carbamate;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] N- tetrahydrofuran- 3 - ylcarb amate ;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] N- (oxetan-3-yl)carbamate;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] N-(3- methyloxetan-3 - yl)c arb amate ;

[l-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] 3- methylthiomorpholine-4-carboxylate;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] 3- methyl-l-oxo-l,4-thiazinane-4-carboxylate;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] 3-methyl- 1 , 1 -dioxo- 1 ,4-thiazinane-4-carboxylate;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] iV-[(lSJ- l-methyl-2-methylsulfanyl-ethyl]carbamate;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] iV-[(lSJ- l-methyl-2-methylsulfinyl-ethyl]carbamate;

[l-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] iV-[(lSJ- l-methyl-2-methylsulfonyl-ethyl]carbamate;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] N-( 1 ,1 - dioxothiolan-3-yl)carbamate; [l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] 3-(3- pyridyloxy ) azetidine- 1 -c arboxylate ;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] 3-(2- pyridyl) azetidine- 1 -carboxylate;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] N-( 1 - cyclopropyl- 1 -deuterio-ethyl)carbamate;

[ 1 -[3-(Mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyndin -5-ylJ-4-pipcndylJ N-( 1 - deuterio- 1 -methyl-ethyl)carbamate;

[2,2,6,6-Tetradeuterio-l-[3-(methylcarbamoyl)-7-(trifluorome thyl)thieno[3,2-h]pyridin-5-yl]- 4-piperidyl] V-cyclopropylcarbamatc;

[2,2,6,6-Tetradeuterio-l-[3-(methylcarbamoyl)-7-(trifluorome thyl)thieno[3,2-h]pyridin-5-yl]- 4-piperidyl] /V-isopropylcarbamate;

[(l ?,5S)-8-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h ]pyridin-5-yl]-8- azabicyclo[3.2.l]octan-3-yl] V-cyclopropylcarbamatc;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] iV-[(lSJ- 2,2-dideuterio-l-methyl-2-(trideuteriomethoxy)ethyl]carbamat e;

[(l ?,5S)-8-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h ]pyridin-5-yl]-8- azabicyclo[3.2.l]octan-3-yl] /V-cyclopropylcarbamate;

[ 1 -[3-(Mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?]pyndin -5-yl]-4-pipcndyl] N-[(IR)- 2-fluoro- 1 -methyl-ethyl] carbamate;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] A/-[(lSj- 2-fluoro- 1 -methyl-ethyl] carbamate;

[l-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] N- [cyclopropyl(dideuterio)methyl]carbamate;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] N-[2- fluoro- 1 -(fluoromethyl)ethyl]carbamate;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] 6- hydroxy-8-oxa-2-azaspiro[3.4]octane-2-carboxylate;

[l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] 6- [(2,2,2-trifluoro-l-methyl-ethyl)amino]-8-oxa-2-azaspiro[3.4 ]octane-2-carboxylate; [l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5-yl]-4-piperidyl] 3-(2,2,2- trifluoroethoxy)azetidine- 1 -carboxylate;

[2-Fluoro-l-(fluoromethyl)ethyl] A/-[l-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?Jpyridin-5-ylJ-4-pipcridylJcarbamatc;

5-[4-[(2-Ethylthiazol-4-yl)methyl]piperazin-l-yl]-/V-methyl- 7-(trifluoromethyl)thieno[3,2-

/?]pyndinc-3-carboxamidc;

/V-Methyl-5-[4-[(4-methyl-2-thienyl)methyl]piperazin-l-yl]-7 -(trifluoromethyl)thieno[3,2-

/?]pyndinc-3-carboxamidc;

A/-Methyl-5-[4-[(2-methyloxazol-4-yl)methyl]piperazin-l-yl]- 7-(trifluoromethyl)thieno[3,2-

/?Jpyridinc-3-carboxamidc;

5-[4-(Isobutylcarbamoyl)- l -pipcridylJ- V- mcthyl-7-(trin uoromcthyl)thicno[ 3, 2-/?J pyridinc-3- carboxamide;

5-[4-(2-Hydroxy-4, 4-dimethyl-pentyl )piperazin-l-yl]-/V-methyl-7-(trifluoromethyl)thieno[3, 2- h]pyridine-3-carboxamide;

5-[4-[l-(4,4-Dimethyl-5H-oxazol-2-yl)ethyl]piperazin-l-yl]-/ V-methyl-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

5- [4- [3 -(Cycloprop ylmethoxy)pyrrolidin- 1 -yl] - 1 -piperidyl] -/V-mcthyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

5-[4-(2-Hydroxy-3-isopropoxy-propyl)piperazin-l-yl]-/V-me thyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

5-[4-(2-Isopropoxyethylamino)-l-piperidyl]-/V-methyl-7-(trif luoromethyl)thieno[3,2- h]pyridine-3-carboxamide;

5-[4-(3-ieri-Butoxy-2-hydroxy-propyl)piperazin-l-yl]-/V-meth yl-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

5 - [4-(3 -Isopropoxypyrrolidin- 1 -yl)- 1 -piperidyl] -N- methyl-7 -(trifluoromethyl)thieno [3 ,2- h]pyridine-3-carboxamide;

5-[4-(4-Hydroxy-4-methyl-pent-2-ynyl)piperazin-l-yl]-/V-meth yl-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

5 - [4-(3 -Hydroxy-3 -methyl -but- 1 -ynyl)- 1 -piperidyl] -/V-methyl-7 -(trifluoromethyl)thieno [3 ,2- h]pyridine-3-carboxamide; 5 - [4-(5-Hydroxy-5-methyl-hexa- 1 ,3 -diynyl)- 1 -piperidyl] -/V-methyl-7- (trinuoromcthyl)thicno[3,2-/?]pyridinc-3-carboxamidc;

5-[4-(4-Hydroxy-4-methyl-pent-2-ynoxy)-l-piperidyl]-/V-me thyl-7- (trifluoromethyl)thieno[3,2-/?]pyridine-3-carboxamide;

[ 1 , 1 -Dimcthyl-4-[ [ 1 -[3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2-/?Jpyrid in-5-ylJ-4- piperidyl]oxy]but-2-ynyl] acetate;

5 - [4-Hydroxy-4-(5-hydroxy-5-methyl-hexa- 1 ,3 -diynyl)- 1 -piperidyl] -/V-methyl-7 - (trifluoromethyl)thieno[3,2-/?]pyridine-3-carboxamide;

5-[2-(Cyclopropylmethoxy)-4-oxa-8-azaspiro[4.5]decan-8-yl ]-/V-methyl-7- (trifluoiOmcthyl)thicno[3,2- ?Jpyridinc-3-carboxamidc;

5-[2-(2-Hydroxy-2-methyl-propoxy)-4-oxa-8-azaspiro[4.5]decan -8-yl]-/V-methyl-7-

(trifluoromethyl)thieno[3,2-/?]pyridine-3-carboxamide;

5-(2-Hydroxy-4-oxa-8-azaspiro[4.5]decan-8-yl)-/V-methyl-7-(t rifluoromethyl)thieno[3,2-

/?]pyridinc-3-carboxamidc;

5-[6-(Cyclopropylmethoxy)-8-oxa-2-azaspiro[3.4]octan-2-yl]-/ V-methyl-7-

(trinuoromcthyl)thicno[3,2-/?]pyridinc-3-carboxamidc;

5-[6-(3,3-Difluoropyrrolidin-l-yl)-8-oxa-2-azaspiro[3.4]octa n-2-yl]-/V-methyl-7-

(trinuoromcthyl)thicno[3,2-/?]pyridinc-3-carboxamidc;

A/-Methyl-7-(trifluoromethyl)-5-[6-[(2,2,2-trifluoro-l-methy l-ethyl)amino]-8-oxa-2- azaspiiO[3.4]octan-2-yl]thicno[3,2-/?]pyndinc-3-carboxamidc trifluoroacetate;

tert- Butyl 2-[3-(mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?]pyrid in-5-yl]-2,6- diazaspiro[3.3]heptane-6-carboxylate;

tert- Butyl 7-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl]-2,7- diazaspiro [3.5] nonane-2-carboxylate;

5-[6-(2-ieri-Butoxyacetyl)-2,6-diazaspiro[3.3]heptan-2-yl]- V-methyl-7-

(tnfluoromcthyl)thicno[3,2-/?]pyridinc-3-carboxamidc;

5 - [2-(2-/er/-Butoxyacetyl)-2,7-diazaspiro [3.5] nonan-7-yl] -/V-methyl-7 - (tnfluoromcthyl)thicno[3,2-/?]pyridinc-3-carboxamidc;

tert- butyl 2-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl]-2,7- diazaspiro [3.5] nonane-7-carboxylate; 5-[7-(2-ieri-butoxyacetyl)-2,7-diazaspiro[3.5]nonan-2-yl]- V-methyl-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

5 - [2- [2-(Isopropylamino)-2-oxo-ethyl] -2,7-diazaspiro [3.5] nonan-7-yl] -N- methyl-7 - (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

/V-Methyl-5-[2-(4-methylpyrimidin-2-yl)-2,7-diazaspiro[3. 5]nonan-7-yl]-7- (tnfluoromcthyl)thicno[3,2-/?Jpyndinc-3-carboxamidc;

5 - [2-(Cyclopropylmethylcarbamoyl)-2,7-diazaspiro [3.5] nonan-7-yl] -/V-methyl-7- (tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

Cyclopropylmethyl 7-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl]- 2,7-diazaspiro[3.5]nonane-2-carboxylate;

/V-Mcthyl-5 - [2- [(25 )- 1 -methylpyrrolidine-2-carbonyl] -2,7-diazaspiro [3.5 ] nonan-7-yl] -7 - (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

/V-methyl-5-[2-(4-methylpiperazine-l-carbonyl)-2,7-diazaspir o[3.5]nonan-7-yl]-7-

(tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5 - [2- [2-(3 ,3 -Difluoropyrrolidin- 1 -yl)acetyl] -2,7-diazaspiro [3.5] nonan-7-yl] - /V-methyl-7- (tnfluoromcthyl)thicno[3,2-/?Jpyridinc-3-carboxamidc;

5 - [2- [2- [(37? )-3 -Fluoropyrrolidin- 1 -yl] acetyl] -2,7-diazaspiro [3.5] nonan-7-yl] -N- methyl-7 - (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

5-[2-(2-Hydroxy-3,3-dimethyl-butyl)-2,7-diazaspiro[3.5]nonan -7-yl]-/V-methyl-7-

(tnfluoromcthyl)thicno[3,2-/?]pyridinc-3-carboxamidc;

5 - [2-(3 -Hydroxy-3 -methyl -butanoyl)-2,7-diazaspiro [3.5] nonan-7-yl] -N- methyl-7 - (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide hydrochloride;

/V-Methyl-5- [2- [2-(trifluoromethoxy)acetyl] -2,7-diazaspiro [3.5] nonan-7-yl] -7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

5 - [2-(2-Methoxypropanoyl)-2,7 -diazaspiro [3.5] nonan-7-yl] - /V-methyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

(2-Methoxy- 1,1 -dimethyl-ethyl) 7-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- h]pyridin-5-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate;

V-Mcthy 1-5- [6-(4- methyl pipcrazinc- 1 -carbonyl )-2,6-diazaspiro[ 3.3] hcptan-2-yl] -7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide; /V-Methyl-5-[2-(3,3,3-trifluoro-2-hydroxy-propanoyl)-2,7-dia zaspiro[3.5]nonan-7-yl]-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide;

(3 -Hydroxy-3 -methyl-butyl) 4-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- b ] pyridin-5 - yl] piperidine- 1 -carboxylate ;

tert- Butyl 7-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl]-2- azaspiro [3.5] nonane-2-carboxylate;

2-(Trifluoromethoxy)ethyl 4-[l-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- h] pyridin-5 - yl] ethyl] piperazine- 1 -c arboxylate ;

2-(Trifluoromethoxy)ethyl 7-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5- yl]-2-azaspiro[3.5]nonane-2-carboxylate;

Methyl 5- [( 1 -ier/-butoxycarbonyl-4-piperidyl)amino] -7-(trifluoromethyl)thieno [3 ,2- h]pyridine-3 -carboxylate ;

Methyl 5-[(l-/eri-butoxycarbonylpyrrolidin-3-yl)amino]-7-(trifluoro methyl)thieno[3,2- h]pyridine-3-carboxylate;

Methyl 5- [( 1 -ier/-butoxycarbonyl-4-piperidyl)methylamino] -7-(trifluoromethyl)thieno [3 ,2- h]pyridine-3-carboxylate;

5-[2-(2-Isopropylthiazol-4-yl)ethylamino]-/V-methyl-7-(trifl uoromethyl)thieno[3,2-h]pyridine-

3-carboxamide;

Methyl 5-[2-(l-ier/-butoxycarbonylpyrrolidin-3-yl)ethynyl]-7-(trifl uoromethyl)thieno[3,2- h]pyridine-3-carboxylate;

Butyl 4-hydroxy-4-[2-[3-(methylcarbamoyl)-7-(trifluoromethyl)thien o[3,2-h]pyridin-5- yl]ethynyl]piperidine-l-carboxylate;

[(lS)-l -Cycloprop ylethyl] 3-[[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din- 5-yl]oxymethyl]azetidine-l-carboxylate;

/ _<?/ 7- Butyl 6-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl]oxy-8-oxa-2- azaspiro[3.4]octane-2-carboxylate;

Butyl 2-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5-yl]oxy-4-oxa-8- azaspiro[4.5]decane-8-carboxylate;

V-Mcthyl-5 - [5- [3 -(3 -pyridyl)azetidine- 1 -carbonyl] -3 -furyl] -7-(trifluoromethyl)thieno [3 ,2- h]pyridine-3-carboxamide; 5- [4- [4-(2-Hydroxy-2-methyl-propyl)piperazin- 1 -yl]phenyl] -/V-methyl-7 - (trifluoromethyl)thieno[3,2-/?]pyridine-3-carboxamide;

5-[6-(6-Chloro-3-pyridyl)-3-pyridyl]-/V-methyl-7-(trifluorom ethyl)thieno[3,2-/?]pyridine-3- carboxamide;

5 - [6-(3 -Isopropoxyazetidin- 1 -yl)-3 -pyridyl] -/V-methyl-7-(trifluoromethyl)thieno [3 ,2- /?]pyridinc-3-carboxamidc; trifluoroacetate;

5- [6- [2-( 1 -hydroxycyclohexyl)ethynyl] -3 -pyridyl] - /V - m c t h y 1 - 7 - ( t ri fl u o ro m c t h y 1 ) t h i c n o [ 3 ,2- /?]pyridinc-3-carboxamidc; trifluoroacetate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl (l-(lH- imidazol- l-yl)propan-2-yl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl 2- methyl-4-( 1H- 1 ,2,4-triazol- 1 -yl)piperidine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-Z?]p yridin-5-yl)piperidin-4-yl (1- (methylsulfonyl)azetidin-3-yl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl 2- methyl-4-(methylsulfonyl)piperazine-l -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-Z?]p yridin-5-yl)piperidin-4-yl (Sj-(l- cyclopropylpropan-2-yl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl (/?)-(l- cyclopropylpropan-2-yl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl (oxetan- 3-ylmethyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-Z?]p yridin-5-yl)piperidin-4-yl ((3- hydroxyoxetan-3-yl)methyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl ((3- fluorooxetan-3-yl)methyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl (R)- 2- methylazetidine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-Z?]p yridin-5-yl)piperidin-4-yl (S)-2- methylazetidine- 1 -carboxylate; l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl 3- methoxyazetidine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl 2-oxa-6- azaspiro[3.3]heptane-6-carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl 6- methyl-2,6-diazaspiro[3.3]heptane-2-carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl 5,8- dioxa-2-azaspiro[3.4]octane-2-carboxylate;

l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl (25/-3- cyclopropyl-3-hydroxy-2-methylazetidine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl (25,35/- 3-hydroxy-2-methylpyrrolidine-l-carboxylate;

Cyclopropylmethyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5- yl)piperazine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-Z?]p yridin-5-yl)piperidin-4-yl (2- fluoroethyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl (2,2- difluoroethyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl (methyl- d3 /carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-Z?]p yridin-5-yl)piperidin-4-yl (3- mcthoxycyclobutyl /carbamate;

(+/-)- l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl ((lr,3r)-3-cyanocyclobutyl)carbamate;

(+/-)- l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-Z?]pyri din-5-yl)piperidin-4-yl (( 1 s,3 s)-3-cyanocyclobutyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl (3- ethoxycyclobutyl/carbamate;

(+/-)- l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl ((lr,3r)-3-(methylsulfonyl)cyclobutyl)carbamate; (+/-)- l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl ((ls,3s)-3-(methylsulfonyl)cyclobutyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl (2- oxaspiro[3.3]heptan-6-yl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl ((2- methyltetraliydrofuran-2-yl)methyl)carbamate;

Cyclopropyl ( 1 -(3-(mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin- 4-yl)carbamate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl (25,35/- 3-(dimethylamino)-2-methylazetidine-l-carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl (25,35/- 3-(dimethylamino)-2-methylazetidine-l-carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl (5/-(l- (oxetan-3-yl)ethyl)carbamate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl (5/-( 1 - (oxetan-3-yl)ethyl)carbamate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl (25,35/- 3-methoxy-2-methylazetidine-l-carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl [1,3'- biazetidine] - l'-carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl (2'5,3'5/- 2'-methyl- [ 1 ,3 '-biazetidine] - 1 '-carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl (25,35/- 3-hydroxy-2-methylpyrrolidine-l-carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl (25,35/- 3-hydroxy-2,3-dimethylpyrrolidine-l-carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl (25,35/- 3-cyano-2-methylazetidine-l-carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl 6- (cyanomethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate; l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (25,35/- 3-(cyanomethyl)-2-methylazetidine-l-carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl (25,35/- 3-(cyanomethyl)-2-methylazetidine-l-carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl 1- methyl-l,6-diazaspiro[3.3]heptane-6-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyri din-5-yl)piperidin-4-yl (5/-pcnt- 3-yn-2-ylcarbamate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl (5/-pcnt- 3-yn-2-ylcarbamate;

(25,35/- 1 ,2-Dimcthylpyrrolidin-3-yl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?]pyndin-5-yl)pipcndin-4-yl /carbamate;

(5/-l-(2,2-Difluoroethyl)pyrrolidin-3-yl (l-(3-(methylcarbamoyl)-7- (trifluoiOmcthyl)thicno[ 3, 2-/?Jpyridin-5-yl)pipcridin-4-yl /carbamate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl 6- methyl- 1 ,6-diazaspiro[3.3]heptane- l-carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl (25,35/-

2-methyl-3 -( 1 H- 1 ,2,4-triazol- 1 -yl)azetidine- 1 -carboxylate;

1 -(3-(mcthylcarbamoyl)-7-(tnfluoiOmcthyl)thicno[3,2-/?Jpyridi n-5-yl)pipcridin-4-yl (5/-( 5- hydroxy-5-methylhex-3-yn-2-yl)carbamate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl (5/-(5- hydroxy-5-methylhex-3-yn-2-yl)carbamate;

l-Methylazetidin-3-yl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5- yl)piperidin-4- yl)c arbamate ;

Isopropyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5-yl)piperidin-4- yl)carbamate;

2,2-Difluoroethyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5- yl)piperidin-4- yl)c arbamate ;

l-(l,3-Difluoropropan-2-yl)azetidin-3-yl (l-(3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-/?]pyridin-5-yl)piperidin-4-yl)c arbamate; Methyl-ch (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5-yl)piperidin-4- yl)carbamate;

2-Fluoroethyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5- yl)piperidin-4- yl)c arbamate ;

l-Fluoropropan-2-yl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]pyr idin-5- yl)piperidin-4- yl)c arbamate ;

s,3s)-3-((3-(Mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- /?Jpyridin-5- yl)oxy)cyclobutyl oxetan-3-ylcarbamate;

(ls,3s)-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3, 2-/?]pyridin-5-yl)oxy)cyclobutyl

3-methoxyazetidine-l-carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl l-oxa-6- azaspiro[3.3]heptane-6-carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl ((SJ-l- ((SJ-oxetan-2-yl)ethyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl ((R)- 1 - ((SJ-oxetan-2-yl)ethyl)carbamate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl (2S,3R)- 3-cyano-2-methylpyrrolidine-l-carboxylate;

(S)- 1 -((5 ₎ -Oxctan-2-yl)cthyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?Jpyridin-5-yl)pipcridin-4-yl)carbamatc;

(SJ-l-(( ?J-Oxetan-2-yl)ethyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?]pyndin-5-yl)pipcndin-4-yl)carbamatc;

s,3s)-3-((3-(Mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- /?Jpyridin-5- yl)oxy)cyclobutyl isopropylcarbamate;

s,3s)-3-((3-(Mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- /?Jpyridin-5- yl)oxy)cyclobutyl 3-(trifluoromethoxy)azetidine- l-carboxylate;

s,3s)-3-((3-(Mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- /?Jpyridin-5- yl)oxy)cyclobutyl 3-hydroxy-3-methylazetidine- l-carboxylate;

(+/-)- 7.s-( l s,3/^-3-((3-(Mcthylcarbamoyl)-7-(tnriuoiOmcthyl)thicno[3,2-/ ?]pyndin-5- yl)oxy)cyclobutyl (( S )- l-(trifluoromethoxy)propan-2-yl)carbamate; (+/-)-c7.s-( 1 s,3s)-3-((3-(Mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- ?Jpyridin-5- yl)oxy)cyclobutyl 3-(dimethylamino)azetidine-l-carboxylate;

4-Fluoro-l-methylpyrrolidin-3-yl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?]pyndin-5-yl)oxy)pipcridinc- l -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl 3-(lH- imidazol- 1 -yl)azetidine- 1 -carboxylate;

1 -(3-(Mcthylcarbamoyl)-7-(trinuoromcthyl)thicno[3,2-/?Jpyndin -5-yl)pipcridin-4-yl 3-(lH- 1,2,3 -triazol- 1 -yl) azetidine- 1 -c arboxylate ;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl 3-(lH- 1, 2, 4-triazol-l-yl)azetidine-l -carboxylate;

(+/-)-/f<ms-3-Fluoro- 1 -(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2- ?Jpyridin-5- yl)piperidin-4-yl 3-(lH-l ,2,4-triazol- l-yl)azetidine- 1 -carboxylate;

(+/-)- .s-3-Fluoro- l -(3-(mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2-/?Jpyrid in-5- yl)piperidin-4-yl 3-(lH-l ,2,4-triazol- l-yl)azetidine- 1 -carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl 1- cyclopropyl-l,6-diazaspiro[3.3]heptane-6-carboxylate;

l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-/?]p yridin-5-yl)piperidin-4-yl l-ethyl- l,6-diazaspiro[3.3]heptane-6-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-Z?]pyri din-5-yl)piperidin-4-yl l-(2,2,2- trifluoroethyl)- 1 ,6-diazaspiro[3.3]heptane-6-carboxylate;

(+/-)-/raH.s-2-(Tnfluoromcthoxy)cthyl 3-methyl-4-((3-(methylcarbamoyl)-7- (trinuoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxylate;

(+/-)-cz5-2-(Trifluoromethoxy)ethyl 3-methyl-4-((3-(methylcarbamoyl)-7- (trinuoromcthyl)thicno[3,2-/?Jpyndin-5-yl)oxy)pipcndinc- 1 -carboxylate;

2-(Trifluoromethoxy)ethyl ( ?J-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?]pyndin-5-yl)oxy)pipcndinc- l -carboxylate;

2-(Trifluoromethoxy)ethyl (SJ-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?Jpyridin-5-yl)oxy)pipcridinc- l -carboxylate;

tert- Butyl 2,2-dimethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thie no[3,2-/z]pyridin-5- yl)oxy)piperidine- 1 -carboxylate; (SJ-l-(Trifluoromethoxy)propan-2-yl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?]pyndin-5-yl)oxy)pipcndinc- l -carboxylatc;

(R)- 1 -(TnfluoiOmcthoxy)propan-2-yl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?Jpyridin-5-yl)oxy)pipcridinc- l -carboxylatc;

(5)-2-(Trifluoromethoxy)propyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?Jpyridin-5-yl)oxy)pipcridinc- l -carboxylatc;

( ?)-2-(Trifluoromethoxy)propyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?Jpyridin-5-yl)oxy)pipcridinc- l -carboxylatc;

(SJ-l-(Trifluoromethoxy)propan-2-yl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- Z?]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

(5)-l-(Trifluoromethoxy)propan-2-yl (5)-3-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-/?]pyridin-5-yl)oxy)pyrrolidine- l-carboxylate;

( 35, 45J-3- ethyl- 1 -(3-( mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2-/?Jpyridin-5- yl)piperidin-4-yl isopropylcarbamate;

(35,45/-3-Mcthyl- l -(3-( mcthylcarbamoyl)-7-(trifluoiOmcthyl)thicno[3,2-/?Jpyridin-5- yl)piperidin-4-yl 3-(trifluoromethoxy)azetidine- l-carboxylate;

(5/ - 2 - (T r i fl u o ro m c t h o x y ) p ro p y 1 ( J-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- Z?]pyridin-5-yl)oxy)pyrrolidine- l-carboxylate;

(5 / - 2 - (T r i P u o ro m c t h o x y ) p ro p y 1 ( J-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?]pyridin-5-yl)oxy)pyrrolidine- l-carboxylate;

(5/ - 2 - (T r i P u o ro m c t h o x y ) p ro p y 1 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

( ?)-2-(Trifluoromethoxy)propyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

2-(Trifluoromethoxy)ethyl 2,2-dimethyl-4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-/?]pyridin-5-yl)oxy)piperidine- l-carboxylate;

(35,45/-3-mcthyl- 1 -(3-( Mcthylcarbamoyl)-7-(tnfluoromcthyl)thicno[3,2-/?Jpyndin-5- yl)piperidin-4-yl isopropylcarbamate;

(35,45/-3-Mcthyl- 1 -(3-( mcthylcarbamoyl)-7-(tnfluoromcthyl)thicno[3,2-/?Jpyndin-5- yl)piperidin-4-yl 3-(trifluoromethoxy)azetidine- l-carboxylate; (S)- 1 -Cyanopropan-2-yl 4-((3-(mcthylcarbamoyl)-7-(trifluoromcthyl)thicno[3,2-/?Jpyn din-5- yl)oxy)piperidine- l-carboxylate;

(S)- 1 -Cyanopropan-2-yl (2 ?,4 ?J-2-methyl-4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)piperidine- l-carboxylate;

(SJ-l -Cycloprop ylethyl (2 ?,4 ?J-2-methyl-4-((6-methyl-3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)piperidine- l-carboxylate;

2-Hydroxy-2-methylpropyl (2 ?,4 ?J-2-methyl-4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)piperidine- l-carboxylate;

1-(2,2,2-Trifluoroethyl)pyrrolidin-3-yl 4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)piperidine- l-carboxylate;

2-(Fluoromethoxy)ethyl 4-((3-(mcthylcarbamoyl)-7-(tnfluoromcthyl)thicno[3,2-/?Jpyri din-5- yl)oxy)piperidine- l-carboxylate; or

(S)- 1 -(3-Fluoroazctidin- 1 -yl)propan-2-yl (2 ?,4 ?J-2-methyl-4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)piperidine- l-carboxylate.

[0021] In another aspect, the present application is directed to a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier or adjuvant.

[0022] In some embodiments, the pharmaceutical composition described herein further comprises one or more additional therapeutic agents.

[0023] In another aspect, the present application is directed to a method of treating or lessening the severity of metachromatic leukodystrophy in a patient, comprising administering to the patient an effective amount of a compound described herein or a pharmaceutical composition comprising a compound described herein.

[0024] In another aspect, the present application is directed to a method of lowering or reducing sulfatides in a patient, comprising administering to the patient an effective amount of a compound described herein or a pharmaceutical composition comprising a compound described herein.

[0025] In another aspect, the present application is directed to a method of treating or lessening the severity of Krabbe’s disease in a patient, comprising administering to the patient an effective amount of a compound described herein or a pharmaceutical composition comprising a compound described herein.

DEFINITIONS [0026] The following definitions apply unless otherwise indicated.

[0027] As used herein, each occurrence of any constituent variable anywhere in the present disclosure is intended to be independently selected from among its indicated options.

[0028] As used herein, the term "pharmaceutically acceptable salt" refers to either a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt of a currently disclosed compound that may be administered without any resultant substantial undesirable biological effect(s) or any resultant deleterious interaction(s) with any other component of a pharmaceutical composition in which it may be contained.

[0029] As used herein, the term "prodrug" means a pharmacological derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug. For example, prodrugs are variations or derivatives of the compounds of Formula I, or any of 1.1-1.300, that have groups cleavable under certain metabolic conditions, which when cleaved, become the compounds of Formula I, or any of 1.1-1.300. Such prodrugs then are pharmaceutically active in vivo, when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. Prodrug compounds herein may be called single, double, triple, etc., depending on the number of biotransformation steps required to release the active drug within the organism, and the number of functionalities present in a precursor- type form. Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (See, Bundgard, Design of Prodrugs, pp. 7-9, 21 -24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, CA, 1992). Prodrugs commonly known in the art include well-known acid derivatives, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, amides prepared by reaction of the parent acid compound with an amine, basic groups reacted to form an acylated base derivative, etc. Of course, other prodrug derivatives may be combined with other features disclosed herein to enhance

bioavailability. As such, those of skill in the art will appreciate that certain of the presently disclosed compounds having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of the presently disclosed compounds. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds having a carbonate, carbamate, amide or alkyl ester moiety covalently bonded to any of the above substituents disclosed herein.

[0030] As used herein, a pharmaceutically acceptable carrier or excipient (adjuvant) refers to compositions included with the compound of Formula I, or any of 1.1-1.300, for delivery, stability or solubility of the compound in formulations, including but not limited to any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.

[0031] As used herein, "effective amount" of an enzyme or small molecule, when delivered to a patient in a combination therapy, is an amount sufficient to improve the clinical course of a lysosomal storage disease, where clinical improvement is measured by any of the variety of defined parameters well known to the skilled artisan.

[0032] As used herein, the terms,“patient”,“subject” and“human” are used interchangeably.

[0033] As used herein,“UGT8” means UDP glycosyltransferase 8— the enzyme that with the co-factor Saposin 1 catalyzes the transfer of galactose from UDP-galactose to ceramide to make galactosyl ceramide (GalCer), also known as galactosyl cerebroside. Other names for UGT8 include UDP-galactose-ceramide galactosyltransferase, 2-hydroxyacylsphingosine 1- betagalactosyl transferase, ceramide UDP galactosyltransferase, ceramide galactosyl transferase and cerebroside synthase. GalCer, in turn, is the substrate for galactose-3-O-sulfotransferase 1 (GAL3ST1), which transfers sulfate to GalCer, yielding sulfatide (SFT), which is a major component of the myelin sheath. Other names for this enzyme include galactosylceramide sulfotransferase. Patients with mutations in arylsulfatase A (ARSA) are unable to degrade SFT back to GalCer and sulfate, resulting in Metachromatic Leukodystrophy (MLD) disease. MLD patients therefore accumulate SFT, which results in demyelination. Similarly, patients with mutations in galactosylcerebrosidase (GalC) are unable to break down GalCer to galactose and ceramide, resulting in Krabbe disease. Krabbe patients accumulate psychosine and to a lesser extent, GalCer, which also result in demyelination. For these two diseases, substrate reduction therapy (SRT) consists of inhibiting biosynthesis of GalCer by UGT8, thereby preventing accumulation of the toxic products SFT and psychosine, respectively, that are responsible for disease manifestations.

[0034] As used herein, the term“combination therapy” means treating a patient with two or more therapeutic platforms (e.g., enzyme replacement therapy and small molecule therapy) in rotating, alternating and/or simultaneous treatment schedules. Examples of treatment schedules may include, but are not limited to: (1) enzyme replacement therapy, then small molecule therapy; (2) small molecule therapy, then enzyme replacement therapy; (3) enzyme replacement therapy concurrent with small molecule therapy, and (4) and any combination of the foregoing.

Combination therapy may provide a temporal overlap of therapeutic platforms, as needed, depending on the clinical course of a given storage disease in a given subject.

[0035] As used herein, the term“enzyme replacement therapy”, or“ERT” means

administering an exogenously-produced natural or recombinant enzyme to a patient who is in need thereof. In the case of a lysosomal storage disease, for example, the patient accumulates harmful levels of a substrate (i.e., material stored) in lysosomes due to a deficiency or defect in an enzyme responsible for metabolizing the substrate, or due to a deficiency in an enzymatic activator required for proper enzymatic function. Enzyme replacement therapy is provided to the patient to reduce the levels of (i.e., debulk) accumulated substrate in affected tissues. Enzyme replacement therapies for treating lysosomal storage diseases are known in the art.

[0036] The components of a disclosed combination may be administered to a patient simultaneously or sequentially. It will be appreciated that the components may be present in the same pharmaceutically acceptable carrier and, therefore, are administered simultaneously.

Alternatively, the active ingredients may be present in separate pharmaceutical carriers, such as, conventional oral dosage forms, that can be administered either simultaneously or sequentially.

[0037] As used herein,“MLD” (Metachromatic Leukodystrophy) refers to a disease in patients with mutations in the enzyme aryl sulfatase A (ARSA) which results in the inability to degrade SFT back to GalCer and sulfate. As a result, SFT accumulates in the central and peripheral nervous tissues, which induces neuropathology leading to demyelination and death.

[0038] As used herein,“Krabbe disease” refers to a disease in patients with mutations in galactosylcerebrosidase (GalC) which results in the inability to degrade GalCer back to galactose and ceramide. The accumulation of UGT8 and psychosine (another substrate for GalC) in the central and peripheral nervous systems also induces neuropathy leading to demyelination and death.

[0039] As used herein, the term“alkyl” refers to monovalent saturated aliphatic free radical groups of up to 20 carbon atoms and a corresponding number of hydrogen atoms. The

hydrocarbon chain may be straight chained or branched. The term“Ci- ₆ alkyl” means a saturated linear or branched free radical consisting essentially of 1 to 6 carbon atoms and a corresponding number of hydrogen atoms. Exemplary“Ci- ₆ alkyl” groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, / _{<? /7} -butyl, etc. Of course, other“Ci- ₆ alkyl” groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. The term“alkyl” also includes“cycloalkyl” groups as further described below.

[0040] As used herein, the term "cycloalkyl" means a nonaromatic saturated or unsaturated free radical forming at least one ring consisting essentially of 3 to 10 carbon atoms and a corresponding number of hydrogen atoms. The term“cycloalkyl” therefore includes cycloalkenyl groups, as further defined below. As such, cycloalkyl groups can be monocyclic or polycyclic. Individual rings of such polycyclic cycloalkyl groups can have different connectivities, e.g., fused, bridged, spiro, etc., in addition to covalent bond substitution. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbomanyl, bicyclo[3.2.l ]octanyl, octahydro-pentalenyl, spiro[4.5]decanyl, cyclopropyl, adamantyl, substituted with cyclobutyl, cyclobutyl substituted with cyclopentyl, cyclohexyl substituted with cyclopropyl, etc. Of course, other cycloalkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. As used herein, the term "heterocycloalkyl" means a nonaromatic free radical having 3 to 10 atoms (i.e., ring atoms) that form at least one ring, wherein 2 to 9 of the ring atoms are carbon and the remaining ring atom(s) (i.e., hetero ring atom(s)) is selected from the group consisting of nitrogen, sulfur, and oxygen. As such, heterocycloalkyl groups can be monocyclic or polycyclic. Individual rings of such polycyclic heterocycloalkyl groups can have different connectivities, e.g., fused, bridged, spiro, etc., in addition to covalent bond substitution.

Exemplary heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, azindinyl, azetidinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl, l,3-oxazolidin-3-yl, isothiazolidinyl, l,3-thiazolidin-3-yl, l,2-pyrazolidin-2-yl, l,3-pyrazolidin-l-yl, piperidinyl, thiomorpholinyl, l,2-tetrahydrothiazin-2- yl, l,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, l,2-tetrahydrodiazin-2-yl, 1,3- tetrahydrodiazin-l-yl, tetrahydroazepinyl, piperazinyl, piperizin-2-onyl, piperizin-3-onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, imidazolidinyl, 2-imidazolidinyl, l,4-dioxanyl, 8- azabicyclo[3.2.l]octanyl, 3-azabicyclo[3.2.l]octanyl, 3,8-diazabicyclo[3.2.l]octanyl, 2,5- diazabicyclo[2.2.l]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[l ,2- a]pyrazinyl, 3-azabicyclo[4.l.0]heptanyl, 3-azabicyclo[3.l.O]hexanyl, 2-azaspiro[4.4]nonanyl, 7- oxa-l-aza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl, octahydro-lH-indolyl, etc. In general, the heterocycloalkyl group typically is attached to the main structure via a carbon atom or a nitrogen atom. Of course, other heterocycloalkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.

[0041] As used herein, the term "heteroaryl" means an aromatic free radical having 5 to 10 atoms (i.e., ring atoms) that form at least one ring, wherein 2 to 9 of the ring atoms are carbon and the remaining ring atom(s) (i.e., hetero ring atom(s)) is selected from the group consisting of nitrogen, sulfur, and oxygen. As such, heteroaryl groups can be monocyclic or polycyclic.

Individual rings of such polycyclic heteroaryl groups can have different connectivities, e.g., fused, etc., in addition to covalent bond substitution. Exemplary heteroaryl groups include furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, l,3,5-oxadiazolyl, l,2,4-oxadiazolyl, l,2,3-oxadiazolyl, l,3,5-thiadiazolyl, l,2,3-thiadiazolyl,

1.2.4-thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, l,2,4-triazinyl, l,2,3-triazinyl,

1.3.5-triazinyl, pyrazo lo [ 3 A-b\ pyridi n y 1 , cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[l ]pyridinyl, benzo[h]thiophenyl, 5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianapthenyl, isothianapthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and benzoxazinyl, etc. In general, the heteroaryl group typically is attached to the main structure via a carbon atom,

[0042] However, those of skill in the art will realize when certain other atoms, e.g., hetero ring atoms, can be attached to the main structure. Of course, other heteroaryl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.

[0043] As used herein, the term "aryl" means phenyl or naphthyl.

[0044] As used herein,“alkenyl” means a linear or branched free radical having a specified number of carbon atoms and having at least one double bond. [0045] As used herein, the term "cycloalkenyl" means an alkenyl free radical having at least one double bond that is contained in a closed ring of carbon atoms, but does not have aromatic character. The at least one cycloalkenyl ring may consist essentially of 3 to 10 carbon atoms and a corresponding number of hydrogen atoms. As such, cycloalkenyl groups can be monocyclic or polycyclic. Individual rings of such polycyclic cycloalkenyl groups can have different connectivities, e.g., fused, bridged, spiro, etc., in addition to covalent bond substitution.

Exemplary cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl,

cyclohexenyl, cycloheptenyl, l,3-cyclohexadienyl, 1 ,4-cyclohexadienyl and l,5-cyclooctadienyl, each of which may or may not be further substituted. Of course, other cycloalkenyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.

[0046] As used herein,“alkynyl” means a linear or branched free radical having a specified number of carbon atoms and having at least one triple bond.

[0047] As used herein, the term "halo" or“halogen” means fluorine, chlorine, bromine, or iodine.

[0048] As used herein, the term“haloalkyl” refers to monovalent saturated aliphatic free radical groups of up to 20 carbon atoms and a corresponding number of hydrogen atoms, wherein one or more hydrogen atoms is replaced by a halogen atom. The hydrocarbon chain may be straight chained or branched. The“Ci- ₆ haloalkyl” means a saturated linear or branched free radical consisting essentially of 1 to 6 carbon atoms and a corresponding number of hydrogen atoms, wherein one or more hydrogen atoms is replaced by a halogen atom. Exemplary“Ci- ₆ haloalkyl” groups include trifluoromethyl, difluoromethyl, fluoromethyl, 2-fluoroethyl, 2,2- difluoroethyl, 2,2,2-trifluoroethyl etc. Of course, other haloalkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.

[0049] As used herein, the term "amino" means a free radical having a nitrogen atom and 0, 1 or 2 hydrogen atoms. As such, the term amino generally refers to primary and secondary amines. In that regard, as used herein and in the appended claims, a tertiary amine is represented by the general formula RR7V-, wherein R and R' are carbon radicals that may or may not be identical. Nevertheless, the term "amino" generally may be used herein to describe a primary, secondary, or tertiary amine, and those of skill in the art will readily be able to ascertain the identification of which in view of the context in which this term is used in the present disclosure. [0050] Although specific embodiments of the present disclosure will now be described with reference to the preparations and schemes, it should be understood that such embodiments are by way of example only and merely illustrative of but a small number of the many possible specific embodiments which can represent applications of the principles of the present disclosure. Various changes and modifications will be obvious to those of skill in the art given the benefit of the present disclosure and are deemed to be within the spirit and scope of the present disclosure as further defined in the appended claims.

[0051] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one having ordinary skill in the art to which this disclosure belongs. Although other compounds or methods can be used in practice or testing, certain preferred methods are now described in the context of the following preparations and schemes.

[0052] A number of synthetic protocols were used to produce the compounds described herein. These synthetic protocols (see schemes below) have common intersections and can be used alternatively for synthesis of the compounds described herein.

Scheme 1

[0053] Scheme 1 provides a general scheme to arrive at the compounds described herein. The appropriate acetoacetate (G-1-2) is reacted with (2-substituted)-4-aminothiophene-3-carboxylate (G-1-1) at 130 °C to provide pyridone G-1-3. Chlorination with POCl ₃ provided thienopyridine G-1-4. The methyl ester of G-1-4 undergoes amidation with an appropriate amine to provide G- 1-5. The ester (G-1-6) is hydrolyzed by metal hydroxide to give acid (G-1-7) which is coupled with an appropriate amine, providing various amides (G-1-8).

Scheme 2

G-2-1 G-2-3 ^{G 2} · ⁴

[0054] Scheme 2 provides a general scheme to arrive at the compounds described herein. The appropriate acetoacetate (G-2-2) is reacted with methyl 4-aminoisothiazole-3-carboxylate (G-2-1) to provide pyridone G-2-3. Chlorination with POCl ₃ provided thienopyridine G-2-4.

Scheme 3

[0055] Scheme 3 provides a general scheme to arrive at the compounds described herein. //77-Butyl (4-methylthiophen-3-yl)carbamate (G-3-1) is reacted with 2,2,2-trifluoro -NN- dimethylacetamide (G-3-2) to provide trifluoroacetyl thiophene G-3-3. Cyclization of de-Boc thiophene with isocyanate (G-3-4) provided thienopyrimidine G-3-5. Chlorination with POCI3 and oxidation of methyl provided aldehyde (G-3-6). Nucleophilic aromatic substitution of the pyrimidinyl chloride (G-3-6) with an appropriate hydroxylated nitrogen containing heterocycle (G-3-7) provided G-3-8. Oxidation with oxone provided acid (G-3-9) which was coupled with an appropriate amine to provide amide (G-3-10).

Scheme 4

[0056] Scheme 4 provides a general scheme to arrive at the compounds described herein.

Malonic acid (G-4-2) is reacted with 3-aminothiophene-4-carboxylate (G-4-1) to provide dichlorothienopyridine G-4-3. Amidation with an appropriate amine and substitution with amine/alcohol provided G-4-4. Pyridone (G-4-5) is chlorinated with NCS to provide chloropyridone (G-4-6). Chlorination with POCl ₃ provided dichloro-thienopyridine G-4-7.

Scheme 5

[0057] Scheme 5 provides a general scheme to arrive at the compounds described herein. Methyl ester (G-5-1) is reduced with metal hydrides to provide alcohol G-5-2. Oxidation with Dess-Martin Periodinate and reaction of corresponding aldehyde with an appropriate Grignard reagent (G-5-3) provided secondary alcohol G-5-4. The methyl ester of G-5-lundergoes hydrolysis with an appropriate metal hydroxide to provide G-5-6. Rearrangement of acid (G-5-6) to carbamate (G-5-7) is carried with sodium azide in the presence of a //77-butyl alcohol.

Removal of the BOC protecting group and acylation provided G-5-8. G-5-6 is coupled with the appropriate amino alcohol (G-5-9) to amide G-5-10. Oxidation with DMP provided ketone (G-5- 11) which is cyclized by a dehydrating reagent to provide oxazole (G-5-12).

Scheme 6

[0058] Scheme 6 provides a general scheme to arrive at the compounds described herein. Nucleophilic aromatic substitution of the pyridinyl chloride (G-6-1) with an appropriate nitrogen containing heterocycle (G-6-2) provided /V-substituted G-6-3. Iodination with metal iodide provided iodo-pyridine G-6-4. The iodine of G-6-4 is coupled with an appropriate zinc reagent (G-6-5) in the presence of palladium catalyst to provide C-substituted G-6-6. Pd-catalyzed Coupling reaction of the pyridinyl chloride (G-6-1) with an appropriate aryl boronic acid (G-6-7) or alkyne (G-6-8) provided aryl (alkyne)-substituted G-6-9. O-substituted G-6-11 is prepared by alkylation of the pyridinyl chloride (G-6-1) or Mitsunobu reaction of pyridone G-6-12.

Nucleophilic aromatic substitution of the pyridinyl chloride (G-6-1) with an appropriate thiol (G- 6-13) provided S-substituted G-6-13 which is oxidized to provide sulfoxide and sulfone (G-6-14). Scheme 7

[0059] Scheme 7 provides a general scheme to arrive at the compounds described herein. Hydroxyl activation of nitrogen containing heterocycle (G-7-1) with carbodiimidazole (CDI) or 4-nitro-phenoxyl chloroformate provided G-7-2 which is reacted with an appropriate amine reagent (G-7-3) to provide G-7-4. The carboxylic acid or amino group of nitrogen containing heterocycles (G-7-5/6) is coupled with an appropriate chloroformate, sulfonyl chloride, acyl chloride, isocyanate, or amine reagent (G-7-7/8/9/10) to provide corresponding products (G-7- 11/12/13). The piperazine of nitrogen containing heterocycles (G-7-14) is coupled with an appropriate chloroformate, ketone/aldehyde, alkyl halide, or epoxide reagent (G-7-15/16/17) to provide corresponding products (G-7-18/19/20/21).

Scheme 8

[0060] Scheme 8 provides a general scheme to arrive at the compounds described herein. The amine of O-linked nitrogen containing heterocycles (G-8-1) or C-linked nitrogen containing heterocycles (G-8-2) is coupled with an appropriate chloroformate or acyl halide (G-8-3) to provide corresponding products (G-8-4/5).

[0061] Unless otherwise stated, the structures depicted herein are also meant to include all isomeric forms of the structure. Certain compounds described herein contain one or more asymmetric centers and may give rise to isomers (e.g., enantiomers, diastereomers, racemates and other stereoisomeric forms that may be defined in terms of absolute chemistry, as ( R )- or (S)-.

The present disclosure is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. The present application is meant to include all possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.

[0062] Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present application can be present in racemic or enantiomerically enriched, for example the ( R )-, ( S )- or (A, 5)-co n P g urati o n . In certain embodiments, each asymmetric atom has at least 50%

enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the ( R )- or (Si-configuration. Substituents at atoms with unsaturated bonds may, if possible, be present in cis-( Z)- or /ran.s-(E)-form.

[0063] Accordingly, as used herein, a compound of the present application can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric ( cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.

[0064] Any resulting mixtures of isomers can be separated on the basis of the

physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.

[0065] Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present application into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di- O,O'-r-toluoyl tartaric acid, mandelic acid, malic acid or camphor- lO-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid

chromatography (HPLC) using a chiral adsorbent.

[0066] Since the compounds of the application are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably from 10 to 59% of a compound described herein.

[0067] Compounds of the present application are either obtained in the free form, or as a salt thereof.

[0068] When both a basic group and an acid group are present in the same molecule, the compounds described herein may also form internal salts, e.g., zwitterionic molecules.

[0069] Atoms making up the compounds of the present disclosure also are intended to include isotopic forms of such atoms.

[0070] In an aspect of the present application, compounds of formula I, or any of 1.1-1.300, are described that contain isotope-labelled forms. An isotope-labelled form of a compound of formula I, or any of 1.1-1.300, is identical in structure to this compound apart from the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs in greater natural abundance. Examples of isotopes which are readily

commercially available and which can be incorporated into a compound of formula I, or any of 1.1-1.300, by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example ¾ (deuterium), ³ H (tritium), ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ 0, ¹⁷ 0, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively. A compound of formula I, or any of 1.1-1.300, or a prodrug thereof, or a pharmaceutically acceptable salt of either, which contains one or more of the above-mentioned isotopes and/or other isotopes of other atoms is intended to be part of the present application. An isotope-labelled compound of formula I, or any of 1.1-1.300, can be used in a number of beneficial ways. For example, an isotope-labelled compound of formula I into which, for example, a radioisotope, such as ¹⁴ C, has been incorporated is suitable for medicament and/or substrate tissue distribution assays. These radioisotopes, i.e. tritium ( ³ H) and carbon- 14 ( ¹⁴ C), are particularly preferred owing to simple preparation and excellent detectability. Incorporation of heavier isotopes, for example deuterium (¾), into a compound of formula I may have therapeutic advantages owing to the higher metabolic stability of this isotope-labelled compound. Higher metabolic stability may translate directly into an increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. An isotope-labelled compound of formula I can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant.

[0071] Deuterium (¾ or D) can also be incorporated into a compound of Formula I, or any of 1.1-1.300, in order to manipulate the oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi product reaction, the product distribution ratios can be altered substantially. For explanation: if deuterium is bonded to a carbon atom at a non-exchangeable position, rate differences of kM/kD=2-7 are typical. If this rate difference is successfully applied to a compound of formulas I, or any of 1.1-1.300, that is susceptible to oxidation, the pharmacodynamic profile of this compound in vivo can be drastically modified and result in improved pharmacokinetic properties. For a further discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, Foster, A. B., "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends in Pharmacological Sciences, 5: 524-527 (1984) AND Foster, A. B., "Deuterium Isotope Effects in the Metabolism of Drugs and Xenobiotics: Implications for Drug Design," Advances in Drug Research, 14: 1-40 (1985) incorporated in their entirety herein by reference.

[0072] When discovering and developing therapeutic agents, the person skilled in the art attempts to optimize pharmacokinetic parameters while retaining desirable in vitro properties. In some cases, compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. In vitro liver microsomal assays currently available may provide valuable information on the course of oxidative metabolism of this type, which in turn may permit the rational design of deuterated compounds of Formula I with improved stability through resistance to such oxidative metabolism. Significant improvements in the pharmacokinetic profiles of compounds of Formula I are thereby possible, and can be expressed quantitatively in terms of increases in the in vivo half-life (tl/2), concentration at maximum therapeutic effect (Cmax), area under the dose response curve (AUC), and bioavailability; and in terms of reduced clearance, dose and materials costs.

[0073] Deuterium-hydrogen exchange in a compound of formula I, or any of 1.1-1.300, can also be used to achieve a favorable modification of the metabolite spectrum of the starting compound in order to diminish or eliminate undesired toxic metabolites. For example, if a toxic metabolite arises through oxidative carbon-hydrogen (C— H) bond cleavage, it may be possible that the deuterated analogue will greatly diminish or eliminate production of the unwanted metabolite, even if the particular oxidation is not a rate-determining step. Further information on the state of the art with respect to deuterium-hydrogen exchange may be found, for example in Hanzlik et ah, J. Org. Chem. 55, 3992-3997, 1990, Reider et ah, J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et al, Biochemistry 33(10) 2927-2937,

1994, and Jarman et al. Carcinogenesis 16(4), 683-688, 1993. It is understood that deuterium in this context is regarded as a substituent of a compound of Formula I, or any of 1.1-1.300. The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound described herein is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0074] The following is intended to illustrate the above: a compound of formulas I, or any of 1.1-1.300, which has multiple potential sites of attack for oxidative metabolism, for example benzylic hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, may be prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms, so that some, most or all of these hydrogen atoms have been replaced by deuterium atoms. Half-life determinations enable favorable and accurate determination of the extent to which the improvement in resistance to oxidative metabolism has improved. In this way, it may be determined that the half-life of the parent compound can be extended by up to 100% as the result of deuterium-hydrogen exchange of this type.

[0075] As indicated above, MLD disease results from mutations in the arylsulfatase A gene responsible for converting sulfatide (SFT) to galactosylceramide (GalCer) and sulfate. ARSA mutations leading to >90% reduction in ARSA activity result in accumulation of SFT, which in turn induces demyelination and death. By inhibiting the biosynthesis of SFT, compounds described herein can prevent the accumulation of SFT that causes MLD disease. Similarly,

Krabbe disease results from mutations in galactosylcerebrosidase (GalC), the enzyme responsible for converting GalCer to galactose and ceramide. Mutations disrupting both alleles of GalC result in complete inactivation of GalC and the subsequent accumulation of GalCer and psychosine (another substrate for GalC). By inhibiting the biosynthesis of GalCer, compounds described herein can prevent the accumulation of GalCer and psychosine that cause Krabbe disease.

[0076] The compounds described herein can be used in combination with other UGT8 modulators or therapeutic agents for treating MLD, Krabbe disease and MLD- or Krabbe- related diseases and conditions. For MLD, other therapeutic modalities focus on ARSA, the enzyme that is defective in MLD patients. These include enzyme replacement therapy (ERT), gene

replacement therapy and gene-transduced hematopoietic stem cell transfer. For ERT, recombinant human ARSA with full enzymatic activity is transfused into MLD patients either via the systemic circulation or by direct transfusion into the brain. In MLD, gene replacement therapy consists of delivering the functional form of the ARSA gene systemically or directly into the brain to augment the defective (or absent) mutant enzyme that causes MLD. In gene-transduced stem cell transfer, hematopoietic stem cells are transduced with copies of the fully functional ARSA gene and are then administered systemically back to the patients. An advantage of using the UGT8 inhibitor compounds described herein in combination with any of these modalities is that the inhibitors will immediately prevent further accumulation of toxic substrates such as SFT and Psychosine before the other therapeutics have become fully effective. EXAMPLES

Preparation of Compounds

[0077] The preparation of exemplary compounds according to the present disclosure is described below. Other compounds within the scope of the disclosure may be made according to the general schemes described above and according to analogous methods and procedures to those described in detail below, and in conjunction with the skill of the art.

[0078] Analytical Methods

[0079] The 1H NMR spectra are run at 400 MHz on a Gemini 400 or Varian Mercury 400 spectrometer with an ASW 5 mm probe, and usually recorded at ambient temperature in a deuterated solvent, such as D ₂ 0, DMSO-c/r, or CDCb unless otherwise noted. Chemical shifts values (d) are indicated in parts per million (ppm) with reference to tetramethylsilane (TMS) as the internal standard.

[0080] High Pressure Liquid Chromatography-Mass Spectrometry (LCMS) experiments to determine retention times (RT) and associated mass ions were performed using one of the following methods.

[0081] Mass Spectra (MS) were recorded using a Micromass mass spectrometer. Generally, the method used was positive electro-spray ionization, scanning mass m/z from 100 to 1000. Liquid chromatography was performed on a Hewlett Packard 1100 Series Binary Pump &

Degasser; Auxiliary detectors used were: Hewlett Packard 1100 Series UV detector, wavelength = 220 nm and Sedere SEDEX 75 Evaporative Light Scattering (ELS) detector temperature = 46 °C, N ₂ pressure = 4 bar.

[0082] LCT: Grad (AcN+0.05% TFA):(H ₂ 0+0.05% TFA) = 5:95 (0 min) to 95:5 (2.5 min) to 95:5 (3 min). Column: YMC Jsphere 33x2 4 mM, 1 ml/min.

[0083] MUX: Column: YMC Jsphere 33x2, 1 ml/min.

[0084] Grad (AcN+0.05% TFA):(H ₂ 0+0.05% TFA) = 5:95 (0 min) to 95:5 (3.4 min) to 95:5 (4.4 min).

[0085] LCT2: YMC Jsphere 33x2 4 pM, (AcN+0.05%TFA):(H ₂ 0+0.05%TFA) = 5:95 (0 min) to 95:5 (3.4 min) to 95:5 (4.4 min). [0086] QU: YMC Jsphere 33x2 lml/min, (AcN+0.08% formic acid):(H ₂ O+0.l% formic acid) = 5:95 (0 min) to 95:5 (2.5min) to 95:5 (3.0min).

Preparation of Intermediates

[0087] Intermediate 1: Methyl 5-oxo-7-(trifluoromethyl)-4,5-dihydrothieno[3,2- 6]pyridine-3-carboxylate

[0088] A stirred mixture of methyl 3-aminothiophene-4-carboxylate hydrochloride (180 g,

929 mmol) and ethyl 4,4,4-trifluoroacetoacetate (540 mL, 3.69 mol) was heated at 130 °C for 18 hours. The reaction was analyzed by LCMS and found to be complete. The mixture was concentrated and the resulting moist, brown solid was triturated with //77-butyl methyl ether (-300 mL). The suspended solid was collected by suction filtration, rinsed with additional tert- butyl methyl ether (2 x -50 mL) and air dried on the frit under house vacuum. The title compound was obtained as a yellow solid (200 g, 74%). 1H NMR (400 MHz, DMSO-zfc) d 11.10 (br s, 1H), 8.88 (s, 1H), 6.98 (s, 1H), 3.92 (s, 3H) ppm.

[0089] Intermediate 3: Methyl 5-chloro-7-(trifluoromethyl)thieno[3,2-Z>]pyridine-3- carboxylate

[0090] A stirred mixture of Intermediate 1 (100 g, 361 mmol) and phosphorus oxychloride (500 mL, 5.4 mol) was heated at 110 °C for five hours. The mixture was cooled to room temperature and then slowly poured into vigorously stirred and cooled (0 °C) water (-2 L). The resulting suspension was extracted with dichloromethane (2 x -1L). The combined organic layers were dried (Na ₂ S0 ₄ ), suction filtered through a pad of silica and concentrated under reduced pressure. The residue was then triturated with methanol (-300 mL) and recollected by suction filtration. The filtercake was air dried on the frit under house vacuum to afford the title compound as a white solid (91.0 g, 85%). 1H NMR (400 MHz, CDCb) d 8.75 (s, 1H), 7.62 (s, 1H), 4.00 (s, 3H) ppm. MS: 296 m/z (M+H ⁺ ).

[0091] Intermediate 4: 5-Chloro-7-(trifluoromethyl)thieno[3,2-6]pyridine-3-carboxyl ic acid

[0092] To a stirred solution of Intermediate 3 (40.0 g, 136 mmol) in tetrahydrofuran (300 mL) was added a solution of lithium hydroxide monohydrate (12.0 g, 286 mmol) in water (300 mL). After 30 minutes at room temperature, the reaction was analyzed by TLC and found to be complete. The mixture was diluted with water (500 mL) and then acidified (to pH 2-3) with the addition of 1.0 N hydrochloric acid. The resulting suspension was extracted with ethyl acetate (3 x -500 mL) and the combined organic layers were dried (Na ₂ S0 ₄ ) and concentrated. The crude title compound, which was used without purification, was afforded as a pale red solid (38.0 g, 99%). 1H NMR (400 MHz, CDCb) d 12.11 (br s, 1H), 8.98 (s, 1H), 7.71 (s, 1H) ppm. MS: 281 m/z (M+H ⁺ ).

[0093] Intermediate 5: 5-Chloro-/V-methyl-7-(trifluoromethyl)thieno[3,2-Z>]pyrid ine-3- carboxamide

[0094] Method 1 (from Intermediate 3):

[0095] Intermediate 3 (9.00 g, 30.4 mmol) and a 2.0 N solution of methylamine in methanol (75.0 mL, 150 mmol) were combined in a pressure vessel equipped with a stir bar. The vessel was sealed and the stirred solution was heated at 50 °C for 90 minutes. The mixture was stirred for an additional one hour at room temperature and then concentrated. The residue was subjected to automated flash chromatography (Combiflash instrument; 0 to 1% methanol in chloroform; 220 g silica column) to afford partially purified product (Ri = 0.25 with 99:1 chloroform/methanol as the eluant) as a light amber solid (6.83 g, 76%). This material was triturated with diethyl ether (-40 mL) and recollected by suction filtration. The filtercake was rinsed with additional ether (2 x -10 mL) and then air dried on the frit under house vacuum to afford the title compound as an off- white solid (6.51 g, 73%). 1H NMR (400 MHz, CDCb) d 9.01-8.80 (m, 2H), 7.62 (s, 1H), 3.12 (d, J = 4.9 Hz, 3H) ppm.

[0096] Method 2 (from Intermediate 4):

[0097] To a stirred and cooled (0 °C) solution of Intermediate 3 (38.0 g, 135 mmol) in dichloromethane (350 mL) was slowly added oxalyl chloride (18.0 mL, 213 mmol) followed by 2-3 drops of /V,/V-dimethylformamide. The cooling bath was removed and the reaction was allowed to warm to room temperature. After one hour, the reaction solution was concentrated to afford the crude acid chloride as an oil. To a stirred solution of this material in dichloromethane (300 mL) was slowly added a 2.0 M solution of methylamine in tetrahydrofuran (254 mL, 510 mmol). The mixture was stirred at room temperature for 30 minutes and then partitioned between dichloromethane (500 mL) and a saturated aqueous ammonium chloride solution (500 mL). The organic layer was removed, dried (Na ₂ S0 ₄ ) and concentrated to afford crude product as a yellow solid. This material was triturated with acetonitrile (-300 mL), recollected by suction filtration and air dried on the frit under house vacuum. The title compound was afforded as a light yellow solid (36.18 g, 91%). 1H NMR (400 MHz, CDCb) d 8.89 (br s, 1H), 8.87 (s, 1H), 7.60 (s, 1H), 3.10 (d, / = 4.8 Hz, 3H) ppm. MS: 295 m/z (M+H ⁺ ).

[0098] Intermediate 6: /V-Methyl-5-(piperazin-l-yl)-7-(trifluoromethyl)thieno[3,2- 6]pyridine-3-carboxamide

[0099] Step 1: Methyl 5-(4-(/eri-butoxycarbonyl)piperazin-l-yl)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate

[00100] A 20 mL microwave reaction vessel equipped with a stir bar was loaded with

Intermediate 3 (2.50 g, 8.46 mmol), //77-butyl piperazine- l-carboxylate (2.76 g, 14.8 mmol), N,N- diisopropylethylamine (3.00 mL, 17.2 mmol) and A-methyl-2-pyrrolidinone (10 mL). A second 20 mL microwave vial was prepared identically and both vessels were then sealed and heated in a microwave reactor for 1.5 hours at 130 °C. The two reaction mixtures were combined and diluted with water (-50 mL). The resulting suspension was subjected to a combination of sonication and vigorous stirring (-30 mins) to disperse the larger solid aggregates. The resulting light brown precipitate was suction filtered off and rinsed with additional water (2 x -25 mL). The filtercake was partially dried on the frit under house vacuum and then rinsed with diethyl ether (3 x -20-25 mL). The solid was then dried in a vacuum oven (-50 °C) to afford the title compound as a tan solid (6.14 g, 82%). 1H NMR (400 MHz, CDCL) d 8.57 (s, 1H), 6.99 (s, 1H), 3.96 (s, 3H), 3.79- 3.70 (m, 4H), 3.64-3.56 (m, 4H), 1.50 (s, 9H) ppm.

[00101] Step 2: /c/7- Butyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5- yl)piperazine- 1 -carboxylate

[00102] A 20 mL microwave reaction vessel equipped with stir bar was loaded step 1 product (3.11 g, 6.98 mmol) and a 2.0 N solution of methylamine in methanol solution (12.0 mL, 24.0 mmol). The vessel was sealed and heated in a microwave reactor for 1.5 hours at 90 °C. TLC analysis indicated that a small amount of ester starting material remained. Additional 2.0 N methylamine solution (4.0 mL, 8.0 mmol) was added and the reaction was heated for another one hour at 90 °C. The reaction mixture was then concentrated to afford the title compound as a tan solid (3.04 g, 98%). 1H NMR (400 MHz, CDCL) d 9.32 (br s, 1H), 8.67 (s, 1H), 7.04 (s, 1H), 3.66 (s, 8H), 3.09 (d, 7 = 4.9 Hz, 3H), 1.51 (s, 9H) ppm.

[00103] Step 3: /V-Methyl-5-(piperazin-l-yl)-7-(trifluoromethyl)thieno[3,2-h ]pyridine-3- carboxamide

[00104] Hydrogen chloride gas was bubbled through a stirred solution of step 2 product (4.06 g, 9.13 mmol) in ethyl acetate (120 mL) for approximately five minutes. The resulting thick yellow suspension was stirred at room temperature for one hour and then concentrated. The residue was partitioned between aqueous sodium carbonate solution (-100 mL) and 4:1 chloroform/isopropanol (-40 mL). The organic layer was combined with additional extracts (4:1 chloroform/isopropanol, 3 x -40 mL), dried (Na ₂ S0 ₄ ) and concentrated. The title compound was afforded as a light yellow solid (3.18 g, 101%; 'H NMR analysis indicated that minor, residual isopropanol accounted for the excess yield). 'H NMR (400 MHz, CDCL) d 9.42 (br s, 1H), 8.66 (s, 1H), 7.04 (s, 1H), 3.69-3.56 (m, 4H), 3.14-3.01 (m, 7H) ppm.

[00105] Intermediate 7: 5-(4-Hydroxypiperidin-l-yl)-/V-methyl-7- (trifluoromethyl)thieno[3,2-Z>]pyridine-3-carboxamide

[00106] Step 1: Methyl 5-(4-hydroxypiperidin-l-yl)-7-(trifluoromethyl)thieno[3,2-h] pyridine- 3-carboxylate

[00107] To a stirred solution of Intermediate 3 (10.0 g, 33.8 mmol) in /V-methyl-2- pyrrolidinone (60 mL), was added piperidin-4-ol (6.00 g, 59.3 mmol, 1.75 eq) and N,N- diisopropylethylamine (11.8 mL, 67.7 mmol, 2.00 eq). The reaction was heated at 130 °C for three hours and then left to stir at room temperature overnight. LCMS analysis indicated that the reaction was complete. The mixture was concentrated to afford a moist brown solid. This material was taken up in water (-200 mL) and the suspended solid was dispersed through a combination of spatula agitation and sonication. When a nearly homogeneous suspension was achieved, the mixture was suction filtered. The filtercake was rinsed with water (2 x -40 mL) and diethyl ether (2 x -25 mL) and then air dried on the frit under house vacuum. The filtercake was further dried in a vacuum oven (-60 °C) to afford the title compound as a light brown solid (10.90 g, 89%). 1H NMR (400 MHz, CDCL) d 8.54 (s, 1H), 7.02 (s, 1H), 4.30-4.20 (m, 2H), 4.08-3.88 (m, 4H), 3.48- 3.29 (m, 2H), 2.10-1.99 (m, 1H), 1.67-1.56 (m, 2H) ppm.

[00108] Step 2: 5-(4-Hydroxypiperidin-l-yl)-/V-methyl-7-(trifluoromethyl)thi eno[3,2- h]pyridine-3-carboxamide

[00109] To a stirred suspension of the product of step 1 (10.85 g, 30.11 mmol) in a 2.0 N solution of methylamine in methanol (75 mL, 150.00 mmol) was added sodium cyanide (0.221 g, 4.51 mmol). The vessel was sealed and heated overnight at 50 °C. Following this time, the reaction was analyzed by LCMS and found to be complete. The mixture was cooled in an ice bath room (the reaction went from clear solution to a heavy suspension). The cold suspension was suction filtered and the collected solid was rinsed with cold methanol (l x -30 mL), water (2 x -40 mL) and, finally, diethyl ether (2 x -30 mL). The filtercake was further dried in a vacuum oven (-50 °C) to afford the title compound as a tan solid (9.60 g, 89%). 1H NMR (400 MHz, CDCL) d 9.47 (s, 1H), 8.65 (s, 1H), 7.07 (s, 1H), 4.10-3.99 (m, 3H), 3.48-3.38 (m, 2H), 3.08 (d, J = 4.8 Hz, 3H), 2.11-2.01 (m, 2H), 1.78-1.64 (m, 3H) ppm. [00110] Intermediate 8: Methyl 5-(2,6-diazaspiro[3.3]heptan-2-yl)-7- (trifluoromethyl)thieno[3,2-6]pyridine-3-carboxylate

[00111] Step 1: Methyl 5-(6-(/er/-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-7 - (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate

[00112] A 20 mL microwave vial equipped with a stir was added Intermediate 3 (0.750 g, 2.54 mmol), ier/-butyl-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.920 g, 3.81 mmol), N,N- diisopropylethylamine (0.90 mL, 5.2 mmol) and /V-methyl-2-pyrrolidinone (10 mL). The vessel was sealed and heated in a microwave reactor for two hours at 80 °C. The mixture was then cooled and suction filtered to remove the solids, which were subsequently rinsed with ethyl acetate. The combined filtrate was concentrated and the residue was dissolved in 4:1

chloroform/isopropanol (50 mL). This solution was washed with aqueous sodium bicarbonate solution and brine, dried (Na ₂ S0 ₄ ) and concentrated. The crude product was purified by automated flash chromatography (Combiflash system; 0.3 to 3% methanol in dichloromethane eluant; 80 g silica column) to afford the title compound as an off-white solid (0.677 g, 58%). LC/MS: retention time = 1.44 min; MS: 458 m/z (M+H ⁺ ).

[00113] Step 2: Methyl 5-(2,6-diazaspiro[3.3]heptan-2-yl)-7-(trifluoromethyl)thieno [3,2- h]pyridine-3-carboxylate

[00114] To a stirred suspension of step 1 product (0.450 g, 0.984 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2.0 mL, 26 mmol). After one hour at room temperature, the reaction was concentrated. The resulting gum was treated with solid sodium bicarbonate (400 mg) and then taken up in 98:2 dichloromethane/methanol solution (30 mL). The suspension was stirred vigorously for several minutes and then suction filtered to remove the solids. The filtercake was rinsed with a 4:1 chloroform/isopropanol solution (-10 mL) and the combined filtrate was washed with a saturated aqueous sodium bicarbonate solution and brine. The organic layer was then dried (Na ₂ S0 ₄ ) and concentrated to afford the title compound as an off-white solid (0.300 g, 85%). LC/MS: retention time = 0.91 min; MS: 358 m/z (M+H ⁺ ).

[00115] Intermediate 11: 2-(Trifluoromethoxy)ethyl 1 //-imidazole- 1 -carboxylate

[00116] To a stirred solution of 2-(trifluoromethoxy)ethan-l-ol (1.20 g, 9.23 mmol) in dichloromethane (50 mL) was added l,l'-carbonyldiimidazole (2.09 g, 12.9 mmol). The reaction was allowed to proceed overnight at room temperature and then washed into a separatory funnel with chloroform (-30 mL). The solution was washed with 0.1 N hydrochloric acid (1 x -75 mL) and aqueous sodium bicarbonate solution (1 x -75 mL). The organic layer was then dried (Na ₂ S0 ₄ ) and concentrated to afford crude title compound as a colorless oil (2.23 g, 108%; yield inflated by residual solvent). The crude product was used, without purification, in subsequent reactions and stored in a freezer. 1H NMR (400 MHz, CDCL) d 8.16 (s, 1H), 7.46-7.41 (m, 1H), 7.10 (s, 1H), 4.69-4.61 (m, 2H), 4.35-4.27 (m, 2H) ppm. MS: 225 m/z (M+H ⁺ ).

[00117] Intermediate 12: (S)-l-(Trifluoromethoxy)propan-2-yl 1 //-imidazole- 1- carboxylate

[00118] Step 1: (S)-(((l-(Trifluoromethoxy)propan-2-yl)oxy)methyl)benzene

[00119] Reaction based on: Liu, J.-B., Xu, X.-H., Qing, F.-L. Org. Lett. 2015, 17, 5048. (S)-2- (Benzyloxy)propan-l-ol (9.70 g, 58.4 mmol), silver trifluoromethanesulfonate (30.29 g, 116.7 mmol), potassium fluoride (10.27 g, 175.1 mmol) and SelectFluor (31.01 g, 87.53 mmol) were combined in a 1L reaction flask. Ethyl acetate (275 mL) was then added and the mixture was stirred for several minutes before adding 2-fluoropyridine (10.1 mL, 117 mmol) and

trifluoromethyltrimethylsilane (17.6 mL, 117 mmol). The reaction, which slowly darkened over the first hour, was stirred overnight at room temperature. After this time, the mixture was suction filtered through a pad of silica gel. The silica was rinsed with additional ethyl acetate (6 x -50 mL) and the combined filtrate was concentrated to afford a brown semi-solid (38.97 g). This material was taken up in ethyl acetate (-100 mL) and sonicated until a homogeneous suspension was achieved. The solid was suction filtered off and then rinsed with ethyl acetate (2 x -25 mL). The combined filtrate was concentrated onto -80 g of silica gel and the impregnated media was subjected to automated flash chromatography (Combiflash instrument; 0 to 15% ethyl acetate in heptane; 330 g silica column). Partially purified title compound (by 1H NMR analysis, purity was estimated to be 90-95%; R _f -0.6 in 85:15 heptane/ethyl acetate) was obtained as colorless oil (5.07 g, 37%). To avoid any possible product loss via evaporation, the oil was only briefly exposed to high vacuum (some minor residual solvent was accepted the product). 'H NMR (400 MHz, CDCb) d 7.41-7.26 (m, 5H), 4.64-4.56 (m, 2H), 3.98 (dd, / = 10.1, 6.1 Hz, 1H), 3.90 (dd, / = 10.1, 4.4 Hz, 1H), 3.84-3.75 (m, 1H), 1.24 (d, / = 6.4 Hz, 3H) ppm.

[00120] Step 2: (S)-l-(Trifluoromethoxy)propan-2-yl 1 //-imidazole- 1 -carboxylatc

[00121] The partially purified step 1 product (5.05 g, <21.6 mmol) was combined with 10% palladium on carbon (50% water) (2.00 g, 0.940 mmol) and taken up in ethyl acetate (150 mL). The stirred suspension was cycled between vacuum and a nitrogen atmosphere three times. The reaction vessel was then evacuated a final time and refilled with hydrogen (via balloon). The reaction was stirred under the hydrogen atmosphere overnight and then suction filtered through a plug of Celite. The filtering agent was rinsed with additional ethyl acetate (5 x -30 mL) and the combined filtrate was stirred at room temperature and treated with l,l’-carbonyldiimidazole (5.24 g, 32.3 mmol). The reaction was stirred overnight and then transferred to a separatory funnel and washed with 0.1 M hydrochloric acid (1 x -150 mL) and aqueous sodium bicarbonate solution (1 x -150 mL). The organic layer was dried (Na ₂ S0 ₄ ) and concentrated (only briefly under high vacuum) to afford a pale amber oil (3.41 g, 67%). 'H NMR analysis indicated that the acylation reaction was not complete (-7:3 ratio of the desired product to hydroxy intermediate was observed). The oil was taken up in tetrahydrofuran (80 mL), stirred at room temperature and treated with additional l,l’-carbonyldiimidazole (2.00 g, 12.3 mmol). The reaction was then placed into a preheated (50 °C) oil bath. After three hours, a sample of the reaction was removed, concentrated and analyzed by 'H NMR. The reaction was determined to be complete. The mixture was concentrated and the residue was partitioned between an aqueous sodium bicarbonate solution (-100 mL) and chloroform (-60 mL). The organic layer was combined with additional extracts (chloroform, 2 x -60 mL), dried (Na ₂ S0 ₄ ) and concentrated to afford crude, title compound as a pale amber oil (3.41 g, 67%, overall two steps). Despite the observation of minor impurity contaminating the desired product (by 'H NMR), the material was deemed sufficiently pure to use without purification in subsequent reactions. The intermediate was stored in a freezer to suppress decomposition. 1H NMR (400 MHz, CDCb) d 8.14 (s, 1H), 7.44-7.40 (m, 1H), 7.10- 7.08 (m, 1H), 5.39-5.29 (m, 1H), 4.19-4.08 (m, 2H), 1.49 (d, / = 6.6 Hz, 3H) ppm. MS: 239 m/z (M+H ⁺ ). [00122] Intermediate 13: Methyl 6-methyl-5-oxo-7-(trifluoromethyl)-4,5- dihydrothieno[3,2-Z>]pyridine-3-carboxylate

[00123] A stirred mixture of methyl 4-aminothiophene-3-carboxylate (8.23 g, 52.36 mmol), ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate (16.5 mL, 104.76 mmol) and water (10 mL, 28 mmol) was heated overnight at 130 °C. The reaction, which LCMS analysis indicated was a mixture of desired product and either the uncyclized amide or cyclized hydrate intermediate, was then cooled to room temperature and concentrated. The residue was dissolved in concentrated sulfuric acid (8 mL). After stirring the solution at room temperature for 45 minutes, the reaction was analyzed by LCMS and found to be complete. The mixture was poured into a stirred crushed ice/water slurry (-400 mL) along with ethyl acetate rinsings of the reaction vessel (-100 mL). After the ice had fully melted, the organic layer was removed and combined with additional ethyl acetate extracts (3 x -100 mL). The pooled extracts were dried (Na ₂ S0 ₄ ) and concentrated to afford a moist, dirty orange solid. This material was taken up in mixture of heptane (-85 mL) and ethyl acetate (-15 mL) and sonicated for several minutes to disperse the larger chunks of solid. The suspension was then suction filtered and the collected solid was rinsed with heptane (3 x -25 mL). The filtercake was further dried in a vacuum oven (-50 °C) to afford the title compound as an amber solid (7.85 g, 52%). 1H NMR (400 MHz, CDCL) d 10.74 (br s, 1H), 8.29 (s, 1H), 3.97 (s, 3H), 2.40 (q, J = 2.4 Hz, 3H) ppm. MS: 292 m/z (M+H ⁺ ).

[00124] Intermediate 14: Methyl 5-chloro-6-methyl-7-(trifluoromethyl)thieno[3,2- Z>]pyridine-3-carboxylate

[00125] A stirred suspension of Intermediate 13 (11.00 g, 37.77 mmol) in phosphorus oxychloride (55.0 mL, 590 mmol, 17.5 eq) was heated at 110 °C for five hours. The mixture was cooled to room temperature and then slowly added, via pipet, to stirred and cooled (0 °C) water (500 mL). The rcscdclBting suspension was extracted with dichloromethane (2 x -200 mL). The combined organic layers were dried (Na ₂ S0 ₄ ), filtered through a pad of silica gel and

concentrated to afford the title compound as a yellow solid (10.00 g, 85%). 'H NMR (400 MHz, CDCb) d 8.63 (s, 1H), 4.00 (s, 3H), 2.68 (s, 3H) ppm.

[00126] Intermediate 15: 5-Chloro-/V,6-dimethyl-7-(trifluoromethyl)thieno[3,2- 6]pyridine-3-carboxamide

[00127] To a stirred suspension of Intermediate 14 (15.00 g, 48.4 mmol) in 2- methyltetrahydrofuran (60 mL) was added a 2.0 M solution of methylamine in methanol (57.0 mL, 114 mmol). The resulting suspension was stirred at room temperature for 24 hours and then partitioned between aqueous ammonium chloride solution (-500 mL) and dichloromethane (-300 mL). The organic layer was combined with an additional extract (dichloromethane, 1 x -300 mL), dried (Na ₂ S0 ₄ ) and concentrated. The crude product was purified by trituration with acetonitrile (-40 mL) to afford the title compound as a white solid (19.60 g, 85%). 'H NMR (400 MHz CDCb) d 8.88 (br, s, 1H), 8.70 (s, 1H), 3.04 (d, J = 4.8 Hz, 3H), 2.61 (s, 3H) ppm. MS: 308 m/z (M+H ⁺ ).

[00128] Intermediate 16: Methyl 5-oxo-4,5-dihydrothieno[3,2-6]pyridine-3-carboxylate

[00129] Step 1: 3-Ethoxyacrylic acid

[00130] To a stirred mixture of ethyl 3-ethoxyacrylate (20.00 g, 138.7 mmol) in water (160 mL) was added solid sodium hydroxide (13.32 g, 332.9 mmol). The reaction was heated at reflux for two hours and then cooled to room temperature. With stirring, the mixture was treated with sufficient concentrated hydrochloric acid to achieve pH 2-3 (-30 mL). The resulting yellow suspension was extracted with ethyl acetate (4 x -100 mL). The combined organic layers were dried (Na ₂ S0 ₄ ) and concentrated to afford crude product as a bright yellow solid (9.21 g, 57%). This material was used, without purification, in the next step. 'H NMR (400 MHz, CDCb) d 7.67 (d, J = 12.6 Hz, 1H), 5.18 (d , J = 12.6 Hz, 1H), 3.95 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H) ppm.

[00131] Step 2: Methyl 4-(3-ethoxyacrylamido)thiophene-3-carboxylate

[00132] To a stirred suspension of the step 1 crude product (9.21 g, 79.3 mmol) in toluene (130 mL) was added thionyl chloride (7.0 mL, 96 mmol). The mixture was heated at reflux for three hours and then cooled to room temperature and concentrated. Crude acid chloride was afforded as a brown oil. This material was taken up in dichloromethane (50 mL) and the resulting solution was slowly added, via pipet, to a stirred solution of methyl 4-aminothiophene-3-carboxylate hydrochloride (10.24 g, 52.88 mmol) and pyridine (12.8 mL, 159 mmol) in dichloromethane (250 mL). The mixture was stirred overnight at room temperature and then washed with -0.2 N hydrochloric acid (l x -200 mL). The aqueous phase was back-extracted with chloroform (2 x -40 mL) and the combined organic layers were washed with aqueous sodium bicarbonate solution (l x -200 mL). The organic solution was then dried (Na ₂ S0 ₄ ) and concentrated to provide the crude product which was subjected to automated flash chromatography (Combiflash instrument; 0 to 25% ethyl acetate in heptane; 330 g silica column). The title compound was obtained as a dirty yellow solid (10.38 g, 77% from the aminothiophene starting material). 'H NMR (400 MHz, CDCL) d 9.83 (br s, 1H), 8.03 (s, 2H), 7.65 (d, J = 12.2 Hz, 1H), 5.37 (d, J = 12.2 Hz, 1H), 3.95 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H) ppm.

[00133] Step 3: Methyl 5-oxo-4,5-dihydrothieno[3,2-h]pyridine-3-carboxylate

[00134] Step 2 product (10.37 g, 40.62 mmol) was taken up in concentrated sulfuric acid (10 mL) and stirred at room temperature. After one hour, the reaction was analyzed by LCMS and found to be complete. The reaction was poured into ice water (-600 mL) and the resulting suspension was stirred until the ice had fully melted. The mixture was then extracted with chloroform (4 x -150 mL) and the combined extracts were dried (Na ₂ S0 ₄ ) and concentrated. The resulting amber solid was taken up in diethyl ether (-60 mL) and sonicated until a near homogenous suspension was achieved. The suspension was then suction filtered and the collected solid was washed with additional diethyl ether (2 x -20 mL). The filtercake was air dried on the frit under house vacuum to afford the title compound as a tan solid (7.90 g, 93%). 'H NMR (400 MHz, CDCL) d 10.47 (br s, 1H), 8.29 (s, 1H), 7.73 (d, J = 9.6 Hz, 1H), 6.60 (d, / = 9.6 Hz, 1H), 3.96 (s, 3H) ppm. MS: 210 mJz (M+H ⁺ ). [00135] Intermediate 17: /V-Methyl-5-(piperidin-4-yloxy)-7-(trifluoromethyl)thieno[3, 2- 6]pyridine-3-carboxamide

[00136] Step 1 : tert- Butyl 4-((3-(mcthylcarbamoyl)-7-(tnfluoromcthyl)thicno[3,2-/?]pynd in-5- yl)oxy)piperidine- 1 -carboxylate

[00137] A stirred solution of Intermediate 5 (8.00 g, 27.2 mmol) and tert- butyl 4- hydroxypiperidine-l -carboxylate (6.56 g, 32.58 mmol) in tetrahydrofuran (150 mL) was placed into an ambient temperature water bath and treated, in one portion, with sodium ie/ -butoxide (3.39 g, 35.3 mmol). The mixture was stirred at room temperature for two hours and then concentrated. The residue was partitioned between aqueous sodium bicarbonate solution (-300 mL) and chloroform (-150 mL). The organic layer was combined with a second extract

(chloroform, 1 x -100 mL), dried (Na ₂ S0 ₄ ) and concentrated onto of silica (-40 g). The impregnated media was subjected to automated flash chromatography (Combiflash instrument; 20 to 50% ethyl acetate in heptane; 330 g silica column). The target component (R _f = 0.24 with 1:1 heptane/ethyl acetate as the eluant) was obtained as a gummy solid. This material was co evaporated with diethyl ether to afford the title compound as a pale amber, foamy solid (10.43 g, 84%). 1H NMR (400 MHz, CDCh) d 9.12-8.98 (m, 1H), 8.75 (s, 1H), 7.12 (s, 1H), 5.21 (tt, / = 7.4, 3.6, 1H), 3.87-3.75 (m, 2H), 3.46-3.35 (m, 2H), 3.08 (d, J = 4.9 Hz, 3H), 2.18-2.03 (m, 2H), 1.98-1.84 (m, 2H), 1.49 (s, 9H) ppm.

[00138] Step 2 : /V-Methyl-5-(piperidin-4-yloxy)-7-(trifluoromethyl)thieno[3, 2-h]pyridine-3- carboxamide

[00139] To a stirred solution of step 1 product (10.41 g, 22.66 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (25.0 mL, 326 mmol). After one hour, the mixture was concentrated and the resulting oil was partitioned between chloroform (-100 mL) and aqueous sodium carbonate solution (-150 mL). The organic layer was combined with a second extract (chloroform, 1 x 100 mL), dried (Na ₂ S0 ₄ ) and concentrated to afford a light brown solid. This material was taken up in diethyl ether (-60 mL) and sonicated until a fine, homogeneous suspension was achieved. The solid was suction filtered off, rinsed with additional diethyl ether (2 x -20 mL) and air dried on the frit under house vacuum and a nitrogen funnel. The title compound was obtained as a sand colored solid (7.93 g, 97%). 1H NMR (400 MHz, CDCL) d 9.26-9.06 (br s, 1H), 8.73 (s, 1H), 7.11 (s, 1H), 5.17-5.06 (m, 1H), 3.34-3.14 (m, 2H), 3.09 (d, / = 4.9 Hz, 3H), 2.88-2.75 (m, 2H), 2.27-2.10 (m, 2H), 1.92-1.74 (m, 2H), 1.70 (br s, 1H) ppm. MS: 360 mJz (M+H ⁺ ).

[00140] Intermediate 18: (S)-l-(Trifluoromethoxy)propan-2-amine hydrochloride

[00141] Step 1 : Butyl (S)-(l-(trifluoromethoxy)propan-2-yl)carbamate

[00142] Reaction based on: Liu, J.-B., Xu, X.-H., Qing, F.-L. Org. Lett. 2015, 17, 5048. A stirred suspension of /V-Boc-L-alaninol (5.00 g, 28.5 mmol), silver trifluoromethanesulfonate (14.8 g, 57.1 mmol), potassium fluoride (5.02 g, 85.6 mmol), and SelectFluor (15.2 g, 42.8 mmol) in ethyl acetate (150 mL) was treated with 2-fluoropyridine (4.90 mL, 57.0 mmol) and

trifluoromethyltrimethylsilane (8.60 mL, 57.0 mmol). The mixture was stirred overnight at room temperature and then suction filtered through a pad of silica. The filtrate was concentrated and the residue was subjected to automated flash chromatography (Combiflash system; 0 to 20% ethyl acetate in heptane; 120 g silica column; ninhydrin staining solution was used to visualize TLC plates). The title compound was obtained as a colorless oil (2.20 g, 32%). 1H NMR (400 MHz, CDCL) d 4.58 (s, 1H), 4.00-3.87 (m, 3H), 1.45 (s, 9H), 1.22 (d, J = 6.7 Hz, 3H) ppm.

[00143] Step 2: ( S) - 1 - ( T r i fl u o ro m c t h o x y ) p ro p a n - 2 - a m i n c hydrochloride

[00144] Hydrogen chloride gas was bubbled into a stirred solution of step 1 product (2.20 g,

9.05 mmol) in ethyl acetate (60 mL) for approximately three minutes. The reaction was maintained at room temperature for another 30 minutes and then concentrated to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO-<i ₆ ) d 8.35 (br s, 3H), 4.29-4.12 (m, 2H), 3.55 (br s, 1H), 1.24 (d, / = 6.8 Hz, 3H) ppm.

[00145] Intermediate 19: Methyl 5-chloro-2-methyl-7-(trifluoromethyl)thieno[3,2- Z>]pyridine-3-carboxylate

[00146] Step 1: Methyl 2-methyl-5-oxo-7-(trifluoromethyl)-4,5-dihydrothieno[3,2-h]p yridine- 3-carboxylate

[00147] A stirred mixture of methyl 4-amino-2-methylthiophene-3-carboxylate hydrochloride (5.00 g, 24.1 mmol) and ethyl 4,4,4-trifluoroacetoacetate (25.2 g, 137 mmol) was heated overnight at 130 °C. The reaction mixture was then concentrated under reduced pressure to afford a moist, brown solid. This crude product was triturated with ethyl acetate (-20 mL). When a homogeneous suspension was achieved, the solid was collected by suction filtration, rinsed with additional ethyl acetate and air dried on the frit under house vacuum. The title compound was obtained as a yellow solid (5.00 g, 71%). 1H NMR (400 MHz, DMSO-ifc) d 10.79 (br s, 1H), 6.78 (s, 1H), 3.97 (s, 3H), 2.81 (s, 3H) ppm. MS: 292 m/z (M+H ⁺ ).

[00148] Step 2: Methyl 5-chloro-2-methyl-7-(trifluoromethyl)thieno[3,2-h]pyridine-3 - carboxylate

[00149] Step 1 product (10.00 g, 34.33 mmol) was taken up in phosphorus oxychloride (43 mL, 460 mmol) and heated, with stirring, for five hours at 110 °C. The mixture was cooled to room temperature and slowly added to stirred and cooled (0 °C) water (-200 mL). The resulting suspension was extracted with dichloromethane (3 x 150 mL). The combined organic layers were dried (Na ₂ S0 ₄ ) and concentrated. The resulting crude product was purified by automated flash chromatography (Combiflash system; 1 to 5% ethyl acetate in petroleum ether; 330 g silica column) to afford the title compound as a white solid (9.22 g, 87%). ' H NMR (400 MHz, CDCL) d 7.50 (s, 1H), 4.00 (s, 3H), 2.87 (s, 3H) ppm. MS: 310 m/z (M+H ⁺ ).

[00150] Intermediate 20: 5-Chloro-/V,2-dimethyl-7-(trifluoromethyl)thieno[3,2- 6]pyridine-3-carboxamide

[00151] Intermediate 19 (2.00 g, 6.46 mmol) and a 2.0 N solution of methylamine in methanol (24.0 mL, 48.0 mmol) were combined in a pressure vessel equipped with a stir bar. The vessel was sealed and the stirred solution was heated at 50 °C for seven hours and then allowed to cool to room temperature and stirred for an additional two days. After this time, the mixture was concentrated and the residue was subjected to automated flash chromatography (Combiflash instrument; 5 to 25% ethyl acetate in heptane; 80 g silica column). The title compound was obtained as a white solid (1.66 g, 83%). 1H NMR (400 MHz, CDCL) d 9.22 (s, 1H), 7.54 (s, 1H), 3.16-3.03 (m, 6H) ppm. MS: 309 m/z (M+H ⁺ ).

[00152] Intermediate 21: l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- 6]pyridin-5-yl)piperidin-4-yl (4-nitrophenyl) carbonate

[00153] To a stirred solution of Intermediate 7 (5.00 g, 13.9 mmol) and triethylamine (2.30 mL, 16.5 mmol) in dichloromethane (40 mL) was added p-nitrophenyl chloroformate (2.89 g, 14.3 mmol) followed by several granules of 4-(dimethylamino)pyridine. The reaction was stirred at room temperature for seven hours and then diluted with sufficient dichloromethane to fully dissolve all solids (-200 mL). The clear solution was then concentrated onto -25 g of silica and the impregnated media was subjected to automated flash chromatography (Combiflash

instrument; 30 to 100% ethyl acetate in heptane; 120 g Gold silica column). The target component

(Rf -0.6 with 7:3 ethyl acetate/heptane as the eluant) was obtained as a light brown solid (3.60 g).

This material was further purified by trituration with a mixture of diethyl ether (-50 mL) and ethyl acetate (-5 mL). The solid was recollected via suction filtration, rinsed with additional diethyl ether (l x -25 mL) and then air dried on the frit under house vacuum. The title compound was obtained as a tan solid (3.44 g, 47%). 1H NMR (400 MHz, CDCL) d 9.37 (br s, 1H), 8.69 (s,

1H), 8.35-8.23 (m, 2H), 7.46-7.37 (m, 2H), 7.10 (s, 1H), 5.15-5.07 (m, 1H), 4.06-3.93 (m, 2H), 3.72-3.57 (m, 2H), 3.09 (d, J = 4.9 Hz, 3H), 2.30-2.16 (m, 2H), 2.12-1.96 (m, 2H) ppm.

[00154] Intermediate 22: tert- Butyl 4-((chlorocarbonyl)oxy)piperidine-l-carboxylate

[00155] To a stirred solution of / _{<? /7} -butyl 4-hydroxypiperidine-l-carboxylate (6.00 g, 29.8 mmol) in tetrahydrofuran (60 mL) was added a 15% (w/w) solution of phosgene in toluene (37.0 mL, 51.9 mmol). The reaction was stirred at room temperature for 90 minutes and then concentrated to afford the crude title compound as a colorless oil (8.04 g, 102%). 'H NMR analysis indicated that the material was sufficiently pure to use, without purification, in subsequent reactions. The intermediate was stored in a freezer, where it solidified. 'H NMR (400 MHz, CDCb) d 5.06-4.97 (m, 1H), 3.78-3.64 (m, 2H), 3.34-3.22 (m, 2H), 2.02-1.89 (m, 2H), 1.82-1.70 (m, 2H), 1.46 (s, 9H) ppm.

[00156] Intermediate 23: Benzyl 4-((chlorocarbonyl)oxy)piperidine-l-carboxylate

[00157] To a stirred solution of benzyl 4-hydroxypiperidine- l-carboxylate (5.00 g, 21.3 mmol) in tetrahydrofuran (60 mL) was added a 15% (w/w) solution of phosgene in toluene (31.0 mL, 43.4 mmol). The reaction was stirred at room temperature for 90 minutes and then concentrated to afford the crude title compound as a colorless oil (6.50 g, 103%). 'H NMR analysis indicated that the material was sufficiently pure to use, without purification, in subsequent reactions. The intermediate was stored in a freezer, where it solidified. 'H NMR (400 MHz, CDCL) d 7.45-7.29 (m, 5H), 5.13 (s, 2H), 5.08-4.99 (m, 1H), 3.83-3.70 (m, 2H), 3.46-3.34 (m, 2H), 2.04-1.89 (m, 2H), 1.87-1.71 (m, 2H) ppm.

[00158] Intermediate 24: Piperidin-4-yl (cyclopropylmethyl)carbamate

[00159] Step 1 : / _<?/7 - Butyl 4-(((cyclopropylmethyl)carbamoyl)oxy)piperidine- l-carboxylate

[00160] To a stirred and cooled (0 °C) solution of Intermediate 22 (31.65 g, 120.0 mmol) in chloroform (400 mL) was added (aminomethyl)cyclopropane (10.3 mL, 120 mmol) followed by triethylamine (25.1 mL, 180 mmol). The mixture was allowed to slowly warm to room

temperature and stirring was continued overnight. The solution was then washed with 0.5 N hydrochloric acid (2 x -200 mL) and aqueous sodium bicarbonate solution (l x -400 mL). The organic layer was dried (Na ₂ S0 ₄ ) and concentrated to afford crude title compound as an off-white solid (38.57 g, 108%; yield inflated by residual chloroform solvent). This material was used in the next step, without purification.

[00161] Step 2: Piperidin-4-yl (cyclopropylmethyl)carbamate

[00162] To a stirred solution of the step 1 product in dichloromethane (300 mL) was added trifluoroacetic acid (100 mL, 1.31 mmol). After 90 minutes at room temperature, the reaction was concentrated to afford a near colorless syrup. This material was partitioned between 1.0 N aqueous sodium hydroxide solution (-300 mL) and chloroform (-200 mL). The organic layer was combined with additional extracts (chloroform, 4 x -200 mL), dried (Na ₂ S0 ₄ ) and concentrated to afford the crude title compound as an off-white solid (23.58 g, 99% overall yield). This intermediate was deemed sufficiently pure to use, without purification, in subsequent reactions.

1H NMR (400 MHz, CDCb) d 4.96-4.55 (m, 2H), 3.17-2.95 (m, 4H), 2.82-2.64 (m, 2H), 2.36 (br s, 1H), 2.03-1.85 (m, 2H), 1.68-1.46 (m, 2H), 1.03-0.90 (m, 1H), 0.58-0.43 (m, 2H), 0.26-0.12 (m, 2H) ppm.

[00163] Intermediate 25: 5-((2-Azaspiro[3.3]heptan-6-yl)oxy)- V-methyl-7- (trifluoromethyl)thieno[3,2-Z>]pyridine-3-carboxamide

[00164] Step 1 : /<?/7- Butyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5- yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate

[00165] To a stirred mixture of Intermediate 5 (2.03 g, 6.89 mmol) and //77-butyl 6-hydroxy-2- azaspiro[3.3]heptane-2-carboxylate (2.17 g, 9.64 mmol) in tetrahydrofuran (30 mL) was added potassium ie/ -butoxide (0.928 g, 8.27 mmol). The reaction heated at 70 °C for two hours and then cooled to room temperature and concentrated. The residue was taken up in ethyl acetate and the solution was washed with aqueous sodium bicarbonate solution and brine. The organic layer was then dried (Na ₂ S0 ₄ ) and concentrated to afford the crude product which was purified by automated flash chromatography (Biotage system; 20 to 100% ethyl acetate in heptane followed by 5% methanol in dichloromethane; 100 g silica column). The title compound was obtained as a foamy, white solid (2.69 g, 83%). 1H NMR (400 MHz, CDCb) d 9.11 (br s, 1H), 8.75 (s, 1H), 7.08 (s, 1H), 5.13 (p, / = 6.9 Hz, 1H), 4.04 (s, 2H), 3.98 (s, 2H), 3.11 (d, / = 4.9 Hz, 3H), 2.93- 2.70 (m, 2H), 2.59-2.36 (m, 2H), 1.45 (s, 9H) ppm. MS: 472 m/z (M+H ⁺ ).

[00166] Step 2: 5-((2-Azaspiro[3.3]heptan-6-yl)oxy)-/V-methyl-7-(trifluorome thyl)thieno[3,2- h]pyridine-3-carboxamide

[00167] To a stirred and cooled (0 °C) solution of step 1 product (2.28 g, 4.84 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (3.7 mL, 48 mmol). The reaction was allowed to warm to room temperature and then stirred for another one hour before concentrating. The residue was partitioned between dichloromethane (200 mL) and aqueous 1.0 N sodium hydroxide solution 100 mL). The organic layer was combined with a backextract of the aqueous layer (dichloromethane, 1 x -50 mL), dried (MgS0 ₄ ) and concentrated to afford the crude title compound as a beige solid (1.60 g, 89%). This intermediate was deemed sufficiently pure to use, without purification, in subsequent reactions. MS: 372 m/z (M+H ⁺ ).

[00168] Intermediate 27: 5-(czs-3-Aminocyclobutoxy)-/V-methyl-7- (trifluoromethyl)thieno[3,2-6]pyridine-3-carboxamide

[00169] Step 1 : tert- Butyl (cA-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?]pyridin-5-yl)oxy)cyclobutyl (carbamate

[00170] To a stirred solution of Intermediate 5 (2.47 g, 8.38 mmol) and tert- butyl (cis- 3 hydroxycyclobutyl)carbamate (1.88 g, 10.1 mmol) in tetrahydrofuran (60 mL) was added potassium ieri-butoxide (1.03 g, 9.22 mmol). The reaction was heated at 90 °C for one hour, cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and aqueous ammonium chloride solution. The organic layer was dried (MgSC ) and

concentrated to afford crude product which was purified by automated flash chromatography (Combiflash instrument; 0 to 100% ethyl acetate in dichloromethane; 120 g silica column). The title compound was obtained as a white solid (2.50 g, 67%). MS: 446 m/z (M+H ⁺ ).

[00171] Step 2: 5-(cA-3-Aminocyclobutoxy)-/V-methyl-7-(trifluoromethyl)thien o[3,2- h]pyridine-3-carboxamide

[00172] To a stirred and cooled (0 °C) solution of step 1 product (1.89 g, 4.24 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (3.3 mL, 42 mmol). The reaction was allowed to warm to room temperature and stirred for another two hours before concentrating. The residue was partitioned between dichloromethane (200 mL) and an aqueous 0.5 N sodium hydroxide solution (100 mL). The organic layer was combined with additional extracts

(dichloromethane, 2 x -100 mL), dried (MgS0 ₄ ) and concentrated to afford the crude title compound as a white solid (1.13 g, 77%). 1H NMR (400 MHz, DMSO-d ₆ ) d 8.90 (s, 1H), 8.86 (d, 7 = 4.9 Hz, 1H), 8.15 (s, 3H), 7.46 (s, 1H), 5.20 (q, 1H), 3.71-3.55 (m, 1H), 2.99 (d, 7 = 4.9 Hz,

3H), 2.96-2.77 (m, 1H), 2.42-2.30 (m, 2H) ppm.

[00173] Intermediate 28: cz.s-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- 6]pyridin-5-yl)oxy)cyclobutyl 1 //-imidazole- 1 -carboxylate

[00174] Step 1: 5-(cA-3-(Benzyloxy)cyclobutoxy)-/V-methyl-7-(trifluoromethyl )thieno[3,2- /?]pyridinc-3-carhoxamidc

[00175] To a stirred solution of cA-3-(benzyloxy)cyclobutanol (0.921 g, 5.17 mmol) in tetrahydrofuran (10 mL) was added potassium ie/ -butoxide (502 mg, 4.47 mmol). The mixture was stirred at room temperature for 15 minutes and then added, via syringe, to a stirred solution of Intermediate 5 (1.16 g, 3.94 mmol) in tetrahydrofuran (20 mL). The reaction was heated at reflux for one hour and then cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate (-100 mL) and washed with aqueous ammonium chloride solution (1 x -100 mL) and brine (1 x -100 mL). The organic layer was then dried (MgSCL) and concentrated to afford crude product which was purified by automated flash chromatography (Combiflash instrument; 0 to 100% ethyl acetate in dichloromethane followed by 0 to 5% methanol in dichloromethane; 40 g silica column) to afford the title compound as an amber oil (1.30 g, 76%). MS: 437 m/z (M+H ⁺ ).

[00176] Step 2: 5-(cA-3-Hydroxycyclobutoxy)-/V-methyl-7-(trifluoromethyl)thi eno[3,2- h]pyridine-3-carboxamide

[00177] A stirred mixture of step 1 product (1.30 g, 2.98 mmol), ethanol (30 mL), acetic acid (171 pL, 2.98 mmol) and 20% palladium hydroxide on carbon (50% water) (0.500 g) was cycled between vacuum and a nitrogen atmosphere three times. The vessel was evacuated a final time and refilled with hydrogen {via balloon). The reaction was stirred under the hydrogen atmosphere overnight and then suction filtered through a plug of Celite and concentrated. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was combined with an additional extract (ethyl acetate), dried (MgS0 ₄ ) and concentrated. The crude product was purified by automated flash chromatography (Biotage system; 0 to 100% ethyl acetate in dichloromethane; 25 g silica column) to afford the title compound as an off-white solid (0.495 g, 48%). 1H NMR (400 MHz, CDCb) d 9.13 (br s, 1H), 8.74 (s, 1H), 7.11 (s, 1H), 4.99- 4.73 (m, 1H), 4.36-4.17 (m, 1H), 3.10 (d, J = 4.9 Hz, 3H), 3.08-2.99 (m, 2H), 2.34-2.21 (m, 2H), 1.98 (d, / = 6.0 Hz, 1H) ppm. MS: 347 m/z (M+H ⁺ ).

[00178] Step 3: cA-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]p yridin-5- yl)oxy)cyclobutyl 1 //-imidazole- 1 -carboxylatc

[00179] To a stirred solution of step 2 product (0.495 g, 1.43 mmol) in dichloromethane (15 mL) was added l,l'-carbonyldiimidazole (0.301 g, 1.86 mmol). The mixture was stirred at room temperature for two hours and then diluted with additional dichloromethane and washed with water and brine. The organic layer was dried (MgS0 ₄ ) and concentrated to furnish crude product. This material was purified by flash chromatography (Combiflash instrument; 0 to 100% ethyl acetate in dichloromethane followed by 2 to 5% methanol in dichloromethane; 25 g silica column). The title compound was obtained as a white solid (0.458 g, 73%). MS: 441 m/z (M+H ⁺ ).

[00180] Intermediate 29: /V-Methyl-5-(piperidin-4-yl)-7-(trifluoromethyl)thieno[3,2- Z>]pyridine-3-carboxamide hydrochloride

[00181] Step 1 : /<?/7- Butyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5- yl)piperidine- 1 -carboxylate

[00182] A 20 mL microwave reaction vial equipped with a stir bar was loaded the title compound of Example 274 (0.633 g, 1.42 mmol) and a 2.0 N methylamine in methanol solution (14.0 mL, 28.0 mmol). The vessel was sealed and heated in a microwave reactor for three hours at 90 °C. The mixture was then concentrated to afford the crude title compound as a foamy, brown solid (0.631 g, 100%). 1H NMR (400 MHz, CDCb) d 9.53 (br s, 1H), 8.82 (s, 1H), 7.49 (s, 1H), 4.33 (br s, 2H), 3.12 (d, / = 5.1 Hz, 3H), 3.06-3.18 (m, 1H), 2.84-3.00 (m, 2H), 2.01-2.10 (m,

2H), 1.76-1.90 (m, 2H), 1.51 (s, 9H) ppm. ¹⁹ F NMR (376 MHz, CDCb) d -64.0 (s) ppm. MS: 444 m/z (M+H ⁺ ).

[00183] Step 2: /V-Methyl-5-(piperidin-4-yl)-7-(trifluoromethyl)thieno[3,2-h ]pyridine-3- carboxamide hydrochloride [00184] To a stirred solution of step 1 product (0.463 g, 1.04 mmol) in methanol (3.0 mL) was added a 1.2 M solution of hydrogen chloride in methanol (15.0 mL, 18.0 mmol). The reaction was allowed to proceed at room temperature over a weekend and then concentrated to afford a yellow oil. This material was redissolved in methanol (2.0 mL) and the solution was added to vigorously stirred diethyl ether (50 mL). The resulting suspension was briefly sonicated to disperse the aggregated solid and then suction filtered. The collected solid was rinsed with additional diethyl ether (-10 mL) and then dried under high vacuum to afford the title compound as a light yellow solid (0.338 g, 85%). 1H NMR (400 MHz, Methanol-iL) d 8.92 (s, 1H), 7.83 (s, 1H), 3.60 (d, / = 12.5 Hz, 2H), 3.48 (tt, J = 11.8, 3.5 Hz, 1H), 3.18-3.33 (m, 3H), 2.28-2.39 (m, 2H), 2.11-2.26 (m, 2H) ppm. ¹⁹ F NMR (376 MHz, CDCL) d -65.4 (s) ppm. MS: 344 m/z (M+H ⁺ ).

[00185] Intermediate 31: (+/-)-5-(frans-3-Fluoro-4-hydroxypiperidin-l-yl)- V-methyl-7- (trifluoromethyl)thieno[3,2-6]pyridine-3-carboxamide

[00186] A 20 mL microwave reaction vial equipped with a stir bar was loaded Intermediate 5 (1.20 g, 4.07 mmol), (+/-)-iran5-3-fluoropiperidin-4-ol hydrochloride (0.824 g, 5.29 mmol), N- methyl-2-pyrrolidinone (14 mL) and /V,/V-diisopropylethylamine (2.1 mL, 12 mmol). The vessel was sealed and heated in a microwave reactor for three hours at 150 °C. The mixture was then cooled and taken up in ethyl acetate (80 mL). The solution was washed with water (4 x 20 mL) and aqueous ammonium chloride solution (1 x 20 mL). The organic layer was dried (Na ₂ S0 ₄ ) and concentrated, yielding crude product as a brown solid. This material was taken up in diethyl ether and the resulting suspension was sonicated and suction filtered. The collected solid was air dried on the frit under house vacuum to afford the title compound as a reddish solid (1.26 g, 82%). 'H NMR (400 MHz, CDCL) d 9.33 (s, 1H), 8.68 (s, 1H), 7.08 (d, / = 1.2 Hz, 1H), 4.53 (dddd, / = 49.0, 8.4, 7.1, 4.3 Hz, 1H), 4.44-4.30 (m, 1H), 4.21-3.99 (m, 2H), 3.53-3.31 (m, 2H), 3.09 (d, J = 4.9 Hz, 3H), 2.48 (d, 7 = 3.8 Hz, 1H), 2.33-2.11 (m, 1H), 1.76 (dtd, / = 13.7, 9.7, 4.2 Hz, 1H) ppm. MS: 378 m/z (M+H ⁺ ).

[00187] Intermediate 32: Methyl 5,7-dichlorothieno[3,2-6]pyridine-3-carboxylate

[00188] Methyl 4-aminothiophene-3-carboxylate hydrochloride (2.55 g, 13.2 mmol) and malonic acid (1.37 g, 13.2 mmol) were taken up in phosphorus oxychloride (40 mL, 430 mmol). The stirred mixture was heated overnight at 90 °C and then cooled to room temperature and slowly added to a vigorously stirred slurry of crushed ice and water (-250 mL). After the ice had fully melted, the mixture was neutralized by the slow, portionwise, addition of solid sodium bicarbonate. The resulting suspension was extracted with dichloromethane (3 x 75 mL). The combined organic layers were washed with water (1 x 100 mL), dried (MgSCL) and filtered. Activated carbon (-1.0 g) was added to the solution and the mixture was stirred at room temperature for 20 minutes. After removing the carbon via suction filtration through Celite, the solution was concentrated. The crude, brown solid was purified by automated flash

chromatography (Combiflash system; 0 to 80% ethyl acetate in heptane; 120 g silica column) to afford the title compound as pale amber solid (1.97 g, 57%). 1H NMR (400 MHz, CDCL) d 8.67 (s, 1H), 7.44 (s, 1H), 4.00 (s, 3H) ppm. MS: 263 m/z (M+H ⁺ ).

[00189] Intermediate 33: 5,7-Dichloro-/V-methylthieno[3,2-Z>]pyridine-3-carboxamid e

[00190] Intermediate 32 (3.10 g, 11.8 mmol) was combined with a 2.0 N solution of methylamine in methanol (25.0 mL, 50.0 mmol) in a sealed reaction flask. The mixture was stirred at room temperature for 20 hours and then concentrated. The resulting solid was purified by automated flash chromatography (Biotage system; 0 to 70% ethyl acetate in heptane; 120 g silica column) to afford the title compound as a pale yellow solid (1.93 g, 63%). 'H NMR (400 MHz, CDCL) d 8.95 (s, 1H), 8.79 (s, 1H), 7.43 (s, 1H), 3.10 (d, J = 4.8 Hz, 3H) ppm. MS: 262 m/z (M+H ⁺ ).

[00191] Intermediate 34: Methyl 5-chloro-7-(diiluoromethyl)thieno[3,2-/>]pyridine-3- carboxylate

[00192] A 20 mL microwave reaction vessel equipped with a stir bar was loaded methyl 4- aminothiophene-3-carboxylate hydrochloride (0.281 g, 1.45 mmol), ethyl 4,4-difluoro-3- oxobutanoate (0.482 g, 2.90 mmol) and phosphorus oxychloride (2.0 mL, 21 mmol). The vessel was sealed and heated in a microwave reactor for six hours at 90 °C. The black mixture was cooled to room temperature and slowly added, via pipet, to a vigorously stirred slurry of crushed ice and water (-40 mL). After the ice had fully melted, the mixture was neutralized by the slow, portionwise, addition of solid sodium bicarbonate. The resulting suspension was extracted with ethyl acetate (1 x 40 mL). The organic layer was washed with water (2 x 20 mL) and brine (1 x 10 mL), dried (MgS0 ₄ ) and filtered. Activated carbon (-0.5 g) was added to the solution and the mixture was stirred at room temperature for 20 minutes. After removing the carbon via suction filtration through Celite, the solution was concentrated. The crude material obtained was purified by automated flash chromatography (Biotage system; 0 to 40% ethyl acetate in heptane; 40 g silica column) to afford the title compound as a pale yellow solid (0.125 g, 31%). MS: 278 m/z (M+H ⁺ ).

Preparation of Compounds

[00193] Example 10: Methyl 5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-l-yl)-7- (trifluoromethyl)thieno[3,2-Z>]pyridine-3-carboxylate

[00194] Step 1: Methyl 5-(4-(2-(benzyloxy)-2-oxoethyl)piperazin-l-yl)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate

[00195] To a stirred solution of Intermediate 3 (0.642 g, 2.17 mmol) in NN- dimethylformamide (15 mL) was added benzyl 2-(piperazin-l-yl)acetate dihydrochloride (800 mg, 2.60 mmol) followed potassium carbonate (0.900 g, 6.51 mmol). The reaction was heated overnight at 90 °C and then concentrated. The residue was partitioned between aqueous sodium bicarbonate solution (-60 mL) and ethyl acetate (-40 mL). The organic layer was combined with a back-extract of the aqueous layer (ethyl acetate, 1 x -40 mL), dried (Na ₂ S0 ₄ ) and concentrated. The crude product was purified by automated flash chromatography (Combiflash system; 30 to 50% ethyl acetate in heptane; 40 g silica column) to afford the title compound ( R _f -0.25 with 1 : 1 heptane/ethyl acetate as the eluant) as a pale yellow solid (0.611 g, 48%). 1H NMR (400 MHz, CDCL) d 8.56 (s, 1H), 7.44-7.29 (m, 5H), 6.98 (s, 1H), 5.19 (s, 2H), 3.95 (s, 3H), 3.88-3.77 (m, 4H), 3.35 (s, 2H), 2.82-2.69 (m, 4H) ppm.

[00196] Step 2: 2-(4-(3-(Methoxycarbonyl)-7-(trifluoromethyl)thieno[3,2-h]py ridin-5- yl)piperazin- l-yl)acetic acid

[00197] To a stirred solution of the of the step 1 product (0.610 g, 1.24 mmol) in a mixture of methanol (25 mL) and ethyl acetate (25 mL) was added 10% palladium on carbon (50% water; 0.300 g). The mixture was cycled between vacuum and a nitrogen atmosphere three times before evacuating a final time and backfilling the reaction vessel with hydrogen (via balloon). After 30 minutes the reaction was analyzed by TLC and found to be complete. The reaction was suction filtered through a plug of Celite which was subsequently rinsed with methanol. The combined filtrate was concentrated to afford crude title compound as a light yellow solid (0.489 g, 98%). This material was deemed to be of sufficient purity to use, without further processing, in the next step. 1H NMR (400 MHz, DMSO-d ₆ ) d 12.20 (s, 1H), 8.89 (s, 1H), 7.37 (s, 1H), 3.86 (s, 3H), 3.82-3.71 (m, 4H), 3.24 (s, 2H), 2.78-2.61 (m, 4H) ppm.

[00198] Step 3: Methyl 5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-l-yl)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate

[00199] To a stirred solution of the step 2 product (0.100 g, 0.247 mmol) and isopropylamine (0.021 g, 0.355 mmol) in L/,LAIί methyl formamidc (5 mL) was added 0-(7-azabenzotriazol- l-yl)- /V, /V, /V’ , /V’ - 1 c t r a m c t h y 1 u ro n i u m hexafluorophosphate (HATU; 0.104 g, 0.274 mmol). The mixture was cooled to 0 °C and treated, via dropwise addition, with triethylamine (0.15 mL, 1.1 mmol). The cooling bath was removed and the reaction was allowed to slowly warm to room temperature. Stirring was continued overnight. After this time, the reaction was concentrated and the residue was partitioned between aqueous sodium carbonate solution (-50 mL) and ethyl acetate (-40 mL). The organic layer was combined with an additional extract (ethyl acetate, 1 x -40 mL), dried (Na ₂ S0 ₄ ) and concentrated. The crude product was purified by automated flash chromatography (Combiflash system; 5 to 10% methanol in ethyl acetate; 40 g Gold silica column) to afford the title compound (R _f -0.65 with 9:1 ethyl acetate/methanol as the eluant) as a yellow solid (0.038 g, 35%). 1H NMR (400 MHz, CDCb) d 8.57 (s, 1H), 7.01 (s, 1H), 6.94 (d, / = 8.5 Hz, 1H), 4.19-4.08 (m, 1H), 3.96 (s, 3H), 3.83-3.75 (m, 4H), 3.06 (s, 2H), 2.74-2.65 (m, 4H), 1.19 (d, / = 6.5 Hz, 6H) ppm. MS: 445 m/z (M+H ⁺ ).

[00200] Example 25: 5-(4-(2-(Ethylamino)-2-oxoethyl)piperazin-l-yl)-/V-methyl-7- (trifluoromethyl)thieno[3,2-Z>]pyridine-3-carboxamide

[00201] Step 1: Methyl 5-(4-(2-(ethylamino)-2-oxoethyl)piperazin-l-yl)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate

[00202] Using the procedure for HATU mediated amide coupling described in step 3 of Example 10, the step 2 product of Example 10 was condensed with ethylamine hydrochloride to afford the title compound as a light yellow solid. 1H NMR (400 MHz, CDCb) d 8.57 (s, 1H), 7.12 (br s, 1H), 7.01 (s, 1H), 3.95 (s, 3H), 3.83-3.75 (m, 4H), 3.41-3.32 (m, 1H), 3.09 (s, 2H), 2.73- 2.66 (m, 4H), 1.18 (t, J = 7.3 Hz, 3H) ppm.

[00203] Step 2: 5-(4-(2-(Ethylamino)-2-oxoethyl)piperazin-l-yl)-/V-methyl-7- (trifluoromethyl)thieno- [3 ,2-/?] pyridinc-3 -carboxamide

[00204] Into a 20 mL microwave reaction vial equipped with a stir bar was loaded step 1 product (0.150 g, 0.348 mmol) and 2.0 N solution of methylamine in methanol (8.0 mL, 16 mmol). The vessel was sealed and heated in a microwave reactor for one hour at 90 °C. TLC analysis indicated that the reaction was complete. The reaction mixture was concentrated and the residue was purified by automated flash (Combiflash system; 0 to 5% methanol in

dichloromethane; 40 g Gold silica column) to afford the title compound ( R _f -0.35 with 19:1 dichloromethane/methanol as the eluant) as a faint yellow solid (0.129 g, 86%). 'H NMR (400 MHz, CDCb) d 9.32 (br s, 1H), 8.68 (s, 1H), 7.11-6.99 (m, 2H), 3.73-3.66 (m, 4H), 3.42-3.32 (m, 2H), 3.12 (s, 2H), 3.08 (d, / = 4.9 Hz, 3H), 2.79-2.71 (m, 4H), 1.20 (t, / = 7.3 Hz, 3H) ppm. MS: 430 mJz (M+H ⁺ ). [00205] Example 39. (+/-)-5-(4-(2-(Cyclopropylmethoxy)propyl)piperazin-l-yl)-/V- methyl-7-(trifluoromethyl)thieno[3,2-6]pyridine-3-carboxamid e

[00206] Step 1: (+/-) -tert- Butyl 4-(2-(cyclopropylmethoxy)propyl)piperazine-l-carboxylate

[00207] To a stirred solution of tert- butyl 4-(2-hydroxypropyl)piperazine-l-carboxylate (0.750 g, 3.07 mmol) in tetrahydrofuran (30 mL) was added a a 60% dispersion of sodium hydride in mineral oil (0.147 g, 3.68 mmol). The suspension was stirred at room temperature for one hour before adding (bromomethyl)cyclopropane (0.45 mL, 4.6 mmol) via syringe. The reaction was heated overnight at reflux. TLC analysis indicated that the reaction contained about equal portions of starting material and product, as judged by relative spot intensity (visualized by iodine staining). Additional sodium hydride (0.123 g, 3.08 mmol) and alkyl bromide (0.30 mL, 3.09 mmol) were added, -30 minutes apart, to the stirred reaction. The mixture was returned to reflux for another night. After this time, the reaction was concentrated and partitioned between aqueous sodium carbonate solution (-40 mL) and chloroform (-40 mL). The organic layer was combined with additional extracts (chloroform, 2 x -40 mL), dried (Na ₂ S0 ₄ ) and concentrated. The residue was subjected to automated flash chromatography (Combiflash system; isocratic 3% 2N ammonia/methanol in dichloromethane; 40 g Gold silica column) to afford the purified title compound ( R _f -0.4 with 19:1 dichloromethane/2N ammonia in methanol as the eluant) as a colorless oil (0.781 g, 85%). 1H NMR (400 MHz, CDCL) d 3.65-3.57 (m, 1H), 3.45-3.39 (m, 4H), 3.35 (dd, / = 10.1, 6.8 Hz, 1H), 3.27 (dd, / = 10.1, 6.8 Hz, 1H), 2.55-2.37 (m, 4H), 2.30 (dd, / = 13.0, 5.0 Hz, 1H), 1.46 (s, 9H), 1.15 (d, 7 = 6.2 Hz, 3H) ppm.

[00208] Step 2: (+/-)- l-(2-(Cyclopropylmethoxy)propyl)piperazine

[00209] To a stirred solution of the step 1 product (0.780 g, 2.61 mmol) in dichloromethane (12 mL) was added trifluoroacetic acid (4.0 mL, 52 mmol). After 2 hours, the reaction was analyzed by TLC and found to be complete. The mixture was concentrated and the residue was partitioned between aqueous sodium carbonate solution (-40 mL) and chloroform (-40 mL). The organic layer was combined with additional extracts (chloroform, 3 x -40 mL), dried (Na ₂ S0 ₄ ) and concentrated to afford crude title compound as a colorless oil (0.527 g, 102%). 'H NMR (400 MHz, CDCh) 5 3.68-3.56 (m, 1H), 3.35 (dd, J = 10.1, 6.8 Hz, 1H), 3.28 (dd, / = 10.1, 6.9 Hz,

1H), 2.88 (t, J = 4.9 Hz, 3H), 2.57-2.37 (m, 5H), 2.27 (dd, 7 = 12.9, 5.1 Hz, 1H), 1.15 (d, J = 6.2 Hz, 3H), 1.10-0.99 (m, 1H), 0.57-0.47 (m, 2H), 0.22-0.16 (m, 2H) ppm.

[00210] Step 3: (+/-)-5-(4-(3-Cyclopropoxy-2-methylpropyl)piperazin-l-yl)-/V -methyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide

[00211] A 20 mL microwave reaction vial equipped with a stir bar was loaded with

Intermediate 5 (0.250 g, 0.848 mmol), step 2 product (0.294 g, 1.48 mmol), N,N- diisopropylethylamine (0.30 mL, 1.7 mmol) and A-methyl-2-pyrrolidinone (6 mL). The vessel was sealed and heated in a microwave reactor at 130 °C for two hours. TLC analysis indicated the reaction was complete. The mixture was concentrated and the residue was partitioned between chloroform (-30 mL) and aqueous sodium carbonate solution (-50 mL). The organic layer was combined with additional extracts (chloroform, 2 x -30 mL), dried (Na ₂ S0 ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system;

isocratic, 2.5% methanol in dichloromethane; 40 g Gold silica column), providing the target component ( R _f -0.4 with 19:1 dichloromethane/methanol as the eluant) as a viscous red-brown oil. This material was co-evaporated with ethyl acetate and vacuum oven dried (-70 °C) to afford the title compound as a red-brown gum (0.266 g, 69%). 1H NMR (400 MHz, CDCL) d 9.44 (br s, 1H), 8.65 (s, 1H), 7.03 (s, 1H), 3.74-3.58 (m, 5H), 3.39 (dd, / = 10.1, 6.9 Hz, 1H), 3.31 (dd, / = 10.1, 6.9 Hz, 1H), 3.08 (d, / = 4.9 Hz, 3H), 2.80-2.65 (m, 4H), 2.60 (dd, / = 13.0, 6.8 Hz, 1H),

2.41 (dd , J = 13.0, 4.8 Hz, 1H), 1.20 (d, J = 6.2 Hz, 3H), 1.12-1.02 (m, 1H), 0.59-0.50 (m, 2H), 0.25-0.17 (m, 2H) ppm. MS: 457 m/z (M+H ⁺ ).

[00212] Example 44. 5-(4-(2-Isopropoxyacetyl)piperazin-l-yl)-/V-methyl-7- (trifluoromethyl)thieno[3,2-6]pyridine-3-carboxamide

[00213] Step 1 : tert- Butyl 4-(2-bromoacetyl)piperazine-l-carboxylate

[00214] To a stirred and cooled (0 °C) solution of 2-bromoacetyl bromide (1.72 mL, 19.8 mmol) in dichloromethane (25 mL) was added a solution of //77-butyl piperazine- l-carboxylate (7.75 g, 41.6 mmol) in dichloromethane (20 mL), dropwise over -20 minutes. The cooling bath was then removed and the reaction was allowed to stir another two hours before transferring to a separatory funnel along with a dichloromethane rinse of the reaction flask (-30 mL). The solution was washed with 1.0 N hydrochloric acid (2 x -50 mL) and aqueous sodium bicarbonate solution (1 x -50 mL). The organic layer was dried (Na ₂ S0 ₄ ) and concentrated to afford title compound as a clear, faint amber gum (5.68 g, 93%). The crude intermediate was deemed sufficiently pure to use, without purification, in the next step. 1H NMR (400 MHz, CDCL) d 3.87 (s, 2H), 3.63-3.57 (m, 2H), 3.55-3.41 (m, 6H), 1.48 (s, 9H) ppm.

[00215] Step 2: / _<?/7 - Butyl 4-(2-isopropoxyacetyl)piperazine-l-carboxylate

[00216] To a stirred and cooled (0 °C) solution of the step 1 product (2.00 g, 6.51 mmol) and isopropanol (0.50 mL, 6.5 mmol) in N,N-d\ methyl formamidc (60 mL) was added a 60% dispersion of sodium hydride in mineral oil (0.290 g, 7.25 mmol). The mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction was then concentrated and partitioned between water (-100 mL) and ethyl acetate (-50 mL). The organic layer was combined with a second extract (ethyl acetate, 1 x -30 mL), dried (Na ₂ S0 ₄ ) and concentrated to afford a pale amber gum. The crude product subjected to automated flash chromatography (Combiflash system; 50 to 75% ethyl acetate in heptane; 80 g Gold silica column) to afford purified title compound ( R _f -0.6 with 3:1 ethyl acetate/heptane as the eluant) as colorless gum which slowly solidified to a white solid (0.515 g, 28%; low yield was the result of failed triggering of automatic fraction collection due to the compound’s weak UV activity). 'H NMR (400 MHz, CDCL) 4.13 (s, 2H), 3.67 (hept, J = 6.1 Hz, 1H), 3.61-3.51 (m, 4H), 3.48-3.39 (m, 4H), 1.47 (s, 9H), 1.19 (d, 7 = 6.1 Hz, 3H) ppm.

[00217] Step 3: 2-Isopropoxy-l-(piperazin-l-yl)ethan-l-one

[00218] Into a stirred solution of step 2 product (0.504 g, 1.76 mmol) in ethyl acetate (30 mL) was bubbled hydrogen chloride gas for approximately five minutes. After two hours, the reaction was analyzed by 'H NMR and found to be complete. The reaction was concentrated and the residue was partitioned between aqueous sodium carbonate solution (-50 mL) and chloroform (-30 mL). The organic layer was combined with additional extracts (chloroform, 3 x -30 mL), dried (Na ₂ S0 ₄ ) and concentrated to afford the title compound as a viscous, faint amber oil (0.317 g, 97%). The crude intermediate was deemed sufficiently pure to use, without purification, in the next step. 1H NMR (400 MHz, CDCL) d 4.13 (s, 2H), 3.63-3.57 (m, 2H), 2.98-2.86 (m, 4H), 1.19 (d, 7 = 6.1 Hz, 6H) ppm. [00219] Step 4: 5-(4-(2-Isopropoxyacetyl)piperazin-l-yl)-/V-methyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide

[00220] Using the conditions described in step 3 of Example 39, Intermediate 5 was subjected to S _N Ar displacement with a piperazine derivative, the step 3 product of the present Example, to afford the title compound as a light yellow solid. 1H NMR (400 MHz, CDCb) d 9.28 (br s, 1H), 8.69 (s, 1H), 7.06 (s, 1H), 4.22 (s, 2H), 3.89-3.80 (m, 4H), 3.77-3.64 (m, 5H), 3.09 (d, J = 4.9 Hz, 3H), 1.23 (d, / = 6.1 Hz, 6H) ppm. MS: 445 m/z (M+H ⁺ ).

[00221] Example 47. 5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-l-yl)-/V,6-dim ethyl- 7-(trifluoromethyl)thieno[3,2-Z>]pyridine-3-carboxamide

[00222] Step 1 : / _<?/7 - Butyl 4-(2-(isopropylamino)-2-oxoethyl)piperazine- l-carboxylate

[00223] To a stirred solution of / _{<? /7} -butyl piperazine- l-carboxylate (5.85 g, 31.4 mmol) and 2- bro mo-/V- i sopropy 1 accta m idc (5.94 g, 33.0 mmol) in acetonitrile (200 mL) was added sodium carbonate (4.99 g, 47.1 mmol). The mixture was heated at reflux overnight and then cooled to room temperature. TLC analysis indicated that the reaction was complete. The mixture was suction filtered to remove solids, which were then rinsed with ethyl acetate (3 x -25 mL). The combined filtrate was concentrated to afford an oil. This material was partitioned between aqueous sodium carbonate solution (-100 mL) and ethyl acetate (-150 mL). The organic layer was combined with additional extracts (ethyl acetate, 2 x -100 mL), dried (Na ₂ S0 ₄ ) and concentrated to afford crude product as an off-white solid (8.70 g, 97%). This material was deemed to be of sufficient purity to use, without further processing, in the next step. 'H NMR (400 MHz, CDCb) d 6.87 (d, J = 6.2 Hz, 1H), 4.17-4.04 (m, 1H), 3.51-3.38 (m, 4H), 2.98 (s, 2H), 2.54-2.38 (m, 4H), 1.46 (s, 9H), 1.17 (d, / = 6.6 Hz, 6H) ppm.

[00224] Step 2: /V-isopropyl-2-(piperazin- l-yl)acetamide

[00225] The crude step 1 product was dissolved in ethyl acetate (300 mL). Into this stirred solution was bubbled hydrogen chloride for approximately five minutes. After another two hours the reaction was analyzed by TLC and found to still contain a minor portion of N-tert- butoxycarbonyl protected starting material. The reaction mixture was saturated with hydrogen chloride gas as before and stirred for another one hour. The mixture was then concentrated and the residue was partitioned between chloroform (-100 mL) and aqueous sodium carbonate solution (-200 mL). The organic layer was combined with additional extracts (chloroform, 5 x -100 mL), dried (Na ₂ S0 ₄ ) and concentrated to afford crude product as an off-white solid. This material was subjected by automated flash chromatography (Combiflash system; 10% methanol in chloroform until the impurity spots had eluted and then 10 to 15% 2N ammonia/methanol in chloroform; 120 g silica column) to afford purified title compound ( R _f -0.2 with 9: 1

chloroform/2N ammonia in methanol as the eluant) as pale yellow solid (4.41 g, 77%). ' H NMR (300 MHz, DMSO -d ₆ ) d 7.37 (d, J = 8.1 Hz, 1H), 3.95-3.79 (m, 1H), 2.81 (s, 2H), 2.76-2.62 (m, 4H), 2.38-2.24 (m, 4H), 2.13 (br s, 1H), 1.07 (d, / = 6.6 Hz, 6H) ppm.

[00226] Step 3: Methyl 5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-l-yl)-6-methyl -7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate

[00227] Into a 20 mL microwave reaction vial equipped with a stir bar was loaded Intermediate 14 (0.300 g, 0.969 mmol), step 2 product (0.314 g, 1.69 mmol), /V- methyl -2-pyrrol idi none (6 mL) and /V,/V-diisopropylethylamine (0.34 mL, 2.0 mmol). The vessel was sealed and heated in a microwave reactor for two hours at 130 °C. LCMS analysis indicated that significant step 2 product remained unreacted. Additional /V-isopropyl-2-(piperazin-l-yl)acetamide (0.180 g, 0.972 mmol) was added to the reaction and microwave heating was continued for another two hours.

The reaction was then concentrated and the residue was partitioned between aqueous sodium carbonate solution (-25 mL) and chloroform (-25 mL). The organic layer was combined with an additional extract (chloroform, 1 x -25 mL), dried (Na ₂ S0 ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system; 0 to 3% methanol in ethyl acetate; 40 g Gold silica column), providing the purified title compound (R _f -0.4 with 97:3 ethyl acetate/methanol as the eluant) as a tan solid (0.208 g, 47%). ' H NMR (400 MHz, CDCL) d 8.53 (s, 1H), 7.03 (d, J = 8.2 Hz, 1H), 4.18-4.07 (m, 1H), 3.97 (s, 3H), 3.41-3.28 (m, 4H), 3.08 (s, 2H), 2.82-2.71 (m, 4H), 2.56-2.50 (m, 3H), 1.18 (d, / = 6.5 Hz, 6H) ppm.

[00228] Step 4: 5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-l-yl)-/V,6-dim ethyl-7- (trinuoromcthyl)-thicno[ 3, 2-/?] pyridinc-3 -carboxamide

[00229] Using the procedure described for step 2 of Example 25, the methyl ester functionality of the step 3 product was converted to the corresponding /V-methyl carboxamide, affording the title compound as a tan solid. 1H NMR (400 MHz, CDCL) d 9.48 (br s, 1H), 8.64 (s, 1H), 6.90 (d, / = 8.4 Hz, 1H), 4.21-4.08 (m, 1H), 3.37-3.21 (m, 4H), 3.18-3.03 (m, 5H), 2.87-2.72 (m, 3H), 2.61-2.49 (m, 2H), 1.20 (d, / = 6.5 Hz, 6H) ppm. MS: 458 m/z (M+H ⁺ ).

[00230] Example 48. 5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin- l-yl)-/V,7- dimethylthieno[3,2-Z>]pyridine-3-carboxamide

[00231] Step 1: Methyl 7-methyl-5-oxo-4,5-dihydrothieno[3,2-h]pyridine-3-carboxylat e

[00232] Into a 100 mL round bottom flask equipped with a stir bar was loaded methyl 4- aminothiophene-3 -carboxylate (4.99 g, 31.8 mmol), ethyl acetoacetate (7.70 mL, 60.9 mmol) and water (1 mL). The mixture was added stirred at room temperature for a few minutes and then placed into a preheated oil bath (125 °C). The reaction flask was fitted was a reflux condenser (no circulating coolant so volatile components could escape after the condenser warmed sufficiently). After six hours, additional portions of ethyl acetoacetate (2.00 mL, 15.8 mmol) and water (1.0 mL) were added to the mixture and the reaction was allowed to proceed over a weekend (-64 hours, total). After this time, the reaction analyzed by LCMS and found to be complete. The mixture was partitioned between chloroform (-200 mL) and aqueous sodium bicarbonate solution (-200 mL). The organic layer was combined with additional extracts (chloroform, 2 x -100 mL), dried (Na ₂ S0 ₄ ) and concentrated to afford a moist, rust-colored solid. This material was taken up in a mixture of heptane (-120 mL) and ethyl acetate (-20 mL) and sonicated until a homogenous suspension was achieved. The suspended solid was suction filtered off and rinsed with additional heptane (2 x -20 mL). The filtercake was air dried on the frit under house vacuum, affording an amber solid. The material was further purified by trituration with a mixture of diethyl ether (-75 mL) and ethyl acetate (-20 mL). Again, the suspended solid was collected by suction filtration and air dried on the frit under house vacuum. The title compound was afforded as a salmon colored solid (3.34 g, 50%). 1H NMR (400 MHz, DMSO-d ₆ ) d 10.39 (br s, 1H), 8.69 (s, 1H), 6.33 (s, 1H), 3.90 (s, 3H), 2.37 (s, 3H) ppm.

[00233] Step 2: Methyl 7-methyl-5-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-h]pyri dine-3- carboxylate [00234] To a stirred and cooled (0 °C) solution of step 1 product (3.28 g, 14.7 mmol) in pyridine (40 mL) was added trifluoromethanesulfonic anhydride (3.10 mL, 18.4 mmol), dropwise over 4-5 minutes. The mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction was then concentrated and the residue was partitioned between water (-125 mL) and chloroform (-75 mL). The organic layer was combined with additional extracts (chloroform, 2 x -75 mL), dried (Na ₂ S0 ₄ ) and concentrated to afford crude title compound as a light brown solid (5.26 g, 100%). 1H NMR analysis indicated that the material was sufficiently pure to use, without purification, in subsequent reactions. 'H NMR (400 MHz, CDCL) d 8.72 (s, 1H), 7.06 (s, 1H), 3.99 (s, 3H), 2.69 (s, 3H) ppm.

[00235] Step 3: Methyl 5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-l-yl)-6-methyl -7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate

[00236] Into a 10 mL microwave reaction vial equipped with a stir bar was loaded step 2 product (0.400 g, 1.13 mmol), /V-isopropyl-2-(piperazin-l-yl)acetamide (0.375 g, 2.02 mmol; prepared as described in step 2 of Example 47), /V-methyl-2-pyrrolidinone (2.5 mL) and N,N- diisopropylethylamine (0.40 mL, 2.3 mmol). The vessel was sealed and heated in a microwave reactor for two hours at 90 °C. TLC analysis indicated that the reaction was complete. The mixture was concentrated and the residue was partitioned between ethyl acetate (-25 mL) and aqueous sodium bicarbonate solution (-50 mL). The organic layer was combined with additional extracts (ethyl acetate, 2 x -25 mL), dried (Na ₂ S0 ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system; 0 to 10% methanol in ethyl acetate; 40 g Gold silica column), affording the purified title compound ( R _f -0.2 with 96:4 dichloromethane/methanol as the eluant) as an amber solid (0.330 g, 75%). 'H NMR (400 MHz, CDCL) d 8.45 (s, 1H), 7.00 (d, / = 8.2 Hz, 1H), 6.63 (s, 1H), 4.18-4.08 (m, 1H), 3.95 (s, 3H), 3.76-3.69 (m, 4H), 3.05 (s, 2H), 2.72-2.62 (m, 4H), 2.51 (s, 3H), 1.19 (d, / = 6.6 Hz, 6H) ppm.

[00237] Step 4: 5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-l-yl)-/V,7-dim ethylthieno[3,2- h]pyridine-3-carboxamide

[00238] Using the procedure described for step 2 of Example 25, the methyl ester functionality of the step 3 product was converted to the corresponding /V-methyl carboxamide, affording the title compound as an off-white solid. 1H NMR (400 MHz, CDCL) d 9.48 (br s, 1H), 8.64 (s, 1H), 6.90 (d, / = 8.4 Hz, 1H), 4.21-4.08 (m, 1H), 3.37-3.21 (m, 4H), 3.18-3.03 (m, 5H), 2.87-2.72 (m, 3H), 2.61-2.49 (m, 2H), 1.20 (d, / = 6.5 Hz, 6H) ppm. MS: 390 m/z (M+H ⁺ ). [00239] Example 49. 5-(4-(2-(Isopropylamino)-2-oxoethyl)-3,3-dimethylpiperazin-l -yl)-A ^/ - methyl-7-(triiluoromethyl)thieno[3,2-/>]pyridine-3-carbox amide

[00240] Step 1 : / _<?/7 - Butyl 4-(2-(isopropylamino)-2-oxoethyl)-3,3-dimethylpiperazine-l- carboxylate

[00241] To a stirred solution of //77-butyl 3,3-dimethylpiperazine-l-carboxylate (1.00 g, 4.67 mmol) and 2-bromo-/V-isopropylacetamide (0.882 g, 4.90 mmol) in butyronitrile (30 mL) was added sodium carbonate (0.742 g, 7.00 mmol). The mixture was heated at reflux overnight. TLC analysis indicated that the reaction was complete. The mixture was cooled to room temperature and suction filtered to remove the solids. The filtercake was rinsed with ethyl acetate (-30 mL) and the combined filtrate was concentrated. The residue was subjected to automated flash chromatography (Combiflash system; 0 to 5% 2N ammonia/methanol in dichloromethane; 80 g Gold silica column), affording the purified title compound ( R _f -0.4 with 19:1 dichloromethane/2N ammonia in methanol as the eluant) as an off-white solid (1.37 g, 94%). 'H NMR (400 MHz,

CDCb) d 7.18 (d, J = 8.4 Hz, 1H), 4.13-4.03 (m, 1H), 3.48-3.42 (m, 2H), 3.20 (br s, 2H), 2.96 (br s, 2H), 2.54-2.47 (m, 2H), 1.46 (s, 9H), 1.16 (d, J = 6.6 Hz, 6H), 1.01 (s, 6H) ppm.

[00242] Step 2: 2-(2,2-Dimcthylpipcrazin-l -ylj-A sopropyl acetamide

[00243] Using the procedure described in step 3 of Example 44, the /V-ieri-butoxycarbonyl amine protecting group of the step 1 product was cleaved using an ethyl acetate solution of hydrogen chloride. The title compound was obtained as a pale amber gum. 'H NMR (400 MHz, CDCb) d 7.26 (br s, 1H), 4.12-4.03 (m, 1H), 2.96 (br s, 2H), 2.93-2.87 (m, 2H), 2.66 (s, 2H),

2.53-2.46 (m, 2H), 1.16 (d, / = 6.5 Hz, 6H), 1.04 (s, 6H) ppm.

[00244] Step 3: Methyl 5-(4-(2-(isopropylamino)-2-oxoethyl)-3,3-dimethylpiperazin-l -yl)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate

[00245] Into a 20 mL microwave reaction vial equipped with a stir bar was loaded Intermediate 3 (0.400 g, 1.35 mmol), step 2 product (0.460 g, 2.16 mmol), -methyl-2-pyrrolidinone (6 mL), and /V,/V-diisopropylethylamine (0.47 mL, 2.7 mmol). The vessel was sealed and heated in a microwave reactor for two hours at 130 °C. TLC analysis indicated that the reaction was nearly complete. The reaction was then concentrated and the residue was partitioned between aqueous sodium bicarbonate solution (-60 mL) and ethyl acetate (-30 mL). The organic layer was combined with an additional extracts (ethyl acetate, 2 x -30 mL), dried (Na ₂ S0 ₄ ) and

concentrated. The crude material was subjected to automated flash chromatography (Combiflash system; 25 to 60% ethyl acetate in heptane; 40 g Gold silica column), providing the purified title compound ( R _f -0.3 with 6:4 heptane/ethyl acetate as the eluant) as an amber solid (0.287 g, 45%). 1H NMR (400 MHz, CDCb) d 8.56 (s, 1H), 7.26 (d, / = 8.3 Hz, 1H), 6.98 (s, 1H), 4.17-4.07 (m, 1H), 3.96 (s, 3H), 3.89-3.80 (m, 2H), 3.50 (br s, 2H), 3.05 (br s, 2H), 2.75-2.69 (m, 2H), 1.19 (d, J = 6.5 Hz, 6H), 1.13 (s, 6H) ppm.

[00246] Step 4: 5-(4-(2-(Isopropylamino)-2-oxoethyl)-3,3-dimethylpiperazin-l -yl)-/V-methyl- 7-(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide

[00247] Using the procedure described for step 2 of Example 25, the methyl ester functionality of the step 3 product was converted to the corresponding /V-methyl carboxamide, affording the title compound as a pale gold solid. 1H NMR (400 MHz, CDCb) d 9.37 (br s, 1H), 8.67 (s, 1H),

7.18 (d, J = 8.4 Hz, 1H), 7.01 (s, 1H), 4.18-4.08 (m, 1H), 3.74-3.67 (m, 2H), 3.47 (s, 2H), 3.09 (d, 7 = 4.9 Hz, 3H), 3.07 (s, 1H), 2.81-2.74 (m, 2H), 1.20 (d, J = 6.6 Hz, 6H), 1.15 (s, 6H) ppm. MS:

472 m/z (M+H ⁺ ).

[00248] Example 60. l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyrid in-5- yl)piperidin-4-yl azetidine-l-carboxylate

[00249] Into a 20 mL microwave reaction vial equipped with a stir bar was loaded Intermediate 21 (0.200 g, 0.381 mmol), N,N-d\ methyl formamidc (6.0 mL), azetidine (77 pL, 1.14 mmol), triethylamine (0.21 mL, 1.5 mmol) and 4-(dimethylamino)pyridine (6 mg, 49 pmol). The vessel was sealed and heated in a microwave reactor for one hour at 90 °C. The mixture was then concentrated and the residue was partitioned between chloroform (-20 mL) and aqueous sodium carbonate solution (-40 mL). The organic layer was combined with additional extracts

(chloroform, 2 x -20 mL), dried (Na ₂ S0 ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system; 0-2% methanol in dichloromethane; 40 g Gold silica column). The target component (Rf -0.2 with 98:2 dichloromethane/methanol as the eluant) was obtained as a faint gold film. This material was co-evaporated with ethyl acetate and vacuum oven dried (-60 °C) to afford the title compound as a pale gold solid (0.144 g, 85%). 'H NMR (400 MHz, CDCb) d 9.43 (s, 1H), 8.66 (s, 1H), 7.06 (s, 1H), 5.02-4.93 (m, 1H), 4.10-3.99

(m, 4H), 3.96-3.85 (m, 2H), 3.64-3.51 (m, 2H), 3.07 (d, J = 4.9 Hz, 3H), 2.33-2.20 (m, 2H), 2.12- 2.00 (m, 2H), 1.90-1.77 (m, 2H) ppm. MS: 443 m/z (M+H ⁺ ).

[00250] Example 63. l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyrid in-5- yl)piperidin-4-yl (S j-sec-butylcarbamate

[00251] Exchanging azetidine for (S)-sec-butylamine, the reaction procedure described in Example 60 was used to prepare the title compound as off-white solid. 'H NMR (400 MHz, CDCb) d 9.43 (br s, 1H), 8.66 (s, 1H), 7.06 (s, 1H), 5.10-4.90 (m, 1H), 4.60-4.28 (m, 1H), 4.02- 3.85 (m, 2H), 3.76-3.44 (m, 3H), 3.07 (d, / = 4.9 Hz, 3H), 2.16-2.02 (m, 2H), 1.94-1.74 (m, 2H), 1.56-1.42 (m, 1H), 1.15 (d, / = 6.6 Hz, 3H), 0.99-0.88 (m, 3H) ppm. MS: 459 m/z (M+H ⁺ ).

[00252] Example 76. l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyrid in-5- yl)piperidin-4-yl isopropylcarbamate

[00253] Exchanging azetidine for isopropylamine, the reaction procedure described in

Example 60 was used to prepare the title compound as an off-white solid. 'H NMR (400 MHz, CDCb) d 9.43 (br s, 1H), 8.66 (s, 1H), 7.06 (s, 1H), 4.97 (br s, 1H), 4.53 (br s, 1H), 4.00-3.73 (m, 3H), 3.64-3.36 (m, 2H), 3.07 (d, / = 4.9 Hz, 3H), 2.14-2.02 (m, 2H), 1.92-1.74 (m, 2H), 1.18 (d, 7 = 6.5 Hz, 6H) ppm. MS: 445 m/z (M+H ⁺ ).

[00254] Example 87. l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyrid in-5- yl)piperidin-4-yl 3-(difluoromethoxy)azetidine-l-carboxylate

[00255] Step 1: l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5- yl)piperidin-4-yl lH-imidazole- l-carboxylate

[00256] To a stirred suspension of Intermediate 7 (2.50 g, 6.96 mmol) in dichloromethane (50 mL) was added l,l'-carbonyldiimidazole (2.26 g, 13.9 mmol). The mixture quickly cleared to an amber solution. Stirring was continued overnight at room temperature. After this time, the mixture was diluted with additional dichloromethane (-100 mL) and washed with 0.1 N hydrochloric acid (1 x -100 mL). The organic layer was dried (Na ₂ S0 ₄ ) and concentrated to afford crude the title compound as foamy, pale gold solid (3.26 g, 103%). The crude intermediate was deemed sufficiently pure to use, without purification, in the next step. 'H NMR (400 MHz, CDCb) d 9.33 (br s, 1H), 8.69 (s, 1H), 8.18-8.15 (m, 1H), 7.44 (t, / = 1.4 Hz, 1H), 7.13-7.07 (m, 2H), 5.38-5.30 (m, 1H), 4.07-3.97 (m, 2H), 3.70-3.59 (m, 2H), 3.08 (d, J = 4.9 Hz, 3H), 2.31-2.21 (m, 2H), 2.10-1.98 (m, 2H) ppm.

[00257] Step 2: l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5- yl)piperidin-4-yl 3-(difluoromethoxy)azetidine- l-carboxylate

[00258] Into a 20 mL microwave reaction vial equipped with a stir bar was loaded step 1 product (0.250 g, 0.551 mmol) and acetonitrile (10 mL). To this stirred solution was added 3- (difluoromethoxy)azetidine (0.082 g, 0.666 mmol) followed by N- h ydro x y s ucc i n i m i dc (0.076 g, 0.660 mmol). The vessel was sealed and heated in a microwave reactor for one hour at 60 °C. LCMS analysis indicated that the reaction was complete. The reaction was analyzed by LCMS and found to be complete. The mixture was concentrated and partitioned between chloroform (-30 mL) and aqueous sodium bicarbonate solution (-50 mL). The organic layer was combined with additional extracts (chloroform, 2 x -30 mL), dried (Na ₂ S0 ₄ ) and concentrated. The residue was subjected to automated flash chromatography (Combiflash system; 40 to 70% ethyl acetate in heptane; 40 g Gold silica column). The target component (Rf -0.4 with 7:3 ethyl acetate/heptane as the eluant) was obtained as a near colorless film. This material was vacuum oven dried (-60 °C) and ground with a spatula to afford the title compound as a pale gold solid (0.270 g, 96%). 'H NMR (400 MHz, CDCb) d 9.42 (br s, 1H), 8.67 (s, 1H), 7.06 (s, 1H), 6.25 (t, / = 73 Hz, 1H), 5.04-4.90 (m, 2H), 4.28 (dd, / = 9.9, 6.8 Hz, 2H), 4.07 (dd, / = 10.2, 4.4 Hz, 2H), 3.98-3.85 (m,

2H), 3.63-3.49 (m, 2H), 3.08 (d, J = 4.8 Hz, 3H), 2.13-2.01 (m, 2H), 1.90-1.77 (m, 2H) ppm. MS: 509 m/z (M+H ⁺ ).

[00259] Example 88. l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyrid in-5- yl)piperidin-4-yl 3-(trifluoromethoxy)azetidine-l-carboxylate

[00260] Exchanging 3-(difluoromethoxy)azetidine for equimolar quantities of 3- (trifluoromethoxy)azetidine hydrochloride and triethylamine, the same reaction procedure described for step 2 of Example 87 was used to prepare the title compound as a pale gold solid. 1H NMR (400 MHz, CDCb) d 9.40 (br s, 1H), 8.66 (s, 1H), 7.07 (s, 1H), 5.07-4.90 (m, 2H), 4.32

(dd, / = 10.2, 6.7 Hz, 2H), 4.14 (dd, / = 10.2, 4.2 Hz, 2H), 4.02-3.86 (m, 2H), 3.08 (d, / = 4.8 Hz, 3H), 2.16-2.02 (m, 2H), 1.92-1.76 (m, 2H) ppm. MS: 527 m/z (M+H ⁺ ).

[00261] Example 90. l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyrid in-5- yl)piperidin-4-yl (S ₎ -(l-(trifluoromethoxy)propan-2-yl)carbamate

[00262] Exchanging 3-(difluoromethoxy)azetidine for equimolar quantities of Intermediate 18 and triethylamine, the same reaction procedure described for step 2 of Example 87 was used to prepare the title compound as a pale gold solid. 'H NMR (400 MHz, CDCb) d 9.42 (br s, 1H), 8.67 (s, 1H), 7.07 (s, 1H), 5.07-4.92 (br s, 1H), 4.87-4.71 (br s, 1H), 4.13-3.84 (m, 5H), 3.62-3.49 (m, 2H), 3.07 (d, / = 4.9 Hz, 3H), 2.16-2.02 (m, 2H), 1.90-1.76 (m, 2H), 1.28 (d, / = 6.6 Hz, 3H) ppm. MS: 529 m/z (M+H ⁺ ).

[00263] Example 91. 3,3-Difluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thien o[3,2- 6]pyridin-5-yl)piperidin-4-yl isopropylcarbamate

[00264] Step 1: Methyl 5-(3,3-difluoro-4-hydroxypiperidin-l-yl)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate

[00265] Into a 20 mL microwave reaction vial equipped with a stir bar was loaded Intermediate 3 (1.35 g, 4.57 mmol), /V-methyl-2-pyrrolidinone (12 mL), 3,3-difluoropiperidin-4-ol (1.02 g,

7.44 mmol) and A/ZV-diisopropylethylamine (1.6 mL, 9.2 mmol). The vessel was sealed and heated in a microwave reactor for five hours at 130 °C. Analysis by LCMS indicated that the reaction was incomplete (-73:27 ratio of product to starting material, by relative peak area). The reaction was heated for another five hours at 130 °C. LCMS analysis indicated that the reaction had progressed sufficiently to proceed to the workup (-85/12 ratio of product and starting material). The solution was concentrated and the residue was partitioned between chloroform (-75 mL) and aqueous sodium bicarbonate solution (-100 mL). The organic layer was combined with additional extracts (chloroform, 2 x -50 mL), dried (Na ₂ S0 ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system; 40 to 60% ethyl acetate in heptane; 120 g silica column) to afford the title compound (Rf -0.4 with 6:4

heptane/ethyl acetate as the eluant) as a gold solid (1.07 g, 59%). 'H NMR (400 MHz, CDCb) d

8.57 (s, 1H), 7.04 (s, 1H), 4.25-3.79 (m, 8H), 2.30 (d, J = 3.7 Hz, 1H), 2.20-2.09 (m, 1H), 2.05-

1.95 (m, 1H) ppm.

[00266] Step 2: 5-(3,3-Difluoro-4-hydroxypiperidin-l-yl)-./V-methyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide

[00267] Using the procedure described for step 2 of Example 25, the methyl ester functionality of the step 1 product was converted to the corresponding /V-mcthyl carboxamide, affording the title compound as an off-white solid. 1H NMR (400 MHz, CDCb) d 9.30 (br s, 1H), 8.69 (s, 1H), 7.08 (br s, 1H), 4.21-4.06 (m, 2H), 4.03-3.69 (m, 3H), 3.09 (d, J = 4.8 Hz, 3H), 2.78 (br s, 1H), 2.22-2.11 (m, 1H), 2.10-2.00 (m, 1H) ppm.

[00268] Step 3: 3,3-Difluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thien o[3,2-h]pyridin- 5-yl)piperidin-4-yl lH-imidazole- l-carboxylate [00269] To a stirred suspension of step 2 product (0.905 g, 2.29 mmol) in dichloromethane (12 mL) was added l,l'-carbonyldiimidazole (0.557 g, 3.44 mmol). Stirring was continued overnight at room temperature. After this time, the reaction was diluted with chloroform (-80 mL). The solution was washed with 0.1 N hydrochloric acid (l x 100 mL) and aqueous sodium bicarbonate solution (1 x -80 mL). The organic layer was dried (Na ₂ S0 ₄ ) and concentrated to afford the title compound as a foamy, pale gold solid (1.12 g, 100%). This material was deemed sufficiently pure to use, without purification, in the next step. 1H NMR (400 MHz, CDCL) 5 9.11 (m, 1H), 8.73 (s, 1H), 8.21-8.18 (m, 1H), 7.47 (t, J = 1.4 Hz, 1H), 7.15-7.10 (m, 1H), 5.52-5.43 (m, 1H), 4.31-4.18 (m, 1H), 4.07-3.92 (m, 2H), 3.83-3.73 (m, 1H), 3.10 (d, / = 4.9 Hz, 3H), 2.46-2.37 (m, 1H), 2.34- 2.23 (m, 1H) ppm.

[00270] Step 4: 3,3-Difluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thien o[3,2-h]pyridin- 5-yl)piperidin-4-yl isoprop ylcarbamate

[00271] Exchanging the step 1 product of Example 87 for the step 3 product of the present Example and 3-(difluoromethoxy)azetidine for isopropylamine, the reaction procedure described for step 2 of Example 87 was used to prepare the title compound as a white solid. 'H NMR (400 MHz, CDCL) d 9.21 (br s, 1H), 8.70 (s, 1H), 7.08 (s, 1H), 5.30-5.14 (m, 1H), 4.83-4.69 (m, 1H), 4.16-3.67 (m, 5H), 3.09 (d, / = 4.9 Hz, 3H), 2.30-2.01 (m, 2H), 1.20 (t, / = 6.5 Hz, 6H) ppm. MS: 481 m/z (M+H ⁺ ).

[00272] Example 95. l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyrid in-5- yl)piperidin-4-yl 6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate

[00273] Step 1: Piperidin-4-yl 6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate

[00274] To a stirred and cooled (0 °C) solution of Intermediate 22 (1.35 g, 5.12 mmol) in chloroform (40 mL) was added 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine dihydrochloride (1.00 g, 5.12 mmol) followed by triethylamine (2.9 mL, 21 mmol, 4.1 eq; the amount of triethylamine used in similar reactions utilizing Intermediate 22 was adjusted to at least two equivalents more than the number of acid equivalents introduced by the amine component, if in a salt form). The ice bath was removed and the reaction was allowed to warm to room temperature and stirred overnight. The mixture was then rinsed into a separatory funnel with chloroform (-20 mL) and washed with aqueous sodium carbonate solution (-50 mL). The organic layer was combined with additional extracts of the aqueous layer (chloroform, 2 x -40 mL), dried (Na ₂ S0 ₄ ) and concentrated to afford the crude carbamate as a faint amber gum (2.13 g, 119%). This material was dissolved in dichloromethane (21 mL), stirred and treated with trifluoroacetic acid (7.0 mL, 92 mmol; the volume of dichloromethane and the number of equivalents of trifluoroacetic acid used in similar reactions with Intermediate 22 was adjusted so that a total of 17-20 equivalents of a 3.0-3.5 M trifluoroacetic acid solution was used). After two hours, the reaction was

concentrated and the residue was partitioned between chloroform (-50 mL) and a 1.0 N aqueous sodium hydroxide solution (-50 mL). The organic layer was combined with additional extracts (chloroform, 3 x -50 mL), dried (Na ₂ S0 ₄ ) and concentrated to afford the crude title compound as a faint amber gum (1.28 g, 100%). This material was deemed sufficiently pure to use, without purification, in the next step. 1H NMR (400 MHz, CDCL) d 7.49 (s, 1H), 6.08 (s, 1H), 4.88-4.78 (m, 1H), 4.72 (s, 2H), 4.27-4.17 (m, 2H), 3.99-3.90 (m, 2H), 3.13-3.01 (m, 2H), 2.80-2.68 (m, 2H), 2.01-1.89 (m, 1H), 1.68-1.51 (m, 3H) ppm.

[00275] Step 2: l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5- yl)piperidin-4-yl 6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate

[00276] Into a 20 mL microwave reaction vial equipped with a stir bar was loaded step 1 product (0.340 g, 1.36 mmol), Intermediate 5 (0.200 g, 0.679 mmol), /V-methyl-2-pyrrolidinone (6 mL) and A N-di isopropyl ethyl amine (0.24 mL, 1.4 mmol). The vessel was sealed and heated in a microwave reactor for two hours at 130 °C. The reaction was concentrated and the residue was partitioned between chloroform (-30 mL) and aqueous sodium bicarbonate solution (-50 mL). The organic layer was combined with additional extracts (chloroform, 2 x -30 mL), dried (Na ₂ S0 ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system; 3 to 8% methanol in ethyl acetate; 40 g Gold silica column). The target component (Rf -0.2 with 19: 1 ethyl acetate/methanol as the eluant), component was obtained as an orange-yellow film (0.339 g, 98%). This material was triturated with diethyl ether/ethyl acetate (-1: 1; -25 mL) and recollected via suction filtration. The filtercake was rinsed with additional diethyl ether (1 x -10 mL) and air-dried on the frit under house vacuum and a nitrogen funnel to afford the title compound as a yellow solid (0.274 g, 79%). ' H NMR (400 MHz, CDCL) d 9.40 (br s, 1H), 8.67 (s, 1H), 7.50 (s, 1H), 7.08 (s, 1H), 6.08 (br s, 1H), 5.15-5.02 (m, 1H), 4.75 (s, 2H), 4.33-4.16 (m, 2H), 4.08-3.87 (m, 4H), 3.67-3.51 (m, 2H), 3.08 (d, 7 = 4.7 Hz, 3H), 2.21-2.07 (m,

2H), 1.96-1.81 (m, 2H) ppm. MS: 509 m/z (M+H ⁺ ).

[00277] Example 109. l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyrid in-5- yl)piperidin-4-yl (S )-(l-cydopropylethyl)carbamate

[00278] Exchanging 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine dihydrochloride for (S)- 1 - cyclopropylethan-l -amine, the synthetic sequence described in Example 95 was used to prepare the title compound as a light yellow solid. 'H NMR (400 MHz, CDCb) d 9.43 (br s, 1H), 8.66 (s,

1H), 7.06 (s, 1H), 4.97 (br s, 1H), 4.72 (br s, 1H), 4.02-3.85 (m, 2H), 3.62-3.45 (m, 2H), 3.22- 3.02 (m, 1H), 3.07 (d, J = 4.7 Hz, 3H), 2.16-2.00 (m, 2H), 1.91-1.68 (m, 2H), 1.23 (d, / = 6.5 Hz,

3H), 0.88-0.76 (m, 1H), 0.57-0.30 (m, 3H), 0.28-0.14 (m, 1H) ppm. MS: 471 m/z (M+H ⁺ ).

[00279] Example 115. l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-Z>]p yridin-5- yl)piperidin-4-yl ((4-methylmorpholin-2-yl)methyl)carbamate

[00280] Step 1: Benzyl 4-((((4-methylmorpholin-2-yl)methyl)carbamoyl)oxy)piperidine -l- carboxylate

[00281] To a stirred and cooled (0 °C) solution of Intermediate 23 (1.46 g, 4.89 mmol) in chloroform (30 mL) was added 2-(aminomethyl)-4-methylmorpholine (0.636 g, 4.89 mmol) followed by triethylamine (1.40 mL, 10.0 mmol, 2.05 eq; the amount of triethylamine used in similar reactions utilizing Intermediate 23 was adjusted to at least 2.0 equivalents more than the number of acid equivalents introduced by the amine component, if in a salt form). The ice bath was removed and the reaction was allowed to warm to room temperature and stirred overnight. The mixture was then rinsed into a separatory funnel with chloroform (-20 mL) and washed with aqueous sodium carbonate solution (-50 mL). The organic layer was combined with additional extracts of the aqueous layer (chloroform, 2 x -40 mL), dried (Na ₂ S0 ₄ ) and concentrated to afford the crude title compound as a faint amber gum (2.01 g, 105%; yield inflated by residual toluene). This material was deemed sufficiently pure to use, without purification, in the next step. 1H NMR (400 MHz, CDCb) d 7.40-7.28 (m, 5H), 5.13 (s, 2H), 5.08-4.99 (m, 1H), 4.90-4.79 (m, 1H), 3.95-3.55 (m, 5H), 3.41-3.25 (m, 3H), 3.18-3.09 (m, 1H), 2.74-2.60 (m, 2H), 2.28 (s, 3H), 2.09 (td, J = 11.5, 3.4 Hz, 1H), 1.95-1.79 (m, 3H), 1.71-1.53 (m, 2H) ppm.

[00282] Step 2: Piperidin-4-yl ((4-methylmorpholin-2-yl)methyl)carbamate

[00283] The crude step 1 product was combined with 10% palladium on carbon (0.400 g) and taken up in methanol (50 mL). The stirred mixture was cycled between vacuum and a nitrogen atmosphere three times. The reaction vessel was evacuated a final time and refilled with hydrogen (via balloon). The reaction was stirred at room temperature overnight and then analyzed by 1H NMR (a few drops of the settled suspension were removed and concentrated to supply the sample) and found to be complete. The mixture was suction filtered through a pad of Celite, which was subsequently rinsed with additional methanol (-80 mL). The combined filtrate was concentrated to afford crude product as an tacky colorless glass (1.32 g, 100%). The crude amine was deemed sufficiently pure to use, without purification, in the next step. 'H NMR (400 MHz, CDCb) d 5.21-5.07 (m, 1H), 4.88-4.77 (m, 1H), 3.90-3.84 (m, 1H), 3.70-3.56 (m, 2H), 3.41-3.30 (m, 1H), 2.98-2.86 (m, 2H), 2.73-2.61 (m, 2H), 2.28 (s, 3H), 2.10 (td, / = 11.5, 3.3 Hz, 1H), 2.09- 1.99 (m, 2H), 1.85 (t, / = 10.7 Hz, 1H), 1.80-1.69 (m, 2H) ppm.

[00284] Step 3: l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5- yl)piperidin-4-yl ((4-methylmorpholin-2-yl)methyl)carbamate

[00285] Into a 20 mL microwave reaction vial equipped with a stir bar was loaded Intermediate 5 (0.200 g, 0.679 mmol), step 2 product (0.306 g, 1.19 mmol), - methyl -2-pyrrol idi none (6 mL) and /V,/V-diisopropylethylamine (0.24 mL, 1.4 mmol). The vessel was sealed and heated in a microwave reactor for two hours at 130 °C. The reaction was concentrated and the residue was partitioned between chloroform (-25 mL) and aqueous sodium carbonate solution (-40 mL). The organic layer was combined with additional extracts (chloroform, 2 x -25 mL), dried (Na ₂ S0 ₄ ) and concentrated. The crude material was subjected to automated flash chromatography

(Combiflash system; 0 to 10% methanol in chloroform; 80 g Gold silica column). The target component (Rf -0.36 with 9:1 chloroform/methanol as the eluant) was obtained as a foamy solid. This material was co-evaporated with ethyl acetate to afford the title compound as an amber solid (0.159 g, 45%). 1H NMR (400 MHz, CDCb) d 9.48-9.39 (m, 1H), 8.66 (s, 1H), 7.06 (s, 1H), 5.17- 4.88 (m, 2H), 3.99-3.83 (m, 3H), 3.74-3.49 (m, 4H), 3.46-3.35 (m, 1H), 3.22-3.12 (m, 1H), 3.07

(d, 7 = 4.9 Hz, 3H), 2.74 (d, / = 11.2 Hz, 1H), 2.66 (d, / = 11.6 Hz, 1H), 2.30 (s, 1H), 2.17-2.01

(m, 3H), 1.92-1.77 (m, 3H) ppm. MS: 516 m/z (M+H ⁺ ).

[00286] Example 142. l-(3-(Methylcarbamoyl)thieno[3,2-6]pyridin-5-yl)piperidin-4- yl (S)-(l-(trifluoromethoxy)propan-2-yl)carbamate

[00287] Step 1: Methyl 5-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-h]pyridine-3-ca rboxylate

[00288] Exchanging the step 1 product of Example 48 for Intermediate 16, the reaction procedure described for step 2 of Example 48 was used to prepare the title compound as a brown solid. This material was deemed sufficiently pure to use, without purification, in the next step. ' H NMR (400 MHz, CDCb) d 8.76 (s, 1H), 8.37 (d, J = 8.6 Hz, 1H), 7.24 (d, / = 8.6 Hz, 1H), 3.99 (s, 3H) ppm.

[00289] Step 2: Piperidin-4-yl (S)-(l-(trifluoromethoxy)propan-2-yl)carbamate

[00290] Exchanging 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine dihydrochloride for

Intermediate 18, the 0-(piperidin-4-yl) carbamate preparation described in step 1 of Example 95 was used to prepare the crude title compound as a waxy, off-white solid. This material was deemed sufficiently pure to use, without purification, in the next step. ' H NMR (400 MHz, CDCb) d 4.99-4.57 (m, 2H), 4.09-3.82 (m, 3H), 3.06 (dt, / = 12.7, 4.5 Hz, 2H), 2.76-2.64 (m, 2H), 1.98-1.85 (m, 2H), 1.62-1.39 (m, 2H), 1.25 (d, / = 6.7 Hz, 3H) ppm.

[00291] Step 3: Methyl (S)-5-(4-(((l-(trifluoromethoxy)propan-2-yl)carbamoyl)oxy)pi peridin- l-yl)thieno[3,2-h]pyridine-3-carboxylate

[00292] Into a 10 mL microwave reaction vial equipped with a stir bar was loaded step 2 product (0.220 g, 0.814 mmol), step 1 product (0.200 g, 0.586 mmol), - m c t h y 1 - 2 - p y ro 1 i d i n o n c (2.5 mL) and /V,/V-diisopropylethylamine (0.18 mL, 1.0 mmol). The reaction vessel was sealed and heated in a microwave reactor for five hours at 90 °C. The reaction was analyzed by LCMS and found to incomplete (approximate 1 : 1 mixture of triflate starting material and putative product, as judged by relative peak size). Heating at was continued at 90 °C for another one hour, but no reaction advancement was observed by LCMS. The mixture was then concentrated and the residue was partitioned between chloroform (-30 mL) and aqueous sodium bicarbonate solution (-50 mL). The organic layer was combined with additional extracts (chloroform, 2 x -15 mL), dried (Na ₂ S0 ₄ ) and concentrated. The crude material was subjected to automated flash

chromatography (Combiflash system; 0 to 40% ethyl acetate in heptane; 40 g Gold silica column) to afford the title compound (Rf -0.35 with 6:4 heptane/ethyl acetate as the eluant) as a colorless solid (0.099 g, 37%). 1H NMR (400 MHz, CDCL) d 8.45 (s, 1H), 7.89 (d, / = 9.1 Hz, 1H), 6.81 (d, / = 9.1 Hz, 1H), 5.00-4.87 (m, 1H), 4.85-4.71 (m, 1H), 4.16-3.87 (m, 8H), 3.56-3.39 (m, 2H), 2.10-1.98 (m, 2H), 1.84- 1.68 (m, 2H), 1.26 (d, / = 6.5 Hz, 3H) ppm.

[00293] Step 4: l-(3-(Methylcarbamoyl)thieno[3,2-h]pyridin-5-yl)piperidin-4- yl (S)-( l - (trifluoromethoxy)propan-2-yl)carbamate

[00294] Using the procedure described for step 2 of Example 25, the methyl ester functionality of the step 3 product was converted to the corresponding /V-methyl carboxamide, affording the title compound as an off-white solid. 1H NMR (400 MHz, CDCL) d 9.72-9.62 (m, 1H), 8.54 (s, 1H), 7.94 (d, / = 9.1 Hz, 1H), 6.83 (d, / = 9.1 Hz, 1H), 5.04-4.86 (s, 2H), 4.10-3.83 (m, 5H), 3.54-3.40 (m, 2H), 3.07 (d, / = 4.8 Hz, 3H), 2.12-1.99 (m, 2H), 1.90-1.72 (m, 2H), 1.27 (d, / =

6.6 Hz, 3H) ppm. MS: 461 m/z (M+H ⁺ ).

[00295] Example 145. N-Methyl-5-(4-((6-methylpyridin-2-yl)oxy)piperidin-l-yl)-7- (trifluoromethyl)thieno[3,2-6]pyridine-3-carboxamide

[00296] Using the conditions described in step 3 of Example 115, Intermediate 5 was subjected to SNAr displacement with a piperidine derivative, 2-methyl-6-(piperidin-4-yloxy)pyridine, to afford the title compound as a tan solid. 1H NMR (400 MHz, CDCL) d 9.56-9.45 (m, 1H), 8.66 (s, 1H), 7.47 (dd, / = 8.2, 7.3 Hz, 1H), 7.09 (s, 1H), 6.73 (d, / = 7.3 Hz, 1H), 6.53 (d, / = 8.2 Hz,

1H), 5.42 (tt, / = 7.2, 3.6 Hz, 1H), 3.96 (ddd, / = 13.2, 7.8, 3.7 Hz, 2H), 3.67 (ddd, / = 13.2, 7.7, 3.7 Hz, 2H), 3.07 (d, / = 4.9 Hz, 3H), 2.45 (s, 3H), 2.22-2.09 (m, 2H), 2.03-1.91 (m, 2H) ppm. MS: 451 m/z (M+H ⁺ ). [00297] Example 151. l-(6-Methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3, 2- 6]pyridin-5-yl)piperidin-4-yl (S)-( 1 -cyclopropylethyl)carbamate

[00298] Exchanging 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine dihydrochloride for (S)- 1 - cyclopropylethan-l -amine and Intermediate 5 for Intermediate 15, the synthetic sequence described in Example 95 was used to prepare the title compound as an off-white solid. 1H NMR (400 MHz, CDCb) d 9.60-9.44 (m, 1H), 8.62 (s, 1H), 5.03-4.84 (m, 1H), 4.80-4.56 (m, 1H), 3.49- 3.33 (m, 2H), 3.28-2.90 (m, 6H), 2.54 (q, J = 2.2 Hz, 3H), 2.25-2.05 (m, 2H), 2.00-1.81 (m, 2H), 1.24 (d, J = 6.6 Hz, 3H), 0.90-0.76 (m, 1H), 0.57-0.32 (m, 3H), 0.28-0.17 (m, 1H) ppm. MS: 485 m/z (M+H ⁺ ).

[00299] Example 171. 2-(Trifluoromethoxy)ethyl 4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)piperidine-l- carboxylate

[00300] Into a 20 mL microwave reaction vial equipped with a stir bar was loaded Intermediate 11 (0.200 g, 0.892 mmol) and acetonitrile (10 mL). To this stirred solution was added

Intermediate 17 (0.400 g, 1.11 mmol) and N- h y dro x y s uc c i m i dc (0.125 g, 1.09 mmol). The vessel was sealed and heated in a microwave reactor for one hour at 60 °C. LCMS analysis indicated that the reaction was complete. The mixture was concentrated and the residue was partitioned between aqueous sodium bicarbonate solution (-100 mL) and chloroform (-75 mL). The organic layer was combined with a second extract (chloroform, 1 x -50 mL), dried (Na ₂ S0 ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system; 40 to 60% ethyl acetate in heptane; 80 g Gold silica column). The target component (Rf -0.25 with 6:4 ethyl acetate/heptane as the eluant) was obtained as a colorless foam. This material was vacuum oven dried (-60 °C) to afford the title compound as a colorless solid (0.392 g, 85%). 1H NMR (400 MHz, CDCb) d 9.07-8.96 (m, 1H), 8.76 (s, 1H), 7.13 (s, 1H), 5.26 (tt, 7 = 7.1, 3.5 Hz, 1H), 4.42-4.32 (m, 2H), 4.23-4.16 (m, 2H), 3.81 (ddd, J = 13.7, 7.9, 3.8 Hz, 2H), 3.54 (ddd, 7 = 13.7, 7.5, 3.9 Hz, 2H), 3.08 (d, J = 4.9 Hz, 3H), 2.18-1.90 (m, 4H) ppm. MS: 516 mJz (M+H ⁺ ).

[00301] Example 175. (S ₎ -l-(Trifluoromethoxy)propan-2-yl (2/?,4/?)-2-methyl-4-((3-

(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyridin -5-yl)oxy)piperidine-l- carboxylate

[00302] Step 1: //77-butyl (2R,4R)-2-methyl-4-((3-(methylcarbamoyl)-7- (trifluoiOmcthyl)thicno[3,2-/?Jpyridin-5-yl)oxy)pipcridinc- 1 -carboxyl ate

[00303] To a stirred solution of Intermediate 5 (1.35 g, 4.58 mmol) and //77-butyl (2R,4R)-4- hydroxy-2-methylpiperidine-l-carboxylate (1.00 g, 4.64 mmol) in tetrahydrofuran (30 mL) was added potassium //77-butoxidc (0.668 g, 5.95 mmol). The mixture was heated at 70 °C for three hours and then analyzed by LCMS. Little or no chloropyridine starting was detected. The reaction was concentrated and the residue was partitioned between aqueous sodium bicarbonate solution (-100 mL) and chloroform (-60 mL). The organic layer was combined with additional extracts (chloroform, 2 x -40 mL), dried (Na ₂ S0 ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system; 20 to 50% ethyl acetate in heptane; 80 g Gold silica column) to afford the title compound (Rf -0.3 with 1:1 heptane/ethyl acetate as the eluant) as light amber solid (1.31 g, 60%). 1H NMR (400 MHz, CDCb) d 9.08-9.01 (m, 1H), 8.75 (s, 1H), 7.11 (s, 1H), 5.38 (p, 7 = 3.1 Hz, 1H), 4.50-4.40 (m, 1H), 4.00 (ddd, 7 = 13.8, 4.7, 1.8 Hz, 1H), 3.29 (td, 7 = 13.4, 2.8 Hz, 1H), 3.07 (d, 7 = 4.9 Hz, 3H), 2.18-2.01 (m, 3H), 1.97-1.85 (m, 1H), 1.49 (s, 9H), 1.32 (d, 7 = 7.1 Hz, 3H) ppm.

[00304] Step 2: /V-methyl-5-(((2R,4R)-2-methylpiperidin-4-yl)oxy)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide

[00305] To a stirred solution of step 1 product (1.30 g, 2.75 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3.0 mL, 39 mmol). After 75 minutes, the reaction was analyzed by 1H NMR (a few drops of the reaction solution were concentrated and partitioned between aqueous sodium carbonate solution and chloroform; the organic layer was concentrated to provide the sample) and found to be complete. The reaction was concentrated and the resulting oil was partitioned between chloroform (-40 mL) and aqueous sodium carbonate solution (-60 mL). The organic layer was combined with additional extracts (chloroform, 2 x -40 mL), dried (Na ₂ S0 ₄ ) and concentrated to afford the crude title compound as a light amber solid (1.05 g, 102%). This material was deemed sufficiently pure to use, without purification, in the next step. 1H NMR (400 MHz, CDCb) d 9.22-9.10 (m, 1H), 8.73 (s, 1H), 7.09 (s, 1H), 5.02 (tt, J = 11.2, 4.4 Hz, 1H), 3.28 (ddd, / = 12.6, 4.4, 2.6 Hz, 1H), 3.08 (d, / = 4.9 Hz, 3H), 2.89-2.78 (m, 2H), 2.34- 2.20 (m, 2H), 1.66 (dq, / = 12.2, 4.4 Hz, 1H), 1.37 (q, / = 11.4 Hz, 1H), 1.20 (d, / = 6.3 Hz, 3H) ppm.

[00306] Step 3: (S)-l-(Trifluoromethoxy)propan-2-yl (2R,4R)-2-methyl-4-((3- (methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyridin-5- yl)oxy)piperidine-l-carboxylate

[00307] Exchanging Intermediate 17 for the product of step 2 and Intermediate 11 for

Intermediate 12, the reaction procedure described in Example 171 was used to prepare the title compound as a glassy, colorless solid. 1H NMR (400 MHz, CDCb) d 9.01 (q, J = 4.8 Hz, 1H), 8.76 (s, 1H), 7.11 (s, 1H), 5.40 (p, / = 3.2 Hz, 1H), 5.14-5.04 (m, 1H), 4.56-4.45 (m, 1H), 4.12- 3.96 (m, 3H), 3.43-3.31 (m, 1H), 3.07 (d, / = 4.8 Hz, 3H), 2.21-2.02 (m, 3H), 1.99-1.86 (m, 1H), 1.40-1.30 (m, 6H) ppm. MS: 544 m/z (M+H ⁺ ).

[00308] Example 176. (S ₎ -l-(Trifluoromethoxy)propan-2-yl (27?,4/? -2-methyl-4-((6- methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]p yridin-5-yl)oxy)piperidine-l- carboxylate

[00309] Step 1: Methyl 5-(((2R,4R)-l-(/eri-butoxycarbonyl)-2-methylpiperidin-4-yl)o xy)-6- methyl-7-(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylat e

[00310] To a stirred and cooled (0 °C) solution of Intermediate 13 (2.00 g, 6.87 mmol), tert- butyl (2R,4S)-4-hydroxy-2-methylpiperidine-l-carboxylate (2.59 g, 12.0 mmol) and

triphenylphosphine (3.96 g, 15.1 mmol) in ethyl acetate (30 mL) was added, dropwise over 15 minutes, a solution of bis-(2-methoxyethyl)diazo-l,2-dicarboxylate (3.22 g, 13.7 mmol) in ethyl acetate (10 mL). The ice bath was allowed to slowly melt and the reaction was stirred overnight at room temperature. LCMS analysis indicated that the reaction was complete. The mixture was rinsed into a separatory funnel with ethyl acetate (-40 mL) and then washed with water (2 x -100 mL). The organic layer was dried (Na ₂ S0 ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system; 0 to 20% ethyl acetate in heptane; 120 g silica column). The title compound (Rf -0.3 with 8:2 heptane/ethyl acetate as the eluant) was obtained as a white solid (3.08 g, 92%). 1H NMR (400 MHz, CDCb) d 8.50 (s, 1H), 5.65 (p, J = 3.2 Hz, 1H), 4.47-4.38 (m, 1H), 4.00-3.90 (m, 4H), 3.26 (td, 7 = 13.3, 2.7 Hz, 1H), 2.48 (q, 7 =

1.9 Hz, 3H), 2.19-2.00 (m, 3H), 1.92-1.81 (m, 1H), 1.48 (s, 9H), 1.33 (d, 7 = 7.1 Hz, 3H) ppm.

[00311] Step 2: Methyl 6-methyl-5-(((2R,4R)-2-methylpiperidin-4-yl)oxy)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate

[00312] Using the procedure described in step 2 of Example 175, the /V-ieri-butoxycarbonyl amine protecting group of the step 1 product was cleaved using a dichloromethane solution of trifluoroacetic acid. The crude product was deemed sufficiently pure to use, without purification, in the next step. 1H NMR (400 MHz, CDCb) d 8.50 (s, 1H), 5.29 (tt, 7 = 11.1, 4.6 Hz, 1H), 3.96 (s, 3H), 3.22 (ddd, 7 = 12.5, 4.5, 2.4 Hz, 1H), 2.94-2.82 (m, 2H), 2.43 (q, 7 = 2.0 Hz, 3H), 2.37- 2.29 (m, 2H), 1.63-1.45 (m, 2H), 1.29 (q, 7 = 11.5 Hz, 1H), 1.17 (d, 7 = 6.3 Hz, 3H) ppm.

[00313] Step 3: N,6-Dimethyl-5-(((2R,4R)-2-methylpiperidin-4-yl)oxy)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide

[00314] Using the procedure described for step 2 of Example 25, the methyl ester functionality of the step 3 product was converted to the corresponding /V-methyl carboxamide. The crude product was subjected to automated flash chromatography (Combiflash system; 0 to 10% 2N ammonia in methanol solution in chloroform; 80 g Gold silica column). The target component (Rf -0.4 with 9:1 chloroform/2N ammonia in methanol as the eluant) was obtained as a glassy, colorless solid. This material was co-evaporated with diethyl ether to afford a colorless foam, which was then ground with a spatula to provide the title compound as a white solid (2.34 g,

93%). 1H NMR (400 MHz, CDCb) d 9.27-9.18 (m, 1H), 8.61 (s, 1H), 5.01 (tt, 7 = 11.1, 4.4 Hz, 1H), 3.29 (ddd, 7 = 12.5, 4.5, 2.5 Hz, 1H), 3.08 (d, 7 = 4.9 Hz, 3H), 2.91-2.78 (m, 2H), 2.44 (q, 7 = 2.0 Hz, 3H), 2.33-2.23 (m, 2H), 1.73-1.62 (m, 1H), 1.39 (q, 7 = 11.5 Hz, 1H), 1.20 (d, 7 = 6.3 Hz, 3H) ppm.

[00315] Step 4: (S)-l-(Trifluoromethoxy)propan-2-yl (2R,4R)-2-methyl-4-((6-methyl-3- (methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyridin-5- yl)oxy)piperidine-l-carboxylate [00316] Exchanging Intermediate 17 for the product of step 3 and Intermediate 11 for

Intermediate 12, the reaction procedure described in Example 171 was used to prepare the title compound as a white solid (0.238 g, 83%). 1H NMR (400 MHz, CDCb) d 9.07 (q, J = 4.9 Hz, 1H), 8.64 (s, 1H), 5.40 (p, / = 3.2 Hz, 1H), 5.14-5.05 (m, 1H), 4.58-4.48 (m, 1H), 4.12-3.96 (m, 3H), 3.36 (tt, J = 13.5, 2.7 Hz, 1H), 3.06 (d, J = 4.9 Hz, 3H), 2.51 (q, / = 2.0 Hz, 3H), 2.24-2.07 (m, 3H), 1.99-1.87 (m, 1H), 1.38 (d, / = 7.0 Hz, 3H), 1.34 (d, 7 = 6.6 Hz, 3H) ppm. MS: 558 m/z (M+H ⁺ ).

[00317] Example 180. 2-(Trifluoromethoxy)ethyl (3S,4/f ₎ -3-fluoro-4-((6-methyl-3-

(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyridin -5-yl)oxy)piperidine-l- carboxylate

[00318] Exchanging //77-butyl (2/74S)-4-hydroxy-2- methyl pipcridinc-l -carboxy late for tert- butyl (3S,4S)-3-fluoro-4-hydroxypiperidine-l-carboxylate in step 1 and Intermediate 12 for Intermediate 11 in step 4, the four step synthetic sequence described in Example 176 was used to prepare the title compound as a white solid. 'H NMR (400 MHz, CDCb) d 8.87 (q, J = 4.9 Hz, 1H), 8.66 (s, 1H), 5.44-5.28 (m, 1H), 4.95 (br d, / = 47.6 Hz, 1H), 4.38 (q, / = 4.2 Hz, 2H), 4.26- 4.11 (m, 3H), 4.05-3.81 (m, 1H), 3.78-3.57 (m, 1H), 3.54-3.37 (m, 1H), 3.08 (d, / = 4.9 Hz, 3H), 2.51 (q, / = 1.9 Hz, 3H), 2.35-2.23 (m, 1H), 2.12-2.00 (m, 1H) ppm. MS: 548 m/z (M+H ⁺ ).

[00319] Example 181. (S ₎ -l-(Trifluoromethoxy)propan-2-yl (3S,4/? -3-lluoro-4-((6- methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]p yridin-5-yl)oxy)piperidine-l- carboxylate

[00320] Exchanging //77-butyl (2/74S)-4-hydroxy-2- methyl pipcridinc-l -carboxy late for tert- butyl (3S,4S)-3-fluoro-4-hydroxypiperidine-l-carboxylate in step 1, the four step synthetic sequence described in Example 176 was used to prepare the title compound as a white solid. 'H NMR (400 MHz, CDCb) d 8.88 (q, J = 4.9 Hz, 1H), 8.65 (s, 1H), 5.43-5.29 (m, 1H), 5.14-5.05 (m, 1H), 4.94 (br d , J = 47.7 Hz, 1H), 4.22-3.54 (m, 5H), 3.54-3.35 (m, 1H), 3.08 (d, / = 4.9 Hz, 3H), 2.51 (q, / = 1.9 Hz, 3H), 2.34-2.22 (m, 1H), 2.12-1.98 (m, 1H), 1.35 (dd, / = 6.6, 1.5 Hz, 3H) ppm. MS: 562 mJz (M+H ⁺ ).

[00321] Example 183. (S ₎ -l-(Trifluoromethoxy)propan-2-yl (3/?,4S ₎ -3-fluoro-4-((6- methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]p yridin-5-yl)oxy)piperidine-l- carboxylate

[00322] Exchanging tert- butyl (2/74S)-4-hydroxy-2- methyl pipcridinc-l -carboxy late for tert- butyl (3R,4RJ-3-fluoro-4-hydroxypiperidine-l-carboxylate in step 1, the four step synthetic sequence described in Example 176 was used to prepare the title compound as a foamy, white solid. 1H NMR (400 MHz, CDCb) d 8.88 (q, / = 4.9 Hz, 1H), 8.65 (s, 1H), 5.45-5.27 (m, 1H), 5.14-5.05 (m, 1H), 4.94 (br d, / = 47.5 Hz, 1H), 4.24-3.54 (m, 5H), 3.54-3.36 (m, 1H), 3.08 (d, /

= 4.9 Hz, 3H), 2.51 (q, 7 = 1.8 Hz, 3H), 2.35-2.22 (m, 1H), 2.12-1.98 (m, 1H), 1.35 (dd, / = 6.6, 1.5 Hz, 3H) ppm. MS: 562 m/z (M+H ⁺ ).

[00323] Example 186. l-(7-(Methylcarbamoyl)-4-(trifluoromethyl)thieno[3,2- d]pyrimidin-2-yl)piperidin-4-yl (S ₎ -(l-methoxypropan-2-yl)carbamate

[00324] Step 1 : //77-Butyl (4-methyl-2-(2,2,2-trifluoroacetyl)thiophen-3-yl)carbamate

[00325] To a stirred and cooled (-25 to -30 °C) solution of //77-butyl (4-methylthiophen-3- yl)carbamate (5.63 g, 26.4 mmol) in tetrahydrofuran (100 mL) was added, dropwise over 15 minutes, a 2.5 M solution of n-butyllithium in hexanes (25.0 mL, 62.5 mmol). Following the addition, the mixture was stirred for another one hour at -20 °C before cooling to -25 to -30 °C and adding a solution of 2,2,2-trifluoro-A(A/-dimethylacetamide (6.4 mL, 55 mmol) in tetrahydrofuran (12 mL), dropwise over 20 minutes. The reaction was then allowed to slowly warm to room temperature and stirred overnight. To quench any remaining n-butyllithium, ethyl acetate (10 mL) was slowly added to the stirred solution. The mixture was then partitioned between ethyl acetate (-100 mL) and an aqueous ammonium chloride solution (-150 mL). The organic layer was washed with brine (2 x -150 mL), dried (Na ₂ S0 ₄ ) and concentrated onto -25 g of silica. The impregnated media was subjected to automated flash chromatography (Combiflash system; 0 to 10% ethyl acetate in heptane; 220 g silica column). The purified title compound (Rf -0.42 with 9:1 heptane/ethyl acetate as the eluant) was obtained as a pale amber solid (3.89 g, 48%). 1H NMR (400 MHz, CDCL) d 8.87 (br s, 1H), 7.46 (s, 1H), 2.27 (d, J = 0.7 Hz, 3H), 1.52 (s, 9H) ppm.

[00326] Step 2: l-(3-Amino-4-methylthiophen-2-yl)-2,2,2-trifluoroethan-l-one

[00327] Into a stirred solution of step 1 product (4.85 g, 15.7 mmol) in ethyl acetate (100 mL) was bubbled hydrogen chloride gas for approximately five minutes. The resulting suspension was stirred for 1.25 hour and was then concentrated. The residue was partitioned between chloroform (-75 mL) and aqueous sodium bicarbonate solution (-100 mL). The organic layer was combined with a second extract (chloroform, 1 x -75 mL), dried (Na ₂ S0 ₄ ) and concentrated to afford the crude title compound as a grey-green solid (3.21 g, 98%). 1H NMR (400 MHz, CDCL) d 7.27 (s, 1H), 6.59 (br s, 2H), 2.10 (s, 9H) ppm.

[00328] Step 3: 2-Chloro-7-methyl-4-(trifluoromethyl)thieno[3,2-d]pyrimidine

[00329] To a stirred and cooled (0 °C) solution of step 2 product (3.20 g, 15.30 mmol) in acetonitrile (20 mL) was added 2,2,2-trichloroacetyl isocyanate (2.5 mL, 20.98 mmol). After 2-3 minutes, the reaction became a thick suspension of off-white solid. The ice bath was removed and the reaction was allowed to warm to room temperature and then stirred for an additional one hour. Following this time, the mixture was concentrated to afford the crude acylurea as a grayish purple solid. The crude intermediate was loaded into a pressure vessel along with a 2.0 N solution of ammonia in methanol (130 mL, 260.00 mmol). The vessel was sealed and heated at 70 °C for 30 minutes and then allowed to cool to room temperature. The mixture was then concentrated to afford a moist, grayish purple solid. This material was tritutated with ethyl acetate (-60 mL) and the suspended solid was recollected by suction filtration and air dried under house vacuum to afford the hydrate of the 7-methyl-4-(trifluoromethyl)thieno[3,2-d]pyrimidin-2(lH)-one intermediate as an off-white solid. This material was taken up in phosphorus oxychloride (15.0 mL, 161 mmol) and heated with stirring at 105 °C. After two hours at this temperature the mixture was cooled to room temperature and slowly added, via pipet, to a stirred suspension of sodium bicarbonate (50 g) in water (200 mL). Following the addition, the mixture was transferred to a separatory funnel and extracted with ethyl acetate (3 x -80 mL). The combined extracts were dried (Na ₂ S0 ₄ ) and concentrated onto -15 g of silica. The impregnated media was subjected to automated flash chromatography (Combiflash system; 0 to 10% ethyl acetate in heptane; 120 g silica column). The title compound (Rf = 0.4 with 9:1 heptane/ethyl acetate as the eluant) was obtained as a colorless, crystalline solid (2.86 g, 74% overall for three steps). 1H NMR (400 MHz, CDCb) 5 7.89 (q, J = 1.2 Hz, 1H), 2.55 (d, / = 1.2 Hz, 3H) ppm.

[00330] Step 4: 2-Chloro-7-(dibromomethyl)-4-(trifluoromethyl)thieno[3,2-d]p yrimidine

[00331] To a stirred solution of step 3 product (2.85 g, 11.3 mmol) in carbon tetrachloride (50 mL) was added N- bro mo s ucc i m i dc (4.62 g, 26.0 mmol) and benzoyl peroxide (0.273 g, 1.13 mmol). The mixture was heated in an 80 °C oil bath for two hours. The reaction was cooled to room temperature and a small sample of clear solution was removed from the suspension and concentrated to afford a 1H NMR sample. Analysis of the obtained spectrum indicated that starting material had been fully consumed and, in its place, a mixture of the corresponding mono- and dibromomethyl derivatives (molar ratio of -17:83, respectively) was observed. An additional portion of benzoyl peroxide (0.050 g, 0.206 mmol, 1.8 mole%) was added to the reaction and heating (80 °C) was continued for another 1.5 hours. The reaction was then cooled to room temperature and suction filtered. After rinsing the filtercake with diethyl ether (3 x -20 mL), the combined filtrate was concentrated onto -15 g of silica. The impregnated media was subjected to automated flash chromatography (Combiflash system; 0 to 10% ethyl acetate in heptane; 120 g silica column) to afford partially purified title compound as a viscous, faint amber oil (4.42 g, 96%). The material was carried into the next step without further purification. 'H NMR (400 MHz, CDCb) d 8.68 (d, / = 0.6 Hz, 1H), 7.25 (d, / = 0.6 Hz, 1H) ppm.

[00332] Step 5: l-(2-Chloro-4-(trifluoromethyl)thieno[3,2-d]pyrimidin-7-yl)e than-l-one

[00333] To a stirred solution of impure step 4 product (4.40 g, 10.72 mmol) in 2:1

acetonitrile/water (60 mL), was added silver nitrate (5.46 g, 32.2 mmol). The resulting suspension was heated in a preheated oil bath (80 °C) for 30 minutes, cooled and suction filtered through a pad of Celite. The filtering agent/gray-green solid mixture was rinsed with ethyl acetate until the UV activity (as judged by TLC spotting) of the filtrate was faint. The combined filtrate was washed with aqueous sodium bicarbonate solution (1 x -150 mL), dried (Na ₂ S0 ₄ ) and concentrated onto -10 g of silica. The impregnated media was subjected to automated flash chromatography (Combiflash system; 0 to 10% ethyl acetate in heptane; 120 g silica column) to afford the purified title compound (Rf -0.2 with 9: 1 heptane/ethyl acetate as eluant) as a white solid (2.17 g, 76%). 1H NMR (400 MHz, CDCb) d 10.50 (s, 1H), 9.07 (s, 1H) ppm.

[00334] Step 6: Piperidin-4-yl (S)-( l -mcthoxypropan-2-yl)carbamatc

[00335] Exchanging 2-(aminomethyl)-4-methylmorpholine for ( S )- 1 -methoxypropan-2-amine, the 0-(piperidin-4-yl) carbamate preparation described in steps 1 and 2 of Example 115 was used to prepare the crude title compound as a gray gum. This material was used, without

characterization or purification, in the next step.

[00336] Step 7: l-(7-Formyl-4-(trifluoromethyl)thieno[3,2-d]pyrimidin-2-yl)p iperidin-4-yl (S)- ( 1 -methoxypropan-2-yl)carbamate

[00337] Into a 20 mL microwave reaction vial equipped with a stir bar was loaded step 5 product (0.250 g, 0.938 mmol), N,N-d\ methyl formamidc (6 mL), step 6 product (0.355 g, 1.64 mmol) and /V,/V-diisopropylethylamine (0.33 mL, 1.9 mmol). The vessel was sealed and heated in a microwave reactor for one hour at 90 °C. LCMS analysis indicated the reaction was complete. The mixture was concentrated and the residue was partitioned between aqueous sodium

bicarbonate solution (-40 mL) and chloroform (-40 mL). The organic layer was combined with additional extracts (chloroform, 2 x -30 mL), dried (Na ₂ S0 ₄ ) and concentrated onto -4 g of silica. The impregnated media was subjected to automated flash chromatography (Combiflash system;

20 to 40% ethyl acetate in heptane; 80 g Gold silica column) to furnish the purified title compound (Rf -0.4 with 6:4 heptane/ethyl acetate as the eluant) as a yellow solid (0.332 g, 79%). 1H NMR (400 MHz, CDCb) d 10.36 (s, 1H), 8.74 (s, 1H), 5.09-4.77 (m, 2H), 4.38-4.21 (m, 2H), 3.98-3.64 (m, 3H), 3.45-3.25 (m, 5H), 2.10-1.91 (m, 2H), 1.84-1.63 (m, 2H), 1.21 (d, / = 6.7 Hz, 3H) ppm.

[00338] Step 8: (S)-2-(4-(((l-Methoxypropan-2-yl)carbamoyl)oxy)piperidin-l-y l)-4- (trifluoromethyl)-thieno[3,2-d]pyrimidine-7-carboxylic acid

[00339] To a stirred solution of step 7 product (0.302 g, 0.676 mmol) in N,N- dimethylformamide (10 mL) was added Oxone (0.523 g, 0.851 mmol). The mixture was stirred at room temperature overnight and then analyzed by LCMS and found to be approximately 88% complete as determined by the relative peak areas of starting material and the putative product. Additional Oxone (0.208 g, 0.338 mmol) was added and stirring was continued for another night, though this resulted in no appreciable advancement in the reaction. The mixture was concentrated and the residue was taken up in water (-30 mL). The resulting suspension was sonicated until the undissolved solid was judged homogenous. The solid was collected by suction filtration and rinsed with additional water. The filtercake vacuum oven dried (-50 °C) to afford the crude title compound as a tan solid (0.280 g, 90%). 1H NMR (400 MHz, DMSO-d ₆ ) d 12.94 (br s, 1H), 9.14 (s, 1H), 7.04 (d, / = 7.8 Hz, 1H), 4.92-4.71 (m, 1H), 4.43-4.05 (m, 2H), 3.75-3.47 (m, 2H), 3.27 (dd, / = 9.4, 6.7 Hz, 1H), 3.15 (dd, / = 9.4, 6.3 Hz, 1H), 2.06-1.86 (m, 2H), 1.71-1.45 (m, 2H),

1.03 (d, 7 = 6.7 Hz, 3H) ppm.

[00340] Step 9: l-(7-(Methylcarbamoyl)-4-(trifluoromethyl)thieno[3,2-d]pyrim idin-2- yl)piperidin-4-yl (S)-(l-methoxypropan-2-yl)carbamate

[00341] Using the procedure for HATU mediated amide coupling described in step 3 of Example 10, step 8 product was condensed with methylamine hydrochloride. The resulting crude product was purified by automated flash chromatography (Combiflash system; 0 to 1% methanol in ethyl acetate; 80 g Gold silica column; see attached pdf for TLC). The target component (Rf -0.40 with 99:1 ethyl acetate/methanol as the eluant) was obtained as an off-white film. This material was ground with a spatula and vacuum oven dried (-60 °C) to afford the title compound as a beige solid (0.226 g, 82%). 1H NMR (400 MHz, CDCb) d 9.07-8.94 (m, 1H), 8.85 (s, 1H), 5.10-4.70 (m, 2H), 4.30-4.10 (m, 2H), 3.90 (br s, 1H), 3.80-3.65 (m, 2H), 3.45-3.30 (m, 5H), 3.08 (d, J = 4.9 Hz, 3H), 2.11-1.97 (m, 2H), 1.88-1.69 (m, 2H), 1.21 (d, / = 6.7 Hz, 3H) ppm. MS: 476 m/z (M+H ⁺ ).

[00342] Example 187. l-(7-(Methylcarbamoyl)-4-(trifluoromethyl)thieno[3,2- d]pyrimidin-2-yl)piperidin-4-yl-(S ₎ -(l-cyclopropylethyl)carbamate

[00343] Step 1: Piperidin-4-yl (5)-( 1 -cyclopropylcthyl)carbamatc

[00344] Exchanging 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine dihydrochloride for (S)- 1 - cyclopropylethan-l -amine, the 0-(piperidin-4-yl) carbamate preparation described in step 1 of Example 95 was used to prepare the crude title compound as an off-white solid. This material was deemed sufficiently pure to use, without purification, in the next step. 'H NMR (400 MHz, CDCL) d 4.83-4.50 (m, 2H), 3.19-2.98 (m, 3H), 2.69 (ddd, / = 12.4, 10.2, 2.8 Hz, 2H), 2.01-1.84 (m, 2H), 1.68-1.38 (m, 2H), 1.20 (d, / = 6.6 Hz, 3H), 0.80 (qt, / = 8.2, 5.0 Hz, 1H), 0.53-0.40 (m, 2H), 0.40-0.30 (m, 1H), 0.25-0.16 (m, 1H) ppm.

[00345] Steps 2-4: l-(7-(Methylcarbamoyl)-4-(trifluoromethyl)thieno[3,2-d]pyrim idin-2- yl)piperidin-4-yl (S)-( 1 -cyclopropylcthyl)carbamatc

[00346] Exchanging piperidin-4-yl (S)-( l -mcthoxypropan-2-yl)carbamatc for step 1 product, the reaction sequence described in steps 7-9 of Example 186 was used to prepare the title compound as a pale yellow solid. 1H NMR (400 MHz, CDCL) d 9.06-8.95 (m, 1H), 8.85 (s, 1H), 4.98 (br s, 1H), 4.78-4.56 (m, 1H), 4.31-4.13 (m, 2H), 3.82-3.63 (m, 2H), 3.22-3.02 (m, 4H),

2.11-1.99 (m, 2H), 1.86-1.70 (m, 2H), 1.23 (d, J = 6.6 Hz, 3H), 0.82 (qt, J = 8.0, 4.9 Hz, 1H), 0.56-0.42 (m, 2H), 0.42-0.31 (m, 1H), 0.28-0.18 (m, 1H) ppm. MS: 472 m/z (M+H ⁺ ).

[00347] Example 190. 5-(3-((5-Fluoropyridin-3-yl)oxy)azetidin-l-yl)-N-methyl-7- (trifluoromethyl)thieno[3,2-6]pyridine-3-carboxamide

[00348] Step 1 : //77-Butyl 3-((5-fluoropyridin-3-yl)oxy)azetidine-l-carboxylate

[00349] A stirred mixture of 5-fluoropyridin-3-ol (0.489 g, 4.33 mmol) and //77-butyl 3- hydroxyazetidine-l-carboxylate (0.500 g, 2.89 mmol) in toluene (5 mL) was sparged with nitrogen for 1-2 minutes. (Tributylphosphoranylidene)acetonitrile (1.1 mL, 4.3 mmol) was added and the mixture was heated at 90 °C for 14 hours. Following this time, the reaction was diluted with ethyl acetate (150 mL) and washed with dilute aqueous sodium bicarbonate solution and brine. The organic solution was then dried (Na ₂ S0 ₄ ) and concentrated to afford the crude product. This material was purified by automated flash chromatography (Biotage Isolera system; 20 to 100% ethyl acetate in heptane; 4 g silica column) to afford the title compound as a brown oil (0.460 g, 59%). 1H NMR (400 MHz, CDCL) d 8.17 (d, / = 2.3 Hz, 1H), 8.01 (br s, 1H), 6.82 (dt,

/ = 9.8, 2.4 Hz, 1H), 4.99-4.87 (m, 1H), 4.40-4.27 (m, 2H), 4.09-3.95 (m, 2H), 1.45 (s, 9H) ppm.

[00350] Step 2: 3-(Azetidin-3-yloxy)-5-fluoropyridine [00351] A stirred and cooled (0 °C) solution of step 1 product (0.460 g, 1.71 mmol) in dichloromethane (1 mL) was treated with trifluoroacetic acid (1.3 mL, 17 mmol). After one hour, the mixture was concentrated. The residue was purified by MPLC using a sulfonated polystyrene resin column that was pre-conditioned with dichloromethane and methanol and eluted with a 4M ammonia in methanol solution to afford the the title compound as an amber oil (0.274 g, 95%). 1H NMR (400 MHz, CDCb) d 8.13 (d, 7 = 2.4 Hz, 1H), 8.03 (dd, 7 = 2.5, 1.0 Hz, 1H), 6.81 (dt, 7 = 10.0, 2.4, 2.4 Hz, 1H), 5.02 (p, 1H), 4.03-3.90 (m, 2H), 3.90-3.74 (m, 2H), 2.05 (s, 1H) ppm. MS: 427 m/z (M+H ⁺ ).

[00352] Step 3: 5-(3-((5-Fluoropyridin-3-yl)oxy)azetidin-l-yl)-/V-methyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide

[00353] Into a 5 mL microwave reaction vial was loaded Intermediate 5 (0.100 g, 0.339 mmol), step 2 product (0.114 g, 0.679 mmol), /V,/V-diisopropylethylamine (118 pL, 0.679 mmol) and N- m ethyl-2- p y rro 1 i d i n o n c (1.8 mL). The vessel was sealed and heated in a microwave reactor for 1.5 hours at 150 °C. The miuxture was poured into a vigorously stirred slurry of crushed ice and water. After the ice had fully melted, the precipitate was collected via filtration and purified by reversed phase HPLC (C18, 30 x 150 mm, 5 pm Waters SunFire OBD column; 20 to 100% acetonitrile/water gradient) to afford the title compound as a white solid (0.046 g, 28%). 1H NMR (400 MHz, DMSO -d ₆ ) d 9.37-9.24 (m, 1H), 8.77 (s, 1H), 8.28 (d, 7 = 2.2 Hz, 1H), 8.26-8.17 (m, 1H), 7.45 (dt, 7 = 10.8, 2.4, 2.4 Hz, 1H), 7.07 (s, 1H), 5.46-5.30 (m, 1H), 4.81-4.61 (m, 2H), 4.34- 4.17 (m, 2H), 2.93 (d, 7 = 4.8 Hz, 3H) ppm. MS: 427 m/z (M+H ⁺ ).

[00354] Example 204. (R)-\ -Cyclopropylethyl 6-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)-2-azaspiro[3 .3]heptane-2-carboxylate

[00355] Step 1: (R)-l -Cyclopropylethyl (4-nitrophenyl) carbonate

[00356] To a stirred solution of (R)-l-cyclopropylethan-l-ol (197 mg, 2.29 mmol) and triethylamine (319 pL, 2.29 mmol) in dichloromethane (4 mL) was added 4-nitrophenyl chloroformate (461 mg, 2.29 mmol) at 0 °C. The suspension was stirred at room temperature for 24 hours and then concentrated. The residue was purified by automated flash chromatography to afford the title product as a clear, colorless oil (330 mg, 57%). 'H NMR (400 MHz, CDCb) d 8.35-8.23 (m, 2H), 7.45-7.33 (m, 2H), 4.47-4.19 (m, 1H), 1.46 (d, J = 6.4 Hz, 3H), 1.22-1.06 (m, 1H), 0.69-0.60 (m, 2H), 0.58-0.48 (m, 1H), 0.38-0.26 (m, 1H) ppm.

[00357] Step 2: (6 ^> )-l -Cyclopropylcthyl 6-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)-2-azaspiro[3 .3]heptane-2-carboxylate

[00358] A mixture of Intermediate 25 (150 mg, 0.404 mmol), step 1 product (101 mg, 0.404 mmol) and triethylamine (56 pL, 0.40 mmol) in N,N-d\ methyl formamidc (2 mL) was stirred at 90 °C for 30 minutes in a microwave reactor. The reaction was then concentrated and the residue was purified by reversed phase HPLC (C18, 30 x 150 mm, 5 pm Waters SunFire OBD column; 20 to 100% acetonitrile/water gradient) to afford the title compound as a white solid (109 mg, 56%). 'H NMR (400 MHz, CDCb) d 9.10 (br s, 1H), 8.75 (s, 1H), 7.08 (s, 1H), 5.14 (p, 1H), 4.25-4.20 (m, 1H), 4.09-4.04 (m, 4H), 3.11 (d,/= 4.9 Hz, 3H), 2.90-2.73 (m, 2H), 2.59-2.39 (m, 2H), 1.29 (d, J = 6.3 Hz, 3H), 0.99-0.93 (m, 1H), 0.58-0.18 (m, 4H) ppm. MS: 484 mJz (M+H ⁺ ).

[00359] Example 212. 2-(Trifluoromethoxy)ethyl 6-((3-(methylcarbamoyl)-7- ( trifluoromethyl)thieno[3,2-/:>]pyridin-5-yl)oxy)-l -azaspiro[3.3]heptane- 1 -carboxylate

[00360] Step 1 : //77-Butyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5- yl)oxy)- 1 - azaspiro[3.3]heptane- 1 -carboxylate

[00361] To a stirred mixture of Intermediate 5 (265 mg, 0.899 mmol) and //77-butyl 6-hydroxy- l-azaspiro[3.3]heptane-l-carboxylate (249 mg, 1.17 mmol) in tetrahydrofuran (10 mL) was added potassium //77-butoxidc (131 mg, 1.17 mmol). The reaction was stirred at 60 °C for two hours, cooled to room temperature and concentrated. The residue was dissolved in dichloromethane and this solution was washed with water and brine, dried (Na ₂ S0 ₄ ) and concentrated. The crude material was purified by automated flash chromatography (Biotage Isolera system; 0 to 100% ethyl acetate in dichloromethane; 10 g silica column) to afford the title compound as a beige solid (0.254 g, 60%). 1H NMR (400 MHz, CDCb) d 9.19 (br s, 1H), 8.74 (s, 1H), 7.08 (s, 1H), 4.97 (p, / = 7.2 Hz, 1H), 3.96-3.80 (m, 2H), 3.48-2.84 (m, 5H), 2.72 (s, 2H), 2.42-2.23 (m, 2H), 1.48 (s, 9H) ppm. MS: 472 m/z (M+H ⁺ ). [00362] Step 2: 5-((l-Azaspiro[3.3]heptan-6-yl)oxy)-/V-methyl-7-(trifluorome thyl)thieno[3,2- /?]pyridinc-3-carboxamidc

[00363] Using the procedure described in step 2 of Example 190, the step 1 product was N- deprotected to afford the title compound as a beige solid. MS: 372 m/z (M+H ⁺ ).

[00364] Step 3: 2-(Trifluoromethoxy)ethyl 6-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)-l-azaspiro[3 .3]heptane-l-carboxylate

[00365] A stirred mixture of step 2 product (0.167 g, 0.450 mmol), Intermediate 11 (0.100 g, 0.450 mmol) and /V-hydroxysuccinimide (0.053 g, 0.40 mmol) in acetonitrile (10 mL) was stirred overnight at 38 °C. The reaction was then concentrated and residue was taken up in

dichloromethane (20 mL). The solution was washed with water (10 mL), dried (MgS04) and concentrated. The crude material was purified by automated flash chromatography (Biotage Isolera system; 50 to 100% ethyl acetate in heptane; 4 g silica column) to afford the title compound as a white solid (0.142 g, 60%). 1H NMR (400 MHz, CDCb) d 9.17 (br s, 1H), 8.74 (s,

1H), 7.10 (br s, 1H), 4.98 (p, 1H), 4.55-3.83 (m, 6H), 3.11 (d, J = 4.9 Hz, 5H), 2.76 (s, 2H), 2.52-

2.34 (m, 2H) ppm. MS: 528 m/z (M+H ⁺ ).

[00366] Example 218. Cyclopropylmethyl ((lS,3S)-3-((6-methyl-3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)cyclobutyl)ca rbamate

[00367] Step 1: 5-((ls,3s)-3-Aminocyclobutoxy)-N,6-dimethyl-7-(trifluorometh yl)thieno[3,2- h]pyridine-3-carboxamide

[00368] Exchanging Intermediate 5 for Intermediate 15 and //77-butyl 6-hydroxy- 1- azaspiro[3.3]heptane-l-carboxylate for //77-butyl ((ls,3s)-3-hydroxycyclobutyl)carbamate, the reaction sequence outlined in steps 1 and 2 of Example 212 was used to prepare the title compound. MS: 460 m/z (M+H ⁺ ).

[00369] Step 2: Cyclopropylmethyl ((ls,3s)-3-((6-methyl-3-(methylcarbamoyl)-7- (tri 11 uoromcthyl)thicno[ 3, 2-/?] pyridin-5-yl)oxy)cyclobutyl (carbamate

[00370] To a stirred solution of step 1 product (74 mg, 0.208 mmol) and triethylamine (57 pL, 0.415 mmol) in chloroform (4 mL) added cyclopropylmethyl chloroformate (33 mg, 0.250 mmol). The mixture was stirred at room temperature for 30 minutes and then concentrated. The residue was partially purified by automated flash chromatography (Biotage Isolera system; 20 to 100% ethyl acetate in heptane; 4 g silica column). The resulting solid was triturated with diethyl ether and air dried on the frit under house vacuum to afford the title compound as a cream solid (65 mg, 68%). 1H NMR (400 MHz, DMSO-d ₆ ) d 8.74 (br d, 1H), 8.52 (s, 1H), 7.33 (d, / = 8.1

Hz, 1H), 4.84 (p, 1H), 3.68 (q, 1H), 3.54 (d, J = 7.2 Hz, 2H), 2.75 (d, J = 4.8 Hz, 3H), 2.70-2.54 (m, 2H), 2.31-2.22 (m, 3H), 2.02-1.86 (m, 2H), 0.85-0.74 (m, 1H), 0.35-0.10 (m, 4H) ppm. MS:

458 m/z (M+H ⁺ ).

[00371] Example 220. (S l-Cyclopropylethyl ((lS,3/? 3-((6-methyl-3- (methylcarbamoyl)-7 (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)cyclobutyl)ca rbamate

[00372] Exchanging Intermediate 27 for the step 1 product of Example 218 and (R)- 1 - cyclopropylethan-l-ol for ( )- 1 -cyclopropylcthan- 1 -of the reaction sequence outlined in Example 204 was used to prepare the title compound as a white solid. 'H NMR (400 MHz, CDCb) d 9.14

(br s, 1H), 8.63 (s, 1H), 4.96 (p, 1H), 4.88 (br s, 1H), 4.23 (br s, 1H), 4.08 (br s, 1H), 3.26-2.96 (m, 5H), 2.47 (q, 3H), 2.28-2.06 (m, 2H), 1.30 (d, J = 6.3 Hz, 3H), 1.05-0.89 (m, 1H), 0.66-0.15

(m, 4H) ppm. MS: 472 m/z (M+H ⁺ ).

[00373] Example 254. 2-(Trifluoromethoxy)ethyl 3-methyl-3-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-Z>]pyridin-5-yl)oxy)azetidine -l-carboxylate

[00374] Step 1: /V-Methyl-5-((3-methylazetidin-3-yl)oxy)-7-(trifluoromethyl) thieno[3,2- h]pyridine-3-carboxamide

[00375] Using the procedure described in step 2 of Example 190, the /V-ieri-butoxycarbonyl protecting group of the title compound of Example 269 was cleaved with trifluoroacetic acid in dichloromethane to afford the title compound as a beige solid. MS: 346 m/z (M+H ⁺ ). [00376] Step 2: 2-(Trifluoromethoxy)ethyl 3-methyl-3-((3-(methylcarbamoyl)-7 (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)azetidine- l-carboxylate

[00377] To a stirred mixture of step 1 product (188 mg, 0.544 mmol) and Intermediate 11 (134 mg, 0.599 mmol) in acetonitrile (5 mL) was added N- h ydro x y s ucc i n i m i dc (63 mg, 0.544 mmol). After two hours at room temperature the reaction was concentrated and the crude material was purified by reversed phase HPLC (C18, 30 x 150 mm, 5 pm Waters Sunfire OBD column; 20 to 100% acetonitrile/water) to afford the title compound as a tan solid (43 mg, 16%). 1H NMR (400 MHz, CDCb) d 8.78 (d, 1H), 8.72 (d, 1H), 7.17-7.08 (m, 1H), 4.43 (d, 2H), 4.32 (s, 2H), 4.22- 4.08 (m, 4H), 3.10 (d, 3H), 1.92 (s, 3H) ppm. MS: 502 m/z (M+H ⁺ ).

[00378] Example 256. 2-(Trifluoromethoxy)ethyl 3-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)azetidine-l-c arboxylate

[00379] Step 1 : / _/ 77-Butyl 3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5- yl)oxy)azetidine- l-carboxylate

[00380] Exchanging //77-butyl 3-hydroxy-3-methylazetidine- l-carboxylate for //77-butyl 3- hydroxyazetidine- l-carboxylate, the same synthetic procedure described in Example 269 was used to prepare the title compound as a white solid. 1H NMR (400 MHz, CDCI ₃ ) d 8.87-8.76 (m,

2H), 7.18 (s, 1H), 5.46-5.36 (m, 1H), 4.44-4.34 (m, 2H), 4.16-4.12 (m, 2H), 3.12 (d, / = 4.9 Hz,

3H), 1.47 (s, 9H) ppm. MS: 432 m/z (M+H ⁺ ).

[00381] Steps 2-3: 2-(Trifluoromethoxy)ethyl 3-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)azetidine- l-carboxylate

[00382] Exchanging the title compound of Example 269 for the present Example’s step 1 product, the two-step reaction sequence described in Example 254 was used to prepare the title compound as a white solid. 1H NMR (400 MHz, CDCb) d 8.79 (br s, 1H), 8.74 (s, 1H), 7.19 (s, 1H), 5.52-5.41 (m, 1H), 4.56-4.42 (m, 2H), 4.42-4.28 (m, 2H), 4.28-4.10 (m, 4H), 3.12 (d, / = 4.9 Hz, 3H) ppm. MS: 488 m/z (M+H ⁺ ).

[00383] Example 269. tert-Butyl 3-methyl-3-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)azetidine-l-c arboxylate

[00384] To a stirred mixture of Intermediate 5 (276 mg, 0.937 mmol) and //77-butyl 3-hydroxy- 3-methylazetidine-l-carboxylate (277 mg, 1.40 mmol) in tetrahydrofuran (5 mL) was added potassium ie/t-butoxide (158 mg, 1.40 mmol). The mixture was heated at 70 °C for three hours and then cooled and concentrated. The residue was taken up in ethyl acetate (-50 mL) and this solution was washed with an aqueous ammonium chloride solution and brine, dried (Na ₂ S0 ₄ ) and concentrated. The crude material was purified by automated flash chromatography (Biotage Isolera system; 50 to 100% ethyl acetate in dichloromethane; 25 g silica column) to afford the title compound as a brown solid (710 mg, 74%). 1H NMR (400 MHz, CDCL) d 8.77 (br s, 2H), 7.12 (s, 1H), 4.41-4.25 (m, 2H), 4.11-3.94 (m, 2H), 3.10 (d, J = 4.9 Hz, 3H), 1.89 (s, 3H), 1.46 (s, 9H) ppm. MS: 446 m/z (M+H ⁺ ).

[00385] Example 274. Methyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-7- (trifluoromethyl)thieno[3,2-6]pyridine-3-carboxylate

[00386] Step 1: Methyl 5-(l-(ie/7-butoxycarbonyl)-l,2,3,6-tetrahydropyridin-4-yl)-7 - (trifluoromethyl)-thieno[3,2-h]pyridine-3-carboxylate

[00387] To a stirred solution of Intermediate 3 (2.00 g, 6.77 mmol) and (l-tert- butoxycarbonyl-l,2,3,6-tetrahydropyridin-4-yl)boronic acid pinacol ester (2.44 g, 7.49 mmol) in l,2-dimethoxyethane (35 mL) was added a 2.0 M aqueous sodium carbonate solution (7.0 mL, 14 mmol). The mixture was sparged with nitrogen for -10 minutes and then treated with [I,G- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.473 g, 0.639 mmol). The dark red- brown mixture was sparged with nitrogen a second time and then heated to reflux. After 19 hours, the reaction was analyzed by LCMS and found to contain comparable quantities of the desired product the corresponding carboxylic acid (via concomitant ester hydrolysis). The mixture was cooled to room temperature and then suction filtered through a pad of Celite. The filtrate was diluted with ethyl acetate (100 mL) and washed with water (2 x 50 mL) and brine (1 x 50 mL). The organic layer was then dried (MgS04) and concentrated. The residue was purified by automated flash chromatography (Combiflash system; 0 to 30% ethyl acetate in heptane; 120 g silica column) to afford the title compound as a white solid (1.33 g, 44%). 1H NMR (400 MHz, CDCb) d 8.70 (s, 1H), 7.70 (s, 1H), 6.82-6.89 (m, 1H), 4.17-4.25 (m, 2H), 4.01 (s, 3H), 3.66-3.76 (m, 2H), 2.79-2.89 (m, 2H), 1.50 (s, 9H) ppm. 19F NMR (376 MHz, CDCB) d -64.0 (s) ppm.

MS: 443 m/z (M+H ⁺ ).

[00388] Step 2: Methyl 5-(l-(/er/-butoxycarbonyl)piperidin-4-yl)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate

[00389] A stirred suspension of step 1 product (1.27 g, 2.87 mmol) and 10% palladium on carbon (0.303 g) in tetrahydrofuran (30 mL) was repeatedly cycled between vacuum and a nitrogen atmosphere. The reaction flask was evacuated a final time and then refilled with hydrogen (via balloon). After 24 hours, the reaction was analyzed by LCMS and found to be incomplete. Additional palladium on carbon (0.440 g) was added and the reaction was restarted as before. After overnight stirring, the reaction was analyzed again and found to be near or at completion. The suspension was suction filtered through a pad of Celite, which was subsequently rinsed with additional tetrahydrofuran. The combined filtrate was concentrated and the resulting dark green, viscous oil was subjected to automated flash chromatography (Combiflash system; 0 to 20% ethyl acetate in heptane; 80 g silica column). The purified title compound was afforded as a yellow foam (0.633 g, 50%). 1H NMR (400 MHz, CDCb) d 8.69 (s, 1H), 7.47 (s, 1H), 4.17-4.43 (m, 2H), 4.00 (s, 3H), 3.19 (tt, J = 11.8, 3.7 Hz, 1H), 2.80-3.02 (m, 2H), 2.00-2.15 (m, 2H), 1.91- 1.81 (m, 2H), 1.50 (s, 9H) ppm. 19F NMR (376 MHz, CDCB) d -64.0 (s) ppm. MS: 445 m/z (M+H ⁺ ).

[00390] Example 297. Isobutyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- 6]pyridin-5-yl)piperidin-4-yl) carbamate

[00391] Step 1: Methyl 5-(4-((ie/ -butoxycarbonyl)amino)piperidin-l-yl)-7- (trifluoromethyl)thieno[3,2-h] pyridine-3 -carboxylate

[00392] Into a 10 mL microwave reaction vessel equipped with a stir bar was loaded 4 -{tert- butoxycarbonylamino)piperidine (1.53 g, 7.50 mmol), Intermediate 3 (1.48 g, 5.00 mmol), N,N- dimethylformamide (3 mL) and /V,/V-diisopropylethylamine (1.31 mL, 7.50 mmol). The vessel was sealed and heated in a microwave reactor for seven hours at 100 °C. The mixture diluted with ethyl acetate (10 mL) and then filtered to remove the solids. The filtercake was rinsed with additional ethyl acetate and the combined filtrate was diluted with ethyl acetate (100 mL), washed with an aqueous sodium bicarbonate solution (1 x 100 mL) and brine (1 x 100 mL). The organic layer was dried (MgS04) and concentrated. The resulting solid was purified by automated flash chromatography (Combiflash system; 0 to 10% methanol in dichloromethane; silica column) to afford the title compound as yellow solid (1.70 g, 74%). MS: 460 m/z (M+H ⁺ ).

[00393] Step 2: //77-Butyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5- yl)piperidin-4-yl) carbamate

[00394] Into a 10 mL microwave reaction vessel equipped with a stir bar was step 1 product (200 mg, 0.435 mmol) and a 2.0 M solution of methylamine in methanol (2.1 mL, 4.2 mmol). The vessel was sealed and heated in a microwave reactor for two hours at 100 °C. The solution was then concentrated and the residue was triturated with a mixture of ethyl acetate and heptane to afford the title compound as yellow solid (199 mg, 100%). MS: 459 m/z (M+H ⁺ ).

[00395] Step 3: 5-(4-Aminopiperidin-l-yl)-/V-methyl-7-(trifluoromethyl)thien o[3,2-h]pyridine- 3-carboxamide trifluoroacetate salt

[00396] To a stirred solution of step 2 product (199 mg, 0.435 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.67 mL, 8.7 mmol). The reaction was stirred overnight at room temperature and then concentrated. The residue was triturated with a mixture ethyl acetate and heptane to afford the title compound as yellow solid (200 mg, 97%). MS: 359 m/z (M+H ⁺ ).

[00397] Step 4: Isobutyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyri din-5- yl)piperidin-4-yl) carbamate

[00398] To a stirred solution of step 3 product (100 mg, 0.212 mmol) and N,N- diisopropylethylamine (85 pL, 0.487 mmol) in dichloromethane (5 mL) was added isobutyl chloroformate (32 mg, 0.233 mmol). The reaction was maintained at room temperature overnight and then partitioned between an aqueous sodium bicarbonate solution (50 mL) and dichloromethane (50 mL). The organic layer was washed with brine (1 x 50 mL), dried (MgS04) and concentrated. The resulting crude material was purified by automated flash chromatography (Combiflash system; 0 to 20% ethyl acetate in dichloromethane; silica column) to afford the title compound as white solid (40 mg, 41%). 1H NMR (400 MHz, DMSO-7 ₆ ) d 9.29 (br, 1H), 8.75 (s,

1H), 7.50 (s, 1H), 7.16 (d, 7 = 7.7 Hz, 1H), 4.29 (d, J = 13.1 Hz, 2H), 3.77-3.71 (m, 2H), 3.69- 3.60 (m, 1H), 3.27-3.12 (m, 2H), 2.94 (d, J = 4.5 Hz, 3H), 1.96-1.76 (m, 3H), 1.54-1.33 (m, 2H),

0.88 (d, J = 6.7 Hz, 6H) ppm. MS: 459 m/z (M+H ⁺ ).

[00399] Example 300. tert-Butyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl) thieno[3,2- Z>]pyridin-5-yl)azetidin-3-yl)carbamate

[00400] Exchanging 4-(/er/-butoxycarbonylamino)piperidine for //77-butyl 3- azetidinylcarbamate, the two-step reaction sequence outlined in steps 1-2 of Example 297 was used to prepare the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-c/ _/ ,) d 9.38 (br,

1H), 8.76 (s, 1H), 7.65 (d, J = 7.5 Hz, 1H), 6.99 (s, 1H), 4.56-4.47 (m, 1H), 4.41 (t, J = 8.1 Hz, 2H), 4.03-3.94 (m, 2H), 2.93 (d, J = 4.7 Hz, 3H), 1.40 (s, 9H) ppm. MS: 431 m/z (M+H ⁺ ).

[00401] Example 339. Oxetan-3-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- Z>]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[00402] Step 1: 4-Nitrophenyl oxetan-3-yl carbonate

[00403] To a stirred solution of oxetan-3-ol (0.500 g, 6.75 mmol) and triethylamine (1.42 mL, 10.1 mmol) in dichloromethane (4 mL) was added p-nitrophenyl chloroformate (1.43 g, 7.09 mmol). After four hours at room temperature, the mixture was diluted with dichloromethane and then washed with aqueous sodium bicarbonate solution and brine. The organic layer was dried (Na ₂ S0 ₄ ) and concentrated to afford the crude product as a viscous, clear yellow oil. This material was used without purification.

[00404] Step 2: Methyl 5-(6-((oxetan-3-yloxy)carbonyl)-2,6-diazaspiro[3.3]heptan-2- yl)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate

[00405] Into a 20 mL microwave reaction vessel equipped with a stir bar was loaded

Intermediate 8 (0.150 g, 0.420 mmol), /V,/V-dimethylformamide (2 mL), step 1 product (0.151 g, 0.630 mmol), triethylamine (0.23 mL, 1.7 mmol) and 4-(dimethylamino)pyridine (7 mg, 59 pmol). The vessel was sealed and then heated in a microwave reactor for one hour at 50 °C. The mixture was then concentrated and the residue was partitioned between 4:1

chloroform/isopropanol and aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried (Na ₂ S0 ₄ ) and concentrated. The crude material was purified by automated flash chromatography (Combiflash system; ethyl acetate/heptane; silica column) to afford the title compound as a white solid (118 mg, 62%). MS: 458 m/z (M+H ⁺ ).

[00406] Step 3 : Oxetan-3-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-

5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[00407] Into a 5 mL microwave reaction vessel equipped with a stir bar was loaded step 2 product (0.118 g, 0.258 mmol) and a 2.0 N solution of methylamine in methanol (0.64 mL, 1.29 mmol). The vessel was sealed and heated in a microwave reactor for five hours at 60 °C. The mixture was then concentrated and the residue was purified by automated flash chromatography (Combiflash system; methanol/dichloromethane; silica column) to afford the title compound as a white solid (83 mg, 71%). 1H NMR (400 MHz, CDCL) d 9.46 (br s, 1H), 8.72 (s, 1H), 6.62 (s,

1H), 5.46-5.36 (m, 1H), 4.94-4.83 (m, 2H), 4.70-4.59 (m, 2H), 4.44-4.17 (m, 8H), 3.07 (d, J = 4.7 Hz, 3H) ppm. MS: 457 m/z (M+H ⁺ ).

[00408] Example 350. l-Cyanopropan-2-yl 6-(3-(methylcarbamoyl)-7- (trifhioromethyl)thieno[3,2-6]pyridin-5-yl)-2,6-diazaspiro[3 .3]heptane-2-carboxylate

[00409] Exchanging oxetan-3-ol for 3-hydroxybutanenitrile, the three-step reaction sequence outlined in Example 339 was used to prepare the title compound. 'H NMR (400 MHz, CDC13) d 9.42 (s, 1H), 8.69 (s, 1H), 6.61 (s, 1H), 5.06-4.94 (m, 1H), 4.41-4.16 (m, 8H), 3.07 (d, J = 4.8 Hz 3H), 2.83-2.71 (m, 1H), 2.66-2.50 (m, 1H), 1.43 (d, / = 6.4 Hz, 3H) ppm. MS: 468 m/z (M+H ⁺ ).

[00410] Example 361. 5-(4-(2-(3,3-Difluoropyrrolidin-l-yl)ethoxy)piperidin-l-yl)- N- methyl-7-(trifluoromethyl)thieno[3,2-6]pyridine-3-carboxamid e

[00411] Step 1 : tert- Butyl 4-(2-((methylsulfonyl)oxy)ethoxy)piperidine-l-carboxylate

[00412] To a stirred and cooled (0 °C) solution of //77-butyl 4-(2-hydroxyethoxy)piperidine-l- carboxylate (330 mg, 1.35 mmol) and triethylamine (377 pL, 2.69 mmol) in tetrahydrofuran (5 mL) was added methanesulfonyl chloride (136 pL, 1.75 mmol), dropwise over five minutes. The reaction was allowed to slowly warm to room temperature and stirred overnight. The mixture was then concentrated and the residue was taken up in dichloromethane. This solution was washed with aqueous sodium bicarbonate solution and brine and then dried (Na ₂ S0 ₄ ) and concentrated to afford the crude mesylate as a clear, pale yellow oil (0.360 g, 83%).

[00413] Step 2: / £77- Butyl 4-(2-(3 ,3-difluoropyrrolidin- 1 -yl)ethoxy)piperidine- 1 -carboxylate

[00414] To a stirred solution of crude step 1 product (0.360 g, 1.11 mmol) in acetonitrile (5 mL) was added /V,/V-diisopropylethylamine (1.4 mL, 8.0 mmol) and 3,3-difluoropyrrolidine hydrochloride (0.383 g, 2.67 mmol). The mixture was stirred at room temperature for two days and then concentrated. The residue was taken up in dichloromethane and this solution was washed with aqueous sodium bicarbonate solution and brine. The organic layer was then dried (Na ₂ S0 ₄ ) and concentrated. The resulting crude material was purified by automated flash chromatography (Combiflash system; methanol/dichloromethane; silica column) to afford the title compound as a colorless oil (0.108 g, 29%). 1H NMR (400 MHz, CDCL) d 3.82-3.68 (m, 2H), 3.58 (t, / = 5.7 Hz, 2H), 3.50-3.38 (m, 1H), 3.15-3.03 (m, 2H), 2.97 (t, / = 13.4 Hz, 2H), 2.84-2.65 (m, 4H), 2.32- 2.19 (m, 2H), 1.86-1.76 (m, 2H), 1.57-1.40 (m, 11H) ppm.

[00415] Step 3: 4-(2-(3,3-Difluoropyrrolidin-l-yl)ethoxy)piperidine dihydrochloride [00416] To a stirred solution of step 2 product (0.108 g, 0.323 mmol) in dichloromethane (2 mL) was added a 2.0 M solution of hydrogen chloride in diethyl ether (2 mL). The reaction was stirred at room temperature for two hours and then concentrated to afford the crude title compound as a tacky, red gum (0.099 g, 100%).

[00417] Step 4: 5-(4-(2-(3,3-Difluoropyrrolidin-l-yl)ethoxy)piperidin-l-yl)- /V-methyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide

[00418] Exchanging the step 2 product of Example 115 for crude step 3 product of the present Example and increasing the equivalents of /V,/V-diisopropylethylamine base used from 2.1 to 4.2, the procedure for the nucleophilic aromatic substitution of Intermediate 5 described in step 3 of Example 115 was used to prepare the title compound as a red-yellow solid. 1H NMR (400 MHz, CDCb) d 9.47 (br s, 1H), 8.65 (s, 1H), 7.06 (s, 1H), 3.98-3.88 (m, 2H), 3.70-3.60 (m, 3H), 3.53- 3.42 (m, 2H), 3.08 (d, J = 4.9 Hz, 3H), 2.99 (t, J = 13.4 Hz, 2H), 2.87-2.69 (m, 4H), 2.34-2.19 (m, 2H), 2.06-1.96 (m, 2H), 1.84-1.71 (m, 2H) ppm. MS: 493 m/z (M+H ⁺ ).

[00419] Example 368. (+/-)-tert-Butyl 6wis-2-methyl-4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)piperidine-l- carboxylate

[00420] Exchanging //77-butyl (2R,4R)-4-hydroxy-2-methylpiperidine-l-carboxylate for (+/-)- //77-butyl /ra/7.s-4-hydiOxy-2-mcthylpipcndinc- 1 -carboxyl ate, the procedure described in step 1 of Example 175 was used to prepare the title compound as a white solid. ' H NMR (400 MHz, CDCb) d 8.96 (s, 1H), 8.76 (s, 1H), 7.08 (s, 1H), 5.43-5.33 (m, 1H), 4.69-4.56 (m, 1H), 4.21 (d, J = 14.2 Hz, 1H), 3.22-2.95 (m, 4H), 2.29-2.18 (m, 1H), 2.13-2.06 (m, 1H), 1.83 (td, 7 = 12.1, 5.8 Hz, 1H), 1.75-1.62 (m, 1H), 1.49 (s, 9H), 1.32 (d, 7 = 7.1 Hz, 3H) ppm. MS: 474 m/z (M+H ⁺ ).

[00421] Example 369. (+/-)-6wis-2-(Trifluoromethoxy)ethyl-2-methyl-4-((3- (methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyridin-5- yl)oxy)piperidine-l- carboxylate

[00422] Step 1 : /V-Mcthyl-5-((/ran.s-2-mcthylpipcridin-4-yl)oxy)-7-(trifluoi Omcthyl)thicno[3,2-

/?]pyridinc-3-carboxamidc

[00423] Into a stirred solution of the title compound of the title compound of Example 368 (0.090 g, 0.190 mmol) in ethyl acetate (6 mL) was bubbled hydrogen chloride gas for

approximately two minutes. The mixture stirred for an additional 20 minutes and then

concentrated to afford the crude title compound as a white solid (0.078 g, 100%). MS: 374 m/z (M+H ⁺ ).

[00424] Step 2: (+/-)-/ran.s-2-(TrifluoiOmcthoxy)cthyl-2-mcthyl-4-((3-(mcthy lcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)piperidine-l- carboxylate

[00425] To a stirred solution of step 1 product (0.075 g, 0.183 mmol) in acetonitrile (3 mL) was added triethylamine (33 pL, 0.24 mmol), a solution of Intermediate 11 (0.049 g, 0.220 mmol) in acetonitrile (2 mL) and N- h y dro x y s u cc i m i dc (0.026 g, 0.220 mmol). The mixture was heated at 50 °C for two hours and then cooled and concentrated. The residue was partitioned between dichloromethane (20 mL) and aqueous sodium bicarbonate solution (20 mL). The organic layer was combined with additional extracts (dichloromethane, 2 x 20 mL) and washed with brine. The organic layer was then dried (Na ₂ S0 ₄ ) and concentrated. The crude material was purified by automated flash chromatography (Combiflash system; 5 to 35% ethyl acetate in heptane; 12 g silica column) to afford the title compound as a glassy, colorless solid (0.058 g, 60%). 1H NMR (400 MHz, CDCb) d 8.92 (s, 1H), 8.77 (s, 1H), 7.09 (s, 1H), 5.41 (tt, / = 11.3, 4.4 Hz, 1H), 4.69 (s, 1H), 4.41-4.15 (m, 5H), 3.21-3.04 (m, 4H), 2.31-2.23 (m, 1H), 2.18-2.10 (m, 1H), 1.85 (td, / = 12.4, 5.8 Hz, 1H), 1.81-1.67 (m, 1H), 1.36 (d, / = 7.1 Hz, 3H) ppm. MS: 530 m/z (M+H ⁺ ).

[00426] Example 370. (+/-)-tert-Butyl cis-2-methyl-4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)piperidine-l- carboxylate

[00427] Exchanging tert- butyl (2R,4R)-4-hydroxy-2-methylpiperidine-l-carboxylate for (+/-)-

/ _{<? /} 7-butyl 7.s-4-hydiOxy-2-mcthylpipcridinc- 1 -carboxyl ate, the procedure described in step 1 of Example 175 was used to prepare the title compound as a white solid. ' H NMR (400 MHz, CDCb) d 9.04 (s, 1H), 8.75 (s, 1H), 7.11 (s, 1H), 5.40-5.34 (m, 1H), 4.50-4.39 (m, 1H), 3.99 (dd, 7 = 13.7, 4.2 Hz, 1H), 3.29 (td, 7 = 13.4, 2.9 Hz, 1H), 3.07 (d, 7 = 4.9 Hz, 3H), 2.16-2.01 (m, 3H), 1.98-1.86 (m, 1H), 1.49 (s, 9H), 1.32 (d, 7 = 7.1 Hz, 3H) ppm. MS: 474 m/z (M+H ⁺ ).

[00428] Example 371. (+/-)-cis-2-(Trifluoromethoxy)ethyl-2-methyl-4-((3-

(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyridin -5-yl)oxy)piperidine-l- carboxylate

[00429] Exchanging the title compound of Example 368 for the title compound of Example 370, the two-step reaction sequence outlined in Example 369 was used to prepare the title compound as a glassy, colorless solid. 1H NMR (400 MHz, CDCb) d 9.01 (s, 1H), 8.76 (s, 1H), 7.12 (s, 1H), 5.47-5.35 (m, 1H), 4.60-4.45 (m, 1H), 4.42-4.30 (m, 2H), 4.19 (t, 7 = 4.6 Hz, 2H), 4.05 (dd, 7 = 14.2, 4.7 Hz, 1H), 3.39 (td, 7 = 13.5, 2.8 Hz, 1H), 3.07 (d, 7 = 4.9 Hz, 3H), 2.22-2.03 (m, 3H), 1.99-1.88 (m, 1H), 1.36 (d, 7 = 7.1 Hz, 3H) ppm. MS: 530 m/z (M+H ⁺ ).

[00430] Example 373. tert-Butyl (2/f,4/f )-2-methyl-4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)piperidine-l- carboxylate

[00431] The procedure described in step 1 of Example 175 was used to prepare the title compound as a pale amber solid. 1H NMR (400 MHz, CDCb) d 9.08-9.01 (m, 1H), 8.75 (s, 1H), 7.11 (s, 1H), 5.38 (p, 7 = 3.1 Hz, 1H), 4.50-4.40 (m, 1H), 4.00 (ddd, 7 = 13.8, 4.7, 1.8 Hz, 1H), 3.29 (td, 7 = 13.4, 2.8 Hz, 1H), 3.07 (d, 7 = 4.9 Hz, 3H), 2.18-2.01 (m, 3H), 1.97-1.85 (m, 1H), 1.49 (s, 9H), 1.32 (d, 7 = 7.1 Hz, 3H) ppm. MS: 474 m/z (M+H ⁺ ). [00432] Example 375. 2-(Trifluoromethoxy)ethyl (2/?,4/? -2-methyl-4-((3-

(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyridin -5-yl)oxy)piperidine-l- carboxylate

[00433] Exchanging the title compound of Example 368 for the title compound of Example 373, the two-step reaction sequence outlined in Example 369 was used to prepare the title compound as a glassy, colorless solid. 1H NMR (400 MHz, CDCb) d 9.00 (s, 1H), 8.76 (s, 1H), 7.12 (s, 1H), 5.47-5.34 (m, 1H), 4.57-4.44 (m, 1H), 4.45-4.28 (m, 2H), 4.19 (t, 7 = 4.6 Hz, 2H), 4.05 (dd, J = 13.3, 4.9 Hz, 1H), 3.39 (td, J = 13.5, 2.9 Hz, 1H), 3.07 (d, J = 4.9 Hz, 3H), 2.22-2.02 (m, 3H), 1.99-1.86 (m, 1H), 1.36 (d, / = 7.1 Hz, 3H) ppm. MS: 530 m/z (M+H ⁺ ).

[00434] Example 387. (+/-)-tert-Butyl cfs-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-&]pyridin-5-yl)oxy)piperidin e-l-carboxylate

[00435] Step 1: Methyl 5-((cA-l-(ie/7-butoxycarbonyl)-3-fluoropiperidin-4-yl)oxy)-6 -methyl- 7-(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate

[00436] To a stirred solution of Intermediate 13 (0.300 g, 1.03 mmol), (+/-)-/ _{<? /7} -butyl cis- 3- fluoro-4-hydroxypiperidine-l-carboxylate (0.339 g, 1.55 mmol) and triphenylphosphine (0.405 g, 1.55 mmol) in ethyl acetate (6 mL) was added bis-(2-methoxyethyl)diazo-l,2-dicarboxylate (0.362 g, 1.55 mmol). After four hours at room temperature, the mixture was diluted with additional ethyl acetate and washed with water. The organic layer was dried (Na ₂ S0 ₄ ) and concentrated to afford a residue which was then purified by automated flash chromatography (Combiflash system; 20 to 55% ethyl acetate in heptane; 12 g silica column). The title compound was obtained as a white solid (0.360 g, 71%). MS: 493 m/z (M+H ⁺ ).

[00437] Step 2: (+/-)-ieri-Butyl cA-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)piperidine-l- carboxylate [00438] Using the procedure described in step 3 of Example 339, step 1 product was condensed with methylamine to afford the title compound as a white solid. 'H NMR (400 MHz, CDCb) d 8.91 (br s, 1H), 8.65 (s, 1H), 5.40-5.28 (m, 1H), 4.91 (d, J = 47.4 Hz, 1H), 4.15-4.04 (m, 1H), 3.94-3.73 (m, 1H), 3.71-3.54 (m, 1H), 3.44-3.33 (m, 1H), 3.08 (d, / = 4.9 Hz, 3H), 2.51 (s, 3H), 2.32-2.20 (m, 1H), 2.06-1.96 (m, 1H), 1.50 (s, 9H) ppm. MS: 492 m/z (M+H ⁺ ).

[00439] Example 389. tert-Butyl 4-((6-methyl-3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-Z>]pyridin-5-yl)oxy)piperidin e-l-carboxylate

[00440] Step 1: Methyl 5-((l-(/eri-Butoxycarbonyl)piperidin-4-yl)oxy)-6-methyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate

[00441] Exchanging (+/-)-/ _{<? /7} -butyl c/5-3-fluoro-4-hydroxypiperidine-l-carboxylate for 4- hydroxypiperidine-l-carboxylate, the procedure described in step 1 of Example 387 was used to prepare the title compound. MS: 475 m/z (M+H ⁺ ).

[00442] Step 2: / _{<? /7} -Butyl 4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2- /?]pyndin-5-yl)oxy)pipcridinc-l -carboxylatc

[00443] Using the procedure described in step 3 of Example 339, step 1 product was condensed with methylamine to afford the title compound as a white solid. 'H NMR (400 MHz, CDCb) d 9.10 (br s, 1H), 8.63 (s, 1H), 5.29-5.16 (m, 1H), 3.80-3.71 (m, 2H), 3.52-3.43 (m, 2H), 3.07 (d, / = 4.9 Hz, 3H), 2.47 (s, 3H), 2.14-2.04 (m, 2H), 1.99-1.88 (m, 2H), 1.49 (s, 9H) ppm. MS: 474 m/z (M+H ⁺ ).

[00444] Example 390. 2-(Trifluoromethoxy)ethyl 4-((6-methyl-3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)piperidine-l- carboxylate

[00445] Exchanging the title compound of Example 368 for the title compound of Example 389, the two-step reaction sequence outlined in Example 369 was used to prepare the title compound as a glassy, colorless solid. 1H NMR (400 MHz, CDCb) d 9.06 (br s, 1H), 8.64 (s, 1H), 5.30-5.24 (m, 1H), 4.42-4.31 (m, 2H), 4.24-4.13 (m, 2H), 3.83-3.71 (m, 2H), 3.65-3.56 (m, 2H), 3.07 (d, / = 4.9 Hz, 3H), 2.48 (s, 3H), 2.15-2.05 (m, 2H), 2.05-1.93 (m, 2H) ppm. MS: 530 m/z (M+H ⁺ ).

[00446] Example 408. 5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-l-yl)-N,2-dime thyl- 7-(trifluoromethyl)thieno[3,2-6]pyridine-3-carboxamide

[00447] Using the conditions described in step 3 of Example 39, Intermediate 20 was subjected to SNAr displacement with a piperazine derivative, the step 2 product of Example 47 (N- isopropyl-2-(piperazin-l-yl)acetamide, to afford the title compound as an off-white solid. 'H NMR (400 MHz, CDCb) d 9.72 (br s, 1H), 6.97 (s, 1H), 6.87 (d, / = 8.3 Hz, 1H), 4.20-4.08 (m, 1H), 3.70-3.61 (m, 4H), 3.09 (s, 2H), 3.07-3.00 (m, 6H), 2.78-2.69 (m, 4H), 1.20 (d, J = 6.6 Hz, 6H) ppm. MS: 458 m/z (M+H ⁺ ).

[00448] Example 415. l-(2-Methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3, 2- 6]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate

[00449] Using the conditions described in step 3 of Example 39, Intermediate 20 was subjected to SNAr displacement with the amine component, Intermediate 24, to afford the title compound as a white solid. 1H NMR (400 MHz, CDCb) d 9.82 (br s, 1H), 6.99 (s, 1H), 4.97 (br s, 1H), 4.79 (br s, 1H), 3.98-3.83 (m, 2H), 3.51 (t, / = 10.7 Hz, 2H), 3.12-2.96 (m, 7H), 2.14-2.02 (m, 2H), 1.90-1.73 (m, 2H), 1.02-0.91 (m, 1H), 0.58-0.46 (m, 2H), 0.26-0.13 (m, 2H) ppm. MS: 471 m/z (M+H ⁺ ). [00450] Example 418. (+/-)-bwis-3-Fluoro-l-(3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-Z>]pyridin-5-yl)piperidin-4-y l ((5 ₎ -l-(trifluoromethoxy)propan-2- yl)carbamate

[00451] Step 1: (+/-)-irafts-3-Fluoro-l-(3-(methylcarbamoyl)-7-(trifluoromet hyl)thieno[3,2- /?]pyndin-5-yl)pipcndin-4-yl lH-imidazole-l-carboxylate

[00452] To a stirred solution of Intermediate 31 (0.126 g, 0.334 mmol) in dichloromethane (5 mL) was added l,l'-carbonyldiimidazole (0.100 g, 0.617 mmol). The reaction was stirred at room temperature for five hours and then diluted with additional dichloromethane and washed with aqueous sodium bicarbonate solution and brine. The organic layer was dried (Na ₂ S0 ₄ ) and concentrated to afford the crude title compound as a colorless oil (157 mg, 100%). MS: 472 m/z (M+H ⁺ ).

[00453] Step 2: (+/-)-irafts-3-Fluoro-l-(3-(methylcarbamoyl)-7-(trifluoromet hyl)thieno[3,2- h]pyridin-5-yl)piperidin-4-yl ((S)-l-(trifluoromethoxy)propan-2-yl)carbamate

[00454] To a stirred solution of step 1 product (0.157 g, 0.333 mmol) in acetonitrile (5 mL) was added Intermediate 11 (0.075 g, 0.416 mmol), /V-hydroxysuccinimide (0.046 g, 0.400 mmol) and triethylamine (60 pL, 0.43 mmol). The reaction was heated overnight at 45 °C and then concentrated. The residue was partitioned between dichloromethane (20 mL) and aqueous sodium bicarbonate solution (20 mL). The organic layer was combined with additional extracts

(dichloromethane, 2 x 20 mL), washed with brine and dried (Na ₂ S0 ₄ ). The solution was then concentrated and the resulting residue was subjected to automated flash chromatography

(Combiflash system; 0.2 to 3% methanol in dichloromethane; 12 g silica column). The title compound was obtained as a white solid (0.101 g, 56%). 1H NMR (400 MHz, CDCL) d 9.31 (br s, 1H), 8.72 (s, 1H), 7.08 (s, 1H), 5.07 (br s, 1H), 4.85 (br s, 1H), 4.76-4.59 (m, 1H), 4.20 (t , J = 16.3 Hz, 1H), 4.11-3.99 (m, 2H), 3.98-3.83 (m, 2H), 3.72-3.54 (m, 2H), 3.09 (d, J = 4.9 Hz, 3H),

2.38-2.27 (m, 1H), 1.86-1.76 (m, 1H), 1.29 (d, J = 6.7 Hz, 3H) ppm. MS: 547 m/z (M+H ⁺ ). [00455] Example 419. N-Isopropyl-7-(trifluoromethyl)-5-(3-((4- (trifluoromethyl)cyclohexyl)amino)pyrrolidin-l-yl)thieno[3,2 -6]pyridine-3-carboxamide

[00456] Step 1: 5-(3-Aminopyrrolidin-l-yl)-/V-isopropyl-7-(trifluoromethyl)t hieno[3,2- /?]pyridinc-3-carhoxamidc hydrochloride

[00457] A 50 mL round-bottomed flask equipped with a stir bar was loaded with Example 642 (0.200 g, 423 pmo) and 2N hydrochloric acid in methanol (8 mL). The resulting solution was stirred at room temparature for 4 hours and concentrated to dryness to give the product as a yellow solid (0.173 g, 100%). MS: 373 m/z (M+H ⁺ ).

[00458] Step 2: /VTsopropyl-7-(trifluoromethyl)-5-(3-((4-

(trifluoromethyl)cyclohexyl)amino)pyrrolidin-l-yl)thieno[ 3,2-h]pyridine-3-carboxamide

[00459] A 100 mL round-bottomed flask equipped with a stir bar was loaded with step 1 product (0.050 g, 120 pmol), dichloroethane (8 mL), /V,/V-diisopropylethylamine (32 pL, 180 pmol), 4-(trifluoromethyl)cyclohexan-l-one (0.040 g, 240 pmol) and acetic acid (14 pL, 240 pmol). The resulting solution was stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (0.077 g, 370 pmol) was added. The reaction mixture was stirred at room temperature for 3 hours and then diluted with ethyl acetate (40 mL) and washed with water (20 mL) and brine (10 mL). The organic layer was dried (Na ₂ S0 ₄ ), filtered and concentrated to give a white solid which was triturated with ether to give the product as a white solid (0.035 g, 55% ).

1H NMR (400 MHz, Methanol-i¾ d 9.85 (d, J = 7.5 Hz, 1H), 8.73 (s, 1H), 7.09 (d, J = 3.0 Hz, 1H), 4.44-4.24 (m, 2H), 4.24-4.06 (m, 1H), 4.00-3.88 (m, 1H), 3.85-3.67 (m, 2H), 3.48 (s, 1H), 2.75-2.60 (m, 1H), 2.45-2.34 (m, 2H), 2.17 (s, 1H), 2.10-1.85 (m, 4H), 1.63-1.42 (m, 2H), 1.39 (dd, J = 6.5, 1.1 Hz, 6H) ppm. MS: 523 m/z (M+H ⁺ ).

[00460] Example 420. 7-Cyclopropyl-N-ethyl-5-(4-(2-(isopropylamino)-2- oxoethyl)piperazin-l-yl)thieno[3,2-6]pyridine-3-carboxamide

[00461] Step 1: Methyl 7-cyclopropyl-5-oxo-4,5-dihydrothieno[3,2-h]pyridine-3-carbo xylate

[00462] A 250 mL round-bottomed flask equipped with a stir bar was loaded with ethyl 3- cyclopropyl-3-oxopropanoate (7.95 g, 50 mmol), and methyl 4-aminothiophene-3-carboxylate (4.00 g, 25 mmol). The resulting solution was stirred at room temperature for 10 minutes. The mixture was placed into pre-heated oil bath (125 °C) and water (0.20 mL) was added via syringe every 30 minutes (up to 4 hours). After 6 hours at 125 °C (bath temperature), 1.0 mL of trifluoroacetic acid was added and stirred at 135 °C overnight. The solution was cooled to room temperature to give a black solid which was treated with ethyl acetate (80 mL), 1 gram of activated carbon and water (40 mL), and stirred at room temperature for 3 hours. The mixture was filtered through Celite to give a brown solution which was washed with brine (20 mL), dried (Na ₂ S0 ₄ ), filtered and concentrated to give a residue which was purified by chromatography using 0-100% ethyl acetate in heptane as eluant to give the title compound as a solid (0.349 g, 5%). 1H NMR (400 MHz, Acetone- e) 8.60 (s, 1H), 6.01 (s, 1H), 3.98 (s, 3H), 2.01 (m, 1H), 1.15 (m, 2H), 0.95(m, 2H) ppm. MS: 250 m/z (M+H ⁺ ).

[00463] Step 2: Methyl 7-cyclopropyl-5-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-h ]pyridine- 3-carboxylate

[00464] A stirred and cooled (0 °C) solution of step 1 product (0.349 g, 1.40 mmol) in pyridine (10 mL) were added trifluoromethanesulfonic anhydride (940 pL, 6 mmol) dropwise over 20 minutes. The reaction was allowed to slowly warm to room temperature and stirred overnight.

The reaction was then concentrated and the residue was partitioned between water (50 mL) and dichloromethane (50 mL). The organic layer was combined with additional extracts, dried (MgS04) and concentrated to afford the title product as a brown solid (0.515 g, 96%).

[00465] Step 3: Methyl 7-cyclopropyl-5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin- l- yl)thieno[3,2-h]pyridine-3-carboxylate

[00466] A 25 mL microwave reaction vessel equipped with a stir bar was loaded with step 2 product (0.515 g, 1.4 mmol), /V-isopropyl-2-(piperazin-l-yl)acetamide (0.300 g, 1.6 mmol), 1- methylpyrrolidin-2-one (8 mL) and /V,/V-diisopropylethylamine (940 pL, 5 mmol). The reaction was sealed and heated in a microwave reactor at 90 °C for 6 hours. The solution was diluted with ethyl acetate (60 mL) and washed with water (4 x 20 mL) and brine (10 mL). The organic layer was dried (Na ₂ S0 ₄ ) and concentrated. The crude product was purified by automated flash chromatography (Combiflash instrument; 50-100% ethyl acetate in heptane) to give the title compound as an amber solid (0.448 g, 80% ). 1H NMR (400 MHz, CDCL) d 8.45 (s, 1H), 7.00 (d, 1H), 6.37 (s, 1H), 4.26-4.06 (m, 1H), 3.94 (d, / = 2.5 Hz, 4H), 3.70 (dd, / = 6.2, 3.9 Hz, 4H), 3.04 (s, 2H), 2.66 (t, / = 5.0 Hz, 4H), 2.17-1.98 (m, 2H), 1.18 (d, / = 6.6 Hz, 6H), 1.15-1.09 (m, 2H), 0.95-0.88 (m, 2H) ppm. MS: 417 m/z (M+H ⁺ ).

[00467] Step 4: 7-Cyclopropyl-/V-ethyl-5-(4-(2-(isopropylamino)-2-oxoethyl)p iperazin-l- yl)thieno[3,2-h]pyridine-3-carboxamide

[00468] A 25 mL microwave reaction vessel equipped with a stir bar was loaded with step 3 product (0.100 g, 240 pmol) and 2.0 M solution of ethylamine in methanol (5.0 mL, 10 mmol). The reaction was sealed and heated in a microwave reactor at 90 °C for 3 hours. The solution was concentrated to give a solid which was triturated with methanol to give the title compound as an amber solid (0.056 g, 54%). 1H NMR (400 MHz, CDCL) d 9.70 (br t, / = 5.1 Hz, 1H), 8.54 (s, 1H), 7.05-6.76 (m, 1H), 6.39 (s, 1H), 4.28-4.03 (m, 1H), 3.72-3.52 (m, 6H), 3.07 (s, 2H), 2.82- 2.62 (m, 4H), 2.08 (tt, / = 8.4, 5.1 Hz, 1H), 1.30 (t, / = 7.3 Hz, 3H), 1.19 (d, / = 6.6 Hz, 6H), 1.17-1.12 (m, 2H), 0.96-0.91 (m, 2H) ppm. MS: 430 m/z (M+H ⁺ ).

[00469] Example 422. l-(3-(Azetidine-l-carbonyl)-7-(trifluoromethyl)thieno[3,2- 6]pyridin-5-yl)piperidin-4-yl tert-butylcarbamate

[00470] Step 1: Methyl 5-(4-hydroxypiperidin-l-yl)-7-(trifluoromethyl)thieno[3,2-h] pyridine- 3-carboxylate

[00471] A stirred solution of Intermediate 3 (10.0 g, 33.4mmol) in A-methyl-2-pyrrolidinone (60 mL), were added piperidin-4-ol (6.00 g, 59 mmol) and /V,/V-diisopropylethylamine (11.8 mL, 68 mmol). The solution was heated at 130 °C for 3 hours and then left to stir at room temperature overnight. The mixture was concentrated and the brown solid was taken up in water (-200 mL). The chunks of suspended solid were dispersed with spatula agitation and sonication. When a nearly homogeneous suspension was achieved, the mixture was filtered. The filtercake was rinsed with water (2 x 40 mL) and diethyl ether (2 x25 mL) and then dried under house vacuum. The filter cake was further dried in a vacuum oven (60 °C) to afford the title compound as a light brown solid (10.90 g, 89%). 1H NMR (400 MHz, CDC13)□ D 8.54 (s, 1H), 7.02 (s, 1H), 4.30-4.20 (m, 2H), 4.08-3.88 (m, 4H), 3.48-3.29 (m, 2H), 2.10-1.99 (m, 2H), 1.67-1.56 (m, 2H) ppm. MS: 360 mJz (M+H ⁺ ).

[00472] Step 2: Methyl 5-(4-((/er/-butylcarbamoyl)oxy)piperidin-l-yl)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate

[00473] A 25 mL microwave vial equipped with a stir bar was loaded with step 1 product (0.510 g, 1.4 mmol), /V,/V-di methyl formamidc (10 mL), and //77-butyl isocyanate (1.40 g, 16.8 mmol). The mixture was heated at 130 °C for 6 hours in the microwave reactor. Additional tert- butyl isocyanate (0.550 g, 6.62 mmol) was added and the reaction was heated at 140 °C for 5 days. The solution was diluted with ethyl acetate (50 mL), washed with water (4 x 20ml), saturated ammonium chloride (20 mL), dried (Na ₂ S0 ₄ ), filtered and concentrated to give a brown solid which was purified by chromatography using 0-100% ethyl acetate in heptane as eluant to afford the title compound as a yellowish solid (0.800 g, 100%). MS: 460 m/z (M+H ⁺ ).

[00474] Step 3: 5-(4-((ier/-Butylcarbamoyl)oxy)piperidin-l-yl)-7-(trifluorom ethyl) thieno[3,2- h]pyridine-3-carboxylic acid

[00475] A 50 mL round-bottom flask equipped with a stir bar was loaded with step 2 product (0.350 g, 760 pmol), methanol (8 mL, tetrahydrofuran (8 mL), water (8 mL) and lithium hydroxide (0.046 g, 1.9 mmol). The mixture was stirred at room temperature for 18 hours and then concentrated, diluted with water and acidified with 2N hydrochloric acid to pH = 4-5 to give a precipitate, which was filtered and washed with water and dried in vacuo to give the product as pale yellow solid (0.338 g, 100%). MS: 446 m/z (M+H ⁺ ).

[00476] Step 4: l-(3-(Azetidine-l-carbonyl)-7-(trifluoromethyl)thieno[3,2-h] pyridin-5- yl)piperidin-4-yl ie/ -butylcarbamate

[00477] A 50 mL round-bottom flask equipped with a stir bar was loaded with step 3 product (0.120 g, 270 pmol), azetidine (0.046 g, 808 pmol), tetrahydrofuran (5 mL), and 2,4,6-tripropyl- l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (0.342 g, 540 pmol) and stirred under nitrogen at room temperature for 18 hours. The solution was diluted with ethyl acetate (40 mL), washed with water (20 mL) and brine (10 mL), dried (Na ₂ S0 ₄ ), filtered and concentrated to give a solid which was purified by chromatography using 0-100% ethyl acetate in heptane as eluant to afford the title compound as a white solid (0.100 g, 771H NMR (400 MHz, CDCb) d 8.06 (s, 1H), 6.99 (s, 1H), 4.92 (d, / = 8.5 Hz, 1H), 4.64 (s, 1H), 4.27 (t, / = 7.8 Hz, 2H), 4.21-4.14 (m, 2H), 4.12 (d, / = 7.2 Hz, 1H), 4.10-4.02 (m, 2H), 3.49 (s, 2H), 2.38-2.26 (m, 2H), 2.09-1.99 (m, 3H), 1.34 (s, 9H) ppm. MS: 485 mJz (M+H ⁺ ).

[00478] Example 428. Methyl 5-(4-(((cyclopropylmethyl)carbamoyl)oxy)piperidin-l-yl)- 7-(trifluoromethyl)thieno[3,2-Z>]pyridine-3-carboxylate

[00479] A 25 mL microwave reaction vessel equipped with a stir bar was loaded with

Intermediate 3 (0.510 g, 1.7 mmol), Intermediate 24 (0.598 g, 3.0 mmol), NN- diisopropylethylamine (602 pL, 3.5 mmol) and acetonitrile (12 mL). The vessel was sealed and heated in a microwave reactor at 130 °C for 5 hours. The solution was treated with ethyl acetate (40 mL) and washed with water (30 mL) and brine (20 mL). The organic layer was dried

(Na ₂ S0 ₄ ), filtered and concentrated to give a brown residue which was purified by

chromatography using 0-50% ethyl acetate in heptane as eluant to afford the title compound as a white solid (0.474 g, 60% ). 1H NMR (400 MHz, CDCb) d 8.55 (s, 1H), 7.02 (s, 1H), 5.04-4.89

(m, 1H), 4.86-4.73 (m, 1H), 4.18-4.04 (m, 2H), 3.95 (d, J = 0.9 Hz, 3H), 3.62-3.46 (m, 2H), 3.07 (t, J = 6.4 Hz, 2H), 2.16-2.01 (m, 2H), 1.90-1.67 (m, 2H), 1.09-0.90 (m, 1H), 0.61-0.43 (m, 2H), 0.24-0.11 (m, 2H) ppm. MS: 458 m/z (M+H ⁺ ).

[00480] Example 441. (+/-)-bwis-l-(3-(Azetidine-l-carbonyl)-7- (trifluoromethyl)thieno[3,2-/:>]pyridin-5-yl)-3-fluoropip eridin-4-yl isopropylcarbamate

[00481] Step 1: Methyl 5-((+/-)-iran5-3-fluoro-4-hydroxypiperidin-l-yl)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate

[00482] A 25 mL microwave vial equipped with a stir bar was loaded with Intermediate 5 (3.75 g, 13 mmol), (+/-)-/raH.s-3-fluoropipcridin-4-ol hydrochloride (1.80 g, 11.6 mmol), N,N- diisopropylethylamine (4.49 g, 35 mmol) and l-methyl-2-pyrrolidinone (14 mL). The mixture was heated at 140 °C for 3 hours in a microwave reactor. The solution was diluted with ethyl acetate (100 mL), washed with water (4 x 20 mL) and saturated ammonium chloride (20 mL), dried (Na ₂ S0 ₄ ), filtered and concentrated to give a brown solid which was triturated with ether to give the product as a beige solid (3.50 g, 80%). MS: 404 m/z (M+H ⁺ ).

[00483] Step 2: Azetidin- l-yl(5-((+/-)-iran5-3-fluoro-4-hydroxypiperidin- l-yl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-3-yl)methanone

[00484] A 25 mL microwave vial equipped with a stir bar was loaded with step 1 product (0.198 g, 520 pmol), azetidine (0.299 g, 5 mmol) and methanol (4 mL). The mixture was stirred at 100 °C for 3 hours and evaporated off to give a brown solid which was purified by

chromatography using 0-10% methanol in dichloromethane as eluant to give the product as a yellowish solid (0.040 g, 19%). MS: 404 m/z (M+H ⁺ ).

[00485] Step 3. (+/-)-iran5-l-(3-(Azetidine-l-carbonyl)-7-(trifluoromethyl)t hieno[3,2- h]pyridin-5-yl)-3-fluoropiperidin-4-yl isopropylcarbamate

[00486] A 25 mL microwave vial equipped with a stir bar was loaded with step 2 product (0.040 g, 100 pmol), l,l'-carbonyldiimidazole (0.032 g, 200 pmol) and dichloromethane (8 mL). The mixture was stirred at room temperature for 3 hours and then concentrated to give a solid which was treated with acetonitrile (10 mL) and N- h ydro x y s ucc i m i dc (0.023 g, 200 pmol). The solution was stirred at room temperature for 15 minutes, then isopropylamine (42 pL, 500 pmol) was added, and stirred at 40 °C for 16 hours. The solution was concentrated to give a residue. The residue was treated with ethyl acetate (50 mL), washed with water (20 mL) and brine (10 mL), dried (Na ₂ S0 ₄ ), filtered and concentrated to give a solid which was purified by chromatography using 0-100% ethyl acetate in heptane as eluant to give the product as a yellowish solid (0.034 g, 70%). 1H NMR (400 MHz, CDCL) d 8.08 (s, 1H), 7.00 (s, 1H), 5.02 (s, 1H), 4.60 (d, / = 42.1 Hz, 2H), 4.37-4.22 (m, 3H), 4.22-4.05 (m, 2H), 4.01-3.80 (m, 2H), 3.79-3.66 (m, 1H), 3.63-3.49 (m, 1H), 2.42-2.27 (m, 2H), 1.70 (s, 2H), 1.19 (d, / = 6.5 Hz, 6H) ppm. MS: 489 m/z (M+H ⁺ ). [00487] Example 449. l-(7-Chloro-3-(methylcarbamoyl)thieno[3,2-Z>]pyridin-5- yl)piperidin-4-yl (cyclopropylmethyl)carbamate

[00488] Using Intermediate 33 and Intermediate 24, the procedure described in step 3 of Example 420 was used to prepare the title compound as a white solid. 'H NMR (400 MHz, CDCb) d 9.38 (br s, 1H), 8.59 (s, 1H), 6.66 (s, 1H), 5.11-4.85 (m, 2H), 3.80-3.67 (m, 2H), 3.54- 3.34 (m, 2H), 3.17-3.01 (m, 5H), 2.21-2.04 (m, 2H), 2.01-1.80 (m, 2H), 1.07-0.92 (m, 1H), 0.60- 0.48 (m, 2H), 0.29-0.15 (m, 2H) ppm. MS: 423 m/z (M+H ⁺ ).

[00489] Example 452. l-(7-(Difluoromethyl)-3-(methylcarbamoyl)thieno[3,2-Z>]py ridin-5- yl)piperidin-4-yl isopropylcarbamate

[00490] Step 1: l-(7-(Difluoromethyl)-3-(methylcarbamoyl)thieno[3,2-h]pyridi n-5- yl)piperidin-4-yl isopropylcarbamate

[00491] Using Intermediate 34 and piperidin-4-yl isopropylcarbamate, the procedure described in step 3 of Example 420 was used to prepare the title compound as a white solid. 'H NMR (400 MHz, CDCb) d 8.52 (s, 1H), 6.97-6.57 (m, 2H), 4.93 (br s, 1H), 4.49 (br s, 1H), 4.10 (br d, J = 12.9 Hz, 2H), 3.95 (s, 3H), 3.80 (br s, 2H), 3.52 (br s, 2H), 2.15-1.99 (m, 2H), 1.17 (d, / = 6.5 Hz, 6H). ppm. MS: 428 m/z (M+H ⁺ ).

[00492] Step 2: l-(7-(Difluoromethyl)-3-(methylcarbamoyl)thieno[3,2-h]pyridi n-5- yl)piperidin-4-yl isopropylcarbamate

[00493] Using step 1 product and methylamine, the procedure described in step 4 of Example 420 was used to prepare the title compound as a white solid. 'H NMR (400 MHz, CDCb) d 9.51 (br s, 1H), 8.60 (s, 1H), 7.05-6.63 (m, 2H), 4.96 (br s, 1H), 4.68 (br s, 1H), 4.04-3.74 (m, 3H), 3.63-3.39 (m, 2H), 3.06 (d, / = 4.8 Hz, 3H), 2.14-1.93 (m, 2H), 1.80 (s, 2H), 1.18 (d, / = 6.7 Hz, 6H) ppm. MS: 427 m/z (M+H ⁺ ).

[00494] Example 473. l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyrid in-5- yl)piperidin-4-yl cyclopropylcarbamate

[00495] Using Intermediate 7 and isocyanatocyclopropane, the procedure described in step 2 of Example 422 was used to prepare the title compound as a white solid. 1H NMR (400 MHz,

CDCb) d 9.43 (s, 1H), 8.66 (s, 1H), 7.06 (s, 1H), 4.99 (br s, 2H), 4.00-3.86 (m, 2H), 3.55 (br s, 2H), 3.07 (d, / = 4.8 Hz, 3H), 2.60 (d, / = 7.8 Hz, 1H), 2.15-1.97 (m, 2H), 1.82 (br s, 2H), 0.86- 0.70 (m, 2H), 0.62-0.43 (m, 2H) ppm. MS: 443 m/z (M+H ⁺ ).

[00496] Example 474. l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-Z>]p yridin-5- yl)piperidin-4-yl (cyclopropylmethyl)carbamate

[00497] Using Intermediate 5 and Intermediate 24, the procedure described in step 3 of Example 420 was used to prepare the title compound as a white solid. 'H NMR (400 MHz, CDCb) d 9.44 (br s, 1H), 8.66 (s, 1H), 7.07 (s, 1H), 5.18-4.91 (m, 1H), 4.91-4.74 (m, 1H), 4.06- 3.86 (m, 2H), 3.71-3.49 (m, 2H), 3.16-3.01 (m, 5H), 2.20-2.02 (m, 2H), 1.95-1.73 (m, 2H), 1.09- 0.89 (m, 1H), 0.63-0.43 (m, 2H), 0.20 (t, J = 5.3 Hz, 2H) ppm. MS: 457 m/z (M+H ⁺ ).

[00498] Example 475. l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyrid in-5- yl)piperidin-4-yl (cyclopropylmethyl)carbamate trifluoroacetate

[00499] Using Intermediate 7 and (isocyanatomethyl)cyclopropane, the procedure described in step 2 of Example 422 was used to prepare the title compound as a white solid. 'H NMR (400

MHz, Methanol-i/4) d 8.59 (s, 1H), 7.25 (s, 1H), 4.97-4.88 (m, 1H), 4.06-3.88 (m, 2H), 3.71-3.53

(m, 2H), 3.03 (s, 3H), 3.00 (d, / = 6.9 Hz, 2H), 2.19-2.01 (m, 2H), 1.91-1.71 (m, 2H), 1.12-0.90 (m, 1H), 0.58-0.41 (m, 2H), 0.34-0.13 (m, 2H) ppm. MS: 457 m/z (M+H ⁺ ).

[00500] Example 488. (+/-)-bwis-3-Fluoro-l-(3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-Z>]pyridin-5-yl)piperidin-4-y l diisopropylcarbamate

[00501] Step 1: (+/-)-iran5-3-Fluoro-l-(3-(methylcarbamoyl)-7-(trifluorometh yl)thieno[3,2- h]pyridin-5-yl)piperidin-4-yl lH-imidazole-l-carboxylate

[00502] To a stirred solution of l,l’-carbonyldiimidazole (0.772 g, 4.76 mmol) in

dichloromethane (10 mL) was added a solution of Intermediate 31 (1.33 g, 3.52 mmol) in dichloromethane (50 mL), dropwise over 20 minutes. The mixture was stirred overnight at at room temperature and then washed with water (3 x 20 mL) and brine (1 x 10 mL). The organic layer was dried (MgS04) and concentrated to afford the crude title compound as a pale pink solid (1.56 g, 94%). MS: 472 m/z (M+H ⁺ ).

[00503] Step 2: (+/-)-iran5-3-Fluoro-l-(3-(methylcarbamoyl)-7-(trifluorometh yl)thieno[3,2- h]pyridin-5-yl)piperidin-4-yl diisopropylcarbamate

[00504] A 100 mL round flask equipped with a stir bar was loaded with the crude step 1 product (0.300 g, 640 pmol), acetonitrile (20 mL) and N- h ydro x y s ucc i m i dc (0.088 g, 760 pmol), stirred at room temperature for 10 minutes, then diisopropylamine (0.257 g, 2.6 mmol) was added under nitrogen and stirred at 40 °C for 2 days. The reaction mixture was concentrated to give a residue. The residue was disolved in ethyl acetate (50 mL) and washed with water (20 mL) and brine (10 mL). The organic layer was dried (Na ₂ S0 ₄ ), filtered, and concentrated to give a residue, which was purified by chromatography using 0-100% ethyl acetate in heptane as eluant to give the product as a white solid (0.240 g, 77%). 1H NMR (400 MHz, CDCb) d 9.30 (br s, 1H), 8.68 (s, 1H), 7.08 (s, 1H), 5.24-5.08 (m, 1H), 4.92-4.63 (m, 1H), 4.27-4.02 (m, 2H), 3.96-3.75 (m, 3H),

3.75-3.58 (m, 2H), 3.09 (d, J = 4.9 Hz, 3H), 2.46-2.27 (m, 1H), 1.93-1.73 (m, 1H), 1.25 (d, / = 6.7 Hz, 12H) ppm. MS: 504 m/z (M+H ⁺ ).

[00505] Example 490. (+/-)-tran-3-Fluoro-l-(3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)piperidin-4-yl isopropylcarbamate

[00506] Exchanging diisopropylamine for iso-propylamine, the procedure described in

Example 488 was used to prepare the title compound as a white solid. 'H NMR (400 MHz, CDCb) d 9.30 (br s, 1H), 8.68 (s, 1H), 7.06 (s, 1H), 5.18-4.97 (m, 1H), 4.84-4.54 (m, 2H), 4.24- 4.00 (m, 1H), 3.99-3.67 (m, 3H), 3.67-3.50 (m, 1H), 3.08 (d, / = 4.8 Hz, 3H), 2.47-2.20 (m, 1H), 1.88-1.66 (m, 1H), 1.19 (d, / = 6.6 Hz, 6H) ppm. MS: 463 m/z (M+H ⁺ ).

[00507] Example 492. (+/-)-bwis~3-Fluoro-l-(3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)piperidin-4-yl cyclopropylcarbamate

[00508] Exchanging diisopropylamine for cyclopropylamine, the procedure described in Example 488 was used to prepare the title compound as a white solid. 'H NMR (400 MHz, CDCb) d 9.31 (br s, 1H), 8.67 (s, 1H), 7.06 (s, 1H), 5.32-4.96 (m, 2H), 4.88-4.51 (m, 1H), 4.26- 4.03 (m, 1H), 3.95-3.53 (m, 3H), 3.08 (d, / = 4.9 Hz, 3H), 2.72-2.52 (m, 1H), 2.49-2.21 (m, 1H), 1.88 (s, 1H), 0.95-0.67 (m, 2H), 0.67-0.48 (m, 2H) ppm. MS: 461 m/z (M+H ⁺ ).

[00509] Example 495 and Example 496. (3/?,4/? -3-Fluoro-l-(3-(methylcarbamoyl)-7-

(trifluoromethyl)thieno[3,2-6]pyridin-5-yl)piperidin-4-yl isopropylcarbamate and (3S,4S -3- Fluoro-l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- Z>]pyridin-5-yl)piperidin-4-yl isopropylcarbamate (separate enantiomers of known absolute stereochemistry)

[00510] The title compounds were obtained by subjecting the title compound of Example 490 to chiral SFC separation (10 x 250 mm CHIRALPAK IA column; 20% methanol modifier with 0.1% diethylamine additive). The absolute configurations of the individual enantiomers was determined by comparison of chiral SFC retention times to that of the authentic enantiomers prepared from optically active fluoro-piperidin-4-ol starting materials of known stereochemistry (commercially available).

[00511] The early elution fraction was concentrated to afford the (3R,4R)-enantiomer as a white solid (Example 495). 1H NMR (400 MHz, CDCb) d 9.31 (br s, 1H), 8.67 (s, 1H), 7.05 (s,

1H), 5.18-4.96 (m, 1H), 4.96-4.54 (m, 2H), 4.21-3.98 (m, 1H), 3.98-3.68 (m, 3H), 3.68-3.55 (m, 1H), 3.08 (d, 7 = 4.8 Hz, 3H), 2.43-2.25 (m, 1H), 1.92-1.72 (m, 1H), 1.20 (d, 7 = 6.5 Hz, 6H) ppm. MS: 463 m/z (M+H ⁺ ).

[00512] The late elution fraction was concentrated to afford the (3 S, 45) -cn anti o mcr as a white solid (Example 496). 1H NMR (400 MHz, CDCb) d 9.31 (br s, 1H), 8.68 (s, 1H), 7.06 (s, 1H),

5.25-4.96 (m, 1H), 4.87-4.51 (m, 2H), 4.27-4.02 (m, 1H), 3.97-3.70 (m, 3H), 3.70-3.55 (m, 1H), 3.08 (d, 7 = 4.9 Hz, 3H), 2.45-2.24 (m, 1H), 1.88-1.65 (m, 1H), 1.19 (d, 7 = 6.5 Hz, 6H) ppm. MS: 463 m/z (M+H ⁺ ).

[00513] Example 505. 2-Cyanoethyl (l-(3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-Z>]pyridin-5-yl)piperidin-4-y l)carbamate

[00514] A 25 mL microwave reaction vial equipped with a stir bar was loaded with 3- hydroxypropanenitrile (0.079 g, 1.10 mmol), - m c t h y 1 - 2 - p y rro 1 i d i n o n c (8 mL), N,N- diisopropylethylamine (0.23 g, 1.8 mmol) and 4-nitrophenyl chloroformate (0.337 g, 1.70 mmol). The resulting solution was stirred at room temperature for two days and then treated with the step 3 product of Example 297 (0.080 g, 220 pmol). The mixture was heated at 90 °C for two hours and then cooled and diluted with EtOAc (50 mL). The solution was washed with water (2 x 20 mL) and brine (1 x 10 mL). The organic layer was dried (Na ₂ S0 ₄ ) and concentrated to give a residue which was purified by automated flash chromatography (0-100% EtOAc in heptane; silica column) to afford the title compound as an off-white solid (0.042 g, 41%). 1H NMR (400 MHz, CDCb) d 9.40 (br s, 1H), 8.65 (s, 1H), 7.06 (s, 1H), 5.15-4.87 (m, 1H), 4.43-4.19 (m, 4H), 4.00- 3.77 (m, 1H), 3.34-3.15 (m, 2H), 3.06 (d, J = 4.8 Hz, 3H), 2.71 (t, J = 6.2 Hz, 2H), 2.27-2.13 (m, 2H), 1.69-1.48 (m, 2H) ppm. MS: 456 m/z (M+H ⁺ ).

[00515] Example 520. 2-(Trifluoromethoxy)ethyl (l-(3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)piperidin-4-yl)ca rbamate

[00516] Exchanging 3-hydroxypropanenitrile for 2-(trifluoromethoxy)ethan-l-ol, the procedure described in Example 505 was used to prepare the title compound as a white solid. 'H NMR (400 MHz, CDCb) d 9.39 (br s, 1H), 8.63 (s, 1H), 7.05 (s, 1H), 5.22-4.98 (m, 1H), 4.39-

4.29 (m, 2H), 4.29-4.09 (m, 4H), 3.95-3.80 (m, 1H), 3.39-3.15 (m, 2H), 3.05 (d, J = 4.9 Hz, 3H), 2.31-2.09 (m, 2H), 1.75-1.49 (m, 2H) ppm. MS: 515 m/z (M+H ⁺ ).

[00517] Example 528. 5-(4-((4-Isopropylthiazol-2-yl)methyl)piperazin-l-yl)-N-meth yl-7- (trifluoromethyl)thieno[3,2-6]pyridine-3-carboxamide

[00518] To a stirred solution of the hydrochloride salt of Intermediate 6 (0.110 g, 260 pmol) in methanol was added 4-isopropylthiazole-2-carboxaldehyde (0.122 g, 790 pmol), N,N- diisopropylethylamine (184 pl, 0.106 mmol), acetic acid (45 pl, 0.79 mmol) and sodium cyanoborohydride (0.049 g, 790 pmol). The reaction was heated overnight at 60 °C and then cooled and concentrated. The residue was partitioned between ethyl acetate (50 mL) and water (20 mL). The organic layer was washed with brine (10 mL) and concentrated. The resulting crude material was purified by automated flash chromatography (0-100% EtOAc in heptane; silica column) to afford the title compound as a white solid (0.095 g, 75%). 'H NMR (400 MHz, CDCb) d 9.39 (br s, 1H), 8.66 (s, 1H), 7.04 (s, 1H), 6.86 (d, / = 0.9 Hz, 1H), 3.94 (s, 2H), 3.70

(dd, J = 4.5, 2.7 Hz, 3H), 3.24-3.02 (m, 4H), 2.80 (dd, / = 6.0, 4.2 Hz, 4H), 1.32 (d, / = 6.9 Hz,

6H) ppm. MS: 484 m/z (M+H ⁺ ).

[00519] Example 552. 5-(4-((4-Isopropylmorpholin-2-yl)methyl)piperazin-l-yl)-N- methyl-7-(trifluoromethyl)thieno[3,2-6]pyridine-3-carboxamid e trifluoroacetate

[00520] Step 1 : //77-Butyl 2-((4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]p yridin-

5-yl)piperazin-l-yl)methyl)morpholine-4-carboxylate

[00521] A 25 mL microwave vial equipped with a stir bar was loaded with the hydrochloride salt of Intermediate 6 (0.300 g, 660 pmol), L/,LAIί methyl form amide (4 mL), ie/7-butyl 2- (bromomethyl)morpholine-4-carboxylate (0.260 g, 920 pmol) and /V,/V-diisopropylethylamine (577 pL, 3.3 mmol) under nitrogen at room temperature. The solution was stirred at 90 °C for 2.5 days. The solution was diluted with ethyl acetate (40 mL), washed with water (4 x 10 mL) and brine (10 mL), dried (Na ₂ S0 ₄ ), filtered and concentrated to give a residue which was purified by chromatography using 20% acetone in ethyl acetate as eluant to afford the title compound as a foam solid (0.136 g, 38%). 1H NMR (400 MHz, CDCb) d 9.49-9.34 (m, 1H), 8.66 (s, 1H), 7.03 (s, 1H), 4.09-3.79 (m, 3H), 3.79-3.60 (m, 5H), 3.60-3.46 (m, 1H), 3.08 (d, J = 4.8 Hz, 3H), 2.94 (d, / = 13.7 Hz, 1H), 2.78-2.56 (m, 6H), 2.42 (dd, / = 13.2, 4.1 Hz, 1H), 1.48 (s, 9H) ppm. MS: 544 m/z (M+H ⁺ ).

[00522] Step 2: /V-Methyl-5-(4-(morpholin-2-ylmethyl)piperazin- l-yl)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide hydrochloride

[00523] A 50 mL round flask equipped with a stir bar was loaded with step 1 product (0.136 g, 250 pmol), 2.0 M solution of hydrogen chloride in methanol (10 mL) at room temperature. The solution was stirred at room temperature for 18 hours and then evaporated to dryness to afford the title compound as a white solid (0.120 g, 87%). 1H NMR (400 MHz, Mcthanol- _< 7 ₄ ) d 8.75 (d, J = 1.9 Hz, 1H), 7.50 (s, 1H), 4.70-4.38 (m, 3H), 4.33-4.16 (m, 1H), 4.02 (t, / = 12.6 Hz, 1H), 3.87 (s, 3H), 3.62 (d, / = 17.5 Hz, 2H), 3.54-3.20 (m, 9H), 3.14-3.01 (m, 4H) ppm. MS: 444 m/z (M+H ⁺ ).

[00524] Step 3: 5-(4-((4-Isopropylmorpholin-2-yl)methyl)piperazin-l-yl)-/V-m ethyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide 2,2,2-trifluoroacetic acid

[00525] A 100 mL round flask equipped with a stir bar was loaded with step 2 product (0.060 g, 110 pmol), methanol (4 mL), propan-2-one (0.025 g, 430 pmol), acetic acid (6 pL, 110 pmol) and /V,/V-diisopropylethylamine (94 pL, 540 pmol). The solution was stirred at room temperature for 30 minutes, then a solution of zinc chloride (0.030 g, 220 pmol) and sodium

cyanoborohydride (0.014 g, 210 pmol) in methanol (1 mL) was added. The solution was stirred at room tmeperature for 3 days. The solution was concentrated to dryness to a residue which was treated with ethyl acetate (40 mL), washed with water (10 mL) and brine (10 mL), dried

(Na ₂ S0 ₄ ), filtered and concentrated to give a solid which was purified by reverse HPLC using 10- 100% acetonitrile in water (0.1% trifluoroacetic acid) as eluant to afford the title compound as a solid (0.008 g, 10%). 1H NMR (400 MHz, Methanol-d4) d 8.75 (s, 1H), 7.49 (s, 1H), 4.55-4.41 (m, 1H), 4.32-4.22 (m, 1H), 4.14-3.91 (m, 5H), 3.75-3.40 (m, 9H), 3.27-3.16 (m, 1H), 3.11-2.95 (m, 4H), 1.41 (d, / = 6.4 Hz, 6H). ppm. MS: 600 m/z (M+H ⁺ ).

[00526] Example 566. (S)-l-Cydopropylethyl 4-(3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)piperidine-l-carb oxylate

[00527] A 25 mL microwave vial equipped with a stir bar was loaded with (5/- 1 - cyclopropylethan-l-ol (0.068 g, 790 pmol), , 4-nitrophenyl chloroformate (0.159 g, 790 pmol), 1- methylpyrrolidin-2-one (5 mL) and /V,/V-diisopropylethylamine (0.136 g, 1.0 mmol). The mixture was stirred at 30 °C for 2 days then Intermediate 29 (0.100 g, 260 pmol) was added and stirred at 90 °C for 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (3 x 20 mL) and brine (10 mL). The organic layer was dried (Na ₂ S0 ₄ ), filtered and concentrated to give a residue, which was purified by chromatography using 0-80% ethyl acetate in heptane as eluant to give the title compound (0.049 g, 41%). 1H NMR (400 MHz, CDC13), 9.51 (br s, 1H), 8.82 (s, 1H), 7.50 (s, 1H), 4.52-4.24 (m, 3H), 3.07 (d, 3H), 3.05-2.88 (m, 2H), 2.12-2.05 (m, 2H), 1.96-1.76 (m, 2H), 1.31 (d, 3H), 1.08-0.96 (m, 1H), 0.92-0.83 (m, 1H), 0.63- 0.38 (m, 3H), 0.33-0.18 (m, 1H) ppm. MS: 456 m/z (M+H ⁺ ).

[00528] Example 574. tert-Butyl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- Z>]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[00529] Step 1: 5-Iodo-/V-methyl-7-(trifluoromethyl)thieno[3,2-h]pyridine-3- carboxamide

[00530] A 100 mL round flask were charged with a stir bar, condensor, Intermediate 5 (2.00 g, 6.79 mmol) and sodium iodide (0.051 g, 339 pmol). The mixture was suspended in

propiononitrile (20 mL). To it was added iodotrimethylsilane (1.93 mL, 14 mmol) to give dark amber mixture. The mixture was stirred at 90 °C for 2 hrs. Added water (60 mL) and solid sodium bissulfite (0.900 g) to remove excess iodine while stirring virgorously. The resulting yellow precipitate was collect via filtration, rinsed with water and air-dried. The solid was transferred into a flask and dissolved with ethyl acetate (80 mL), dried (Na ₂ S0 ₄ ), filtered and evaporated solvent to give a white solid which was purified by chromatography using 0-50% ethyl acetate in heptane as eluant to give the product as a white solid (1.523 g, 58%). MS: 387 m/z (M+H ⁺ ).

[00531] Step 2: //77-Butyl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5- yl)-2-azaspiro[3.3]heptane-2-carboxylate

[00532] A 10 mL microwave vial were charged with a stir bar //77-butyl 6-iodo-2- azaspiro[3.3]heptane-2-carboxylate (0.502 g, 1.6 mmol) and L/,/V-dimethylacetamide (6 mL) . The vial was kept under nitrogen environment and heated at 65 °C. To it was then added zinc (0.101 g, 1.6 mmol) powder at once and stirred at 65 °C for 20 min. A separate 10-20 mL microwave vial were charged a stir bar, step 1 product (0.200 g, 520 pmol), copper (I) iodide (0.002 g, 13 pmol), palladiumCl2(dppf)2 (0.0019 g, 30 pmol) and A,/V-dimethylacetamide (6 mL). The vial was sealed a septum and was heated at 85 °C under nitrogen. While the second vial was heating the reaction mixture of the first vial was withdrawn into a syringe and added into the second vial. Upon adition reaction color changes to light amber then changed back to dark amber mixture. The solution was poured into saturated ammonium chloride (50ml) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was back washed with water (2 x 30ml) and brine (10 mL). The organic layer was dried (Na ₂ S0 ₄ ) and concentrated to a dark oil. The crude oil was purified on 10 g silica eluting with 0-80% ethyl acetate in heptane to give the title compound as a white solid (0.125 g, 53%). 1H NMR (400 MHz, CDCb) d 9.57 (br s, 1H), 8.82 (s, 1H), 7.40 (s, 1H), 4.12 (s, 2H), 3.93 (s, 2H), 3.78 (p, / = 8.6 Hz, 1H), 3.13 (d, / = 4.9 Hz, 3H), 2.90-2.68 (m, 2H), 2.68-2.51 (m, 2H), 1.46 (s, 9H) ppm. MS: 456 m/z (M+H ⁺ ).

[00533] Example 576. 2-(Trifluoromethoxy)ethyl 6-(3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)-2-azaspiro[3.3]h eptane-2-carboxylate

[00534] Step 1: /V-Methyl-5-(2-azaspiro[3.3]heptan-6-yl)-7-(trifluoromethyl) thieno[3,2- /?]pyridinc-3-carhoxamidc hydrogen chloride

[00535] A 10 mL microwave vial was charged with a stir bar and Example 574 (0.108 g, 237 pmol) and 5-10% solution of hydrogen chloride in methanol (4 mL). The solution was stirred at room temperature for 16 hours and concentrated to give the title compound as a white solid (0.94 g, 100%). MS: 356 m/z (M+H ⁺ ).

[00536] Step 2: 2-(Trifluoromethoxy)ethyl 6-(3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)-2-azaspiro[3.3]h eptane-2-carboxylate

[00537] Using step 1 product and 2-(trifluoromethoxy)ethan-l-ol, the procedure described in Example 566 was used to prepare the title compound as a pale amber solid. 'H NMR (400 MHz, CDCb) d 9.55 (br s, 1H), 8.83 (s, 1H), 7.41 (s, 1H), 4.30 (t, / = 4.6 Hz, 2H), 4.21 (s, 2H), 4.20- 4.11 (m, 2H), 4.02 (s, 2H), 3.80 (p, / = 8.7 Hz, 1H), 3.13 (d, 7 = 4.9 Hz, 3H), 2.84-2.73 (m, 2H), 2.68-2.56 (m, 2H) ppm. MS: 512 mJz (M+H ⁺ ). [00538] Example 585. tert-Butyl 3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- b ] pyridin-5-yl)oxy)methyl)azetidine- 1 -carboxylate

[00539] A 10 mL microwave vial equipped with a stir bar was loaded with Intermediate 5 (0.500 g, 1.7 mmol), tert- butyl 3-(hydroxymethyl)azetidine-l-carboxylate (0.381 g, 2.0 mmol), cesium carbonate (0.663 g, 2.0 mmol) and N,N-d\ methyl form amide (8 mL). The reaction mixture was stirred at 150 °C under microwave for 2.5 hours, then diluted with ethyl acetate (60 mL) and washed with water (4 xl5 mL) and brine (15 mL). the organic layer was dried (Na ₂ S0 ₄ ), filtered and concentrated to give a solid which was purified by chromatography using 10-100% ethyl acetate in heptane as eluant to give the product as a white solid (0.428 g, 57%). 'H NMR (400

MHz, CDCb) d 9.01 (br s, 1H), 8.76 (s, 1H), 7.14 (s, 1H), 4.56 (d, J = 6.5 Hz, 2H), 4.16 (t, J =

8.5 Hz, 2H), 4.06-3.67 (m, 3H), 3.10 (d, J = 4.9 Hz, 3H), 1.45 (d, J = 12.9 Hz, 9H) ppm. MS: 446 m/z (M+H ⁺ ).

[00540] Example 589. tert-Butyl 3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- />]pyridin-5-yl)oxy)pyrrolidine-l -carboxylate

[00541] Exchanging //77-butyl 3-(hydroxymethyl)azetidine-l-carboxylate for //77-butyl 3- hydroxypyrrolidine-l-carboxylate, the procedure described in Example 585 was used to prepare the title compound as a white solid. 1H NMR (400 MHz, CDCL) d 9.00 (br s, 1H), 8.76 (s, 1H),

7.13 (s, 1H), 5.60-5 48 (m, 1H), 3.90-3.74 (m, 2H), 3.74-3.50 (m, 2H), 3.09 (d, / = 4.8 Hz, 3H),

2.44-2.26 (m, 2H), 1.48 (s, 9H) ppm. MS: 446 m/z (M+H ⁺ ).

[00542] Example 590. 5-((l-((Cyclopropylmethyl)carbamoyl)pyrrolidin-3-yl)oxy)-N- methyl-7-(trifluoromethyl)thieno[3,2-Z>]pyridine-3-carbox amide

[00543] Step 1: /V-Methyl-5-(pyrrolidin-3-yloxy)-7-(trifluoromethyl)thieno[3 ,2-h]pyridine-3- carboxamide hydrogen chloride

[00544] A 25 mL microwave vial equipped with a stir bar was loaded with Example 589 (0.440 g, 988 pmol) and 2N hydrochloric acid (15 mL) in methanol. The solution was stirred at 8O0C for 3 hours and concentrated to dryness to give the product as a white solid (0.420 g, >99% ). MS: 346 m/z (M+H ⁺ ).

[00545] Step 2: 5-((l-((Cyclopropylmethyl)carbamoyl)pyrrolidin-3-yl)oxy)-/V- methyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide

[00546] Using step 1 product and (isocyanatomethyl)cyclopropane, the procedure described in step 2 of Example 422 was used to prepare the title compound as a white solid. 1H NMR (400

MHz, Methanol-d4) d 8.77 (s, 1H), 7.29 (s, 1H), 5.73 (br s, 1H), 3.95-3.74 (m, 2H), 3.74-3.50 (m, 2H), 3.08 (d, J = 1.0 Hz, 3H), 3.03 (d, J = 6.8 Hz, 2H), 2.52-2.35 (m, 2H), 1.07-0.91 (m, 1H), 0.57-0.33 (m, 2H), 0.29-0.11 (m, 2H) ppm. MS: 443 m/z (M+H ⁺ ).

[00547] Example 593. tert-Butyl (S^-^-imethylcarbamoyl)^- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)pyrrolidine-l -carboxylate

hiral

[00548] Exchanging //77-butyl 3-(hydroxymethyl)azetidine-l-carboxylate for ie/7-butyl (S/-3- hydroxypyrrolidine-l-carboxylate, the procedure described in Example 585 was used to prepare the title compound as a white solid. 1H NMR (400 MHz, CDCb) d 9.00 (br s, 1H), 8.77 (s, 1H),

7.13 (s, 1H), 5.68-5.44 (m, 1H), 3.95-3.49 (m, 4H), 3.09 (d, J = 4.8 Hz, 3H), 2.49-2.14 (m, 2H),

1.48 (s, 9H) ppm. MS: 446 m/z (M+H ⁺ ).

[00549] Example 594. (S ₎ -5-((l-((Cyclopropylmethyl)carbamoyl)pyrrolidin-3-yl)o xy)-N- methyl-7-(trifluoromethyl)thieno[3,2-Z>]pyridine-3-carbox amide Chiral

[00550] Step 1: (,S ^, )-/V-Methyl-5-(pyrrolidin-3-yloxy)-7-(trifluoromethyl) thieno[3,2-h]pyridine- 3 -carboxamide hydrogen chloride

[00551] Using Example 593 and 2N hydrochloric acid in methanol, the procedure described in step 1 of Example 590 was used to prepare the title compound as a white solid. MS: 346 m/z (M+H ⁺ ).

[00552] Step 2: (SJ-5-((l-((Cyclopropylmethyl)carbamoyl)pyrrolidin-3-yl)oxy) -A/-methyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide

[00553] Using step 1 product and (isocyanatomethyl)cyclopropane, the procedure described in step 2 of Example 422 was used to prepare the title compound as a white solid. 1H NMR (400 MHz, Methanol-d4) d 8.75 (s, 1H), 7.28 (s, 1H), 5.87-5.61 (m, 1H), 3.94-3.76 (m, 2H), 3.75-3.50 (m, 2H), 3.39-3.29 (m, 1H), 3.08 (s, 3H), 3.06 (s, 2H), 2.47-2.35 (m, 2H), 1.12-0.91 (m, 1H), 0.60-0.36 (m, 2H), 0.36-0.12 (m, 2H) ppm. MS: 443 m/z (M+H ⁺ ).

[00554] Example 595. Cyclopropylmethyl (S -3-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)pyrrolidine-l -carboxylate

[00555] A 25 mL microwave vial equipped with a stir bar was loaded with

cyclopropylmethanol (0.250 g, 3.5 mmol), l-methylpyrrolidin-2-one (8 mL), N,N- diisopropylethylamine (0.089 g, 690 pmol) and 4-nitrophenyl chloroformate (1.05 g, 5.2 mmol). The solution was stirred at 20 °C for 2 days. Step 1 product of Example 594(0.080 g, 230 pmol) was added and stirred at 90 °C for 16 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (3 x 20 mL) and brine (10 mL). The organic layer was dried (Na ₂ S0 ₄ ), filtered and concentrated to give a residue, which was purified by chromatography using 0-100% ethyl acetate in heptane as eluant to give the product as a white solid (0.095 g, 92%). 1H NMR (400 MHz, CDCb) d 9.00 (br s, 1H), 8.77 (s, 1H), 7.13 (s, 1H), 5.72-5.43 (m,

1H), 4.01-3.89 (m, 2H), 3.87-3.77 (m, 2H), 3.77-3.68 (m, 1H), 3.68-3.58 (m, 1H), 3.10 (d, J = 4.8 Hz, 3H), 2.48-2.20 (m, 2H), 1.79 (s, 1H), 1.22-1.06 (m, 1H), 0.65-0.46 (m, 2H), 0.38-0.21 (m, 2H) ppm. MS: 444 m/z (M+H ⁺ ).

[00556] Example 600. 2-(Trifluoromethoxy)ethyl (S)-3-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)pyrrolidine-l -carboxylate

[00557] Exchanging cycloprop ylmethanol for 3-(trifluoromethoxy)ethan-l-ol, the procedure described in Example 595 was used to prepare the title compound as a white solid. 'H NMR (400 MHz, CDCb) d 8.94 (br s, 1H), 8.77 (s, 1H), 7.13 (s, 1H), 5.66-5.48 (m, 1H), 4.48-4.27 (m, 2H), 4.27-4.14 (m, 2H), 3.97-3.61 (m, 4H), 3.10 (d, / = 4.9 Hz, 3H), 2.53-2.25 (m, 2H) ppm. MS: 502 m/z (M+H ⁺ ).

[00558] Example 609. tert-Butyl (+/-)-c7s-3-fluoro-4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)pyrrolidine-l -carboxylate

[00559] Exchanging tert- butyl 3-(hydroxymethyl)azetidine-l-carboxylate for //77-butyl (+/-)- iran5-3-fluoro-4-hydroxypyrrolidine-l-carboxylate, the procedure described in Example 585 was used to prepare the title compound as a white solid. 'H NMR (400 MHz, CDCI3) d 8.78 (br s, 2H), 7.25 (s, 1H), 5.51-5.29 (m, 2H), 4.18-4.01 (m, 1H), 3.95-3.56 (m, 3H), 3.08 (d, J = 4.9 Hz, 3H), 1.50 (s, 9H) ppm. MS: 464 m/z (M+H ⁺ ).

[00560] Example 610. Cyclopropylmethyl (+/-)-cE-3-fluoro-4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)pyrrolidine-l -carboxylate

[00561] Step 1: 5-(((+/-)-cz ^' 5-4-Fluoropyrrolidin-3-yl)oxy)-A/-methyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide hydrogen chloride.

[00562] Using Example 609 and 2N hydrochloric acid in methanol, the procedure described in step 1 of Example 590 was used to prepare the title compound as a white solid. MS: 364 m/z (M+H ⁺ ).

[00563] Step 2: 2-(Trifluoromethoxy)ethyl (+/-)-czs-3-fluoro-4-((3-(methylcarbamoyl)-7-

(trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)pyrrolidin e-l-carboxylate

[00564] Using step 1 product and cycloprop ylmethanol, the procedure described in Example

595 was used to prepare the title compound as a white solid. 1H NMR (400 MHz, CDCb) d 8.77

(br s, 2H), 7.25 (s, 1H), 5.58-5.23 (m, 2H), 4.29-4.10 (m, 1H), 3.98 (d, J = 1.4 Hz, 1H), 3.97-3.56 (m, 4H), 3.08 (d, J = 4.9 Hz, 3H), 1.23-1.03 (m, 1H), 0.65-0.52 (m, 2H), 0.46-0.22 (m, 2H) ppm.

MS: 462 m/z (M+H ⁺ ).

[00565] Example 611. 2-(Trifluoromethoxy)ethyl (+/-)-crs-3-fluoro-4-((3-

(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyridin -5-yl)oxy)pyrrolidine-l- carboxylate

[00566] Using step 1 product of Example 610 and 3-(trifluoromethoxy)ethan-l-ol, the procedure described in Example 595 was used to prepare the title compound as a white solid. 'H NMR (400 MHz, CDCb) d 8.78 (s, 1H), 8.71 (br s, 1H), 7.25 (s, 1H), 5.59-5.34 (m, 2H), 4.51- 4.30 (m, 2H), 4.30-4.07 (m, 3H), 4.04-3.66 (m, 3H), 3.08 (t, / = 4.4 Hz, 3H) ppm. MS: 520 m/z

(M+H ⁺ ).

[00567] Example 628. tert-Butyl (+/-)-endo7-((3-(methylcarbamoyl)-7-

(trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)-3-oxa-9-a zabicyclo[3.3.1]nonane-9- carboxylate

[00568] A 10 mL microwave vial equipped with a stir bar was loaded with Intermediate 5 (0.200 g, 680 pmol), ieri-butyl (+/-)-endo7-hydroxy-3-oxa-9-azabicyclo[3.3.l]nonane-9- carboxylate (0.165 g, 680 pmol), tetrahydrofuran (8 mL) and potassium 2-methylpropan-2-olate (0.084 g, 750 pmol). The solution was stirred at 70 °C for 2 hours, then diluted with ethyl acetate (40 mL) and washed with water (40 mL) and brine (10 mL). The organic layer was dried (Na ₂ S0 ₄ ), filtered and concentrated to give a red residue which was purified by reverse HPLC chromatography using 20-100% acetonitrile in water as eluant to give the title compound as a white solid (0.038 g, 11% ). 1H NMR (400 MHz, CDCb) d 9.03 (br s, 1H), 8.74 (s, 1H), 7.13 (t, /

= 0.8 Hz, 1H), 5.22-5.05 (m, 1H), 4.39-4.25 (m, 1H), 4.25-4.11 (m, 1H), 3.85-3.61 (m, 4H), 3.13 (d, J = 4.8 Hz, 3H), 2.71-2.55 (m, 1H), 2.55-2.37 (m, 1H), 2.23-1.97 (m, 2H), 1.50 (s, 9H). ppm.

MS: 502 m/z (M+H ⁺ ).

[00569] Example 629. 2-(Trifluoromethoxy)ethyl (+/-)-endo7-((3-(methylcarbamoyl)-7-

(trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)-3-oxa-9-a zabicyclo[3.3.1]nonane-9- carboxylate

[00570] Step 1: (+/-)-5-((endo-3-Oxa-9-azabicyclo[3.3.l]nonan-7-yl)oxy)-/V-m ethyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide hydrochloride

[00571] Using the procedure described in step 2 of Example 552, the /V-ieri-butoxycarbonyl protecting group of the title compound of Example 628 was cleaved using a 2.0 M solutio of hydrogen chloride in methanol.

[00572] Step 2: (+/-)-2-(Trifluoromethoxy)ethyl endo-7-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)-3-oxa-9-azab icyclo[3.3.l]nonane-9-carboxylate [00573] A 25 mL round flask equipped with a stir bar was loaded with 2- (trifluoromethoxy)ethan-l-ol (0.026 g, 200 pmol), l,l’-carbonyldiimidazole (0.033 g, 200 pmol) and dichloromethane (4 mL). The reaction mixture was stirred at rt for 16 hours and then concentrated. The residue was taken up in acetonitrile (6 mL). To this stirred solution was added /V-hydroxysuccimide (0.023 g, 210 pmol), step 1 product (0.030 g, 70 pmol) and NN- diisopropylethylamine (0.009 g, 70 pmol), in order. The reaction was heated overnight at 40 °C and then cooled and concentrated. The crude residue was purified by column chromatography using 0-100% EtOAc in heptane as eluant to give the title compound as a white solid (0.030 g, 78%). 1H NMR (400 MHz, CDCL) d 9.01 (br s, 1H), 8.74 (s, 1H), 7.14 (s, 1H), 5.30-5.06 (m,

1H), 4.44-4.38 (m, 2H), 4.35-4.29 (m, 1H), 4.25 (d, / = 8.0 Hz, 1H), 4.23-4.18 (m, 2H), 3.83-3.76 (m, 2H), 3.76-3.68 (m, 2H), 3.09 (d, / = 4.9 Hz, 3H), 2.67-2.53 (m, 1H), 2.52-2.40 (m, 1H), 2.27- 2.07 (m, 2H) ppm. MS: 558 m/z (M+H ⁺ ).

[00574] Example 632. 2-(Trifluoromethoxy)ethyl 4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)methyl)piperidine -l-carboxylate

[00575] Step 1: /V-methyl-5-(piperidin-4-ylmethyl)-7-(trifluoromethyl)thieno [3,2-h]pyridine-3- carboxamide hydrogen chloride

[00576] Using Example 634 and 2N hydrochloric acid in methanol, the procedure described in step 1 of Example 590 was used to prepare the title compound as a white solid. MS: 358 m/z (M+H ⁺ ).

[00577] Step 2: 2-(Trifluoromethoxy)ethyl 4-((3-(methylcarbamoyl)-7- (trirhioromcthyl)thicno[ 3, 2-/?] pyridin-5-yl) methyl (piperidine- 1 -carboxylatc

[00578] Using step 1 product and 3-(trifluoromethoxy)ethan-l-ol, the procedure described in Example 629 was used to prepare the title compound as a white solid. 'H NMR (400 MHz, CDCL) d 9.52 (br s, 1H), 8.82 (s, 1H), 7.43 (s, 1H), 4.32 (t, / = 4.6 Hz, 2H), 4.29-4.03 (m, 4H), 3.12 (d, / = 4.8 Hz, 3H), 3.00 (d, / = 7.1 Hz, 2H), 2.96-2.72 (m, 2H), 2.18-2.00 (m, 1H), 1.73 (d, / = 12.0 Hz, 2H), 1.45-1.21 (m, 2H) ppm. MS: 514 m/z (M+H ⁺ ). [00579] Example 634. tert-Butyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- 6]pyridin-5-yl)methyl)piperidine- 1 -carboxylate

[00580] Exchanging tert- butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate for //77-butyl 4- (iodomethyl)piperidine-l-carboxylate, the procedure described in Example 574 was used to prepare the title compound as a white solid. 1H NMR (400 MHz, CDCb) d 9.73-9.29 (br s, 1H), 8.81 (s, 1H), 7.42 (s, 1H), 4.29-4.02 (m, 2H), 3.12 (d, / = 4.8 Hz, 3H), 2.99 (d, 7 = 7.1 Hz, 2H), 2.71 (t, J = 12.6 Hz, 2H), 2.10-1.92 (m, 1H), 1.81-1.64 (m, 2H), 1.46 (s, 9H), 1.42-1.22 (m, 2H) ppm. MS: 458 m/z (M+H ⁺ ).

[00581] Example 636 and Example 637. 6-Chloro-5-[4-[2-(isopropylamino)-2-oxo- ethyl]piperazin-l-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2 -6]pyridine-3-carboxamide and 6-Chloro-5-[4-[2-(isopropylamino)-2-oxo-ethyl]piperazin-l-yl ]-2-methoxy-N-methyl-7- (trifluoromethyl)thieno[3,2-6]pyridine-3-carboxamide (two compounds isolated from one reaction)

[00582] Step 1: 5,6-Dichloro-/V-methyl-7-(trifluoromethyl)thieno[3,2-h]pyrid ine-3- carboxamide and 5,6-dichloro-2-methoxy-/V-methyl-7-(trifluoromethyl)thieno[3 ,2-h]pyridine-3- carboxamide

[00583] In a 50 mL round-bottomed flask were placed Intermediate 3 (800 mg, 2.71 mmol), 1- chloropyrrolidine-2,5-dione (3.25 g, 24.35 mmol), and acetic acid (5 mL). The mixture was heated at 130 °C for 20 hours, concentrated, and diluted with ethyl acetate (75 mL) and water (75 mL). The organic layer was separated, washed with saturated sodium bicarbonate (50 mL) and brine (50 mL), dried (Na ₂ S0 ₄ ), filtered, and concentrated to give a residue, which was triturated with acetonitrile to give 300 mg of products, methyl 6-chloro-5-hydroxy-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate (MS: 311 m/z (M+H ⁺ )) and methyl 2,6- dichloro-5-hydroxy-7-(trifluoromethyl)thieno[3,2-h]pyridine- 3-carboxylate (MS: 346 m/z

(M+H ⁺ )) appeared in LCMS. The mixture was used for a next step without further purification. In a 20 mL vial were placed a mixture of above hydroxy pyridines (300 mg) and POC13 (2.24 mL, 24.06 mmol). The mixture was heated at 110 °C for 2 hours and poured into a solution of dichloromethane and ice water. The organic layer was separated, washed with brine (20 mL), dried (Na ₂ S0 ₄ ), filtered, and concentrated to give a mixture of chlorinated products (-320 mg), methyl 5,6-dichloro-7-(trifluoromethyl)thieno[3,2-h]pyridine-3-carb oxylate (MS: 330 m/z

(M+H ⁺ )) and methyl 2,5,6-trichloro-7-(trifluoromethyl)thieno[3,2-h]pyridine-3-c arboxylate (MS: 364 m/z (M+H ⁺ )), which were used for a next step without further purification. In a 50 mL round- bottomed flask were placed a mixture of above chlorinated products (-320 mg) and methanamine (4.81 mL, 9.63 mmol) in methanol (2M). After 12 hours at 20 °C, the mixture was concentrated to give a mixture (-320 mg) of the title compounds, which was used for a next step without further purification.

[00584] Step 2: 6 -Chloro-5-[4-[2-(isopropylamino)-2-oxo-ethyl]piperazin-l-yl] -/V-methyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide and 6-chloro-5-[4-[2-(isopropylamino)-2- oxo-ethyl]piperazin-l-yl]-2-methoxy-/V-methyl-7-(trifluorome thyl)thieno[3,2-h]pyridine-3- carboxamide

[00585] In a 10 mL microwave vial were placed /V,/V-diisopropylethylamine (636 pL, 3.65 mmol), /V-isopropyl-2-(piperazin-l-yl)acetamide (202 mg, 1.09 mmol), prepared in step 2 of Example 47, the products (-320 mg) of step 1, and /V-methyl-2-pyrrolidinone (3 mL). The mixture was heated at 150 °C for 1 hour in a microwave reactor and diluted with ethyl acetate (25 mL) and water (25 mL). The organic layer was separated, washed with water (3 x 20 mL) and brine (20 mL), dried (MgS04), filtered, and concentrated to give a residue, which was purified by automated flash chromatography (silica gel loading, 5:1 ethyl acetate:heptane to 10:1 ethyl acetate: methanol; 12S column) to afford a mixture of products which was further purified by HPLC to give the title compounds. Example 636 (48 mg, 100 pmol, 11% yield). 'H NMR (400 MHz, CDCb) d 9.31-9.19 (m, 1H), 8.73 (s, 1H), 6.90 (d, / = 8.8 Hz, 1H), 4.22-4.08 (m, 1H), 3.49 (t, / = 4.9 Hz, 4H), 3.14-3.07 (m, 5H), 2.81 (t, / = 4.8 Hz, 4H), 1.20 (d, / = 6.5 Hz, 6H) ppm. MS: 478 m/z (M+H ⁺ ) and Example 637 (30 mg, 60 pmol, 6% yield). 1H NMR (400 MHz, CDCb) d 8.6-8.52 (m, 1H), 7.18-6.94 (m, 1H), 4.19-4.04 (m, 1H), 3.93 (s, 3H), 3.55-3.43 (m, 4H), 3.15 (d, / = 5.2 Hz, 3H), 3.07 (s, 2H), 2.74 (t, / = 4.9 Hz, 4H), 1.18 (d, / = 6.6 Hz, 6H) ppm. MS: 508 m/z (M+H ⁺ ).

[00586] Example 638. [l-[6-Chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2- 6]pyridin-5-yl]-4-piperidyl] N-(cyclopropylmethyl)carbamate

[00587] In a 5 mL vial were placed Example 669 (20 mg, 40 pmol) and /V-methyl-2- pyrrolidinone (1 mL). 3-Chloroperbenzoic acid (15 mg, 60 pmol) was added at 20 °C. After 1 hour at 20 °C, the mixture was directly subjected to reversed phase HPLC for purification to give the title compound. 1H NMR (400 MHz, CDCb) d 9.25 (brs, 1H), 8.70 (s, 1H), 4.97 (brs, 1H),

4.82 (brs, 1H), 3.68-56 (m, 2H), 3.30 (t, J = 10.8 Hz, 2H), 3.07-3.1 (m, 5H), 2.15 (brs, 2H), 1.94

(brs, 2H), 1.06-0.93 (m, 1H), 0.59-0.42 (m, 2H), 0.23-0.21 (m, 2H) ppm. MS: 491 m/z (M+H ⁺ ).

[00588] Example 639. [l-[6-Fluoro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2- 6]pyridin-5-yl]-4-piperidyl] N-[(LS -l-cydopropylethyl]carbamate

[00589] In a 5 mL vial were placed Example 109 (62 mg, 131 pmol) and acetonitrile (2 mL). l-Chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (140 mg, 395 pmol) was added at 20 °C. After 15 hours at 20 °C, the mixture was directly subjected to reversed phase HPLC providing the title compound (2 mg, 5 pmol, 3% yield) as a solid after

lyophilization. 1H NMR (400 MHz, CDCb) d 9.23 (brs, 1H), 8.62 (s, 1H), 4.95 (brs, 1H), 4.69

(brs, 1H), 3.87-3.75 (m, 2H), 3.47-3.3 (m, 2H), 3.25-3.11 (m, 1H), 3.07 (d, J = 4.9 Hz, 3H), 2.10 (brs, 2H), 1.94-1.81 (m, 2H), 1.32-1.11 (m, 3H), 0.88-0.75 (m, 3H), 0.56-0.43 (m, 2H) ppm. MS:

489 m/z (M+H ⁺ ).

[00590] Example 640. [l-[6-Chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2- 6]pyridin-5-yl]-4-piperidyl] N-cyclopropylcarbamate

[00591] In a 5 mL vial were placed Example 473 (100 mg, 226 pmol) and /V-methyl-2- pyrrolidinone (2 mL). Hydrogen chloride (113 pL, 452 pmol) in dioxane (4M) was added at 0 °C and after 10 minutes at room temperature, 3-chloroperbenzoic acid (83 mg, 339 pmol) was added at 0 °C. After 1 hour at room temperature, the mixture was directly subjected to reversed phase HPLC to give the title compound (52 mg, 109 pmol, 48% yield) as a solid after lyophilization. 1H NMR (400 MHz, DMSO-d ₆ ) d 9.05 (brs, 1H), 8.85 (s, 1H), 7.32 (brs, 1H), 4.82 (brs, 1H), 3.63-

3.5 (m, 5H), 2.95 (d, J = 4.8 Hz, 3H), 2.12-2.01 (m, 2H), 1.87-0.62 (m, 2H), 0.57 (td, J = 7.0, 4.7 Hz, 2H), 0.45-0.38 (m, 2H) ppm. MS: 477 m/z (M+H ⁺ ).

[00592] Example 641. [l-[6-fluoro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3 ,2- 6]pyridin-5-yl]-4-piperidyl] N-cyclopropylcarbamate

[00593] Using Example 473, the procedure described in Example 639 was used to prepare the title compound (8 mg, 18 pmol, 8% yield) as a solid after lyophilization. 'H NMR (400 MHz, CDCb) d 9.22 (brs, 1H), 8.62 (s, 1H), 5.02-4.9 (m, 2H), 3.88-3.70 (m, 2H), 3.52-3.37 (m, 2H), 3.07 (d, J = 4.9 Hz, 3H), 2.61 (brs, 1H), 2.19-2.06 (m, 2H), 1.94-1.7 (m, 2H), 0.76-0.68 (m, 2H), 0.62-0.51 (m, 2H) ppm. MS: 461 m/z (M+H ⁺ ).

[00594] Example 642. tert-Butyl N-[l-[3-(isopropylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl]pyrrolidin-3-yl]c arbamate

[00595] Using 5-(3-((/eri-butoxycarbonyl)amino)pyrrolidin-l-yl)-7-

(trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylic acid, in which the ester in Example 659 was hydrolyzed by lithium hydroxide, and propan-2-amine, the procedure described in Example 649 was used to prepare the title compound (200 mg, 63%) as a solid. 1H NMR (400 MHz, CDCb) d

9.59 (d, J = 7.5 Hz, 1H), 8.58 (s, 1H), 6.68 (s, 1H), 5.49 (brs, 1H), 4.44 (brs, 1H), 4.34-4.17 (m, 1H), 3.88-3.7 (m, 1H), 3.74-3.53 (m, 2H), 3.45 (dd, J = 10.6, 4.3 Hz, 1H), 2.45-2.31 (m, 1H),

2.23-2.11 (m, 1H), 1.47 (s, 9H), 1.35-1.16 (m, 6H) ppm. MS: 473 m/z (M+H ⁺ ).

[00596] Example 649. 2-[4-[3-(Azetidine-l-carbonyl)-7-(trifluoromethyl)thieno[3,2 - b ]pyridin-5-yl] piperazin- 1 -yl] -N-isopropyl-acetamide

[00597] Step 1: 5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-l-yl)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylic acid

[00598] In a 100 mL round-bottomed flask were placed Example 10 (143 mg, 321 pmol), methanol (3 mL), tetrahydrofuran (3 mL), and lithium hydroxide (77 mg, 3.22 mmol). After 3 hours at 60 °C, the mixture was concentrated and diluted with ethyl acetate (50 mL) and water (50 mL), and its pH was adujsted to 1-2 with dilute hydrochloric acid solution. The insoluble product was filtered and dissolved in methanol/dichloromethane. The solution was dried (Na ₂ S0 ₄ )and combined with extractive work-up solution. The organic phase of the filtrate was separated, washed with brine (25 mL), dried (MgS04), filtered and concentrated to give the title compound (110 mg, 255 pmol, 79% yield). MS: 431 m/z (M+H ⁺ )

[00599] Step 2: 2-[4-[3-(Azetidine-l-carbonyl)-7-(trifluoromethyl)thieno[3,2 -h]pyridin-5- yl]piperazin- 1 -yl] -/V-isopropyl-acetamide

[00600] In a 100 mL round-bottomed flask were placed step 1 product (110 mg, 255 pmol), /V,/V-diisopropylethylamine (357 pL, 2.04 mmol), and acetonitrile (10 mL). 0-(Benzotriazol-l- yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) (169 mg, 511 pmol) was added at 20 °C, after 10 minutes, followed by addtion of azetidine (44 mg, 767 pmol). After 2 hours at 20 °C, the mixture was diluted with ethyl acetate (50 mL) and saturated sodium bicarbonate (20 mL). The organic layer was separated, washed ammonium chloride (20 mL) and brine (25 mL), dried (MgS04), filtered, and concentrated to give the residue, which was purified by automated flash chromatography (1:1 heptane/ethyl acetate to 0:100 heptane/ethyl acetate; 12S column, silica gel loading) to provide the title compound (63 mg, 134 pmol, 52% yield) as a solid. 'H NMR (400 MHz, CDCb) d 8.06 (s, 1H), 7.01 (s, 1H), 6.94 (d, / = 8 Hz, 1H), 4.28 (t, / = 7.8 Hz, 2H), 4.22- 4.06 (m, 3H), 3.84-3.64 (m, 4H), 3.07 (s, 2H), 2.79-2.62 (m, 4H), 2.37-2.29 (m, 2H), 1.20 (d, / = 6.6 Hz, 6H) ppm. MS: 470 m/z (M+H ⁺ ).

[00601] Example 653. [l-[3-(Trideuteriomethylcarbamoyl)-7-(trifluoromethyl)thieno [3,2- 6]pyridin-5-yl]-4-piperidyl] N-cyclopropylcarbamate

[00602] In a 20 mL microwave vial were placed methyl 5-(4-

((cyclopropylcarbamoyl)oxy)piperidin-l-yl)-7-(trifluorome thyl)thieno[3,2-h]pyridine-3- carboxylate (120 mg, 270 pmol), which was prepared by a similar procedure as in Example 428, and methanol (5 mL). Methan-d3- amine (92 mg, 2.71 mmol) was bubbled into the reaction mixture for 2-3 minutes at room temperature. After 2 hours at 80 °C, LCMS showed some product (-50% conversion) with remaining starting material. The mixture was bubbled again with methylamine-d3 and heated at 40 °C for 2 days (reaction completed). The mixture was concentrated to give a residue, which was suspended in acetonitrile and water and lyophilized to afford the title compound (101 mg, 228 pmol, 84% yield) as a solid. 1H NMR (400 MHz,

DMSO -de) d 9.24 (s, 1H), 8.75 (s, 1H), 7.51 (s, 1H), 7.33 (s, 1H), 4.82 (brs, 1H), 4.02 (brs, 2H), 3.50 (brs, 2H), 2.50-2.42 (m, 1H), 2.00-1.96 (m, 2H), 1.73-1.50 (m, 2H), 0.57 (dt, / = 6.9, 3.3 Hz, 2H), 0.48-0.28 (m, 2H) ppm. MS: 446 m/z (M+H ⁺ ).

[00603] Example 659. Methyl 5-[3-(tert-butoxycarbonylamino)pyrrolidin-l-yl]-7- (trifluoromethyl)thieno[3,2-6]pyridine-3-carboxylate

[00604] In a 10 mL microwave vial were placed /V,/V-diisopropylethylamine (472 pL, 2.71 mmol), Intermediate 3 (400 mg, 1.35 mmol), and tert- butyl pyrrolidin-3-ylcarbamate (377 mg, 2.03 mmol) and /V-methyl-2-pyrrolidinone (4 mL). After 30 minutes at 130 °C for in a microwave reactor, the mixture was diluted with ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, washed with water (3 x 20 mL) and saturated ammonium chloride (20 mL), dried (MgS04), filtered, and concentrated to give a solid, which was purified by automated flash chromatography (5: 1 heptane/ethyl acetate to 1:5 heptane/ethyl acetate; 12S column, solid loading) to afford the title compound (480 mg, 1.08 mmol, 79% yield). 1H NMR (400 MHz, CDCL) d 8.54 (s, 1H), 6.72 (s, 1H), 4.70 (brs, 1H), 4.41 (brs, 1H), 3.96 (s, 3H), 3.89 (dd, J =

10.9, 6.1 Hz, 1H), 3.74-3.70 (m, 2H), 3.51 (dd, / = 11.0, 4.2 Hz, 1H), 2.44-2.25 (m, 1H), 2.06- 2.01 (m, 1H), 1.46 (s, 9H) ppm. MS: 446 m/z (M+H ⁺ ).

[00605] Example 669. [l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyri din- 5-yl]-4-piperidyl] N-(cyclopropylmethyl)carbamate hydrochloride

[00606] In a 50 mL round-bottomed flask were placed Example 474 (35 mg, 76 pmol) and acetonitrile (5 mL). The mixture was treated with hydrochloric acid (958 pL, 3.83 mmol) in 4 M dioxane and concentrated to give a residue, which was diluted with acetonitrile and water, and lyophilized to afford the title compound (32 mg, 65 pmol, 85% yield) as a solid. 1H NMR (400 MHz, DMSO-de) d 9.26 (q, / = 4.8 Hz, 1H), 8.75 (s, 1H), 7.50 (s, 1H), 7.21 (t, / = 5.8 Hz, 1H), 4.88-4.77 (m, 1H), 4.12-3.97 (m, 2H), 3.70-3.63 (m, 1H), 3.56-3.45 (m, 1H), 2.95 (d, / = 4.7 Hz, 3H), 2.88 (t, / = 6.3 Hz, 2H), 2.1-1.94 (m, 2H), 1.73-1.6 (m, 2H), 0.94-0.8 (m, 1H), 0.45-0.32 (m, 2H), 0.15 (d, J = 4.9 Hz, 2H) ppm. MS: 493 m/z (M+H ⁺ ). [00607] Example 670. [l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyri din- 5-yl]-4-piperidyl] N-(2,2-difluoro-l-methyl-ethyl)carbamate

[00608] In a 5 mL vial were placed methyl 5-(4-hydroxypiperidin-l-yl)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxylate (50 mg, 138 pmol), which was prepared in step 1 of Example 422, /V,/V-diisopropylethylamine (121 pL, 693 pmol), 4-nitrophenyl chloroformate (55 mg, 277 pmol) and /V-methyl-2-pyrrolidinone (3 mL). After 15 hours at 20 °C, l,l-difluoropropan-2-amine hydrochloride (54 mg, 416 pmol) was added at room temperature. After 2 hours at room temperature, the mixture was diluted with ethyl acetate (20 mL) and saturated sodium bicarbonate (20 mL). The organic layer was separated, washed with water (3 x 15 mL), ammonium chloride (15 mL), and brine (20 mL), dried (Na ₂ S0 ₄ ), filtered, and concentrated to give a residue, which was purified by automated flash chromatography (5:1 heptane/ethyl acetate to 1:1 heptane/ethyl acetate; 4 g column) to afford methyl 5-(4-((( 1,1- difluoropropan-2-yl)carbamoyl)oxy)piperidin-l-yl)-7-(trifluo romethyl)thieno[3,2-h]pyridine-3- carboxylate (60 mg, 124 pmol, 89% yield). MS: 482 m/z (M+H ⁺ ).

[00609] In a 25 mL round-bottomed flask were placed above methyl ester (60 mg, 124 pmol) and methanamine (6.23 mL, 12.46 mmol) in methanol (2M). After 5 hours at 50 °C, the mixture was concentrated to give the residue, which was purified by reversed phase HPLC to give the title compound (27 mg, 57 pmol, 45% yield) as a solid. 1H NMR (400 MHz, DMSO-<i ₆ ) d 9.26 (q, J = 4.8 Hz, 1H), 8.75 (s, 1H), 7.52-7.51 (m, 2H), 5.91 (td, 7 = 56.1, 3.2 Hz, 1H), 4.94-4.81 (m, 1H), 4.09-4.0 (m, 2H), 3.89 (brs, 1H), 3.59-3.48 (m, 2H), 2.95 (d, / = 4.7 Hz, 3H), 2.00 (brs, 2H), 1.75-1.63 (m, 2H), 1.11 (d, / = 7.0 Hz, 3H) ppm. MS: 481 m/z (M+H ⁺ ).

[00610] Example 671. [l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyri din- 5-yl]-4-piperidyl] N-(2-fluoro-l-methyl-ethyl)carbamate

[00611] Using l-fluoropropan-2-amine hydrochloride, the procedure described in Example 670 was used to prepare the title compound as a solid. 1H NMR (400 MHz, DMSO-<i ₆ ) d 9.30-9.22 (m, 1H), 8.75 (s, 1H), 7.51 (s, 1H), 7.26 (d, / = 8.1 Hz, 1H), 4.84 (brs, 1H), 4.28 (dd, / = 46.7, 5.1 Hz, 2H), 4.07-4.02 (m, 2H), 3.84-3.78 (m, 1H), 3.56-3.46 (m, 2H), 2.95 (d, J = 4.7 Hz, 3H), 1.99 (brs, 2H), 1.68-1.62 (m, 2H), 1.07 (d, / = 6.9 Hz, 3H) ppm. MS: 463 m/z (M+H ⁺ ).

[00612] Example 692 and Example 693. [l-[3-(Methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl]-4-piperidyl] N-[(l/?)-2-fluoro-l-methyl- ethyl] carbamate and [l-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyri din-5-yl]- 4-piperidyl] N-[(lS)-2-fluoro-l-methyl-ethyl]carbamate (separate enantiomers of known absolute configurations)

[00613] The title compounds were obtained by subjecting racemic Example 671 to chiral SFC (4.6 x 250 mm CHIRALPAK IC column; 15:85 ethanol/heptane modifier with 0.1% diethylamine additive). The absolute configurations of the individual enantiomers were determined by comparison of chiral SFC retention times to that of the authentic enantiomers prepared from optically active (S)-l-fluoropropan-2-amine hydrochloride starting materials of known stereochemistry (commercially available).

[00614] lst elution fraction Example 692, 1H NMR (400 MHz, DMSO-d ₆ ) d 9.26 (d, / = 4.9 Hz, 1H), 8.75 (s, 1H), 7.51 (s, 1H), 7.25 (d, / = 8.0 Hz, 1H), 4.83 (brs, 1H), 4.28 (dd, / = 48, 4 Hz, 2H), 4.13-4.01 (m, 2H), 3.88-3.72 (m, 1H), 3.56-3.31 (m, 2H), 2.95 (d, / = 4.8 Hz, 3H), 2.12- 1.94 (m, 2H), 1.68-1.56 (m, 2H), 1.07 (dd, / = 6.9, 1.4 Hz, 3H) ppm. MS: 463 m/z (M+H ⁺ )

[00615] 2nd elution fraction, Example 693, 1H NMR (400 MHz, DMSO-d ₆ ) d 9.27 (q, / = 4 Hz, 1H), 8.76 (s, 1H), 7.51 (s, 1H), 7.26 (d, / = 8.0 Hz, 1H), 4.84 (brs, 1H), 4.28 (dd, / = 48, 4 Hz, 2H), 4.13-4.01 (m, 2H), 3.89-3.71 (m, 1H), 3.56-3.31 (m, 2H), 2.95 (d, J = 4.8 Hz, 3H), 2.13- 1.93 (m, 2H), 1.69-1.55 (m, 2H), 1.07 (dd, / = 6.9, 1.4 Hz, 3H) ppm. MS: 463 mJz (M+H ⁺ ).

[00616] Example 780. Cyclopropylmethyl 4-(3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)piperazine-l-carb oxylate

[00617] Using Intermediate 6 and cycloprop ylmethanol, the procedure described in step 3 of Example 793 was used to prepare the title compound (160 mg, 43%) as white solid. 'H NMR (400 MHz, CDCb) d 9.34 (br, 1H), 8.70 (s, 1H), 7.05 (s, 1H), 3.99 (d, / = 7.2 Hz, 2H), 3.68-3.75

(m, 8H), 3.10 (d / = 4.4 Hz, 3H), 1.15-1.19 (m, 1H), 0.61 (q, / = 5.6 Hz, 2H), 0.34 (q, / = 5.2 Hz, 2H) ppm. MS: 443 mJz (M+H ⁺ )

[00618] Example 793 and Example 794. l-(3-(Methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)piperidin-4-yl (2S,3S)-3-(dimethylamino)-2- methylazetidine-l-carboxylate and l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- 6]pyridin-5-yl)piperidin-4-yl (2S,3/?)-3-(dimethylamino)-2-methylazetidine-l-carboxylate (separate enantiomers of known absolute configurations)

[00619] Step 1: Benzyl (2S)-3-(dimethylamino)-2-methylazetidine-l-carboxylate

[00620] Benzyl (5)-2-mcthyl-3-oxoazctidinc-l -carhoxylatc (205 mg, 1.0 mmol) and dimethylamine (150 mg, 3.0 mmol) were dissolved in dichloromethane (10 mL). Acetic acid (2 drops) and sodium triacetoxyborohydride (736 mg, 3.0 mmol) were added and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and saturated sodium bicarbonate solution (100 mL). The organic layer was separated and washed with saturated ammonium chloride solution (100 mL) and brine (100 mL), dried over Na ₂ S0 ₄ , filtered and concentrated. The crude material was purified by silica gel column chromatography (pentane/ethyl acetate v/v=3:l) to give the title compound (150 mg,

60%) as colorless oil. MS; (M ⁺ l) 249.1

[00621] Step 2: (25)-N,N,2-Tri mcthylazctidin-3-aminc

[00622] To a solution of step 1 product (150 mg, 0.6 mmol) in methanol (15 mL) was added palladium on carbon (50 mg, 10%). The reaction mixture was stirred at room temperature under H2 overnight. After completion of the reaction, palladium on carbon was filtrated and the filtrate was concentrated to give crude the title compound (100 mg, crude) as a white solid.

[00623] Step 3: l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyrid in-5- yl)piperidin-4-yl (25, 35)-3-(di methyl ami no)-2-mcthylazctidinc-l -carboxy late and l-(3- (methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-h]pyridin-5- yl)piperidin-4-yl (2S, K)-3- (dimethylamino)-2-methylazetidine- 1 -carboxylate

[00624] To a solution of Intermediate 7 (300 mg, 0.84 mmol) in dichloromethane (5 mL) were added /V,/V-diisopropylethylamine (215 mg, 1.67 mmol), 4-dimethylaminopyridine(l05 mg, 0.84 mmol) and 4-nitrophenyl chloroformate (217 mg, 1.08 mmol). Then the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solvent was removed to give a crude intermediate. The intermediate was dissolved in dry N,N-d\ methyl formamidc (3 mL) and then added AN-diisopropylcthylaminc (325 mg, 2.46 mmol) and (25)-N,N,2-trimethylazetidin-3- amine (430 mg, crude). The reaction mixture was stirred at 50 °C overnight. The resulting mixture was poured into water and extracted with dichloromethane (3x 10 mL). The combined extracts were concentrated in vacuo. The residue was purified by reversed phase HPLC to afford the cis title compounds (19 mg, 4%) 1H NMR (400 MHz, CDCL) d 9.45 (br, 1H), 8.66 (s, 1H), 7.06 (s, 1H), 4.99 (s, 1H), 4.30 (s, 1H), 3.90-3.59 (m, 4H), 3.60 (s, 2H), 3.07-3.01 (m, 4H), 2.10- 2.02 (m, 8H), 1.83 (s, 2H), 1.43 (s, 3H) ppm. MS: 500 m/z (M+H ⁺ ).

[00625] and the trans title compound (46 mg, 11%) 1H NMR (400 MHz, CDCL) d 9.44 (br, 1H), 8.66 (s, 1H), 7.06 (s, 1H), 4.99 (s, 1H), 4.12 (s, 1H), 3.94-3.85 (m, 3H), 3.73-3.70 (m, 1H), 3.60 (s, 2H), 3.07 (d, J = 4.8 Hz, 3H), 2.54 (s, 1H), 2.16 (s, 6H), 2.06-2.01 (m, 2H), 1.89-1.80 (m, 4H), 1.42 (s, 3H) ppm. MS: 500 m/z (M+H ⁺ ).

[00626] Example 806. l-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyrid in-5- yl)piperidin-4-yl l-methyl-l,6-diazaspiro[3.3]heptane-6-carboxylate

[00627] Using Intermediate 7 and l-methyl-l,6-diazaspiro[3.3]heptane, the procedure described in step 3 of Example 793 was used to prepare the title compound (203 mg, crude) as brown oil. 1H NMR (400 MHz, CDCb) d 9.46 (s, 1H), 8.67 (s, 1H), 7.07 (s, 1H), 4.96 (s, 1H),

4.26 (d, / = 9.3 Hz, 2H), 3.95 (d, / = 9.9 Hz, 2H), 3.90 (d, / = 7.7 Hz, 1H), 3.61-3.51 (m, 2H), 3.18 (s, 2H), 3.08 (d, / = 4.9 Hz, 2H), 2.38 (s, 2H), 2.35 (d, 7 = 7.1 Hz, 2H), 2.04 (s, 3H) ppm.

.0% ; MS: 498 m/z (M+H ⁺ ).

[00628] Example 809. (2S,3S)-l,2-Dimethylpyrrolidin-3-yl (l-(3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)piperidin-4-yl)ca rbamate

[00629] Step 1: (25, 35) - 2 - c t h y 1 p y ro 1 i d i n - 3 - o 1

[00630] A mixture of benzyl (2S,3S)-3-hydroxy-2-methylpyrrolidine-l-carboxylate (300 mg, 1.28 mmol) and 10% palladium on carbon (100 mg) in methanol (20 mL) was flushed with hydrogen atmosphere and stirred at room temperature overnight. The resulting mixture was filtered through celite. The filtrate was concentrated in vacuo to afford the title compound (130 mg, > 100%) as a yellow oil. LCMS UV absorption is weak; MS: 102 m/z (M+H ⁺ ).

[00631] Step 2: //77-Butyl (25,35)-3-hydroxy-2-mcthylpynolidinc- l -carboxyl ate

[00632] To a solution of step 1 product (110 mg, 1.09 mmol), triethylamine (221 mg, 2.18 mmol) in dichloromethane (10 mL) was added di-ie/7-butyl pyrocarbonate (262 mg, 1.20 mmol) dropwise.at 0-10 °C. After stirring overnight at room temperature, the mixture was concentrated to afford the title compound (320 mg, > 100%) as a yellow oil. MS: m/z 146 (M+H ⁺ ).

[00633] Step 3 : / £77- Butyl (2S,3S)-2-methyl-3-(((4-nitrophenoxy)carbonyl)oxy)pyrrolidin e-l- carboxylate

[00634] A mixture of step 2 product (320 mg, 1.09 mmol), 4-nitrophenyl chloroformate (285 mg, 1.42 mmol), /V,/V-diisopropylethylamine (281 mg, 2.18 mmol) and 4-dimethylaminopyridine (133 mg, 1.09 mmol) in dimethylformamide (5 mL) was stirred at 25 °C for 4 hours. The resulting mixture was concentrated and purified by silica gel chromatography (eluting with ethyl acetate) to afford the title compound (194 mg, 42%) as a yellow oil. MS: 311 mJz (M-55).

[00635] Step 4: //77-Butyl (2S,3S)-2-mcthyl-3-(((l -(3-(mcthylcarbamoyl)-7-

(trifluoromethyl)thieno[3,2-h]pyridin-5-yl)piperidin-4-yl )carbamoyl)oxy)pyrrolidine-l- carboxylate

[00636] A mixture of step 3 product of Example 297 (750 mg, 0.80 mmol), step 3 product (194 mg, 0.53 mmol), /V,/V-diisopropylethylamine (340 mg, 1.60 mmol), and 4-dimethylaminopyridine (105 mg, 0.53 mmol) in dimethylformamide (5 mL) was stirred at 50 °C overnight. The resulting mixture was poured into water and extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (2x50 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase HPLC to afford the title compound (35 mg, 6%) as a white solid. MS: 586 mJz (M+H ⁺ ).

[00637] Step 5: (2S,3S)-2-Methylpyrrolidin-3-yl (l-(3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)piperidin-4-yl)ca rbamate

[00638] To a solution of step 4 product (35 mg, 0.06 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). After stirring overnight at room temperature, the resulting mixture was concentrated in vacuo and was adjusted to pH = 9-10 with ammonia-methanol solution. The solution was concentrated and purified by silica gel chromatogarphy (eluting with dichloromethane/methanol, v/v, 1/2) to afford the title compound (136 mg, > 100%) as a yellow oil. MS: 486 m/z (M+H ⁺ ).

[00639] Step 6: (25,35)- l ,2-Dimcthylpyrrolidin-3-yl (l-(3-(methylcarbamoyl)-7-

(trifluoromethyl)thieno[3,2-h]pyridin-5-yl)piperidin-4-yl )carbamate

[00640] A mixture of step 5 product (136 mg, 0.28 mmol), 37% formaldehyde aqueous solution (68 mg, 0.84 mmol) and sodium cyanoborohydride (53 mg, 0.84 mmol) in methanol (5 mL) was stirred overnight at room temperature. The mixture was concentrated and purified by reversed phase HPLC to afford the title compound (10 mg, 9%) as a brown solid. 1H NMR (400

MHz, MeOD) d 8.69 (s, 1H), 7.36 (s, 1H), 5.14 (s, 1H), 4.33 (d, 7 = 13.4 Hz, 2H), 3.74 (d, 7 =

10.5 Hz, 1H), 3.26 (d, 7 = 13.7 Hz, 2H), 3.15 (t, 7 = 8.4 Hz, 1H), 3.07 (s, 3H), 2.40-2.22 (m, 5H), 2.23-2.13 (m, 1H), 2.07 (d, 7 = 9.8 Hz, 2H), 1.76 (dd, 7 = 20.2, 9.2 Hz, 1H), 1.59 (dd, 7 = 20.3, 10.7 Hz, 2H), 1.14 (t, 7 = 14.1 Hz, 3H) ppm. MS: 500 m/z (M+H ⁺ ). [00641] Example 816. Isopropyl (l-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- 6]pyridin-5-yl)piperidin-4-yl)carbamate

[00642] Using step 3 product of Example 297 and propan-2-ol, the procedure described in Example 809 was used to prepare the title compound (82 mg, 25%)) as a white solid. 1H NMR

(400 MHz, CDC13): d 9.41 (br, 1H), 8.66 (s, 1H), 7.05 (s, 1H), 4.92 (s, 1H), 4.60 (s, 1H), 4.21 (d, J = 13.2 Hz, 2H), 3.80 (s, 1H), 3.21 (m, 2H), 3.06 (d, 7 = 4.8 Hz, 3H), 2.15 (d, / = 18 Hz, 2H), 1.54 (m, 2H), 1.24 (d, / = 6 Hz, 6H) ppm. MS: 445 m/z (M+H ⁺ ).

[00643] Example 822. (+/-)- s-(lS,3S)-3-((3-(Methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)cyclobutyl oxetan-3-ylcarbamate

[00644] Step 1: (+/-)-cA-(ls,3s)-3-(Benzyloxy)cyclobutan-l-ol

[00645] To a solution of 3-(benzyloxy)cyclobutan-l-one (10 g, 57.0 mmol) in

tetrahydrofuran(75 mL) was added L-selectride (62.5 mL, 62.5 mmol) drop-wise at -78 °C and stirred at -78 °C for 1 hour. Then the mixture was warmed to room temperature for 1 hour. A saturated solution of sodium bicarbonate (30 mL) was added and then cooled to 0 °C and 30% hydrogen peroxide (10 mL) was added. The reaction mixture was diluted with water and extracted with ethyl acetate (100 mLx3). The combined extracts were dried over anhydrous Na ₂ S0 ₄ and concentrated to give the crude title compound (11.2 g, 100%) as a white solid. MS: 179 m/z

(M+H ⁺ ).

[00646] Step 2: (+/-)-cA-5-((ls,3s)-3-(Benzyloxy)cyclobutoxy)-/V-methyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide

[00647] To a solution of Intermediate 5 (12 g, 40.8 mmol) in tetrahydrofuran (150 mL) was added step 1 product (11.2 g, crude) and potassium ieri-butoxide (12 g, 107 mmol). The mixture was stirred at 90 °C for 2 hours. Then the reaction mixture was washed with water (100 mL) and extracted with dichloromethane (l00mLx3). The combined extracts were dried over anhydrous Na ₂ S0 ₄ , concentrated and purified by chromatography to give the title compound (5.3 g, 30%) as white solid. MS: 347 m/z (M+H ⁺ ).

[00648] Step 3: (+/-)-cA-5-((ls,3s)-3-Hydroxycyclobutoxy)-/V-methyl-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide

[00649] To a solution of step 2 product (5.3 g, 12.2 mmol) in methanol (100 mL) was added palladium on carbon (500 mg, 10%) and acetic acid (lmL). The reaction mixture was stirred at room temperature under H2 overnight. After completion of the reaction, palladium on carbon was filtrated and the filtrate was concentrated to give the crude title compound (4.6 g) as a white solid.

[00650] Step 4: (+/-)-cA-(ls,3s)-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl) thieno[3,2- h]pyridin-5-yl)oxy)cyclobutyl oxetan-3-ylcarbamate

[00651] Using step 3 product and oxetan-3-amine, the procedure described in step 3 product of Example 793 was used to prepare the title compound (59 mg, 36%) as white solid. 1H NMR (400 MHz, CDCb) d 9.05 (br, 1H), 8.75 (s, 1H), 7.10 (s, 1H), 5.38 (s, 1H), 4.94-4.85 (m, 5H), 4.53 (s, 2H), 3.10-3.08 (m, 6H), 2.40-2.34 (m, 2H) ppm. MS: 445 m/z (M+H ⁺ ).

[00652] Example 833. (+/-)-cz.s-(LS ^, ,3/?)-3-((3-(Methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)cyclobutyl ((S ₎ -l-(trifluoromethoxy)propan- 2-yl)carbamate

[00653] Using Intermediate 28, the procedure described in Example 822 was used to prepare the title compound (60 mg, 24%) as a white solid. 1H NMR (400 MHz, CDCB): d 9.08 (br, 1H), 8.76 (s, 1H), 7.11 (s, 1H), 4.95-4.87 (m, 3H), 4.02-3.92 (m, 3H), 3.11 (d, J = 4.8 Hz, 3H), 3.09- 3.05 (m, 1H), 2.42-2.35 (m, 2H), 1.28 (d, J = 6.8 Hz, 3H) ppm. MS: 516 m/z (M+H ⁺ ).

[00654] Example 835. 4-Fluoro-l-methylpyrrolidin-3-yl 4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)piperidine-l- carboxylate

[00655] Step 1: l-(ie/7-Butoxycarbonyl)-4-fluoropyrrolidin-3-yl 4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)piperidine-l- carboxylate

[00656] To a solution of Intermediate 17 (205 mg, 1.00 mmol) in dichloromethane (5 mL) were added /V,/V-diisopropylethylamine (387 mg, 3.00 mmol), 4-dimethylaminopyridine (122 mg, 1.00 mmol) and 4-nitrophenyl chloroformate (200 mg, 1.00 mmol). After 4 hours at room temperature, the mixture was concentrated, dissolved in N,N-d\ methyl form amide (3 mL) and treated with /V,/V-diisopropylethylamine (387 mg, 3.00 mmol) and //77-butyl 3-fluoro-4- hydroxypyrrolidine-l-carboxylate (433 mg, 0.95 mmol). After stirring at 90 °C overnight, the resulting mixture was poured into water and extracted with dichloromethane (3 xlO mL). The combined extracts were concentrated in vacuo to give a redidue which was purified by silica gel column chromatography (pentane/ethyl acetate v/v=l: l) to afford the title compound (267 mg, 47%) as a yellow solid. Purity: > 92% MS; 591 m/z (M+H ⁺ ).

[00657] Step 2: 4-Fluoropyrrolidin-3-yl 4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)piperidine-l- carboxylate

[00658] To a solution of step 1 product (267 mg, 0.46 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL). After stirring overnight at room temperature, the resulting mixture was concentrated in vacuo and the methanol solution was adjusted to pH = 9-10 with ammonia-methanol solution. The solution was concentrated, triturated with dichloromethane, and filtered. The filtrate was concentrated to afford the title compound (205 mg, 92%) as a ligh- yellow solid. MS: 491 m/z (M+H ⁺ ), Purity: 92%. )

[00659] Step 3: 4 -Fluoro- l-methylpyrrolidin-3-yl 4-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)piperidine-l- carboxylate

[00660] A mixture of step 2 product (205 mg, 0.42 mmol), 37% formaldehyde aqueous solution (102 mg, 1.26 mmol), sodium cyanoborohydride (80 mg, 1.26 mmol), and methanol (5 mL) was stirred at room temperature overnight. The resulting mixture was concentrated and purified by reversed phase HPLC to afford the title compound (86 mg, 42%) as a white solid. 1H NMR (400 MHz, CDC13): d 9.05 (s, 1 H), 8.78 (s, 1 H), 7.15 (s, 1 H), 5.22 (m, 3 H), 3.83 (m, 2 H), 3.56 (m, 2 H), 3.18 (m, 5 H), 2.83 (m, 1 H), 2.77 (m, 1 H), 2.45 (s, 3 H), 2.11 (m, 4H) ppm. MS: 505 m/z (M+H ⁺ ).

[00661] Example 853. (S)-l-(Trifluoromethoxy)propan-2-yl 6-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)-2-azaspiro[3 .3]heptane-2-carboxylate

[00662] Using Intermediate 25 and (SJ-l-(trifluoromethoxy)propan-2-ol, the procedure described in step 1 of Example 835 was used to prepare the title compound (36 mg, 12%) as a white solid. 1H NMR (400 MHz, CDC13): d 9.13 (s, 1 H), 8.76 (s, 1 H), 7.10 (s, 1 H), 5.19 (m, 1

H), 5.04 (m, 1 H), 4.03 (m, 6 H), 3.13 (d, 7=5.2 Hz, 3 H), 2.38 (m, 2 H), 1.35 (m, 3 H) ppm. MS:

542 m/z (M+H ⁺ ).

[00663] Example 858. (/? -2-(Trifluoromethoxy)propyl (S -3-((3-(methylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-6]pyridin-5-yl)oxy)pyrrolidine-l -carboxylate

[00664] Step 1: (R)-2-(Trifluoromethoxy)propyl lH-imidazole-l-carboxylate

[00665] A mixture of (R)-2-(trifluoromethoxy)propan-l-ol (260 mg, 1.81 mmol) and 1,1 '- carbonyldiimidazole (440 mg, 2.72 mmol) was dissolved in dichloromethane (5 mL) After 16 hours at 25 °C, the reaction mixture was quenched with saturated. ammonium chloride (30 mL) and extracted with dichloromethane (30 mL). The organic layer was dried over Na ₂ S0 ₄ , filtered, and concentrated and to give the title compound (300 mg, crude), which was used next step without further purification. MS: 239 m/z (M+H ⁺ ).

[00666] Step 2: //77-Butyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2- /?]pyridin-5-yl)oxy)pym lidinc- l -carboxyl ate

[00667] To a solution of //77-butyl (S)-3-hydroxypyrrolidine-l-carboxylate (477 mg, 2.6 mmol) in tetrahydrofuran (10 mL) was added potassium //77-butoxidc (286 mg, 2.6 mmol) in one portion. After 10 minutes, Intermediate 5 (500 mg, 1.7 mmol) was added and the reaction mixture was stirred at reflux for 1 hour. The reaction was quenched by addition of water (10 mL) and the mixture was diluted with saturated aqueous sodium bicarbonate (10 mL) and ethyl acetate (10 mL) and extracted with ethyl acetate (3x20 mL). The extracts were washed with brine (50 mL), dried (Na ₂ S0 ₄ ), filtered and concentrated in vacuo to give a yellow oil, which was purified by column chromatography on silica gel (pentane/ethyl acetate: 1/1) to give the title compound (655 mg, 87%) as a yellow oil. MS: 346 m/z (M+H ⁺ ).

[00668] Step 3: (S)-/V-Methyl-5-(pyrrolidin-3-yloxy)-7-(trifluoromethyl)thie no[3,2-h]pyridine- 3 -carboxamide

[00669] A mixture of step 2 product (655 mg, 1.47 mmol) and hydrochloric acid dioxane solution (10 mL, 40 mmol, 4M) was stirred at room temperature for 2 hours. After concentration in vacuo the residue was stirred in ether (20 mL) at room temperature for 1 hour to give a solid which was filtered. The solid was dissolved in dichloromethane (20 mL) and its pH was adjusted to 8 with aqueous sodium bicarbonate solution. The organic layer was separated, dried over Na ₂ S0 ₄ , and concentrated in vacuo to give the title compound (195 mg, yield: 64%) as a brown solid. MS: 346 m/z (M+H ⁺ ).

[00670] Step 4: (R)-2-(Trifluoromethoxy)propyl (5)-3-((3-(mcthylcarbamoyl)-7- (trifluoromethyl)thieno[3,2-h]pyridin-5-yl)oxy)pyrrolidine-l -carboxylate

[00671] A mixture of step 3 product (195 mg, 0.565 mmol), step 1 product (135 mg, 0.565 mmol), and /V-hydroxysuccinimide (97 mg, 0.85 mmol) in acetonitrile (10 mL) was stirred at 60 °C under nitrogen atmosphere for 6 hours. After cooling down to room temperature, the solvent was removed in vacuo and the residue was purified by reversed phase HPLC to give the title compound (84 mg, yield: 24%) as light yellow solid. 1H NMR (400 MHz, CDC13): d 8.98 (d, / = 3.4 Hz, 1H), 8.77 (s, 1H), 7.13 (d, J = 4.1 Hz, 1H), 5.57 (s, 1H), 4.65-4.47 (m, 1H), 4.32-3.97 (m, 2H), 3.94-3.54 (m, 4H), 3.10 (d, J = 4.8 Hz, 3H), 2.32 (m, 2H), 1.45-1.28 (m, 3H) ppm. MS: 516 m/z (M+H ⁺ ).

[00672] Example 866. (Sj-l-Cyclopropylethyl (2/f,4/f ₎ -2-methyl-4-((6-methyl-3- (methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-6]pyridin-5- yl)oxy)piperidine-l- carboxylate

[00673] Using N,6-dimethyl-5-(((2S,4S)-2-methylpiperidin-4-yl)oxy)-7- (trifluoromethyl)thieno[3,2-h]pyridine-3-carboxamide (MS: 388 m/z (M+H ⁺ )), which was prepared from Intermediate 15 and //77-butyl (2R,4S)-4-hydroxy-2-methylpiperidine-l- carboxylate as in Intermediate 17, and (S)-l -cyclopropylcthyl lH-imidazole-l-carboxylate, the procedure described in Example 858 was used to prepare the title compound (43 mg, 68%) as a colorless oil. 1H NMR (400 MHz, CDCb) d 9.14 (br, 1H), 8.65 (s, 1H), 5.41-5.40 (m, 1H), 4.57- 4.54 (m, 1H), 4.36-4.28 (m, 1H), 4.10-4.06 (m, 1H), 3.38-3.31 (m, 1H), 3.10 (d, J = 7.2 Hz, 3H), 2.51 (s, 3H), 2.21-2.06 (m, 3H), 1.99-1.90 (m, 1H), 1.39 (d, J = 6.8 Hz, 3H), 1.35 (d, / = 6.0 Hz, 3H), 1.04-0.98 (m, 1H), 0.55-0.40 (m, 3H), 0.23-0.26 (m, 1H) ppm. MS: No desired mass was detected.

[00674] UGT8 ACTIVITY

[00675] Assays for Detecting and measuring UGT8 Inhibition Properties of Compounds

[00676] Example 871: In vitro assays for Sulfatide (SFT) synthesis inhibition:

[00677] For medium throughput screening, library compounds were dispensed into CellBIND 384 well plates to a final concentration of 10 mM. OE19 cells (Sigma) were grown in to 70-90% confluency in RPMI 1640 ⁺ L- glutamine and XX % Hyclone; were trypsinized to achieve suspension and were aliquoted at 2,500 cells/well, total well volume 50 pl. Plates were incubated 72 hr at 37oC in 5% C02; supernatant was removed and plates were dried, heat-sealed and stored at -20oC until analysis.

[00678] For IC50 determinations, the same procedure was followed except that test compounds were added to the plate as dose-downs in triplicate to yield concentration response curves.

[00679] Mass spectrometer analysis of sulfatide (SFT):

[00680] Assay plates were thawed and 85 mΐ mobile phase B (5 mM ammonium formate ⁺

0.2% formic acid in 50:50 methanol: acetonitrile). Fifteen mΐ 20 ng/ml C17 SFT in mobile phase B was added as an internal standard.

[00681] SFT was analyzed using an Applied Biosystems API-4000 triple quad mass spectrometer interfaced to a Thermo Scientific Multiplex system (FX-4) equipped with four pumps. Chromatography of OE19 cell samples or 2B5-mouse cells treated with compounds was performed using a Waters Acquity UPFC BEH C8 2.1 x 50 mm column with 1.7 um particle size. The chromatography was performed using the following mobile phases. Mobile phase A (MPA): 0.2% formic acid and 5 mM ammonium formate in deionized water; MPB: see above. The FC method was run in isocratic mode for 4 sequentially running columns using 95% MPB and 5% MPA with flow rate of 1 ml/min and a column temperature of 60o C.

[00682] The Triple quad mass spectrometer was run in Negative Ionization mode monitoring the following MRM transitions and using the following parameters:

[00683] Electrospray voltage was -4500 kV, and source temperature was 550° C.

Sulfatide Ql (m/z) Q3 (m/z) DP (V) CE (eV)

Isoforms

C16 778.7 97.1 -200 -120

C24 890.8 97.1 -200 -120

IS 792.8 97.1 -200 -120

[00684] Mass spectrometer analysis of Galactosylceramide (GalCer):

[00685] GalCer and glucosylceramide (GlcCer) were analyzed using Applied Biosystem API- 5000 MS/MS System interfaced to a Thermo Scientific Multiplex system (LX-4) equipped with four pumps. Chromatography of cells treated with compounds was performed using Waters Cortecs HILIC 2.7um, 2.1 x 100 mm column under the following conditions: Mobile phase A (MPA): 96% acetonitrile, 1% deionized water, 2% methanol , 1% acetic acid and 5 mM ammonium acetate; Mobile phase B: 80% methanol, 20% deionized water, 1% acetic acid and 5 mM ammonium acetate.

[00686] The liquid chromatography (LC) method was developed for 4 sequentially running columns. The initial gradient starts with 100% MPA going down to 75% MPA in 2 minutes, followed by a column wash step at 75% MPA for 0.08 minutes, and back to initial conditions at 2.28 minutes. Column was equilibrated for 2.54 minutes with total run time of 4.82 minutes. Flow rate was 0.5 ml/min and column was maintained at room temperature.

[00687] MS/MS Method: Positive Ionization mode; parameters:

GalCer/GluCer Ql (m/z) Q3 (m/z) DP (V) CE (eV)

Isoforms

C16 700.7 264.3 120 50

C24 812.8 264.3 120 50 IS 763.9 246.3 120 54

[00688] Electrospray voltage was 4500kV, and source temperature was 50oC.

[00689] The IC ⁵⁰ determinations for compounds disclosed herein are provided below in Table 3:

Table 3

Potency of compounds, In-vitro SFT

Potency range: A<0.1 uM; 0.1 uM<B<l uM; 1 uM<C

[00690] Example 872: Acute in vivo models: target engagement in mouse kidney

[00691] In vivo target engagement was initially assessed in an adult mouse kidney model assessing de novo synthesis inhibition. This model was selected because the high rate of GalCer and SFT synthesis and turnover in kidney facilitated development of an acute one-day model assessing the effect of a single administration of compound at different doses. Inhibition of de novo synthesis was determined by measuring the amount of 13C6 galactose (l3C-Gal; CIL, cat #CLM-l570-pk) incorporated into GalCer and SFT.

[00692] Groups of 5 male C57B1/6 mice, 6-9 wks of age (Charles River Laboratories) were maintained in an ALAAC-accredited vivarium with food and water ad libitum and were allowed to acclimate one week before initiating studies. Three to 5 dose groups received test article formulated in a clinically-acceptable formulation, administered by oral gavage; the control group received vehicle alone. One hr after administration of test article, animals received an intra- peritoneal (i.p.) injection of l3C-Gal (3 g/kg); 5 hr after administration of test article, animals were euthanized and a kidney was removed and divided into two longitudinal samples that were snap-frozen and stored at -80°C until processing for test article tissue exposure and lipid analysis (GalCer and SFT). Typically, brain and plasma samples were also collected for test article exposure. The resulting kidney tissue exposure and lipid analysis for individual compounds are presented in Table 4 below.

[00693] Example 873: Acute in vivo models: target engagement in mouse brain

[00694] Because MLD is a disease primarily of the central nervous system (CNS), it was essential to demonstrate target engagement in the brain. SFT biosynthesis and turnover in the myelin of adult mice is very low, necessitating development of a short-term acute model of de novo synthesis inhibition. To do this, we took advantage of the fact that unlike primates in which most developmental myelination occurs in utero, in rodents, peak myelination °Ccurs between postnatal day 14 (P14) and P22.

[00695] Groups of 5 neonatal mice age-matched between P14 and P21 received test article formulated in a clinically-acceptable formulation, administered by oral gavage; the control group received vehicle alone. One hr after administration of test article, animals received an i.p.

injection of l3C-Gal (3 g/kg); 5 hr after administration of test article, animals were euthanized, brains were removed and dissected for recovery of mid- and hind brain which was snap-frozen and stored at -80°C. until analysis. Plasma samples were also collected for test article exposure analysis. The resulting brain exposure and lipid analysis for individual compounds are presented in Table 4 below.

[00696] Mass spectrometer analysis of SFT

[00697] Quantitative analysis of sphingolipids (SLs) was performed using liquid

chromatography with tandem mass spectrometry analysis (LC-MS/MS). Briefly, to extract glucosylceramide (GlcCer), galactosylceramide (GalCer), and sulfatide (ST), an aliquot of 10 pL of mouse tissue homogenate (100 mg/ml in water) was mixed with 1 mL of extraction solution (0.2% Formic Acid; 5mM Ammonium formate in (50:50) Methanol: Acetonitrile (v/v) with internal standards (IS)). C17-ST and D35 labeled Cl8-GalCer were used for IS. The mixtures were vortexed and centrifuged. The resulting supernatants were transferred to HPLC vials for LC- MS/MS analysis. GlcCer and GalCer were separated using a Waters Acquity UPLC and Atlantis HILIC Silica column (2.1 mm x 150 mm, 3 pm particles, Waters Corp., Milford, MA) and analyzed by an API 5000 triple quadrupole mass spectrometer in MRM mode (Applied

Biosystems, Foster City, CA). ST were analyzed using a Waters Acquity UPLC and BEH C18 column (2.1 mm x 50 mm, 1.7 pm particles, Waters Corp., Milford, MA) and analyzed by an API 6500 triple quadrupole mass spectrometer in MRM mode (Applied Biosystems, Foster City, CA).

[00698] Analytical method for MLD compounds

[00699] Plasma and tissue concentrations of the test compounds from MLD program were determined using exploratory liquid chromatography with tandem mass spectrometry

(LC-MS/MS) methods. Briefly, tissue samples were first homogenized with a solution of 20% acetonitrile in water at a ratio of 1:4 (1.00 g of the tissue with 4.00 mL of the solution). Plasma and tissue homogenate samples were then processed using protein precipitation via the internal standard solution (RP-107 in acetonitrile). Chromatographic separation was performed using a Phenomenex Kinetex C8 column. Multiple mass transitions were monitored with tandem mass spectrometry (MS/MS). Calibration standards and quality control samples were prepared in blank control plasma or tissue homogenate. Calibration curves were generated using weighted linear regression analysis (l/x2) of peak area ratio (analyte to IS) versus analyte concentration. The appropriate calibration curve for each analyte was used to calculate the concentration of the analyte in plasma or tissue samples.

Table 4

Potency of compounds, In-vivo GalCer and Sulfatide inhibition

Potency range: A>80%; 40%<B<80%; C<40%

[00700] DOSING

[00701] Dosage regimens for the compounds described herein for monotherapy and combination therapy are generally determined by the skilled clinician and are expected to vary significantly depending the clinical status of the particular affected individual. The general principles for determining a dosage regimen for the treatment of cystic fibrosis or (and/or) CFTR modulation are well known to the skilled artisan. Guidance for dosage regimens can be obtained from any of the many well-known references in the art on this topic. Further guidance is available, inter alia, from a review of the specific references cited herein. In certain embodiments, such dosages may range from about 0.5 mg/kg to about 300 mg/kg, for example, from about 5 mg/kg to about 60 mg/kg (e.g., 5 mg/kg, 10 mg/kg, 15, mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg and 60 mg/kg) by intraperitoneal, oral or equivalent administration from one to five times daily. Such dosages may range from about 5 mg/kg to about 5 g/kg, preferably from about 10 mg/kg to about 1 g/kg by oral, intraperitoneal or equivalent administration from one to five times daily. In one embodiment, doses range from about about 10 mg/day to about 500 mg/day (e.g., 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 1 80 mg/day, 190 mg/day, 200 mg/day, 210 mg/day, 220 mg/day, 230 mg/day, 240 mg/day, 250 mg/day, 260 mg/day, 270 mg/day, 280 mg/day, 290 mg/day, 300 mg/day). A particularly preferred

[00702] Oral dose range is from about 50 mg to about 100 mg, wherein the dose is

administered for example once daily. A particular oral dose range for a compound described herein is from about 5 mg/kg/day to about 600 mg/kg/day. In a particular oral dose range for a compound described herein is from about 1 mg/kg/day to about 120 mg/kg/day, e.g., 1 mg/kg/day , 5 mg/kg/day, 10 mg/kg/day, 15 mg/kg/day, 20 mg/kg/day, 25 mg/kg/day, 30 mg/kg/day, 35 mg/kg/day, 40 mg/kg/day , 45 mg/kg/day , 50 mg/kg/day , 55 mg/kg/day or 60 mg/kg/day, 65 mg/kg/day, 70 mg/kg/day, 75 mg/kg/day, 80 mg/kg/day, 85 mg/kg/day, 90 mg/kg/day, 95 mg/kg/day, 100 mg/kg/day, 105 mg/kg/day, 1 10 mg/kg/day , 1 15 mg/kg/day or 120 mg/kg/day.

[00703] The teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.

[00704] While the embodiments described herein have been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope encompassed by the appended claims.