RU2810928C2 - Uridine-5-diphosphate (udp) glycosyltransferase inhibitors and methods of their use - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, where (a) X² represents either CR² or N; (b) X⁵ represents either CR⁷ or N; (c) X⁶ represents either CR¹ or N; (d) Y represents either -C(O)NR^aR^b or -C(O)O-C_1-4 alkyl; (e) each R^a is independently either H, C_1-4 alkyl, C_1-4 haloalkyl, -C_1-4 alkyl-C_3-9 cycloalkyl or C_3-9 cycloalkyl; (f) each R^b is independently either C_1-4 alkyl, C_1-4 alkoxy, C_3-9 cycloalkyl or -C_1-4 alkyl-C_1-4 alkoxy; or, when Y represents -C(O)NR^aR^b, R^a and R^b can be taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl, which is a free non-aromatic radical having from 3 to 10 rings atoms, wherein 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen substituted with 0-3 R^x substituents; (g) R⁷ is either hydrogen, C_1-4 alkyl, C_1-4 alkoxy, -S(O)₂-NR^aR^b- or heteroaryl having from 5 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen; (h) R¹ is hydrogen, halogen, -OH, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 haloalkyl, C_1-4 haloalkoxy, -NH₂, -NH(C_1-4 alkyl) or -N(C_1-4 alkyl)₂, C_3-9 cycloalkyl or azetidinyl, wherein each -NH(C_1-4 alkyl) or cycloalkyl is substituted with 0-5 R^x substituents and where each azetidinyl is substituted with 0-5 substituents R^x; (i) R² is hydrogen, halogen, -OH, C_1-4 alkyl, C_1-4 alkoxy or C_3-9 cycloalkyl; (j) A¹ represents a chemical bond, C_1-4 alkylene, -O-, -OC_1-4 alkylene, -C_2-4 alkenylene, -C_2-4 alkynylene, -NR^a, -NR^a -C_1-4 alkylene-, -S-, -S(O)-, -S(O)₂-, -C(O)-, -C(O)-O- or -OC(O)-; (k) L represents a heteroaryl having from 5 to 10 ring atoms, wherein from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen, C_{3- 12} cycloalkyl, heterocycloalkyl, which denotes a free non-aromatic radical having from 3 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen, or 1,2,3,6-tetrahydropyridinyl, each of which may be substituted with 0-5 R^x ; (l) A² represents a chemical bond, -O-, -NR^a-, -C_1-4 -alkyl-NR^a-, -C(O)-, -C_1-4 alkyl-C(O)-, -OC(O)-, -C_1-4 alkyl-OC(O)-, -C(O)-O-, -C_1-4 alkyl-C(O)-O-, -OC(O) -O-, -S(O)₂-, -NR^a-S(O)-, -C_1-4 -alkyl-NR^a-S(O)-, -NR^a-S(O)₂-, -C_1-4 -alkyl-NR ^a -S(O)₂-, -C(O)-NR^a-, -C_1-4 alkyl-C(O)-NR^a-, -NR ^a -C( O)-, -C_1-4-alkyl-NR^a-C(O)-, -OC(O)-NR^a-, -C_1-4 -alkyl-OC(O)-NR^a-, -NR^a-C(O)-O-, -NR^a-C(O)-NR^a-, -NR^a-CH ₂ -C(O)-NR^a-, -O-CH₂-C(O)- NR^a-, -C(O)-O-CH₂-C(O)- or -C(O)-NR^a-CH₂ -C(O)-; (m) R⁴ represents -OH, C_1-6 alkyl, C_2-6 alkenyle, C_2-6 alkynyle, C_3-9 cycloalkyl, heterocycloalkyl, which denotes a free non-aromatic radical having from 3 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen, naphthyl or heteroaryl, where the said heteroaryl is selected from the group consisting of imidazolyl, pyrimidinyl, pyridinyl, pyrazinyl, oxadiazolyl, thiadiazolyl and thiazolyl, where each alkyl, cycloalkyl, heterocycloalkyl, phenyl, naphthyl or heteroaryl R⁴ is substituted with 0-5 substituents R⁵; (n) R⁵ represents OH, halogen, CO₂H, C_1-4 alkyl, C_2-6 alkynyle, C_1-4 alkoxy, C_1-4 haloalkyl, -O-C_1-4 haloalkyl, -C_1-4 alkyl-O-C_1-4 alkyl, -S-C_1-4 alkyl, -S(O)₂-C_1-4 alkyl, -S(O)-C_1-4 alkyl, -N(R^a)₂, -CH₂N(R^a)₂, -N(R^a)-S(O)-C_1-4 alkyl, -N(R^a)-S(O)₂-C_1-4 alkyl, -NO₂, -CN, -CH₂CN, C_3-9 cycloalkyl, -O-C_3-9 cycloalkyl, -C_1-4 alkyl-C_3-9 cycloalkyl, -O-C_1-4 alkyl-C_3-9 cycloalkyl, -C_1-4 alkyl-O-C_1-4 haloalkyl, heterocycloalkyl, which denotes a free non-aromatic radical, having from 3 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen, -C_1-4 alkyl-heterocycloalkyl, phenyl, naphthyl, -O-phenyl, -O-naphthyl, heteroaryl, where heteroaryl denotes heteroaromatic ring, having from 5 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen, -O-heteroaryl, C_1-4-alkyl-heteroaryl, aralkyl or -O-aralkyl, where each alkyl, phenyl, naphthyl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 substituents R^w; (o) each R^w independently represents halogen, -OH, C_1-4 alkyl, C_1-4 haloalkyl or -C_1-4 alkoxy; and (p) each R^x independently represents halogen, -OH, C_1-4 alkyl, -C_1-4 alkoxy, -C_1-4 alkyl-O-C_1-4 alkyl, -C(O)-N(R^a)₂, -O-C(O)-N(R^a)₂, -N(R^a)₂, -CH₂N(R^a)₂, heterocycloalkyl, which denotes a free non-aromatic radical, having from 3 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen, -O-heterocycloalkyl, -O-phenyl, -O-naphthyl or -O-heteroaryl, where heteroaryl denotes heteroaromatic ring, having from 5 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen. The invention also relates to a pharmaceutical composition for the treatment of lysosomal storage disease based on these compounds.

EFFECT: new compounds and a pharmaceutical composition based on them have been obtained, which can be used in medicine for the treatment of lysosomal storage disease, in particular Krabbe disease (KD) and metachromatic leukodystrophy (MLD).

26 cl, 4 tbl, 858 ex

Description

This application is an international application claiming priority to U.S. Provisional Patent Application No. 62/739,405, filed Oct. 1, 2018, the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE ART

[0001] Uridine 5-diphosphate (UDP)-glycosyltransferase 8 (UGT8) is an enzyme from the UDP-glycosyltransferase family of enzymes. UGT8 catalyzes the transfer of galactose to ceramide, a key enzymatic step in galactoylceramide biosynthesis. These molecules are numerous sphingolipids of the myelin membrane of the central and peripheral nervous systems. Galactocerebrosides also serve as precursors in the biosynthetic pathway of glycosphingolipid metabolism and are further modified by cerebroside sulfotransferase, an enzyme that converts galactocerebrosides to sulfatides. Sulfatides are also extremely important components of the central nervous system (CNS) and peripheral nervous system (PNS) as a component of myelin, which is an important insulator sheath surrounding axons as a bilayer membrane. Inadequate recycling of sulfatides can lead to changes in myelin structure, which affects the physiological transmission of electrical impulses between nerve cells.

[0002] Krabbe disease (KD) is a lysosomal storage disease in which galactosylceramide (a specific galactocerebroside) and psychosine fail to be adequately degraded due to deficiency of the enzyme galactosylceramidase. To correct the balance between the formation and degradation of galactosylceramide and psychosine, reduction of glycosphingolipid biosynthesis through inhibition of UGT8 is considered a proven therapeutic approach.

[0003] Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficiency of arylsulfatase A (ASA), a lysosomal sulfatase that hydrolyzes the 3-O ester bond of sulfatides, including 3-O-sulfogalactosylceramide and 3-O-sulfolactosylceramide . The deficiency seen in metachromatic leukodystrophy (MLD) causes accumulation of sulfatides in the central nervous system (CNS) and peripheral nervous system (PNS.) In order to allow correction of the resulting accumulation of sulfatides, a therapeutic approach similar to Krabbe's has been proposed, consisting of inhibition of UGT8 ( resulting in inhibition of sulfatide production).

[0004] Despite the accumulated scientific evidence and ongoing research, both in the case of Krabbe disease and in the case of metachromatic leukodystrophy (MLD), there are currently no drugs available to cure these fatal and disabling diseases. Thus, there is a need to find new compounds and new therapeutic methods, as well as new methods to treat or reduce the severity of Krabbe disease, metachromatic leukodystrophy (MLD) and other UGT8-related conditions and diseases in the patient.

SUMMARY OF THE INVENTION

[0005] In one aspect, the present invention provides a compound of formula (I):

(I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

(a) X ² represents CR ² or N;

(b) X ⁵ represents CR ⁷ or N;

(c) X ⁶ represents CR ¹ or N;

(d) Y is -CN, C _1-4 alkyl, -C(O)NR ^a R ^b , -NR ^a -C(O)-R ^b , -C(O)OR ^a , -C(O) R ^a , heteroaryl or -S(O) ₂ NR ^a R ^b , where C _1-4 alkyl or heteroaryl can be substituted with 0-3 substituents R ^z ;

(e) each R ^a is independently H, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkyl-C _3-9 cycloalkyl or C _3-9 cycloalkyl;

(f) each R ^b is independently C _1-4 alkyl, C _1-4 alkoxy, C _3-9 cycloalkyl or C _1-4 alkyl-C _1-4 alkoxy; or

when Y is -C(O)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 R ^x substituents;

(g) R ⁷ represents hydrogen, C _1-4 alkyl, C _1-4 alkoxy, -S(O) ₂ -NR ^a R ^b - or heteroaryl;

(h) R ¹ is hydrogen, halogen, -OH, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, -NH _3, -NH(C _1-4 alkyl ) or -N(C _1-4 alkyl) ₂ , C _3-9 cycloalkyl or heterocycloalkyl, where each -NH(C _1-4 alkyl), cycloalkyl or heterocycloalkyl is substituted with 0-5 R ^x substituents;

(i) R ² is hydrogen, halogen, -OH, C _1-4 alkyl, C _1-4 alkoxy or C _3-9 cycloalkyl;

(j) A ¹ represents a chemical bond, C _1-4 alkylene, -O-, -OC _1-4 alkylene, -C _2-4 alkenylene, -C _2-4 alkynylene, -NR ^a , -NR ^a -C _1-4 alkylene-, -S-, -S(O)-, -S(O) ₂ -, -C(O)-, -C(O)-O- or -OC(O)-;

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

(l) A ² represents a chemical bond, -O-, -NR ^a -, -C _1-4 -alkyl-NR ^a -, -C(O)-, -C _1-4 alkyl-C(O)- , -OC(O)-, -C _1-4 alkyl-OC(O)-, -C(O)-O-, -C _1-4 alkyl-C(O)-O-, -OC(O) -O-, -S(O) ₂ -, -NR ^a -S(O)-, -C _1-4 -alkyl-NR ^a -S(O)-, -NR ^a -S(O) ₂ -, -C _1-4 -alkyl-NR ^a -S(O) ₂ -, -C(O)-NR ^a -, -C _1-4 alkyl-C(O)-NR ^a -, -NR ^a -C( O)-, -C _1-4 -alkyl-NR ^a -C(O)-, -OC(O)-NR ^a -, -C _1-4 -alkyl-OC(O)-NR ^a -, -NR ^a -C(O)-O- or -NR ^a -C(O)-NR ^a -, -NR ^a -CH ₂ -C(O)-NR ^a -, -O-CH ₂ -C(O)- NR ^a -, -C(O)-O-CH ₂ -C(O)-, -C(O)-NR ^a -CH ₂ -C(O)-;

(m) R ⁴ is hydrogen, -OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-9 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, where each alkyl, cycloalkyl, heterocycloalkyl, the aryl or heteroaryl of R ⁴ is substituted with 0-5 R ⁵ substituents;

(n) R ⁵ is OH, halogen, CO ₂ H, C _1-4 alkyl, C _2-6 alkynyl, C _1-4 alkoxy, C _1-4 haloalkyl, -OC _1-4 haloalkyl, -C _{1- 4} alkyl-OC _1-4 alkyl, -SC _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -S(O)-C _1-4 alkyl, -N(R ^a ) ₂ , - CH ₂ N(R ^a ) ₂ , -N(R ^a )-S(O)-C _1-4 alkyl, -N-(R ^a )-S(O) ₂ -C _1-4 alkyl, -NO ₂ , -CN, -CH ₂ CN, C _3-9 cycloalkyl, -OC _3-9 cycloalkyl, -C _1-4 alkyl-C _3-9 cycloalkyl, -OC _1-4 alkyl-C _3-9 cycloalkyl, -C _1-4 alkyl-OC _1-4 haloalkyl, heterocycloalkyl, -C _1-4 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 R ^w ;

(o) each R ^w is independently halogen, -OH, C _1-4 alkyl, C _1-4 haloalkyl or -C _1-4 alkoxy;

(p) each R ^x is independently halogen, -OH, C _1-4 alkyl, -C _1-4 alkoxy, -C _1-4 alkyl-OC _1-4 alkyl, -C(O)-N(R ^a ) ₂ , -OC(O)-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, halogen, -OH, C _1-4 alkyl, C _1-4 alkoxy or C _3-9 cycloalkyl.

[0006] The invention further describes various embodiments. It should be understood that the features specified in each embodiment may be combined with other specified features to form additional embodiments.

[0007] In some embodiments of the present invention, the compound of formula I may be a compound of formula Ia, shown below:

(Ia).

[0008] In some embodiments of the present invention, the compound of formula I may be a compound of formula Ib, shown below:

(Ib).

[0009] In some embodiments of the present invention, the compound of formula I may be a compound of formula Ic, shown below:

(Ic).

[0010] In some embodiments of the present invention, the compound of formula I may be a compound of formula Id, shown below:

(Id).

[0011] In some embodiments of the present invention, the compound of formula I may be a compound of formula Ie, shown below:

(Ie).

[0012] In some embodiments of the present invention, the compound of formula I may be a compound of formula If, shown below:

(If).

[0013] In some embodiments of the present invention, a compound of Formula I may be a compound of Formula II, IIa, IIb, or IIc, as shown below:

(II), (IIa),

(IIb), (IIc).

[0014] In some embodiments of the present invention, a compound of Formula I may be a compound of Formula III, IIIa, IIIb, or IIIc, as shown below:

(III), (IIIa),

(IIIb), (IIIc).

DETAILED DESCRIPTION OF THE INVENTION

[0015] The following is a description of embodiments of the invention.

[0016] In one aspect, the present invention provides a compound (compound 1) of formula (I):

(I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

(a) X ² represents CR ² or N;

(b) X ⁵ represents CR ⁷ or N;

(c) X ⁶ represents CR ¹ or N;

(d) Y is -CN, C _1-4 alkyl, -C(O)NR ^a R ^b , -NR ^a -C(O)-R ^b , -C(O)OR ^a , -C(O) R ^a , heteroaryl or -S(O) ₂ NR ^a R ^b , where C _1-4 alkyl or heteroaryl can be substituted with 0-3 substituents R ^z ;

(e) each R ^a is independently H, C _1-4 alkyl, C _1-4 haloalkyl, -C _1-4 alkyl-C _3-9 cycloalkyl or C _3-9 cycloalkyl;

(f) each R ^b is independently C _1-4 alkyl, C _1-4 alkoxy, C _3-9 cycloalkyl or -C _1-4 alkyl-C _1-4 alkoxy; or when Y is -C(O)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 R ^x ;

(g) R ⁷ represents hydrogen, C _1-4 alkyl, C _1-4 alkoxy, -S(O) ₂ -NR ^a R ^b - or heteroaryl;

(h) R ¹ is hydrogen, halogen, -OH, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, -NH _3, -NH(C _1-4 alkyl ) or -N(C _1-4 alkyl) ₂ , C _3-9 cycloalkyl or heterocycloalkyl, where each -NH(C _1-4 alkyl), cycloalkyl or heterocycloalkyl is substituted with 0-5 R ^x substituents;

(i) R ² is hydrogen, halogen, -OH, C _1-4 alkyl, C _1-4 alkoxy or C _3-9 cycloalkyl;

(j) A ¹ represents a chemical bond, C _1-4 alkylene, -O-, -OC _1-4 alkylene, -C _2-4 alkenylene, -C _2-4 alkynylene, -NR ^a , -NR ^a -C _1-4 alkylene-, -S-, -S(O)-, -S(O) ₂ -, -C(O)-, -C(O)-O- or -OC(O)-;

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

(l) A ² represents a chemical bond, -O-, -NR ^a -, -C _1-4 -alkyl-NR ^a -, -C(O)-, -C _1-4 alkyl-C(O)- , -OC(O)-, -C _1-4 alkyl-OC(O)-, -C(O)-O-, -C _1-4 alkyl-C(O)-O-, -OC(O) -O-, -S(O) ₂ -, -NR ^a -S(O)-, -C _1-4 -alkyl-NR ^a -S(O)-, -NR ^a -S(O) ₂ -, -C _1-4 -alkyl-NR ^a -S(O) ₂ -, -C(O)-NR ^a -, -C _1-4 alkyl-C(O)-NR ^a -, -NR ^a -C( O)-, -C _1-4 -alkyl-NR ^a -C(O)-, -OC(O)-NR ^a -, -C _1-4 -alkyl-OC(O)-NR ^a -, -NR ^a -C(O)-O- or -NR ^a -C(O)-NR ^a -, -NR ^a -CH ₂ -C(O)-NR ^a -, -O-CH ₂ -C(O)- NR ^a -, -C(O)-O-CH ₂ -C(O)-, -C(O)-NR ^a -CH ₂ -C(O)-;

(m) R ⁴ is hydrogen, -OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-9 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, where each alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R ⁴ is substituted with 0-5 R ⁵ substituents;

(n) R ⁵ is OH, halogen, CO ₂ H, C _1-4 alkyl, C _2-6 alkynyl, C _1-4 alkoxy, C _1-4 haloalkyl, -OC _1-4 haloalkyl, -C _{1- 4} alkyl-OC _1-4 alkyl, -SC _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -S(O)-C _1-4 alkyl, -N(R ^a ) ₂ , - CH ₂ N(R ^a ) ₂ , -N(R ^a )-S(O)-C _1-4 alkyl, -N-(R ^a )-S(O) ₂ -C _1-4 alkyl, -NO ₂ , -CN, -CH ₂ CN, C _3-9 cycloalkyl, -OC _3-9 cycloalkyl, -C _1-4 alkyl-C _3-9 cycloalkyl, -OC _1-4 alkyl-C _3-9 cycloalkyl, -C _1-4 alkyl-OC _1-4 haloalkyl, heterocycloalkyl, -C _1-4 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 R ^w ;

(o) each R ^w is independently halogen, -OH, C _1-4 alkyl, C _1-4 haloalkyl or -C _1-4 alkoxy;

(p) each R ^x is independently halogen, -OH, C _1-4 alkyl, -C _1-4 alkoxy, -C _1-4 alkyl-OC _1-4 alkyl, -C(O)-N(R ^a ) ₂ , -OC(O)-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, halogen, -OH, C _1-4 alkyl, C _1-4 alkoxy or C _3-9 cycloalkyl.

[0017] In specific embodiments of the first aspect, the present invention further provides:

1.1 Compound 1, where X ⁶ represents N.

1.2 Compound 1, where X ⁶ represents CR ¹ .

1.3 Compound 1, 1.1 or 1.2, where X ² represents N.

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

1.5 Any of connection 1 or 1.1 and subsequent connections, where X² represents CR², and X⁶ represents N (formula Ia).

1.6 Any of compound 1 or 1.1 and subsequent compounds where X ² is N and X ⁶ is CR ¹ (formula Ib).

1.7 Any of connection 1 or 1.1 and subsequent connections, where X² represents CR², and X⁶ represents CR¹(formula Ic).

1.8 Any of connection 1 or 1.1 and subsequent connections, where X² represents CR², and X⁶ represents N, and X⁵ represents CR⁷(formula Id).

1.9 Any of compound 1 or 1.1 and subsequent compounds where 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 and subsequent compounds where X ² is CR ² and X ⁶ is CR ¹ and X ⁵ is CR ⁷ (Formula If).

1.11 Any of compound 1 or 1.1 and subsequent compounds where R ² represents hydrogen, C _1-4 alkyl (eg, methyl) or halogen (eg, fluorine, chlorine or bromine).

1.12 Any of connection 1 or 1.1-1.11. where R ² represents hydrogen.

1.13 Any of connection 1 or 1.1-1.11. where R ² represents halogen, where optionally R ² is selected from fluorine, chlorine and bromine.

1.14 Any of connection 1 or 1.1-1.11. where R ² represents C _1-4 alkyl, where R ² optionally represents methyl.

1.15 Any of connection 1 or 1.1-1.11. where R ² represents C _1-4 alkoxy, where optionally R ² represents methoxy.

1.16 Any of connection 1 or 1.1-1.11. where R ² represents C _3-9 cycloalkyl, where optionally R ² represents cyclopropyl.

1.17 Any of connection 1 or 1.1-1.11. where R ² represents hydroxyl.

1.18 Any of compound 1 or 1.1 and subsequent compounds wherein R ⁷ is C _1-4 alkyl, where optionally R ⁷ is methyl.

1.19 Any of compound 1 or 1.1-1.17, where R ⁷ represents hydrogen.

1.20 Any of compound 1 or 1.1 and subsequent compounds where Y is CN.

1.21 Any of compound 1 or 1.1 and subsequent compounds where Y is -C(O)R ^a .

1.22 Connection 1.21. where R ^a represents hydrogen.

1.23 Connection 1.21. where R ^a represents C _1-4 alkyl, where optionally R ^a represents methyl, or R ^a represents ethyl.

1.24 Any of compound 1 or 1.1 and subsequent compounds where Y is -NR ^a -C(O)-R ^b .

1.25 Compound 1.24, wherein R ^a is hydrogen and R ^b is C _1-4 alkyl or C _1-4 alkoxy.

1.26 Compound 1.24, wherein R ^a is hydrogen and R ^b is C _1-4 alkyl, where optionally R ^b is methyl.

1.27 Compound 1.24, wherein R ^a is hydrogen and R ^b is C _1-4 alkoxy, where optionally R ^b is methoxy or R ^b is tert-butoxy.

1.28 Any of compound 1 or 1.1 and subsequent compounds where Y is heteroaryl substituted with 0-3 R ² substituents, for example where Y is heteroaryl substituted with 0 R ² substituents and Y is heteroaryl substituted by 1 R ² substituent, where optionally any one or more R ² substituents are the same or different.

1.29 Compound 1.28 wherein Y is oxazolyl (eg, 2-oxazolyl) substituted with 1 R ² substituent, wherein optionally Y is 4-methyl-2-oxazolyl or 5-methyl-2-oxazolyl.

1.30 Any of compound 1 or 1.1 and subsequent compounds where Y is -C(O)OR ^a .

1.31 Compound 1.30, where R ^a is hydrogen

1.32 Compound 1.30, wherein R ^a is C _1-4 alkyl (eg, methyl or t-butyl), where optionally Y is -C(O)OMe.

1.33 Any of compound 1 or 1.1 and subsequent compounds wherein Y is C _1-4 alkyl substituted with 0-3 R ² substituents, where optionally any one or more R ² substituents are the same or different.

1.34 Compound 1.33, wherein Y is C _1-4 alkyl (e.g., methyl or propyl) substituted with 0 R ² substituents or with 1 R ² substituent, where optionally Y is methyl or propyl substituted with 0 R ² substituents or using 1 R ² substituent.

1.35 Compound 1.34 wherein R ² is -OH, where optionally Y is 1-hydroxypropyl.

1.36 Any of compound 1 or 1.1 and subsequent compounds where Y is -C(O)NR ^a R ^b .

1.37 Compound 1.36, wherein R ^a is C _1-4 alkyl (eg, methyl) and R ^b is C _1-4 alkyl (eg, methyl).

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

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

1.40 Compound 1.38 or 1.39, where R ^x is a halogen (eg chlorine).

1.41 Compound 1.38 or 1.39 wherein R ^x is C _1-4 alkoxy (eg methoxy).

1.42 Compound 1.38 or 1.39, where R ^x is -O-heteroaryl (eg, -O-2-pyridyl).

1.43 Compound 1.36, wherein R ^a is hydrogen and R ^b is C _1-4 alkyl, C _1-4 alkoxy, C _3-9 cycloalkyl, or C _1-4 alkyl-C _1-4 alkoxy.

1.44 Compound 1.43, wherein R ^a is hydrogen and R ^b is C _1-4 alkoxy (eg, methoxy).

1.45 Compound 1.43, wherein R ^a is hydrogen and R ^b is C _3-9 cycloalkyl (eg, cyclopropyl).

1.46 Compound 1.43, wherein R ^a is hydrogen and R ^b is C _1-4 alkyl-C _1-4 alkoxy (eg, 2-methoxyethyl).

1.47 Compound 1.43, wherein R ^a is hydrogen and R ^b is C _1-4 alkyl (e.g., methyl, ethyl, propyl, isopropyl or n-butyl), where optionally 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 n-butyl, or R ^a is hydrogen and R ^b is methyl.

1.48 Any of compound 1 or 1.1 and subsequent compounds where X ² is CR ² , X ⁶ is CR ^1. X ⁵ is CR ⁷ , and R ⁷ is hydrogen, and Y is -C(O)NR ^a R ^b and R ^a is hydrogen and R ^b is methyl (formula II).

1.49 Compound 1.48, where R ² represents hydrogen (formula IIa).

1.50 Any of compound 1 or 1.1 and subsequent compounds where X ² is CR ² , X ⁶ is CR ^1. X ⁵ is CR ⁷ , and R ⁷ is hydrogen, and Y is -C(O)OR ^a and R ^a is methyl (formula IIb).

1.51 Compound 1.50, where R ² represents hydrogen (formula IIc).

1.52 Any of compound 1 or 1.1 and the following compounds, where R ¹ represents hydrogen, halogen, (eg, chlorine), C _1-4 haloalkyl (eg, difluoromethyl or trifluoromethyl).

1.53 Compound 1.52, where R ¹ represents hydrogen.

1.54 Compound 1.52, wherein R ¹ is halogen, where optionally R ¹ is chlorine.

1.55 Any of compound 1 or 1.1 and subsequent compounds where R ¹ represents -OH.

1.56 Any of compound 1 or 1.1 and subsequent compounds where R ¹ represents -NH(C _1-4 alkyl) (for example, -NHMe).

1.57 Any of compound 1 or 1.1 and subsequent compounds where R ¹ is -N(C _1-4 alkyl) ₂ (for example, -N(Me) ₂ ).

1.58 Any of compound 1 or 1.1 and subsequent compounds wherein R ¹ is C _3-9 cycloalkyl substituted with 0 to 3 R ^x substituents, where optionally R ¹ is C _3-9 cycloalkyl substituted with 0 substituents R ^x .

1.59 Compound 1.58, where R ¹ is cyclopropyl or cyclopentyl substituted with 0 R ^x substituents.

1.60 Any of compound 1 or 1.1 and subsequent compounds wherein R ¹ is heterocycloalkyl (eg, azetidinyl) substituted with 0-3 R ^x substituents.

1.61 Compound 1.60, wherein R ¹ is azetidinyl substituted with 0 to 3 R ^x substituents, wherein optionally R ¹ is azetidinyl substituted with 0 or 2 R ^x substituents.

1.62 Any of compounds 1.58-1.61. where each R ^x is independently a halogen (eg fluorine), for example where R ¹ is 2,2-difluoroazetidinyl.

1.63 Any of compound 1 or 1.1 and subsequent compounds wherein R ¹ is C _1-4 alkyl (for example, methyl, isopropyl or t-butyl), where optionally R ¹ is methyl, or R ¹ is isopropyl, or R ¹ is tert-butyl.

1.64 Any of compound 1 or 1.1 and subsequent compounds wherein R ¹ is C _1-4 alkoxy, where optionally R ¹ is methoxy.

1.65 Any of compound 1 or 1.1 and subsequent compounds wherein R ¹ is a C _1-4 haloalkoxy (for example, difluoromethoxy or 2,2,2-trifluoroethoxy), where optionally R ¹ is difluoromethoxy, or where R ¹ is is 2,2,2-trifluoroethoxy.

1.66 Any of compound 1 or 1.1 and subsequent compounds wherein R ¹ is a C _1-4 haloalkyl, where optionally R ¹ is trifluoromethyl or difluoromethyl, or 1.1-difluoroethyl.

1.67 Any of compound 1 or 1.1 and subsequent compounds 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 is -C(O)NR ^a R ^b and R ^a is hydrogen and R ^b is methyl (formula III).

1.68 Compound 1.67, where R ² represents hydrogen (formula IIIa).

1.69 Any of compound 1 or 1.1 and the following compounds, where X ² represents CR ² , X ⁶ represents CR ¹ , and R ¹ represents trifluoromethyl, X ⁵ represents CR ⁷ , and R ⁷ represents hydrogen, and Y represents is -C(O)OR ^a and R ^a is methyl (formula IIIb).

1.70 Compound 1.69, where R ² represents hydrogen (formula IIIc).

1.71 Any of compound 1 or 1.1 and subsequent compounds where A ¹ represents -O-, C _1-4 alkylene, -OC _1-4 alkylene, a chemical bond, -OC(O)-, -C(O)-, -S-, -S(O)-, -S(O) ₂ -, C _2-4 alkylene, -NR ^a - or -NR ^a -C _1-4 alkylene.

1.72 Connection 1.71. where A ¹ represents a chemical bond, -O-, -OC _1-4 alkylene or C _1-4 alkylene.

1.73 Compound 1.72, where A ¹ represents a chemical bond or -O-.

1.74 Compound 1.73, where A ¹ represents a chemical bond.

1.75 Compound 1.73, where A ¹ represents -O-.

1.76 Compound 1.72, wherein A ¹ is C _1-4 alkylene, where optionally A ¹ is -CH ₂ - or -CH(CH ₃ )-.

1.77 Any of compound 1 or 1.1 and subsequent compounds where A ¹ is -OC(O)-.

1.78 Any of compound 1 or 1.1 and subsequent compounds where A ¹ is -S-, or A ¹ is -S(O) ₂ -, or A ¹ is -S(O)-.

1.79 Any of compound 1 or 1.1 and subsequent compounds wherein A ¹ is C _2-4 alkynylene, where optionally A ¹ is -C≡C- or -C≡C-CH ₂ -.

1.80 Any of compound 1 or 1.1 and subsequent compounds where A ¹ is -NR ^a -.

1.81 Any of compound 1 or 1.1 and the following compounds, where A ¹ represents -NR ^a -C _1-4 alkylene-.

1.82 Any of compound 1 or 1.1 and subsequent compounds where A ¹ is -NR ^a -CH ₂ -.

1.83 Any of compound 1 or 1.1 and the following compounds, where L represents aryl or heteroaryl, each of which is optionally substituted with 0-3 R ^x substituents.

1.84 Any of compound 1 or 1.1 and subsequent compounds, where L represents C _3-12 cycloalkyl, optionally substituted with 0-3 R ^x substituents.

1.85 Any of compound 1 or 1.1 and subsequent compounds, where L represents 3-12 membered heterocycloalkyl or 3-12 membered heterocycloalkenyl, optionally substituted with 0-3 R ^x substituents.

1.86 Any of compound 1 or 1.1 and subsequent compounds, where L is selected from:

where and each of the fragments L is substituted with 0-5 substituents R ^x .

1.87 Any of compound 1 or 1.1 and subsequent compounds where L is substituted with 1 R ^x substituent, or with 2 R ^x substituents, or with 3 R ^x substituents, or with 4 R ^x substituents.

1.88 Any of compound 1 or 1.1 and subsequent compounds, where L is selected from any one of:

1.89 Any of compound 1 or 1.1 and subsequent compounds, where L is selected from any one of:

1.90 Any of compound 1 or 1.1 and subsequent compounds, where L is selected from any one of:

1.91 Any of compound 1 or 1.1 and subsequent compounds, where L is selected from any one of:

1.92 Any of compound 1 or 1.1 and subsequent compounds, where L is selected from any one of:

1.93 Any of compound 1 or 1.1 and subsequent compounds, where L represents .

1.94 Any of compound 1 or 1.1 and subsequent compounds, where L represents

1.95 Any of compound 1 or 1.1 and subsequent compounds, where L represents .

1.96 Any of compound 1 or 1.1 and subsequent compounds, where L represents

1.97 Any of compound 1 or 1.1 and subsequent compounds, where L represents

1.98 Any of compound 1 or 1.1 and subsequent compounds, where L represents

1.99 Any of compound 1 or 1.1 and subsequent compounds, where L represents

1.100 Any of compound 1 or 1.1 and subsequent compounds, where L represents .

1.101 Any of compound 1 or 1.1 and subsequent compounds, where L represents .

1.102 Any of compound 1 or 1.1 and subsequent compounds, where L represents .

1.103 Any of compound 1 or 1.1 and subsequent compounds, where L represents .

1.104 Any of compound 1 or 1.1 and subsequent compounds, where L represents .

1.105 Any of compound 1 or 1.1 and subsequent compounds, where L represents .

1.106 Any of compound 1 or 1.1 and subsequent compounds, where L represents .

1.107 Any of compound 1 or 1.1 and subsequent compounds, where L represents .

1.108 Any of compound 1 or 1.1 and subsequent compounds, where L represents .

1.109 Any of compound 1 or 1.1 and subsequent compounds, where L represents .

1.110 Any of compound 1 or 1.1 and subsequent compounds, where L represents .

1.111 Any of compound 1 or 1.1 and subsequent compounds, where L represents .

1.112 Any of compound 1 or 1.1 and subsequent compounds, where L represents .

1.113 Any of compound 1 or 1.1 and subsequent compounds, where A ² represents the chemical bond, -C(O)-O-, -OC(O)-NR ^a -, -OC(O)-, -O-, - C(O)-, -NR ^a -C(O)-O-, -NR ^a -C(O)-NR ^a -, -C(O)-NR ^a -, -C _1-4 alkyl-C( O)-NR ^a -, -C _1-4 alkyl-OC(O)-NR ^a -, -OC(O)-O-, -NR ^a -C(O)-, -NR ^a -, -S( O) ₂ -, -C _1-4 alkyl-C(O)-, -C _1-4 alkyl-NR ^a -, -C _1-4 alkyl-NR ^a -S(O)- or -C _1-4 alkyl-C(O)-O-.

1.114 Compound 1.113, where A ² represents the chemical bond, -C(O)-O-, -OC(O)-NR ^a -, -OC(O)-, -O-, -NR ^a -C(O) -O-, -C _1-4 alkyl-C(O)-NR ^a -, -C _1-4 alkyl-OC(O)-NR ^a - or -NR ^a -.

1.115 Compound 1.113, where A ² represents -OC(O)-O.

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

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

1.118 Compound 1.113, where A ² is -S(O) ₂ -.

1.119 Compound 1.113, wherein A ² is -C(O)-NR ^a -, where, optionally, R ^a is H, or where, optionally, R ^a is C _1-4 alkyl (for example, methyl or ethyl) .

1.120 Compound 1.119, where A ² represents -C(O)-NH-, -C(O)-N(Me)- or -C(O)-N(Et)-.

1.121 Compound 1.113, wherein A ² is -NR ^a -C(O)-NR ^a -, where optionally both R ^a are H.

1.122 Compound 1.113 wherein A ² is -C _1-4 alkyl-C(O)-, where optionally A ² is -CH ₂ -C(O)-, or A ² is -CH(CH ₃ )-C(O)-.

1.123 Compound 1.113, where A ² represents -C _1-4 alkyl-NR ^a -.

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

1.125 Compound 1.123 wherein R ^a is C _1-4 alkyl, where optionally R ^a is methyl, for example where A ² is -C _1-4 alkyl-N(Me)-, for example A ² is is -CH ₂ -N(Me)-.

1.126 Compound 1.113 wherein A ² is -C _1-4 alkyl-NR ^a -S(O)-, where optionally R ^a is H, for example where A ² is -CH ₂ -NH-S( O)-.

1.127 Compound 1.113 wherein A ² is -C _1-4 alkyl-C(O)-O-, where optionally A ² is -CH ₂ -C(O)-O- or -CH(CH ₃ ) -C(O)-O-.

1.128 Compound 1.113 wherein A ² is -C _1-4 alkyl-OC(O)-NR ^a -, where optionally R ^a is H, for example where A ² is -CH ₂ -OC(O) -NH-.

1.129 Compound 1.113, where A ² represents -C _1-4 alkyl-C(O)-NR ^a -.

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

1.131 Compound 1.129, where R ^a represents C _1-4 alkyl (for example, methyl), for example, where A ² represents -CH ₂ -C(O)-N(Me)-,

1.132 Compound 1.113, where or A ² represents -C(O)-.

1.133 Compound 1.113, where A ² represents -O-.

1.134 Compound 1.113 wherein A ² is -NR ^a -C(O)-O-, where optionally R ^a is H, or where R ^a is C _1-4 alkyl, for example where A ² is -N(Me)-C(O)-O-.

1.135 Compound 1.113, where A ² represents a chemical bond.

1.136 Compound 1.113, where A ² represents -OC(O)-.

1.137 Compound 1.113, where A ² represents -OC(O)-NR ^a -, where optionally R ^a represents H, or where R ^a represents C _1-4 alkyl (for example, methyl, ethyl or isopropyl), for example, where A ² is -OC(O)-N(Me)-, or A ² is -OC(O)-N(Et)-, or A ² is -OC(O)-N(iPr )-.

1.138 Compound 1.113, where A ² represents -C(O)-O-.

1.139 Any of compound 1 or 1.1 and subsequent compounds where R ⁴ represents hydrogen.

1.140 Any of compound 1 or 1.1 and subsequent compounds where R ⁴ represents -OH.

1.141 Any of compound 1 or 1.1 and the following compounds, where R ⁴ represents C _1-6 alkyl, C _2-6 alkynyl, heterocycloalkyl, C _3-9 cycloalkyl or heteroaryl, each of which is optionally substituted with 0-5 R substituents ⁵ , wherein, optionally, any one or more R ⁵ are the same or different.

1.142 Connection 1.141. where R ⁴ represents C _1-6 alkyl, substituted with 0-5 R ⁵ substituents.

1.143 Compound 1.142, where R ⁴ is C _1-6 alkyl substituted with 0 R ⁵ substituents, or with 1 R ⁵ substituent, or with 2 R ⁵ substituents, or with 3 R ⁵ substituents, or with 4 ^R5 substituents, or using 5 ^R5 substituents.

1.144 Compound 1.142 or 1.143, where the C _1-6 alkyl for R ⁴ is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, 3,3-dimethylbutyl or 4-methylpentan-2-yl.

1.145 Compound 1.142 or 1.143, wherein C _1-6 alkyl for R ⁴ is methyl.

1.146 Compound 1.142 or 1.143, wherein the C _1-6 alkyl for R ⁴ is ethyl.

1.147 Compound 1.142 or 1.143, wherein the C _1-6 alkyl for R ⁴ is n-propyl.

1.148 Compound 1.142 or 1.143, wherein the C _1-6 alkyl for R ⁴ is isopropyl.

1.149 Compound 1.142 or 1.143, wherein the C _1-6 alkyl for R ⁴ is isobutyl.

1.150 Compound 1.142 or 1.143, wherein the C _1-6 alkyl for R ⁴ is sec-butyl.

1.151 Compound 1.142 or 1.143, wherein the C _1-6 alkyl for R ⁴ is t-butyl.

1.152 Compound 1.142 or 1.143, wherein the C _1-6 alkyl for R ⁴ is isopentyl.

1.153 Compound 1.142 or 1.143, wherein the C _1-6 alkyl for R ⁴ is n-pentyl.

1.154 Compound 1.142 or 1.143, wherein the C _1-6 alkyl for R ⁴ is neopentyl.

1.155 Compound 1.142 or 1.143, wherein the C _1-6 alkyl for R ⁴ is 4-methylpentan-2-yl.

1.156 Compound 1.142 or 1.143, where the C _1-6 alkyl for R ⁴ is 3,3-dimethylbutyl.

1.157 Any of compounds 1.144-1.156 wherein the indicated C _1-6 alkyl for R ⁴ is substituted with 0 R ⁵ substituents.

1.158 Any of compounds 1.144-1.156, wherein the indicated C _1-6 alkyl for R ⁴ is replaced by 1 R ⁵ substituent.

1.159 Any of compounds 1.144-1.156 wherein the indicated C _1-6 alkyl for R ⁴ is substituted with 2 R ⁵ substituents.

1.160 Any of compounds 1.144-1.156 wherein the indicated C _1-6 alkyl for R ⁴ is substituted with 3 R ⁵ substituents.

1.161 Connection 1.141. where R ⁴ represents C _2-6 alkynyl, substituted with 0-5 R ⁵ substituents.

1.162 Connection 1.161. where R ⁴ is C _2-6 alkynyl substituted with 0 R ⁵ substituents, or 1 R ⁵ substituent, or 2 R ⁵ substituents, or 3 R ⁵ substituents, or 4 R ⁵ substituents , or using 5 R ⁵ substituents.

1.163 Compound 1.161 or 1.162, wherein the C _2-6 alkynyl for R ⁴ is selected from ethynyl, 2-propynyl, 1-butynyl, 2-butynyl, 2-pentynyl and 1-hexa-1,3-diynyl.

1.164 Compound 1.161 or 1.162, wherein C _2-6 alkynyl for R ⁴ is ethynyl.

1.165 Compound 1.161 or 1.162, where C _2-6 alkynyl for R ⁴ is 2-propynyl.

1.166 Compound 1.161 or 1.162, where C _2-6 alkynyl for R ⁴ is 1-butynyl.

1.167 Compound 1.161 or 1.162, where C _2-6 alkynyl for R ⁴ is 2-butynyl

1.168 Compound 1.161 or 1.162, wherein C _2-6 alkynyl for R ⁴ is 2-pentenyl.

1.169 Compound 1.161 or 1.162, wherein the C _2-6 alkynyl for R ⁴ is 1-hexa-1.3-diinyl.

1.170 Any of compounds 1.163-1.169, wherein the specified C _2-6 alkynyl for R ⁴ is substituted with 0 R ⁵ substituents.

1.171 Any of compounds 1.163-1.169, wherein the specified C _2-6 alkynyl for R ⁴ is substituted with 1 R ⁵ substituent.

1.172 Any of compounds 1.163-1.169, wherein the specified C _2-6 alkynyl for R ⁴ is substituted with 2 R ⁵ substituents.

1.173 Any of compounds 1.163-1.169, wherein the specified C _2-6 alkynyl for R ⁴ is substituted with 3 R ⁵ substituents.

1.174 Connection 1.141. where R ⁴ represents C _3-9 cycloalkyl substituted with 0-5 R ⁵ substituents.

1.175 Compound 1.174, where R ⁴ is C _3-9 cycloalkyl substituted with 0 R ⁵ substituents, or with 1 R ⁵ substituent, or with 2 R ⁵ substituents, or with 3 R ⁵ substituents, or with 4 ^R5 substituents or using 5 ^R5 substituents.

1.176 Compound 1.174 or 1.175, wherein the C _3-9 cycloalkyl for R ⁴ is selected from cyclopropyl, cyclobutyl and cyclohexyl.

1.177 Compound 1.174 or 1.175, wherein C _3-9 cycloalkyl for R ⁴ is cyclopropyl.

1.178 Compound 1.174 or 1.175, wherein C _3-9 cycloalkyl for R ⁴ is cyclobutyl.

1.179 Compound 1.174 or 1.175, wherein C _3-9 cycloalkyl for R ⁴ is cyclohexyl.

1.180 Any of compounds 1.176-1.179, wherein the specified C _3-9 cycloalkyl for R ⁴ is substituted with 0 R ⁵ substituents.

1.181 Any of compounds 1.176-1.179, wherein the specified C _3-9 cycloalkyl for R ⁴ is substituted with 1 R ⁵ substituent.

1.182 Any of compounds 1.176-1.179, wherein the specified C _3-9 cycloalkyl for R ⁴ is substituted with 2 R ⁵ substituents.

1.183 Connection 1.141. where R ⁴ is aryl substituted with 0-5 R ⁵ substituents.

1.184 Compound 1.183, where R ⁴ is aryl substituted with 0 R ⁵ substituents or 1 R ⁵ substituent, or 2 R ⁵ substituents, or 3 R ⁵ substituents, or 4 R ⁵ substituents, or using 5 R ⁵ substituents.

1.185 Compound 1.183 or 1.184, where the aryl for R ⁴ is phenyl.

1.186 Compound 1.185, wherein said aryl is aryl substituted with 0 R ⁵ substituents.

1.187 Compound 1.185, wherein said aryl is aryl substituted with 1 R ⁵ substituent.

1.188 Compound 1.185, wherein said aryl is aryl substituted with 2 R ⁵ substituents.

1.189 Connection 1.141. where R ⁴ represents heteroaryl substituted with 0-5 R ⁵ substituents.

1.190 Compound 1.189, where R ⁴ is heteroaryl substituted with 0 R ⁵ substituents, or 1 R ⁵ substituent, or 2 R ⁵ substituents, or 3 R ⁵ substituents, or 4 R ⁵ substituents , or using 5 R ⁵ substituents.

1.191 Compound 1.189 or 1.190, wherein the heteroaryl for R ⁴ is selected from imidazolyl, pyrimidinyl, pyridinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, thiazolyl and thiophenyl.

1.192 Compound 1.189 or 1.190, where the heteroaryl for R ⁴ is imidazolyl, for example 2-imidazolyl.

1.193 Compound 1.189 or 1.190, wherein the heteroaryl for R ⁴ is pyrimidinyl, for example 2-pyrimidinyl, 2-pyrimidinyl, 4-pyrimidinyl, or 5-pyrimidinyl.

1.194 Compound 1.189 or 1.190, wherein the heteroaryl for R ⁴ is pyridinyl, for example 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl.

1.195 Compound 1.189 or 1.190, wherein the heteroaryl for R ⁴ is pyrazinyl, for example 2-pyrazinyl.

1.196 Compound 1.189 or 1.190, where the heteroaryl for R ⁴ is oxadiazolyl, for example 2-(1,3,4-oxadiazolyl).

1.197 Compound 1.189 or 1.190, where the heteroaryl for R ⁴ is thiadiazolyl, for example 5-(1,2,4-thiadiazolyl).

1.198 Compound 1.189 or 1.190, where the heteroaryl for R ⁴ is thiazolyl, for example 2-thiazolyl, or 4-thiazolyl.

1.199 Compound 1.189 or 1.190, where the heteroaryl for R ⁴ is thiophenyl, for example 2-thiophenyl.

1.200 Any of compounds 1.191-1.199, wherein the said heteroaryl for R ⁴ is substituted with 0 R ⁵ substituents.

1.201 Any of compounds 1.191-1.199, where the specified heteroaryl for R ⁴ is substituted with 1 R ⁵ substituent.

1.202 Any of compounds 1.191-1.199, where the specified heteroaryl for R ⁴ is substituted with 2 R ⁵ substituents.

1.203 Connection 1.141. where R ⁴ represents heterocycloalkyl, substituted with 0-5 R ⁵ substituents.

1.204 Compound 1.203, where R ⁴ is heterocycloalkyl substituted with 0 R ⁵ substituents, or with 1 R ⁵ substituent, or with 2 R ⁵ substituents, or with 3 R ⁵ substituents, or with 4 R ⁵ substituents, or with 5 ^R5 substituents.

1.205 Compound 1.203 or 1.204, where the heterocycloalkyl for R ⁴ is selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, dioxanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, azaspiro[2,3]hexanyl, diazaspiro[3.3]heptane silt, 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-(tetrahydrothiophen-1.1-dioxide ), 2-(octahydro-pyrrolo[3,4-c]pyrrolyl), 7-(5,6,7,8-tetrahydro[1.2,4]triazolo-[1.5]pyrazinyl), 5-(4,5, 6,7-tetrahydropyrazolo[1.5]pyrazinyl, 7-(5,6,7,8-tetrahydroimidazo[1.5]pyrazinyl, 7-(5,6,7,8-tetrahydroimidazo[1.2]pyrazinyl, 3-pyrrolidin- 2-onyl and 3-(oxazolidin-2-onyl).

1.206 Compound 1.203 or 1.204, where the heterocycloalkyl for R ⁴ is azetidinyl, for example 2-azetidinyl or 3-azetidinyl.

1.207 Compound 1.203 or 1.204, where the heterocycloalkyl for R ⁴ is oxetanyl, for example 2-oxetanyl or 3-oxetanyl.

1.208 Compound 1.203 or 1.204, wherein the heterocycloalkyl for R ⁴ is pyranyl, for example 4-pyranyl.

1.209 Compound 1.203 or 1.204, wherein the heterocycloalkyl for R ⁴ is pyrrolidinyl, for example 1-pyrrolidinyl, 2-pyrrolidinyl, or 3-pyrrolidinyl.

1.210 Compound 1.203 or 1.204, where the heterocycloalkyl for R ⁴ is 3-pyrrolidin-2-onyl.

1.211 Compound 1.203 or 1.204, where the heterocycloalkyl for R ⁴ is piperidinyl, for example 3-piperidinyl or 4-piperidinyl.

1.212 Compound 1.203 or 1.204, where the heterocycloalkyl for R ⁴ is piperazinyl, for example piperazin-3-onyl.

1.213 Compound 1.203 or 1.204, where the heterocycloalkyl for R ⁴ is tetrahydrofuranyl, for example 2-tetrahydrofuranyl or 3-tetrahydrofuranyl.

1.214 Compound 1.203 or 1.204, where the heterocycloalkyl for R ⁴ is dioxanyl, for example 5-(1,3-dioxanyl).

1.215 Compound 1.203 or 1.204, where the heterocycloalkyl for R ⁴ is morpholinyl, for example 2-morpholinyl.

1.216 Compound 1.203 or 1.204, where the heterocycloalkyl for R ⁴ is azaspiro[2,3]hexanyl, for example 5-(5-azaspiro[2,3]hexanyl).

1.217 Compound 1.203 or 1.204, where the heterocycloalkyl for R ⁴ is oxaspiro[3.3]heptanyl, for example 6-(2-oxaspiro[3.3]heptanyl).

1.218 Compound 1.203 or 1.204, where the heterocycloalkyl for R ⁴ is diazaspiro[3.3]heptanyl, for example 6-(1.6-diazaspiro[3.3]heptanyl) or 1-(1.6-diazaspiro[3.3]heptanyl), or 2-(2 ,6-diazaspiro[3.3]heptanyl).

1.219 Compound 1.203 or 1.204, where the heterocycloalkyl for R ⁴ is oxaazaspiro[3.3]heptanyl, for example 6-(1-oxa-6-azaspiro[3.3]heptanyl) or 1-(6-oxa-1-azaspiro[3.3] -heptanyl), or 6-(2-oxa-6-azaspiro[3.3]heptanyl).

1.220 Compound 1.203 or 1.204, where the heterocycloalkyl for R ⁴ is diazabicyclo[4.1.0]heptanyl, for example 2-(2,5-diazabicyclo[4.1.0]heptanyl).

1.221 Compound 1.203 or 1.204, where the heterocycloalkyl for R ⁴ is oxaazaspiro[3.4]octanyl, for example 2-(5-ooxa-2-azaspiro[3.4]octanyl).

1.222 Compound 1.203 or 1.204, where the heterocycloalkyl for R ⁴ is dioxaazaspiro[3.4]octanyl, for example 2-(5,8-dioxa-2-azaspiro[3.4]octanyl).

1.223 Compound 1.203 or 1.204, where the heterocycloalkyl for R ⁴ is oxaazaspiro[3,5]nonanyl, for example 7-(1-oxa-7-azaspiro[3,5]nonanyl).

1.224 Compound 1.203 or 1.204, where the heterocycloalkyl for R ⁴ is thiomorpholinyl, for example thiomorpholinyl-1-oxide or thiomorpholinyl-1,1-dioxide.

1.225 Any of compounds 1.205-1.224, wherein the indicated heterocycloalkyl for R ⁴ is substituted with 0 R ⁵ substituents.

1.226 Any of compounds 1.205-1.224, where the specified heterocycloalkyl for R ⁴ is replaced by 1 R ⁵ substituent.

1.227 Any of compounds 1.205-1.224, where the specified heterocycloalkyl for R ⁴ is substituted with 2 R ⁵ substituents.

1.228 Any of compound 1 or 1.1 and subsequent compounds, wherein each R ⁵ is independently selected from OH, halogen, CO ₂ H, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, -OC _1-4 haloalkyl , -C _1-4 alkyl-OC _1-4 alkyl, -SC _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -S(O)-C _1-4 alkyl, -N(R ^a ) ₂ , -CH ₂ N(R ^a ) ₂ , -N(R ^a )-S(O)-C _1-4 alkyl, -NO ₂ , -CN, -CH ₂ CN, C _3-9 cycloalkyl, -C _1-4 alkyl-C _3-9 cycloalkyl, -OC _1-4 alkyl-C _3-9 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -O-heteroaryl and -O-aralkyl, where each alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 R ^w substituents, where optionally any one or more R ^w are the same or different.

1.229 Compound 1.228, where R ⁵ is halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, OC _1-4 haloalkyl, -CN, C _3-9 cycloalkyl, C _1-4 alkyl- C _3-9 cycloalkyl, -OC _1-4 alkyl, -C _3-9 cycloalkyl, -C _1-4 alkyl, -OC _1-4 haloalkyl, or heterocycloalkyl, and wherein each of said cycloalkyl, aryl, heteroaryl or heterocycloalkyl is substituted with 0-3 substituents R ^w .

1.230 Compound 1.228, wherein each R ⁵ is independently selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, -OC _1-4 haloalkyl, N(R ^a ) ₂ , -N(R ^a )-S(O)-C _1-4 alkyl, -CN, C _3-9 cycloalkyl, -C _1-4 alkyl-C _3-9 cycloalkyl, -OC _1-4 alkyl-C _3-9 cycloalkyl and heterocycloalkyl, wherein each alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 ^Rw substituents.

1.231 Compound 1.228, wherein each R ⁵ is independently selected from halogen, OH, C _1-4 alkoxy, -OC _1-4 haloalkyl, N(R ^a ) ₂ , -CH ₂ -N(R ^a ) ₂ , -CN, C _3-9 cycloalkyl, -C _1-4 alkyl-C _3-9 cycloalkyl, heteroaryl and heterocycloalkyl, wherein each alkyl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 R ^w substituents.

1.232 Compound 1.228, wherein each R ⁵ is independently selected from OH, CO ₂ H, C _1-4 alkoxy, C _1-4 haloalkyl, -OC _1-4 haloalkyl, -S(O) ₂ -C _1-4 alkyl, - N(R ^a ) ₂ , C _3-9 cycloalkyl, heterocycloalkyl, heteroaryl, where each alkyl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 R ^w substituents.

1.233 Compound 1.228, wherein R ⁵ is independently selected from OH, halogen, -CN, C _1-4 alkoxy, SC _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -S(O)-C _{1 -4} alkyl, C _3-9 cycloalkyl, heterocycloalkyl and heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is substituted with 0-3 R ^w substituents.

1.234 Compound 1.228, wherein each R ⁵ is independently selected from halogen, OH, C _1-4 alkoxy, -OC _1-4 haloalkyl, N(R ^a ) ₂ , -S(O) ₂ -C _1-4 alkyl, -CN and O-aralkyl, where each alkyl or aryl is substituted with 0-3 R ^w substituents.

1.235 Compound 1.228, wherein each R ⁵ is independently selected from OH, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, N(R ^a ) ₂ and O-heterocycloalkyl, wherein each alkyl or heterocycloalkyl is substituted using 0-3 substituents R ^w .

1.236 Compound 1.228, wherein R ⁵ is independently selected from C _1-4 alkyl, C _1-4 haloalkyl, SC _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -S(O)-C _{1- 4} alkyl, C _3-9 cycloalkyl and heteroaryl, where each alkyl, cycloalkyl or heteroaryl is substituted with 0-3 R ^w substituents.

1.237 Compound 1.228, wherein R ⁵ is independently selected from C _1-4 alkyl, C _1-4 alkoxy, -CH ₂ CN and -S(O) ₂ -C _1-4 alkyl, wherein each alkyl, cycloalkyl or heteroaryl is substituted with 0-3 substituents R ^w .

1.238 Compound 1.228, wherein R ⁵ is independently selected from OH, halogen, C _1-4 alkyl, -CN, -CH ₂ CN and heteroaryl, wherein each alkyl or heteroaryl is substituted with 0-3 R ^w substituents.

1.239 Compound 1.228, wherein R ⁵ is independently selected from C _1-4 alkyl, C _1-4 haloalkyl and C _3-9 cycloalkyl, wherein each alkyl or cycloalkyl is substituted with 0-3 R ^w substituents.

1.240 Compound 1.228, wherein R ⁵ is independently selected from C _1-4 haloalkyl, C _3-9 cycloalkyl, aryl, heteroaryl and heterocycloalkyl, wherein each alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 R ^w substituents.

1.241 Compound 1.228, wherein R ⁵ is independently selected from C _3-9 cycloalkyl, aryl, heteroaryl and heterocycloalkyl, wherein each alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 R ^w substituents.

1.242 Compound 1.228, wherein each R ⁵ is independently selected from halogen, C _1-4 alkoxy and -OC _1-4 haloalkyl, wherein each alkyl is substituted with 0-3 R ^w substituents.

1.243 Compound 1.228, wherein each R ⁵ is independently selected from OH, C _1-4 alkyl, and C _3-9 cycloalkyl, wherein each alkyl is substituted with 0-3 R ^w substituents.

1.244 Compound 1.228, wherein each R ⁵ is independently selected from C _1-4 haloalkyl and -OC _1-4 alkoxy, wherein each alkyl is substituted with 0-3 R ^w substituents.

1.245 Compound 1.228, wherein R ⁵ is independently selected from C _3-9 cycloalkyl and heteroaryl, wherein each cycloalkyl or heteroaryl is substituted with 0-3 R ^w substituents.

1.246 Compound 1.228, wherein each R ⁵ is independently selected from OH and C _1-4 alkyl, wherein each alkyl is substituted with 0-3 R ^w substituents.

1.247 Compound 1.228, wherein each R ⁵ is independently selected from C _1-4 alkyl, C _3-9 cycloalkyl, and C _1-4 alkyl-C _3-9 cycloalkyl, wherein each alkyl is substituted with 0-3 R ^w substituents.

1.248 Compound 1.228, wherein each R ⁵ is independently selected from C _1-4 alkyl and C _1-4 alkyl-OC _1-4 alkyl, wherein each alkyl is substituted with 0-3 R ^w substituents.

1.249 Compound 1.228, where R ⁵ is independently OH.

1.250 Compound 1.228, wherein R ⁵ is independently a halogen, optionally selected from fluorine, chlorine or bromine.

1.251 Compound 1.228, where R ⁵ independently represents CO ₂ H.

1.252 Compound 1.228, wherein R ⁵ is independently C _1-4 alkyl substituted with 0, 1, 2 or 3 R ^w substituents, wherein optionally said C _1-4 alkyl is selected from methyl, ethyl and isopropyl.

1.253 Compound 1.228 wherein R ⁵ is independently C _1-4 alkoxy substituted with 0, 1, 2 or 3 R ^w substituents, wherein optionally said C _1-4 alkoxy is selected from methoxy, ethoxy, isopropoxy and t-butoxy.

1.254 Compound 1.228 wherein R ⁵ is independently a C _1-4 haloalkyl substituted with 0, 1, 2 or 3 R ^w substituents, wherein optionally said C _1-4 haloalkyl is selected from trifluoromethyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2,-trifluoroethyl, 3-fluoropropyl, 1.1.1-trifluoroisopropyl and 1.3-difluoroisopropyl.

1.255 Compound 1.228 wherein R ⁵ is independently -OC _1-4 haloalkyl substituted with 0, 1, 2 or 3 R ^w substituents, wherein optionally said -OC _1-4 haloalkyl is selected from fluoromethoxy, difluoromethoxy, 2, 2-difluoroethoxy, trifluoromethoxy and 2,2,2-trifluoroethoxy.

1.256 Compound 1.228 wherein R ⁵ is independently -C _1-4 alkyl-OC _1-4 alkyl substituted with 0, 1, 2 or 3 R ^w substituents, wherein optionally said -C _1-4 alkyl-OC _1-4 alkyl is CH ₂ -O-CH ₃ .

1.257 Compound 1.228 wherein R ⁵ is independently -C _1-4 alkyl-OC _1-4 haloalkyl substituted with 0, 1, 2 or 3 R ^w substituents, wherein optionally said -C _1-4 alkyl-OC _1-4 haloalkyl is CH ₂ -O-CF ₃ .

1.258 Compound 1.228 wherein R ⁵ is independently -SC _1-4 alkyl substituted with 0, 1, 2 or 3 R ^w substituents, wherein optionally said -SC _1-4 alkyl is -S-CH ₃ .

1.259 Compound 1.228 wherein R ⁵ is independently -S(O) ₂ -C _1-4 alkyl substituted with 0, 1, 2 or 3 R ^w substituents, where optionally the specified -S(O) ₂ -C _1-4 alkyl is -S(O) ₂ -CH ₃ .

1.260 Compound 1.228 wherein R ⁵ is independently -S(O)-C _1-4 alkyl substituted with 0, 1, 2 or 3 R ^w substituents, wherein optionally said -S(O)-C _{1- 4} alkyl is -S(O)-CH ₃ .

1.261 Compound 1.228, where R ⁵ is independently -N(R ^a ) ₂ .

1.262 Connection 1.261. wherein each R ^a is independently H, C _1-4 alkyl, or C _3-9 cycloalkyl, wherein optionally said R ^a is methyl or cyclopropyl, and further wherein optionally each R ^a is the same or each R ^a is different.

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

1.264 Compound 1.263, wherein each R ^a is independently H, C _1-4 alkyl, or C _3-9 cycloalkyl, wherein optionally said R ^a is methyl or cyclopropyl, and further wherein optionally each R ^a is the same or each R ^a is different.

1.265 Compound 1.228 wherein R ⁵ is independently -N(R ^a )-S(O)-C _1-4 alkyl substituted with 0, 1, 2 or 3 R ^w substituents, where optionally the specified -N( R ^a )-S(O)-C _1-4 alkyl is -N(R ^a )-S(O)-tert-butyl.

1.266 Compound 1.228, where R ⁵ independently represents -NO ₂ .

1.267 Compound 1.228 wherein R ⁵ is independently -CN.

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

1.269 Compound 1.228 wherein R ⁵ is independently C _3-9 cycloalkyl substituted with 0, 1, 2 or 3 R ^w substituents, wherein optionally said C _3-9 cycloalkyl is selected from cyclopropyl, cyclobutyl and cyclohexyl.

1.270 Compound 1.228 wherein R ⁵ is independently -C _1-4 alkyl-C _3-9 cycloalkyl substituted with 0, 1, 2 or 3 R ^w substituents, wherein optionally said -C _1-4 alkyl-C _3-9 cycloalkyl is methylcyclopropyl.

1.271 Compound 1.228 wherein R ⁵ is independently -OC _1-4 alkyl-C _3-9 cycloalkyl substituted with 0, 1, 2 or 3 R ^w substituents, where optionally the specified -OC _1-4 alkyl-C _3-9 cycloalkyl is O-methyl-cyclopropyl.

1.272 Compound 1.228 wherein R ⁵ is independently heterocycloalkyl substituted with 0, 1, 2 or 3 R ^w substituents, wherein optionally 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-tetrahydro-furanyl), pyrrolidinyl, dioxanyl (e.g. 1,4-dioxanyl), morpholinyl (e.g. 2-morpholinyl), piperidinyl and dihydrooxazolyl (e.g. 2 -(4,5-dihydrooxazolyl).

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

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

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

1.276 Compound 1.228 wherein R ⁵ is independently -O-aralkyl substituted with 0, 1, 2 or 3 R ^w substituents, wherein optionally said -O-aralkyl is O-benzyl (benzoxy).

1.277 Compound 1. or any of 1.1 and subsequent compounds, where R ⁴ is substituted with 2 R ⁵ substituents and both R ⁵ substituents are the same.

1.278 Compound 1. or any of compounds 1.1 and subsequent compounds, where R ⁴ is substituted by 2 R ⁵ substituents and both R ⁵ substituents are different.

1.279 Compound 1 or any of compounds 1.1 and subsequent compounds wherein R ⁴ is substituted with 3 R ⁵ substituents and all three R ⁵ substituents are the same.

1.280 Compound 1. or any of compounds 1.1 and subsequent compounds, where R ⁴ is substituted by 3 R ⁵ substituents and two of the three R ⁵ substituents are the same.

1.281 Compound 1. or any of compounds 1.1 and subsequent compounds where R ⁴ is substituted with 3 R ⁵ substituents and all three R ⁵ substituents are different from each other.

1.282 Compound 1. or any of compounds 1.1 and subsequent compounds, where the alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl of any R ⁵ is independently substituted with 0 R ^w substituents, or with 1 R ^w substituent, or with 2 R ^w substituents , or using 3 substituents R ^w .

1.283 Compound 1.282, wherein each R ^w is independently a halogen, optionally selected from fluorine, chlorine and bromine.

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

1.285 Compound 1.282, wherein each R ^w is independently C _1-4 alkyl, optionally selected from methyl, ethyl and isopropyl.

1.286 Compound 1.282, wherein each R ^w is independently C _1-4 alkoxy, optionally selected from methoxy and isopropoxy.

1.287 Compound 1.282, wherein each R ^w is independently a C _1-4 haloalkyl, optionally selected from trifluoromethyl and 2,2-difluoroethyl.

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

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

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

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

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

1.293 Compound 1 or any compound from 1.1-1.292, where: X ² represents CR ² and R ² represents hydrogen, halogen (eg, fluorine) or C _1-4 alkyl (eg, methyl); X ⁵ represents CR ⁷ and R ⁷ represents hydrogen; X ⁶ represents CR ¹ and R ¹ represents C _1-4 haloalkyl (eg trifluoromethyl); Y is -C(O)NR ^a R ^b and R ^a is H and R ^b is C _1-4 alkyl (eg methyl), or R ^a and R ^b taken together with a nitrogen atom, to to which they are attached form a heterocycloalkyl ring substituted with 0 R ^x substituents (for example, R ^a and R ^b form 1-azetidinyl); A ¹ represents a chemical bond, C _1-4 alkylene (eg, CH ₂ ) or -O-; L is a 3-12 membered heterocycloalkyl substituted with 0, 1 or 2 R ^x substituents, and R ^x is a halogen (eg fluorine) or C _1-4 alkyl (eg methyl); A ² is selected from -O-, -NR ^a -, -OC(O)-, -C(O)-O-, CH ₂ -C(O)-NR ^a , -OC(O)-NR ^a and NR ^a -C(O)-O-, and R ^a represents hydrogen; R ⁴ is C _1-4 alkyl (eg methyl, ethyl, propyl, isopropyl or butyl), C _3-9 cycloalkyl (eg cyclopropyl or cyclohexyl), heterocycloalkyl (eg azetidinyl) or heteroaryl (eg 2-pyridyl ), each of which is substituted with 0 or 1 R ⁵ substituents, and each R ⁵ is independently selected from halogen (for example, fluorine), C _1-4 alkyl (for example, methyl or isopropyl), C _1-4 alkoxy (for example, methoxy), C _1-4 haloalkyl (eg trifluoromethyl), -OC _1-4 haloalkyl (eg trifluoromethoxy), CN, C _3-9 cycloalkyl (eg cyclopropyl), heteroaryl (eg 2-thiazolyl) or heterocycloalkyl ( eg 1-pyrrolidinyl), and said heteroaryl or heterocycloalkyl is substituted with 0, 1 or 2 halogens (eg fluorine) or C _1-4 alkyls (eg isopropyl).

1.294 Compound 1.293, wherein L is selected from one of the following moieties, wherein each moiety is substituted with 0, 1, or 2 R ^x substituents, and where R ^x is halogen (eg, fluorine) or C _1-4 alkyl (eg, methyl ):

1.295 Compound 1.294, where L is the following fragment substituted with 0 R ^x substituents: .

1.296 Compound 1.295, where X ² represents CR ² and R ² represents hydrogen; X ⁵ represents CR ⁷ and R ⁷ represents hydrogen; X ⁶ represents CR ¹ and R ¹ represents trifluoromethyl; Y is -C(O)NR ^a R ^b and R ^a is H and R ^b is methyl; A ¹ represents a chemical bond; A ² is selected from -OC(O)-, -C(O)-O-, CH ₂ -C(O)-NR ^a , -OC(O)-NR ^a and NR ^a -C(O)-O- , and R ^a represents hydrogen; R ⁴ is C _1-4 alkyl (eg, methyl, ethyl, propyl, isopropyl, or butyl), C _3-9 cycloalkyl (eg, cyclopropyl or cyclohexyl), or heterocycloalkyl (eg, azetidinyl), each of which is substituted with 0 or 1 ^R5 substituent, and each ^R5 is independently selected from halogen (eg fluorine), _C1-4 alkyl (eg methyl or isopropyl), _C1-4 alkoxy (eg methoxy), _C1-4 haloalkyl (eg trifluoromethyl), -OC _1-4 haloalkyl (eg trifluoromethoxy) and C _3-9 cycloalkyl (eg cyclopropyl).

1.297 Compound 1.296, wherein A ² is selected from -OC(O)-NR ^a and NR ^a -C(O)-O-, and R ^a is hydrogen;

1.298 Compound 1.296 or 1.297, wherein R ⁴ is C _1-4 alkyl (for example, methyl, ethyl, propyl, isopropyl, or butyl), C _3-9 cycloalkyl (for example, cyclopropyl or cyclohexyl), each of which is substituted with 0 or 1 ^R5 substituent, and each ^R5 is independently selected from halogen (eg fluorine), _C1-4 alkyl (eg methyl or isopropyl), _C1-4 alkoxy (eg methoxy), _C1-4 haloalkyl (eg trifluoromethyl), -OC _1-4 haloalkyl (eg trifluoromethoxy) and C _3-9 cycloalkyl (eg cyclopropyl).

1.299 Compound 1.298, where R ⁴ is substituted with 0 R ⁵ substituents.

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

[0018] In additional embodiments, the present invention provides Compound 1 or any of Compounds 1.1-1.300, where the compound is selected from one or more of the compounds presented in Table 1 below.

Table 1 Compound # Compound # 474 109 76 693 90 88 496 375 390 180 151 639 653 441 449 452 142 300 49 475 692 63 806 490 492 418 91 816 520 528 145 780 361 350 632 576 256 853 833 220 600 611 171 371 866 176 181 183 186 187 636 637 408 415 47 638 640 641 419 473 669

[0019] In additional embodiments, the present invention provides Compound 1 or any of Compounds 1.1-1.300, wherein the compound is selected from one or more of the compounds presented in Table 2 below.

table 2 Compound # Compound # 474 109 76 693 90 88 496 375 390 180

473 475

[0020] In additional embodiments, the present invention provides Compound 1 or any of Compounds 1.1-1.300, wherein the compound is selected from the following compounds named below.

N-Methyl-5-(4-((5-methylpyridin-2-yl)methyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

5-(4-Benzylpiperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno-[3,2-b]pyridin-3-carboxamide;

N-Methyl-5-(4-((2-methylpyrimidin-4-yl)methyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

5-(4-((6-Ethylpyridin-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

5-(4-((6-(Methoxymethyl)pyridin-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

N-Methyl-5-(4-((4-methylpyridin-2-yl)methyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

N-Methyl-5-(4-((3-methylpyridin-2-yl)methyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

5-(4-((6-Methoxypyridin-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

N-Methyl-5-(4-((6-methylpyridin-2-yl)methyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

Methyl 5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate;

5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-1-yl)-N,N-dimethyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

Methyl 5-(4-(2-(benzylamino)-2-oxoethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate;

Methyl 5-(4-(2-oxo-2-(phenylamino)ethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate;

Methyl 5-(4-(2-(cyclohexylamino)-2-oxoethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate;

Methyl 5-(4-(2-oxo-2-(piperidin-1-yl)ethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxylate;

Methyl 5-(4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxylate;

Methyl 5-(4-(2-(methylamino)-2-oxoethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate;

Methyl 5-(4-(4-methylpentanoyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate;

Methyl 5-(4-(4-methylpentyl)piperazin-1-yl)-7-(trifluoromethyl)-thieno[3,2-b]pyridine-3-carboxylate;

Isobutyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperazine-1-carboxylate;

N-Methyl-5-(4-(pyridin-2-ylmethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

N-Methyl-5-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-7-(tri-fluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

N-Methyl-5-(4-(pyridin-4-ylmethyl)piperazin-1-yl)-7-(tri-fluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

5-(4-(2-(Ethylamino)-2-oxoethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(2-(Cyclopropylamino)-2-oxoethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(2-(Isobutylamino)-2-oxoethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

(+/-)-5-(4-(1-(Isopropylamino)-1-oxobutan-2-yl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide;

5-(4-(1-(Isopropylamino)-2-methyl-1-oxopropan-2-yl)-piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide;

Tertbutyl 2-(4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperazin-1-yl)acetate;

(+/-)-Tertbutyl 2-(4-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperazin-1-yl)propanoate;

(+/-)-Isopropyl 2-(4-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperazin-1-yl)propanoate;

(+/-)-5-(4-(1-(Isopropylamino)-1-oxopropan-2-yl)-piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b ]pyridine-3-carboxamide;

Isopropyl 2-(4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperazin-1-yl)acetate;

5-(4-(2-(tertbutylamino)-2-oxoethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

(S)-5-(4-(1-(Isopropylamino)-1-oxopropan-2-yl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin- 3-carboxamide;

(R)-5-(4-(1-(Isopropylamino)-1-oxopropan-2-yl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin- 3-carboxamide;

N-Methyl-5-(4-((6-methylpyrazin-2-yl)methyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

(+/-)-5-(4-(2-(Cyclopropylmethoxy)propyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

(+/-)-5-(4-(1-(Cyclopropylmethoxy)propan-2-yl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3 -carboxamide;

5-(4-(2-(Cyclopropylmethoxy)ethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(2-Cyclopropoxyethyl)piperazin-1-yl)-N-methyl-7-(tri-fluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(2-Isopropoxyethyl)piperazin-1-yl)-N-methyl-7-(tri-fluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(2-Isopropoxyacetyl)piperazin-1-yl)-N-methyl-7-(tri-fluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(2-(Isopropyl(methyl)amino)-2-oxoethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(1-isopropyl-2-oxopyrrolidin-3-yl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-1-yl)-N,6-dimethyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-1-yl)-N,7-dimethylthieno[3,2-b]pyridine-3-carboxamide;

5-(4-(2-(Isopropylamino)-2-oxoethyl)-3,3-dimethylpiperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide ;

(+/-)-5-(3-Isopropyl-4-(2-(isopropylamino)-2-oxoethyl)-piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b ]pyridine-3-carboxamide;

(+/-)-5-(3-Ethyl-4-(2-(isopropylamino)-2-oxoethyl)-piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b ]pyridine-3-carboxamide;

(+/-)-5-(4-(2-(Isopropylamino)-2-oxoethyl)-2-methyl-piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b ]pyridine-3-carboxamide;

5-(8-(2-(Isopropylamino)-2-oxoethyl)-3,8-diazabicyclo-[3,2,1]octan-3-yl)-N-methyl-7-(trifluoromethyl)thieno[3, 2-b]pyridine-3-carboxamide;

5-(4-(2-(isopropylamino)-2-oxoethyl)-4,7-diazaspiro[2,5]-octan-7-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2- b]pyridine-3-carboxamide;

(+/-)-5-(4-(2-(Isopropylamino)-2-oxoethyl)-3-methyl-piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b ]pyridine-3-carboxamide;

5-(4-(2-(Isopropylamino)-2-oxoethyl)-1,4-diazepan-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide ;

N-Isopropyl-2-(4-(3-isopropyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperazin-1-yl)acetamide;

2-(4-(3-(Hydroxymethyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperazin-1-yl)-N-isopropylacetamide;

5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylic acid;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl azetidin-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-pentan-2-ylcarbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(3-methylbutan-2-yl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-secbutylcarbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl cyclobutylcarbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-(trifluoromethoxy)ethyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 5-azaspiro[2,3]hexane-5-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 1,1-difluoro-5-azaspiro[2,3]hexane-5 -carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(methoxymethyl)azetidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(dimethylamino)-3-methylazetidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-((dimethylamino)methyl)azetidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(oxetan-3-yl)azetidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-hydroxy-3-(trifluoromethyl)azetidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (1R,6S)-5-methyl-2,5-diazabicyclo[4.1 .0]-heptane-2-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (1S,6R)-5-methyl-2,5-diazabicyclo[4.1 .0]-heptane-2-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-cyclopropyl azetidin-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclobutylmethyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-but-3-yn-2-ylcarbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (3S,5S)-3,5-dimethylmorpholine-4-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-2-methylpiperidin-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-2-methylpyrrolidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-cyanoethyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 5,6,7,8-tetrahydro-[1,2,4] triazolo[1,5-a]-pyrazine-7-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 6-oxa-1-azaspiro[3.3]heptane-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropyl(methyl)carbamate;

(1α,5α,6α)-3-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)-3-azabicyclo[3.1.0]hexane-6- yl (cyclopropylmethyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(difluoromethoxy)azetidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(trifluoromethoxy)azetidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-((trifluoromethoxy)methyl)azetidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-(trifluoromethoxy)propan-2-yl)carbamate ;

3,3-Difluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate;

3,3-Difluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl 4-cyclopropylpiperazine-1-carboxylate;

3,3-Difluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S)-2,4-dimethylpiperazin-1 -carboxylate;

3,3-Dimethyl-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl 4-methylpiperazin-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H )-carboxylate;

1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 5,6-dihydroimidazo[1,5-a]pyrazin-7(8H )-carboxylate;

1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 5,6-dihydroimidazo[1,5-a]pyrazin-7(8H )-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]- pyrrole-2(1H)-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(dimethylamino)azetidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-(thiazol-2-yl)ethyl)carbamate ;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-2-ethyl-4-methylpiperazine-1-carboxylate;

(+/-)-trans-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl 4-methoxy-1-methylpyrrolidin- 3-yl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-2,4-dimethylpiperazine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-2,4-dimethylpiperazine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-(pyrrolidin-1-yl)ethyl)carbamate;

(+/-)-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl (2-(3-fluoropyrrolidin-1- yl)ethyl)-carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-(3,3-difluoropyrrolidin-1-yl)ethyl)carbamate ;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-(1-cyclopropylethyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-cyclopropylethyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl pyrrolidin-1-ylcarbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)(methyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 4-(cyclopropylmethyl)piperazine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-isopropoxyethyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 4-methylpiperazin-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((4-methylmorpholin-2-yl)methyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-3,4-dimethylpiperazine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-3,4-dimethylpiperazine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-2-(hydroxymethyl)-4-methylpiperazine-1-carboxylate ;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((2S,3R)-3-hydroxybutan-2-yl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-3-methylmorpholine-4-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl cis-3-hydroxycyclobutyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl trans-3-hydroxycyclobutyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-cyanopropan-2-yl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-hydroxypropan-2-yl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-hydroxyazetidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-methoxypropan-2-yl)carbamate;

(+/-)-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl trans-4-hydroxy-1-methylpyrrolidin-3 -yl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-hydroxy-2-methylpropyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-2-methylpiperazine-1-carboxylate;

4-((Dimethylamino)methyl)-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-2- methyl pyrrolidine-1-carboxylate;

4-((Dimethylamino)methyl)-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate;

4-(Methoxymethyl)-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate;

1-(3-(Dimethylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl (S)-(1-cyanopropan-2-yl)carbamate;

1-(3-(Azetidin-1-carbonyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl (S)-(1-cyanopropan-2-yl )carbamate;

(+/-)-trans-3-(Dimethylamino)-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclo- propyl methyl)carbamate;

(+/-)-cis-3-Methyl-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 4-methylpiperazin- 1-carboxylate;

1-(3-(Methoxycarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate;

(+/-)-trans-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl 4-fluoro-1-methylpyrrolidin- 3-yl)carbamate;

(+/-)-cis-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 4-fluoro-1-methylpyrrolidin-3 -yl)-carbamate;

5-(3-Isopropyl-2-oxo-1-oxa-3,8-diazaspiro[4,5]decan-8-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide;

5-(2-Isopropyl-2,8-diazaspiro[4,5]decan-8-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

1-(3-(Methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-(trifluoromethoxy)propan-2-yl)carbamate;

1-(7-Methyl-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)-piperidin-4-yl isopropylcarbamate;

1-(7-Methyl-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)-piperidin-4-yl (S)-(1-(trifluoromethoxy)propan-2-yl)carbamate;

N-Methyl-5-(4-((6-methylpyridin-2-yl)oxy)piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

5-(4-((6-Ethylpyridin-2-yl)oxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

N-Methyl-5-(4-((2-methylpyrimidin-4-yl)oxy)piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

(+/-)-N-Methyl-5-(cis-3-methyl-4-((2-methylpyrimidin-4-yl)-oxy)piperidin-1-yl)-7-(trifluoromethyl)thieno[3, 2-b]pyridine-3-carboxamide;

(+/-)-N-Methyl-5-(trans-3-methyl-4-((2-methylpyrimidin-4-yl)-oxy)piperidin-1-yl)-7-(trifluoromethyl)thieno[3, 2-b]pyridine-3-carboxamide;

5-(4-((3-Cyclopropyl-1,2,4-thiadiazol-5-yl)oxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide;

1-(6-Methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl (S)-(1-cyclopropylethyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-cyanopropan-2-yl)(methyl)carbamate ;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((1-(2,2-difluoroethyl)azetidin-3-yl) methyl)-carbamate;

Methyl 5-(4-(2-(isopropylamino)-2-oxoethyl)piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate;

5-(4-(2-(Isopropylamino)-2-oxoethyl)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(2-((1-Methoxypropan-2-yl)amino)-2-oxoethyl)-piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide;

5-(4-(2-((1,3-Dimethoxypropan-2-yl)amino)-2-oxoethyl)-piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2- b]pyridine-3-carboxamide;

(S)-1-Methoxypropan-2-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbonate;

Isopropyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbonate;

(R)-1-Cyclopropylethyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

(S)-1-Cyclopropylethyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

Isopropyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

Tertbutyl 3,3-difluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

N-Methyl-5-((1-(6-methylpyridin-2-yl)piperidin-4-yl)oxy)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

2-Cyanoethyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

2-Isopropoxyethyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

2-(Tretbutoxy)ethyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

(3-Fluoroazetidin-3-yl)methyl 4-((3-(methylcarbamoyl)-7-(tri-fluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

1-(Prop-2-in-1-yl)azetidin-3-yl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine -1-carboxylate;

1-(Cyanomethyl)azetidin-3-yl 4-((3-(methylcarbamoyl)-7-(tri-fluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl 4-((6-chloro-3-(methylcarbamoyl)thieno-[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl 4-((6-bromo-3-(methylcarbamoyl)thieno-[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl 4-((6-cyclopropyl-3-(methyl-carbamoyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

(S)-1-(Trifluoromethoxy)propan-2-yl (2R,4R)-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-5 -yl)oxy)-piperidine-1-carboxylate;

(S)-1-(Trifluoromethoxy)propan-2-yl (2R,4R)-2-methyl-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b ]pyridin-5-yl)oxy)piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl (2R,4R)-2-methyl-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate;

(S)-1-(Trifluoromethoxy)propan-2-yl 4-((6-methyl-3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl (2R,4S)-2-methyl-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl (3S,4R)-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate;

(S)-1-(Trifluoromethoxy)propan-2-yl (3S,4R)-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b ]pyridin-5-yl)oxy)piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl (3R,4S)-3-fluoro-4-((6-methyl-3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl )-hydroxy)-piperidine-1-carboxylate;

(S)-1-(Trifluoromethoxy)propan-2-yl (3R,4S)-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b ]pyridin-5-yl)oxy)piperidine-1-carboxylate;

(S)-1-(Trifluoromethoxy)propan-2-yl (2R,4S)-2-methyl-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b ]pyridin-5-yl)oxy)piperidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)isothiazolo[4,5-b]-pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate;

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

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

1-(7-(Methylcarbamoyl)-4-(trifluoromethyl)thieno[3,2-d]-pyrimidin-2-yl)piperidin-4-yl (S)-2,4-dimethylpiperazine-1-carboxylate;

1-(3-Propionyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-piperidin-4-yl 4-methylpiperazin-1-carboxylate dihydrochloride;

5-(3-((5-Fluoropyridin-3-yl)oxy)azetidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

N-Methyl-5-(3-((3-methylpyridin-2-yl)oxy)azetidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

5-(3-((3-Fluoropyridin-2-yl)oxy)azetidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2b]pyridin-3-carboxamide;

N-Methyl-5-(3-((2-methylpyridin-3-yl)oxy)azetidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

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

Cyclopropylmethyl 3-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)azetidin-1-carboxylate;

Isopropyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

1-Fluoropropan-2-yl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2- carboxylate;

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

2,2-Difluoroethyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

Oxetan-3-ylmethyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

Cyclopropyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

Oxetan-3-yl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

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

(R)-1-Cyclopropylethyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2 -carboxylate;

(S)-1-Cyclopropylethyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-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)-N-methyl-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide;

5-((2-(2,2-Dimethyl-3-(trifluoromethoxy)propanoyl)-2-aza-spiro[3.3]heptan-6-yl)oxy)-N-methyl-7-(trifluoromethyl)thieno[3 ,2-b]pyridine-3-carboxamide;

5-((2-Isobutyryl-2-azaspiro[3.3]heptan-6-yl)oxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-((2-(5-Fluoropyridin-3-yl)-2-azaspiro[3.3]heptan-6-yl)-oxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide;

5-((2-(6-Fluoropyridin-2-yl)-2-azaspiro[3.3]heptan-6-yl)-oxy)-N-methyl-7(trifluoromethyl)thieno[3,2-b]pyridin- 3-carboxamide;

N-Methyl-5-((2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl)oxy)-7-(trifluoromethyl)thieno[3,2-b]pyridin- 3-carboxamide;

2-(Trifluoromethoxy)ethyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-1-azaspiro[3.3]heptan-1- carboxylate;

Tertbutyl 2-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)-7-azaspiro[3,5]nonane-7-carboxylate;

2-(Trifluoromethoxy)ethyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-3-azabicyclo[3,1,1] 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-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]-heptane -2-carboxylate;

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

Cyclopropylmethyl ((1s,3s)-3-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate;

Isopropyl ((1s,3s)-3-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate;

(S)-1-Cyclopropylethyl ((1s,3R)-3-((6-methyl-3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )cyclo-butyl)carbamate;

(R)-1-Cyclopropylethyl ((1s,3S)-3-((6-methyl-3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )cyclo-butyl)carbamate;

Cyclopropylmethyl ((1r,3r)-3-((6-methyl-3-(methylcarbamoyl)-7(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)-carbamate;

2-(Trifluoromethoxy)ethyl (2R,4R)-4-((6-chloro-3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- 2-methylpiperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl (2S,4S)-4-((6-chloro-3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- 2-methylpiperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl 4-((6-chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

Tertbutyl (2R,4R)-4-((6-fluoro-3-(methylcarbamoyl)-7-(tri-fluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-2-methylpiperidin-1 -carboxylate;

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

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

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

5-(cis-3-(3-(Cyclopropylmethyl)ureido)cyclobutoxy)-N,2-dimethyl 7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

(S)-1-cyclopropylethyl ((1s,3R)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate;

(R)-1-cyclopropylethyl ((1s,3S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate;

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

(S)-1-Methoxypropan-2-yl (cis-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate;

(R)-1-Methoxypropan-2-yl (cis-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate;

2-(Trifluoromethoxy)ethyl (cis-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate;

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

2-(4-Chloro-1H-pyrazol-1-yl)ethyl (cis-3-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl) hydroxy)-cyclobutyl)carbamate;

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

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

Isopropyl (cis-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate;

(+/-)-trans-4-Fluoro-1-methylpyrrolidin-3-yl (cis-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl )oxy)-cyclobutyl)carbamate;

2-Chloroethyl (cis-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate;

cis-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)oxy)cyclobutyl 3,3-difluoroazetidine-1-carboxylate;

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

cis-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)oxy)cyclobutyl 1-oxa-7-azaspiro[3,5]nonan-7 -carboxylate;

cis-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)oxy)cyclobutyl (S)-2,4-dimethylpiperazine-1-carboxylate;

cis-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)oxy)cyclobutyl ((S)-1-cyclopropylethyl)carbamate;

cis-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)oxy)cyclobutyl 5,6-dihydro-[1,2,4]triazolo[ 1,5-a]-pyrazine-7(8H)-carboxylate;

cis-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)oxy)cyclobutyl 3-chlorazetidine-1-carboxylate;

cis-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)oxy)cyclobutyl (S)-3-methylmorpholine-4-carboxylate;

cis-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)oxy)cyclobutyl (cyclopropylmethyl)carbamate;

N-Methyl-5-(cis-3-(pyridin-2-yloxy)cyclobutoxy)-7-(tri-fluoromethyl)thieno[3,2-b]pyridin-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-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)azetidine-1-carboxylate;

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

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

(1-(Trifluoromethyl)cyclopropyl)methyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

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

trans-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)oxy)cyclobutyl (cyclopropylmethyl)carbamate;

3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl (cyclopropylmethyl)carbamate;

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

1-(Tertiary)4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperazine-1,4-dicarboxylate;

Tertbutyl (2R,4R)-4-((6-chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-2-methylpiperidine-1-carboxylate ;

Tertbutyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate;

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

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

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

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

Tertbutyl 4-((6-chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl 4-((5-chloro-3-(methylcarbamoyl)-7 (trifluoromethyl)thieno[3,2-b]pyridin-6-yl)oxy)piperidine-1-carboxylate;

Methyl 6-fluoro-5-((1-((2-(trifluoromethoxy)ethoxy)carbonyl)-piperidin-4-yl)oxy)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate ;

2-(Trifluoromethoxy)ethyl 4-((6-fluoro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

Methyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate;

Isobutyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine-1-carboxylate;

5-(1-(4-Fluorophenethyl)piperidin-4-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide hydrochloride;

Benzyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidine-1-carboxylate;

N-Methyl-5-(1-(4-methylpentyl)piperidin-4-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(1-(2-(Benzyloxy)ethyl)piperidin-4-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide hydrochloride;

Isopentyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine-1-carboxylate;

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

Tertbutyl 2,6-dimethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

Tertbutyl (2S,4r,6R)-2,6-dimethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidin-1- carboxylate;

2-(Trifluoromethoxy)ethyl (2S,4r,6R)-2,6-dimethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate;

(+/-)-Tertbutyl (2R,6R)-2,6-dimethyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl) hydroxy)-piperidine-1-carboxylate;

(+/-)-2-Trifluoromethoxy)ethyl (2R,6R)-2,6-dimethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-5- yl)oxy)-piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl (2R,6R)-2,6-dimethyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl (2S,6S)-2,6-dimethyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate;

4-Nitrophenyl (2S,4r,6R)-2,6-dimethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidin- 1-carboxylate;

Tert-butyl 4-((7-methoxy-3-(methylcarbamoyl)thieno[3,2-b]-pyridin-5-yl)oxy)piperidine-1-carboxylate;

Methyl 5-(4-(((cyclopropylmethyl)carbamoyl)oxy)piperidin-1-yl)-7-methoxythieno[3,2-b]pyridine-3-carboxylate;

Methyl 5-(4-((cyclopropylcarbamoyl)oxy)piperidin-1-yl)-7-methoxythieno[3,2-b]pyridine-3-carboxylate;

Isobutyl 4-((7-methoxy-3-(methylcarbamoyl)thieno[3,2-b]-pyridin-5-yl)oxy)piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl 4-((7-hydroxy-3-(methylcarbamoyl)-thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl 4-((7-(difluoromethoxy)-3-(methyl-carbamoyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

Tertbutyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

Isobutyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl) carbamate;

Cyclopropylmethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

Neopentyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

Tertbutyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)azetidin-3-yl)carbamate;

Isobutyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)azetidin-3-yl) carbamate;

Cyclopropylmethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)azetidin-3-yl)carbamate;

Neopentyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)azetidin-3-yl)carbamate;

Tertbutyl methyl(1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

Isobutyl methyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl) piperidin-4-yl) carbamate;

1-(7-Cyclopentyl-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate;

Tert-butyl (1-(7-cyclopentyl-3-(methylcarbamoyl)thieno[3,2-b]-pyridin-5-yl)azetidin-3-yl)carbamate;

1-(7-(tert-butyl)-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate;

1-(7-Isopropyl-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate;

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

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

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

2-(Trifluoromethoxy)ethyl 4-fluoro-4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)methyl)piperidine-1-carboxylate;

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

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

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

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

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

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

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

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

Tertbutyl 4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)methyl)piperidine-1-carboxylate;

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

2-(Trifluoromethoxy)ethyl 4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)methyl)piperidine-1-carboxylate;

Tertbutyl 4-methyl-4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)methyl)piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl 4-methyl-4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)methyl)piperidine-1-carboxylate;

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

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

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

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

Tertbutyl (3aR,5r,6aS)-5-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)hexahydrocyclopenta[c]-pyrrole-2 (1H)-carboxylate;

2-(Trifluoromethoxy)ethyl (3aR,5r,6aS)-5-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-hexahydrocyclopenta[ c]pyrrole-2(1H)-carboxylate;

trans-3-(Trifluoromethoxy)cyclobutyl (2R,4R)-4-((6-chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- 2-methylpiperidine-1-carboxylate;

trans-3-((Trifluoromethoxy)methyl)cyclobutyl 4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-piperidine-1-carboxylate ;

trans-3-(Trifluoromethoxy)cyclobutyl (2R,4R)-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- piperidine-1-carboxylate;

cis-3-Hydroxycyclobutyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

trans-3-(Trifluoromethoxy)cyclobutyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

cis-3-(Trifluoromethoxy)cyclobutyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

Oxetan-3-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate;

N-Methyl-5-(6-(2-morpholinoacetyl)-2,6-diazaspiro[3.3]-heptan-2-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

3-Methyloxetan-3-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2- carboxylate;

1-Cyclopropylethyl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate;

(R)-5-(6-(2-Methoxypropanoyl)-2,6-diazaspiro[3.3]heptan-2-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3 -carboxamide;

(S)-5-(6-(2-Methoxypropanoyl)-2,6-diazaspiro[3.3]heptan-2-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3 -carboxamide;

1-Methoxypropan-2-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2- carboxylate;

Oxetan-3-ylmethyl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate;

1-Methylpiperidin-3-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2- carboxylate;

1-(1-Methylazetidin-3-yl)ethyl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]- heptane-2-carboxylate;

1-Methylazetidin-3-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2- carboxylate;

1-Cyanopropan-2-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate ;

1-(2-Fluoroethyl)azetidin-3-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]- heptane-2-carboxylate;

1-(Cyanomethyl)azetidin-3-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]-heptan- 2-carboxylate;

2-(Trifluoromethoxy)ethyl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate ;

5-(4-((1-Isopropylpyrrolidin-3-yl)oxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

5-(4-((1-(2,2-Difluoroethyl)pyrrolidin-3-yl)oxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin- 3-carboxamide;

5-(4-((1-(2-Fluoroethyl)pyrrolidin-3-yl)oxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3- carboxamide;

5-(4-((1-(1,3-Difluoropropan-2-yl)pyrrolidin-3-yl)oxy)-piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2 -b]pyridine-3-carboxamide;

5-(4-((1-(2,2-Difluoroethyl)azetidin-3-yl)oxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin- 3-carboxamide;

5-(4-((1-(2-Fluoroethyl)azetidin-3-yl)oxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3- carboxamide;

5-(4-((1-(1,3-Difluoropropan-2-yl)azetidin-3-yl)oxy)-piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2 -b]pyridine-3-carboxamide;

5-(4-(2-(3,3-Difluoropyrrolidin-1-yl)ethoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide ;

5-(4-(2-(3-Fluoropyrrolidin-1-yl)ethoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

5-(4-(2-(4,4-Difluoropiperidin-1-yl)ethoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide ;

5-(4-(2-(3-Hydroxypyrrolidin-1-yl)ethoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

5-(4-(2-(trans-3-Fluoro-4-hydroxypyrrolidin-1-yl)ethoxy)-piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide;

N-Methyl-5-(4-(2-morpholinoethoxy)piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-((6-Isopropylpyridin-2-yl)oxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

(+/-)-Tertbutyl trans-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

(+/-)-trans-2-(Trifluoromethoxy)ethyl-2-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl) hydroxy)-piperidine-1-carboxylate;

(+/-)-Tertbutyl cis-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

(+/-)-cis-2-(Trifluoromethoxy)ethyl-2-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl) hydroxy)-piperidine-1-carboxylate;

(S)-1-Cyclopropylethyl (2R,4R)-2-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -piperidine-1-carboxylate;

(S)-1-Cyclopropylethyl (2S,4S)-2-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -piperidine-1-carboxylate;

Tertbutyl (2R,4R)-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

Tertbutyl (2S,4S)-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl (2R,4R)-2-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl (2S,4S)-2-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- piperidine-1-carboxylate;

(+/-)-Tertbutyl trans-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

(+/-)-2-(Trifluoromethoxy)ethyl trans-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate;

(S)-1-Cyclopropylethyl (3R,4R)-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -piperidine-1-carboxylate;

(S)-1-Cyclopropylethyl (3S,4S)-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -piperidine-1-carboxylate;

(+/-)-Tertbutyl cis-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

(+/-)-cis-2-(Trifluoromethoxy)ethyl-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl) hydroxy)-piperidine-1-carboxylate;

(S)-1-cyclopropylethyl (3R,4S)-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -piperidine-1-carboxylate;

(S)-1-cyclopropylethyl (3S,4R)-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -piperidine-1-carboxylate;

Tertbutyl (3S,4R)-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

Tertbutyl (3R,4S)-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl (3S,4R)-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl (3R,4S)-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- piperidine-1-carboxylate;

(+/-)-Tretbutyl cis-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidin- 1-carboxylate;

(+/-)-cis-2-(Trifluoromethoxy)ethyl-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-5- yl)-hydroxy)piperidine-1-carboxylate;

Tertbutyl 4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl 4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

Tertbutyl (2R,4R)-2-ethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl (2R,4R)-2-ethyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- piperidine-1-carboxylate;

Tertbutyl (2R,4S)-2-ethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl-(2R,4S)-2-ethyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -piperidine-1-carboxylate;

2-Hydroxyethyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

Tertbutyl 7-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3,5]nonane-2-carboxylate;

(R)-5-(4-(2-Cyclopropoxyethyl)-3-methylpiperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

(S)-5-(4-(2-Cyclopropoxyethyl)-3-methylpiperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(cis-4-(2-Cyclopropoxyethyl)-3,5-dimethylpiperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-((4-Methoxy-6-methylpyridin-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide ;

5-(4-(3-((Dimethylamino)methyl)benzyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(1-((4-Methoxycyclohexyl)amino)-1-oxopropan-2-yl)-piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide;

N-Methyl-5-(4-(1-oxo-1-((tetrahydro-2H-pyran-4-yl)amino)-propan-2-yl)piperazin-1-yl)-7-(trifluoromethyl)thieno [3,2-b]pyridine-3-carboxamide;

N-Methyl-5-(4-((2-morpholinoethyl)sulfonyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

N-Methyl-5-(4-((3-morpholinopropyl)sulfonyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

(R)-N-(Cyclopropylmethyl)-2-(2-methyl-4-(3-propionyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperazin-1-yl)acetamide ;

(S)-N-(Cyclopropylmethyl)-2-(2-methyl-4-(3-propionyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperazin-1-yl)acetamide ;

5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-1-yl)-N,2-dimethyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(2-(3-Fluoropyrrolidin-1-yl)-1-hydroxyethyl)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3- carboxamide;

5-(4-(2-(4,4-Difluoropiperidin-1-yl)-1-hydroxyethyl)-piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide;

5-(4-(1-Hydroxy-2-morpholinoethyl)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(3-(4,4-Difluoropiperidin-1-yl)-2-hydroxypropyl)-piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide;

5-(4-(3-(3,3-Difluoropyrrolidin-1-yl)-2-hydroxypropyl)-piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide;

5-(4-(2-(1-(2,2-Difluoroethyl)pyrrolidin-3-yl)-2-hydroxy-ethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3 ,2-b]-pyridine-3-carboxamide;

1-(2-Methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-2-(methoxymethyl)pyrrolidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-(2,2-difluoroethoxy)propane-2 -yl)-carbamate;

(+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((S) -1-(trifluoromethoxy)propan-2-yl)carbamate;

N-Isopropyl-7-(trifluoromethyl)-5-(3-((4-(trifluoromethyl)-cyclohexyl)amino)pyrrolidin-1-yl)thieno[3,2-b]pyridine-3-carboxamide;

7-Cyclopropyl-N-ethyl-5-(4-(2-(isopropylamino)-2-oxoethyl)-piperazin-1-yl)thieno[3,2-b]pyridine-3-carboxamide;

N-butyl-7-cyclopropyl-5-(4-(2-(isopropylamino)-2-oxoethyl)-piperazin-1-yl)thieno[3,2-b]pyridine-3-carboxamide;

1-(3-(Azetidin-1-carbonyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl tert-butylcarbamate;

1-(3-(3-Methoxyazetidin-1-carbonyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl tert-butylcarbamate;

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

2-(4-(3-Acetamido-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperazin-1-yl)-N-isopropylacetamide;

1-(3-Acetamido-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-piperidin-4-yl (cyclopropylmethyl)carbamate;

1-(3-Acetyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-piperidin-4-yl (cyclopropylmethyl)carbamate;

Methyl 5-(4-(((cyclopropylmethyl)carbamoyl)oxy)piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate;

1-(3-(Ethylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate;

1-(3-(Cyclopropylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate;

2-(4-(3-Acetyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-piperazin-1-yl)-N-isopropylacetamide;

1-(3-(Azetidin-1-carbonyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate;

1-(3-((2-Methoxyethyl)carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate;

1-(3-Propionyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-piperidin-4-yl (S)-(1-cyclopropylethyl)carbamate;

1-(3-(1-Hydroxypropyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl ((S)-1-cyclopropylethyl)carbamate;

Tertbutyl 7-(3-acetyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,7-diazaspiro[3,5]nonane-2-carboxylate;

1-(7-(3-Acetyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,7-diazaspiro[3,5]nonan-2-yl)-3-methylbutane -1-on;

1-(3-(Azetidin-1-carbonyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl 3-fluoroazetidin-1-carboxylate;

1-(3-(Azetidin-1-carbonyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl 3-chlorazetidin-1-carboxylate;

1-(3-(3-Chlorazetidin-1-carbonyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-chlorazetidin-1-carboxylate;

(+/-)-trans-1-(3-(Azetidin-1-carbonyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)-3-fluoropiperidin-4-yl isopropyl -carbamate;

7-Cyclopropyl-5-(4-(2-(isopropylamino)-2-oxoethyl)-piperazin-1-yl)-N-methylthieno[3,2-b]pyridine-3-carboxamide;

7-Ethyl-5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-1-yl)-N-methylthieno[3,2-b]pyridine-3-carboxamide;

7-Chloro-5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-1-yl)-N-methylthieno[3,2-b]pyridine-3-carboxamide;

5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-1-yl)-7-methoxy-N-methylthieno[3,2-b]pyridine-3-carboxamide;

7-(Difluoromethyl)-5-(4-(2-(isopropylamino)-2-oxoethyl)-piperazin-1-yl)-N-methylthieno[3,2-b]pyridine-3-carboxamide;

7-(Dimethylamino)-5-(4-(2-(isopropylamino)-2-oxoethyl)-piperazin-1-yl)-N-methylthieno[3,2-b]pyridine-3-carboxamide;

5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-1-yl)-N-methyl-7-(2,2,2-trifluoroethoxy)thieno[3,2-b]pyridin-3- carboxamide;

1-(7-Chloro-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)-piperidin-4-yl (cyclopropylmethyl)carbamate;

1-(7-(Dimethylamino)-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate;

1-(7-(Difluoromethyl)-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate;

1-(7-(Difluoromethyl)-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate;

1-(7-(Difluoromethyl)-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl cyclopropylcarbamate;

1-(7-Methoxy-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)-piperidin-4-yl isopropylcarbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)azetidin-3-yl (cyclopropylmethyl)carbamate trifluoroacetate;

5-(3-(2,2-Diethoxyethoxy)azetidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(3-(2-Hydroxy-2-methylpropoxy)azetidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide trifluoroacetate;

5-(3-(2-(Cyclopropylmethoxy)ethoxy)azetidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

(1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)azetidin-3-yl)methyl (cyclopropylmethyl)carbamate;

(1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)azetidin-3-yl)methyl (1-cyanopropan-2-yl)carbamate;

5-(3-((2-(Isopropylamino)-2-oxoethyl)amino)pyrrolidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(3-(2-(Isopropylamino)-2-oxoethoxy)pyrrolidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(3-((2-(Isopropylamino)-2-oxoethyl)(methyl)amino)-pyrrolidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3 -carboxamide;

5-(3-(3-(tert-butyl)ureido)pyrrolidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(3-(((5-Isopropyloxazol-2-yl)methyl)amino)pyrrolidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

N-Methyl-5-(3-(((4-methylthiazol-2-yl)methyl)amino)pyrrolidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)pyrrolidin-3-yl (cyclopropylmethyl)carbamate;

5-(4-(2-(Cyclopropylamino)-2-oxoethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide hydrochloride;

5-(4-(3-(tert-butyl)ureido)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(3,3-Dimethyl-2-oxobutyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(1-(Cyclopropylamino)-1-oxopropan-2-yl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl tert-butylcarbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl cyclopropylcarbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate trifluoroacetate;

((+/-)-cis-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-3,4-diyl bis((cyclopropylmethyl) -carbamate);

(+/-)-cis-4-Hydroxy-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-3-yl (cyclopropyl- methyl)carbamate;

(+/-)-cis-3-Hydroxy-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropyl- methyl)carbamate;

3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((tetrahydrofuran-2-yl)methyl)carbamate;

(+/-)-cis-3-methoxy-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropyl- methyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-hydroxy-3-methoxypropyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-cyanoazetidin-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-cyanomorpholine-4-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((1,4-dioxan-2-yl)methyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (5-fluoropyridin-3-yl)carbamate trifluoroacetate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-chlorazetidin-1-carboxylate;

(+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl diisopropylcarbamate;

(+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl oxetan-3- ylcarbamate;

(+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate;

(+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-methoxyazetidine -1-carboxylate;

(+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl cyclopropyl carbamate ;

(+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 4-methylpiperazine -1-carboxylate;

(+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((S) -1-cyclopropylethyl)-carbamate;

(3R,4R)-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate;

(3S,4S)-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate;

(+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (3-fluorocyclobutyl )-carbamate;

(+/-)-cis-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate;

(+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl cyclopropyl carbamate ;

(+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-( trifluoromethoxy)ethyl)-carbamate;

(3R,4R)-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl cyclopropylcarbamate;

(3S,4S)-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl cyclopropylcarbamate;

(+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-( trifluoromethoxy)ethyl)-carbamate;

(+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(trifluoromethoxy )-azetidine-1-carboxylate;

2-Cyanoethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

3-Cyanocyclobutyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

1-Cyanopropan-2-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

4-Methyl-N-(1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)morpholine-2-carboxamide;

1-Methoxypropan-2-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

1,3-Dimethoxypropan-2-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

(1,4-Dioxan-2-yl)methyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate ;

Octan-3-ylmethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

(4-Methylmorpholin-3-yl)methyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

1-Methylpyrrolidin-3-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate trifluoroacetate;

Oxetan-3-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

4-Methylpentan-2-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

(S)-1-Cyclopropylethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

(R)-1-Cyclopropylethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate trifluoroacetate;

1-Cyclopropylpropan-2-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

2-(Trifluoromethoxy)ethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

N-Methyl-5-(4-((4-methylthiazol-2-yl)methyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

5-(4-((4,5-Dimethyloxazol-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

5-(4-((5-Isopropyloxazol-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

5-(4-((5-Isopropyl-1,3,4-oxadiazol-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide;

5-(4-((4,5-Dimethyl-1H-imidazol-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3 -carboxamide;

5-(4-((1-((4,5-dimethyl-1H-imidazol-2-yl)methyl)-4,5-dimethyl-1H-imidazol-2-yl)methyl)piperazin-1-yl) -N-methyl-7-(trifluoromethyl)-thieno[3,2-b]pyridine-3-carboxamide;

N-Methyl-5-(4-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide;

5-(4-((4-Isopropylthiazol-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

N-Methyl-5-(4-(1-(4-methylthiazol-2-yl)ethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

N-Methyl-5-(4-(1-(5-methylthiazol-2-yl)ethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

N-Methyl-5-(1-((4-methylthiazol-2-yl)methyl)piperidin-4-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

N-Methyl-5-(4-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)-piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide;

N-Methyl-5-(4-(1-(6-methylpyridin-2-yl)ethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

N-Methyl-5-(4-(2-methylthiazol-4-carbonyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3- carboxamide;

5-(4-((2-(Cyclopropylamino)ethyl)sulfonyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide trifluoroacetate;

5-(4-((2-Isopropoxyethyl)sulfonyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-((2-(Cyclopropylmethoxy)ethyl)sulfonyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-((2-(Cyclopropyl(methyl)amino)ethyl)sulfonyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-((2-(3-Methoxyazetidin-1-yl)ethyl)sulfonyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3- carboxamide;

5-(4-((2-(Isopropylamino)-2-oxoethyl)amino)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide trifluoroacetate;

5-(4-(((tertbutylsulfinyl)amino)methyl)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(((Cyclopropylmethyl)amino)methyl)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide trifluoroacetate;

5-(4-(2-Isopropoxyethoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

5-(4-(1-(Cyclopropylmethoxy)-3-hydroxypropan-2-yl)-piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide ;

5-(4-(3-Formamidopropyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(2-(Bis(cyclopropylmethyl)amino)ethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(3-(Cyclopropanecarboxamido)propyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide trifluoroacetate;

5-(4-(2-(Cyclopropylmethoxy)ethoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(2-(Isopropylsulfonyl)ethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-(2-Hydroxy-3-morpholinopropoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-((4-Isopropylmorpholin-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide trifluoroacetate;

Methyl 5-(4-((3-isopropoxyazetidin-1-yl)methyl)piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate;

5-(4-((3-Isopropoxyazetidin-1-yl)methyl)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

5-(4-(3-(3,3-Difluoropyrrolidin-1-yl)-2-hydroxypropoxy)-piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide;

5-(4-(2-hydroxy-3-isopropoxypropoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-(4-((5-Isopropyl-1,3,4-oxadiazol-2-yl)methoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide;

(S)-1-Cyclopropylethyl 7-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,7-diazaspiro[3,5]nonan- 2-carboxylate;

Cyclopropyl 7-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)-2,7-diazaspiro[3,5]nonane-2-carboxylate;

Oxetan-3-yl 7-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)-2,7-diazaspiro[3,5]nonane-2-carboxylate ;

Isopropyl 7-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,7-diazaspiro[3,5]nonane-2-carboxylate;

5-(2-(Ethyl(isopropyl)carbamoyl)-2,7-diazaspiro[3,5]nonan-7-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3 -carboxamide;

Tertbutyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine-1-carboxylate;

5-(1-(1-(Cyclopropylamino)-1-oxopropan-2-yl)piperidin-4-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

N-Methyl-5-(1-((4-methylthiazol-2-yl)methyl)piperidin-4-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide hydrochloride;

(S)-1-Cyclopropylethyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine-1-carboxylate;

4-Methylpentan-2-yl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-1-carboxylate;

4-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)cyclohex-3-en-1-yl (cyclopropylmethyl)carbamate;

2-Cyclopropylethyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidine-1-carboxylate;

Tertbutyl (3S,4S)-3,4-dihydroxy-4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine-1-carboxylate;

2-Cyclopropyl-2-oxoethyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine-1-carboxylate;

4-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)cyclohexyl (cyclopropylmethyl)carbamate;

2-(Trifluoromethoxy)ethyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine-1-carboxylate;

Tertbutyl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate;

Tertbutyl 2-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-7-azaspiro[3,5]nonane-7-carboxylate;

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

2-(Trifluoromethoxy)ethyl 2-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-7-azaspiro[3,5]nonane-7-carboxylate ;

Tertbutyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)thio)piperidine-1-carboxylate;

Tertbutyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)sulfinyl)piperidine-1-carboxylate;

Tertbutyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)sulfonyl)piperidine-1-carboxylate;

5-(4-(2-(Cyclopropylamino)-2-oxoethoxy)phenyl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

(1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)-1H-imidazol-4-yl)methyl (cyclopropylmethyl)carbamate;

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

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

5-((6-Methoxypyridin-3-yl)methoxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide trifluoroacetate;

5-((1-(Cyclopropylcarbamoyl)azetidin-3-yl)methoxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

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

Tertbutyl 3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

5-((1-((Cyclopropylmethyl)carbamoyl)pyrrolidin-3-yl)oxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

Tertbutyl (R)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

(R)-5-((1-((Cyclopropylmethyl)carbamoyl)pyrrolidin-3-yl)-oxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

Tertbutyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

(S)-5-((1-((Cyclopropylmethyl)carbamoyl)pyrrolidin-3-yl)-oxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

Cyclopropylmethyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

1-Methoxypropan-2-yl (3S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

1-Cyanoethyl (3R)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

1,3-Difluoropropan-2-yl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidin-1- carboxylate;

Tertbutyl 3-hydroxy-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

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

Isopropyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

(S)-1-Cyclopropylethyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

3-(Trifluoromethoxy)propyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

2,2,2-Trifluoroethyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

Tertbutyl (+/-)-trans-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl (+/-)-trans-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-pyrrolidine-1-carboxylate;

Cyclopropylmethyl (+/-)-trans-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

2-Cyclopropylethyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

Tertbutyl (+/-)-cis-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

Cyclopropylmethyl (+/-)-cis-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl (+/-)-cis-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-pyrrolidine-1-carboxylate;

3,3,3-Trifluoropropyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

(2,2-Difluorocyclopropyl)methyl (3S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

4,4,4-Trifluorobutyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

Tertbutyl (+/-)-trans-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-4-morpholinopyrrolidine-1-carboxylate ;

(5-(Trifluoromethyl)isoxazol-3-yl)methyl (S)-3-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -pyrrolidine-1-carboxylate;

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

Tertbutyl ((+/-)-trans-3-(dimethylamino)-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- pyrrolidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl (+/-)-trans-3-(dimethylamino)-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-pyrrolidine-1-carboxylate;

Tertbutyl (S)-3-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

Tert-butyl (+/-)-trans-3-methoxy-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate;

2-(Trifluoromethoxy)ethyl ((+/-)-trans-3-methoxy-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl) hydroxy)-pyrrolidine-1-carboxylate;

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

Tertbutyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

5-((1-(2-(Isopropylamino)-2-oxoethyl)piperidin-4-yl)oxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

Tert-butyl (+/-)-cis-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclohexyl)carbamate;

Isopropyl (+/-)-cis-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclohexyl)carbamate;

Tertbutyl (+/-)-endo-7-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-3-oxa-9-azabicyclo [3,3,1]-nonane-9-carboxylate;

2-(Trifluoromethoxy)ethyl (+/-)-endo-7-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-3-oxa- 9-aza-bicyclo[3,3,1]nonane-9-carboxylate;

Tertbutyl (+/-)-exo-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)-8-azabicyclo[3.2. 1]octane-8-carboxylate;

Tertbutyl (+/-)-endo-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-8-azabicyclo[3.2.1 ]octane-8-carboxylate;

2-(Trifluoromethoxy)ethyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)methyl)piperidine-1-carboxylate;

5-(4-((Cyclopropylmethyl)carbamoyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide trifluoroacetate;

Tertbutyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)methyl)piperidin-1-carboxylate;

2-(Trifluoromethoxy)ethyl (+/-)-exo-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-8-azabicyclo- [3,2,1]octane-8-carboxylate;

6-Chloro-5-[4-[2-(isopropylamino)-2-oxoethyl]piperazin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

6-Chloro-5-[4-[2-(isopropylamino)-2-oxoethyl]piperazin-1-yl]-2-methoxy-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridinium- 3-carboxamide;

[1-[6-Chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-(cyclopropylmethyl)carbamate;

[1-[6-Fluoro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-[(1S)-1-cyclopropylethyl]carbamate ;

[1-[6-Chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-cyclopropylcarbamate;

[1-[6-fluoro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-cyclopropylcarbamate;

Tert-butyl N-[1-[3-(isopropylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl]pyrrolidin-3-yl]carbamate;

N-Isopropyl-2-[4-[3-(5-methyloxazol-2-yl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl]piperazin-1-yl]acetamide;

N-[(4-Fluorophenyl)methyl]-5-[4-[2-(isopropylamino)-2-oxo-ethyl]piperazin-1-yl]-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide;

5-[4-[2-(Isopropylamino)-2-oxo-ethyl]piperazin-1-yl]-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

N-Isopropyl-2-[4-[3-(4-methyloxazol-2-yl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl]piperazin-1-yl]acetamide;

2-[4-[3-(1-Hydroxypropyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]piperazin-1-yl]-N-isopropyl-acetamide;

N-Isopropyl-2-[4-[3-propanoyl-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]piperazin-1-yl]acetamide;

2-[4-[3-(Azetidin-1-carbonyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]piperazin-1-yl]-N-isopropyl-acetamide;

N-Isopropyl-2-[4-[3-(methoxymethyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl]piperazin-1-yl]acetamide;

N-Isopropyl-2-[4-[3-methyl-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]piperazin-1-yl]acetamide;

[1-[3-Propanoyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-(cyclopropylmethyl)carbamate;

[1-[3-(Trideuteriomethylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-cyclopropylcarbamate;

7-(1,1-Difluoroethyl)-5-[4-[2-(isopropylamino)-2-oxoethyl]-piperazin-1-yl]-N-methyl-thieno[3,2-b]pyridin-3- carboxamide;

[1-[7-(1,1-Difluoroethyl)-3-(methylcarbamoyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl]N-(cyclopropylmethyl)carbamate hydrochloride;

[1-[3-(Methylcarbamoyl)-7-(2,2,2-trifluoroethoxy)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-isopropylcarbamate;

5-[3-(4-Hydroxy-4-methyl-pent-2-inoxy)azetidin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-[3-[3-(Cyclopropylmethoxy)azetidin-1-yl]azetidin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

Methyl 5-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate;

5-[3-[[(1R,2R)-2-Hydroxycyclohexyl]amino]pyrrolidin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-[3-(2-Isopropoxyethylamino)pyrrolidin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-[3-(3-Hydroxy-3-methyl-but-1-yl)pyrrolidin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-[3-(Cyclopropylmethoxy)pyrrolidin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

Methyl 5-[4-(tert-butoxycarbonylamino)-1-piperidyl]-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate;

5-[4-[2-[(2-Hydroxy-1,1-dimethyl-ethyl)amino]-1-methyl-2-oxo-ethyl]piperazin-1-yl]-N-methyl-7-(trifluoromethyl )thieno[3,2-b]-pyridine-3-carboxamide;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-(2-methoxy-2-methyl-propyl)carbamate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-(3-methoxy-2,2-dimethylpropyl) -carbamate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] 3,3-dimethylpiperazine-1-carboxylate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl]N-(cyclopropylmethyl)carbamate hydrochloride;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-(2,2-difluoro-1-methyl-ethyl) carbamate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-(2-fluoro-1-methyl-ethyl)carbamate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-[2-hydroxy-1-(hydroxymethyl)ethyl]- carbamate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-tetrahydrofuran-3-ylcarbamate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-(oxetan-3-yl)carbamate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-(3-methyloxetan-3-yl)carbamate;

[1-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] 3-methylthiomorpholine-4-carboxylate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] 3-methyl-1-oxo-1,4-thiazinan-4 -carboxylate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] 3-methyl-1,1-dioxo-1,4-thiazinan- 4-carboxylate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-[(1S)-1-methyl-2-methylsulfanyl- ethyl]carbamate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-[(1S)-1-methyl-2-methylsulfinyl- ethyl]carbamate;

[1-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-[(1S)-1-methyl-2-methylsulfonyl-ethyl ]-carbamate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-(1,1-yl-3-yl)carbamate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] 3-(3-pyridyloxy)azetidine-1-carboxylate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] 3-(2-pyridyl)azetidine-1-carboxylate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-(1-cyclopropyl-1-deuterioethyl)-carbamate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-(1-deuterio-1-methylethyl)carbamate;

[2,2,6,6-Tetradeuterio-1-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-cyclopropyl- carbamate;

[2,2,6,6-Tetradeuterio-1-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-isopropyl- carbamate;

[(1R,5S)-8-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-8-azabicyclo[3.2.1]octan-3-yl] N-cyclopropyl carbamate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-[(1S)-2,2-dideuterio-1- methyl 2-(trideuteriomethoxy)ethyl]carbamate;

[(1R,5S)-8-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-8-azabicyclo[3.2.1]octan-3-yl] N-cyclopropyl carbamate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-[(1R)-2-fluoro-1-methylethyl] carbamate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-[(1S)-2-fluoro-1-methylethyl]carbamate ;

[1-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-[cyclopropyl(dideuterio)methyl]-carbamate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-[2-fluoro-1-(fluoromethyl)ethyl]carbamate ;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] 6-hydroxy-8-oxa-2-azaspiro[3.4]- octane-2-carboxylate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] 6-[(2,2,2-trifluoro-1-methylethyl )amino]-8-oxa-2-azaspiro[3.4]octane-2-carboxylate;

[1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] 3-(2,2,2-trifluoroethoxy)azetidine-1- carboxylate;

[2-Fluoro-1-(fluoromethyl)ethyl] N-[1-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl]carbamate;

5-[4-[(2-Ethylthiazol-4-yl)methyl]piperazin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

N-Methyl-5-[4-[(4-methyl-2-thienyl)methyl]piperazin-1-yl]-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

N-Methyl-5-[4-[(2-methyloxazol-4-yl)methyl]piperazin-1-yl]-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

5-[4-(Isobutylcarbamoyl)-1-piperidyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-[4-(2-Hydroxy-4,4-dimethylpentyl)piperazin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-[4-[1-(4,4-Dimethyl-5H-oxazol-2-yl)ethyl]piperazin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide;

5-[4-[3-(Cyclopropylmethoxy)pyrrolidin-1-yl]-1-piperidyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

5-[4-(2-Hydroxy-3-isopropoxypropyl)piperazin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-[4-(2-Isopropoxyethylamino)-1-piperidyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-[4-(3-tert-butoxy-2-hydroxy-propyl)piperazin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-[4-(3-Isopropoxypyrrolidin-1-yl)-1-piperidyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide;

5-[4-(4-Hydroxy-4-methyl-pent-2-ynyl)piperazin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-[4-(3-Hydroxy-3-methyl-but-1-ynyl)-1-piperidyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-[4-(5-Hydroxy-5-methyl-hexa-1,3-diinyl)-1-piperidyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide ;

5-[4-(4-Hydroxy-4-methyl-pent-2-inoxy)-1-piperidyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

[1,1-Dimethyl-4-[[1-[3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl]-4-piperidyl]oxy]but-2 -inyl]acetate;

5-[4-Hydroxy-4-(5-hydroxy-5-methylhexa-1,3-diinyl)-1-piperidyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3 -carboxamide;

5-[2-(Cyclopropylmethoxy)-4-oxa-8-azaspiro[4,5]decan-8-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide ;

5-[2-(2-Hydroxy-2-methylpropoxy)-4-oxa-8-azaspiro[4,5]-decan-8-yl]-N-methyl-7-(trifluoromethyl)thieno[3, 2-b]pyridine-3-carboxamide;

5-(2-Hydroxy-4-oxa-8-azaspiro[4,5]decan-8-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-[6-(Cyclopropylmethoxy)-8-oxa-2-azaspiro[3.4]octan-2-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-[6-(3,3-Difluoropyrrolidin-1-yl)-8-oxa-2-azaspiro[3.4]-octan-2-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2- b]pyridine-3-carboxamide;

N-Methyl-7-(trifluoromethyl)-5-[6-[(2,2,2-trifluoro-1-methyl-ethyl)amino]-8-oxa-2-azaspiro[3.4]octan-2-yl] thieno[3,2-b]-pyridine-3-carboxamide trifluoroacetate;

Tertbutyl 2-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-2,6-diazaspiro[3.3]heptane-6-carboxylate;

Tertbutyl 7-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-2,7-diazaspiro[3,5]nonane-2-carboxylate;

5-[6-(2-tertbutoxyacetyl)-2,6-diazaspiro[3.3]heptan-2-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-[2-(2-tertbutoxyacetyl)-2,7-diazaspiro[3,5]nonan-7-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide ;

tert-butyl 2-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-2,7-diazaspiro[3,5]nonane-7-carboxylate;

5-[7-(2-tertbutoxyacetyl)-2,7-diazaspiro[3,5]nonan-2-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]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-b]pyridine-3-carboxamide;

N-Methyl-5-[2-(4-methylpyrimidin-2-yl)-2,7-diazaspiro[3,5]-nonan-7-yl]-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide;

5-[2-(Cyclopropylmethylcarbamoyl)-2,7-diazaspiro[3,5]nonan-7-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

Cyclopropylmethyl 7-[3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl]-2,7-diazaspiro[3,5]nonane-2-carboxylate;

N-Methyl-5-[2-[(2S)-1-methylpyrrolidin-2-carbonyl]-2,7-diazaspiro[3,5]nonan-7-yl]-7-(trifluoromethyl)thieno[3,2 -b]pyridine-3-carboxamide;

N-methyl-5-[2-(4-methylpiperazin-1-carbonyl)-2,7-diazaspiro-[3,5]nonan-7-yl]-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide;

5-[2-[2-(3,3-Difluoropyrrolidin-1-yl)acetyl]-2,7-diazaspiro-[3,5]nonan-7-yl]-N-methyl-7-(trifluoromethyl)thieno [3,2-b]pyridine-3-carboxamide;

5-[2-[2-[(3R)-3-Fluoropyrrolidin-1-yl]acetyl]-2,7-diazaspiro-[3,5]nonan-7-yl]-N-methyl-7-(trifluoromethyl )thieno[3,2-b]pyridine-3-carboxamide;

5-[2-(2-Hydroxy-3,3-dimethylbutyl)-2,7-diazaspiro[3,5]-nonan-7-yl]-N-methyl-7-(trifluoromethyl)thieno[3, 2-b]pyridine-3-carboxamide;

5-[2-(3-Hydroxy-3-methyl-butanoyl)-2,7-diazaspiro[3,5]-nonan-7-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2- b]pyridine-3-carboxamide hydrochloride;

N-Methyl-5-[2-[2-(trifluoromethoxy)acetyl]-2,7-diazaspiro-[3,5]nonan-7-yl]-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide;

5-[2-(2-Methoxypropanoyl)-2,7-diazaspiro[3,5]nonan-7-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide ;

(2-Methoxy-1,1-dimethylethyl) 7-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-2,7-diazaspiro[3,5] -nonane-2-carboxylate;

N-Methyl-5-[6-(4-methylpiperazine-1-carbonyl)-2,6-diazaspiro-[3,3]heptan-2-yl]-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide;

N-Methyl-5-[2-(3,3,3-trifluoro-2-hydroxypropanoyl)-2,7-diazaspiro[3,5]nonan-7-yl]-7-(trifluoromethyl)thieno[3 ,2-b]pyridine-3-carboxamide;

(3-Hydroxy-3-methyl-butyl)4-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]piperidine-1-carboxylate;

Tertbutyl 7-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-2-azaspiro[3,5]nonane-2-carboxylate;

2-(Trifluoromethoxy)ethyl 4-[1-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]ethyl]piperazine-1-carboxylate;

2-(Trifluoromethoxy)ethyl 7-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-2-azaspiro[3,5]nonane-2-carboxylate ;

Methyl 5-[(1-tert-butoxycarbonyl-4-piperidyl)amino]-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate;

Methyl 5-[(1-tert-butoxycarbonylpyrrolidin-3-yl)amino]-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate;

Methyl 5-[(1-tert-butoxycarbonyl-4-piperidyl)methylamino]-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate;

5-[2-(2-Isopropylthiazol-4-yl)ethylamino]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

Methyl 5-[2-(1-tert-butoxycarbonylpyrrolidin-3-yl)ethynyl]-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate;

tert-butyl 4-hydroxy-4-[2-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]ethynyl]piperidine-1-carboxylate;

[(1S)-1-Cyclopropylethyl] 3-[[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]oxymethyl]azetidine-1-carboxylate;

Tertbutyl 6-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]oxy-8-oxa-2-azaspiro[3.4]octane-2-carboxylate;

Tertbutyl 2-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]oxy-4-oxa-8-azaspiro[4,5]decane-8-carboxylate;

N-Methyl-5-[5-[3-(3-pyridyl)azetidine-1-carbonyl]-3-furyl]-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-[4-[4-(2-Hydroxy-2-methyl-propyl)piperazin-1-yl]phenyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide ;

5-[6-(6-Chloro-3-pyridyl)-3-pyridyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide;

5-[6-(3-Isopropoxyazetidin-1-yl)-3-pyridyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide trifluoroacetate;

5-[6-[2-(1-hydroxycyclohexyl)ethynyl]-3-pyridyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide trifluoroacetate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (1-(1H-imidazol-1-yl)propan-2-yl )carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 2-methyl-4-(1H-1,2,4-triazol- 1-yl)piperidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (1-(methylsulfonyl)azetidin-3-yl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 2-methyl-4-(methylsulfonyl)piperazine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-cyclopropylpropan-2-yl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-(1-cyclopropylpropan-2-yl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl(oxetan-3-ylmethyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((3-hydroxyoxetan-3-yl)methyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((3-fluoroxetan-3-yl)methyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-2-methylazetidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-2-methylazetidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-methoxyazetidin-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 2-oxa-6-azaspiro[3.3]heptane-6-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 6-methyl-2,6-diazaspiro[3.3]heptane-2-carboxylate ;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 5,8-dioxa-2-azaspiro[3.4]octane-2-carboxylate ;

1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S)-3-cyclopropyl-3-hydroxy-2-methyl-azetidine -1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3S)-3-hydroxy-2-methylpyrrolidine-1-carboxylate ;

Cyclopropylmethyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperazine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-fluoroethyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2,2-difluoroethyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (methyl-d3)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (3-methoxycyclobutyl)carbamate;

(+/-)-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl ((1r,3r)-3-cyanocyclobutyl )-carbamate;

(+/-)-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl ((1s,3s)-3-cyanocyclobutyl )carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (3-ethoxycyclobutyl)carbamate;

(+/-)-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl ((1r,3r)-3-( methylsulfonyl)-cyclobutyl)carbamate;

(+/-)-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl ((1s,3s)-3-( methylsulfonyl)-cyclobutyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-oxaspiro[3.3]heptan-6-yl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((2-methyltetrahydrofuran-2-yl)methyl)carbamate;

Cyclopropyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3S)-3-(dimethylamino)-2-methylazetidin-1 -carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3R)-3-(dimethylamino)-2-methylazetidin-1 -carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-(oxetan-3-yl)ethyl)carbamate ;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-(1-(oxetan-3-yl)ethyl)carbamate ;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3S)-3-methoxy-2-methylazetidine-1-carboxylate ;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl[1,3'-biazetidine]-1'-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2'S,3'S)-2'-methyl-[1,3'- biazetidine]-1'-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3R)-3-hydroxy-2-methylpyrrolidine-1-carboxylate ;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3S)-3-hydroxy-2,3-dimethylpyrrolidin-1 -carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3S)-3-cyano-2-methylazetidine-1-carboxylate ;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 6-(cyanomethyl)-2,6-diazaspiro[3.3]heptan-2 -carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3R)-3-(cyanomethyl)-2-methylazetidin-1 -carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3S)-3-(cyanomethyl)-2-methylazetidin-1 -carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 1-methyl-1,6-diazaspiro[3.3]heptane-6-carboxylate ;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-pent-3-yn-2-ylcarbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-pent-3-yn-2-ylcarbamate;

(2S,3S)-1,2-Dimethylpyrrolidin-3-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl) -carbamate;

(S)-1-(2,2-Difluoroethyl)pyrrolidin-3-yl (1-(3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine -4-yl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 6-methyl-1,6-diazaspiro[3.3]heptane-1-carboxylate ;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3R)-2-methyl-3-(1H-1, 2,4-triazol-1-yl)-azetidine-1-carboxylate;

1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(5-hydroxy-5-methylhex-3-yne- 2-yl)-carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-(5-hydroxy-5-methylhex-3-yne- 2-yl)-carbamate;

1-Methylazetidin-3-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

Isopropyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

2,2-Difluoroethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

1-(1,3-Difluoropropan-2-yl)azetidin-3-yl (1-(3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine -4-yl)carbamate;

Methyl-d ₃ (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

2-Fluoroethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

1-Fluoropropan-2-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate;

(+/-)-cis-(1s,3s)-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl oxetane-3 -ylcarbamate;

(1s,3s)-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl 3-methoxyazetidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 1-oxa-6-azaspiro[3.3]heptane-6-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((S)-1-((S)-oxetan-2-yl )ethyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((R)-1-((S)-oxetan-2-yl )ethyl)carbamate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3R)-3-cyano-2-methylpyrrolidine-1-carboxylate ;

(S)-1-((S)-Oxetan-2-yl)ethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4 -yl)carbamate;

(S)-1-((R)-Oxetan-2-yl)ethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4 -yl)carbamate;

(+/-)-cis-(1s,3s)-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl isopropylcarbamate;

(+/-)-cis-(1s,3s)-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl 3-( trifluoromethoxy)azetidine-1-carboxylate;

(+/-)-cis-(1s,3s)-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl 3-hydroxy -3-methyl-azetidine-1-carboxylate;

(+/-)-cis-(1s,3R)-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl ((S )-1-(trifluoro-methoxy)propan-2-yl)carbamate;

(+/-)-cis-(1s,3s)-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl 3-( dimethylamino)-azetidine-1-carboxylate;

4-Fluoro-1-methylpyrrolidin-3-yl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(1H-imidazol-1-yl)azetidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(1H-1,2,3-triazol-1-yl) azetidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(1H-1,2,4-triazol-1-yl) azetidine-1-carboxylate;

(+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(1H -1,2,4-triazol-1-yl)azetidine-1-carboxylate;

(+/-)-cis-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(1H -1,2,4-triazol-1-yl)azetidine-1-carboxylate;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 1-cyclopropyl-1,6-diazaspiro[3.3]heptane-6-carboxylate ;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 1-ethyl-1,6-diazaspiro[3.3]heptane-6-carboxylate ;

1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 1-(2,2,2-trifluoroethyl)-1,6-diazaspiro [3.3]-heptane-6-carboxylate;

(+/-)-trans-2-(Trifluoromethoxy)ethyl 3-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate;

(+/-)-cis-2-(Trifluoromethoxy)ethyl 3-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate;

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

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

tert-butyl 2,2-dimethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

(S)-1-(Trifluoromethoxy)propan-2-yl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate ;

(R)-1-(Trifluoromethoxy)propan-2-yl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate ;

(S)-2-(Trifluoromethoxy)propyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

(R)-2-(Trifluoromethoxy)propyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

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

(S)-1-(Trifluoromethoxy)propan-2-yl (S)-3-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-pyrrolidine-1-carboxylate;

(3S,4S)-3-Methyl-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate;

(3R,4R)-3-Methyl-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(trifluoromethoxy)- azetidine-1-carboxylate;

(S)-2-(Trifluoromethoxy)propyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate ;

(R)-2-(Trifluoromethoxy)propyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate ;

(S)-2-(Trifluoromethoxy)propyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]-heptane -2-carboxylate;

(R)-2-(Trifluoromethoxy)propyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]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-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

(3R,4S)-3-methyl-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate;

(3R,4S)-3-Methyl-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(trifluoromethoxy)- azetidine-1-carboxylate;

(S)-1-Cyanopropan-2-yl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate;

(S)-1-Cyanopropan-2-yl (2R,4R)-2-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-5- yl)oxy)-piperidine-1-carboxylate;

(S)-1-Cyclopropylethyl (2R,4R)-2-methyl-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl) hydroxy)-piperidine-1-carboxylate;

2-Hydroxy-2-methylpropyl (2R,4R)-2-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -piperidine-1-carboxylate;

1-(2,2,2-Trifluoroethyl)pyrrolidin-3-yl 4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- piperidine-1-carboxylate;

2-(Fluoromethoxy)ethyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; or

(S)-1-(3-Fluoroazetidin-1-yl)propan-2-yl (2R,4R)-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2 -b]pyridin-5-yl)-oxy)piperidine-1-carboxylate.

[0021] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier or excipient.

[0022] In some embodiments, the pharmaceutical composition described herein further includes one or more additional therapeutic agents.

[0023] In another aspect, the present invention provides a method of treating or alleviating 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 invention provides a method of reducing or restoring sulfatide levels in a patient, comprising administering to the patient an effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

[0025] In another aspect, the present invention relates to a method of treating or alleviating the severity of Krabbe 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 to the invention unless otherwise noted.

[0027] In the description of the present invention, it is understood that whenever any variable constituent component is present anywhere in the present invention, that variable constituent component can be independently selected from among these 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 compound of the invention that can be administered without exhibiting any significant undesirable biological effect(s). or without exhibiting any harmful interaction(s) with any other component of the pharmaceutical composition in which it may be contained.

[0029] As used herein, the term “prodrug” refers to a pharmacological derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the body to release the active drug. For example, prodrugs are variants or derivatives of compounds of Formula I or any of the compounds 1.1-1.300 that have moieties capable of being cleaved under particular metabolic conditions, thereby converting the prodrugs into compounds of Formula I or any of the compounds 1.1-1.300. Such prodrugs are therefore pharmaceutically active in vivo when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. Compounds in prodrug form may be referred to herein as single, double, ternary, etc., depending on the number of biotransformation steps required to release the active drug in the body and the number of functionalities present in the compound in the precursor form. Prodrug forms often achieve a number of advantages in terms of solubility, histocompatibility or delayed release in the mammalian body (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 known in the art include generally known acid derivatives, such as, for example, esters prepared by reacting the parent acid with a suitable alcohol, amides prepared by reacting the parent compound with acidic properties with an amine, groups with basic properties resulting from the reaction acylated derivative with basic properties, and so on. Of course, other prodrug derivatives can be combined with other characteristic properties disclosed in the invention to increase bioavailability. As such, it will be apparent to those skilled in the art that the compounds disclosed herein having free amino groups, amido groups, hydroxyl groups or carboxyl groups can be converted into prodrugs. Prodrugs include compounds having an amino acid residue or polypeptide chain of two or more (eg, two, three or four) amino acid residues that are covalently linked via peptide bonds to the free amino groups, hydroxyl groups or carboxylic acid groups of the compounds disclosed herein. Amino acid residues include 20 naturally occurring amino acids, usually designated by three letter symbols, and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone Prodrugs also include compounds having a carbonate moiety, carbamate moiety, amide moiety, or alkyl ether moiety covalently linked to any of the substituents described above.

[0030] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient (adjuvant)" refers to compositions into which a compound of Formula I, or any of compounds 1.1-1.300, is included to deliver, provide stability or solubility of the compound in medicinal products. forms, where the compositions include, but are not limited to, any solvents, diluents or other liquid vehicles, dispersing or suspending agents, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like excipients suitable for the preparation of the specific dosage form required.

[0031] As used herein, the term "effective amount" of an enzyme or synthetic drug, 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 a variety of predetermined parameters well known to one skilled in the art. in this area.

[0032] As used herein, the terms “patient,” “subject,” and “person” are used interchangeably.

[0033] As used herein, the term "UGT8" refers to UDP-glycosyltransferase 8, an enzyme that, together with the cofactor saposin 1, catalyzes the transfer of galactose from UDP-galactose to ceramide to form galactosylceramide (GalCer), also known as galactosylcerebroside. Other names for UGT8 include UDP-galactose-ceramide galactosyltransferase, 2-hydroxy-acylsphingosine-1-betagalactosyltransferase, ceramide-UDP-galactosyltransferase, ceramide galactosyltransferase, and cerebroside synthase. GalCer in turn is a 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 sulfatide (SFT) back to GalCer and sulfate, resulting in the disease metachromatic leukodystrophy (MLD). Therefore, SFT accumulates in patients with MLD, leading to demyelination. Similarly, patients with galactosylcerebrosidase (GalC) mutations are unable to break down GalCer into galactose and ceramide, resulting in Krabbe disease. Patients with Krabbe disease accumulate psychosine and, to a lesser extent, GalCer, which also leads to demyelination. In the case of these two diseases, substrate reduction therapy (SRT) consists of inhibiting GalCer biosynthesis by UGT8, thereby preventing the accumulation of the toxic products SFT and psychosine, respectively, which are responsible for disease manifestations.

[0034] As used herein, the term “combination therapy” refers to treating a patient using two or more therapeutic approaches (eg, enzyme replacement therapy and drug therapy) in cyclic, alternating and/or simultaneous courses of treatment. Examples of treatment courses may include, but are not limited to: (1) enzyme replacement therapy followed by drug therapy; (2) drug therapy, then enzyme replacement therapy; (3) enzyme replacement therapy concurrently with drug therapy, and (4) and any combination of the above-mentioned therapies. If necessary, combination therapy may provide temporary overlapping of therapeutic approaches, 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" refers to the administration of an exogenously produced natural or recombinant enzyme to a patient in need thereof. In the case of lysosomal storage disease, for example, the patient accumulates dangerous levels of substrate (i.e., stored material) in the lysosomes due to deficiency or absence of the enzyme responsible for metabolizing the substrate, or due to deficiency of the enzyme activator required for the corresponding enzymatic function. Enzyme replacement therapy is offered to the patient to reduce the levels (ie, reduce the mass) of accumulated substrate in the affected tissues. Enzyme replacement therapies for the treatment of lysosomal storage diseases are well known.

[0036] The components of the combination disclosed herein can be administered to a patient simultaneously or sequentially. It should be understood 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, which can be administered either simultaneously or sequentially.

[0037] As used herein, the term "MLD" (metachromatic leukodystrophy) refers to a disease in patients with mutations in the enzyme arylsulfatase A (ARSA) that result in an inability to degrade sulfatide (SFT) back to GalCer and sulfate. As a result, SFT accumulates in tissues of the central and peripheral nervous system, causing neuropathology leading to demyelination and death.

[0038] As used herein, the term “Krabbe disease” refers to a disease in patients with mutations in galactosylcerebrosidase (GalC) that result in an inability to degrade GalCer back to galactose and ceramide. Accumulation of UGT8 and psychosine (another substrate for GalC) in the central and peripheral nervous system also causes neuropathy, leading to demyelination and death.

[0039] As used herein, the term “alkyl” refers to monovalent saturated aliphatic free radical groups containing up to 20 carbon atoms and a corresponding number of hydrogen atoms. The hydrocarbon chain can be linear or branched. The term "C _1-6 alkyl" refers to a saturated linear or branched free radical consisting generally of 1 to 6 carbon atoms and the corresponding number of hydrogen atoms. Examples of "C _1-6 alkyl" groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and so on. Of course, other “C _1-6 alkyl” groups are well known to those skilled in the art and may have beneficial effects when used in the present invention. The term "alkyl" also includes "cycloalkyl" groups, further described below.

[0040] As used herein, the term “cycloalkyl” refers to a non-aromatic saturated or unsaturated free radical forming at least one ring consisting generally of 3 to 10 carbon atoms and a corresponding number of hydrogen atoms. Therefore, the term "cycloalkyl" includes cycloalkenyl groups, further described below. As such, cycloalkyl groups can be monocyclic or polycyclic. The individual rings of such polycyclic cycloalkyl groups may have various bonds among themselves, for example, fused, bridged, spiro, and so on, in addition to substitution with a covalent bond. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornanyl, bicyclo[3,2,1]octanyl, octahydropentalenyl, spiro[4,5]decanyl, cyclopropyl, adamantyl substituted with cyclobutyl, cyclobutyl substituted with cyclopentyl, cyclohexyl substituted with cyclopropyl, and so on. Of course, other cycloalkyl groups are well known to those skilled in the art and may have beneficial effects when used in the present invention. As used herein, the term “heterocycloalkyl” means a non-aromatic free radical having from 3 to 10 atoms (i.e., ring atoms) that form at least one ring, wherein from 2 to 9 of the ring atoms are carbon atoms and the remaining ring atom(s) (ie, ring heteroatom(s)) are selected from the group consisting of nitrogen, sulfur and oxygen. As such, heterocycloalkyl groups can be monocyclic or polycyclic. The individual rings of such polycyclic cycloalkyl groups may have various bonds among themselves, for example, fused, bridged, spiro, and so on, in addition to substitution with a covalent bond. Examples of heterocyclic groups include pyrrolidinyl, tetrahydrofuranil, dihydrofuranil, tetrahydinyl, pirate, thiopiralil, azindinyl, azithidinyl, oxyranyl, methyndoxil, chromenil, barbitral, Izoxazolidinyl, 1.3-oxasoline-3-il, isotiazoladinyl, 1.3-3- Zolidin-3- yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, piperisin-2-onyl, piperisin-3-onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, imidazolidinyl, 2-imidazolidinyl, 1,4-dioxanyl, 8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo-[3.2.1]octanyl, 2,5-diazabicyclo[ 2.2.1]heptanyl, 2,5-diaza-bicyclo[2.2.2]octanyl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptanyl, 3-azabicyclo[3.1. 0]hexanyl, 2-azaspiro[4.4]nonanyl, 7-oxa-1-azaspiro[4.4]nonanyl, 7-aza-bicyclo[2.2.2]heptanyl, octahydro-1H-indolyl, and so on. In most cases, the heterocycloalkyl group is usually attached to the main structure via a carbon atom or a nitrogen atom. Of course, other heterocycloalkyl groups are well known to those skilled in the art and may have beneficial effects when used in the present invention.

[0041] As used herein, the term “heteroaryl” means a free aromatic radical having from 5 to 10 atoms (i.e., ring atoms) that form at least one ring, wherein from 2 to 9 of the ring atoms are carbon atoms, and the remaining ring atom(s) (ie, ring heteroatom(s)) are selected from the group consisting of nitrogen, sulfur and oxygen. By themselves, heteroaryl groups can be monocyclic or polycyclic. The individual rings of such polycyclic heteroaryl groups may have various bonds among themselves, for example, fused ones, and so on, in addition to substitution with a covalent bond. Examples of heteroaryl groups include furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, thiazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1, 3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyridinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydro -quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and benzoxa zinil, and so on. In most cases, the heteroaryl group is usually attached to the main structure via a carbon atom.

[0042] However, it will be apparent to those skilled in the art that certain other atoms, such as ring heteroatoms, may be attached to the main structure. Of course, other heteroaryl groups are well known to those skilled in the art and may be beneficial when used in the present invention.

[0043] As used herein, the term “aryl” means phenyl or naphthyl.

[0044] As used herein, the term “alkenyl” means a linear or branched free radical having the specified number of carbon atoms and having at least one double bond.

[0045] As used herein, the term “cycloalkenyl” refers to an alkenyl free radical having at least one double bond contained in a closed ring of carbon atoms, but not having aromatic properties. The at least one cycloalkenyl ring may consist essentially of 3 to 10 carbon atoms and a corresponding number of hydrogen atoms. By themselves, cycloalkenyl groups can be monocyclic or polycyclic. The individual rings of such polycyclic cycloalkenyl groups may have various bonds among themselves, for example, fused, bridged, spiro, etc., in addition to substitution with a covalent bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl and 1,5-cyclooctadienyl, each of which may or may not be further substituted. Of course, other cycloalkenyl groups are well known to those skilled in the art, the use of which in the present invention can have beneficial effects.

[0046] As used herein, the term “alkynyl” means a linear or branched free radical having the specified number of carbon atoms and having at least one triple bond.

[0047] As used herein, the term “halogen” means fluorine, chlorine, bromine or iodine.

[0048] As used herein, the term “haloalkyl” refers to monovalent saturated aliphatic free radical groups containing up to 20 carbon atoms and a corresponding number of hydrogen atoms, where one or more hydrogen atoms are replaced by a halogen atom. The hydrocarbon chain can be linear or branched. "C _1-6 haloalkyl" means a saturated linear or branched free radical consisting essentially of 1 to 6 carbon atoms and a corresponding number of hydrogen atoms, where one or more hydrogen atoms are replaced by a halogen atom. Examples of the "C _1-6 haloalkyl" groups include trifluoromethyl, difluoromethyl, fluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and so on. Of course, other haloalkyl groups are well known to those skilled in the art and may have beneficial effects when used in the present invention.

[0049] As used herein, the term "amino" refers to a free radical having a nitrogen atom and 0, 1 or 2 hydrogen atoms. By itself, the term "amino" generally refers to primary and secondary amines. In this regard, as used in the specification and appended claims, the tertiary amine is represented by the general formula RR'N-, wherein R and R' are carbon radicals which may or may not be the same. However, the term "amino" may be used in the invention to describe a primary, secondary or tertiary amine, and those skilled in the art will readily recognize what is meant by this term when used herein based on the context.

[0050] While specific embodiments of the present invention will now be described with reference to syntheses and designs, it should be understood that such embodiments are exemplary only and merely illustrate a small number of many possible specific embodiments that implement the principles of the present invention. It will be apparent to those skilled in the art that various changes and modifications of the present invention can be made that may have beneficial effects, and such changes and modifications are intended to be within the spirit and scope of the present invention as further defined in the appended claims.

[0051] Unless otherwise specified, all technical and scientific terms used in the invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention relates. Although other compounds or methods may be used in practice or testing, specific preferred methods in relation to the following syntheses and schemes are described below.

[0052] A number of synthetic techniques have been used to prepare the compounds described herein. These synthetic procedures (see diagrams below) have common overlaps and can alternatively be used for the synthesis of the compounds described in the invention.

Scheme 1

[0053] Scheme 1 shows a general scheme for preparing the compounds described in the invention. The corresponding acetoacetate (G-1-2) is reacted with (2-substituted)-4-aminothiophene-3-carboxylate (G-1-1) at 130°C to give pyridone G-1-3. Chlorination with POCl ₃ gives thienopyridine G-1-4. The methyl ester of G-1-4 is amidated with the appropriate amine to give G-1-5. The ester (G-1-6) is hydrolyzed with a metal hydroxide to produce an acid (G-1-7), which is coupled with a corresponding amine to produce various amides (G-1-8).

Scheme 2

[0054] Scheme 2 shows a general scheme for preparing the compounds described in the invention. The corresponding acetoacetate (G-2-2) is reacted with methyl 4-aminoisothiazol-3-carboxylate (G-2-1) to give pyridone G-2-3. Chlorination with POCl ₃ gives thienopyridine G-2-4.

Scheme 3

[0055] Scheme 3 shows a general scheme for preparing the compounds described in the invention. Tert-butyl (4-methylthiophen-3-yl)carbamate (G-3-1) is reacted with 2,2,2-trifluoro-N,N-dimethylacetamide (G-3-2) to produce trifluoroacetylthiophene G-3-3. Cyclization of de-Boc thiophene with isocyanate (G-3-4) gives thienopyrimidine G-3-5. Chlorination with POCl ₃ and methyl oxidation gives the aldehyde (G-3-6). Nucleophilic aromatic substitution of pyrimidinyl chloride (G-3-6) with the corresponding hydroxylated nitrogen heterocycle (G-3-7) gives G-3-8. Oxidation with an oxon produces an acid (G-3-9), which is reacted with the corresponding amine to produce the amide (G-3-10).

Scheme 4

[0056] Scheme 4 shows a general scheme for preparing the compounds described in the invention. Malonic acid (G-4-2) to produce dichlorothienopyridine G-4-3. Amidation with the appropriate amine and substitution with the amine/alcohol gives G-4-4. Pyridone (G-4-5) is chlorinated with N-chlorosuccinimide (NCS) to give chlorpyridone (G-4-6). Chlorination with POCl ₃ gives dichlorothienopyridine G-4-7.

Scheme 5

[0057] Scheme 5 shows a general scheme for preparing the compounds described in the invention. Methyl ester (G-5-1) is reduced with metal hydrides to give alcohol G-5-2. Oxidation with Dess-Martin periodinane and reaction of the corresponding aldehyde with the appropriate Grignard reagent (G-5-3) gives the secondary alcohol G-5-4. The methyl ester of G-5-1 is hydrolyzed with the appropriate metal hydroxide to give G-5-6. The reaction of acid (G-5-6) rearrangement into carbamate (G-5-7) is carried out using sodium azide in the presence of tert-butyl alcohol. Removal of the BOC protecting group and acylation gives G-5-8. G-5-6 is coupled with the corresponding amino alcohol (G-5-9) to produce amide G-5-10. Oxidation with Dess-Martin periodinane (DMP) produces the ketone (G-5-11), which is cyclized by exposure to a dehydrating reagent to produce oxazole (G-5-12).

Scheme 6

[0058] Scheme 6 shows a general scheme for preparing the compounds described in the invention. Nucleophilic aromatic substitution of pyridinyl chloride (G-6-1) with the corresponding nitrogen-containing heterocycle (G-6-2) gives N-substituted G-6-3. Iodination with metal iodide gives iodopyridine G-6-4. The iodine of compound G-6-4 is coupled with the corresponding zinc reagent (G-6-5) in the presence of a palladium catalyst to produce C-substituted G-6-6. The Pd-catalyzed coupling reaction of pyridinyl chloride (G-6-1) with the corresponding arylboronic acid (G-6-7) or alkyne (G-6-8) produces the aryl(alkyne)-substituted G-6-9. O-substituted G-6-11 is prepared by alkylation of pyridinyl chloride (G-6-1) or by performing the Mitsunobu reaction with pyridone G-6-12. Nucleophilic aromatic substitution of pyridinyl chloride (G-6-1) with the corresponding thiol (G-6-13) produces S-substituted G-6-13, which is oxidized to give the sulfoxide and sulfone (G-6-14).

Scheme 7

[0059] Scheme 7 shows a general scheme for preparing the compounds described in the invention. Activation of the hydroxyl group of the nitrogen heterocycle (G-7-1) with carbodiimidazole (CDI) or 4-nitro-phenoxyl chloroformate gives G-7-2, which is reacted with the corresponding amine reagent (G-7-3) to give G-7 -4. A coupling reaction is carried out between the carboxylic acid group or the amino group of nitrogen-containing heterocycles (G-7-5/6) with the corresponding chloroformate, sulfonyl chloride, acyl chloride, isocyanate or amine reagent (G-7-7/8/9/10) to obtain the corresponding products (G -7-11/12/13). Couple piperazine nitrogen-containing heterocycles (G-7-14) with the corresponding chloroformate, ketone/aldehyde, alkyl halide or epoxy reagent (G-7-15/16/17) to obtain the corresponding products (G-7-18/19/20 /21).

Scheme 8

[0060] Scheme 8 shows a general scheme for preparing the compounds described in the invention. The amine coupling of O-linked nitrogen heterocycles (G-8-1) or C-linked nitrogen heterocycles (G-8-2) is carried out with the corresponding chloroformate or acyl halide (G-8-3) to obtain the corresponding products (G-8- 4/5).

[0061] Unless otherwise indicated, the structures depicted herein are intended to also include all isomeric forms of the structure. The specific compounds described herein contain one or more centers of asymmetricity and can form isomers (e.g., enantiomers, diastereomers, racemates, and other stereoisomeric forms, which can be defined in terms of absolute configuration as (R) - or (S) -. It is intended that the present invention includes all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.The present invention is intended to include all possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.

[0062] Any asymmetric atom (e.g., carbon atom or other similar atom) of the compound(s) of the present invention may be present in a racemic or enantiomerically enriched, e.g., (R)-, (S)-, or (R, S)-configuration . In specific 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 (S) configuration. Substituents on unsaturated atoms may, if possible, be present in cis (Z) or trans (E) form.

[0063] Accordingly, the compound of the present invention used in the invention may be present in the form of one of possible isomers, rotamers, atropoisomers, 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 based on the physicochemical differences of their components into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization methods.

[0065] Any resulting racemates of the final products or intermediates can be resolved into optical antipodes by known methods, for example, by separating their diastereomeric salts obtained with an optically active acid or base and releasing the optically active compound with acidic or basic properties. In particular, a fragment with basic properties can be used in this way to optically resolve the compounds of the present invention into their optical antipodes, for example by fractional crystallization of a salt formed with an optically active acid, for example tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di- O,O'-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.

[0066] Since the compounds of the invention are intended for use in pharmaceutical compositions, it is obvious that it is preferable that each of them be obtained in substantially pure form, for example, at least 60% purity, more suitably if in purity at least 75% and preferably at least 85% pure, in particular at least 98% pure (% by weight). Contaminated preparations of compounds can be used to obtain purer forms for use in pharmaceutical compositions; these less pure preparations of compounds should contain at least 1%, more suitably at least 5% and preferably from 10 to 59% of the compound described in the invention.

[0067] The compounds of the present invention are obtained either in free form or in the form of salts thereof.

[0068] When both a group with basic properties and a group with acidic properties are present in the same molecule, the compounds described in the invention can also form internal salts, for example, zwitterionic molecules.

[0069] It is intended that the atoms comprising the compounds of the present invention also include isotopic forms of those atoms.

[0070] In an aspect of the present invention, compounds of formula I or any of compounds 1.1-1.300 that contain isotopically labeled forms are described. The isotopically labeled form of the compound of Formula I or any of the compounds 1.1-1.300 is identical in structure to that compound except that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number that is different from the atomic mass or mass number atom, which is usually more common in nature. Examples of isotopes that are commercially available and that can be introduced into a compound of formula I or any of compounds 1.1-1.300 by well known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example ² H (deuterium), ³ H (tritium), ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively. It is contemplated that a compound of formula I or any of compounds 1.1-1.300, or a prodrug thereof, or a pharmaceutically acceptable salt of any of them, which contain one or more of the above-mentioned isotopes and/or other isotopes of other atoms, is part of the present invention. The isotopically labeled compound of Formula I or any of the compounds 1.1-1.300 can be used to achieve a variety of beneficial effects. For example, an isotopically labeled compound of formula I, into which, for example, a radioisotope such as ¹⁴ C is introduced, is used for drug and/or substrate tissue distribution studies. Radioisotopes such as tritium ( ^3H ) and carbon-14 ( ^14C ) are particularly preferred due to their ease of preparation and high detectability. The introduction of heavier isotopes, such as deuterium ( ^2H ), into a compound of Formula I may provide therapeutic benefits due to the greater metabolic stability of the isotope-labeled compound. Higher metabolic stability may directly lead to an increase in half-life in vivo or to a reduction in the required dose or an improvement in the therapeutic index. An isotopically labeled compound of formula I can generally be prepared using the methods disclosed in the synthesis schemes and their corresponding descriptions, examples and synthesis sections of the present invention by replacing the non-isotopically labeled reagent with a readily available isotope-labeled reagent.

[0071] Deuterium ( ^2H or D) may also be introduced into the compound of Formula I or any of the compounds 1.1-1.300 to influence the oxidative metabolism of the compound through the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction that occurs as a result of the exchange of isotopic nuclei, which in turn is caused by a change in the ground state energies required to form a covalent bond after this isotope exchange. Exchange of a heavier isotope usually results in a decrease in the ground state energy of a chemical bond and thus causes a decrease in the rate limit of bond cleavage. If bond cleavage occurs in or near the saddle point region along the coordinate of a multiproduct reaction, then the product distribution ratios can be significantly changed. To clarify, if deuterium is bonded to a carbon atom in a non-substituted position, rate differences of kM/kD=2-7 are typical. If this rate difference is successfully applied to a compound of formula I or any of the compounds 1.1-1.300 that are sensitive to oxidation, the pharmacodynamic profile of this compound in vivo may be radically altered, resulting in improved pharmacokinetic properties. For more information, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, Foster, AB, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends in Pharmacological Sciences, 5: 524-527 (1984) AND Foster, AB, "Deuterium Isotope Effects in the Metabolism of Drugs and Xenobiotics: Implications for Drug Design," Advances in Drug Research, 14: 1-40 (1985), the entire contents of which are incorporated herein by reference.

[0072] When creating and developing therapeutic agents, one skilled in the art attempts to optimize pharmacokinetic parameters while maintaining desired in vitro properties. In some cases, compounds with unsatisfactory pharmacokinetic profiles are susceptible to oxidative metabolism. Currently available in vitro assays of the microsomal fraction of liver hepatocytes can provide valuable information on the course of this type of oxidative metabolism, which in turn may allow the rational design of deuterated compounds of formula I with improved stability due to resistance to such oxidative metabolism. Thus, significant improvements in the pharmacokinetic profiles of compounds of formula I are possible, which can be quantified by an increase in parameters such as half-life in vivo (t1/2), concentration at maximum therapeutic effect (Cmax), area under the dose-response curve " (AUC) and bioavailability, and a decrease in clearance, dose and material costs.

[0073] Deuterium-hydrogen exchange in a compound of formula I or in any of compounds 1.1-1.300 can also be used to achieve beneficial modification of the metabolite spectrum of the parent compound to reduce or eliminate unwanted toxic metabolites. For example, if a toxic metabolite arises from oxidative cleavage of a carbon-hydrogen (C-H) bond, then it is likely that the deuterated analogue will significantly reduce or prevent the production of the unwanted metabolite, even if the particular oxidation is not the rate-limiting step. Additional information on the current state of knowledge in the field of deuterium-hydrogen exchange can be found, for example, in the publications of Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., 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. In this case, deuterium is considered in this case as a substituent in the compound of formula I or in any of the compounds 1.1-1.300. The concentration of such a heavier isotope, in particular deuterium, can be determined by the isotope enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the relationship between the abundance of an isotope and the natural abundance of a particular isotope. If a substituent in a compound described herein is designated deuterium, then such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium input for each designated deuterium atom), at least 4000 (60 % deuterium injection), at least 4500 (67.5% deuterium injection), at least 5000 (75% deuterium injection), at least 5500 (82.5% deuterium injection), at least 6000 (90% deuterium injection), at least 6333.3 (95% deuterium injection), at least 6466.7 (97% deuterium injection), at least 6600 (99% deuterium injection) or at least at least 6633.3 (99.5% introduction of deuterium).

[0074] The following is an illustration of the above considerations: a compound of formula I, or any of compounds 1.1-1.300, which has several potential sites for oxidative metabolism to occur, for example, benzyl hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, can be prepared in as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms, such that some, most or all of those hydrogen atoms are replaced by deuterium atoms. Determination of the half-life allows a convenient and accurate determination of the degree of improvement in resistance to oxidative metabolism. Thus, it can be determined that the half-life of the parent compound can be increased by 100% as a result of this type of deuterium-hydrogen exchange.

[0075] As stated above, metachromatic leukodystrophy (MLD) results from mutations in the arylsulfatase A (ARSA) gene, responsible for converting sulfatide (SFT) to galactosylceramide (GalCer) and sulfate. ARSA mutations that reduce ARSA activity by more than 90% lead to the accumulation of SFT, which in turn causes demyelination and death. By inhibiting the biosynthesis of SFT, the compounds described herein can prevent the accumulation of SFT that causes metachromatic leukodystrophy (MLD). Similarly, Krabbe disease results from mutations in galactosylcerebrosidase (GalC), the enzyme responsible for converting GalCer to galactose and ceramide. Mutations that disrupt both GalC alleles result in complete inactivation of GalC and subsequent accumulation of GalCer and psychosine (another substrate for GalC). By inhibiting GalCer biosynthesis, the compounds described herein can prevent the accumulation of GalCer and psychosine, which cause Krabbe disease.

[0076] The compounds described herein may be used in combination with other UGT8 modulators or therapeutic agents for the treatment of metachromatic leukodystrophy (MLD), Krabbe disease, and diseases and conditions associated with MLD or Krabbe disease. In the case of metachromatic leukodystrophy (MLD), other therapeutic methods target ARSA, an enzyme that is defective in patients with MLD. These therapeutic modalities include enzyme replacement therapy (ERT), gene replacement therapy, and gene transduced hematopoietic stem cell transfer. In enzyme replacement therapy (ERT), recombinant human ARSA with full enzymatic activity is given to patients with MLD either through the systemic circulation or by direct transfusion into the brain. For MLD, gene replacement therapy involves delivering a functional form of the ARSA gene systemically or directly to the brain to enhance the action of the defective (or missing) 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 then systemically infused back into patients. The advantage of using the UGT8 inhibitor compounds described in the present invention in combination with any of these methods is that the inhibitors immediately prevent further accumulation of toxic substrates such as SFT and psychosine until other therapeutic agents are fully effective. impact.

EXAMPLES

Receiving connections

[0077] The following are examples of the preparation of the compounds of the present invention. Other compounds within the scope of the present invention can be prepared in accordance with the general schemes described above and in accordance with methods and techniques similar to those described in detail below, and in combination with the professional knowledge of specialists in the field.

[0078] Analytical methods

[0079] ¹ H NMR spectra are recorded at 400 MHz on a Gemini 400 or Varian Mercury 400 spectrometer with a 5 mm ASW probe typically at ambient temperature in a deuterated solvent such as D ₂ O, DMSO-d6 or CDCl ₃ unless otherwise noted . Chemical shift values (δ) are reported in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard.

[0080] High performance liquid chromatography mass spectrometry (LCMS) experiments to determine retention time (RT) and associated ion masses were performed using one of the following methods.

[0081] Mass spectra (MS) were recorded using a Micromass mass spectrometer. Typically, the method used was positive electrospray ionization, mass scanning m/z from 100 to 1000. Liquid chromatography was performed on a Hewlett Packard 1100 Series system with a binary pump and degasser. A Hewlett Packard 1100 Series UV detector, wavelength = 220 nm, and a Sedere SEDEX 75 evaporative light scattering (ELS) detector, temperature = 46°C, N ₂ pressure = 0.4 MPa were used as auxiliary detectors.

[0082] LCT: gradient (AcN+0.05% TFA):(H ₂ O+0.05% TFA) = 5:95 (0 min) to 95:5 (2.5 min) to 95:5 ( 3 min). Column: YMC Jsphere 33×2 4 µm, 1 ml/min.

[0083] MUX: Column: YMC Jsphere 33×2, 1 ml/min.

[0084] Gradient (AcN+0.05% TFA):(H ₂ O+0.05% TFA) = 5:95 (0 min) to 95:5 (3.4 min) to 95:5 (4, 4 min).

[0085] LCT2: YMC Jsphere 33×2 4 µm, (AcN+0.05%TFA):(H ₂ O+0.05%TFA) = 5:95 (0 min) to 95:5 (3.4 min) up to 95:5 (4.4 min).

[0086] QU: YMC Jsphere 33×2 1 ml/min, (AcN+0.08% formic acid):(H ₂ O+0.1% formic acid) = 5:95 (0 min) to 95:5 (2.5 min) to 95:5 (3.0 min).

Obtaining intermediate compounds

[0087] Intermediate 1: Methyl 5-oxo-7-(trifluoromethyl)-4,5-dihydrothieno[3,2-b]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 mixture was analyzed by LCMS and it was found that the reaction was complete. The mixture was concentrated and the resulting wet brown solid was triturated with t-butyl methyl ether (~300 ml). The suspended solid was collected by suction filtration, rinsed with additional t-butyl methyl ether (2 x ~50 ml) and air dried on the filter at low pressure. The title compound was obtained as a yellow solid (200 g, 74%). ^1H NMR (400 MHz, DMSO- _d6 ) δ 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-b]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 ~1 l). The combined organic layers were dried (Na ₂ SO ₄ ), filtered with suction through a pad of silica gel and concentrated under reduced pressure. The residue was then triturated with methanol (~300 ml) and recollected by suction filtration. The filter cake was air dried on the filter under low pressure to give the title compound as a white solid (91.0 g, 85%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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-b]pyridine-3-carboxylic 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 mixture was analyzed by TLC and the reaction was found to be complete. The mixture was diluted with water (500 ml) and then acidified (to pH 2-3) by adding 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 SO ₄ ) and concentrated. The crude title compound was obtained as a pale red solid (38.0 g, 99%) which was used without purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-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 magnetic stirrer. The vessel was sealed and the stirred solution was heated at 50°C for 90 minutes. The mixture was stirred for another hour at room temperature and then concentrated. The residue was subjected to automated flash chromatography (Combiflash; 0 to 1% methanol in chloroform; 220 g silica gel column) to give the partially purified product (R _f =0.25 with 99:1 chloroform/methanol as eluent) as light amber solid (6.83 g, 76%). This material was triturated with diethyl ether (~40 ml) and recollected by suction filtration. The filter cake was rinsed with additional ether (2 x ~10 ml) and then air-dried on the filter under low pressure to give the title compound as a yellowish-white solid (6.51 g, 73%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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), oxalyl chloride (18.0 ml, 213 mmol) was slowly added, followed by 2-3 drops of N , N-dimethylformamide. The cooling bath was removed and the reaction mixture was warmed to room temperature. After one hour, the reaction solution was concentrated to obtain 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 saturated aqueous ammonium chloride (500 ml). The organic layer was separated, dried (Na ₂ SO ₄ ) and concentrated to give the crude product as a yellow solid. This material was ground with acetonitrile (~300 ml), recollected by suction filtration and air-dried on a filter at low pressure. The title compound was obtained as a pale yellow solid (36.18 g, 91%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.89 (br.s, 1H), 8.87 (s, 1H), 7.60 (s, 1H), 3.10 (d, J=4, 8 Hz, 3H) ppm. MS: 295 m/z (M+H ⁺ ).

[0098] Intermediate 6. N-Methyl-5-(piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[0099] Step 1: Methyl 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate

[00100] A 20 mL microwave reaction vessel equipped with a magnetic stirrer was charged with Intermediate 3 (2.50 g, 8.46 mmol), tert-butyl piperazine-1-carboxylate (2.76 g, 14 .8 mmol), N,N-diisopropylethylamine (3.00 ml, 17.2 mmol) and N-methyl-2-pyrrolidinone (10 ml). In the same way, a 20 ml reaction vessel was prepared for reactions under microwave irradiation, and both vessels were sealed and heated in a microwave reactor for 1.5 hours at 130°C. These two reaction mixtures were combined and diluted with water (~50 ml). The resulting suspension was subjected to a combination of ultrasound and vigorous stirring (~30 minutes) to disperse larger solid aggregates. The resulting light brown precipitate was filtered with suction and rinsed with additional water (2 x ~25 ml). The filter cake was partially dried under low pressure and then rinsed with diethyl ether (3 x ~20-25 ml). The solid was then dried in a vacuum oven (~50°C) to give the title compound as a beige solid (6.14 g, 82%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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: Tert-butyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperazine-1-carboxylate

[00102] A 20 mL microwave reaction vessel equipped with a magnetic stirrer was charged with the product from Step 1 (3.11 g, 6.98 mmol) and a 2.0 N solution of methylamine in methanol (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 the original ester remained. Additional 2.0 N methylamine solution (4.0 mL, 8.0 mmol) was added and the reaction mixture was heated for another hour at 90°C. The reaction mixture was then concentrated to give the title compound as a beige solid (3.04 g, 98%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.32 (br.s, 1H), 8.67 (s, 1H), 7.04 (s, 1H), 3.66 (s, 8H), 3 .09 (d, J=4.9 Hz, 3H), 1.51 (s, 9H) ppm.

[00103] Step 3: N-Methyl-5-(piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00104] Hydrogen chloride gas was bubbled through a stirred solution of the product from Step 2 (4.06 g, 9.13 mmol) in ethyl acetate (120 mL) for approximately five minutes. The resulting yellow thick suspension was stirred at room temperature for one hour and then concentrated. The residue was partitioned between aqueous sodium carbonate (~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 SO ₄ ) and concentrated. The title compound was obtained as a pale yellow solid (3.18 g, 101%, ¹ H NMR analysis indicating excess yield due to the presence of a small amount of isopropanol). ^1H NMR (400 MHz, CDCl ₃ ) δ 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-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00106] Step 1: Methyl 5-(4-hydroxypiperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate

[00107] To a stirred solution of intermediate 3 (10.0 g, 33.8 mmol) in N-methyl-2-pyrrolidinone (60 ml) was added piperidin-4-ol (6.00 g, 59.3 mmol, .75 eq) and N,N-diisopropylethylamine (11.8 ml, 67.7 mmol, 2.00 eq). The reaction mixture was heated at 130°C for three hours and then stirred at room temperature overnight. LCMS analysis indicated that the reaction was complete. The mixture was concentrated to obtain a wet brown solid. This material was transferred to water (~200 ml) and the suspended solid was dispersed by stirring with a spatula and sonication. When the suspension became almost homogeneous, the mixture was filtered with suction. The filter cake was rinsed with water (2 x ~40 ml) and diethyl ether (2 x ~25 ml), and then air-dried on the filter at low vacuum. The filter cake was further dried in a vacuum oven (~60°C) to obtain the title compound as a light brown solid (10.90 g, 89%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00109] To a stirred suspension of the product from 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. After this, the reaction mixture was analyzed by LCMS and it was found that the reaction was completed. The mixture was cooled in an ice bath (the reaction mixture turned from a clear solution to a heavy suspension). The cold suspension was filtered with suction and the collected solid was rinsed with cold methanol (1 x ~30 ml), water (2 x ~40 ml) and finally diethyl ether (2 x ~30 ml). The filter cake was further dried in a vacuum oven (~50°C) to obtain the title compound as a beige solid (9.60 g, 89%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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-b]pyridine-3-carboxylate

[00111] Step 1: Methyl 5-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate

[00112] Intermediate 3 (0.750 g, 2.54 mmol), tert-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 N-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 solids, which were then 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 and brine, dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by automated flash chromatography (Combiflash system, eluent 0.3 to 3% methanol in dichloromethane; 80 g silica gel column) to give the title compound as a yellowish-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-b]pyridine-3-carboxylate

[00114] Trifluoroacetic acid (2.0 mL, 26 mmol) was added to a stirred suspension of the product from Step 1 (0.450 g, 0.984 mmol) in dichloromethane (2 mL). After one hour, the reaction mixture was concentrated at room temperature. The resulting resin was treated with solid sodium bicarbonate (400 mg) and then transferred to a 98:2 dichloromethane/methanol solution (30 ml). The suspension was stirred vigorously for several minutes and then filtered with suction to remove solids. The filter cake was rinsed with a 4:1 chloroform/isopropanol solution (~10 mL) and the combined filtrate was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was then dried (Na ₂ SO ₄ ) and concentrated to give 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 1H-imidazole-1-carboxylate

[00116] To a stirred solution of 2-(trifluoromethoxy)ethan-1-ol (1.20 g, 9.23 mmol) in dichloromethane (50 mL) was added 1,1'-carbonyldiimidazole (2.09 g, 12.9 mmol ). The reaction was carried out overnight at room temperature, and then the reaction mixture was washed in 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 (1 x ~75 ml). The organic layer was then dried (Na ₂ SO ₄ ) and concentrated to give the crude title compound as a colorless oil (2.23 g, 108%; increased yield due to residual solvent). The crude product was used without purification in subsequent reactions and stored in a freezer. ^1H NMR (400 MHz, CDCl ₃ ) δ 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)-1-(Trifluoromethoxy)-propan-2-yl 1H-imidazol-1-carboxylate

[00118] Step 1. (S)-(((1-(Trifluoromethoxy)propan-2-yl)oxy)-methyl)benzene

[00119] The reaction was carried out in accordance with the procedure given in Liu, J.-B., Xu, X.-H., Qing, F.-L. Org. Lett. 2015, 17, 5048. (S)-2-(Benzyloxy)propan-1-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 1 L reaction flask. Ethyl acetate (275 ml) was then added and the mixture was stirred for several minutes, then 2-fluoropyridine (10.1 ml, 117 mmol) and trifluoromethyltrimethylsilane (17.6 ml, 117 mmol) were added. The reaction mixture, which darkened slowly over the first hour, was stirred overnight at room temperature. After this, the mixture was filtered with suction through a layer of silica gel. The silica gel was rinsed with additional ethyl acetate (6 x ~50 ml) and the combined filtrate was concentrated to give a brown semi-solid (38.97 g). This material was transferred to ethyl acetate (~100 ml) and sonicated until the suspension became homogeneous. The solid was filtered with suction and then rinsed with ethyl acetate (2 x ~25 ml). The combined filtrate was concentrated on ~80 g silica gel and the impregnated medium was subjected to automated flash chromatography (Combiflash instrument; 0 to 15% ethyl acetate in heptane; 330 g silica gel column). The partially purified title compound was obtained ( ¹ H NMR purity 90-95%; R _f ~0.6 in 85:15 heptane/ethyl acetate) as a colorless oil (5.07 g, 37%). To avoid loss of product due to evaporation, the oil was only briefly exposed to high vacuum (the product contained some small amounts of residual solvent). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.26 (m, 5H), 4.64-4.56 (m, 2H), 3.98 (dd, J=10.1, 6 ,1 Hz, 1H), 3.90 (dd, J=10.1, 4.4 Hz, 1H), 3.84-3.75 (m, 1H), 1.24 (d, J=6, 4 Hz, 3H) ppm.

[00120] Step 2. (S)-1-(Trifluoromethoxy)propan-2-yl 1H-imidazol-1-carboxylate

[00121] The partially purified product from step 1 (5.05 g, <21.6 mmol) was combined with 10% palladium on carbon (50% water) (2.00 g, 0.940 mmol) and placed in ethyl acetate (150 ml) . The stirred suspension was subjected to three successive cycles of evacuation and nitrogen filling. The reaction vessel was then evacuated one last time and filled with hydrogen (from a cylinder). The reaction mixture was stirred under hydrogen atmosphere overnight and then suction filtered through a pad of celite. The filter media was rinsed with additional ethyl acetate (5 x ~30 ml) and the combined filtrate was stirred at room temperature and treated with 1,1'-carbonyldiimidazole (5.24 g, 32.3 mmol). The reaction mixture 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 (1 x ~150 ml). The organic layer was dried (Na ₂ SO ₄ ) and concentrated (only briefly under high vacuum) to give a pale amber oil (3.41 g, 67%). ¹ H NMR analysis indicated that the acylation reaction was not complete (a ~7:3 ratio of the desired product to the hydroxyl intermediate was detected). The oil was taken into tetrahydrofuran (80 ml), stirred at room temperature and treated with additional 1,1'-carbonyldiimidazole (2.00 g, 12.3 mmol). The reaction mixture was then placed in a preheated (50°C) oil bath. After three hours, a sample of the reaction mixture was taken, concentrated and analyzed by ¹ H NMR. The reaction was found to be complete. The mixture was concentrated and the residue was partitioned between aqueous sodium bicarbonate (~100 ml) and chloroform (~60 ml). The organic layer was combined with additional extracts (chloroform, 2 x ~60 ml), dried (Na ₂ SO ₄ ) and concentrated to give the crude title compound as a pale amber oil (3.41 g, 67%, two steps). Although a small amount of impurity was found to contaminate the desired product (by ¹ H NMR), the material was considered pure enough to be used without purification in subsequent reactions. The intermediate was stored in a freezer to prevent degradation. ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J=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-b]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) were heated overnight at 130°C. The reaction mixture, which was determined by LCMS to be a mixture of the desired product and either the uncyclized amide or the cyclized hydrate of the 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 mixture was analyzed by LCMS and the reaction was found to be complete. The mixture was poured into a stirred crushed ice/water slurry (~400 mL) while rinsing the reaction vessel with ethyl acetate (~100 mL). After the ice had completely melted, the organic layer was removed and combined with additional ethyl acetate extracts (3 x ~100 ml). The collected extracts were dried (Na ₂ SO ₄ ) and concentrated to obtain a wet contaminated orange solid. This material was placed in a mixture of heptane (~85 ml) and ethyl acetate (~15 ml) and sonicated for several minutes to disperse larger pieces of solid. The suspension was then suction filtered and the collected solid was rinsed with heptane (3 x ~25 ml). The filter cake was then dried in a vacuum oven (~50°C) to give the title compound as an amber solid (7.85 g, 52%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.74 (br.s, 1H), 8.29 (s, 1H), 3.97 (s, 3H), 2.40 (sq, 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-b]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 by pipette to stirred and cooled (0°C) water (500 ml). The resulting suspension was extracted with dichloromethane (2 x ~200 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered through a pad of silica gel and concentrated to give the title compound as a yellow solid (10.00 g, 85%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.63 (s, 1H), 4.00 (s, 3H), 2.68 (s, 3H) ppm.

[00126] Intermediate 15. 5-Chloro-N,6-dimethyl-7-(trifluoromethyl)thieno[3,2-b]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 (~500 ml) and dichloromethane (~300 ml). The organic layer was combined with additional extract (dichloromethane, 1 x ~300 ml), dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by trituration with acetonitrile (~40 ml) to give the title compound as a white solid (19.60 g, 85%). ¹ H NMR (400 MHz CDCl ₃ ) δ 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-b]pyridine-3-carboxylate

[00129] Step 1: 3-Ethoxyacrylic acid

[00130] Solid sodium hydroxide (13.32 g, 332.9 mmol) was added to a stirred mixture of ethyl 3-ethoxyacrylate (20.00 g, 138.7 mmol) in water (160 mL). The reaction mixture was refluxed for two hours and then cooled to room temperature. The mixture, while stirring, was treated with sufficiently concentrated hydrochloric acid until a pH value of 2-3 was reached (~30 ml). The resulting yellow suspension was extracted with ethyl acetate (4 x ~100 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give the crude product as a bright yellow solid (9.21 g, 57%). This material was used without purification in the next step. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67 (d, J=12.6 Hz, 1H), 5.18 (d, J=12.6 Hz, 1H), 3.95 (sq, 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 crude product from Step 1 (9.21 g, 79.3 mmol) in toluene (130 mL) was added thionyl chloride (7.0 mL, 96 mmol). The mixture was refluxed for three hours and then cooled to room temperature and concentrated. The crude acid chloride was obtained as a brown oil. This material was placed in dichloromethane (50 ml) and the resulting solution was slowly added by pipette 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 (1 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 (1 x ~200 ml). The organic solution was then dried (Na ₂ SO ₄ ) and concentrated to obtain the crude product, which was subjected to automated flash chromatography (Combiflash device; 0 to 25% ethyl acetate in heptane; 330 g silica gel column). The title compound was obtained as a dirty yellow solid (10.38 g, 77% from aminothiophene starting material). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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 (kv, 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-b]-pyridine-3-carboxylate

[00134] The product from step 2 (10.37 g, 40.62 mmol) was placed in concentrated sulfuric acid (10 ml) and stirred at room temperature. After one hour, the reaction mixture was analyzed by LCMS and the reaction was found to be complete. The reaction mixture was poured into ice water (~600 ml), and the resulting suspension was stirred until the ice completely melted. The mixture was then extracted with chloroform (4 x ~150 ml) and the combined extracts were dried (Na ₂ SO ₄ ) and concentrated. The resulting amber solid was placed in diethyl ether (~60 ml) and sonicated until the suspension became homogeneous. The suspension was then filtered with suction and the collected solid was washed with additional diethyl ether (2 x ~20 ml). The filter cake was air dried under low pressure to give the title compound as a beige solid (7.90 g, 93%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.47 (br.s, 1H), 8.29 (s, 1H), 7.73 (d, J=9.6 Hz, 1H), 6.60 (d, J=9.6 Hz, 1H), 3.96 (s, 3H) ppm. MS: 210 m/z (M+H ⁺ ).

[00135] Intermediate 17. N-Methyl-5-(piperidin-4-yloxy)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00136] Step 1: Tert-butyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate

[00137] A stirred solution of intermediate 5 (8.00 g, 27.2 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (6.56 g, 32.58 mmol) in tetrahydrofuran (150 ml) was placed in a water bath with room temperature and treated with one portion of sodium tert-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 (~300 ml) and chloroform (~150 ml). The organic layer was combined with the second extract (chloroform, 1 x ~100 ml), dried (Na ₂ SO ₄ ) and concentrated on silica gel (~40 g). The impregnated medium was subjected to automated flash chromatography (Combiflash device; 20 to 50% ethyl acetate in heptane; 330 g silica gel column). The target component (R _f =0.24 with 1:1 heptane/ethyl acetate as eluent) was obtained as a resinous solid. This material was co-evaporated with diethyl ether to give the title compound as a pale amber foamy solid (10.43 g, 84%). ^1H NMR (400 MHz, CDCl ₃ ) δ 9.12-8.98 (m, 1H), 8.75 (s, 1H), 7.12 (s, 1H), 5.21 (tt, J= 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: N-Methyl-5-(piperidin-4-yloxy)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00139] Trifluoroacetic acid (25.0 mL, 326 mmol) was added to the stirred product from Step 1 (10.41 g, 22.66 mmol) in dichloromethane (100 mL). After one hour, the mixture was concentrated and the resulting oil was partitioned between chloroform (~100 ml) and aqueous sodium carbonate (~150 ml). The organic layer was combined with the second extract (chloroform, 1×100 ml), dried (Na ₂ SO ₄ ) and concentrated to give a light brown solid. This material was placed in diethyl ether (~60 ml) and subjected to ultrasound until a fine homogeneous suspension was formed. The solid was filtered with suction, rinsed with additional diethyl ether (2 x ~20 ml) and air dried on the filter at low pressure and purged with nitrogen. The title compound was obtained as a sandy solid (7.93 g, 97%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=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 m/z (M+H ⁺ ).

[00140] Intermediate 18. (S)-1-(Trifluoro-methoxy)propan-2-amine hydrochloride

[00141] Step 1: Tert-butyl (S)-(1-(trifluoromethoxy)propan-2-yl)carbamate

[00142] The reaction was carried out in accordance with the procedure given in the publication: Liu, J.-B., Xu, X.-H., Qing, F.-L. Org. Lett. 2015, 17, 5048. Stirred suspension of N-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) were 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 filtered with suction through a pad of silica gel. 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 gel 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 ₃ ) δ 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-(Trifluoromethoxy)propan-2-amine hydrochloride

[00144] Hydrogen chloride gas was bubbled through a stirred solution of the product from Step 1 (2.20 g, 9.05 mmol) in ethyl acetate (60 mL) for approximately three minutes. The reaction mixture was kept at room temperature for an additional 30 minutes and then concentrated to give the title compound as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.35 (br.s, 3H), 4.29-4.12 (m, 2H), 3.55 (br.s, 1H), 1, 24 (d, J=6.8 Hz, 3H) ppm.

[00145] Intermediate 19. Methyl 5-chloro-2-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate

[00146] Step 1: Methyl 2-methyl-5-oxo-7-(trifluoromethyl)-4,5-dihydrothieno[3,2-b]pyridine-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 for overnight at 130°C. The reaction mixture was then concentrated under reduced pressure to obtain a wet brown solid. This crude product was triturated with ethyl acetate (~20 ml). Once a homogeneous suspension had formed, the solid was collected by suction filtration, rinsed with additional ethyl acetate, and air-dried on a low-pressure filter. The title compound was obtained as a yellow solid (5.00 g, 71%). ^1H NMR (400 MHz, DMSO- _d6 ) δ 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-b]pyridine-3-carboxylate

[00149] The product from step 1 (10.00 g, 34.33 mmol) was placed 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 water (0°C) (~200 ml). The resulting suspension was extracted with dichloromethane (3×150 ml). The combined organic layers were dried (Na ₂ SO 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 gel column) to give the title compound as a white solid (9.22 g, 87%). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.50 (s, 1H), 4.00 (s, 3H), 2.87 (s, 3H) ppm. MS: 310 m/z (M+H ⁺ ).

[00150] Intermediate 20. 5-Chloro-N,2-dimethyl-7-(trifluoromethyl)thieno[3,2-b]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 magnetic stirrer. The vessel was sealed and the stirred solution was heated at 50°C for seven hours and then cooled to room temperature and stirred for a further two days. Thereafter, the mixture was concentrated and the residue was subjected to automated flash chromatography (Combiflash device; 5 to 25% ethyl acetate in heptane; 80 g silica gel column). The title compound was obtained as a white solid (1.66 g, 83%). ^1H NMR (400 MHz, CDCl ₃ ) δ 9.22 (s, 1H), 7.54 (s, 1H), 3.16-3.03 (m, 6H) ppm. MS: 309 m/z (M+H ⁺ ).

[00152] Intermediate 21. 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]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), then a few granules of 4-(dimethylamino)pyridine. The reaction mixture was stirred at room temperature for seven hours and then diluted with sufficient dichloromethane to completely dissolve all solids (~200 ml). The clear solution was then concentrated on ~25 g silica gel and the impregnated medium was subjected to automated flash chromatography (Combiflash instrument; 30 to 100% ethyl acetate in heptane; Gold column with 120 g silica gel). The target component (Rf ~0.6 using 7:3 ethyl acetate/heptane as eluent) 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 by suction filtration, rinsed with additional diethyl ether (1 x ~25 ml) and then air dried on the filter at low pressure. The title compound was obtained as a beige solid (3.44 g, 47%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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-((chloro-carbonyl)oxy)piperidine-1-carboxylate

[00155] To a stirred solution of tert-butyl 4-hydroxy-piperidine-1-carboxylate (6.00 g, 29.8 mmol) in tetrahydrofuran (60 mL) was added a 15% (by weight) solution of phosgene in toluene (37.0 mL, 51.9 mmol). The reaction mixture was stirred at room temperature for 90 minutes and then concentrated to give the crude title compound as a colorless oil (8.04 g, 102%). ¹ H NMR analysis indicated that the material was sufficiently pure to be used without purification in subsequent reactions. The intermediate was stored in the freezer where it solidified. ^1H NMR (400 MHz, CDCl ₃ ) δ 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-1-carboxylate

[00157] To a stirred solution of benzyl 4-hydroxy-piperidine-1-carboxylate (5.00 g, 21.3 mmol) in tetrahydrofuran (60 mL) was added a 15% (by weight) solution of phosgene in toluene (31.0 mL, 43.4 mmol). The reaction mixture was stirred at room temperature for 90 minutes and then concentrated to give the crude title compound as a colorless oil (6.50 g, 103%). ¹ H NMR analysis indicated that the material was sufficiently pure to be used without purification in subsequent reactions. The intermediate was stored in the freezer where it solidified. ^1H NMR (400 MHz, CDCl ₃ ) δ 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. Tert-butyl 4-(((cyclopropylmethyl)-carbamoyl)oxy)piperidine-1-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 slowly warmed 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 (1 x ~400 ml). The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give the crude title compound as an off-white solid (38.57 g, 108%; excess yield due to residual solvent chloroform). This material was used in the next step without purification.

[00161] Step 2: Piperidin-4-yl (cyclopropylmethyl)carbamate

[00162] Trifluoroacetic acid (100 mL, 1.31 mmol) was added to a stirred solution of the product from Step 1 in dichloromethane (300 mL). After 90 minutes, the reaction mixture was concentrated at room temperature to give an almost colorless syrup. This material was partitioned between 1.0 N aqueous sodium hydroxide (~300 ml) and chloroform (~200 ml). The organic layer was combined with additional extracts (chloroform, 4 x ~200 ml), dried (Na ₂ SO ₄ ) and concentrated to give the crude title compound as a yellowish-white solid (23.58 g, 99% overall yield). This intermediate was considered sufficiently pure to be used without purification in subsequent reactions. ^1H NMR (400 MHz, CDCl ₃ ) δ 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)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00164] Step 1. Tert-butyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-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 tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (2.17 g, 9.64 mmol) in tetrahydrofuran (30 ml) potassium tert-butoxide (0.928 g, 8.27 mmol) was added. The reaction mixture was 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 and brine. The organic layer was then dried (Na ₂ SO ₄ ) and concentrated to give the crude product, which was purified by automated flash chromatography (Biotage system; 20 to 100% ethyl acetate in heptane, then 5% methanol in dichloromethane; 100 g silica gel column). The title compound was obtained as a foamy white solid (2.69 g, 83%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.11 (br.s, 1H), 8.75 (s, 1H), 7.08 (s, 1H), 5.13 (p, J=6, 9 Hz, 1H), 4.04 (s, 2H), 3.98 (s, 2H), 3.11 (d, J=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)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00167] Trifluoroacetic acid (3.7 mL, 48 mmol) was added to a stirred and cooled (0°C) solution of the product from Step 1 (2.28 g, 4.84 mmol) in dichloromethane (5 mL). The reaction mixture was warmed to room temperature and then stirred for another hour and concentrated. The residue was partitioned between dichloromethane (200 ml) and 1.0 N aqueous sodium hydroxide (100 ml). The organic layer was combined with re-extract of the aqueous layer (dichloromethane, 1 x ~50 ml), dried (MgSO ₄ ) and concentrated to give the crude title compound as a beige solid (1.60 g, 89%). This intermediate was considered sufficiently pure to be used without purification in subsequent reactions. MS: 372 m/z (M+H ⁺ ).

[00168] Intermediate 27. 5-(cis-3-Amino-cyclobutoxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00169] Step 1. Tert-butyl (cis-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]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 tert-butoxide (1.03 g, 9.22 mmol). The reaction mixture 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. The organic layer was dried (MgSO ₄ ) and concentrated to give the crude product, which was purified by automated flash chromatography (Combiflash device; 0 to 100% ethyl acetate in dichloromethane; 120 g silica gel column). The title compound was obtained as a white solid (2.50 g, 67%). MS: 446 m/z (M+H ⁺ ).

[00171] Step 2: 5-(cis-3-Aminocyclobutoxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00172] Trifluoroacetic acid (3.3 mL, 42 mmol) was added to a stirred and cooled (0° C.) solution of the product from Step 1 (1.89 g, 4.24 mmol) in dichloromethane (15 mL). The reaction mixture was warmed to room temperature and stirred for another two hours and then concentrated. The residue was partitioned between dichloromethane (200 ml) and 0.5 N aqueous sodium hydroxide (100 ml). The organic layer was combined with additional extracts (dichloromethane, 2 x ~100 ml), dried (MgSO ₄ ) and concentrated to give the crude title compound as a white solid (1.13 g, 77%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (s, 1H), 8.86 (d, J=4.9 Hz, 1H), 8.15 (s, 3H), 7.46 (s, 1H), 5.20 (kv, 1H), 3.71-3.55 (m, 1H), 2.99 (d, J=4.9 Hz, 3H), 2.96-2, 77 (m, 1H), 2.42-2.30 (m, 2H) ppm.

[00173] Intermediate 28. cis-3-((3-(Methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-cyclobutyl 1H-imidazol-1- carboxylate

[00174] Step 1: 5-(cis-3-(Benzyloxy)cyclobutoxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00175] Potassium tert-butoxide (502 mg, 4.47 mmol) was added to a stirred solution of cis-3-(benzyloxy)-cyclobutanol (0.921 g, 5.17 mmol) in tetrahydrofuran (10 mL). 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 mixture was refluxed 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 (1 x ~100 ml) and saline (1 x ~100 ml). The organic layer was then dried (MgSO ₄ ) and concentrated to give the crude product, which was purified by automated flash chromatography (Combiflash instrument; 0 to 100% ethyl acetate in dichloromethane, then 0 to 5% methanol in dichloromethane; 40 g silica gel column) to give the title compound as an amber oil (1.30 g, 76%). MS: 437 m/z (M+H ⁺ ).

[00176] Step 2: 5-(cis-3-Hydroxycyclobutoxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00177] Stir mixture of product from step 1 (1.30 g, 2.98 mmol), ethanol (30 mL), acetic acid (171 μL, 2.98 mmol) and 20% palladium hydroxide on carbon (50% water) (0.500 g) was subjected to three cycles of vacuum and nitrogen filling. The vessel was evacuated for the last time and filled with hydrogen (from a cylinder). The reaction mixture was stirred under hydrogen atmosphere overnight and then suction filtered through a pad of celite and concentrated. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was combined with additional extract (ethyl acetate), dried (MgSO ₄ ) and concentrated. The crude product was purified by automated flash chromatography (Biotage system; 0 to 100% ethyl acetate in dichloromethane; 25 g silica gel column) to give the title compound as a yellowish-white solid (0.495 g, 48%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=6.0 Hz, 1H) ppm. MS: 347 m/z (M+H ⁺ ).

[00178] Step 3: cis-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl 1H-imidazole-1-carboxylate

[00179] To a stirred solution of the product from Step 2 (0.495 g, 1.43 mmol) in dichloromethane (15 ml) was added 1,1'-carbonyl-diimidazole (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 (MgSO ₄ ) and concentrated to give the crude product. This material was purified by flash chromatography (Combiflash device; 0 to 100% ethyl acetate in dichloromethane, then 2 to 5% methanol in dichloromethane; 25 g silica gel column). The title compound was obtained as a white solid (0.458 g, 73%). MS: 441 m/z (M+H ⁺ ).

[00180] Intermediate 29. N-Methyl-5-(piperidin-4-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide hydrochloride

[00181] Step 1: Tert-butyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine-1-carboxylate

[00182] A 20 mL microwave reaction vessel equipped with a magnetic stirrer was charged with the title compound from Example 274 (0.633 g, 1.42 mmol) and a 2.0 N solution of methylamine in methanol (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 give the crude title compound as a foamy brown solid (0.631 g, 100%). ^1H NMR (400 MHz, CDCl ₃ ) δ 9.53 (br.s, 1H), 8.82 (s, 1H), 7.49 (s, 1H), 4.33 (br.s, 2H) , 3.12 (d, J=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, CDCl ₃ ) δ 64.0 (s) ppm. MS: 444 m/z (M+H ⁺ ).

[00183] Step 2: N-Methyl-5-(piperidin-4-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide hydrochloride

[00184] To the stirred product from Step 1 (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 carried out at room temperature over the weekend and then concentrated to give a yellow oil. This material was redissolved in methanol (2.0 ml) and the solution was added to vigorously stirring 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 give the title compound as a pale yellow solid (0.338 g, 85%). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.92 (s, 1H), 7.83 (s, 1H), 3.60 (d, J=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 ₃ ) δ 65.4 (s) ppm. MS: 344 m/z (M+H ⁺ ).

[00185] Intermediate 31. (+/-)-5-(trans-3-Fluoro-4-hydroxypiperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide

[00186] A 20 mL microwave reaction vessel equipped with a magnetic stirrer was charged with Intermediate 5 (1.20 g, 4.07 mmol), (+/-)-trans-3-fluoropiperidine-4- ol hydrochloride (0.824 g, 5.29 mmol), N-methyl-2-pyrrolidinone (14 ml) and N,N-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 placed in ethyl acetate (80 ml). The solution was washed with water (4 x 20 ml) and aqueous ammonium chloride (1 x 20 ml). The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give the crude product as a brown solid. This material was placed in diethyl ether and the resulting suspension was sonicated and suction filtered. The collected solid was air dried on a low vacuum filter to give the title compound as a reddish solid (1.26 g, 82%). ^1H NMR (400 MHz, CDCl ₃ ) δ 9.33 (s, 1H), 8.68 (s, 1H), 7.08 (d, J=1.2 Hz, 1H), 4.53 (dddd , J=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, J=3.8 Hz, 1H), 2.33-2, 11 (m, 1H), 1.76 (dtd, J=13.7, 9.7, 4.2 Hz, 1H) ppm. MS: 378 m/z (M+H ⁺ ).

[00187] Intermediate 32: Methyl 5,7-dichlorothieno[3,2-b]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 placed 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 completely melted, the mixture was neutralized by slowly adding portions of solid sodium bicarbonate. The resulting suspension was extracted with dichloromethane (3×75 ml). The combined organic layers were washed with water (1×100 ml), dried (MgSO ₄ ) 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 by 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 gel column) to give the title compound as a pale amber solid (1.97 g, 57%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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-N-methylthieno[3,2-b]pyridine-3-carboxamide

[00190] Intermediate 32 (3.10 g, 11.8 mmol) was combined with 2.0 N 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 gel column) to give the title compound as a pale yellow solid (1.93 g, 63%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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-(difluoromethyl)thieno[3,2-b]pyridine-3-carboxylate

[00192] A 20 mL microwave reaction vessel equipped with a magnetic stirrer was charged with 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 by pipette to a vigorously stirred suspension of crushed ice and water (~40 ml). After the ice had completely melted, the mixture was neutralized by slowly adding portions of solid sodium bicarbonate. The resulting suspension was extracted with ethyl acetate (1×40 ml). The organic layer was washed with water (2×20 ml) and brine (1×10 ml), dried (MgSO 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 by suction filtration through Celite, the solution was concentrated. The resulting crude material was purified by automated flash chromatography (Biotage system; 0 to 40% ethyl acetate in heptane; 40 g silica gel column) to give the title compound as a pale yellow solid (0.125 g, 31%). MS: 278 m/z (M+H ⁺ ).

Receiving connections

[00193] Example 10 Methyl 5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate

[00194] Step 1: Methyl 5-(4-(2-(benzyloxy)-2-oxoethyl)-piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate

[00195] Benzyl 2-(piperazin-1-yl)acetate dihydrochloride (800 mg, 2.60 mmol) was added to a stirred solution of intermediate 3 (0.642 g, 2.17 mmol) in N,N-dimethylformamide (15 mL). , then potassium carbonate (0.900 g, 6.51 mmol). The reaction mixture was heated overnight at 90°C and then concentrated. The residue was partitioned between aqueous sodium bicarbonate (~60 ml) and ethyl acetate (~40 ml). The organic layer was combined with re-extract of the aqueous layer (ethyl acetate, 1 x ~40 ml), dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by automated flash chromatography (Combiflash system, 30 to 50% ethyl acetate in heptane; 40 g silica gel column) to give the title compound (R _f ~0.25 with 1:1 heptane/ethyl acetate as eluent) in as a pale yellow solid (0.611 g, 48%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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-b]pyridin-5-+yl)piperazin-1-yl)acetic acid

[00197] To a stirred solution of the product from step 1 (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 subjected to three successive cycles of evacuation and filling with nitrogen, then a final evacuation was carried out and the reaction vessel was filled with hydrogen (via balloon). After 30 minutes, the reaction mixture was analyzed by TLC and the reaction was found to be complete. The reaction mixture was filtered with suction through a pad of celite, which was then rinsed with methanol. The combined filtrate was concentrated to give the crude title compound as a pale yellow solid (0.489 g, 98%). The material was considered to be of sufficient purity to be used without further purification in the next step. ^1H NMR (400 MHz, DMSO- _d6 ) δ 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-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate

[00199] To a stirred solution of the product from step 2 (0.100 g, 0.247 mmol) and isopropylamine (0.021 g, 0.355 mmol) in N,N-dimethylformamide (5 ml) was added O-(7-azabenzotriazol-1-yl)-N , N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 0.104 g, 0.274 mmol). The mixture was cooled to 0°C and worked up by adding triethylamine (0.15 ml, 1.1 mmol) dropwise. The cooling bath was removed and the reaction mixture was slowly warmed to room temperature. Stirring was continued overnight. Thereafter, the reaction mixture was concentrated and the residue was partitioned between aqueous sodium carbonate (~50 ml) and ethyl acetate (~40 ml). The organic layer was combined with additional extract (ethyl acetate, 1 x ~40 ml), dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by automated flash chromatography (Combiflash system, 5 to 10% methanol in ethyl acetate; Gold column with 40 g silica gel) to give the title compound ( _Rf ~0.65 using 9:1 ethyl acetate/methanol as eluent ) as a yellow solid (0.038 g, 35%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.57 (s, 1H), 7.01 (s, 1H), 6.94 (d, J=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, J=6.5 Hz, 6H) ppm. MS: 445 m/z (M+H ⁺ ).

[00200] Example 25 5-(4-(2-(Ethylamino)-2-oxoethyl)-piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3 -carboxamide

[00201] Step 1: Methyl 5-(4-(2-(ethylamino)-2-oxoethyl)-piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate

[00202] Using the procedure for the amide coupling reaction in the presence of HATU described in step 3 of Example 10, the product from step 2 of Example 10 was subjected to a condensation reaction with ethylamine hydrochloride to obtain the title compound as a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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-1-yl)-N-methyl-7-(trifluoromethyl)thieno-[3,2-b]pyridin-3 -carboxamide

[00204] A 20 mL microwave reaction vessel was charged with the product from Step 1 (0.150 g, 0.348 mmol) and a 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 chromatography (Combiflash system, 0 to 5% methanol in dichloromethane; Gold column with 40 g silica gel) to give the title compound ( _Rf ~0.35 using 19:1 dichloromethane/methanol as eluent) as a pale yellow solid (0.129 g, 86%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=4.9 Hz, 3H), 2.79-2 .71 (m, 4H), 1.20 (t, J=7.3 Hz, 3H) ppm. MS: 430 m/z (M+H ⁺ ).

[00205] Example 39: (+/-)-5-(4-(2-(Cyclopropylmethoxy)-propyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b] -pyridine-3-carboxamide

[00206] Step 1: (+/-)-tert-butyl 4-(2-(cyclopropylmethoxy)propyl)piperazine-1-carboxylate

[00207] To a stirred solution of tert-butyl 4-(2-hydroxypropyl)piperazine-1-carboxylate (0.750 g, 3.07 mmol) in tetrahydrofuran (30 ml) was added 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, then (bromomethyl)cyclopropane (0.45 mL, 4.6 mmol) was added via syringe. The reaction mixture was refluxed overnight. TLC analysis indicated that the reaction mixture contained approximately equal amounts of starting material and product, as determined by the relative intensity of the spot (visualized by iodine staining). Additional sodium hydride (0.123 g, 3.08 mmol) and alkyl bromide (0.30 mL, 3.09 mmol) were added to the stirred reaction mixture at approximately 30-minute intervals. The mixture was re-refluxed for another night. After this, the reaction mixture was concentrated and partitioned between aqueous sodium carbonate (~40 ml) and chloroform (~40 ml). The organic layer was combined with additional extracts (chloroform, 2 x ~40 ml), dried (Na ₂ SO ₄ ) and concentrated. The residue was subjected to automated flash chromatography (Combiflash system, isocratic 3% 2N ammonia/methanol in dichloromethane; Gold column with 40 g silica gel) to give the purified title compound (R _f ~0.4 using 19:1 dichloromethane/2N ammonia in methanol as eluent) as a colorless oil (0.781 g, 85%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.65-3.57 (m, 1H), 3.45-3.39 (m, 4H), 3.35 (dd, J=10.1, 6 .8 Hz, 1H), 3.27 (dd, J=10.1, 6.8 Hz, 1H), 2.55-2.37 (m, 4H), 2.30 (dd, J=13, 0, 5.0 Hz, 1H), 1.46 (s, 9H), 1.15 (d, J=6.2 Hz, 3H) ppm.

[00208] Step 2: (+/-)-1-(2-(Cyclopropylmethoxy)propyl)-piperazine

[00209] Trifluoroacetic acid (4.0 mL, 52 mmol) was added to a stirred solution of the product from Step 1 (0.780 g, 2.61 mmol) in dichloromethane (12 mL). After 2 hours, the reaction mixture was analyzed by TLC and it was found that the reaction was complete. The mixture was concentrated and the residue was partitioned between aqueous sodium carbonate (~40 ml) and chloroform (~40 ml). The organic layer was combined with additional extracts (chloroform, 3 x ~40 ml), dried (Na ₂ SO ₄ ) and concentrated to give the crude title compound as a colorless oil (0.527 g, 102%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.68-3.56 (m, 1H), 3.35 (dd, J=10.1, 6.8 Hz, 1H), 3.28 (dd, J=10.1, 6.9 Hz, 1H), 2.88 (t, J=4.9 Hz, 3H), 2.57-2.37 (m, 5H), 2.27 (dd, J =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-methyl-propyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2- b]-pyridine-3-carboxamide

[00211] A 20 mL microwave reaction vessel was charged with Intermediate 5 (0.250 g, 0.848 mmol), product from Step 2 (0.294 g, 1.48 mmol), N,N-diisopropylethylamine (0. 30 ml, 1.7 mmol) and N-methyl-2-pyrrolidinone (6 ml). The vessel was sealed and heated in a microwave reactor at 130°C for two hours. TLC analysis indicated that the reaction was complete. The mixture was concentrated and the residue was partitioned between chloroform (~30 ml) and aqueous sodium carbonate (~50 ml). The organic layer was combined with additional extracts (chloroform, 2 x ~30 ml), dried (Na ₂ SO ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system, isocratic 2.5% methanol in dichloromethane; Gold column with 40 g silica gel) to give the title compound ( _Rf ~0.4 using 19:1 dichloromethane/methanol as eluent) in the form of a viscous red-brown oil. This material was co-evaporated with ethyl acetate and dried in a vacuum oven (~70°C) to obtain the title compound as a red-brown gum (0.266 g, 69%). ^1H NMR (400 MHz, CDCl ₃ ) δ 9.44 (br.s, 1H), 8.65 (s, 1H), 7.03 (s, 1H), 3.74-3.58 (m, 5H), 3.39 (dd, J=10.1, 6.9 Hz, 1H), 3.31 (dd, J=10.1, 6.9 Hz, 1H), 3.08 (d, J =4.9 Hz, 3H), 2.80-2.65 (m, 4H), 2.60 (dd, J=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-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00213] Step 1: Tert-butyl 4-(2-bromoacetyl)piperazine-1-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 dropwise a solution of tert-butyl piperazine-1-carboxylate (7.75 g, 41 .6 mmol) in dichloromethane (20 ml) for ~20 minutes. The cooling bath was then removed and the reaction mixture was stirred for a further two hours, then transferred to a separatory funnel, rinsing the reaction vessel with dichloromethane (~30 ml). The solution was washed with 1.0 N hydrochloric acid (2 x ~50 ml) and aqueous sodium bicarbonate (1 x ~50 ml). The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give the title compound as a clear pale amber gum (5.68 g, 93%). The crude intermediate was considered to be sufficiently pure to be used without purification in the next step. ^1H NMR (400 MHz, CDCl ₃ ) δ 3.87 (s, 2H), 3.63-3.57 (m, 2H), 3.55-3.41 (m, 6H), 1.48 ( s, 9H) ppm.

[00215] Step 2: Tert-butyl 4-(2-isopropoxyacetyl)piperazine-1-carboxylate

[00216] To a stirred and cooled (0°C) solution of the product from step 1 (2.00 g, 6.51 mmol) and isopropanol (0.50 mL, 6.5 mmol) in N,N-dimethylformamide (60 mL ) a 60% dispersion of sodium hydride in mineral oil (0.290 g, 7.25 mmol) was added. The mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was then concentrated and partitioned between water (~100 ml) and ethyl acetate (~50 ml). The organic layer was combined with the second extract (ethyl acetate, 1 x ~30 ml), dried (Na ₂ SO ₄ ) and concentrated to give a pale amber gum. The crude product was subjected to automated flash chromatography (Combiflash system, 50 to 75% ethyl acetate in heptane; Gold column with 80 g silica gel) to obtain the purified title compound ( _Rf ~0.6 using 3:1 ethyl acetate/heptane as eluent) as a colorless resin that slowly solidified into a white solid (0.515 g, 28%; low yield was the result of an automated fraction collection failure to run correctly due to the weak UV activity of the activity). ¹ H NMR (400 MHz, CDCl ₃ ) 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, J=6.1 Hz, 3H) ppm.

[00217] Step 3: 2-Isopropoxy-1-(piperazin-1-yl)ethan-1-one

[00218] Hydrogen chloride gas was bubbled through a stirred solution of the product from Step 2 (0.504 g, 1.76 mmol) in ethyl acetate (30 mL) for approximately five minutes. After two hours, the reaction mixture was analyzed by ¹ H NMR and the reaction was found to be complete. The reaction mixture was concentrated and the residue was partitioned between aqueous sodium carbonate (~50 ml) and chloroform (~30 ml). The organic layer was combined with additional extracts (chloroform, 3 x ~30 ml), dried (Na ₂ SO ₄ ) and concentrated to give the title compound as a viscous pale amber oil (0.317 g, 97%). The crude intermediate was considered to be sufficiently pure to be used without purification in the next step. ^1H NMR (400 MHz, CDCl ₃ ) δ 4.13 (s, 2H), 3.63-3.57 (m, 2H), 2.98-2.86 (m, 4H), 1.19 ( d, J=6.1 Hz, 6H) ppm.

[00219] Step 4: 5-(4-(2-Isopropoxyacetyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00220] Using the conditions described in step 3 of Example 39, intermediate 5 was subjected to an S _N Ar substitution reaction with the piperazine derivative, the product of step 3 of this example, to obtain the title compound as a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=6 ,1 Hz, 6H) ppm. MS: 445 m/z (M+H ⁺ ).

[00221] Example 47 5-(4-(2-(Isopropylamino)-2-oxoethyl)-piperazin-1-yl)-N,6-dimethyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide

[00222] Step 1: Tert-butyl 4-(2-(isopropylamino)-2-oxoethyl)piperazine-1-carboxylate

[00223] The carbonate sodium (4.99 g, 47.1 mmol). The mixture was refluxed overnight and then cooled to room temperature. TLC analysis indicated that the reaction was complete. The mixture was filtered with suction to remove solids, which were then rinsed with ethyl acetate (3 x ~25 ml). The combined filtrate was concentrated to give an oil. This material was partitioned between aqueous sodium carbonate (~100 ml) and ethyl acetate (~150 ml). The organic layer was combined with additional extracts (ethyl acetate, 2 x ~100 ml), dried (Na ₂ SO ₄ ) and concentrated to give the crude product as an off-white solid (8.70 g, 97%). The material was considered to be of sufficient purity to be used without further purification in the next step. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=6.6 Hz, 6H) ppm .

[00224] Step 2: N-isopropyl-2-(piperazin-1-yl)acetamide

[00225] The crude product from step 1 was dissolved in ethyl acetate (300 ml). Hydrogen chloride was bubbled through this stirred solution for approximately five minutes. After another two hours, the reaction mixture was analyzed by TLC and was found to still contain a small amount of N-tert-butoxycarbonyl-substituted starting material. The reaction mixture was saturated with hydrogen chloride gas as before and stirred for another hour. The mixture was then concentrated and the residue was partitioned between chloroform (~100 ml) and aqueous sodium carbonate (~200 ml). The organic layer was combined with additional extracts (chloroform, 5 x ~100 ml), dried (Na ₂ SO ₄ ) and concentrated to give the crude product as a yellowish-white solid. This material was subjected to automated flash chromatography (Combiflash system, 10% methanol in chloroform until spots of impurities eluted, and then 10 to 15% 2N ammonia/methanol in chloroform; 120 g silica gel column) to obtain the purified title compound (R _f ~0.2 using 9:1 chloroform/2N ammonia in methanol as eluent) as a pale yellow solid (4.41 g, 77%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 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, J=6.6 Hz , 6H) ppm.

[00226] Step 3: Methyl 5-(4-(2-(isopropylamino)-2-oxo-ethyl)piperazin-1-yl)-6-methyl-7-(trifluoromethyl)thieno[3,2-b]- pyridine-3-carboxylate

[00227] A 20 mL microwave reaction vessel was charged with Intermediate 14 (0.300 g, 0.969 mmol), product from Step 2 (0.314 g, 1.69 mmol), N-methyl-2-pyrrolidinone (6 ml) and N,N-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 a significant portion of the product from Step 2 remained unreacted. Additional N-isopropyl-2-(piperazin-1-yl)acetamide (0.180 g, 0.972 mmol) was added to the reaction mixture and microwave heating was continued for an additional two hours. The reaction mixture was then concentrated and the residue was partitioned between aqueous sodium carbonate (~25 ml) and chloroform (~25 ml). The organic layer was combined with additional extract (chloroform, 1 x ~25 ml), dried (Na ₂ SO ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system, 0 to 3% methanol in ethyl acetate; Gold column with 40 g silica gel) to obtain the purified title compound ( _Rf ~0.4 using 97:3 ethyl acetate/methanol as eluent ) as a beige solid (0.208 g, 47%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=6.5 Hz, 6H) ppm.

[00228] Step 4: 5-(4-(2-(Isopropylamino)-2-oxoethyl)-piperazin-1-yl)-N,6-dimethyl-7-(trifluoromethyl)-thieno[3,2-b] -pyridine-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 N-methylcarboxamide to give the title compound as a beige solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.48 (br.s, 1H), 8.64 (s, 1H), 6.90 (d, J=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, J=6.5 Hz, 6H) ppm. MS: 458 m/z (M+H ⁺ ).

[00230] Example 48 5-(4-(2-(Isopropylamino)-2-oxoethyl)-piperazin-1-yl)-N,7-dimethylthieno[3,2-b]pyridine-3-carboxamide

[00231] Step 1: Methyl 7-methyl-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-3-carboxylate

[00232] A 100 mL round bottom flask equipped with a magnetic stirrer was charged with methyl 4-aminothiophene-3-carboxylate (4.99 g, 31.8 mmol), ethyl acetoacetate (7.70 mL, 60.9 mmol) and water ( 1 ml). The added mixture was stirred at room temperature for several minutes and then placed in a preheated oil bath (125°C). The reaction flask was equipped with a reflux condenser (without refrigerant circulation, so that volatile components could be removed after the condenser was sufficiently heated). After six hours, additional ethyl acetoacetate (2.00 mL, 15.8 mmol) and water (1.0 mL) were added to the mixture and the reaction was carried out over the weekend (~64 hours total). After this, the reaction mixture was analyzed by LCMS and it was found that the reaction was completed. The mixture was distributed between chloroform (~200 ml) and aqueous sodium bicarbonate (~200 ml). The organic layer was combined with additional extracts (chloroform, 2 x ~100 ml), dried (Na ₂ SO ₄ ) and concentrated to obtain a wet, rust-colored solid. This material was placed in a mixture of heptane (~120 ml) and ethyl acetate (~20 ml) and subjected to ultrasound until the suspension became homogeneous. The suspended solid was filtered with suction and rinsed with additional heptane (2 x ~20 ml). The filter cake was air dried on the filter under low pressure to obtain an amber solid. The material was further purified by trituration with a mixture of diethyl ether (~75 ml) and ethyl acetate (~20 ml). The suspended solid was again collected by suction filtration and air dried on the filter under low pressure. The title compound was obtained as an orange-yellow solid (3.34 g, 50%). ^1H NMR (400 MHz, DMSO- _d6 ) δ 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-b]pyridine-3-carboxylate

[00234] To a stirred and cooled (0°C) solution of the product from step 1 (3.28 g, 14.7 mmol) in pyridine (40 ml) was added dropwise trifluoromethanesulfonic anhydride (3.10 ml, 18.4 mmol) within 4-5 minutes. The mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture 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 SO ₄ ) and concentrated to give the crude title compound as a light brown solid (5.26 g, 100%). ¹ H NMR analysis indicated that the material was sufficiently pure to be used in subsequent reactions without purification. ^1H NMR (400 MHz, CDCl ₃ ) δ 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-oxo-ethyl)piperazin-1-yl)-6-methyl-7-(trifluoromethyl)thieno[3,2-b]- pyridine-3-carboxylate

[00236] A 10 mL microwave reaction vessel equipped with a magnetic stirrer was charged with the product from Step 2 (0.400 g, 1.13 mmol), N-isopropyl-2-(piperazin-1-yl)acetamide (0.375 g, 2.02 mmol; synthesized as described in step 2 of Example 47), N-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 (~50 ml). The organic layer was combined with additional extracts (ethyl acetate, 2 x ~25 ml), dried (Na ₂ SO ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system, 0 to 10% methanol in ethyl acetate; Gold column with 40 g silica gel) to give the purified title compound (R _f ~0.2 using 96:4 dichloromethane/methanol as eluent ) as an amber solid (0.330 g, 75%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (s, 1H), 7.00 (d, J=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, J=6.6 Hz, 6H) ppm.

[00237] Step 4: 5-(4-(2-(Isopropylamino)-2-oxoethyl)-piperazin-1-yl)-N,7-dimethylthieno[3,2-b]pyridine-3-carboxamide

[00238] Using the procedure described for step 2 of example 25, the methyl ester functionality of the product from step 3 was converted to the corresponding N-methylcarboxamide, obtaining the title compound as a yellowish-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.48 (br.s, 1H), 8.64 (s, 1H), 6.90 (d, J=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, J=6.5 Hz, 6H) ppm. MS: 390 m/z (M+H ⁺ ).

[00239] Example 49 5-(4-(2-(Isopropylamino)-2-oxoethyl)-3,3-dimethylpiperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b ]-pyridine-3-carboxamide

[00240] Step 1: Tert-butyl 4-(2-(isopropylamino)-2-oxoethyl)-3,3-dimethylpiperazine-1-carboxylate

[00241] To a stirred solution of tert-butyl 3,3-dimethylpiperazine-1-carboxylate (1.00 g, 4.67 mmol) and 2-bromo-N-isopropylacetamide (0.882 g, 4.90 mmol) in butyronitrile (30 ml) sodium carbonate (0.742 g, 7.00 mmol) was added. The mixture was refluxed overnight. TLC analysis indicated that the reaction was complete. The mixture was cooled to room temperature and suction filtered to remove solids. The filter cake 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; Gold column with 80 g silica gel) to give the purified title compound (R _f ~0.4 using 19:1 dichloromethane/2N ammonia in methanol as eluent) as a yellowish-white solid (1.37 g, 94%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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-Dimethylpiperazin-1-yl)-N-isopropyl-acetamide

[00243] Using the procedure described in step 3 of example 44, the N-tert-butoxycarbonylamine protecting group of the product from step 1 was cleaved using a solution of hydrogen chloride in ethyl acetate. The title compound was obtained in the form of a pale amber resin. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=6.5 Hz, 6H), 1.04 (s, 6H) ppm.

[00244] Step 3: Methyl 5-(4-(2-(isopropylamino)-2-oxoethyl)-3,3-dimethylpiperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin- 3-carboxylate

[00245] Intermediate 3 (0.400 g, 1.35 mmol), product from Step 2 (0.460 g, 2.16 mmol), N-methyl-2-pyrrolidinone, was loaded into a 20 mL microwave reaction vessel. (6 ml) and N,N-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 almost complete. The reaction mixture was then concentrated and the residue was partitioned between aqueous sodium bicarbonate (~60 ml) and ethyl acetate (~30 ml). The organic layer was combined with additional extracts (ethyl acetate, 2 x ~30 ml), dried (Na ₂ SO ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system, 25 to 60% ethyl acetate in heptane; Gold column with 40 g silica gel) to obtain the purified title compound ( _Rf ~0.3 using 6:4 heptane/ethyl acetate as eluent ) as an amber solid (0.287 g, 45%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.56 (s, 1H), 7.26 (d, J=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-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b ]-pyridine-3-carboxamide

[00247] Using the procedure described for Step 2 of Example 25, the methyl ester functionality of the product from Step 3 was converted to the corresponding N-methylcarboxamide, yielding the title compound as a pale gold solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=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 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl azetidin-1-carboxylate

[00249] A 20 mL microwave reaction vessel was charged with Intermediate 21 (0.200 g, 0.381 mmol), N,N-dimethylformamide (6.0 mL), Azetidine (77 μL, 1.14 mmol), triethylamine (0.21 ml, 1.5 mmol) and 4-(dimethylamino)pyridine (6 mg, 49 μmol). 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 (~40 ml). The organic layer was combined with additional extracts (chloroform, 2 x ~20 ml), dried (Na ₂ SO ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system, 0-2% methanol in dichloromethane; Gold column with 40 g silica gel). The target component (Rf ~0.2 using 98:2 dichloromethane/methanol as eluent) was obtained as a light gold film. This material was co-evaporated with ethyl acetate and dried in a vacuum oven (~60°C) to obtain the title compound as a pale gold solid (0.144 g, 85%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-secbutylcarbamate

[00251] Replacing azetidine with (S)-sec-butylamine, the procedure described in Example 60 was used to obtain the title compound as a yellowish-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J= 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, J=6.6 Hz, 3H), 0.99-0.88 (m, 3H) ppm. MS: 459 m/z (M+H ⁺ ).

[00252] Example 76 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate

[00253] Substituting isopropylamine for azetidine, the procedure described in Example 60 was used to obtain the title compound as a yellowish-white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J=4.9 Hz , 3H), 2.14-2.02 (m, 2H), 1.92-1.74 (m, 2H), 1.18 (d, J=6.5 Hz, 6H) ppm. MS: 445 m/z (M+H ⁺ ).

[00254] Example 87 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(difluoromethoxy)-azetidine-1- carboxylate

[00255] Step 1. 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 1H-imidazol-1-carboxylate

[00256] To a stirred suspension of intermediate 7 (2.50 g, 6.96 mmol) in dichloromethane (50 ml) was added 1,1'-carbonyldiimidazole (2.26 g, 13.9 mmol). The mixture quickly turned into a clear amber solution. Stirring was continued overnight at room temperature. Thereafter, 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 SO ₄ ) and concentrated to give the crude title compound as a foamy pale gold solid (3.26 g, 103%). The crude intermediate was considered to be sufficiently pure to be used without purification in the next step. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.33 (br.s, 1H), 8.69 (s, 1H), 8.18-8.15 (m, 1H), 7.44 (t, J=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. 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(difluoromethoxy)-azetidine-1- carboxylate

[00258] A 20 mL microwave reaction vessel was charged with the product from Step 1 (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-hydroxysuccinimide (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 mixture was concentrated and partitioned between chloroform (~30 ml) and aqueous sodium bicarbonate (~50 ml). The organic layer was combined with additional extracts (chloroform, 2 x ~30 ml), dried (Na ₂ SO ₄ ) and concentrated. The residue was subjected to automated flash chromatography (Combiflash system, 40 to 70% ethyl acetate in heptane; Gold column with 40 g silica gel). The target component (Rf ~0.4 using a 7:3 ethyl acetate/heptane mixture as eluent) was obtained in the form of an almost colorless film. This material was dried in a vacuum oven (~60°C) and ground with a spatula to obtain the title compound as a pale gold solid (0.270 g, 96%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.42 (br.s, 1H), 8.67 (s, 1H), 7.06 (s, 1H), 6.25 (t, J=73 Hz , 1H), 5.04-4.90 (m, 2H), 4.28 (dd, J=9.9, 6.8 Hz, 2H), 4.07 (dd, J=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 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(trifluoromethoxy)-azetidine-1- carboxylate

[00260] To obtain the title compound as a pale gold solid, a synthesis procedure similar to that described in Step 2 of Example 87 was used, replacing 3-(difluoromethoxy)azetidine with equimolar amounts of 3-(trifluoromethoxy)azetidine hydrochloride and triethylamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.40 (br.s, 1H), 8.66 (s, 1H), 7.07 (s, 1H), 5.07-4.90 (m, 2H), 4.32 (dd, J=10.2, 6.7 Hz, 2H), 4.14 (dd, J=10.2, 4.2 Hz, 2H), 4.02-3.86 (m, 2H), 3.08 (d, J=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 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-(trifluoromethoxy)propane -2-yl)carbamate

[00262] To obtain the title compound as a pale gold solid, a synthesis procedure similar to that described in Step 2 of Example 87 was used, replacing 3-(difluoromethoxy)azetidine with equimolar amounts of intermediate 18 and triethylamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=4.9 Hz, 3H), 2.16-2.02 (m, 2H), 1.90-1.76 (m, 2H), 1.28 (d, J=6.6 Hz , 3H) ppm. MS: 529 m/z (M+H ⁺ ).

[00263] Example 91 3,3-Difluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate

[00264] Step 1: Methyl 5-(3,3-difluoro-4-hydroxypiperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate

[00265] A 20 mL microwave reaction vessel was charged with Intermediate 3 (1.35 g, 4.57 mmol), N-methyl-2-pyrrolidinone (12 mL), 3,3-difluoropiperidine-4 -ol (1.02 g, 7.44 mmol) and N,N-diisopropylethylamine (1.6 ml, 9.2 mmol). The vessel was sealed and heated in a microwave reactor for five hours at 130°C. LCMS analysis indicated that the reaction was not complete (~73:27 ratio of product to starting material, determined by peak area). The reaction mixture was heated for another five hours at 130°C. LCMS analysis indicated that the reaction had progressed sufficiently to permit recovery of the desired product (~85/12 product to starting material ratio). The solution was concentrated and the residue was partitioned between chloroform (~75 ml) and aqueous sodium bicarbonate (~100 ml). The organic layer was combined with additional extracts (chloroform, 2 x ~50 ml), dried (Na ₂ SO ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system, 40 to 60% ethyl acetate in heptane; 120 g silica gel column) to give the title compound (Rf ~0.4, using 6:4 heptane/ethyl acetate as eluent) in as a golden solid (1.07 g, 59%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00267] Using the procedure described for Step 2 of Example 25, the methyl ester functionality of the product from Step 1 was converted to the corresponding N-methylcarboxamide to give the title compound as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 1H-imidazol-1 -carboxylate

[00269] To a stirred suspension of the product from Step 2 (0.905 g, 2.29 mmol) in dichloromethane (12 ml) was added 1,1'-carbonyldiimidazole (0.557 g, 3.44 mmol). Stirring was continued overnight at room temperature. After this, the reaction mixture was diluted with chloroform (~80 ml). The solution was washed with 0.1 N hydrochloric acid (1 x 100 ml) and aqueous sodium bicarbonate (1 x ~80 ml). The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give the title compound as a foamy pale gold solid (1.12 g, 100%). This material was considered pure enough to be used without purification in the next step. ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J=4.9 Hz, 3H), 2.46-2.37 (m, 1H ), 2.34-2.23 (m, 1H) ppm.

[00270] Step 4: 3,3-Difluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropyl carbamate

[00271] To obtain the title compound as a white solid, the procedure described in Step 2 of Example 87 was used, replacing the product from Step 1 of Example 87 with the product from Step 3 of this Example and 3-(difluoromethoxy)azetidine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=4.9 Hz, 3H), 2.30-2 .01 (m, 2H), 1.20 (t, J=6.5 Hz, 6H) ppm. MS: 481 m/z (M+H ⁺ ).

[00272] Example 95 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate

[00273] Step 1. Piperidin-4-yl 6,7-dihydropyrazolo[1,5-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[1,5-a] pyrazine dihydrochloride (1.00 g, 5.12 mmol), then triethylamine (2.9 mL, 21 mmol, 4.1 eq; the amount of triethylamine used in similar reactions using intermediate 22 was adjusted by at least two equivalents is greater than the number of acid equivalents introduced by the amine component if it was in salt form). The ice bath was removed and the reaction mixture was warmed to room temperature and stirred overnight. The mixture was then rinsed in a separatory funnel with chloroform (~20 ml) and washed with aqueous sodium carbonate (~50 ml). The organic layer was combined with additional aqueous layer extracts (chloroform, 2 x ~40 ml), dried (Na ₂ SO ₄ ) and concentrated to give the crude carbamate as a light 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 trifluoroacetic acid equivalents used in similar reactions with intermediate 22 were adjusted so that a total of 17-20 were used equivalents of 3.0-3.5 M trifluoroacetic acid solution). After two hours, the reaction mixture was concentrated and the residue was partitioned between chloroform (~50 ml) and 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 SO ₄ ) and concentrated to give the crude title compound as a light amber gum (1.28 g, 100%). This material was considered pure enough to be used without purification in the next step. ^1H NMR (400 MHz, CDCl ₃ ) δ 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. 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate

[00276] A 20 mL microwave reaction vessel was charged with the product from Step 1 (0.340 g, 1.36 mmol), Intermediate 5 (0.200 g, 0.679 mmol), N-methyl-2-pyrrolidinone (6 ml) and N,N-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 mixture was concentrated and the residue was partitioned between chloroform (~30 ml) and aqueous sodium bicarbonate (~50 ml). The organic layer was combined with additional extracts (chloroform, 2 x ~30 ml), dried (Na ₂ SO ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system, 3 to 8% methanol in ethyl acetate; Gold column with 40 g silica gel). The target component (Rf ~0.2 using 19:1 ethyl acetate/methanol as eluent) 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 by suction filtration. The filter cake was rinsed with additional diethyl ether (1 x ~10 ml) and air dried on the filter under slight vacuum and a stream of nitrogen to give the title compound as a yellow solid (0.274 g, 79%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J=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 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-cyclopropylethyl)- carbamate

[00278] To obtain the title compound as a pale yellow solid, the synthetic sequence described in Example 95 was used, replacing 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine dihydrochloride with (S)-1-cyclopropylethane -1-amine ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J =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 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((4-methylmorpholin-2-yl )methyl)carbamate

[00280] Step 1: Benzyl 4-((((4-methylmorpholin-2-yl)methyl)-carbamoyl)oxy)piperidine-1-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), then triethylamine (1.40 ml, 10.0 mmol, 2.05 eq; the amount of triethylamine used in similar reactions using intermediate 23 was adjusted to be at least two equivalents more than the amount of acid equivalents, introduced using the amine component if it was in salt form). The ice bath was removed and the reaction mixture was warmed to room temperature and stirred overnight. The mixture was then rinsed in a separatory funnel with chloroform (~20 ml) and washed with aqueous sodium carbonate (~50 ml). The organic layer was combined with additional extracts of the aqueous layer (chloroform, 2 x ~40 ml), dried (Na ₂ SO ₄ ) and concentrated to give the crude title compound as a light amber gum (2.01 g, 105%; yield overestimated). residual toluene account). This material was considered pure enough to be used without purification in the next step. ^1H NMR (400 MHz, CDCl ₃ ) δ 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 product from step 1 was combined with 10% palladium on carbon (0.400 g) and placed in methanol (50 ml). The stirred mixture was subjected to three successive cycles of evacuation and nitrogen filling. The reaction vessel was evacuated one last time and filled with hydrogen (from a cylinder). The reaction mixture was stirred at room temperature overnight and then analyzed by ¹ H NMR (a few drops of the settled suspension were collected and concentrated to obtain a sample for analysis) and the reaction was found to be complete. The mixture was filtered with suction through a pad of celite, which was then rinsed with additional methanol (~80 ml). The combined filtrate was concentrated to give the crude product as a tacky colorless glass (1.32 g, 100%). The crude amine was considered pure enough to be used without purification in the next step. ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J=11.5, 3.3 Hz, 1H), 2.09-1.99 (m, 2H), 1.85 (t, J=10.7 Hz, 1H), 1.80-1.69 (m, 2H) ppm.

[00284] Step 3. 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((4-methylmorpholin-2-yl) -methyl)carbamate

[00285] A 20 mL microwave reaction vessel was charged with Intermediate 5 (0.200 g, 0.679 mmol), product from Step 2 (0.306 g, 1.19 mmol), N-methyl-2-pyrrolidinone (6 ml) and N,N-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 mixture was concentrated and the residue was partitioned between chloroform (~25 ml) and aqueous sodium carbonate (~40 ml). The organic layer was combined with additional extracts (chloroform, 2 x ~25 ml), dried (Na ₂ SO ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system, 0 to 10% methanol in chloroform; Gold column with 80 g silica gel). The target component (Rf ~0.36 using 9:1 chloroform/methanol as eluent) was obtained as a foamy solid. This material was co-evaporated with ethyl acetate to give the title compound as an amber solid (0.159 g, 45%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J=4.9 Hz, 3H), 2.74 (d, J=11.2 Hz, 1H), 2.66 (d, J=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 1-(3-(Methylcarbamoyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl (S)-(1-(trifluoromethoxy)propan-2-yl) -carbamate

[00287] Step 1: Methyl 5-(((trifluoromethyl)sulfonyl)oxy)-thieno[3,2-b]pyridine-3-carboxylate

[00288] To obtain the title compound as a brown solid, the procedure described in Step 2 of Example 48 was used, replacing the product from Step 1 of Example 48 with Intermediate 16. This material was considered pure enough to be used without purification in the next step. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.76 (s, 1H), 8.37 (d, J=8.6 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H ), 3.99 (s, 3H) ppm.

[00289] Step 2: Piperidin-4-yl (S)-(1-(trifluoromethoxy)-propan-2-yl)carbamate

[00290] To obtain the crude title compound as a waxy yellowish-white solid, the synthesis procedure described in step 1 of Example 95 was used, replacing 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine dihydrochloride with intermediate 18 , O-(piperidin-4-yl)carbamate. This material was considered pure enough to be used without purification in the next step. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.99-4.57 (m, 2H), 4.09-3.82 (m, 3H), 3.06 (dt, J=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, J=6.7 Hz, 3H) ppm.

[00291] Step 3: Methyl (S)-5-(4-(((1-(trifluoromethoxy)propan-2-yl)carbamoyl)oxy)piperidin-1-yl)thieno[3,2-b]pyridin- 3-carboxylate

[00292] A 10 mL microwave reaction vessel equipped with a magnetic stirrer was charged with product from Step 2 (0.220 g, 0.814 mmol), product from Step 1 (0.200 g, 0.586 mmol), N-methyl- 2-pyrrolidinone (2.5 ml) and N,N-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 mixture was analyzed by LCMS and found to be incomplete (approximately 1:1 mixture of triflate starting material and expected product based on the corresponding peak size). Heating was continued at 90°C for another hour, but LCMS analysis showed no further reaction. The mixture was then concentrated and the residue was partitioned between chloroform (~30 ml) and aqueous sodium bicarbonate (~50 ml). The organic layer was combined with additional extracts (chloroform, 2 x ~15 ml), dried (Na ₂ SO ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system, 0 to 40% ethyl acetate in heptane; Gold column with 40 g silica gel) to give the title compound (Rf ~0.35, using 6:4 heptane/ethyl acetate as eluent) as a colorless solid (0.099 g, 37%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.45 (s, 1H), 7.89 (d, J=9.1 Hz, 1H), 6.81 (d, J=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, J=6.5 Hz, 3H) ppm.

[00293] Step 4. 1-(3-(Methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-(trifluoromethoxy)propan-2-yl)carbamate

[00294] Using the procedure described for Step 2 of Example 25, the methyl ester functionality of the product from Step 3 was converted to the corresponding N-methylcarboxamide to give the title compound as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.72-9.62 (m, 1H), 8.54 (s, 1H), 7.94 (d, J=9.1 Hz, 1H), 6 .83 (d, J=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, J=4.8 Hz, 3H), 2.12-1.99 (m, 2H), 1.90-1.72 (m, 2H), 1.27 ( d, J=6.6 Hz, 3H) ppm. MS: 461 m/z (M+H ⁺ ).

[00295] Example 145 N-Methyl-5-(4-((6-methylpyridin-2-yl)oxy)piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3 -carboxamide

[00296] Using the conditions described in step 3 of Example 115, intermediate 5 was SNAr-substituted with a piperidine derivative, 2-methyl-6-(piperidin-4-yloxy)pyridine, to give the title compound as a beige solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.56-9.45 (m, 1H), 8.66 (s, 1H), 7.47 (dd, J=8.2, 7.3 Hz, 1H), 7.09 (s, 1H), 6.73 (d, J=7.3 Hz, 1H), 6.53 (d, J=8.2 Hz, 1H), 5.42 (tm, J=7.2, 3.6 Hz, 1H), 3.96 (ddd, J=13.2, 7.8, 3.7 Hz, 2H), 3.67 (ddd, J=13.2, 7.7, 3.7 Hz, 2H), 3.07 (d, J=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 1-(6-Methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1- cyclopropylethyl)carbamate

[00298] To obtain the title compound as a yellowish-white solid, the synthetic sequence described in Example 95 was used, replacing 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine dihydrochloride with (S)-1-cyclopropylethane -1-amine, and intermediate 5 per intermediate 15. ^1H NMR (400 MHz, CDCl ₃ ) δ 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 (kv, 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-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-piperidin-1- carboxylate

[00300] A 20 mL microwave reaction vessel was charged with Intermediate 11 (0.200 g, 0.892 mmol) and acetonitrile (10 mL). To this stirred solution were added intermediate 17 (0.400 g, 1.11 mmol) and N-hydroxysuccinimide (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 (~100 ml) and chloroform (~75 ml). The organic layer was combined with the second extract (chloroform, 1 x ~50 ml), dried (Na ₂ SO ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system, 40 to 60% ethyl acetate in heptane; Gold column with 80 g silica gel). The target component (Rf ~0.25, using 6:4 ethyl acetate/heptane as eluent) was obtained as a colorless foam. This material was dried in a vacuum oven (~60°C) to obtain the title compound as a colorless solid (0.392 g, 85%). ^1H NMR (400 MHz, CDCl ₃ ) δ 9.07-8.96 (m, 1H), 8.76 (s, 1H), 7.13 (s, 1H), 5.26 (tt, J= 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 (dd, J=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 m/z (M+H ⁺ ).

[00301] Example 175: (S)-1-(Trifluoromethoxy)propan-2-yl (2R,4R)-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3, 2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate

[00302] Step 1. Tert-butyl (2R,4R)-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-piperidine -1-carboxylate

[00303] To a stirred solution of intermediate 5 (1.35 g, 4.58 mmol) and tert-butyl (2R,4R)-4-hydroxy-2-methylpiperidine-1-carboxylate (1.00 g, 4.64 mmol) in tetrahydrofuran (30 ml) potassium tert-butoxide (0.668 g, 5.95 mmol) was added. The mixture was heated at 70°C for three hours and then subjected to LCMS analysis. Little or no starting chloropyridine was detected. The reaction mixture was concentrated and the residue was partitioned between aqueous sodium bicarbonate (~100 ml) and chloroform (~60 ml). The organic layer was combined with additional extracts (chloroform, 2 x ~40 ml), dried (Na ₂ SO ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system, 20 to 50% ethyl acetate in heptane; Gold column with 80 g silica gel) to give the title compound (Rf ~0.3 using 1:1 heptane/ethyl acetate as eluent) as a light amber solid (1.31 g, 60%). ^1H NMR (400 MHz, CDCl ₃ ) δ 9.08-9.01 (m, 1H), 8.75 (s, 1H), 7.11 (s, 1H), 5.38 (p, J= 3.1 Hz, 1H), 4.50-4.40 (m, 1H), 4.00 (ddd, J=13.8, 4.7, 1.8 Hz, 1H), 3.29 (td , J=13.4, 2.8 Hz, 1H), 3.07 (d, J=4.9 Hz, 3H), 2.18-2.01 (m, 3H), 1.97-1, 85 (m, 1H), 1.49 (s, 9H), 1.32 (d, J=7.1 Hz, 3H) ppm.

[00304] Step 2: N-methyl-5-(((2R,4R)-2-methylpiperidin-4-yl)oxy)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00305] Trifluoroacetic acid (3.0 mL, 39 mmol) was added to the stirred product from Step 1 (1.30 g, 2.75 mmol) in dichloromethane (10 mL). After 75 minutes, the reaction mixture was analyzed by ¹ H NMR (a few drops of the reaction solution were concentrated and partitioned between aqueous sodium carbonate and chloroform; the organic layer was concentrated to obtain a sample for analysis) and the reaction was found to be complete. The reaction mixture was concentrated and the resulting oil was partitioned between chloroform (~40 ml) and aqueous sodium carbonate (~60 ml). The organic layer was combined with additional extracts (chloroform, 2 x ~40 ml), dried (Na ₂ SO ₄ ) and concentrated to give the crude title compound as a light amber solid (1.05 g, 102%). This material was considered pure enough to be used without purification in the next step. ^1H NMR (400 MHz, CDCl ₃ ) δ 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 (dd, J=12.6, 4.4, 2.6 Hz, 1H), 3.08 (d, J=4.9 Hz, 3H ), 2.89-2.78 (m, 2H), 2.34-2.20 (m, 2H), 1.66 (dkv, J=12.2, 4.4 Hz, 1H), 1, 37 (kv, J=11.4 Hz, 1H), 1.20 (d, J=6.3 Hz, 3H) ppm.

[00306] Step 3. (S)-1-(Trifluoromethoxy)propan-2-yl (2R,4R)-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2 -b]-pyridin-5-yl)oxy)piperidine-1-carboxylate

[00307] To obtain the title compound as a glassy, colorless solid, the procedure described in Example 171 was used, replacing intermediate 17 with the product from step 2, and intermediate 11 with intermediate 12. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.01 (kv, J=4.8 Hz, 1H), 8.76 (s, 1H), 7.11 (s, 1H), 5.40 (p, J=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, J=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)-1-(Trifluoromethoxy)propan-2-yl (2R,4R)-2-methyl-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)- thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate

[00309] Step 1: Methyl 5-(((2R,4R)-1-(tert-butoxycarbonyl)-2-methylpiperidin-4-yl)oxy)-6-methyl-7-(trifluoromethyl)thieno[3,2-b ]pyridine-3-carboxylate

[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-1-carboxylate (2.59 g, 12.0 mmol) and triphenylphosphine (3.96 g, 15.1 mmol) in ethyl acetate (30 ml), a solution of bis-(2-methoxyethyl)diazo-1,2-dicarboxylate (3 .22 g, 13.7 mmol) in ethyl acetate (10 ml). The ice slowly melted in the ice bath and the reaction mixture was stirred overnight at room temperature. LCMS analysis indicated that the reaction was complete. The mixture was rinsed in a separatory funnel with ethyl acetate (~40 ml) and then washed with water (2 x ~100 ml). The organic layer was dried (Na ₂ SO ₄ ) and concentrated. The crude material was subjected to automated flash chromatography (Combiflash system, 0 to 20% ethyl acetate in heptane; 120 g silica gel column). The title compound (Rf ~0.3 using 8:2 heptane/ethyl acetate as eluent) was obtained as a white solid (3.08 g, 92%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=13.3, 2.7 Hz, 1H), 2.48 (kv, J=1.9 Hz, 3H), 2, 19-2.00 (m, 3H), 1.92-1.81 (m, 1H), 1.48 (s, 9H), 1.33 (d, J=7.1 Hz, 3H) ppm.

[00311] Step 2: Methyl 6-methyl-5-(((2R,4R)-2-methylpiperidin-4-yl)oxy)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate

[00312] Using the procedure described in Step 2 of Example 175, the N-tert-butoxycarbonylamine protecting group of the product from Step 1 was cleaved using dichloromethane trifluoroacetic acid solution. The crude product was considered pure enough to be used without purification in the next step. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.50 (s, 1H), 5.29 (tt, J=11.1, 4.6 Hz, 1H), 3.96 (s, 3H), 3 .22 (ddd, J=12.5, 4.5, 2.4 Hz, 1H), 2.94-2.82 (m, 2H), 2.43 (kv, J=2.0 Hz, 3H ), 2.37-2.29 (m, 2H), 1.63-1.45 (m, 2H), 1.29 (kV, J=11.5 Hz, 1H), 1.17 (d, J=6.3 Hz, 3H) ppm.

[00313] Step 3. N,6-Dimethyl-5-(((2R,4R)-2-methylpiperidin-4-yl)oxy)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3- carboxamide

[00314] Using the procedure described for Step 2 of Example 25, the methyl ester functionality of the product from Step 3 was converted to the corresponding N-methylcarboxamide. The crude product was subjected to automated flash chromatography (Combiflash system, 0 to 10% 2N ammonia in methanol in chloroform; Gold column with 80 g silica gel). The target component (Rf ~0.4 using 9:1 chloroform/2N ammonia in methanol as eluent) was obtained as a glassy, colorless solid. This material was co-evaporated with diethyl ether to obtain a colorless foam, which was then triturated with a spatula to obtain the title compound as a white solid (2.34 g, 93%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.27-9.18 (m, 1H), 8.61 (s, 1H), 5.01 (tt, J=11.1, 4.4 Hz, 1H), 3.29 (ddd, J=12.5, 4.5, 2.5 Hz, 1H), 3.08 (d, J=4.9 Hz, 3H), 2.91-2.78 (m, 2H), 2.44 (kv, J=2.0 Hz, 3H), 2.33-2.23 (m, 2H), 1.73-1.62 (m, 1H), 1, 39 (kv, J=11.5 Hz, 1H), 1.20 (d, J=6.3 Hz, 3H) ppm.

[00315] Step 4. (S)-1-(Trifluoromethoxy)propan-2-yl (2R,4R)-2-methyl-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno -[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate

[00316] To obtain the title compound as a white solid (0.238 g, 83%), the procedure described in Example 171 was used, replacing intermediate 17 with the product from step 3, and intermediate 11 with intermediate 12. ¹ H NMR ( 400 MHz, CDCl ₃ ) δ 9.07 (kv, J=4.9 Hz, 1H), 8.64 (s, 1H), 5.40 (p, J=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 (kv, J=2.0 Hz, 3H), 2.24-2.07 (m, 3H ), 1.99-1.87 (m, 1H), 1.38 (d, J=7.0 Hz, 3H), 1.34 (d, J=6.6 Hz, 3H) ppm. MS: 558 m/z (M+H ⁺ ).

[00317] Example 180 2-(Trifluoromethoxy)ethyl (3S,4R)-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]- pyridin-5-yl)oxy)piperidine-1-carboxylate

[00318] To obtain the title compound as a white solid, the four synthetic steps described in Example 176 were used, replacing tert-butyl (2R,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate with tert-butyl (3S,4S)-3 -fluoro-4-hydroxypiperidine-1-carboxylate in step 1, and intermediate 12 to intermediate 11 in step 4. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.87 (kv, J=4.9 Hz, 1H), 8.66 (s, 1H), 5.44-5.28 (m, 1H), 4.95 (br.d, J=47.6 Hz, 1H), 4.38 (sq, J =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, J=4.9 Hz, 3H), 2.51 (kv, J=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)-1-(Trifluoromethoxy)propan-2-yl (3S,4R)-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)- thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate

[00320] To obtain the title compound as a white solid, the four steps of the synthetic sequence described in Example 176 were used, replacing tert-butyl (2R,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate with tert-butyl (3S,4S)- 3-fluoro-4-hydroxypiperidine-1-carboxylate in step 1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.88 (sq, 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, J=4.9 Hz, 3H), 2.51 (kv, J=1.9 Hz, 3H), 2.34-2.22 (m, 1H), 2.12-1.98 (m, 1H), 1.35 (dd, J=6.6, 1.5 Hz, 3H) ppm. MS: 562 m/z (M+H ⁺ ).

[00321] Example 183: (S)-1-(Trifluoromethoxy)propan-2-yl (3R,4S)-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)- thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate

[00322] To obtain the title compound as a foamy white solid, the four steps of the synthetic sequence described in Example 176 were used, replacing tert-butyl (2R,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate with tert-butyl (3R,4R) -3-fluoro-4-hydroxypiperidine-1-carboxylate in step 1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.88 (sq, J=4.9 Hz, 1H), 8.65 (s, 1H ), 5.45-5.27 (m, 1H), 5.14-5.05 (m, 1H), 4.94 (br.d, J=47.5 Hz, 1H), 4.24- 3.54 (m, 5H), 3.54-3.36 (m, 1H), 3.08 (d, J=4.9 Hz, 3H), 2.51 (kv, J=1.8 Hz , 3H), 2.35-2.22 (m, 1H), 2.12-1.98 (m, 1H), 1.35 (dd, J=6.6, 1.5 Hz, 3H) ppm . MS: 562 m/z (M+H ⁺ ).

[00323] Example 186 1-(7-(Methylcarbamoyl)-4-(trifluoromethyl)-thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl (S)-(1-methoxypropan-2 -yl)carbamate

[00324] Step 1: Tert-butyl (4-methyl-2-(2,2,2-trifluoroacetyl)thiophen-3-yl)carbamate

[00325] To a stirred and cooled (-25 to -30°C) solution of tert-butyl (4-methylthiophen-3-yl)carbamate (5.63 g, 26.4 mmol) in tetrahydrofuran (100 ml) was added dropwise to for 15 minutes 2.5 M solution of n-butyllithium in hexanes (25.0 ml, 62.5 mmol). After addition, the mixture was stirred for another hour at -20°C, then cooled to -25 to -30°C and a solution of 2,2,2-trifluoro-N,N-dimethylacetamide (6,4 ml, 55 mmol) in tetrahydrofuran (12 ml) for 20 minutes. The reaction mixture was slowly warmed 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 aqueous ammonium chloride (~150 ml). The organic layer was washed with brine (2 x ~150 ml), dried (Na ₂ SO ₄ ) and concentrated on ~25 g silica gel. The impregnated medium was subjected to automated flash chromatography (Combiflash system, 0 to 10% ethyl acetate in heptane; 220 g silica gel column). The purified title compound (Rf ~0.42 using 9:1 heptane/ethyl acetate as eluent) was obtained as a pale amber solid (3.89 g, 48%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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: 1-(3-Amino-4-methylthiophen-2-yl)-2,2,2-trifluoroethan-1-one

[00327] Hydrogen chloride gas was bubbled through the stirred product from Step 1 (4.85 g, 15.7 mmol) in ethyl acetate (100 mL) for approximately five minutes. The resulting suspension was stirred for 1.25 hours and then concentrated. The residue was partitioned between chloroform (~75 ml) and aqueous sodium bicarbonate (~100 ml). The organic layer was combined with the second extract (chloroform, 1 x ~75 ml), dried (Na ₂ SO ₄ ) and concentrated to give the crude title compound as a grey-green solid (3.21 g, 98%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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 the product from step 2 (3.20 g, 15.30 mmol) in acetonitrile (20 ml) was added 2,2,2-trichloroacetylisocyanate (2.5 ml, 20, 98 mmol). After 2-3 minutes, the reaction mixture turned into a thick suspension of a yellowish-white solid. The ice bath was removed and the reaction mixture was warmed to room temperature and then stirred for another hour. Thereafter, the mixture was concentrated to obtain crude acyl urea as a greyish-purple solid. The crude intermediate was charged to a pressure vessel along with 2.0 N ammonia in methanol (130 mL, 260.00 mmol). The vessel was sealed and heated at 70°C for 30 minutes and then cooled to room temperature. The mixture was then concentrated to give a wet grayish-purple solid. This material was triturated with ethyl acetate (~60 mL) and the suspended solid was recollected by suction filtration and air dried under low pressure to yield the 7-methyl-4-(trifluoromethyl)thieno-[3,2-d] hydrate intermediate. pyrimidin-2(1H)-one as a yellowish-white solid. This material was taken into phosphorus oxychloride (15.0 mL, 161 mmol) and heated with stirring at 105°C. After two hours, the mixture was cooled to room temperature and added slowly by pipette to a stirred suspension of sodium bicarbonate (50 g) in water (200 ml). After 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 SO ₄ ) and concentrated on ~15 g silica gel. The impregnated medium was subjected to automated flash chromatography (Combiflash system, 0 to 10% ethyl acetate in heptane; 120 g silica gel column). The title compound (Rf=0.4 using 9:1 heptane/ethyl acetate as eluent) was obtained as a colorless crystalline solid (2.86 g, 74% total over three steps). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (kv, J=1.2 Hz, 1H), 2.55 (d, J=1.2 Hz, 3H) ppm.

[00330] Step 4: 2-Chloro-7-(dibromomethyl)-4-(trifluoromethyl)-thieno[3,2-d]pyrimidine

[00331] To a stirred solution of the product from Step 3 (2.85 g, 11.3 mmol) in carbon tetrachloride (50 mL) was added N-bromosuccimide (4.62 g, 26.0 mmol) and benzoyl peroxide (0.273 g, 1.13 mmol). The mixture was heated in an oil bath at 80°C for two hours. The reaction mixture was cooled to room temperature and a small aliquot of the clear solution was removed from the suspension and concentrated to obtain a sample for ¹ H NMR analysis. Analysis of the resulting spectrum indicated that the starting material had completely reacted and, instead, a mixture of the corresponding mono- and dibromomethyl derivatives was detected (molar ratio ~17:83, respectively). Additional benzoyl peroxide (0.050 g, 0.206 mmol, 1.8 mol%) was added to the reaction mixture and heating was continued (80°C) for an additional 1.5 hours. The reaction mixture was then cooled to room temperature and filtered with suction. After rinsing the filter cake with diethyl ether (3 x ~20 ml), the combined filtrate was concentrated on ~15 g silica gel. The impregnated medium was subjected to automated flash chromatography (Combiflash system, 0 to 10% ethyl acetate in heptane; 120 g silica gel column) to obtain the partially purified title compound as a viscous pale amber oil (4.42 g, 96%). The material was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.68 (d, J=0.6 Hz, 1H), 7.25 (d, J=0.6 Hz, 1H) ppm.

[00332] Step 5: 1-(2-Chloro-4-(trifluoromethyl)thieno[3,2-d]-pyrimidin-7-yl)ethan-1-one

[00333] Silver nitrate (5.46 g, 32.2 mmol) was added to a stirred solution of the contaminated product from Step 4 (4.40 g, 10.72 mmol) in 2:1 acetonitrile/water (60 mL). The resulting suspension was heated in a preheated oil bath (80°C) for 30 minutes, cooled and filtered with suction through a pad of celite. The filter bed/greyish green solid mixture was rinsed with ethyl acetate until the UV activity of the filtrate (as assessed by the spot on the TLC plate) waned. The combined filtrate was washed with aqueous sodium bicarbonate (1 x ~150 ml), dried (Na ₂ SO ₄ ) and concentrated on ~10 g silica gel. The impregnated medium was subjected to automated flash chromatography (Combiflash system, 0 to 10% ethyl acetate in heptane; 120 g silica gel column) to obtain the purified title compound (Rf ~0.2 using 9:1 heptane/ethyl acetate as eluent) as a white solid (2.17 g, 76%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.50 (s, 1H), 9.07 (s, 1H) ppm.

[00334] Step 6: Piperidin-4-yl (S)-(1-methoxypropan-2-yl)carbamate

[00335] To obtain the crude title compound as a gray gum, the O-(piperidin-4-yl)carbamate synthesis described in steps 1 and 2 of Example 115 was used, replacing 2-(aminomethyl)-4-methylmorpholine with (S)-1 -methoxypropan-2-amine. This material was used without analysis or purification in the next step.

[00336] Step 7: 1-(7-Formyl-4-(trifluoromethyl)thieno[3,2-d]-pyrimidin-2-yl)piperidin-4-yl (S)-(1-methoxypropan-2-yl) )carbamate

[00337] A 20 mL microwave reaction vessel was charged with product from Step 5 (0.250 g, 0.938 mmol), N,N-dimethylformamide (6 mL), product from Step 6 (0.355 g, 1.64 mmol ) and N,N-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 that the reaction was complete. The mixture was concentrated and the residue was partitioned between aqueous sodium bicarbonate (~40 ml) and chloroform (~40 ml). The organic layer was combined with additional extracts (chloroform, 2 x ~30 ml), dried (Na ₂ SO ₄ ) and concentrated on ~4 g silica gel. The impregnated medium was subjected to automated flash chromatography (Combiflash system, 20 to 40% ethyl acetate in heptane; Gold column with 80 g silica gel) to obtain the purified title compound (Rf ~0.4, using 6:4 heptane/ethyl acetate as eluent ) as a yellow solid (0.332 g, 79%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J=6.7 Hz, 3H) ppm.

[00338] Step 8. (S)-2-(4-(((1-Methoxypropan-2-yl)-carbamoyl)oxy)piperidin-1-yl)-4-(trifluoromethyl)-thieno[3,2- d]-pyrimidine-7-carboxylic acid

[00339] Oxon (0.523 g, 0.851 mmol) was added to a stirred solution of the product from Step 7 (0.302 g, 0.676 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred at room temperature overnight and then analyzed by LCMS, and the reaction was found to be approximately 88% complete, as determined by the respective peak areas of the starting material and the expected product. Additional oxon (0.208 g, 0.338 mmol) was added and stirring was continued for another night, but this did not result in a significant increase in conversion. The mixture was concentrated and the residue was placed in water (~30 ml). The resulting suspension was subjected to ultrasound until the undissolved solid became homogeneous. The solid was collected by suction filtration and rinsed with additional water. The filter cake was dried in a vacuum oven (~50°C) to obtain the crude title compound as a beige solid (0.280 g, 90%). 1H NMR (400 MHz, DMSO-d ₆ ) δ 12.94 (br.s, 1H), 9.14 (s, 1H), 7.04 (d, J=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, J=9.4, 6 .7 Hz, 1H), 3.15 (dd, J=9.4, 6.3 Hz, 1H), 2.06-1.86 (m, 2H), 1.71-1.45 (m, 2H), 1.03 (d, J=6.7 Hz, 3H) ppm.

[00340] Step 9. 1-(7-(Methylcarbamoyl)-4-(trifluoromethyl)-thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl (S)-(1-methoxypropan-2 -yl)carbamate

[00341] Using the procedure for the amide coupling reaction in the presence of HATU described in step 3 of Example 10, the product from step 8 was condensed with methylamine hydrochloride. The resulting crude product was purified by automated flash chromatography (Combiflash system, 0 to 1% methanol in ethyl acetate; Gold column with 80 g silica gel; see attached pdf for TLC analysis results). The target component (Rf ~0.40 using 99:1 ethyl acetate/methanol as eluent) was obtained as a yellowish-white film. This material was crushed using a spatula and dried in a vacuum oven (~60°C) to obtain the title compound as a beige solid (0.226 g, 82%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J=6.7 Hz , 3H) ppm. MS: 476 m/z (M+H ⁺ ).

[00342] Example 187 1-(7-(Methylcarbamoyl)-4-(trifluoromethyl)-thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl-(S)-(1-cyclopropyl- ethyl)carbamate

[00343] Step 1. Piperidin-4-yl (S)-(1-cyclopropylethyl)-carbamate

[00344] To obtain the crude title compound as a yellowish-white solid, the O-(piperidin-4-yl)carbamate synthesis described in Step 1 of Example 95 was used, replacing 4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine dihydrochloride on (S)-1-cyclopropylethan-1-amine. This material was considered pure enough to be used without purification in the next step. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.83-4.50 (m, 2H), 3.19-2.98 (m, 3H), 2.69 (ddd, J=12.4, 10 ,2, 2.8 Hz, 2H), 2.01-1.84 (m, 2H), 1.68-1.38 (m, 2H), 1.20 (d, J=6.6 Hz, 3H), 0.80 (qt, J=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] Stages 2-4. 1-(7-(Methylcarbamoyl)-4-(trifluoromethyl)-thieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl (S)-(1-cyclopropyl-ethyl)carbamate

[00346] To obtain the title compound as a pale yellow solid, the sequence of syntheses described in steps 7-9 of Example 186 was used, replacing piperidin-4-yl (S)-(1-methoxypropan-2-yl)carbamate with the product stage 1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin- 3-carboxamide

[00348] Step 1: Tert-butyl 3-((5-fluoropyridin-3-yl)oxy)-azetidine-1-carboxylate

[00349] A stirred mixture of 5-fluoropyridin-3-ol (0.489 g, 4.33 mmol) and tert-butyl 3-hydroxyazetidine-1-carboxylate (0.500 g, 2.89 mmol) in toluene (5 ml) was purged 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. Thereafter, the reaction mixture was diluted with ethyl acetate (150 ml) and washed with dilute aqueous sodium bicarbonate and brine. The organic solution was then dried (Na ₂ SO ₄ ) and concentrated to give the crude product. This material was purified by automated flash chromatography (Biotage Isolera system; 20 to 100% ethyl acetate in heptane; 4 g silica gel column) to give the title compound as a brown oil (0.460 g, 59%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.17 (d, J=2.3 Hz, 1H), 8.01 (br.s, 1H), 6.82 (dt, J=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 the product from Step 1 (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 which had been pretreated with dichloromethane and methanol and eluted with 4M ammonia in methanol to give the title compound as an amber oil (0.274 g, 95%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, J=2.4 Hz, 1H), 8.03 (dd, J=2.5, 1.0 Hz, 1H), 6.81 (dt, J=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-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3 -carboxamide

[00353] A 5 mL microwave reaction vessel was charged with Intermediate 5 (0.100 g, 0.339 mmol), product from Step 2 (0.114 g, 0.679 mmol), N,N-diisopropylethylamine (118 μL, 0.679 mmol) and N-methyl-2-pyrrolidinone (1.8 ml). The vessel was sealed and heated in a microwave reactor for 1.5 hours at 150°C. The mixture was poured into a vigorously stirred suspension of crushed ice and water. Once the ice had completely melted, the precipitate was collected by filtration and purified by reverse phase HPLC (Waters SunFire OBD column, 30 x 150 mm, 5 µm C18; gradient 20 to 100% acetonitrile/water) to give the title compound as a white solid ( 0.046 g, 28%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37-9.24 (m, 1H), 8.77 (s, 1H), 8.28 (d, J=2.2 Hz, 1H) , 8.26-8.17 (m, 1H), 7.45 (dt, J=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, J=4.8 Hz, 3H ) ppm. MS: 427 m/z (M+H ⁺ ).

[00354] Example 204: (R)-1-Cyclopropylethyl 6-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro [3.3]heptane-2-carboxylate

[00355] Step 1. (R)-1-Cyclopropylethyl(4-nitrophenyl)carbonate

[00356] To a stirred solution of (R)-1-cyclopropylethan-1-ol (197 mg, 2.29 mmol) and triethylamine (319 μL, 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 give the title product as a clear, colorless oil (330 mg, 57%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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. (R)-1-Cyclopropylethyl 6-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro [3.3]heptane-2-carboxylate

[00358] A mixture of intermediate 25 (150 mg, 0.404 mmol), product from step 1 (101 mg, 0.404 mmol) and triethylamine (56 μl, 0.40 mmol) in N,N-dimethylformamide (2 ml) was stirred at 90 °C for 30 minutes in a microwave reactor. The reaction mixture was then concentrated and the residue was purified by reverse phase HPLC (Waters SunFire OBD C18 column, 30 x 150 mm, 5 μm; gradient 20 to 100% acetonitrile/water) to give the title compound as a white solid (109 mg , 56%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J= 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 m/z (M+H ⁺ ).

[00359] Example 212 2-(Trifluoromethoxy)ethyl 6-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-1-azaspiro[ 3.3]heptane-1-carboxylate

[00360] Step 1. Tert-butyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-1-azaspiro[3.3]-heptane-1- carboxylate

[00361] To a stirred mixture of intermediate 5 (265 mg, 0.899 mmol) and tert-butyl 6-hydroxy-1-azaspiro[3.3]heptane-1-carboxylate (249 mg, 1.17 mmol) in tetrahydrofuran (10 ml) was added tert-butoxide potassium (131 mg, 1.17 mmol). The reaction mixture 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 SO 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 gel column) to give the title compound as a beige solid (0.254 g, 60%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (br.s, 1H), 8.74 (s, 1H), 7.08 (s, 1H), 4.97 (p, J=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-((1-Azaspiro[3.3]heptan-6-yl)oxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00363] Using the procedure described in Step 2 of Example 190, the product from Step 1 was de-protected to give 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-b]pyridin-5-yl)oxy)-1-azaspiro[3.3] heptane-1-carboxylate

[00365] A stirred mixture of product from step 2 (0.167 g, 0.450 mmol), intermediate 11 (0.100 g, 0.450 mmol) and N-hydroxysuccinimide (0.053 g, 0.40 mmol) in acetonitrile (10 ml) was stirred overnight at 38°C. The reaction mixture was then concentrated and the residue was taken up in dichloromethane (20 ml). The solution was washed with water (10 ml), dried (MgSO ₄ ) and concentrated. The crude material was purified by automated flash chromatography (Biotage Isolera system; 50 to 100% ethyl acetate in heptane; 4 g silica gel column) to give the title compound as a white solid (0.142 g, 60%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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 ((1S,3S)-3-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-oxy) cyclobutyl)carbamate

[00367] Step 1. 5-((1s,3s)-3-Aminocyclobutoxy)-N,6-dimethyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00368] To prepare the title compound, the sequence of syntheses described in steps 1 and 2 of Example 212 was used, replacing intermediate 5 with intermediate 15, and tert-butyl 6-hydroxy-1-azaspiro[3.3]heptane-1-carboxylate with tert-butyl ((1s ,3s)-3-hydroxycyclobutyl)carbamate. MS: 460 m/z (M+H ⁺ ).

[00369] Step 2. Cyclopropylmethyl ((1s,3s)-3-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- cyclobutyl)carbamate

[00370] To the stirred product from Step 1 (74 mg, 0.208 mmol) and triethylamine (57 μL, 0.415 mmol) in chloroform (4 mL) was added cyclopropyl methyl 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 gel column). The resulting solid was triturated with diethyl ether and air dried on a low vacuum filter to give the title compound as a cream solid (65 mg, 68%). 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (br.d, 1H), 8.52 (s, 1H), 7.33 (d, J=8.1 Hz, 1H), 4, 84 (p, 1H), 3.68 (kv, 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)-1-Cyclopropylethyl ((1S,3R)-3-((6-methyl-3-(methylcarbamoyl)-7(trifluoromethyl)thieno[3,2-b]pyridine-5- yl)oxy)cyclobutyl)carbamate

[00372] To obtain the title compound as a white solid, the sequence of syntheses described in Example 204 was used, replacing intermediate 27 with the product from step 1 of Example 218, and (R)-1-cyclopropylethan-1-ol with (S)- 1-cyclopropylethan-1-ol. ^1H NMR (400 MHz, CDCl ₃ ) δ 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 (kv, 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-b]pyridin-5-yl)oxy)-azetidin- 1-carboxylate

[00374] Step 1. N-Methyl-5-((3-methylazetidin-3-yl)oxy)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00375] Using the procedure described in step 2 of Example 190, the N-tert-butoxycarbonyl protecting group of the title compound of Example 269 was cleaved with trifluoroacetic acid in dichloromethane to obtain 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-b]pyridin-5-yl)oxy)-azetidine-1 -carboxylate

[00377] To a stirred mixture of the product from Step 1 (188 mg, 0.544 mmol) and intermediate 11 (134 mg, 0.599 mmol) in acetonitrile (5 ml) was added N-hydroxysuccinimide (63 mg, 0.544 mmol). After two hours, the reaction mixture was concentrated at room temperature and the crude material was purified by reverse phase HPLC (Waters Sunfire OBD C18 column, 30 x 150 mm, 5 µm; 20 to 100% acetonitrile/water) to give the title compound as beige solids (43 mg, 16%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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-b]pyridin-5-yl)oxy)-azetidine-1-carboxylate

[00379] Step 1. Tert-butyl 3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)azetidine-1-carboxylate

[00380] To obtain the title compound as a white solid, the same synthesis procedure as described in Example 269 was used, replacing tert-butyl 3-hydroxy-3-methylazetidine-1-carboxylate with tert-butyl 3-hydroxyazetidine-1-carboxylate. ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J=4.9 Hz, 3H), 1.47 (s, 9H) ppm. MS: 432 m/z (M+H ⁺ ).

[00381] Stages 2-3. 2-(Trifluoromethoxy)ethyl 3-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-azetidine-1-carboxylate

[00382] To obtain the title compound as a white solid, the two-step synthesis sequence described in Example 254 was used, replacing the title compound of Example 269 with the product from Step 1 of this Example. ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J= 4.9 Hz, 3H) ppm. MS: 488 m/z (M+H ⁺ ).

[00383] Example 269 Tert-butyl 3-methyl-3-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-azetidine-1-carboxylate

[00384] To a stirred mixture of intermediate 5 (276 mg, 0.937 mmol) and tert-butyl 3-hydroxy-3-methylazetidine-1-carboxylate (277 mg, 1.40 mmol) in tetrahydrofuran (5 ml) was added potassium tert-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 aqueous ammonium chloride and brine, dried (Na ₂ SO 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 gel column) to give the title compound as a brown solid (710 mg, 74%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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-(1-(tert-butoxycarbonyl)-piperidin-4-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate

[00386] Step 1: Methyl 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-7-(trifluoromethyl)-thieno[3,2-b]pyridine-3-carboxylate

[00387] To a stirred solution of intermediate 3 (2.00 g, 6.77 mmol) and (1-tert-butoxy-carbonyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid pinacol ester (2.44 g, 7.49 mmol) to 1,2-dimethoxyethane (35 ml) was added 2.0 M aqueous sodium carbonate (7.0 ml, 14 mmol). The mixture was purged with nitrogen for ~10 minutes and then treated with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.473 g, 0.639 mmol). The dark red-brown mixture was purged with nitrogen a second time and then refluxed. After 19 hours, the reaction mixture was analyzed by LCMS and was found to contain comparable amounts of the corresponding carboxylic acid of the desired product (as a result of concurrent 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 (MgSO4) and concentrated. The residue was purified by automated flash chromatography (Combiflash system, 0 to 30% ethyl acetate in heptane; 120 g silica gel column) to give the title compound as a white solid (1.33 g, 44%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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, CDCl3) δ -64.0 (s) ppm. MS: 443 m/z (M+H ⁺ ).

[00388] Step 2: Methyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate

[00389] A stirred suspension of the product from Step 1 (1.27 g, 2.87 mmol) and 10% palladium on carbon (0.303 g) in tetrahydrofuran (30 ml) was subjected to two successive cycles of vacuum and nitrogen flushing. The reaction flask was evacuated one last time and then filled with hydrogen (from a cylinder). After 24 hours, the reaction mixture was analyzed by LCMS and it was found that the reaction was not complete. Additional palladium on carbon (0.440 g) was added and the reaction was resumed as before. After stirring overnight, the reaction mixture was analyzed again and it was found that the reaction was almost complete. The suspension was filtered with suction through a pad of celite, which was then 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 gel column). The purified title compound was obtained as a yellow foam (0.633 g, 50%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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, CDCl3) δ -64.0 (s) ppm. MS: 445 m/z (M+H ⁺ ).

[00390] Example 297 Isobutyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate

[00391] Step 1: Methyl 5-(4-((tert-butoxycarbonyl)amino)-piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate

[00392] A 10 mL microwave reaction vessel equipped with a magnetic stirrer was charged with 4-(tert-butoxycarbonylamino)piperidine (1.53 g, 7.50 mmol), intermediate 3 (1.48 g, 5. 00 mmol), N,N-dimethylformamide (3 ml) and N,N-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 was diluted with ethyl acetate (10 ml) and then filtered to remove solids. The filter cake was rinsed with additional ethyl acetate and the combined filtrate was diluted with ethyl acetate (100 ml), washed with aqueous sodium bicarbonate (1 x 100 ml) and saline (1 x 100 ml). The organic layer was dried (MgSO ₄ ) and concentrated. The resulting solid was purified by automated flash chromatography (Combiflash system, 0 to 10% methanol in dichloromethane; silica gel column) to give the title compound as a yellow solid (1.70 g, 74%). MS: 460 m/z (M+H ⁺ ).

[00393] Step 2: Tert-butyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate

[00394] A 10 mL microwave reaction vessel equipped with a magnetic stirrer was charged with the product from Step 1 (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 ethyl acetate and heptane to give the title compound as a yellow solid (199 mg, 100%). MS: 459 m/z (M+H ⁺ ).

[00395] Step 3: 5-(4-Aminopiperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide trifluoroacetate salt

[00396] Trifluoroacetic acid (0.67 mL, 8.7 mmol) was added to a stirred solution of the product from Step 2 (199 mg, 0.435 mmol) in dichloromethane (3 mL). The reaction mixture was stirred overnight at room temperature and then concentrated. The residue was triturated with ethyl acetate and heptane to give the title compound as a yellow solid (200 mg, 97%). MS: 359 m/z (M+H ⁺ ).

[00397] Step 4: Isobutyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate

[00398] Isobutyl chloroformate (32 mg, 0.233 mmol) was added to a stirred solution of the product from Step 3 (100 mg, 0.212 mmol) and N,N-diisopropylethylamine (85 μL, 0.487 mmol) in dichloromethane (5 mL). The reaction mixture was kept at room temperature overnight and then partitioned between aqueous sodium bicarbonate (50 ml) and dichloromethane (50 ml). The organic layer was washed with brine (1×50 ml), dried (MgSO ₄ ) and concentrated. The resulting crude material was purified by automated flash chromatography (Combiflash system, 0 to 20% ethyl acetate in dichloromethane; silica gel column) to give the title compound as a white solid (40 mg, 41%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.29 (br.s, 1H), 8.75 (s, 1H), 7.50 (s, 1H), 7.16 (d, J= 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 (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)azetidin-3-yl)carbamate

[00400] To obtain the title compound as a yellow solid, the sequence of two synthetic steps described in steps 1-2 of Example 297 was used, replacing 4-(t-butoxycarbonylamino)piperidine with t-butyl 3-azetidinyl-carbamate. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.38 (br.s, 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-b]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, the mixture was diluted with dichloromethane at room temperature and then washed with aqueous sodium bicarbonate and saline. The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give 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-b ]-pyridine-3-carboxylate

[00405] A 20 mL microwave reaction vessel equipped with a magnetic stirrer was charged with Intermediate 8 (0.150 g, 0.420 mmol), N,N-dimethylformamide (2 mL), product from Step 1 (0.151 g, 0.630 mmol), triethylamine (0.23 ml, 1.7 mmol) and 4-(dimethyl-amino)pyridine (7 mg, 59 μmol). 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. The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by automated flash chromatography (Combiflash system, ethyl acetate/heptane; silica gel column) to give 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-b]pyridin-5-yl)-2,6-diazaspiro[3.3]-heptane -2-carboxylate

[00407] A 5 mL microwave reaction vessel equipped with a magnetic stirrer was charged with the product from Step 2 (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 gel column) to give the title compound as a white solid (83 mg, 71%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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 1-Cyanopropan-2-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3] heptane-2-carboxylate

[00409] To obtain the title compound, the three-step synthesis described in Example 339 was used, replacing oxetan-3-ol with 3-hydroxybutanenitrile. ^1H NMR (400 MHz, CDCl3) δ 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, J=6.4 Hz, 3H) ppm. MS: 468 m/z (M+H ⁺ ).

[00410] Example 361 5-(4-(2-(3,3-Difluoropyrrolidin-1-yl)ethoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b ]pyridine-3-carboxamide

[00411] Step 1: Tert-butyl 4-(2-((methylsulfonyl)oxy)-ethoxy)piperidine-1-carboxylate

[00412] To a stirred and cooled (0°C) solution of tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (330 mg, 1.35 mmol) and triethylamine (377 μL, 2.69 mmol) in tetrahydrofuran (5 ml) methanesulfonyl chloride (136 µl, 1.75 mmol) was added dropwise over five minutes. The reaction mixture was slowly warmed 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 and brine and then dried (Na ₂ SO ₄ ) and concentrated to give the crude mesylate as a clear pale yellow oil (0.360 g, 83%).

[00413] Step 2: Tert-butyl 4-(2-(3,3-difluoropyrrolidin-1-yl)ethoxy)piperidine-1-carboxylate

[00414] N,N-Diisopropylethylamine (1.4 mL, 8.0 mmol) and 3,3-difluoro- pyrrolidine 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 the solution was washed with aqueous sodium bicarbonate and brine. The organic layer was then dried (Na ₂ SO ₄ ) and concentrated. The resulting crude material was purified by automated flash chromatography (Combiflash system, methanol/dichloromethane; silica gel column) to give the title compound as a colorless oil (0.108 g, 29%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.82-3.68 (m, 2H), 3.58 (t, J=5.7 Hz, 2H), 3.50-3.38 (m, 1H), 3.15-3.03 (m, 2H), 2.97 (t, J=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-1-yl)ethoxy)-piperidine dihydrochloride

[00416] To a stirred solution of the product from Step 2 (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 mixture was stirred at room temperature for two hours and then concentrated to give the crude title compound as a sticky red gum (0.099 g, 100%).

[00417] Step 4. 5-(4-(2-(3,3-Difluoropyrrolidin-1-yl)-ethoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2- b]-pyridine-3-carboxamide

[00418] To obtain the title compound as a red-yellow solid, the nucleophilic aromatic substitution procedure for intermediate 5 described in Step 3 of Example 115 was used, replacing the product from Step 2 of Example 115 with the crude product from Step 3 of this Example and increasing the amount used the number of equivalents of N,N-diisopropylethylamine base is from 2.1 to 4.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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: (+/-)-Tertiary butyl trans-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -piperidine-1-carboxylate

[00420] To obtain the title compound as a white solid, the procedure described for step 1 of Example 175 was used, replacing tert-butyl (2R,4R)-4-hydroxy-2-methyl-piperidine-1-carboxylate with (+/-)- tert-butyl trans-4-hydroxy-2-methylpiperidine-1-carboxylate. ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J=12.1, 5.8 Hz, 1H), 1.75-1.62 (m, 1H ), 1.49 (s, 9H), 1.32 (d, J=7.1 Hz, 3H) ppm. MS: 474 m/z (M+H ⁺ ).

[00421] Example 369: (+/-)-trans-2-(Trifluoromethoxy)ethyl-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridine -5-yl)oxy)piperidine-1-carboxylate

[00422] Step 1. N-Methyl-5-((trans-2-methylpiperidin-4-yl)oxy)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00423] Hydrogen chloride gas was bubbled through a stirred solution of the title compound of Example 368 (0.090 g, 0.190 mmol) in ethyl acetate (6 mL) for approximately two minutes. The mixture was stirred for an additional 20 minutes and then concentrated to give the crude title compound as a white solid (0.078 g, 100%). MS: 374 m/z (M+H ⁺ ).

[00424] Step 2. (+/-)-trans-2-(Trifluoromethoxy)ethyl-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridinium- 5-yl)oxy)piperidine-1-carboxylate

[00425] To the stirred product from step 1 (0.075 g, 0.183 mmol) in acetonitrile (3 ml) was added triethylamine (33 μl, 0.24 mmol), a solution of intermediate 11 (0.049 g, 0.220 mmol) in acetonitrile (2 ml ) and N-hydroxysuccimide (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 (20 ml). The organic layer was combined with additional extracts (dichloromethane, 2×20 ml) and washed with brine. The organic layer was then dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by automated flash chromatography (Combiflash system, 5 to 35% ethyl acetate in heptane; 12 g silica gel column) to give the title compound as a glassy, colorless solid (0.058 g, 60%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.92 (s, 1H), 8.77 (s, 1H), 7.09 (s, 1H), 5.41 (tt, J=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, J=12.4, 5.8 Hz, 1H), 1.81-1.67 (m, 1H ), 1.36 (d, J=7.1 Hz, 3H) ppm. MS: 530 m/z (M+H ⁺ ).

[00426] Example 370: (+/-)-Tetbutyl cis-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -piperidine-1-carboxylate

[00427] To obtain the title compound as a white solid, the procedure described for step 1 of Example 175 was used, replacing tert-butyl (2R,4R)-4-hydroxy-2-methyl-piperidine-1-carboxylate with (+/-)- tert-butyl cis-4-hydroxy-2-methylpiperidine-1-carboxylate. ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J=13.7, 4.2 Hz, 1H), 3.29 (td, J=13.4, 2.9 Hz , 1H), 3.07 (d, J=4.9 Hz, 3H), 2.16-2.01 (m, 3H), 1.98-1.86 (m, 1H), 1.49 ( s, 9H), 1.32 (d, J=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-b]-pyridine -5-yl)oxy)piperidine-1-carboxylate

[00429] To obtain the title compound as a glassy, colorless solid, the two-step synthesis sequence described in Example 369 was used, replacing the title compound of Example 368 with the title compound of Example 370. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=4.6 Hz, 2H), 4.05 (dd, J=14.2, 4.7 Hz, 1H), 3.39 (td, J=13.5, 2.8 Hz, 1H), 3.07 (d, J=4.9 Hz, 3H), 2.22-2.03 (m, 3H), 1.99- 1.88 (m, 1H), 1.36 (d, J=7.1 Hz, 3H) ppm. MS: 530 m/z (M+H ⁺ ).

[00430] Example 373 Tert-butyl (2R,4R)-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-piperidine -1-carboxylate

[00431] The procedure described in Step 1 of Example 175 was used to obtain the title compound as a pale amber solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 9.08-9.01 (m, 1H), 8.75 (s, 1H), 7.11 (s, 1H), 5.38 (p, J= 3.1 Hz, 1H), 4.50-4.40 (m, 1H), 4.00 (ddd, J=13.8, 4.7, 1.8 Hz, 1H), 3.29 (td , J=13.4, 2.8 Hz, 1H), 3.07 (d, J=4.9 Hz, 3H), 2.18-2.01 (m, 3H), 1.97-1, 85 (m, 1H), 1.49 (s, 9H), 1.32 (d, J=7.1 Hz, 3H) ppm. MS: 474 m/z (M+H ⁺ ).

[00432] Example 375 2-(Trifluoromethoxy)ethyl (2R,4R)-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl )oxy)piperidine-1-carboxylate

[00433] To obtain the title compound as a glassy, colorless solid, the two-step synthesis sequence described in Example 369 was used, replacing the title compound of Example 368 with the title compound of Example 373. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=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, J=7.1 Hz, 3H) ppm. MS: 530 m/z (M+H ⁺ ).

[00434] Example 387: (+/-)-tert-butyl cis-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-5- yl)-hydroxy)piperidine-1-carboxylate

[00435] Step 1. Methyl 5-((cis-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)oxy)-6-methyl-7-(trifluoromethyl)thieno[3,2-b]-pyridin- 3-carboxylate

[00436] To a stirred solution of intermediate 13 (0.300 g, 1.03 mmol), (+/-)-tert-butyl cis-3-fluoro-4-hydroxypiperidine-1-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-1,2-dicarboxylate (0.362 g, 1.55 mmol). After four hours, the mixture was diluted at room temperature with additional ethyl acetate and washed with water. The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give a residue, which was then purified by automated flash chromatography (Combiflash system, 20 to 55% ethyl acetate in heptane; 12 g silica gel column). The title compound was obtained as a white solid (0.360 g, 71%). MS: 493 m/z (M+H ⁺ ).

[00437] Step 2. (+/-)-Tetbutyl cis-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-5- yl)oxy)-piperidine-1-carboxylate

[00438] Using the procedure described in Step 3 of Example 339, the product from Step 1 was condensed with methylamine to obtain the title compound as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J=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-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-piperidine-1-carboxylate

[00440] Step 1: Methyl 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-6-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate

[00441] To prepare the title compound, the procedure described in step 1 of Example 387 was used, replacing (+/-)-tert-butyl cis-3-fluoro-4-hydroxypiperidine-1-carboxylate with 4-hydroxypiperidine-1-carboxylate. MS: 475 m/z (M+H ⁺ ).

[00442] Step 2: Tert-butyl 4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate

[00443] Using the procedure described in Step 3 of Example 339, the product from Step 1 was condensed with methylamine to obtain the title compound as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=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-b]pyridin-5-yl)oxy)-piperidin- 1-carboxylate

[00445] To obtain the title compound as a glassy, colorless solid, the two-step synthesis sequence described in Example 369 was used, replacing the title compound of Example 368 with the title compound of Example 389. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=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-1-yl)-N,2-dimethyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide

[00447] Using the conditions described in step 3 of Example 39, intermediate 20 was subjected to an SNAr substitution reaction with the piperazine derivative, the product of step 2 of Example 47 (N-isopropyl-2-(piperazin-1-yl)acetamide, to give the title compound as a yellowish-white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 9.72 (br.s, 1H), 6.97 (s, 1H), 6.87 (d, J=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 1-(2-Methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl(cyclopropylmethyl)carbamate

[00449] Using the conditions described in step 3 of Example 39, intermediate 20 was subjected to an SNAr displacement reaction with the amine moiety, intermediate 24, to obtain the title compound as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=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: (+/-)-trans-3-Fluoro-1-(3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin- 4-yl ((S)-1-(trifluoromethoxy)propan-2-yl)carbamate

[00451] Step 1. (+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4- yl 1H-imidazole-1-carboxylate

[00452] To a stirred solution of intermediate 31 (0.126 g, 0.334 mmol) in dichloromethane (5 ml) was added 1,1'-carbonyldiimidazole (0.100 g, 0.617 mmol). The reaction mixture was stirred at room temperature for five hours and then diluted with additional dichloromethane and washed with aqueous sodium bicarbonate and brine. The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give the crude title compound as a colorless oil (157 mg, 100%). MS: 472 m/z (M+H ⁺ ).

[00453] Step 2. (+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4- yl ((S)-1-(trifluoromethoxy)propan-2-yl)carbamate

[00454] Intermediate 11 (0.075 g, 0.416 mmol), N-hydroxysuccinimide (0.046 g, 0.400 mmol) and triethylamine (60 μL, 0.43 mmol). The reaction mixture was heated overnight at 45 °C and then concentrated. The residue was partitioned between dichloromethane (20 ml) and aqueous sodium bicarbonate (20 ml). The organic layer was combined with additional extracts (dichloromethane, 2×20 ml), washed with brine and dried (Na ₂ SO 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 gel column). The title compound was obtained as a white solid (0.101 g, 56%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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-1-yl)thieno[3,2-b]-pyridine-3 -carboxamide

[00456] Step 1. 5-(3-Aminopyrrolidin-1-yl)-N-isopropyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide hydrochloride

[00457] A 50 mL round bottom flask equipped with a magnetic stirrer was charged with Example 642 (0.200 g, 423 μmol) and 2N hydrochloric acid in methanol (8 mL). The resulting solution was stirred at room temperature 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. N-Isopropyl-7-(trifluoromethyl)-5-(3-((4-(trifluoromethyl)cyclohexyl)amino)pyrrolidin-1-yl)thieno[3,2-b]-pyridine-3 -carboxamide

[00459] A 100 mL round bottom flask equipped with a magnetic stirrer was charged with product from Step 1 (0.050 g, 120 μmol), dichloroethane (8 mL), N,N-diisopropylethylamine (32 μL, 180 μmol), 4-(trifluoromethyl )cyclohexan-1-one (0.040 g, 240 µmol) and acetic acid (14 µl, 240 µmol). The resulting solution was stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (0.077 g, 370 μmol) 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 SO 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-d4) δ 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-1-yl)thieno[3,2-b]pyridine-3-carboxamide

[00461] Step 1: Methyl 7-cyclopropyl-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-3-carboxylate

[00462] Ethyl 3-cyclopropyl-3-oxopropanoate (7.95 g, 50 mmol) and methyl 4-aminothiophene-3-carboxylate (4.00 g, 25 mmol) were charged into a 250 mL round bottom flask equipped with a magnetic stirrer. . The resulting solution was stirred at room temperature for 10 minutes. The mixture was placed in a preheated oil bath (125°C) and water (0.20 ml) was added by syringe every 30 minutes (up to 4 hours). After 6 hours, 1.0 ml trifluoroacetic acid was added at 125°C (bath temperature) and stirred at 135°C overnight. The solution was cooled to room temperature to obtain 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 obtain a brown solution, which was washed with brine (20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to obtain a residue, which was purified by chromatography using 0-100% ethyl acetate in heptane as eluent, with obtaining the title compound as a solid (0.349 g, 5%). ^1H NMR (400 MHz, acetone- _d6 ) 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-b]pyridine-3-carboxylate

[00464] To a stirred and cooled (0°C) solution of the product from Step 1 (0.349 g, 1.40 mmol) in pyridine (10 mL), trifluoromethanesulfonic anhydride (940 μL, 6 mmol) was added dropwise over 20 minutes. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture 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 (MgSO ₄ ) and concentrated to give the title product as a brown solid (0.515 g, 96%).

[00465] Step 3: Methyl 7-cyclopropyl-5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-1-yl)thieno[3,2-b]pyridine-3-carboxylate

[00466] A 25 mL microwave reaction vessel equipped with a magnetic stirrer was charged with the product from Step 2 (0.515 g, 1.4 mmol), N-isopropyl-2-(piperazin-1-yl)acetamide (0.300 g, 1.6 mmol), 1-methylpyrrolidin-2-one (8 ml) and N,N-diisopropylethylamine (940 μl, 5 mmol). The reaction mixture 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 (4×20 ml) and saline (10 ml). The organic layer was dried (Na ₂ SO 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 ₃ ) δ 8.45 (s, 1H), 7.00 (d, 1H), 6.37 (s, 1H), 4.26-4.06 (m, 1H) , 3.94 (d, J=2.5 Hz, 4H), 3.70 (dd, J=6.2, 3.9 Hz, 4H), 3.04 (s, 2H), 2.66 ( t, J=5.0 Hz, 4H), 2.17-1.98 (m, 2H), 1.18 (d, J=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-N-ethyl-5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-1-yl)thieno[3,2-b]pyridine-3-carboxamide

[00468] A 25 mL microwave reaction vessel equipped with a magnetic stirrer was charged with the product from Step 3 (0.100 g, 240 μmol) and a 2.0 M solution of ethylamine in methanol (5.0 mL, 10 mmol ). The reaction mixture 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%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.70 (br.t, J=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, J=8.4, 5.1 Hz, 1H), 1.30 (t, J=7.3 Hz, 3H), 1.19 (d, J=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 1-(3-(Azetidin-1-carbonyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl tert-butylcarbamate

[00470] Step 1: Methyl 5-(4-hydroxypiperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate

[00471] To a stirred solution of intermediate 3 (10.0 g, 33.4 mmol) in N-methyl-2-pyrrolidinone (60 ml) was added piperidin-4-ol (6.00 g, 59 mmol) and N, N-diisopropylethylamine (11.8 ml, 68 mmol). The solution was heated at 130°C for 3 hours and then stirred at room temperature overnight. The mixture was concentrated and the brown solid was taken into water (~200 ml). The lumps of suspended solid were dispersed by stirring with a spatula and ultrasonication. After the formation of a homogeneous suspension, the mixture was filtered. The filter cake was rinsed with water (2×40 ml) and diethyl ether (2×25 ml) and then dried under low pressure. The filter cake was further dried in a vacuum oven (60°C) to obtain the title compound as a light brown solid (10.90 g, 89%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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 m/z (M+H ⁺ ).

[00472] Step 2: Methyl 5-(4-((tert-butylcarbamoyl)-oxy)piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate

[00473] A 25 mL microwave reaction vessel equipped with a magnetic stirrer was charged with the product from Step 1 (0.510 g, 1.4 mmol), N,N-dimethylformamide (10 mL), and tert-butyl isocyanate (1. 40 g, 16.8 mmol). The mixture was heated at 130°C for 6 hours in a microwave reactor. Additional t-butyl isocyanate (0.550 g, 6.62 mmol) was added and the reaction mixture was heated at 140°C for 5 days. The solution was diluted with ethyl acetate (50 ml), washed with water (4 x 20 ml), saturated aqueous ammonium chloride (20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to give a brown solid, which was purified by chromatography using 0- 100% ethyl acetate in heptane as eluent to give the title compound as a yellowish solid (0.800 g, 100%). MS: 460 m/z (M+H ⁺ ).

[00474] Step 3: 5-(4-((T-butylcarbamoyl)oxy)piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylic acid

[00475] A 50 mL round bottom flask equipped with a magnetic stirrer was charged with the product from Step 2 (0.350 g, 760 μmol), 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 obtain a precipitate, which was filtered and washed with water, and dried under vacuum to obtain the product in as a pale yellow solid (0.338 g, 100%) MS: 446 m/z (M+H ⁺ ).

[00476] Step 4: 1-(3-(Azetidin-1-carbonyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl tert-butylcarbamate

[00477] A 50 mL round bottom flask equipped with a magnetic stirrer was charged with the product from Step 3 (0.120 g, 270 μmol), azetidine (0.046 g, 808 μmol), tetrahydrofuran (5 mL) and 2,4,6-tripropyl- 1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (0.342 g, 540 µmol) 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 SO ₄ ), filtered and concentrated to give a solid, which was purified by chromatography using 0-100% ethyl acetate in heptane as eluent to give the title compound as a white solid (0.100 g, 77 ^1H NMR (400 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 6.99 (s, 1H), 4.92 (d, J=8.5 Hz, 1H), 4.64 (s, 1H), 4.27 (t, J=7.8 Hz, 2H), 4.21-4.14 (m, 2H) , 4.12 (d, J=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 m/z (M+H ⁺ ).

[00478] Example 428 Methyl 5-(4-(((cyclopropylmethyl)-carbamoyl)oxy)piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]-pyridine-3-carboxylate

[00479] A 25 mL microwave reaction vessel equipped with a magnetic stirrer was charged with Intermediate 3 (0.510 g, 1.7 mmol), Intermediate 24 (0.598 g, 3.0 mmol), N, N-diisopropylethylamine (602 µl, 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 saline (20 ml). The organic layer was dried ( _Na2SO4 ), filtered and concentrated to give a brown residue, which was purified by chromatography _using 0-50% ethyl acetate in heptane as eluent to give the title compound as a white solid (0.474 g, 60%) . ^1H NMR (400 MHz, CDCl ₃ ) δ 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: (+/-)-trans-1-(3-(Azetidine-1-carbonyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-3-fluoropiperidine -4-yl isopropylcarbamate

[00481] Step 1. Methyl 5-((+/-)-trans-3-fluoro-4-hydroxy-piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3- carboxylate

[00482] A 25 mL microwave reaction vessel equipped with a magnetic stirrer was charged with Intermediate 5 (3.75 g, 13 mmol), (+/-)-trans-3-fluoropiperidin-4-ol hydrochloride (1.80 g, 11.6 mmol), N,N-diisopropylethylamine (4.49 g, 35 mmol) and 1-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 aqueous ammonium chloride (20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to give a brown solid, which was triturated with ether to give product as a beige solid (3.50 g, 80%). MS: 404 m/z (M+H ⁺ ).

[00483] Step 2: Azetidin-1-yl(5-((+/-)-trans-3-fluoro-4-hydroxypiperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-yl)methanone

[00484] A 25 mL microwave reaction vessel equipped with a magnetic stirrer was charged with the product from Step 1 (0.198 g, 520 μmol), azetidine (0.299 g, 5 mmol), and methanol (4 mL). The mixture was stirred at 100°C for 3 hours and evaporated to give a brown solid, which was purified by chromatography using 0-10% methanol in dichloromethane as eluent to give the product as a yellowish solid (0.040 g, 19%). MS: 404 m/z (M+H ⁺ ).

[00485] Step 3. (+/-)-trans-1-(3-(Azetidine-1-carbonyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-3-fluoropiperidine -4-yl isopropylcarbamate

[00486] A 25 mL microwave reaction vessel equipped with a magnetic stirrer was charged with the product from Step 2 (0.040 g, 100 μmol), 1,1′-carbonyldiimidazole (0.032 g, 200 μmol) 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-hydroxysuccimide (0.023 g, 200 μmol). The solution was stirred at room temperature for 15 minutes, then isopropylamine (42 μl, 500 μmol) was added and stirred at 40°C for 16 hours. The solution was concentrated to obtain a residue. The residue was treated with ethyl acetate (50 ml), washed with water (20 ml) and brine (10 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to give a solid, which was purified by chromatography using 0-100% ethyl acetate in heptane as eluent to give the product as a yellowish solid (0.034 g, 70%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (s, 1H), 7.00 (s, 1H), 5.02 (s, 1H), 4.60 (d, J=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, J=6 .5 Hz, 6H) ppm. MS: 489 m/z (M+H ⁺ ).

[00487] Example 449 1-(7-Chloro-3-(methylcarbamoyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl(cyclopropylmethyl)carbamate

[00488] To obtain the title compound as a white solid, the procedure described in step 3 of Example 420 was used using intermediate 33 and intermediate 24. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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 1-(7-(Difluoromethyl)-3-(methylcarbamoyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate

[00490] Step 1. 1-(7-(Difluoromethyl)-3-(methylcarbamoyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate

[00491] To obtain the title compound as a white solid, the procedure described in step 3 of Example 420 was used using intermediate 34 and piperidin-4-yl isopropyl carbamate. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.52 (s, 1H), 6.97-6.57 (m, 2H), 4.93 (br.s, 1H), 4.49 (br. s, 1H), 4.10 (br.s, 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, J=6.5 Hz, 6H). ppm MS: 428 m/z (M+H ⁺ ).

[00492] Step 2: 1-(7-(Difluoromethyl)-3-(methylcarbamoyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate

[00493] The procedure described in Step 4 of Example 420 was used to obtain the title compound as a white solid using the product from Step 1 and methylamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J= 4.8 Hz, 3H), 2.14-1.93 (m, 2H), 1.80 (s, 2H), 1.18 (d, J=6.7 Hz, 6H) ppm. MS: 427 m/z (M+H ⁺ ).

[00494] Example 473 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl cyclopropylcarbamate

[00495] To obtain the title compound as a white solid, the procedure described in step 2 of Example 422 was used using intermediate 7 and isocyanatocyclopropane. ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J=4.8 Hz, 3H), 2.60 (d, J=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 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl(cyclopropylmethyl)-carbamate

[00497] To obtain the title compound as a white solid, the procedure described in step 3 of Example 420 was used using intermediate 5 and intermediate 24. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl(cyclopropylmethyl)-carbamate trifluoroacetate

[00499] To obtain the title compound as a white solid, the procedure described in step 2 of Example 422 was used using intermediate 7 and (isocyanatomethyl)cyclopropane. ^1H NMR (400 MHz, methanol- _d4 ) δ 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, J=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: (+/-)-trans-3-Fluoro-1-(3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin- 4-yl diisopropylcarbamate

[00501] Step 1. (+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4- yl 1H-imidazole-1-carboxylate

[00502] To a stirred solution of 1,1'-carbonyldiimidazole (0.772 g, 4.76 mmol) in dichloromethane (10 ml) was added dropwise a solution of intermediate 31 (1.33 g, 3.52 mmol) in dichloromethane (50 ml ) for 20 minutes. The mixture was stirred overnight at room temperature and then washed with water (3x20 ml) and brine (1x10 ml). The organic layer was dried (MgSO ₄ ) and concentrated to give the crude title compound as a pale pink solid (1.56 g, 94%). MS: 472 m/z (M+H ⁺ ).

[00503] Step 2. (+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4- silt diisopropylcarbamate

[00504] A 100 mL round bottom flask equipped with a magnetic stirrer was charged with the crude product from Step 1 (0.300 g, 640 μmol), acetonitrile (20 mL) and N-hydroxysuccimide (0.088 g, 760 μmol), stirred at room temperature in 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 obtain a residue. The residue was dissolved in ethyl acetate (50 ml) and washed with water (20 ml) and brine (10 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated to give a residue, which was purified by chromatography using 0-100% ethyl acetate in heptane as eluent to give the product as a white solid (0.240 g, 77%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=6.7 Hz, 12H) ppm. MS: 504 m/z (M+H ⁺ ).

[00505] Example 490: (+/-)-trans-3-Fluoro-1-(3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin- 4-yl isopropylcarbamate

[00506] To obtain the title compound as a white solid, the procedure described in Example 488 was used, replacing diisopropylamine with isopropylamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=4.8 Hz, 3H), 2.47-2.20 (m, 1H), 1.88-1.66 (m, 1H), 1.19 (d, J=6.6 Hz, 6H) ppm. MS: 463 m/z (M+H ⁺ ).

[00507] Example 492: (+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-piperidin-4 -yl cyclopropylcarbamate

[00508] To obtain the title compound as a white solid, the procedure described in Example 488 was used, replacing diisopropylamine with cyclopropylamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J= 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. (3R,4R)-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-piperidin- 4-yl isopropylcarbamate and (3S,4S)-3-fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-piperidin-4-yl isopropylcarbamate (separated enantiomers with known absolute stereochemistry)

[00510] The title compounds were prepared by resolving the title compound of Example 490 using chiral supercritical fluid chromatography (SFC) (CHIRALPAK IA 10 x 250 mm column; modifier 20% methanol supplemented with 0.1% diethylamine). The absolute configurations of individual enantiomers were determined by comparing the retention times obtained by chiral SFC with those of authentic enantiomers obtained from optically active fluoro-piperidin-4-ol of known stereochemistry (commercially available).

[00511] The first fraction eluted was concentrated to give the (3R,4R) enantiomer as a white solid (Example 495). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=4.8 Hz, 3H), 2.43-2.25 (m, 1H), 1.92-1.72 (m, 1H), 1.20 (d, J=6.5 Hz, 6H) ppm. MS: 463 m/z (M+H ⁺ ).

[00512] The next fraction eluted was concentrated to give the (3S,4S) enantiomer as a white solid (Example 496). ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J=4.9 Hz, 3H), 2.45-2.24 (m, 1H), 1.88-1.65 (m, 1H), 1.19 (d, J=6.5 Hz, 6H) ppm. MS: 463 m/z (M+H ⁺ ).

[00513] Example 505 2-Cyanoethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate

[00514] A 25 mL microwave reaction vessel equipped with a magnetic stirrer was charged with 3-hydroxypropanenitrile (0.079 g, 1.10 mmol), N-methyl-2-pyrrolidinone (8 mL), N, N -diisopropylethylamine (0.23 g, 1.8 mmol) and 4-nitrophenylchloroformate (0.337 g, 1.70 mmol). The resulting solution was stirred at room temperature for two days and then treated with the product from step 3 of Example 297 (0.080 g, 220 µmol). 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 (2×20 ml) and saline (1×10 ml). The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give a residue, which was purified by automated flash chromatography (0-100% EtOAc in heptane; silica gel column) to give the title compound as a yellowish-white solid (0.042 g, 41 %). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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 (1-(3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate

[00516] To obtain the title compound as a white solid, the procedure described in Example 505 was used, replacing 3-hydroxypropanenitrile with 2-(trifluoromethoxy)ethan-1-ol. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin- 3-carboxamide

[00518] To a stirred solution of the hydrochloride salt of intermediate 6 (0.110 g, 260 µmol) in methanol was added 4-isopropylthiazole-2-carboxaldehyde (0.122 g, 790 µmol), N,N-diisopropylethylamine (184 µl, 0.106 mmol), acetic acid acid (45 μl, 0.79 mmol) and sodium cyanoborohydride (0.049 g, 790 μmol). The reaction mixture 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 gel column) to give the title compound as a white solid (0.095 g, 75%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.39 (br.s, 1H), 8.66 (s, 1H), 7.04 (s, 1H), 6.86 (d, J=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, J=6.0, 4.2 Hz, 4H), 1.32 (d, J=6.9 Hz, 6H) ppm. MS: 484 m/z (M+H ⁺ ).

[00519] Example 552 5-(4-((4-Isopropylmorpholin-2-yl)methyl)-piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin- 3-carboxamide trifluoroacetate

[00520] Step 1. Tert-butyl 2-((4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperazin-1-yl)methyl)-morpholine- 4-carboxylate

[00521] A 25 mL microwave reaction vessel equipped with a magnetic stirrer was charged with Intermediate 6 hydrochloride salt (0.300 g, 660 μmol), N,N-dimethylformamide (4 mL), tert-butyl 2-(bromomethyl )morpholine-4-carboxylate (0.260 g, 920 µmol) and N,N-diisopropylethylamine (577 µl, 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 SO ₄ ), filtered and concentrated to give a residue, which was purified by chromatography using 20% acetone in ethyl acetate in as eluent to give the title compound as a foamy solid (0.136 g, 38%). ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J=13.7 Hz, 1H), 2.78-2.56 (m, 6H), 2.42 (dd, J=13.2, 4.1 Hz, 1H), 1.48 ( s, 9H) ppm. MS: 544 m/z (M+H ⁺ ).

[00522] Step 2. N-Methyl-5-(4-(morpholin-2-ylmethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide hydrochloride

[00523] A 50 mL round bottom flask equipped with a magnetic stirrer was charged with the product from Step 1 (0.136 g, 250 μmol), a 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 obtain the title compound as a white solid (0.120 g, 87%). 1H NMR (400 MHz, methanol-d ₄ ) δ 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, J=12.6 Hz, 1H), 3.87 (s, 3H), 3.62 (d, J=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-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin- 3-carboxamide-2,2,2-trifluoroacetic acid

[00525] A 100 mL round bottom flask equipped with a magnetic stirrer was charged with the product from step 2 (0.060 g, 110 μmol), methanol (4 mL), propan-2-one (0.025 g, 430 μmol), acetic acid (6 µl, 110 µmol) and N,N-diisopropylethylamine (94 µl, 540 µmol). The solution was stirred at room temperature for 30 minutes, then a solution of zinc chloride (0.030 g, 220 µmol) and sodium cyanoborohydride (0.014 g, 210 µmol) in methanol (1 ml) was added. The solution was stirred at room temperature for 3 days. The solution was concentrated to a dry residue, which was treated with ethyl acetate (40 ml), washed with water (10 ml) and brine (10 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to obtain a solid, which was purified by reverse HPLC. phase using 10-100% acetonitrile in water (0.1% trifluoroacetic acid) as eluent to give the title compound as a solid (0.008 g, 10%). 1H NMR (400 MHz, methanol-d4) δ 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, J=6.4 Hz, 6H). ppm MS: 600 m/z (M+H ⁺ ).

[00526] Example 566: (S)-1-Cyclopropylethyl 4-(3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine-1-carboxylate

[00527] A 25 mL microwave reaction vessel equipped with a magnetic stirrer was charged with (S)-1-cyclopropylethan-1-ol (0.068 g, 790 μmol), 4-nitrophenylchloroformate (0.159 g, 790 μmol ), 1-methylpyrrolidin-2-one (5 ml) and N,N-diisopropylethylamine (0.136 g, 1.0 mmol). The mixture was stirred at 30°C for 2 days. Intermediate 29 (0.100 g, 260 µmol) was then added and stirred at 90°C for 2 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (3×20 ml) and brine (10 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated to give a residue, which was purified by chromatography using 0-80% ethyl acetate in heptane as eluent to give the title compound (0.049 g, 41%). 1H NMR (400 MHz, CDCl3), 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-b]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[00529] Step 1: 5-Iodo-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00530] A 100 mL round bottom flask equipped with a magnetic stirrer and condenser was charged with Intermediate 5 (2.00 g, 6.79 mmol) and sodium iodide (0.051 g, 339 μmol). The mixture was suspended in propiononitrile (20 ml). Iodotrimethylsilane (1.93 mL, 14 mmol) was added to give a dark amber mixture. The mixture was stirred at 90°C for 2 hours. Water (60 ml) and solid sodium bisulfite (0.900 g) were added with vigorous stirring to remove excess iodine. The resulting yellow precipitate was collected by filtration, rinsed with water and air dried. The solid was transferred to a flask and dissolved in ethyl acetate (80 ml), dried (Na ₂ SO ₄ ), filtered and the solvent was evaporated to give a white solid, which was purified by chromatography using 0-50% ethyl acetate in heptane as eluent, with yielding the product as a white solid (1.523 g, 58%). MS: 387 m/z (M+H ⁺ ).

[00531] Step 2: Tert-butyl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[00532] A 10 mL microwave reaction flask equipped with a magnetic stirrer was charged with tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (0.502 g, 1.6 mmol) and N, N- dimethylacetamide (6 ml). A nitrogen atmosphere was created in the flask and heated at 65°C. Zinc powder (0.101 g, 1.6 mmol) was then immediately added to it and stirred at 65°C for 20 minutes. The product from stage 1 (0.200 g, 520 µmol), copper(I) iodide (0.002 g, 13 µmol), PdCl ₂ (dppf) was loaded into a separate 10-20 ml flask for reactions under microwave radiation, equipped with a magnetic stirrer. ₂ (0.0019 g, 30 µmol) and N,N-dimethylacetamide (6 ml). The flask was sealed with a membrane and heated at 85°C under a nitrogen atmosphere. While the second flask was heating, the reaction mixture from the first flask was withdrawn using a syringe and added to the second flask. Upon addition, the color of the reaction mixture changed to light amber and then returned to dark amber. The solution was poured into saturated aqueous ammonium chloride (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layer was again washed with water (2×30 ml) and brine (10 ml). The organic layer was dried (Na ₂ SO ₄ ) and concentrated to a dark oil. The crude oil was purified on 10 g of silica gel, eluting with 0-80% ethyl acetate in heptane to give the title compound as a white solid (0.125 g, 53%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.57 (br.s, 1H), 8.82 (s, 1H), 7.40 (s, 1H), 4.12 (s, 2H), 3 .93 (s, 2H), 3.78 (p, J=8.6 Hz, 1H), 3.13 (d, J=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-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2-azaspiro-[3.3] heptane-2-carboxylate

[00534] Step 1. N-Methyl-5-(2-azaspiro[3.3]heptan-6-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide hydrochloride

[00535] A 10 mL microwave reaction flask equipped with a magnetic stirrer was charged with Example 574 (0.108 g, 237 μmol) and a 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-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2-azaspiro-[3.3] heptane-2-carboxylate

[00537] The procedure described in Example 566 was used to obtain the title compound as a pale amber solid using the product from Step 1 and 2-(trifluoro-methoxy)ethan-1-ol. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.55 (br.s, 1H), 8.83 (s, 1H), 7.41 (s, 1H), 4.30 (t, J=4, 6 Hz, 2H), 4.21 (s, 2H), 4.20-4.11 (m, 2H), 4.02 (s, 2H), 3.80 (p, J=8.7 Hz, 1H), 3.13 (d, J=4.9 Hz, 3H), 2.84-2.73 (m, 2H), 2.68-2.56 (m, 2H) ppm. MS: 512 m/z (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 reaction flask equipped with a magnetic stirrer was charged with Intermediate 5 (0.500 g, 1.7 mmol), tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (0.381 g, 2 .0 mmol), cesium carbonate (0.663 g, 2.0 mmol) and N, N-dimethylformamide (8 ml). The reaction mixture was stirred at 150°C under microwave irradiation for 2.5 hours, then diluted with ethyl acetate (60 ml) and washed with water (4×15 ml) and brine (15 ml). The organic layer was dried (Na ₂ SO 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%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate

[00541] To obtain the title compound as a white solid, the procedure described in Example 585 was used, replacing tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate with tert-butyl 3-hydroxypyrrolidine-1-carboxylate. ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J=4.8 Hz, 3H), 2.44-2, 26 (m, 2H), 1.48 (s, 9H) ppm. MS: 446 m/z (M+H ⁺ ).

[00542] Example 590 carboxamide

[00543] Step 1. N-Methyl-5-(pyrrolidin-3-yloxy)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide hydrochloride

[00544] A 25 mL microwave reaction vessel equipped with a magnetic stirrer was charged with Example 589 (0.440 g, 988 μmol) and 2N hydrochloric acid (15 mL) in methanol. The solution was stirred at 80°C 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-((1-((Cyclopropylmethyl)carbamoyl)-pyrrolidin-3-yl)oxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]-pyridin-3- carboxamide

[00546] To obtain the title compound as a white solid, the procedure described in Step 2 of Example 422 was used, using the product from Step 1 and (isocyanatomethyl)cyclopropane. ^1H NMR (400 MHz, methanol-d4) δ 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)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate

[00548] The procedure described in Example 585 was used to obtain the title compound as a white solid, replacing tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate with tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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-((1-((Cyclopropylmethyl)-carbamoyl)pyrrolidin-3-yl)oxy)-N-methyl-7-(trifluoromethyl)thieno-[3,2-b] pyridine-3-carboxamide

[00550] Step 1. (S)-N-Methyl-5-(pyrrolidin-3-yloxy)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide hydrochloride

[00551] To obtain the title compound as a white solid, the procedure described in step 1 of Example 590 was used, using the compound of Example 593 and 2N hydrochloric acid in methanol. MS: 346 m/z (M+H ⁺ ).

[00552] Step 2. (S)-5-((1-((Cyclopropylmethyl)carbamoyl)-pyrrolidin-3-yl)oxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]- pyridine-3-carboxamide

[00553] To obtain the title compound as a white solid, the procedure described in Step 2 of Example 422 was used, using the product from Step 1 and (isocyanatomethyl)cyclopropane. ^1H NMR (400 MHz, methanol-d4) δ 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-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-pyrrolidine-1-carboxylate

[00555] A 25 mL microwave reaction vessel equipped with a magnetic stirrer was charged with cyclopropylmethanol (0.250 g, 3.5 mmol), 1-methylpyrrolidin-2-one (8 mL), N, N-diisopropylethylamine (0.089 g, 690 µmol) and 4-nitrophenyl chloroformate (1.05 g, 5.2 mmol). The solution was stirred at 20°C for 2 days. The product from step 1 of Example 594 (0.080 g, 230 µmol) was added and stirred at 90°C for 16 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (3×20 ml) and brine (10 ml). The organic layer was dried (Na ₂ SO 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%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- pyrrolidine-1-carboxylate

[00557] To obtain the title compound as a white solid, the procedure described in Example 595 was used, replacing cyclopropylmethanol with 3-(trifluoromethoxy)ethan-1-ol. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J= 4.9 Hz, 3H), 2.53-2.25 (m, 2H) ppm. MS: 502 m/z (M+H ⁺ ).

[00558] Example 609: Tert-butyl (+/-)-cis-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl) hydroxy)-pyrrolidine-1-carboxylate

[00559] To obtain the title compound as a white solid, the procedure described in Example 585 was used, replacing tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate with tert-butyl (+/-)-trans-3-fluoro-4-hydroxypyrrolidine- 1-carboxylate. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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 (+/-)-cis-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -pyrrolidine-1-carboxylate

[00561] Step 1. 5-(((+/-)-cis-4-Fluoropyrrolidin-3-yl)oxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3- carboxamide hydrochloride.

[00562] To obtain the title compound as a white solid, the procedure described in step 1 of Example 590 was used, using the compound of Example 609 and 2N hydrochloric acid in methanol. MS: 364 m/z (M+H ⁺ ).

[00563] Step 2. 2-(Trifluoromethoxy)ethyl (+/-)-cis-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-5 -yl)-hydroxy)pyrrolidine-1-carboxylate

[00564] The procedure described in Example 595 was used to obtain the title compound as a white solid using the product from Step 1 and cyclopropylmethanol. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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 (+/-)-cis-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-5 -yl)oxy)pyrrolidine-1-carboxylate

[00566] The procedure described in Example 595 was used to obtain the title compound as a white solid using the product from Step 1 of Example 610 and 3-(trifluoromethoxy)-ethan-1-ol. ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J= 4.4 Hz, 3H) ppm. MS: 520 m/z (M+H ⁺ ).

[00567] Example 628 Tert-butyl (+/-)-endo7-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-3-oxa -9-azabicyclo[3,3,1]nonane-9-carboxylate

[00568] A 10 mL microwave reaction vessel equipped with a magnetic stirrer was charged with Intermediate 5 (0.200 g, 680 μmol), tert-butyl (+/-)-endo7-hydroxy-3-oxa-9- azabicyclo-[3,3,1]nonane-9-carboxylate (0.165 g, 680 µmol), tetrahydrofuran (8 ml) and potassium 2-methylpropane-2-oleate (0.084 g, 750 µmol). The solution was stirred at 70°C for 2 hours, then diluted with ethyl acetate (40 ml) and washed with water (40 ml) and saline (10 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated to give a red precipitate, which was purified by reverse phase HPLC using 20-100% acetonitrile in water as eluent to give the title compound as a white solid (0.038 g , eleven% ). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.03 (br.s, 1H), 8.74 (s, 1H), 7.13 (t, J=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-b]pyridin-5-yl)oxy)- 3-oxa-9-azabicyclo[3,3,1]nonane-9-carboxylate

[00570] Step 1. (+/-)-5-((endo-3-Oxa-9-azabicyclo[3,3,1]-nonan-7-yl)oxy)-N-methyl-7-(trifluoromethyl )thieno[3,2-b]pyridine-3-carboxamide hydrochloride

[00571] Using the procedure described in step 2 of Example 552, the N-tert-butoxycarbonyl protecting group of the title compound of Example 628 was cleaved using a 2.0 M solution of hydrogen chloride in methanol.

[00572] Step 2. (+/-)-2-(Trifluoromethoxy)ethyl endo-7-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-3-oxa-9-azabicyclo[3,3,1]nonane-9-carboxylate

[00573] A 25 mL round bottom flask equipped with a magnetic stirrer was charged with 2-(trifluoromethoxy)ethan-1-ol (0.026 g, 200 μmol), 1,1'-carbonyldiimidazole (0.033 g, 200 μmol), and dichloromethane (4 ml). The reaction mixture was stirred at room temperature for 16 hours and then concentrated. The residue was taken up in acetonitrile (6 ml). To this stirred solution were added N-hydroxysuccimide (0.023 g, 210 µmol), the product from step 1 (0.030 g, 70 µmol) and N,N-diisopropylethylamine (0.009 g, 70 µmol) in that order. The reaction mixture 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 eluent to give the title compound as a white solid (0.030 g, 78%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, J=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, J=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-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)methyl)-piperidin-1- carboxylate

[00575] Step 1. N-methyl-5-(piperidin-4-ylmethyl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide hydrochloride

[00576] To obtain the title compound as a white solid, the procedure described in step 1 of Example 590 was used, using the compound of Example 634 and 2N hydrochloric acid in methanol. MS: 358 m/z (M+H ⁺ ).

[00577] Step 2. 2-(Trifluoromethoxy)ethyl 4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)methyl)-piperidin-1- carboxylate

[00578] The procedure described in Example 629 was used to obtain the title compound as a white solid using the product from Step 1 and 3-(trifluoromethoxy)ethan-1-ol. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.52 (br.s, 1H), 8.82 (s, 1H), 7.43 (s, 1H), 4.32 (t, J=4, 6 Hz, 2H), 4.29-4.03 (m, 4H), 3.12 (d, J=4.8 Hz, 3H), 3.00 (d, J=7.1 Hz, 2H) , 2.96-2.72 (m, 2H), 2.18-2.00 (m, 1H), 1.73 (d, J=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-b]pyridin-5-yl)methyl)piperidine-1-carboxylate

[00580] To obtain the title compound as a white solid, the procedure described in Example 574 was used, replacing tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate with tert-butyl 4-(iodomethyl)piperidine-1-carboxylate. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.73-9.29 (br.s, 1H), 8.81 (s, 1H), 7.42 (s, 1H), 4.29-4, 02 (m, 2H), 3.12 (d, J=4.8 Hz, 3H), 2.99 (d, J=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-(isopropyl-amino)-2-oxo-ethyl]piperazin-1-yl]-N-methyl-7-(trifluoromethyl)- thieno[3,2-b]pyridin-3-carboxamide and 6-chloro-5-[4-[2-(isopropyl-amino)-2-oxo-ethyl]piperazin-1-yl]-2-methoxy-N -methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide (two compounds isolated from the same reaction mixture)

[00582] Step 1: 5,6-Dichloro-N-methyl-7-(trifluoromethyl)thieno-[3,2-b]pyridine-3-carboxamide and 5,6-dichloro-2-methoxy-N-methyl- 7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00583] A 50 mL round bottom flask was charged with 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 aqueous sodium bicarbonate (50 ml) and brine (50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to obtain a residue, which was triturated with acetonitrile to obtain 300 mg of products, methyl 6- chloro-5-hydroxy-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate (MS: 311 m/z (M+H ⁺ )) and methyl 2,6-dichloro-5-hydroxy- 7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate (MS: 346 m/z (M+H ⁺ )), identified by LCMS. The mixture was used in the next step without further purification. A mixture of the above-mentioned hydroxypyridines (300 mg) and POCl ₃ (2.24 ml, 24.06 mmol) was loaded into a 20 ml flask. 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 SO ₄ ), filtered and concentrated to obtain a mixture of chlorinated products (~320 mg), methyl 5,6-dichloro-7-(trifluoromethyl)thieno[3, 2-b]pyridine-3-carboxylate (MS: 330 m/z (M+H ⁺ )) and methyl 2,5,6-trichloro-7-(trifluoromethyl)thieno[3,2-b]pyridine-3- carboxylate (MS: 364 m/z (M+H ⁺ )), which was used in the next step without further purification. A mixture of the above chlorinated products (~320 mg) and methanamine (4.81 mL, 9.63 mmol) in methanol (2M) was charged into a 50 mL round bottom flask. After 12 hours, the mixture was concentrated at 20°C to obtain a mixture (~320 mg) of the title compounds, which was used in the next step without further purification.

[00584] Step 2. 6-Chloro-5-[4-[2-(isopropylamino)-2-oxo-ethyl]piperazin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2- b]-pyridin-3-carboxamide and 6-chloro-5-[4-[2-(isopropylamino)-2-oxo-ethyl]piperazin-1-yl]-2-methoxy-N-methyl-7-(trifluoromethyl )thieno-[3,2-b]pyridine-3-carboxamide

[00585] N,N-Diisopropylethylamine (636 μL, 3.65 mmol), N-isopropyl-2-(piperazin-1-yl)acetamide (202 mg, 1 .09 mmol) obtained from step 2 of example 47, products (~320 mg) from step 1 and N-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 (3×20 ml) and brine (20 ml), dried (MgSO ₄ ), filtered and concentrated to obtain a residue, which was purified by automated flash chromatography (12S silica gel column, 5:1 ethyl acetate :heptane to 10:1 ethyl acetate:methanol;) to obtain a mixture of products, which was further purified by HPLC to obtain the named compounds. Example 636 (48 mg, 100 µmol, 11% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31-9.19 (m, 1H), 8.73 (s, 1H), 6.90 (d, J=8.8 Hz, 1H), 4 .22-4.08 (m, 1H), 3.49 (t, J=4.9 Hz, 4H), 3.14-3.07 (m, 5H), 2.81 (t, J=4 .8 Hz, 4H), 1.20 (d, J=6.5 Hz, 6H) ppm. MS: 478 m/z (M+H ⁺ ) and example 637 (30 mg, 60 µmol, 6% yield). ^1H NMR (400 MHz, CDCl ₃ ) δ 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, J=5.2 Hz, 3H), 3.07 (s, 2H), 2.74 (t, J=4.9 Hz, 4H), 1.18 (d, J=6.6 Hz, 6H) ppm. MS: 508 m/z (M+H ⁺ ).

[00586] Example 638 [1-[6-Chloro-3-(methylcarbamoyl)-7-(tri-fluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl]N-(cyclopropyl -methyl)carbamate

[00587] A 5 mL vessel was charged with Example 669 (20 mg, 40 μmol) and N-methyl-2-pyrrolidinone (1 mL). 3-chloroperbenzoic acid (15 mg, 60 μmol) was added at 20°C. After 1 hour, the mixture at 20°C was directly purified by reverse phase HPLC to obtain the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.25 (br.s, 1H), 8.70 (s, 1H), 4.97 (br.s, 1H), 4.82 (br.s, 1H), 3.68-56 (m, 2H), 3.30 (t, J=10.8 Hz, 2H), 3.07-3.1 (m, 5H), 2.15 (br.s , 2H), 1.94 (br.s, 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 [1-[6-Fluoro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl]N-[(1S) -1-cyclopropylethyl]carbamate

[00589] A 5 mL vessel was charged with Example 109 (62 mg, 131 μmol) and acetonitrile (2 mL). 1-Chloromethyl-4-fluoro-1,4-diazoniumbicyclo[2,2,2]octane bis(tetrafluoroborate) (140 mg, 395 μmol) was added at 20°C. After 15 hours, the mixture at 20°C was directly subjected to reverse phase HPLC to obtain, after lyophilization, the title compound (2 mg, 5 μmol, 3% yield) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.23 (br.s, 1H), 8.62 (s, 1H), 4.95 (br.s, 1H), 4.69 (br.s, 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 (br.s, 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 [1-[6-Chloro-3-(methylcarbamoyl)-7-(tri-fluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl]N-cyclopropyl- carbamate

[00591] A 5 mL flask was charged with Example 473 (100 mg, 226 μmol) and N-methyl-2-pyrrolidinone (2 mL). A solution of hydrogen chloride (113 µl, 452 µmol) in dioxane (4M) was added at 0°C and, after 10 minutes at room temperature, 3-chloroperbenzoic acid (83 mg, 339 µmol) was added at 0°C. After 1 hour at room temperature, the mixture was directly subjected to reverse phase HPLC to obtain, after lyophilization, the title compound (52 mg, 109 μmol, 48% yield) as a solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (br.s, 1H), 8.85 (s, 1H), 7.32 (br.s, 1H), 4.82 (br.s. s, 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 [1-[6-Fluoro-3-(methylcarbamoyl)-7-(tri-fluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl]N-cyclopropyl- carbamate

[00593] To obtain the title compound (8 mg, 18 μmol, 8% yield) as a solid after lyophilization, the procedure described in Example 639 was used using the compound of Example 473. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9, 22 (br.s, 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 (br.s, 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-[1-[3-(isopropylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]pyrrolidin-3-yl]-carbamate

[00595] To obtain the title compound (200 mg, 63%) as a solid, the procedure described in Example 649 was used using 5-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-7-(trifluoromethyl) thieno[3,2-b]pyridine-3-carboxylic acid in which the ester in Example 659 was hydrolyzed with lithium hydroxide, and propan-2-amine. ^1H NMR (400 MHz, CDCl ₃ ) δ 9.59 (d, J=7.5 Hz, 1H), 8.58 (s, 1H), 6.68 (s, 1H), 5.49 (br .s, 1H), 4.44 (br.s, 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-(Azetidin-1-carbonyl)-7-(tri-fluoromethyl)thieno[3,2-b]pyridin-5-yl]piperazin-1-yl]- N-isopropyl acetamide

[00597] Step 1: 5-(4-(2-(Isopropylamino)-2-oxoethyl)-piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylic acid

[00598] A 100 mL round bottom flask was charged with Example 10 (143 mg, 321 μmol), 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 the pH was adjusted to 1-2 with dilute hydrochloric acid solution. The insoluble product was filtered and dissolved in methanol/dichloromethane. The solution was dried (Na ₂ SO ₄ ) and combined with the resulting solution extract. The organic phase of the filtrate was separated, washed with brine (25 ml), dried (MgSO ₄ ), filtered and concentrated to give the title compound (110 mg, 255 µmol, 79% yield). MS: 431 m/z (M+H ⁺ )

[00599] Step 2. 2-[4-[3-(Azetidin-1-carbonyl)-7-(tri-fluoromethyl)thieno[3,2-b]pyridin-5-yl]piperazin-1-yl]- N-isopropyl acetamide

[00600] A 100 mL round bottom flask was charged with the product from Step 1 (110 mg, 255 μmol), N,N-diisopropylethylamine (357 μL, 2.04 mmol) and acetonitrile (10 mL). O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (169 mg, 511 µmol) was added at 20°C, then azetidine (44 mg, 767 µmol) was added after 10 minutes ). After 2 hours at 20°C, the mixture was diluted with ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate (20 ml). The organic layer was separated, washed with aqueous ammonium chloride (20 ml) and brine (25 ml), dried (MgSO ₄ ), filtered and concentrated to give a residue, which was purified by automated flash chromatography (1:1 heptane/ethyl acetate to 0 :100 heptane/ethyl acetate; 12S silica gel column) to give the title compound (63 mg, 134 µmol, 52% yield) as a solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 7.01 (s, 1H), 6.94 (d, J=8 Hz, 1H), 4.28 (t, J =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, J=6.6 Hz, 6H) ppm. MS: 470 m/z (M+H ⁺ ).

[00601] Example 653 [1-[3-(Trideuteriomethylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl]N-cyclo-propylcarbamate

[00602] Methyl 5-(4-((cyclopropylcarbamoyl)oxy)piperidin-1-yl)-7-(trifluoromethyl)-thieno[3,2-b]pyridine was loaded into a 20 ml reaction vessel under microwave irradiation -3-carboxylate (120 mg, 270 µmol), which was prepared according to the same procedure as in example 428, and methanol (5 ml). Methane-d3-amine (92 mg, 2.71 mmol) was bubbled through the reaction mixture for 2-3 minutes at room temperature. After 2 hours of reaction at 80°C, LCMS analysis indicated the presence of some product (~50% conversion) and unreacted starting material. Methylamine-d3 was again bubbled through the mixture and heated at 40°C for 2 days (the reaction was completed). The mixture was concentrated to give a residue, which was suspended in acetonitrile and water and lyophilized to give the title compound (101 mg, 228 μmol, 84% yield) as a solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.24 (s, 1H), 8.75 (s, 1H), 7.51 (s, 1H), 7.33 (s, 1H), 4 .82 (br.s, 1H), 4.02 (br.s, 2H), 3.50 (br.s, 2H), 2.50-2.42 (m, 1H), 2.00-1 .96 (m, 2H), 1.73-1.50 (m, 2H), 0.57 (dt, J=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-1-yl]-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate

[00604] A 10 mL microwave reaction vessel was charged with N,N-diisopropylethylamine (472 μL, 2.71 mmol), intermediate 3 (400 mg, 1.35 mmol) and tert-butyl pyrrolidin-3-ylcarbamate (377 mg, 2.03 mmol) and N-methyl-2-pyrrolidinone (4 ml). After 30 minutes of heating at 130°C 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 (3×20 ml) and saturated aqueous ammonium chloride (20 ml), dried (MgSO ₄ ), 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 silica gel column) to give the title compound (480 mg, 1.08 mmol, 79% yield). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.54 (s, 1H), 6.72 (s, 1H), 4.70 (br.s, 1H), 4.41 (br.s, 1H) , 3.96 (s, 3H), 3.89 (dd, J=10.9, 6.1 Hz, 1H), 3.74-3.70 (m, 2H), 3.51 (dd, J =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 [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl]N-(cyclopropyl-methyl)carbamate hydrochloride

[00606] A 50 mL round bottom flask was charged with Example 474 (35 mg, 76 μmol) and acetonitrile (5 mL). The mixture was treated with a solution of hydrochloric acid (958 μl, 3.83 mmol) in 4 M dioxane and concentrated to give a residue, which was diluted with acetonitrile and water, and lyophilized to give the title compound (32 mg, 65 μmol, 85% yield) as a solid substances. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.26 (kv, J=4.8 Hz, 1H), 8.75 (s, 1H), 7.50 (s, 1H), 7.21 (t, J=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, J=4.7 Hz, 3H), 2.88 (t, J=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 [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl]N-(2,2-difluoro -1-methylethyl)carbamate

[00608] A 5 mL vessel was charged with methyl 5-(4-hydroxypiperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate (50 mg, 138 μmol) to obtain in step 1 of example 422, N,N-diisopropylethylamine (121 µl, 693 µmol), 4-nitrophenylchloroformate (55 mg, 277 µmol) and N-methyl-2-pyrrolidinone (3 ml). After reacting for 15 hours at 20°C, 1,1-difluoropropan-2-amine hydrochloride (54 mg, 416 µmol) was added at room temperature. After 2 hours of reaction at room temperature, the mixture was diluted with ethyl acetate (20 ml) and saturated aqueous sodium bicarbonate (20 ml). The organic layer was separated, washed with water (3×15 ml), ammonium chloride solution (15 ml) and brine (20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to obtain a residue, which was purified by automated flash chromatography ( 5:1 heptane/ethyl acetate to 1:1 heptane/ethyl acetate; 4 g silica gel column) to give methyl 5-(4-(((1,1-difluoropropan-2-yl)carbamoyl)oxy)piperidine-1- yl)-7-(trifluoromethyl)thieno[3,2-b]-pyridine-3-carboxylate (60 mg, 124 µmol, 89% yield). MS: 482 m/z (M+H ⁺ ).

[00609] A 25 mL round bottom flask was charged with the above methyl ester (60 mg, 124 μmol) and methanamine (6.23 mL, 12.46 mmol) in methanol (2M). After 5 reactions at 50°C, the mixture was concentrated to give a residue, which was purified by reverse phase HPLC to give the title compound (27 mg, 57 μmol, 45% yield) as a solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.26 (q, J=4.8 Hz, 1H), 8.75 (s, 1H), 7.52-7.51 (m, 2H) , 5.91 (td, J=56.1, 3.2 Hz, 1H), 4.94-4.81 (m, 1H), 4.09-4.0 (m, 2H), 3.89 (br.s, 1H), 3.59-3.48 (m, 2H), 2.95 (d, J=4.7 Hz, 3H), 2.00 (br.s, 2H), 1, 75-1.63 (m, 2H), 1.11 (d, J=7.0 Hz, 3H) ppm. MS: 481 m/z (M+H ⁺ ).

[00610] Example 671 [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl]N-(2-fluoro-1 -methyl-ethyl)carbamate

[00611] To obtain the title compound as a solid, the procedure described in Example 670 was used using 1-fluoropropan-2-amine hydrochloride. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.30-9.22 (m, 1H), 8.75 (s, 1H), 7.51 (s, 1H), 7.26 (d, J=8.1 Hz, 1H), 4.84 (br.s, 1H), 4.28 (dd, J=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 ( br.s, 2H), 1.68-1.62 (m, 2H), 1.07 (d, J=6.9 Hz, 3H) ppm. MS: 463 m/z (M+H ⁺ ).

[00612] Example 692 and Example 693. [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl]N-[(1R)- 2-fluoro-1-methylethyl]carbamate and [1-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-[( 1S)-2-fluoro-1-methyl-ethyl]carbamate (separated enantiomers of known absolute configurations)

[00613] The title compounds were prepared by resolving the racemic mixture of Example 671 using chiral SFC (CHIRALPAK IC 4.6 x 250 mm column; 15:85 ethanol/heptane modifier plus 0.1% diethylamine). The absolute configurations of individual enantiomers were determined by comparing the retention times obtained from chiral SFC with those of authentic enantiomers obtained from optically active (S)-1-fluoropropan-2-amine hydrochloride starting materials of known stereochemistry (commercially available).

[00614] First eluting fraction of compound of Example 692, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.26 (d, J=4.9 Hz, 1H), 8.75 (s, 1H), 7. 51 (s, 1H), 7.25 (d, J=8.0 Hz, 1H), 4.83 (br.s, 1H), 4.28 (dd, J=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, J=4.8 Hz, 3H), 2.12-1.94 (m, 2H), 1.68-1.56 (m, 2H), 1.07 (dd, J=6.9, 1.4 Hz, 3H) ppm MS: 463 m/z (M+H ⁺ )

[00615] Second eluting fraction of compound of Example 693, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 (sq, J=4 Hz, 1H), 8.76 (s, 1H), 7.51 ( s, 1H), 7.26 (d, J=8.0 Hz, 1H), 4.84 (br.s, 1H), 4.28 (dd, J=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, J=6.9, 1.4 Hz, 3H) ppm. MS: 463 m/z (M+H ⁺ ).

[00616] Example 780: Cyclopropylmethyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperazine-1-carboxylate

[00617] To obtain the title compound (160 mg, 43%) as a white solid, the procedure described in step 3 of Example 793 was used using intermediate 6 and cyclopropylmethanol. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (br.s, 1H), 8.70 (s, 1H), 7.05 (s, 1H), 3.99 (d, J=7, 2 Hz, 2H), 3.68-3.75 (m, 8H), 3.10 (d J=4.4 Hz, 3H), 1.15-1.19 (m, 1H), 0.61 (kv, J=5.6 Hz, 2H), 0.34 (kv, J=5.2 Hz, 2H) ppm. MS: 443 m/z (M+H ⁺ )

[00618] Example 793 and Example 794 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3S)-3- (dimethylamino)-2-methylazetidin-1-carboxylate and 1-(3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S, 3R)-3-(dimethylamino)-2-methylazetidine-1-carboxylate (separated enantiomers of known absolute configurations)

[00619] Step 1: Benzyl (2S)-3-(dimethylamino)-2-methyl-azetidine-1-carboxylate

[00620] Benzyl (S)-2-methyl-3-oxoazetidine-1-carboxylate (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 aqueous sodium bicarbonate (100 ml). The organic layer was separated and washed with saturated aqueous ammonium chloride (100 ml) and brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by silica gel column chromatography (pentane/ethyl acetate v/v=3:1) to give the title compound (150 mg, 60%) as a colorless oil. MS; (M ⁺ 1) 249.1

[00621] Step 2. (2S)-N,N,2-Trimethylazetidine-3-amine

[00622] Palladium on carbon (50 mg, 10%) was added to a solution of the product from Step 1 (150 mg, 0.6 mmol) in methanol (15 mL). The reaction mixture was stirred at room temperature under H ₂ atmosphere overnight. After completion of the reaction, the palladium-carbon was filtered and the filtrate was concentrated to obtain the crude title compound (100 mg, crude) as a white solid.

[00623] Step 3. 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl(2S,3S)-3-(dimethylamino )-2-methylazetidin-1-carboxylate and 1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3R) -3-(dimethyl-amino)-2-methylazetidine-1-carboxylate

[00624] To a solution of intermediate 7 (300 mg, 0.84 mmol) in dichloromethane (5 ml) was added N,N-diisopropylethylamine (215 mg, 1.67 mmol), 4-dimethylaminopyridine (105 mg, 0.84 mmol ) and 4-nitrophenylchloroformate (217 mg, 1.08 mmol). The mixture was then stirred at room temperature for 4 hours. After completion of the reaction, the solvent was removed to obtain the crude intermediate. The intermediate was dissolved in dried N,N-dimethylformamide (3 ml) and then N,N-diisopropylethylamine (325 mg, 2.46 mmol) and (2S)-N,N,2-trimethylazetidine-3-amine (430 mg) were added , unrefined). The reaction mixture was stirred at 50°C overnight. The resulting mixture was poured into water and extracted with dichloromethane (3×10 ml). The combined extracts were concentrated in vacuo. The residue was purified by reverse phase HPLC to give the cis form of the title compound (19 mg, 4%) ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.45 (br.s, 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 trans form of the title compound (46 mg, 11%) ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.44 (br.s, 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 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 1-methyl-1,6-diazaspiro- [3.3]heptane-6-carboxylate

[00627] To obtain the title compound (203 mg, crude) as a brown oil, the procedure described in step 3 of Example 793 was used using intermediate 7 and 1-methyl-1,6-diazaspiro[3.3]heptane. ^1H NMR (400 MHz, CDCl ₃ ) δ 9.46 (s, 1H), 8.67 (s, 1H), 7.07 (s, 1H), 4.96 (s, 1H), 4.26 (d, J=9.3 Hz, 2H), 3.95 (d, J=9.9 Hz, 2H), 3.90 (d, J=7.7 Hz, 1H), 3.61-3 .51 (m, 2H), 3.18 (s, 2H), 3.08 (d, J=4.9 Hz, 2H), 2.38 (s, 2H), 2.35 (d, J= 7.1 Hz, 2H), 2.04 (s, 3H) ppm. .0% ; MS: 498 m/z (M+H ⁺ ).

[00628] Example 809: (2S,3S)-1,2-Dimethylpyrrolidin-3-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl) -piperidin-4-yl)carbamate

[00629] Step 1. (2S,3S)-2-Methylpyrrolidin-3-ol

[00630] A mixture of benzyl (2S,3S)-3-hydroxy-2-methylpyrrolidine-1-carboxylate (300 mg, 1.28 mmol) and 10% palladium on carbon (100 mg) in methanol (20 ml) was purged with hydrogen and stirred at room temperature overnight. The resulting mixture was filtered through celite. The filtrate was concentrated in vacuo to give the title compound (130 mg, >100%) as a yellow oil. LCMS absorption in the UV range is weak; MS: 102 m/z (M+H ⁺ ).

[00631] Step 2: Tert-butyl (2S,3S)-3-hydroxy-2-methylpyrrolidine-1-carboxylate

[00632] To a solution of the product from Step 1 (110 mg, 1.09 mmol), triethylamine (221 mg, 2.18 mmol) in dichloromethane (10 mL), was added dropwise ditert-butyl pyrocarbonate (262 mg, 1.20 mmol) at 0 -10°C. After stirring overnight at room temperature, the mixture was concentrated to give the title compound (320 mg, >100%) as a yellow oil. MS: m/z 146 (M+H ⁺ ).

[00633] Step 3: Tert-butyl (2S,3S)-2-methyl-3-(((4-nitrophenoxy)carbonyl)oxy)pyrrolidine-1-carboxylate

[00634] A mixture of the product from step 2 (320 mg, 1.09 mmol), 4-nitrophenylchloroformate (285 mg, 1.42 mmol), N,N-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 give the title compound (194 mg, 42%) as a yellow oil. MS: 311 m/z (M-55).

[00635] Step 4. Tert-butyl (2S,3S)-2-methyl-3-(((1-(3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-5- yl)piperidin-4-yl)carbamoyl)oxy)pyrrolidine-1-carboxylate

[00636] Mixture of product from step 3 of example 297 (750 mg, 0.80 mmol), product from step 3 (194 mg, 0.53 mmol), N,N-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 (3×20 ml). The combined extracts were washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, concentrated and purified by reverse phase HPLC to give the title compound (35 mg, 6%) as a white solid. MS: 586 m/z (M+H ⁺ ).

[00637] Step 5. (2S,3S)-2-Methylpyrrolidin-3-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-piperidine -4-yl)carbamate

[00638] To a solution of the product from step 4 (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 adjusted to pH=9-10 with a solution of ammonia in methanol. The solution was concentrated and purified by silica gel chromatography (eluting with 1/2 v/v dichloromethane/methanol) to give the title compound (136 mg, >100%) as a yellow oil. MS: 486 m/z (M+H ⁺ ).

[00639] Step 6. (2S,3S)-1,2-Dimethylpyrrolidin-3-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl) -piperidin-4-yl)carbamate

[00640] A mixture of the product from step 5 (136 mg, 0.28 mmol), 37% aqueous formaldehyde (68 mg, 0.84 mmol) and sodium cyanoborohydride (53 mg, 0.84 mmol) in methanol (5 ml) stirred overnight at room temperature. The mixture was concentrated and purified by reverse phase HPLC to give the title compound (10 mg, 9%) as a brown solid. ¹ H NMR (400 MHz, MeOD) δ 8.69 (s, 1H), 7.36 (s, 1H), 5.14 (s, 1H), 4.33 (d, J=13.4 Hz, 2H), 3.74 (d, J=10.5 Hz, 1H), 3.26 (d, J=13.7 Hz, 2H), 3.15 (t, J=8.4 Hz, 1H) , 3.07 (s, 3H), 2.40-2.22 (m, 5H), 2.23-2.13 (m, 1H), 2.07 (d, J=9.8 Hz, 2H ), 1.76 (dd, J=20.2, 9.2 Hz, 1H), 1.59 (dd, J=20.3, 10.7 Hz, 2H), 1.14 (t, J= 14.1 Hz, 3H) ppm. MS: 500 m/z (M+H ⁺ ).

[00641] Example 816: Isopropyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate

[00642] The procedure described in Example 809 was used to obtain the title compound (82 mg, 25%) as a white solid using the product from Step 3 of Example 297 and propan-2-ol. ^1H NMR (400 MHz, CDCl3): δ 9.41 (br.s, 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, J= 4.8 Hz, 3H), 2.15 (d, J=18 Hz, 2H), 1.54 (m, 2H), 1.24 (d, J=6 Hz, 6H) ppm. MS: 445 m/z (M+H ⁺ ).

[00643] Example 822: (+/-)-cis-(1S,3S)-3-((3-(Methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl )oxy)-cyclobutyloxetan-3-ylcarbamate

[00644] Step 1. (+/-)-cis-(1s,3s)-3-(Benzyloxy)-cyclobutan-1-ol

[00645] To a solution of 3-(benzyloxy)cyclobutan-1-one (10 g, 57.0 mmol) in tetrahydrofuran (75 mL) was added L-selectride (62.5 mL, 62.5 mmol) dropwise at -78 °C and stirred at -78°C for 1 hour. The mixture was then warmed to room temperature for 1 hour. Saturated aqueous 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 ml×3). The combined extracts were dried over anhydrous Na ₂ SO 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. (+/-)-cis-5-((1s,3s)-3-(Benzyloxy)-cyclobutoxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide

[00647] To a solution of intermediate 5 (12 g, 40.8 mmol) in tetrahydrofuran (150 ml) was added the product from step 1 (11.2 g, crude) and potassium t-butoxide (12 g, 107 mmol). The mixture was stirred at 90°C for 2 hours. The reaction mixture was then washed with water (100 ml) and extracted with dichloromethane (100 ml×3). The combined extracts were dried over anhydrous Na ₂ SO ₄ , concentrated and purified by chromatography to give the title compound (5.3 g, 30%) as a white solid. MS: 347 m/z (M+H ⁺ ).

[00648] Step 3. (+/-)-cis-5-((1s,3s)-3-Hydroxycyclobutoxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3 -carboxamide

[00649] To a solution of the product from Step 2 (5.3 g, 12.2 mmol) in methanol (100 ml) was added palladium on carbon (500 mg, 10%) and acetic acid (1 ml). The reaction mixture was stirred at room temperature under H ₂ atmosphere overnight. After completion of the reaction, the palladium-carbon was filtered and the filtrate was concentrated to give the crude title compound (4.6 g) as a white solid.

[00650] Step 4. (+/-)-cis-(1s,3s)-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )cyclobutyl oxetan-3-ylcarbamate

[00651] To obtain the title compound (59 mg, 36%) as a white solid, the procedure described for the preparation of the product from Step 3 of Example 793 was used, using the product from Step 3 and oxetan-3-amine. ^1H NMR (400 MHz, CDCl ₃ ) δ 9.05 (br.s, 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: (+/-)-cis-(1S,3R)-3-((3-(Methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl )oxy)-cyclobutyl ((S)-1-(trifluoromethoxy)propan-2-yl)carbamate

[00653] To obtain the title compound (60 mg, 24%) as a white solid, the procedure described in Example 822 was used using intermediate 28. ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.08 (br. s, 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-1-methylpyrrolidin-3-yl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-piperidine -1-carboxylate

[00655] Step 1. 1-(T-Butoxycarbonyl)-4-fluoropyrrolidin-3-yl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) piperidine-1-carboxylate

[00656] To a solution of intermediate 17 (205 mg, 1.00 mmol) in dichloromethane (5 ml) was added N,N-diisopropylethylamine (387 mg, 3.00 mmol), 4-dimethylaminopyridine (122 mg, 1.00 mmol ) and 4-nitrophenylchloroformate (200 mg, 1.00 mmol). After 4 hours of reaction at room temperature, the mixture was concentrated, dissolved in N,N-dimethylformamide (3 ml) and treated with N,N-diisopropylethylamine (387 mg, 3.00 mmol) and tert-butyl 3-fluoro-4-hydroxypyrrolidine-1 -carboxylate (433 mg, 0.95 mmol). After stirring at 90°C overnight, the resulting mixture was poured into water and extracted with dichloromethane (3 x 10 ml). The combined extracts were concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (pentane/ethyl acetate v/v=1:1) to give 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-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-piperidin-1 -carboxylate

[00658] Trifluoroacetic acid (2 mL) was added to a solution of the product from Step 1 (267 mg, 0.46 mmol) in dichloromethane (5 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 give the title compound (205 mg, 92%) as a light yellow solid. MS: 491 m/z (M+H ⁺ ), purity: 92%.)

[00659] Step 3: 4-Fluoro-1-methylpyrrolidin-3-yl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-piperidine -1-carboxylate

[00660] A mixture of the product from step 2 (205 mg, 0.42 mmol), 37% aqueous formaldehyde (102 mg, 1.26 mmol), sodium cyanoborohydride (80 mg, 1.26 mmol) and methanol (5 ml) stirred at room temperature overnight. The resulting mixture was concentrated and purified by reverse phase HPLC to give the title compound (86 mg, 42%) as a white solid. ^1H NMR (400 MHz, _CDCl3 ): δ 9.05 (s, 1H), 8.78 (s, 1H), 7.15 (s, 1H), 5.22 (m, 3H ), 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, 3H), 2.11 (m, 4H) ppm. MS: 505 m/z (M+H ⁺ ).

[00661] Example 853: (S)-1-(Trifluoromethoxy)propan-2-yl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-2-azaspiro[3.3]heptane-2-carboxylate

[00662] To obtain the title compound (36 mg, 12%) as a white solid, the procedure described in step 1 of Example 835 was used using intermediate 25 and (S)-1-(trifluoromethoxy)propan-2-ol. ^1H NMR (400 MHz, CDCl3): δ 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, J=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: (R)-2-(Trifluoromethoxy)propyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-pyrrolidine-1-carboxylate

[00664] Step 1. (R)-2-(Trifluoromethoxy)propyl 1H-imidazole-1-carboxylate

[00665] A mixture of (R)-2-(trifluoromethoxy)propan-1-ol (260 mg, 1.81 mmol) and 1,1′-carbonyldiimidazole (440 mg, 2.72 mmol) was dissolved in dichloromethane (5 ml) . After 16 hours of reaction at 25°C, the reaction mixture was quenched with saturated aqueous ammonium chloride (30 ml) and extracted with dichloromethane (30 ml). The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated to give the title compound (300 mg, crude), which was used in the next step without further purification. MS: 239 m/z (M+H ⁺ ).

[00666] Step 2: Tert-butyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate

[00667] To a solution of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (477 mg, 2.6 mmol) in tetrahydrofuran (10 ml) was added potassium tert-butoxide (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 mixture was quenched by adding water (10 ml), and the mixture was diluted with a saturated aqueous solution of sodium bicarbonate (10 ml) and ethyl acetate (10 ml), and extracted with ethyl acetate (3×20 ml). The extracts were washed with saline (50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a yellow oil, which was purified by silica gel column chromatography (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)-N-Methyl-5-(pyrrolidin-3-yloxy)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide

[00669] A mixture of the product from step 2 (655 mg, 1.47 mmol) and a solution of hydrochloric acid in dioxane (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 obtain a solid, which was filtered. The solid was dissolved in dichloromethane (20 ml) and the pH was adjusted to 8 with aqueous sodium bicarbonate. The organic layer was separated, dried over Na ₂ SO 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 (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-pyrrolidine-1-carboxylate

[00671] A mixture of the product from step 3 (195 mg, 0.565 mmol), the product from step 1 (135 mg, 0.565 mmol) and N-hydroxysuccinimide (97 mg, 0.85 mmol) in acetonitrile (10 ml) was stirred at 60° C in a nitrogen atmosphere for 6 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by reverse phase HPLC to give the title compound (84 mg, yield: 24%) as a light yellow solid. ^1H NMR (400 MHz, CDCl3): δ 8.98 (d, J=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: (S)-1-Cyclopropylethyl (2R,4R)-2-methyl-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b] -pyridin-5-yl)oxy)piperidine-1-carboxylate

[00673] To obtain the title compound (43 mg, 68%) as a colorless oil, the procedure described in Example 858 was used using N,6-dimethyl-5-(((2S,4S)-2-methylpiperidin-4-yl )-hydroxy)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide (MS: 388 m/z (M+H ⁺ )), which was prepared from intermediate 15, and tert-butyl (2R, 4S)-4-hydroxy-2-methylpiperidine-1-carboxylate as intermediate 17 and (S)-1-cyclopropylethyl 1H-imidazole-1-carboxylate. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.14 (br.s, 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, J=6.0 Hz, 3H), 1.04-0.98 (m, 1H), 0.55-0.40 ( m, 3H), 0.23-0.26 (m, 1H) ppm. MS: did not detect the required mass.

[00674] UGT8 ACTIVITY

[00675] Studies to identify and quantify the UGT8 inhibition properties of compounds

[00676] Example 871: In vitro sulfatide synthesis (SFT) inhibition studies.

[00677] For medium throughput screening, library compounds were added to CellBIND 384-well plates to a final concentration of 10 μM. OE19 cells (Sigma) were grown to 70-90% confluency in RPMI 1640+L-glutamine and XX% Hyclone, trypsinized to obtain a suspension and aliquoted at 2500 cells/well for a total well volume of 50 μl. The plates were incubated for 72 hours at 37°C in an atmosphere of 5% CO ₂ , the supernatant was removed, and the plates were dried, heat sealed and stored at -20°C until analyzed.

[00678] For the determinations of IC ₅₀ values, the same procedure was followed except that the test compounds were added to the plate in triplicate in decreasing doses to obtain concentration-response curves.

[00679] Sulfatide mass spectrometry (SFT) analysis.

[00680] The assay plates were thawed and 85 μl of mobile phase B (5 mM ammonium formate + 0.2% formic acid in 50:50 methanol:acetonitrile) was added. Fifteen μL of 20 ng/mL C17 SFT in mobile phase B was added as an internal standard.

[00681] Sulfatide (SFT) was analyzed using an Applied Biosystems API-4000 triple quadrupole mass spectrometer connected to a Thermo Scientific Multiplex (LX-4) system equipped with four pumps. Chromatography of compound-treated OE19 or mouse 2B5 cell samples was performed using a Waters Acquity UPLC BEH C8 2.1 x 50 mm column with a particle size of 1.7 μm. Chromatography was carried out using the following mobile phases. Mobile phase A (MPA): 0.2% formic acid and 5 mM ammonium formate in deionized water; mobile phase B (MPB): see above. Liquid chromatography (LC) was carried out in isocratic mode on 4 columns running in series using 95% MPB and 5% MPA at a flow rate of 1 ml/min and a column temperature of 60°C.

[00682] The triple quadrupole mass spectrometer was operated in negative ionization mode, allowing monitoring of the following MRM transitions and using the following parameters:

[00683] The electrospray potential was -4500 kV and the source temperature was 550°C.

Sulfatide isoforms Q1 (m/z) Q3 (m/z) DP(V) CE(eV) C16 778.7 97.1 -200 -120 C24 890.8 97.1 -200 -120 IS 792.8 97.1 -200 -120

[00684] Mass spectrometric analysis of galactosylceramide (GalCer).

[00685] Galactosylceramide (GalCer) and glucocerebroside (GlcCer) were analyzed using an Applied Biosystem API-5000 tandem mass spectrometry (MS/MS) system connected to a Thermo Scientific Multiplex (LX-4) system equipped with four pumps. Chromatography of cells treated with compounds was performed using a Waters Cortecs HILIC 2.1 x 100 mm 2.7 μm 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] Liquid chromatography (LC) was performed in 4 columns running in series. The initial gradient is 100% MPA, decreases to 75% MPA in 2 minutes, followed by a column wash step at 75% MPA for 0.08 minutes and returns to initial conditions after 2.28 minutes. The column was equilibrated for 2.54 minutes, for a total cycle time of 4.82 minutes. The flow rate was 0.5 mL/min and the column temperature was maintained at room temperature.

[00687] Tandem mass spectrometry (MS/MS) method: positive ionization mode; options:

GalCer/GluCer isoforms Q1 (m/z) Q3 (m/z) DP(V) CE(eV) C16 700.7 264.3 120 50 C24 812.8 264.3 120 50 IS 763.9 246.3 120 54

[00688] The electrospray potential was 4500 kV and the source temperature was 500°C.

[00689] The results of determining the IC ₅₀ values for the compounds disclosed in the invention are shown below in Table 3.

Example No. Activity range Example 1 B Example 2 B Example 3 B Example 4 A Example 5 B Example 6 B Example 7 C Example 8 B Example 9 A Example 10 A Example 11 A Example 12 C Example 13 B Example 14 B Example 15 B Example 16 B Example 17 B Example 18 C Example 19 B Example 20 B Example 21 B Example 22 B Example 23 C Example 24 C Example 25 B Example 26 B Example 27 A Example 28 B Example 29 B Example 30 B Example 31 B Example 32 B Example 33 A Example 34 B Example 35 A Example 36 B Example 37 A Example 38 B Example 39 B Example 40 B Example 41 B Example 42 B Example 43 B Example 44 B Example 45 B Example 46 C Example 47 B Example 48 B Example 49 A Example 50 B Example 51 A Example 52 B Example 53 A Example 54 A Example 55 A Example 56 B Example 57 C Example 58 C Example 59 C Example 60 A Example 61 A Example 62 A Example 63 A Example 64 A Example 65 A Example 66 A Example 67 A Example 68 A Example 69 A Example 70 B Example 71 A Example 72 A Example 73 A Example 74 A Example 75 A Example 76 A Example 77 A Example 78 A Example 79 B Example 80 A Example 81 A Example 82 A Example 83 A Example 84 A Example 85 A Example 86 A Example 87 A Example 88 A Example 89 A Example 90 A Example 91 A Example 92 A Example 93 A Example 94 A Example 95 A Example 96 A Example 97 A Example 98 B Example 99 A Example 100 A Example 101 A Example 102 B Example 103 B Example 104 A Example 105 B Example 106 A Example 107 A Example 108 A Example 109 A Example 110 A Example 111 A Example 112 B Example 113 A Example 114 B Example 115 C Example 116 B Example 117 B Example 118 A Example 119 A Example 120 A Example 121 B Example 122 B Example 123 A Example 124 A Example 125 B Example 126 A Example 127 C Example 128 B Example 129 B Example 130 B Example 131 B Example 132 A Example 133 A Example 134 A Example 135 A Example 136 A Example 137 A Example 138 A Example 139 B Example 140 A Example 141 C Example 142 A Example 143 A Example 144 A Example 145 A Example 146 A Example 147 A Example 148 A Example 149 B Example 150 A Example 151 A Example 152 A Example 153 B Example 154 A Example 155 A Example 156 A Example 157 B Example 158 A Example 159 A Example 160 B Example 161 A Example 162 A Example 163 B Example 164 C Example 165 A Example 166 A Example 167 B Example 168 C Example 169 B Example 170 B Example 171 A Example 172 A Example 173 A Example 174 A Example 175 A Example 176 A Example 177 A Example 178 A Example 179 A Example 180 A Example 181 A Example 182 A Example 183 A Example 184 A Example 185 A Example 186 A Example 187 A Example 188 A Example 189 B Example 190 B Example 191 B Example 192 B Example 193 B Example 194 B Example 195 C Example 196 A Example 197 A Example 198 A Example 199 A Example 200 B Example 201 A Example 202 B Example 203 A Example 204 A Example 205 A Example 206 A Example 207 A Example 208 B Example 209 B Example 210 B Example 211 B Example 212 B Example 213 C Example 214 B Example 215 A Example 216 A Example 217 A Example 218 A Example 219 A Example 220 A Example 221 A Example 222 C Example 223 A Example 224 A Example 225 A Example 226 A Example 227 A Example 228 A Example 229 B Example 230 B Example 231 A Example 232 A Example 233 B Example 234 A Example 235 B Example 236 A Example 237 A Example 238 B Example 239 B Example 240 A Example 241 A Example 242 C Example 243 A Example 244 B Example 245 A Example 246 C Example 247 C Example 248 B Example 249 C Example 250 B Example 251 B Example 252 A Example 253 C Example 254 A Example 255 A Example 256 A Example 257 C Example 258 A Example 259 B Example 260 B Example 261 A Example 262 B Example 263 B Example 264 A Example 265 A Example 266 A Example 267 B Example 268 A Example 269 B Example 270 A Example 271 B Example 272 A Example 273 A Example 274 B Example 275 A Example 276 B Example 277 B Example 278 C Example 279 C Example 280 A Example 281 A Example 282 B Example 283 B Example 284 A Example 285 B Example 286 A Example 287 A Example 288 A Example 289 A Example 290 B Example 291 B Example 292 B Example 293 B Example 294 C Example 295 A Example 296 A Example 297 A Example 298 A Example 299 A Example 300 A Example 301 A Example 302 A Example 303 A Example 304 B Example 305 A Example 306 B Example 307 B Example 308 B Example 309 B Example 310 A Example 311 B Example 312 A Example 313 A Example 314 A Example 315 B Example 316 B Example 317 A Example 318 A Example 319 B Example 320 A Example 321 A Example 322 A Example 323 A Example 324 A Example 325 A Example 326 A Example 327 B Example 328 B Example 329 B Example 330 B Example 331 C Example 332 B Example 333 A Example 334 A Example 335 A Example 336 B Example 337 A Example 338 A Example 339 A Example 340 C Example 341 A Example 342 A Example 343 A Example 344 B Example 345 A Example 346 A Example 347 C Example 348 C Example 349 C Example 350 A Example 351 B Example 352 A Example 353 A Example 354 C Example 355 A Example 356 B Example 357 B Example 358 B Example 359 B Example 360 B Example 361 A Example 362 B Example 363 A Example 364 B Example 365 B Example 366 B Example 367 B Example 368 B Example 369 A Example 370 A Example 371 A Example 372 A Example 373 A Example 374 B Example 375 A Example 376 A Example 377 B Example 378 A Example 379 A Example 380 B Example 381 A Example 382 A Example 383 B Example 384 B Example 385 A Example 386 A Example 387 A Example 388 A Example 389 A Example 390 A Example 391 A Example 392 A Example 393 C Example 394 A Example 395 B Example 396 B Example 397 B Example 398 B Example 399 B Example 400 B Example 401 C Example 402 B Example 403 B Example 404 C Example 405 C Example 406 A Example 407 B Example 408 B Example 409 C Example 410 B Example 411 C Example 412 B Example 413 B Example 414 C Example 415 A Example 416 A Example 417 A Example 418 A Example 419 C Example 420 C Example 421 C Example 422 B Example 423 B Example 424 B Example 425 B Example 426 A Example 427 A Example 428 A Example 429 A Example 430 B Example 431 B Example 432 A Example 433 B Example 434 B Example 435 B Example 436 A Example 437 B Example 438 B Example 439 A Example 440 B Example 441 A Example 442 B Example 443 B Example 444 B Example 445 C Example 446 B Example 447 B Example 448 C Example 449 A Example 450 A Example 451 A Example 452 A Example 453 A Example 454 A Example 455 B Example 456 C Example 457 B Example 458 B Example 459 B Example 460 B Example 461 C Example 462 B Example 463 C Example 464 B Example 465 B Example 466 C Example 467 B Example 468 B Example 469 A Example 470 B Example 471 B Example 472 A Example 473 A Example 474 A Example 475 A Example 476 B Example 477 C Example 478 A Example 479 A Example 480 A Example 481 A Example 482 B Example 483 A Example 484 A Example 485 A Example 486 B Example 487 A Example 488 A Example 489 A Example 490 A Example 491 A Example 492 A Example 493 A Example 494 A Example 495 A Example 496 A Example 497 A Example 498 A Example 499 A Example 500 A Example 501 A Example 502 A Example 503 A Example 504 A Example 505 A Example 506 A Example 507 A Example 508 B Example 509 A Example 510 A Example 511 B Example 512 A Example 513 C Example 514 C Example 515 A Example 516 A Example 517 A Example 518 A Example 519 A Example 520 A Example 521 A Example 522 C Example 523 B Example 524 B Example 525 C Example 526 B Example 527 C Example 528 A Example 529 B Example 530 B Example 531 B Example 532 B Example 533 B Example 534 C Example 535 B Example 536 B Example 537 B Example 538 B Example 539 B Example 540 C Example 541 B Example 542 C Example 543 C Example 544 A Example 545 B Example 546 C Example 547 C Example 548 B Example 549 A Example 550 C Example 551 C Example 552 C Example 553 C Example 554 C Example 555 B Example 556 B Example 557 B Example 558 A Example 559 A Example 560 A Example 561 A Example 562 A Example 563 B Example 564 C Example 565 B Example 566 A Example 567 A Example 568 A Example 569 A Example 570 C Example 571 B Example 572 B Example 573 A Example 574 A Example 575 B Example 576 A Example 577 A Example 579 B Example 580 C Example 581 C Example 582 C Example 583 C Example 584 B Example 585 B Example 586 C Example 587 C Example 588 B Example 589 B Example 590 B Example 591 B Example 592 B Example 593 B Example 594 B Example 595 A Example 596 B Example 597 B Example 598 B Example 599 B Example 600 A Example 601 B Example 602 A Example 603 A Example 604 A Example 605 A Example 606 A Example 607 B Example 608 A Example 609 A Example 610 A Example 611 A Example 612 A Example 613 A Example 614 A Example 615 B Example 616 B Example 617 A Example 618 B Example 619 A Example 620 B Example 621 B Example 622 A Example 623 A Example 624 B Example 625 C Example 626 B Example 627 B Example 628 B Example 629 A Example 630 C Example 631 A Example 632 A Example 633 A Example 634 B Example 635 B Example 636 B Example 637 B Example 638 A Example 639 A Example 640 A Example 641 A Example 642 B Example 643 C Example 644 C Example 645 C Example 646 C Example 647 B Example 648 A Example 649 B Example 650 C Example 651 C Example 652 A Example 653 A Example 654 B Example 655 A Example 656 A Example 657 B Example 658 B Example 659 B Example 660 B Example 661 C Example 662 B Example 663 C Example 664 B Example 665 B Example 666 A Example 667 A Example 668 C Example 669 A Example 670 A Example 671 A Example 672 C Example 673 A Example 674 A Example 675 A Example 676 A Example 677 B Example 678 A Example 679 A Example 680 B Example 681 B Example 682 A Example 683 B Example 684 B Example 685 A Example 686 A Example 687 A Example 688 A Example 689 A Example 690 A Example 691 B Example 692 A Example 693 A Example 694 A Example 695 A Example 696 B Example 697 B Example 698 A Example 699 A Example 700 B Example 701 B Example 702 B Example 703 B Example 704 B Example 705 C Example 706 C Example 707 B Example 708 B Example 709 B Example 710 C Example 711 C Example 712 B Example 713 A Example 714 A Example 715 A Example 716 B Example 717 A Example 718 B Example 719 C Example 720 B Example 721 A Example 722 A Example 723 A Example 724 A Example 725 A Example 726 A Example 727 B Example 728 B Example 729 B Example 730 B Example 731 A Example 732 A Example 733 B Example 734 B Example 735 A Example 736 B Example 737 B Example 738 B Example 739 A Example 740 A Example 741 A Example 742 B Example 743 A Example 744 B Example 745 B Example 746 A Example 747 A Example 748 B Example 749 B Example 750 C Example 751 C Example 752 C Example 754 B Example 755 B Example 756 B Example 757 B Example 758 B Example 759 C Example 760 B Example 761 B Example 762 C Example 763 B Example 764 B Example 765 A Example 766 A Example 767 A Example 768 A Example 769 A Example 770 B Example 771 A Example 772 A Example 773 A Example 774 A Example 775 A Example 776 C Example 777 A Example 778 A Example 779 A Example 780 A Example 781 A Example 782 A Example 783 A Example 784 A Example 785 A Example 786 A Example 787 A Example 788 C Example 789 C Example 790 A Example 791 A Example 792 A Example 793 B Example 794 A Example 795 A Example 796 A Example 797 A Example 798 B Example 799 B Example 800 A Example 801 A Example 802 A Example 803 B Example 804 A Example 805 A Example 806 A Example 807 A Example 808 A Example 809 C Example 810 A Example 811 C Example 812 A Example 813 B Example 814 A Example 815 B Example 816 A Example 817 A Example 818 B Example 819 A Example 820 A Example 821 A Example 822 B Example 823 C Example 824 A Example 825 A Example 826 A Example 827 A Example 828 A Example 829 A Example 830 B Example 831 B Example 832 C Example 833 A Example 834 C Example 835 B Example 836 B Example 837 A Example 838 A Example 839 A Example 840 A Example 841 A Example 842 A Example 843 A Example 844 A Example 845 A Example 846 C Example 847 C Example 848 B Example 849 A Example 850 A Example 851 A Example 852 A Example 853 A Example 854 A Example 855 A Example 856 A Example 857 A Example 858 A Example 859 A Example 860 A Example 861 A Example 862 A Example 863 A Example 864 A Example 865 A Example 866 A Example 867 A Example 868 A Example 869 B Example 870 A

Activity of compounds, in-vitro SFT

Activity range: A<0.1 µM; 0.1 µM<B<1 µM; 1 µM<C

[00690] Example 872 Single Dose In Vivo Models: Targeting the Mouse Kidney

[00691] Targeting was initially assessed in an adult mouse kidney model to determine tumor inhibition. This model was chosen because the high rate of synthesis and turnover of GalCer and SFT in the kidney facilitated the development of a 1-day, single-dose model to evaluate the effect of single administration of the compound at different doses. Neoplasm inhibition was determined by measuring the amount of 13C6 galactose (13C-Gal; CIL, cat. no. CLM-1570-pk) introduced into GalCer and SFT.

[00692] Groups of 5 male C57Bl/6 mice, 6-9 weeks of age (Charles River Laboratories), were housed in an ALAAC-accredited animal facility with unlimited access to food and water, and provided them with the opportunity to acclimatize for one week before the start of the study. Three to five dosing groups received the test drug as a clinically acceptable formulation administered by gastric tube, with a control group receiving placebo only. An hour after administration of the test drug, the animals were injected intraperitoneally (intraperitoneally) with 13C-Gal (3 g/kg), 5 hours after administration of the test drug, the animals were sacrificed, the kidney was removed and divided into two longitudinal samples, which were flash frozen and stored at - 80°C until tissue exposure testing and lipid analysis (GalCer and SFT) were performed. Typically, brain and plasma samples were also collected to evaluate the effects of the test drug. The results obtained for the effects of individual compounds on kidney tissue and lipid analysis are presented in Table 4 below.

[00693] Example 873: Single Dose In Vivo Models: Targeting in Mice Brain

[00694] Since metachromatic leukodystrophy (MLD) is primarily a disease of the central nervous system (CNS), it was important to demonstrate a targeted effect on the brain. The biosynthesis and turnover of SFT in adult mouse myelin is very low, necessitating the development of a short-term, single-dose model for inhibiting tumor initiation. This took advantage of the fact that, unlike primates, in which the majority of myelination development occurs in utero, in rodents peak myelination occurs between postnatal day 14 (P14) and postnatal day 22 (P22).

[00695] Groups consisting of 5 newborn mice aged P14 to P21 received the test compound formulated as a clinically acceptable drug administered by gavage; a control group received placebo only. One hour after the administration of the test compound, the animals were administered intraperitoneally with 13C-Gal (3 g/kg), 5 hours after the administration of the test compound, the animals were sacrificed, the brain was removed and dissected to extract the mid and posterior parts of the brain, which were flash frozen and stored at -80°C until analyzed. Plasma samples were also collected to analyze the effects of the test compound. The resulting brain effects and lipid analysis data for individual compounds are presented in Table 4 below.

[00696] SFT Mass Spectrometry Analysis

[00697] Quantitative analysis of sphingolipids (SL) was performed using liquid chromatography with tandem mass spectrometry analysis (LC-MS/MS). Briefly, for the extraction of glucosylceramide (GlcCer), galactosylceramide (GalCer) and sulfatide (ST), a 10 μl aliquot of mouse tissue homogenate (100 mg/ml in water) was mixed with 1 ml of extraction solution (0.2% formic acid, 5 mM ammonium formate (50:50) methanol:acetonitrile (v/v) with internal standards (IS)). C17-ST and D35-labeled C18-GalCer were used as internal standards (IS). The mixtures were shaken 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 system with an Atlantis HILIC silica gel column (2.1 mm x 150 mm, 3 µm particles, Waters Corp., Milford, MA) and analyzed on an API 5000 Triple Quadrupole Mass Spectrometer in MRM mode (Applied Biosystems, Foster City, CA). ST was analyzed using a Waters Acquity UPLC system with a BEH C18 column (2.1 mm x 50 mm, 1.7 µm particles, Waters Corp., Milford, MA) and analyzed on an API 6500 Triple Quadrupole Mass Spectrometer in MRM mode (Applied Biosystems, Foster City, CA).

[00698] Compound Analysis Method for Metachromatic Leukodystrophy (MLD)

[00699] Plasma and tissue concentrations of test compounds in the MLD study were determined by liquid chromatography tandem mass spectrometry (LC MS/MS). Briefly, tissue samples were first homogenized with a 1:4 solution of 20% acetonitrile in water (1.00 g tissue with 4.00 mL solution). Plasma and tissue homogenate samples were then processed using protein precipitation with an internal standard solution (RP-107 in acetonitrile). Chromatographic separation was carried out on a Phenomenex Kinetex C8 column. Multiple mass transitions were continuously detected by tandem mass spectrometry (MS/MS). Calibration standards and quality control samples were prepared from plasma or tissue homogenate blanks. Calibration curves were generated using weighted linear regression analysis (1/x2) of peak area ratio (analyte to IS) as a function of analyte concentration. The corresponding calibration curve for each analyte was used to calculate the analyte concentration in plasma or tissue samples.

Table 4 Example No. PD dose (mg/kg) kidney % GalCer inhibition
in the kidney % inhibition of sulfatide
in the kidney 496 10, 30, 100 A, A, A A, A, A 375 1, 3, 10, 30, 100 C, C, B, A, A C, C, B, A, A 90 0.3, 1, 3, 10, 30 C, C, A, A, A C, B, A, A, A 693 1, 3, 10 C, C, B C, C, A 76 1, 3, 10 C, B, B C, B, B 109 5, 10, 50 C, B, A 473 3, 10, 50 C, C, B C, B, A 475 3, 10, 50 C, B, B Example No. PD dose (mg/kg) brain % GalCer inhibition
in the brain % inhibition sulfatide
in the brain 375 1, 3, 10 B, B, A B, B, A 90 3, 10, 30 A, A, A A, A, A 76 3, 10, 30 B, A, A B, A, A 109 10, 30, 100 B, B, B A, A, A 473 10, 30, 100 A, A, A A, A, A

Compound activity, in-vivo inhibition of GalCer and sulfatide

Activity range: A>80%; 40%<B<80%; C<40%

[00700] DOSING

[00701] Dosage regimens of the compounds described herein for monotherapy and combination therapy are generally determined by an appropriately qualified physician, and dosage regimens are expected to vary significantly depending on the clinical status of the individual subject suffering from the disease. One skilled in the art is well aware of the general principles for determining a dosage regimen for the treatment of cystic fibrosis and/or modulation of the cystic fibrosis transmembrane regulator (CFTR). Recommendations for dosage regimens can be found in any of the many well-known publications on this topic. Additional advice is given, among others, in a review of specific publications cited in the description of the present invention. In specific embodiments, such dosages may range from about 0.5 mg/kg to about 300 mg/kg, such as 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), administered intraperitoneally, orally, or equivalent one to five times a day. Such doses may range from about 5 mg/kg to about 5 g/kg, preferably from about 10 mg/kg to about 1 g/kg, administered orally, intraperitoneally, or equivalent, one to five times daily. In one embodiment, dosages range from 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, 180 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).

[00702] The oral dose range ranges from about 50 mg to about 100 mg, where the dose is administered, for example, once daily. A specific oral dosage range for a compound of the invention is from about 5 mg/kg/day to about 600 mg/kg/day. Specifically, the oral dosage range for a compound of the invention 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, 110 mg/kg/day, 115 mg/kg/day or 120 mg/kg/day.

[00703] The entire contents of all patents, published applications, and publications cited herein are incorporated herein by reference.

[00704] Although the embodiments of the invention have been specifically demonstrated and described by way of examples of their embodiments, it will be apparent to those skilled in the art that various changes in form and form may be made to these embodiments. in detail, without going beyond the scope of the invention as defined by the appended claims.

Claims (958)

1. Compound of formula (I) (I) or a pharmaceutically acceptable salt thereof, where: (a) X ² represents CR ² or N; (b) X ⁵ represents CR ⁷ or N; (c) X ⁶ represents CR ¹ or N; (d) Y is -C(O)NR ^a R ^b or -C(O)OC _1-4 alkyl; (e) each R ^a is independently H, C _1-4 alkyl, C _1-4 haloalkyl, -C _1-4 alkyl-C _3-9 cycloalkyl or C _3-9 cycloalkyl; (f) each R ^b is independently C _1-4 alkyl, C _1-4 alkoxy, C _3-9 cycloalkyl or -C _1-4 alkyl-C _1-4 alkoxy; or, when Y is -C(O)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, which is a free non-aromatic radical having from 3 to 10 rings atoms, wherein 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen substituted with 0-3 R ^x substituents; (g) R ⁷ is hydrogen, C _1-4 alkyl, C _1-4 alkoxy, -S(O) ₂ -NR ^a R ^b - or heteroaryl having from 5 to 10 ring atoms, where from 2 to 9 ring atoms the atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen; (h) R ¹ is hydrogen, halogen, -OH, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, -NH _2, -NH(C _1-4 alkyl ) or -N(C _1-4 alkyl) ₂ , C _3-9 cycloalkyl or azetidinyl, wherein each -NH(C _1-4 alkyl) or cycloalkyl is substituted with 0-5 R ^x substituents and where each azetidinyl is substituted with 0-5 substituents R ^x ; (i) R ² is hydrogen, halogen, -OH, C _1-4 alkyl, C _1-4 alkoxy or C _3-9 cycloalkyl; (j) A ¹ represents a chemical bond, C _1-4 alkylene, -O-, -OC _1-4 alkylene, -C _2-4 alkenylene, -C _2-4 alkynylene, -NR ^a , -NR ^a -C _1-4 alkylene-, -S-, -S(O)-, -S(O) ₂ -, -C(O)-, -C(O)-O- or -OC(O)-; (k) L is a heteroaryl having from 5 to 10 ring atoms, wherein from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen, C _{3- 12} cycloalkyl, heterocycloalkyl, which denotes a free non-aromatic radical having from 3 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen, or 1,2,3,6-tetrahydropyridinyl, each of which may be substituted with 0-5 R ^x ; (l) A ² represents a chemical bond, -O-, -NR ^a -, -C _1-4 -alkyl-NR ^a -, -C(O)-, -C _1-4 alkyl-C(O)- , -OC(O)-, -C _1-4 alkyl-OC(O)-, -C(O)-O-, -C _1-4 alkyl-C(O)-O-, -OC(O) -O-, -S(O) ₂ -, -NR ^a -S(O)-, -C _1-4 -alkyl-NR ^a -S(O)-, -NR ^a -S(O) ₂ -, -C _1-4 -alkyl-NR ^a -S(O) ₂ -, -C(O)-NR ^a -, -C _1-4 alkyl-C(O)-NR ^a -, -NR ^a -C( O)-, -C _1-4 -alkyl-NR ^a -C(O)-, -OC(O)-NR ^a -, -C _1-4 -alkyl-OC(O)-NR ^a -, -NR ^a -C(O)-O-, -NR ^a -C(O)-NR ^a -, -NR ^a -CH ₂ -C(O)-NR ^a -, -O-CH ₂ -C(O)- NR ^a -, -C(O)-O-CH ₂ -C(O)- or -C(O)-NR ^a -CH ₂ -C(O)-; (m) R ⁴ represents -OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-9 cycloalkyl, heterocycloalkyl, which denotes a free non-aromatic radical having from 3 to 10 ring atoms, wherein 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen, naphthyl or heteroaryl, wherein said heteroaryl is selected from the group consisting of imidazolyl, pyrimidinyl, pyridinyl, pyrazinyl, oxadiazolyl, thiadiazolyl and thiazolyl, wherein each alkyl, cycloalkyl, heterocycloalkyl, phenyl, naphthyl or heteroaryl R ⁴ is substituted with 0-5 R ⁵ substituents; (n) R ⁵ is OH, halogen, CO ₂ H, C _1-4 alkyl, C _2-6 alkynyl, C _1-4 alkoxy, C _1-4 haloalkyl, -OC _1-4 haloalkyl, -C _{1- 4} alkyl-OC _1-4 alkyl, -SC _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -S(O)-C _1-4 alkyl, -N(R ^a ) ₂ , - CH ₂ N(R ^a ) ₂ , -N(R ^a )-S(O)-C _1-4 alkyl, -N(R ^a )-S(O) ₂ -C _1-4 alkyl, -NO ₂ , -CN, -CH ₂ CN, C _3-9 cycloalkyl, -OC _3-9 cycloalkyl, -C _1-4 alkyl-C _3-9 cycloalkyl, -OC _1-4 alkyl-C _3-9 cycloalkyl, -C _{1 -4} alkyl-OC _1-4 haloalkyl, heterocycloalkyl, which denotes a free non-aromatic radical having from 3 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of from nitrogen, sulfur and oxygen, -C _1-4 alkyl-heterocycloalkyl, phenyl, naphthyl, -O-phenyl, -O-naphthyl, heteroaryl, where heteroaryl denotes a heteroaromatic ring having from 5 to 10 ring atoms, where from 2 to The 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen, -O-heteroaryl, C _1-4 -alkyl-heteroaryl, aralkyl or -O-aralkyl, wherein each alkyl, phenyl, naphthyl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 substituents R ^w ; (o) each R ^w is independently halogen, -OH, C _1-4 alkyl, C _1-4 haloalkyl or -C _1-4 alkoxy; And (p) every R^x represents independently halogen, -OH, C_1-4 alkyl, -C_1-4 alkoxy, -C_1-4 alkyl-O-C_1-4 alkyl, -C(O)-N(R^a)₂, -O-C(O)-N(R^a)₂, -N(R^a)₂, -CH₂N(R^a)₂, heterocycloalkyl, which denotes a free non-aromatic radical having from 3 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen, -O- heterocycloalkyl, -O-phenyl, -O-naphthyl or -O-heteroaryl, where heteroaryl denotes a heteroaromatic ring having from 5 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atom(s) selected from the group consisting of nitrogen, sulfur and oxygen. 2. A compound according to claim 1, where R ² represents hydrogen, C _1-4 alkyl or halogen. 3. A compound according to claim 1 or 2, where R ⁷ represents C _1-4 alkyl or hydrogen. 4. Connection according to any one of paragraphs. 1-3, where the compound is a compound of formula II, IIa, IIb or IIc: (II); (IIa); (IIb); or (IIc). 5. Connection according to any one of paragraphs. 1-4, where R ¹ represents hydrogen, -OH, halogen, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, -NH(C _1-4 alkyl), -N(C _{1- 4} alkyl) _2, C _3-9 cycloalkyl or azetidinyl. 6. Connection according to any one of paragraphs. 1-5, where the compound is a compound of formula III, IIIa, IIIb or IIIc: (III); (IIIa); (IIIb); or (IIIc). 7. Connection according to any one of paragraphs. 1-6, where A ¹ represents -O-, C _1-4 alkylene, a chemical bond, -OC(O)-, -C(O)-, -NR ^a - or -NR ^a -C _1-4 alkylene . 8. Connection according to any one of paragraphs. 1-7, where L is one of the following: each of which is substituted with 0-5 R ^x substituents. 9. Connection according to any one of paragraphs. 1-7, where L is one of the following: 10. Connection according to any one of paragraphs. 1-7, where L is one of the following: 11. Connection according to any one of paragraphs. 1-7, where L is one of the following: 12. Connection according to any one of paragraphs. 1-7, where L is one of the following: , , , , , , , , , , , , , or . 13. Connection according to any one of paragraphs. 1-12, where A ² represents a chemical bond, -C(O)-O-, -OC(O)-NR ^a -, -OC(O)-, -O-, -C(O)-, - NR ^a -C(O)-O-, -NR ^a -C(O)-NR ^a -, -C(O)-NR ^a -, -C _1-4 alkyl-C(O)-NR ^a -, -C _1-4 alkyl-OC(O)-NR ^a -, -OC(O)-O-, -NR ^a -C(O)-, -NR ^a -, -S(O) ₂ -, -C _1-4 alkyl-C(O)-, -C _1-4 alkyl-NR ^a -, -C _1-4 alkyl-NR ^a -S(O)- or -C _1-4 alkyl-C(O)- O-. 14. The compound according to claim 13, where A ² represents a chemical bond, -C(O)-O-, -OC(O)-NR ^a -, -OC(O)-, -O-, -NR ^a - C(O)-O-, -C _1-4 alkyl-C(O)-NR ^a -, -C _1-4 alkyl-OC(O)-NR ^a - or -NR ^a -. 15. Connection according to any one of paragraphs. 1-14, where R ⁴ represents hydrogen, -OH, C _1-6 alkyl, substituted with 0-5 R ⁵ substituents, heterocycloalkyl, which denotes a free non-aromatic radical having from 3 to 10 ring atoms, where from 2 to The 9 ring atoms are carbon atoms and the remaining ring atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen, C _3-9 cycloalkyl or heteroaryl, wherein said heteroaryl is selected from the group consisting of imidazolyl, pyrimidinyl, pyridinyl, pyrazinyl, oxadiazolyl, thiadiazolyl and thiazolyl. 16. Connection according to any one of paragraphs. 1-15, where R ⁵ represents halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, -OC _1-4 haloalkyl, cyano, C _3-9 cycloalkyl, C _1-4 alkyl- C _3-9 cycloalkyl, -OC _1-4 alkyl-C _3-9 cycloalkyl or heterocycloalkyl, which denotes a free non-aromatic radical having from 3 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atom the atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen, wherein each cycloalkyl or heterocycloalkyl is substituted with 0-3 R ^w substituents. 17. Connection according to claim 1, where: (a) X ² represents CR ² or N; (b) X ⁵ represents CR ⁷ ; (c) X ⁶ represents CR ¹ ; (d) is -C(O)NR ^a R ^b or -C(O)ORa; (e) each R ^a is independently H or C _1-4 alkyl; (f) each R ^b is independently C _1-4 alkyl; or, when Y is –C(O)NR ^a R ^b , R ^a and R ^b can be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring; (g) R ⁷ represents hydrogen, C _1-4 alkyl or C _1-4 alkoxy; (h) R ¹ is hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl or C _3-6 cycloalkyl; (i) R ² represents hydrogen, halogen or C _1-4 alkyl; (j) A ¹ represents a bond, C _1-4 alkylene, -O- or -OC _1-4 alkylene; (k) L represents C _3-6 cycloalkyl or 4-9 membered heterocycloalkyl, which denotes a free non-aromatic radical having from 4 to 9 ring atoms, where from 3 to 7 ring atoms are carbon atoms and the remaining ring atoms (atom ) selected from the group consisting of nitrogen and oxygen, each of which may be substituted with 0-3 substituents R ^x ; (l) A ² represents a bond, -O-, -NR ^a -, -C(O)-, -OC(O)-, -C(O)-O-, -C(O)-NR ^a - , -C _1-4 alkyl-C(O)-NR ^a -, -OC(O)-NR ^a - or -NR ^a -C(O)-O)-; (m) R ⁴ represents C _1-6 alkyl, C _3-6 cycloalkyl, heterocycloalkyl, which denotes a free non-aromatic radical having from 4 to 7 ring atoms, where from 3 to 5 ring atoms are carbon atoms and the remaining ring atoms the atoms or atom is selected from the group consisting of nitrogen and oxygen, or heteroaryl, wherein said heteroaryl is selected from the group consisting of imidazolyl, pyrimidinyl, pyridinyl, pyrazinyl, oxadiazolyl, thiadiazolyl and thiazolyl, wherein each alkyl, cycloalkyl, heterocycloalkyl or heteroaryl R ⁴ substituted with 0-5 R ⁵ substituents; (n) R ⁵ is halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, -OC _1-4 haloalkyl, -N(R ^a ) ₂ , -CN, -CH ₂ CN, C _3-6 cycloalkyl, -OC _1-4 alkyl-C _3-6 cycloalkyl, morpholinyl, pyrrolidinyl or thiazolyl, wherein said morpholinyl, pyrrolidinyl or thiazolyl is substituted with 0-3 Rw substituents; (o) each R ^w is independently halogen or C _1-4 alkyl; And (p) each R ^x is independently halogen or C _1-4 alkyl. 18. A compound according to claim 1, selected from the group consisting of the following compounds: N-Methyl-5-(4-((5-methylpyridin-2-yl)methyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 5-(4-Benzylpiperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno-[3,2-b]pyridin-3-carboxamide; N-Methyl-5-(4-((2-methylpyrimidin-4-yl)methyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 5-(4-((6-Ethylpyridin-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 5-(4-((6-(Methoxymethyl)pyridin-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; N-Methyl-5-(4-((4-methylpyridin-2-yl)methyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; N-Methyl-5-(4-((3-methylpyridin-2-yl)methyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 5-(4-((6-Methoxypyridin-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; N-Methyl-5-(4-((6-methylpyridin-2-yl)methyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; Methyl 5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate; 5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-1-yl)-N,N-dimethyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; Methyl 5-(4-(2-(benzylamino)-2-oxoethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate; Methyl 5-(4-(2-(cyclohexylamino)-2-oxoethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate; Methyl 5-(4-(2-oxo-2-(piperidin-1-yl)ethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxylate; Methyl 5-(4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxylate; Methyl 5-(4-(2-(methylamino)-2-oxoethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate; Methyl 5-(4-(4-methylpentanoyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate; Methyl 5-(4-(4-methylpentyl)piperazin-1-yl)-7-(trifluoromethyl)-thieno[3,2-b]pyridine-3-carboxylate; Isobutyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperazine-1-carboxylate; N-Methyl-5-(4-(pyridin-2-ylmethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; N-Methyl-5-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-7-(tri-fluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; N-Methyl-5-(4-(pyridin-4-ylmethyl)piperazin-1-yl)-7-(tri-fluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 5-(4-(2-(Ethylamino)-2-oxoethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(2-(Cyclopropylamino)-2-oxoethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(2-(Isobutylamino)-2-oxoethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; (+/-)-5-(4-(1-(Isopropylamino)-1-oxobutan-2-yl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide; 5-(4-(1-(Isopropylamino)-2-methyl-1-oxopropan-2-yl)-piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide; Tertbutyl 2-(4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperazin-1-yl)acetate; (+/-)-Tertbutyl 2-(4-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperazin-1-yl)propanoate; (+/-)-Isopropyl 2-(4-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperazin-1-yl)propanoate; (+/-)-5-(4-(1-(Isopropylamino)-1-oxopropan-2-yl)-piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b ]pyridine-3-carboxamide; Isopropyl 2-(4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperazin-1-yl)acetate; 5-(4-(2-(tertbutylamino)-2-oxoethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; (S)-5-(4-(1-(Isopropylamino)-1-oxopropan-2-yl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin- 3-carboxamide; (R)-5-(4-(1-(Isopropylamino)-1-oxopropan-2-yl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin- 3-carboxamide; N-Methyl-5-(4-((6-methylpyrazin-2-yl)methyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; (+/-)-5-(4-(2-(Cyclopropylmethoxy)propyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; (+/-)-5-(4-(1-(Cyclopropylmethoxy)propan-2-yl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3 -carboxamide; 5-(4-(2-(Cyclopropylmethoxy)ethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(2-Cyclopropoxyethyl)piperazin-1-yl)-N-methyl-7-(tri-fluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(2-Isopropoxyethyl)piperazin-1-yl)-N-methyl-7-(tri-fluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(2-Isopropoxyacetyl)piperazin-1-yl)-N-methyl-7-(tri-fluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(2-(Isopropyl(methyl)amino)-2-oxoethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(1-Isopropyl-2-oxopyrrolidin-3-yl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-1-yl)-N,6-dimethyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-1-yl)-N,7-dimethylthieno[3,2-b]pyridine-3-carboxamide; 5-(4-(2-(Isopropylamino)-2-oxoethyl)-3,3-dimethylpiperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide ; (+/-)-5-(3-Isopropyl-4-(2-(isopropylamino)-2-oxoethyl)-piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b ]pyridine-3-carboxamide; (+/-)-5-(3-Ethyl-4-(2-(isopropylamino)-2-oxoethyl)-piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b ]pyridine-3-carboxamide; (+/-)-5-(4-(2-(Isopropylamino)-2-oxoethyl)-2-methyl-piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b ]pyridine-3-carboxamide; 5-(8-(2-(Isopropylamino)-2-oxoethyl)-3,8-diazabicyclo-[3,2,1]octan-3-yl)-N-methyl-7-(trifluoromethyl)thieno[3, 2-b]pyridine-3-carboxamide; 5-(4-(2-(Isopropylamino)-2-oxoethyl)-4,7-diazaspiro[2,5]-octan-7-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2- b]pyridine-3-carboxamide; (+/-)-5-(4-(2-(Isopropylamino)-2-oxoethyl)-3-methyl-piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b ]pyridine-3-carboxamide; 5-(4-(2-(Isopropylamino)-2-oxoethyl)-1,4-diazepan-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide ; N-Isopropyl-2-(4-(3-isopropyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperazin-1-yl)acetamide; 2-(4-(3-(Hydroxymethyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperazin-1-yl)-N-isopropylacetamide; 5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylic acid; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl azetidin-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-pentan-2-ylcarbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(3-methylbutan-2-yl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-secbutylcarbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl cyclobutylcarbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-(trifluoromethoxy)ethyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 5-azaspiro[2,3]hexane-5-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 1,1-difluoro-5-azaspiro[2,3]hexane-5 -carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(methoxymethyl)azetidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(dimethylamino)-3-methylazetidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-((dimethylamino)methyl)azetidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(oxetan-3-yl)azetidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-hydroxy-3-(trifluoromethyl)azetidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (1R,6S)-5-methyl-2,5-diazabicyclo[4.1 .0]-heptane-2-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (1S,6R)-5-methyl-2,5-diazabicyclo[4.1 .0]-heptane-2-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-cyclopropyl azetidin-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclobutylmethyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-but-3-yn-2-ylcarbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (3S,5S)-3,5-dimethylmorpholine-4-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-2-methylpiperidin-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-2-methylpyrrolidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-cyanoethyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 5,6,7,8-tetrahydro-[1,2,4] triazolo[1,5-a]-pyrazine-7-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 6-oxa-1-azaspiro[3.3]heptane-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropyl(methyl)carbamate; (1α,5α,6α)-3-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)-3-azabicyclo[3.1.0]hexane-6- yl (cyclopropylmethyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(difluoromethoxy)azetidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(trifluoromethoxy)azetidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-((trifluoromethoxy)methyl)azetidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-(trifluoromethoxy)propan-2-yl)carbamate ; 3,3-Difluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate; 3,3-Difluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl 4-cyclopropylpiperazine-1-carboxylate; 3,3-Difluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S)-2,4-dimethylpiperazin-1 -carboxylate; 3,3-Dimethyl-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl 4-methylpiperazin-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H )-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 5,6-dihydroimidazo[1,5-a]pyrazin-7(8H )-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 5,6-dihydroimidazo[1,2-a]pyrazin-7(8H )-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]- pyrrole-2(1H)-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(dimethylamino)azetidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-(thiazol-2-yl)ethyl)carbamate ; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-2-ethyl-4-methylpiperazine-1-carboxylate; (+/-)-trans-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl 4-methoxy-1-methylpyrrolidin- 3-yl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-2,4-dimethylpiperazine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-2,4-dimethylpiperazine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-(pyrrolidin-1-yl)ethyl)carbamate; (+/-)-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl (2-(3-fluoropyrrolidin-1- yl)ethyl)-carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-(3,3-difluoropyrrolidin-1-yl)ethyl)carbamate ; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-(1-cyclopropylethyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-cyclopropylethyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl pyrrolidin-1-ylcarbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)(methyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 4-(cyclopropylmethyl)piperazine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-isopropoxyethyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 4-methylpiperazin-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((4-methylmorpholin-2-yl)methyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-3,4-dimethylpiperazine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-3,4-dimethylpiperazine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-2-(hydroxymethyl)-4-methylpiperazine-1-carboxylate ; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((2S,3R)-3-hydroxybutan-2-yl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-3-methylmorpholine-4-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl cis-3-hydroxycyclobutyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl trans-3-hydroxycyclobutyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-cyanopropan-2-yl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-hydroxypropan-2-yl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-hydroxyazetidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-methoxypropan-2-yl)carbamate; (+/-)-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl trans-4-hydroxy-1-methylpyrrolidin-3 -yl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-hydroxy-2-methylpropyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-2-methylpiperazine-1-carboxylate; 4-((Dimethylamino)methyl)-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-2- methyl pyrrolidine-1-carboxylate; 4-((Dimethylamino)methyl)-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate; 4-(Methoxymethyl)-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate; 1-(3-(Dimethylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl (S)-(1-cyanopropan-2-yl)carbamate; 1-(3-(Azetidin-1-carbonyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl (S)-(1-cyanopropan-2-yl )carbamate; (+/-)-trans-3-(Dimethylamino)-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclo- propyl methyl)carbamate; (+/-)-cis-3-Methyl-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 4-methylpiperazin- 1-carboxylate; 1-(3-(Methoxycarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate; (+/-)-trans-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl 4-fluoro-1-methylpyrrolidin- 3-yl)carbamate; (+/-)-cis-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 4-fluoro-1-methylpyrrolidin-3 -yl)-carbamate; 5-(3-Isopropyl-2-oxo-1-oxa-3,8-diazaspiro[4,5]decan-8-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide; 5-(2-Isopropyl-2,8-diazaspiro[4,5]decan-8-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 1-(3-(Methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-(trifluoromethoxy)propan-2-yl)carbamate; 1-(7-Methyl-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)-piperidin-4-yl isopropylcarbamate; 1-(7-Methyl-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)-piperidin-4-yl (S)-(1-(trifluoromethoxy)propan-2-yl)carbamate; N-Methyl-5-(4-((6-methylpyridin-2-yl)oxy)piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 5-(4-((6-Ethylpyridin-2-yl)oxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; N-Methyl-5-(4-((2-methylpyrimidin-4-yl)oxy)piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; (+/-)-N-Methyl-5-(cis-3-methyl-4-((2-methylpyrimidin-4-yl)-oxy)piperidin-1-yl)-7-(trifluoromethyl)thieno[3, 2-b]pyridine-3-carboxamide; (+/-)-N-Methyl-5-(trans-3-methyl-4-((2-methylpyrimidin-4-yl)-oxy)piperidin-1-yl)-7-(trifluoromethyl)thieno[3, 2-b]pyridine-3-carboxamide; 5-(4-((3-Cyclopropyl-1,2,4-thiadiazol-5-yl)oxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide; 1-(6-Methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl (S)-(1-cyclopropylethyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-cyanopropan-2-yl)(methyl)carbamate ; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((1-(2,2-difluoroethyl)azetidin-3-yl) methyl)-carbamate; Methyl 5-(4-(2-(isopropylamino)-2-oxoethyl)piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate; 5-(4-(2-(Isopropylamino)-2-oxoethyl)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(2-((1-Methoxypropan-2-yl)amino)-2-oxoethyl)-piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide; 5-(4-(2-((1,3-Dimethoxypropan-2-yl)amino)-2-oxoethyl)-piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2- b]pyridine-3-carboxamide; (S)-1-Methoxypropan-2-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbonate; Isopropyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbonate; (R)-1-Cyclopropylethyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; (S)-1-Cyclopropylethyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; Isopropyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; Tertbutyl 3,3-difluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; N-Methyl-5-((1-(6-methylpyridin-2-yl)piperidin-4-yl)oxy)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 2-Cyanoethyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; 2-Isopropoxyethyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; 2-(Tretbutoxy)ethyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; (3-Fluoroazetidin-3-yl)methyl 4-((3-(methylcarbamoyl)-7-(tri-fluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; 1-(Prop-2-in-1-yl)azetidin-3-yl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine -1-carboxylate; 1-(Cyanomethyl)azetidin-3-yl 4-((3-(methylcarbamoyl)-7-(tri-fluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl 4-((6-chloro-3-(methylcarbamoyl)thieno-[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl 4-((6-bromo-3-(methylcarbamoyl)thieno-[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl 4-((6-cyclopropyl-3-(methyl-carbamoyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; (S)-1-(Trifluoromethoxy)propan-2-yl (2R,4R)-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-5 -yl)oxy)-piperidine-1-carboxylate; (S)-1-(Trifluoromethoxy)propan-2-yl (2R,4R)-2-methyl-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b ]pyridin-5-yl)oxy)piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (2R,4R)-2-methyl-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate; (S)-1-(Trifluoromethoxy)propan-2-yl 4-((6-methyl-3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (2R,4S)-2-methyl-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (3S,4R)-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate; (S)-1-(Trifluoromethoxy)propan-2-yl (3S,4R)-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b ]pyridin-5-yl)oxy)piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (3R,4S)-3-fluoro-4-((6-methyl-3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl )-hydroxy)-piperidine-1-carboxylate; (S)-1-(Trifluoromethoxy)propan-2-yl (3R,4S)-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b ]pyridin-5-yl)oxy)piperidine-1-carboxylate; (S)-1-(Trifluoromethoxy)propan-2-yl (2R,4S)-2-methyl-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b ]pyridin-5-yl)oxy)piperidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)isothiazolo[4,5-b]-pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate; 1-(7-(Methylcarbamoyl)-4-(trifluoromethyl)thieno[3,2-d]-pyrimidin-2-yl)piperidin-4-yl (S)-(1-methoxypropan-2-yl)-carbamate; 1-(7-(Methylcarbamoyl)-4-(trifluoromethyl)thieno[3,2-d]-pyrimidin-2-yl)piperidin-4-yl (S)-(1-cyclopropylethyl)carbamate; 1-(7-(Methylcarbamoyl)-4-(trifluoromethyl)thieno[3,2-d]-pyrimidin-2-yl)piperidin-4-yl (S)-2,4-dimethylpiperazine-1-carboxylate; 1-(3-Propionyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-piperidin-4-yl 4-methylpiperazin-1-carboxylate dihydrochloride; 5-(3-((5-Fluoropyridin-3-yl)oxy)azetidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; N-Methyl-5-(3-((3-methylpyridin-2-yl)oxy)azetidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 5-(3-((3-Fluoropyridin-2-yl)oxy)azetidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2b]pyridin-3-carboxamide; N-Methyl-5-(3-((2-methylpyridin-3-yl)oxy)azetidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; Isopentyl 3-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)azetidine-1-carboxylate; Cyclopropylmethyl 3-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)azetidin-1-carboxylate; Isopropyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate; 1-Fluoropropan-2-yl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2- carboxylate; 1-Methoxy-2-methylpropan-2-yl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]- heptane-2-carboxylate; 2,2-Difluoroethyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate; Oxetan-3-ylmethyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate; Cyclopropyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate; Oxetan-3-yl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate; 2-(Trifluoromethoxy)ethyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2- carboxylate; (R)-1-Cyclopropylethyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2 -carboxylate; (S)-1-Cyclopropylethyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-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)-N-methyl-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide; 5-((2-(2,2-Dimethyl-3-(trifluoromethoxy)propanoyl)-2-aza-spiro[3.3]heptan-6-yl)oxy)-N-methyl-7-(trifluoromethyl)thieno[3 ,2-b]pyridine-3-carboxamide; 5-((2-Isobutyryl-2-azaspiro[3.3]heptan-6-yl)oxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-((2-(5-Fluoropyridin-3-yl)-2-azaspiro[3.3]heptan-6-yl)-oxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide; 5-((2-(6-Fluoropyridin-2-yl)-2-azaspiro[3.3]heptan-6-yl)-oxy)-N-methyl-7(trifluoromethyl)thieno[3,2-b]pyridin- 3-carboxamide; N-Methyl-5-((2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl)oxy)-7-(trifluoromethyl)thieno[3,2-b]pyridin- 3-carboxamide; 2-(Trifluoromethoxy)ethyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-1-azaspiro[3.3]heptan-1- carboxylate; Tertbutyl 2-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)-7-azaspiro[3,5]nonane-7-carboxylate; 2-(Trifluoromethoxy)ethyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-3-azabicyclo[3,1,1] 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-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]-heptane -2-carboxylate; (S)-1-Cyclopropylethyl 6-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]- heptane-2-carboxylate; Cyclopropylmethyl ((1s,3s)-3-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate; Isopropyl ((1s,3s)-3-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate; (S)-1-Cyclopropylethyl ((1s,3R)-3-((6-methyl-3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )cyclo-butyl)carbamate; (R)-1-Cyclopropylethyl ((1s,3S)-3-((6-methyl-3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )cyclo-butyl)carbamate; Cyclopropylmethyl ((1r,3r)-3-((6-methyl-3-(methylcarbamoyl)-7(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)-carbamate; 2-(Trifluoromethoxy)ethyl (2R,4R)-4-((6-chloro-3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- 2-methylpiperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (2S,4S)-4-((6-chloro-3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- 2-methylpiperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl 4-((6-chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; Tertbutyl (2R,4R)-4-((6-fluoro-3-(methylcarbamoyl)-7-(tri-fluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-2-methylpiperidin-1 -carboxylate; 2-(Trifluoromethoxy)ethyl 6-((6-chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]-heptane -2-carboxylate; (S)-1-Cyclopropylethyl 6-((6-chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]- heptane-2-carboxylate; 2-(Trifluoromethoxy)ethyl 6-((2-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]-heptane -2-carboxylate; 5-(cis-3-(3-(Cyclopropylmethyl)ureido)cyclobutoxy)-N,2-dimethyl 7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; (S)-1-cyclopropylethyl ((1s,3R)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate; (R)-1-cyclopropylethyl ((1s,3S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate; Oxetan-3-yl (cis-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate; (S)-1-Methoxypropan-2-yl (cis-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate; (R)-1-Methoxypropan-2-yl (cis-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate; 2-(Trifluoromethoxy)ethyl (cis-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate; 2,2-Difluoroethyl (cis-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate; 2-(4-Chloro-1H-pyrazol-1-yl)ethyl (cis-3-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl) hydroxy)-cyclobutyl)carbamate; Thiazol-2-ylmethyl (cis-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate; Cyclopropylmethyl (cis-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate; Isopropyl (cis-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate; (+/-)-trans-4-Fluoro-1-methylpyrrolidin-3-yl (cis-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl )oxy)-cyclobutyl)carbamate; 2-Chloroethyl (cis-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate; cis-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)oxy)cyclobutyl 3,3-difluoroazetidine-1-carboxylate; cis-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)oxy)cyclobutyl (2-(trifluoromethoxy)ethyl)carbamate; cis-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)oxy)cyclobutyl 1-oxa-7-azaspiro[3,5]nonan-7 -carboxylate; cis-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)oxy)cyclobutyl (S)-2,4-dimethylpiperazine-1-carboxylate; cis-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)oxy)cyclobutyl ((S)-1-cyclopropylethyl)carbamate; cis-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)oxy)cyclobutyl 5,6-dihydro-[1,2,4]triazolo[ 1,5-a]-pyrazine-7(8H)-carboxylate; cis-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)oxy)cyclobutyl 3-chlorazetidine-1-carboxylate; cis-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)oxy)cyclobutyl (S)-3-methylmorpholine-4-carboxylate; cis-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)oxy)cyclobutyl (cyclopropylmethyl)carbamate; N-Methyl-5-(cis-3-(pyridin-2-yloxy)cyclobutoxy)-7-(tri-fluoromethyl)thieno[3,2-b]pyridin-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-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)azetidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl 3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)azetidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl 2-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)methyl)azetidine-1-carboxylate; (1-(Trifluoromethyl)cyclopropyl)methyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; Cyclopropylmethyl (trans-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl)carbamate; trans-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)oxy)cyclobutyl (cyclopropylmethyl)carbamate; 3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl (cyclopropylmethyl)carbamate; 3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl 4-(3,3,3-trifluoropropoxy)piperidine-1-carboxylate; 1-(Tertiary)4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperazine-1,4-dicarboxylate; Tertbutyl (2R,4R)-4-((6-chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-2-methylpiperidine-1-carboxylate ; Tertbutyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate; Tertbutyl 6-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate; Tertbutyl 6-((2-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate; Tertbutyl 6-((6-chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate; Tertbutyl 3-methyl-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)azetidine-1-carboxylate; Tertbutyl 4-((6-chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl 4-((5-chloro-3-(methylcarbamoyl)-7 (trifluoromethyl)thieno[3,2-b]pyridin-6-yl)oxy)piperidine-1-carboxylate; Methyl 6-fluoro-5-((1-((2-(trifluoromethoxy)ethoxy)carbonyl)-piperidin-4-yl)oxy)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate ; 2-(Trifluoromethoxy)ethyl 4-((6-fluoro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; Methyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate; Isobutyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine-1-carboxylate; 5-(1-(4-Fluorophenethyl)piperidin-4-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide hydrochloride; Benzyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidine-1-carboxylate; N-Methyl-5-(1-(4-methylpentyl)piperidin-4-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(1-(2-(Benzyloxy)ethyl)piperidin-4-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide hydrochloride; Isopentyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine-1-carboxylate; Isopropoxyethyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidine-1-carboxylate; Tertbutyl 2,6-dimethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; Tertbutyl (2S,4r,6R)-2,6-dimethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidin-1- carboxylate; 2-(Trifluoromethoxy)ethyl (2S,4r,6R)-2,6-dimethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate; (+/-)-Tertbutyl (2R,6R)-2,6-dimethyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl) hydroxy)-piperidine-1-carboxylate; (+/-)-2-Trifluoromethoxy)ethyl (2R,6R)-2,6-dimethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-5- yl)oxy)-piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (2R,6R)-2,6-dimethyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (2S,6S)-2,6-dimethyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate; 4-Nitrophenyl (2S,4r,6R)-2,6-dimethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidin- 1-carboxylate; Tert-butyl 4-((7-methoxy-3-(methylcarbamoyl)thieno[3,2-b]-pyridin-5-yl)oxy)piperidine-1-carboxylate; Methyl 5-(4-(((cyclopropylmethyl)carbamoyl)oxy)piperidin-1-yl)-7-methoxythieno[3,2-b]pyridine-3-carboxylate; Methyl 5-(4-((cyclopropylcarbamoyl)oxy)piperidin-1-yl)-7-methoxythieno[3,2-b]pyridine-3-carboxylate; Isobutyl 4-((7-methoxy-3-(methylcarbamoyl)thieno[3,2-b]-pyridin-5-yl)oxy)piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl 4-((7-hydroxy-3-(methylcarbamoyl)-thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl 4-((7-(difluoromethoxy)-3-(methyl-carbamoyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; Tertbutyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; Isobutyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl) carbamate; Cyclopropylmethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; Neopentyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; Tertbutyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)azetidin-3-yl)carbamate; Isobutyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)azetidin-3-yl) carbamate; Cyclopropylmethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)azetidin-3-yl)carbamate; Neopentyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)azetidin-3-yl)carbamate; Tertbutyl methyl(1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; Isobutyl methyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl) piperidin-4-yl) carbamate; 1-(7-Cyclopentyl-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate; Tert-butyl (1-(7-cyclopentyl-3-(methylcarbamoyl)thieno[3,2-b]-pyridin-5-yl)azetidin-3-yl)carbamate; 1-(7-(Tretbutyl)-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate; 1-(7-Isopropyl-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate; Tertbutyl 4-fluoro-4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)methyl)piperidine-1-carboxylate; Isobutyl 4-fluoro-4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)methyl)piperidine-1-carboxylate; 2,2,2-Trifluoroethyl 4-fluoro-4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)methyl)piperidine-1-carboxylate ; 2-(Trifluoromethoxy)ethyl 4-fluoro-4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)methyl)piperidine-1-carboxylate; Tertbutyl 3-fluoro-3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)methyl)azetidine-1-carboxylate; Isobutyl 3-fluoro-3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)methyl)azetidine-1-carboxylate; 2,2,2-Trifluoroethyl 3-fluoro-3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)methyl)azetidine-1-carboxylate ; 2-(Trifluoromethoxy)ethyl 3-fluoro-3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)methyl)azetidine-1-carboxylate; Tertbutyl 3-methyl-3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)methyl)azetidine-1-carboxylate; Isobutyl 3-methyl-3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)methyl)azetidine-1-carboxylate; 2,2,2-Trifluoroethyl 3-methyl-3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)methyl)azetidine-1-carboxylate ; 2-(Trifluoromethoxy)ethyl 3-methyl-3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)methyl)azetidine-1-carboxylate; Tertbutyl 4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)methyl)piperidine-1-carboxylate; 2,2,2-Trifluoroethyl 4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)methyl)piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl 4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)methyl)piperidine-1-carboxylate; Tertbutyl 4-methyl-4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)methyl)piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl 4-methyl-4-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)methyl)piperidine-1-carboxylate; Tertbutyl (2r,4s)-2-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)-6-azaspiro[3.4]octane-6- carboxylate; Tertbutyl (2s,4r)-2-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)-6-azaspiro[3.4]octane-6- carboxylate; 2-(Trifluoromethoxy)ethyl (2s,4r)-2-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-6-azaspiro[3.4] -octane-6-carboxylate; 2-(Trifluoromethoxy)ethyl (2r,4s)-2-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-6-azaspiro[3.4] -octane-6-carboxylate; Tertbutyl (3aR,5r,6aS)-5-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)hexahydrocyclopenta[c]-pyrrole-2 (1H)-carboxylate; 2-(Trifluoromethoxy)ethyl (3aR,5r,6aS)-5-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-hexahydrocyclopenta[ c]pyrrole-2(1H)-carboxylate; trans-3-(Trifluoromethoxy)cyclobutyl (2R,4R)-4-((6-chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- 2-methylpiperidine-1-carboxylate; trans-3-((Trifluoromethoxy)methyl)cyclobutyl 4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-piperidine-1-carboxylate ; trans-3-(Trifluoromethoxy)cyclobutyl (2R,4R)-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- piperidine-1-carboxylate; cis-3-Hydroxycyclobutyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; trans-3-(Trifluoromethoxy)cyclobutyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; cis-3-(Trifluoromethoxy)cyclobutyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; Oxetan-3-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate; N-Methyl-5-(6-(2-morpholinoacetyl)-2,6-diazaspiro[3.3]-heptan-2-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 3-Methyloxetan-3-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2- carboxylate; 1-Cyclopropylethyl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate; (R)-5-(6-(2-Methoxypropanoyl)-2,6-diazaspiro[3.3]heptan-2-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3 -carboxamide; (S)-5-(6-(2-Methoxypropanoyl)-2,6-diazaspiro[3.3]heptan-2-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3 -carboxamide; 1-Methoxypropan-2-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2- carboxylate; Oxetan-3-ylmethyl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate; 1-Methylpiperidin-3-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2- carboxylate; 1-(1-Methylazetidin-3-yl)ethyl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]- heptane-2-carboxylate; 1-Methylazetidin-3-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2- carboxylate; 1-Cyanopropan-2-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate ; 1-(2-Fluoroethyl)azetidin-3-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]- heptane-2-carboxylate; 1-(Cyanomethyl)azetidin-3-yl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]-heptan- 2-carboxylate; 2-(Trifluoromethoxy)ethyl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate ; 5-(4-((1-Isopropylpyrrolidin-3-yl)oxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 5-(4-((1-(2,2-Difluoroethyl)pyrrolidin-3-yl)oxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin- 3-carboxamide; 5-(4-((1-(2-Fluoroethyl)pyrrolidin-3-yl)oxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3- carboxamide; 5-(4-((1-(1,3-Difluoropropan-2-yl)pyrrolidin-3-yl)oxy)-piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2 -b]pyridine-3-carboxamide; 5-(4-((1-(2,2-Difluoroethyl)azetidin-3-yl)oxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin- 3-carboxamide; 5-(4-((1-(2-Fluoroethyl)azetidin-3-yl)oxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3- carboxamide; 5-(4-((1-(1,3-Difluoropropan-2-yl)azetidin-3-yl)oxy)-piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2 -b]pyridine-3-carboxamide; 5-(4-(2-(3,3-Difluoropyrrolidin-1-yl)ethoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide ; 5-(4-(2-(3-Fluoropyrrolidin-1-yl)ethoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 5-(4-(2-(4,4-Difluoropiperidin-1-yl)ethoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide ; 5-(4-(2-(3-Hydroxypyrrolidin-1-yl)ethoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 5-(4-(2-(trans-3-Fluoro-4-hydroxypyrrolidin-1-yl)ethoxy)-piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide; N-Methyl-5-(4-(2-morpholinoethoxy)piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-((6-Isopropylpyridin-2-yl)oxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; (+/-)-Tertbutyl trans-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; (+/-)-trans-2-(Trifluoromethoxy)ethyl-2-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl) hydroxy)-piperidine-1-carboxylate; (+/-)-Tertbutyl cis-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; (+/-)-cis-2-(Trifluoromethoxy)ethyl-2-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl) hydroxy)-piperidine-1-carboxylate; (S)-1-Cyclopropylethyl (2R,4R)-2-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -piperidine-1-carboxylate; (S)-1-Cyclopropylethyl (2S,4S)-2-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -piperidine-1-carboxylate; Tertbutyl (2R,4R)-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; Tertbutyl (2S,4S)-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (2R,4R)-2-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (2S,4S)-2-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- piperidine-1-carboxylate; (+/-)-Tertbutyl trans-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; (+/-)-2-(Trifluoromethoxy)ethyl trans-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate; (S)-1-Cyclopropylethyl (3R,4R)-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -piperidine-1-carboxylate; (S)-1-Cyclopropylethyl (3S,4S)-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -piperidine-1-carboxylate; (+/-)-Tertbutyl cis-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; (+/-)-cis-2-(Trifluoromethoxy)ethyl-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl) hydroxy)-piperidine-1-carboxylate; (S)-1-cyclopropylethyl (3R,4S)-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -piperidine-1-carboxylate; (S)-1-cyclopropylethyl (3S,4R)-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -piperidine-1-carboxylate; Tertbutyl (3S,4R)-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; Tertbutyl (3R,4S)-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (3S,4R)-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (3R,4S)-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- piperidine-1-carboxylate; (+/-)-Tretbutyl cis-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidin- 1-carboxylate; (+/-)-cis-2-(Trifluoromethoxy)ethyl-3-fluoro-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-5- yl)-hydroxy)piperidine-1-carboxylate; Tertbutyl 4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl 4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; Tertbutyl (2R,4R)-2-ethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (2R,4R)-2-ethyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- piperidine-1-carboxylate; Tertbutyl (2R,4S)-2-ethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl-(2R,4S)-2-ethyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -piperidine-1-carboxylate; 2-Hydroxyethyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; Tertbutyl 7-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3,5]nonane-2-carboxylate; (R)-5-(4-(2-Cyclopropoxyethyl)-3-methylpiperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; (S)-5-(4-(2-Cyclopropoxyethyl)-3-methylpiperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(cis-4-(2-Cyclopropoxyethyl)-3,5-dimethylpiperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-((4-Methoxy-6-methylpyridin-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide ; 5-(4-(3-((Dimethylamino)methyl)benzyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(1-((4-Methoxycyclohexyl)amino)-1-oxopropan-2-yl)-piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide; N-Methyl-5-(4-(1-oxo-1-((tetrahydro-2H-pyran-4-yl)amino)-propan-2-yl)piperazin-1-yl)-7-(trifluoromethyl)thieno [3,2-b]pyridine-3-carboxamide; N-Methyl-5-(4-((2-morpholinoethyl)sulfonyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; N-Methyl-5-(4-((3-morpholinopropyl)sulfonyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; (R)-N-(Cyclopropylmethyl)-2-(2-methyl-4-(3-propionyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperazin-1-yl)acetamide ; (S)-N-(Cyclopropylmethyl)-2-(2-methyl-4-(3-propionyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperazin-1-yl)acetamide ; 5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-1-yl)-N,2-dimethyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(2-(3-Fluoropyrrolidin-1-yl)-1-hydroxyethyl)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3- carboxamide; 5-(4-(2-(4,4-Difluoropiperidin-1-yl)-1-hydroxyethyl)-piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide; 5-(4-(1-Hydroxy-2-morpholinoethyl)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(3-(4,4-Difluoropiperidin-1-yl)-2-hydroxypropyl)-piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide; 5-(4-(3-(3,3-Difluoropyrrolidin-1-yl)-2-hydroxypropyl)-piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide; 5-(4-(2-(1-(2,2-Difluoroethyl)pyrrolidin-3-yl)-2-hydroxy-ethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3 ,2-b]-pyridine-3-carboxamide; 1-(2-Methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-2-(methoxymethyl)pyrrolidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-(2,2-difluoroethoxy)propane-2 -yl)-carbamate; (+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((S) -1-(trifluoromethoxy)propan-2-yl)carbamate; N-Isopropyl-7-(trifluoromethyl)-5-(3-((4-(trifluoromethyl)-cyclohexyl)amino)pyrrolidin-1-yl)thieno[3,2-b]pyridine-3-carboxamide; 7-Cyclopropyl-N-ethyl-5-(4-(2-(isopropylamino)-2-oxoethyl)-piperazin-1-yl)thieno[3,2-b]pyridine-3-carboxamide; N-butyl-7-cyclopropyl-5-(4-(2-(isopropylamino)-2-oxoethyl)-piperazin-1-yl)thieno[3,2-b]pyridine-3-carboxamide; 1-(3-(Azetidin-1-carbonyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl tert-butylcarbamate; 1-(3-(3-Methoxyazetidin-1-carbonyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl tert-butylcarbamate; 1-(3-((3-Chloropropyl)carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl tert-butylcarbamate hydrochloride; 2-(4-(3-Acetamido-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperazin-1-yl)-N-isopropylacetamide; 1-(3-Acetamido-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-piperidin-4-yl (cyclopropylmethyl)carbamate; 1-(3-Acetyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-piperidin-4-yl (cyclopropylmethyl)carbamate; Methyl 5-(4-(((cyclopropylmethyl)carbamoyl)oxy)piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate; 1-(3-(Ethylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate; 1-(3-(Cyclopropylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate; 2-(4-(3-Acetyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-piperazin-1-yl)-N-isopropylacetamide; 1-(3-(Azetidin-1-carbonyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate; 1-(3-((2-Methoxyethyl)carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate; 1-(3-Propionyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-piperidin-4-yl (S)-(1-cyclopropylethyl)carbamate; 1-(3-(1-Hydroxypropyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl ((S)-1-cyclopropylethyl)carbamate; Tertbutyl 7-(3-acetyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,7-diazaspiro[3,5]nonane-2-carboxylate; 1-(7-(3-Acetyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,7-diazaspiro[3,5]nonan-2-yl)-3-methylbutane -1-on; 1-(3-(Azetidin-1-carbonyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl 3-fluoroazetidin-1-carboxylate; 1-(3-(Azetidin-1-carbonyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl 3-chlorazetidin-1-carboxylate; 1-(3-(3-Chlorazetidin-1-carbonyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-chlorazetidin-1-carboxylate; (+/-)-trans-1-(3-(Azetidin-1-carbonyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)-3-fluoropiperidin-4-yl isopropyl -carbamate; 7-Cyclopropyl-5-(4-(2-(isopropylamino)-2-oxoethyl)-piperazin-1-yl)-N-methylthieno[3,2-b]pyridine-3-carboxamide; 7-Ethyl-5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-1-yl)-N-methylthieno[3,2-b]pyridine-3-carboxamide; 7-Chloro-5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-1-yl)-N-methylthieno[3,2-b]pyridine-3-carboxamide; 5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-1-yl)-7-methoxy-N-methylthieno[3,2-b]pyridine-3-carboxamide; 7-(Difluoromethyl)-5-(4-(2-(isopropylamino)-2-oxoethyl)-piperazin-1-yl)-N-methylthieno[3,2-b]pyridine-3-carboxamide; 7-(Dimethylamino)-5-(4-(2-(isopropylamino)-2-oxoethyl)-piperazin-1-yl)-N-methylthieno[3,2-b]pyridine-3-carboxamide; 5-(4-(2-(Isopropylamino)-2-oxoethyl)piperazin-1-yl)-N-methyl-7-(2,2,2-trifluoroethoxy)thieno[3,2-b]pyridin-3- carboxamide; 1-(7-Chloro-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)-piperidin-4-yl (cyclopropylmethyl)carbamate; 1-(7-(Dimethylamino)-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate; 1-(7-(Difluoromethyl)-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate; 1-(7-(Difluoromethyl)-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate; 1-(7-(Difluoromethyl)-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl cyclopropylcarbamate; 1-(7-Methoxy-3-(methylcarbamoyl)thieno[3,2-b]pyridin-5-yl)-piperidin-4-yl isopropylcarbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)azetidin-3-yl (cyclopropylmethyl)carbamate trifluoroacetate; 5-(3-(2,2-Diethoxyethoxy)azetidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(3-(2-Hydroxy-2-methylpropoxy)azetidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide trifluoroacetate; 5-(3-(2-(Cyclopropylmethoxy)ethoxy)azetidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; (1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)azetidin-3-yl)methyl (cyclopropylmethyl)carbamate; (1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)azetidin-3-yl)methyl (1-cyanopropan-2-yl)carbamate; 5-(3-((2-(Isopropylamino)-2-oxoethyl)amino)pyrrolidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(3-(2-(Isopropylamino)-2-oxoethoxy)pyrrolidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(3-((2-(Isopropylamino)-2-oxoethyl)(methyl)amino)-pyrrolidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3 -carboxamide; 5-(3-(3-(tert-butyl)ureido)pyrrolidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(3-(((5-Isopropyloxazol-2-yl)methyl)amino)pyrrolidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; N-Methyl-5-(3-(((4-methylthiazol-2-yl)methyl)amino)pyrrolidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)pyrrolidin-3-yl (cyclopropylmethyl)carbamate; 5-(4-(2-(Cyclopropylamino)-2-oxoethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide hydrochloride; 5-(4-(3-(tert-butyl)ureido)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(3,3-Dimethyl-2-oxobutyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(1-(Cyclopropylamino)-1-oxopropan-2-yl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl tert-butylcarbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl cyclopropylcarbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate trifluoroacetate; ((+/-)-cis-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-3,4-diyl bis((cyclopropylmethyl) -carbamate); (+/-)-cis-4-Hydroxy-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-3-yl (cyclopropyl- methyl)carbamate; (+/-)-cis-3-Hydroxy-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropyl- methyl)carbamate; 3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl (cyclopropylmethyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((tetrahydrofuran-2-yl)methyl)carbamate; (+/-)-cis-3-methoxy-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (cyclopropyl- methyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-hydroxy-3-methoxypropyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-cyanoazetidin-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-cyanomorpholine-4-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((1,4-dioxan-2-yl)methyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (5-fluoropyridin-3-yl)carbamate trifluoroacetate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-chlorazetidin-1-carboxylate; (+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl diisopropylcarbamate; (+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl oxetan-3- ylcarbamate; (+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate; (+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-methoxyazetidine -1-carboxylate; (+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl cyclopropyl carbamate ; (+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 4-methylpiperazine -1-carboxylate; (+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((S) -1-cyclopropylethyl)-carbamate; (3R,4R)-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate; (3S,4S)-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate; (+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (3-fluorocyclobutyl )-carbamate; (+/-)-cis-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate; (+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl cyclopropyl carbamate ; (+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-( trifluoromethoxy)ethyl)-carbamate; (3R,4R)-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl cyclopropylcarbamate; (3S,4S)-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl cyclopropylcarbamate; (+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-( trifluoromethoxy)ethyl)-carbamate; (+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(trifluoromethoxy )-azetidine-1-carboxylate; 2-Cyanoethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; 3-Cyanocyclobutyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; 1-Cyanopropan-2-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; 4-Methyl-N-(1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)morpholine-2-carboxamide; 1-Methoxypropan-2-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; 1,3-Dimethoxypropan-2-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; (1,4-Dioxan-2-yl)methyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate ; Octan-3-ylmethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; (4-Methylmorpholin-3-yl)methyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; 1-Methylpyrrolidin-3-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate trifluoroacetate; Oxetan-3-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; 4-Methylpentan-2-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; (S)-1-Cyclopropylethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; (R)-1-Cyclopropylethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate trifluoroacetate; 1-Cyclopropylpropan-2-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; 2-(Trifluoromethoxy)ethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; N-Methyl-5-(4-((4-methylthiazol-2-yl)methyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 5-(4-((4,5-Dimethyloxazol-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 5-(4-((5-Isopropyloxazol-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 5-(4-((5-Isopropyl-1,3,4-oxadiazol-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide; 5-(4-((4,5-Dimethyl-1H-imidazol-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3 -carboxamide; 5-(4-((1-((4,5-dimethyl-1H-imidazol-2-yl)methyl)-4,5-dimethyl-1H-imidazol-2-yl)methyl)piperazin-1-yl) -N-methyl-7-(trifluoromethyl)-thieno[3,2-b]pyridine-3-carboxamide; N-Methyl-5-(4-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide; 5-(4-((4-Isopropylthiazol-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; N-Methyl-5-(4-(1-(4-methylthiazol-2-yl)ethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; N-Methyl-5-(4-(1-(5-methylthiazol-2-yl)ethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; N-Methyl-5-(1-((4-methylthiazol-2-yl)methyl)piperidin-4-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; N-Methyl-5-(4-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)-piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide; N-Methyl-5-(4-(1-(6-methylpyridin-2-yl)ethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; N-Methyl-5-(4-(2-methylthiazol-4-carbonyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3- carboxamide; 5-(4-((2-(Cyclopropylamino)ethyl)sulfonyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide trifluoroacetate; 5-(4-((2-Isopropoxyethyl)sulfonyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-((2-(Cyclopropylmethoxy)ethyl)sulfonyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-((2-(Cyclopropyl(methyl)amino)ethyl)sulfonyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-((2-(3-Methoxyazetidin-1-yl)ethyl)sulfonyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3- carboxamide; 5-(4-((2-(Isopropylamino)-2-oxoethyl)amino)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide trifluoroacetate; 5-(4-(((Tetbutylsulfinyl)amino)methyl)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(((Cyclopropylmethyl)amino)methyl)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide trifluoroacetate; 5-(4-(2-Isopropoxyethoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 5-(4-(1-(Cyclopropylmethoxy)-3-hydroxypropan-2-yl)-piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide ; 5-(4-(3-Formamidopropyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(2-(Bis(cyclopropylmethyl)amino)ethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(3-(Cyclopropanecarboxamido)propyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide trifluoroacetate; 5-(4-(2-(Cyclopropylmethoxy)ethoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(2-(Isopropylsulfonyl)ethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-(2-Hydroxy-3-morpholinopropoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-((4-Isopropylmorpholin-2-yl)methyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide trifluoroacetate; Methyl 5-(4-((3-isopropoxyazetidin-1-yl)methyl)piperidin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate; 5-(4-((3-Isopropoxyazetidin-1-yl)methyl)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 5-(4-(3-(3,3-Difluoropyrrolidin-1-yl)-2-hydroxypropoxy)-piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide; 5-(4-(2-hydroxy-3-isopropoxypropoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-(4-((5-Isopropyl-1,3,4-oxadiazol-2-yl)methoxy)piperidin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide; (S)-1-Cyclopropylethyl 7-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,7-diazaspiro[3,5]nonan- 2-carboxylate; Cyclopropyl 7-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)-2,7-diazaspiro[3,5]nonane-2-carboxylate; Oxetan-3-yl 7-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)-2,7-diazaspiro[3,5]nonane-2-carboxylate ; Isopropyl 7-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2,7-diazaspiro[3,5]nonane-2-carboxylate; 5-(2-(Ethyl(isopropyl)carbamoyl)-2,7-diazaspiro[3,5]nonan-7-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3 -carboxamide; Tertbutyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine-1-carboxylate; 5-(1-(1-(Cyclopropylamino)-1-oxopropan-2-yl)piperidin-4-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; N-Methyl-5-(1-((4-methylthiazol-2-yl)methyl)piperidin-4-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide hydrochloride; (S)-1-Cyclopropylethyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine-1-carboxylate; 4-Methylpentan-2-yl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-1-carboxylate; 4-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)cyclohex-3-en-1-yl (cyclopropylmethyl)carbamate; 2-Cyclopropylethyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidine-1-carboxylate; Tertbutyl (3S,4S)-3,4-dihydroxy-4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine-1-carboxylate; 2-Cyclopropyl-2-oxoethyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine-1-carboxylate; 4-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)cyclohexyl (cyclopropylmethyl)carbamate; 2-(Trifluoromethoxy)ethyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine-1-carboxylate; Tertbutyl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate; Tertbutyl 2-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-7-azaspiro[3,5]nonane-7-carboxylate; 2-(Trifluoromethoxy)ethyl 6-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate; 2-(Trifluoromethoxy)ethyl 2-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)-7-azaspiro[3,5]nonane-7-carboxylate ; Tertbutyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)thio)piperidine-1-carboxylate; Tertbutyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)sulfinyl)piperidine-1-carboxylate; Tertbutyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)sulfonyl)piperidine-1-carboxylate; 5-(4-(2-(Cyclopropylamino)-2-oxoethoxy)phenyl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; (1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)-1H-imidazol-4-yl)methyl (cyclopropylmethyl)carbamate; Tertbutyl 3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)methyl)pyrrolidine-1-carboxylate; Tertbutyl 3-(((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)methyl)azetidine-1-carboxylate; 5-((6-Methoxypyridin-3-yl)methoxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide trifluoroacetate; 5-((1-(Cyclopropylcarbamoyl)azetidin-3-yl)methoxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; Tertbutyl 3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)azetidine-1-carboxylate; Tertbutyl 3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; 5-((1-((Cyclopropylmethyl)carbamoyl)pyrrolidin-3-yl)oxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; Tertbutyl (R)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; (R)-5-((1-((Cyclopropylmethyl)carbamoyl)pyrrolidin-3-yl)-oxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; Tertbutyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; (S)-5-((1-((Cyclopropylmethyl)carbamoyl)pyrrolidin-3-yl)-oxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; Cyclopropylmethyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; 1-Methoxypropan-2-yl (3S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; 1-Cyanoethyl (3R)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; 1,3-Difluoropropan-2-yl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidin-1- carboxylate; Tertbutyl 3-hydroxy-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; Isopropyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; (S)-1-Cyclopropylethyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; 3-(Trifluoromethoxy)propyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; 2,2,2-Trifluoroethyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; Tertbutyl (+/-)-trans-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (+/-)-trans-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-pyrrolidine-1-carboxylate; Cyclopropylmethyl (+/-)-trans-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; 2-Cyclopropylethyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; Tertbutyl (+/-)-cis-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; Cyclopropylmethyl (+/-)-cis-3-fluoro-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (+/-)-cis-3-fluoro-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-pyrrolidine-1-carboxylate; 3,3,3-Trifluoropropyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; (2,2-Difluorocyclopropyl)methyl (3S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; 4,4,4-Trifluorobutyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; Tertbutyl (+/-)-trans-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-4-morpholinopyrrolidine-1-carboxylate ; (5-(Trifluoromethyl)isoxazol-3-yl)methyl (S)-3-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -pyrrolidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (R)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; Tertbutyl ((+/-)-trans-3-(dimethylamino)-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- pyrrolidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (+/-)-trans-3-(dimethylamino)-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-pyrrolidine-1-carboxylate; Tertbutyl (S)-3-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; Tert-butyl (+/-)-trans-3-methoxy-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl ((+/-)-trans-3-methoxy-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl) hydroxy)-pyrrolidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (S)-3-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate ; Tertbutyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; 5-((1-(2-(Isopropylamino)-2-oxoethyl)piperidin-4-yl)oxy)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; Tert-butyl (+/-)-cis-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclohexyl)carbamate; Isopropyl (+/-)-cis-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclohexyl)carbamate; Tertbutyl (+/-)-endo-7-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-3-oxa-9-azabicyclo [3,3,1]-nonane-9-carboxylate; 2-(Trifluoromethoxy)ethyl (+/-)-endo-7-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-3-oxa- 9-aza-bicyclo[3,3,1]nonane-9-carboxylate; Tertbutyl (+/-)-exo-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)-8-azabicyclo[3.2. 1]octane-8-carboxylate; Tertbutyl (+/-)-endo-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-8-azabicyclo[3.2.1 ]octane-8-carboxylate; 2-(Trifluoromethoxy)ethyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)methyl)piperidine-1-carboxylate; 5-(4-((Cyclopropylmethyl)carbamoyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide trifluoroacetate; Tertbutyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)methyl)piperidin-1-carboxylate; 2-(Trifluoromethoxy)ethyl (+/-)-exo-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-8-azabicyclo- [3,2,1]octane-8-carboxylate; 6-Chloro-5-[4-[2-(isopropylamino)-2-oxoethyl]piperazin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 6-Chloro-5-[4-[2-(isopropylamino)-2-oxoethyl]piperazin-1-yl]-2-methoxy-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridinium- 3-carboxamide; [1-[6-Chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-(cyclopropylmethyl)carbamate; [1-[6-Fluoro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-[(1S)-1-cyclopropylethyl]carbamate ; [1-[6-Chloro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-cyclopropylcarbamate; [1-[6-fluoro-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-cyclopropylcarbamate; Tert-butyl N-[1-[3-(isopropylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl]pyrrolidin-3-yl]carbamate; N-Isopropyl-2-[4-[3-(5-methyloxazol-2-yl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl]piperazin-1-yl]acetamide; N-[(4-Fluorophenyl)methyl]-5-[4-[2-(isopropylamino)-2-oxo-ethyl]piperazin-1-yl]-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide; 5-[4-[2-(Isopropylamino)-2-oxo-ethyl]piperazin-1-yl]-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; N-Isopropyl-2-[4-[3-(4-methyloxazol-2-yl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl]piperazin-1-yl]acetamide; 2-[4-[3-(1-Hydroxypropyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]piperazin-1-yl]-N-isopropyl-acetamide; N-Isopropyl-2-[4-[3-propanoyl-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]piperazin-1-yl]acetamide; 2-[4-[3-(Azetidin-1-carbonyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]piperazin-1-yl]-N-isopropyl-acetamide; N-Isopropyl-2-[4-[3-(methoxymethyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl]piperazin-1-yl]acetamide; N-Isopropyl-2-[4-[3-methyl-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]piperazin-1-yl]acetamide; [1-[3-Propanoyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-(cyclopropylmethyl)carbamate; [1-[3-(Trideuteriomethylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-cyclopropylcarbamate; 7-(1,1-Difluoroethyl)-5-[4-[2-(isopropylamino)-2-oxoethyl]-piperazin-1-yl]-N-methyl-thieno[3,2-b]pyridin-3- carboxamide; [1-[7-(1,1-Difluoroethyl)-3-(methylcarbamoyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl]N-(cyclopropylmethyl)carbamate hydrochloride; [1-[3-(Methylcarbamoyl)-7-(2,2,2-trifluoroethoxy)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-isopropylcarbamate; 5-[3-(4-Hydroxy-4-methyl-pent-2-inoxy)azetidin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-[3-[3-(Cyclopropylmethoxy)azetidin-1-yl]azetidin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; Methyl 5-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate; 5-[3-[[(1R,2R)-2-Hydroxycyclohexyl]amino]pyrrolidin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-[3-(2-Isopropoxyethylamino)pyrrolidin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-[3-(3-Hydroxy-3-methyl-but-1-yl)pyrrolidin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-[3-(Cyclopropylmethoxy)pyrrolidin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; Methyl 5-[4-(tert-butoxycarbonylamino)-1-piperidyl]-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate; 5-[4-[2-[(2-Hydroxy-1,1-dimethyl-ethyl)amino]-1-methyl-2-oxo-ethyl]piperazin-1-yl]-N-methyl-7-(trifluoromethyl )thieno[3,2-b]-pyridine-3-carboxamide; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-(2-methoxy-2-methyl-propyl)carbamate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-(3-methoxy-2,2-dimethylpropyl) -carbamate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] 3,3-dimethylpiperazine-1-carboxylate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl]N-(cyclopropylmethyl)carbamate hydrochloride; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-(2,2-difluoro-1-methyl-ethyl) carbamate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-(2-fluoro-1-methyl-ethyl)carbamate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-[2-hydroxy-1-(hydroxymethyl)ethyl]- carbamate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-tetrahydrofuran-3-ylcarbamate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-(oxetan-3-yl)carbamate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-(3-methyloxetan-3-yl)carbamate; [1-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] 3-methylthiomorpholine-4-carboxylate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] 3-methyl-1-oxo-1,4-thiazinan-4 -carboxylate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] 3-methyl-1,1-dioxo-1,4-thiazinan- 4-carboxylate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-[(1S)-1-methyl-2-methylsulfanyl- ethyl]carbamate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-[(1S)-1-methyl-2-methylsulfinyl- ethyl]carbamate; [1-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-[(1S)-1-methyl-2-methylsulfonyl-ethyl ]-carbamate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-(1,1-yl-3-yl)carbamate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] 3-(3-pyridyloxy)azetidine-1-carboxylate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] 3-(2-pyridyl)azetidine-1-carboxylate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-(1-cyclopropyl-1-deuterioethyl)-carbamate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-(1-deuterio-1-methylethyl)carbamate; [2,2,6,6-Tetradeuterio-1-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-cyclopropyl- carbamate; [2,2,6,6-Tetradeuterio-1-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-isopropyl- carbamate; [(1R,5S)-8-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-8-azabicyclo[3.2.1]octan-3-yl] N-cyclopropyl carbamate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-[(1S)-2,2-dideuterio-1- methyl 2-(trideuteriomethoxy)ethyl]carbamate; [(1R,5S)-8-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-8-azabicyclo[3.2.1]octan-3-yl] N-cyclopropyl carbamate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-[(1R)-2-fluoro-1-methylethyl] carbamate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl] N-[(1S)-2-fluoro-1-methylethyl]carbamate ; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-[cyclopropyl(dideuterio)methyl]-carbamate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] N-[2-fluoro-1-(fluoromethyl)ethyl]carbamate ; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] 6-hydroxy-8-oxa-2-azaspiro[3.4]- octane-2-carboxylate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] 6-[(2,2,2-trifluoro-1-methylethyl )amino]-8-oxa-2-azaspiro[3.4]octane-2-carboxylate; [1-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl]-4-piperidyl] 3-(2,2,2-trifluoroethoxy)azetidine-1- carboxylate; [2-Fluoro-1-(fluoromethyl)ethyl] N-[1-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-4-piperidyl]carbamate; 5-[4-[(2-Ethylthiazol-4-yl)methyl]piperazin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; N-Methyl-5-[4-[(4-methyl-2-thienyl)methyl]piperazin-1-yl]-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; N-Methyl-5-[4-[(2-methyloxazol-4-yl)methyl]piperazin-1-yl]-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 5-[4-(Isobutylcarbamoyl)-1-piperidyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-[4-(2-Hydroxy-4,4-dimethylpentyl)piperazin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-[4-[1-(4,4-Dimethyl-5H-oxazol-2-yl)ethyl]piperazin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide; 5-[4-[3-(Cyclopropylmethoxy)pyrrolidin-1-yl]-1-piperidyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 5-[4-(2-Hydroxy-3-isopropoxypropyl)piperazin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-[4-(2-Isopropoxyethylamino)-1-piperidyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-[4-(3-tert-butoxy-2-hydroxy-propyl)piperazin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-[4-(3-Isopropoxypyrrolidin-1-yl)-1-piperidyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide; 5-[4-(4-Hydroxy-4-methyl-pent-2-ynyl)piperazin-1-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-[4-(3-Hydroxy-3-methyl-but-1-ynyl)-1-piperidyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-[4-(5-Hydroxy-5-methyl-hexa-1,3-diinyl)-1-piperidyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide ; 5-[4-(4-Hydroxy-4-methyl-pent-2-inoxy)-1-piperidyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; [1,1-Dimethyl-4-[[1-[3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl]-4-piperidyl]oxy]but-2 -inyl]acetate; 5-[4-Hydroxy-4-(5-hydroxy-5-methylhexa-1,3-diinyl)-1-piperidyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3 -carboxamide; 5-[2-(Cyclopropylmethoxy)-4-oxa-8-azaspiro[4,5]decan-8-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide ; 5-[2-(2-Hydroxy-2-methylpropoxy)-4-oxa-8-azaspiro[4,5]-decan-8-yl]-N-methyl-7-(trifluoromethyl)thieno[3, 2-b]pyridine-3-carboxamide; 5-(2-Hydroxy-4-oxa-8-azaspiro[4,5]decan-8-yl)-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-[6-(Cyclopropylmethoxy)-8-oxa-2-azaspiro[3.4]octan-2-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-[6-(3,3-Difluoropyrrolidin-1-yl)-8-oxa-2-azaspiro[3.4]-octan-2-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2- b]pyridine-3-carboxamide; N-Methyl-7-(trifluoromethyl)-5-[6-[(2,2,2-trifluoro-1-methyl-ethyl)amino]-8-oxa-2-azaspiro[3.4]octan-2-yl] thieno[3,2-b]-pyridine-3-carboxamide trifluoroacetate; Tertbutyl 2-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-2,6-diazaspiro[3.3]heptane-6-carboxylate; Tertbutyl 7-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-2,7-diazaspiro[3,5]nonane-2-carboxylate; 5-[6-(2-tertbutoxyacetyl)-2,6-diazaspiro[3.3]heptan-2-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-[2-(2-tertbutoxyacetyl)-2,7-diazaspiro[3,5]nonan-7-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide ; tert-butyl 2-[3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-2,7-diazaspiro[3,5]nonane-7-carboxylate; 5-[7-(2-tertbutoxyacetyl)-2,7-diazaspiro[3,5]nonan-2-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]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-b]pyridine-3-carboxamide; N-Methyl-5-[2-(4-methylpyrimidin-2-yl)-2,7-diazaspiro[3,5]-nonan-7-yl]-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide; 5-[2-(Cyclopropylmethylcarbamoyl)-2,7-diazaspiro[3,5]nonan-7-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; Cyclopropylmethyl 7-[3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl]-2,7-diazaspiro[3,5]nonane-2-carboxylate; N-Methyl-5-[2-[(2S)-1-methylpyrrolidin-2-carbonyl]-2,7-diazaspiro[3,5]nonan-7-yl]-7-(trifluoromethyl)thieno[3,2 -b]pyridine-3-carboxamide; N-methyl-5-[2-(4-methylpiperazin-1-carbonyl)-2,7-diazaspiro-[3,5]nonan-7-yl]-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide; 5-[2-[2-(3,3-Difluoropyrrolidin-1-yl)acetyl]-2,7-diazaspiro-[3,5]nonan-7-yl]-N-methyl-7-(trifluoromethyl)thieno [3,2-b]pyridine-3-carboxamide; 5-[2-[2-[(3R)-3-Fluoropyrrolidin-1-yl]acetyl]-2,7-diazaspiro-[3,5]nonan-7-yl]-N-methyl-7-(trifluoromethyl )thieno[3,2-b]pyridine-3-carboxamide; 5-[2-(2-Hydroxy-3,3-dimethylbutyl)-2,7-diazaspiro[3,5]-nonan-7-yl]-N-methyl-7-(trifluoromethyl)thieno[3, 2-b]pyridine-3-carboxamide; 5-[2-(3-Hydroxy-3-methyl-butanoyl)-2,7-diazaspiro[3,5]-nonan-7-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2- b]pyridine-3-carboxamide hydrochloride; N-Methyl-5-[2-[2-(trifluoromethoxy)acetyl]-2,7-diazaspiro-[3,5]nonan-7-yl]-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-carboxamide; 5-[2-(2-Methoxypropanoyl)-2,7-diazaspiro[3,5]nonan-7-yl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide ; (2-Methoxy-1,1-dimethylethyl) 7-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-2,7-diazaspiro[3,5] -nonane-2-carboxylate; N-Methyl-5-[6-(4-methylpiperazine-1-carbonyl)-2,6-diazaspiro-[3,3]heptan-2-yl]-7-(trifluoromethyl)thieno[3,2-b] pyridine-3-carboxamide; N-Methyl-5-[2-(3,3,3-trifluoro-2-hydroxypropanoyl)-2,7-diazaspiro[3,5]nonan-7-yl]-7-(trifluoromethyl)thieno[3 ,2-b]pyridine-3-carboxamide; (3-Hydroxy-3-methyl-butyl)4-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]piperidine-1-carboxylate; Tertbutyl 7-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-2-azaspiro[3,5]nonane-2-carboxylate; 2-(Trifluoromethoxy)ethyl 4-[1-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]ethyl]piperazine-1-carboxylate; 2-(Trifluoromethoxy)ethyl 7-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]-2-azaspiro[3,5]nonane-2-carboxylate ; Methyl 5-[(1-tert-butoxycarbonyl-4-piperidyl)amino]-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate; Methyl 5-[(1-tert-butoxycarbonylpyrrolidin-3-yl)amino]-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate; Methyl 5-[(1-tert-butoxycarbonyl-4-piperidyl)methylamino]-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate; 5-[2-(2-Isopropylthiazol-4-yl)ethylamino]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; Methyl 5-[2-(1-tert-butoxycarbonylpyrrolidin-3-yl)ethynyl]-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate; Tertbutyl 4-hydroxy-4-[2-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]ethynyl]piperidine-1-carboxylate; [(1S)-1-Cyclopropylethyl] 3-[[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]oxymethyl]azetidine-1-carboxylate; Tertbutyl 6-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]oxy-8-oxa-2-azaspiro[3.4]octane-2-carboxylate; Tertbutyl 2-[3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl]oxy-4-oxa-8-azaspiro[4,5]decane-8-carboxylate; N-Methyl-5-[5-[3-(3-pyridyl)azetidine-1-carbonyl]-3-furyl]-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-[4-[4-(2-Hydroxy-2-methyl-propyl)piperazin-1-yl]phenyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide ; 5-[6-(6-Chloro-3-pyridyl)-3-pyridyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide; 5-[6-(3-Isopropoxyazetidin-1-yl)-3-pyridyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridin-3-carboxamide trifluoroacetate; 5-[6-[2-(1-Hydroxycyclohexyl)ethynyl]-3-pyridyl]-N-methyl-7-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxamide trifluoroacetate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (1-(1H-imidazol-1-yl)propan-2-yl )carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 2-methyl-4-(1H-1,2,4-triazol- 1-yl)piperidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (1-(methylsulfonyl)azetidin-3-yl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 2-methyl-4-(methylsulfonyl)piperazine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-cyclopropylpropan-2-yl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-(1-cyclopropylpropan-2-yl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl(oxetan-3-ylmethyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((3-hydroxyoxetan-3-yl)methyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((3-fluoroxetan-3-yl)methyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-2-methylazetidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-2-methylazetidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-methoxyazetidin-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 2-oxa-6-azaspiro[3.3]heptane-6-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 6-methyl-2,6-diazaspiro[3.3]heptane-2-carboxylate ; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 5,8-dioxa-2-azaspiro[3.4]octane-2-carboxylate ; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S)-3-cyclopropyl-3-hydroxy-2-methyl-azetidine -1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3S)-3-hydroxy-2-methylpyrrolidine-1-carboxylate ; Cyclopropylmethyl 4-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperazine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-fluoroethyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2,2-difluoroethyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (methyl-d3)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (3-methoxycyclobutyl)carbamate; (+/-)-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl ((1r,3r)-3-cyanocyclobutyl )-carbamate; (+/-)-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl ((1s,3s)-3-cyanocyclobutyl )carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (3-ethoxycyclobutyl)carbamate; (+/-)-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl ((1r,3r)-3-( methylsulfonyl)-cyclobutyl)carbamate; (+/-)-1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]-pyridin-5-yl)piperidin-4-yl ((1s,3s)-3-( methylsulfonyl)-cyclobutyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2-oxaspiro[3.3]heptan-6-yl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((2-methyltetrahydrofuran-2-yl)methyl)carbamate; Cyclopropyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno-[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3S)-3-(dimethylamino)-2-methylazetidin-1 -carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3R)-3-(dimethylamino)-2-methylazetidin-1 -carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(1-(oxetan-3-yl)ethyl)carbamate ; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-(1-(oxetan-3-yl)ethyl)carbamate ; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3S)-3-methoxy-2-methylazetidine-1-carboxylate ; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl[1,3'-biazetidine]-1'-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2'S,3'S)-2'-methyl-[1,3'- biazetidine]-1'-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3R)-3-hydroxy-2-methylpyrrolidine-1-carboxylate ; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3S)-3-hydroxy-2,3-dimethylpyrrolidin-1 -carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3S)-3-cyano-2-methylazetidine-1-carboxylate ; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 6-(cyanomethyl)-2,6-diazaspiro[3.3]heptan-2 -carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3R)-3-(cyanomethyl)-2-methylazetidin-1 -carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3S)-3-(cyanomethyl)-2-methylazetidin-1 -carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 1-methyl-1,6-diazaspiro[3.3]heptane-6-carboxylate ; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-pent-3-yn-2-ylcarbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-pent-3-yn-2-ylcarbamate; (2S,3S)-1,2-Dimethylpyrrolidin-3-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl) -carbamate; (S)-1-(2,2-Difluoroethyl)pyrrolidin-3-yl (1-(3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine -4-yl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 6-methyl-1,6-diazaspiro[3.3]heptane-1-carboxylate ; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3R)-2-methyl-3-(1H-1, 2,4-triazol-1-yl)-azetidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (S)-(5-hydroxy-5-methylhex-3-yne- 2-yl)-carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (R)-(5-hydroxy-5-methylhex-3-yne- 2-yl)-carbamate; 1-Methylazetidin-3-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; Isopropyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; 2,2-Difluoroethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; 1-(1,3-Difluoropropan-2-yl)azetidin-3-yl (1-(3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidine -4-yl)carbamate; Methyl-d ₃ (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; 2-Fluoroethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; 1-Fluoropropan-2-yl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl)carbamate; (+/-)-cis-(1s,3s)-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl oxetane-3 -ylcarbamate; (1s,3s)-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl 3-methoxyazetidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 1-oxa-6-azaspiro[3.3]heptane-6-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((S)-1-((S)-oxetan-2-yl )ethyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl ((R)-1-((S)-oxetan-2-yl )ethyl)carbamate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl (2S,3R)-3-cyano-2-methylpyrrolidine-1-carboxylate ; (S)-1-((S)-Oxetan-2-yl)ethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4 -yl)carbamate; (S)-1-((R)-Oxetan-2-yl)ethyl (1-(3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4 -yl)carbamate; (+/-)-cis-(1s,3s)-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl isopropylcarbamate; (+/-)-cis-(1s,3s)-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl 3-( trifluoromethoxy)azetidine-1-carboxylate; (+/-)-cis-(1s,3s)-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl 3-hydroxy -3-methyl-azetidine-1-carboxylate; (+/-)-cis-(1s,3R)-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl ((S )-1-(trifluoro-methoxy)propan-2-yl)carbamate; (+/-)-cis-(1s,3s)-3-((3-(Methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)cyclobutyl 3-( dimethylamino)-azetidine-1-carboxylate; 4-Fluoro-1-methylpyrrolidin-3-yl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(1H-imidazol-1-yl)azetidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(1H-1,2,3-triazol-1-yl) azetidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(1H-1,2,4-triazol-1-yl) azetidine-1-carboxylate; (+/-)-trans-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(1H -1,2,4-triazol-1-yl)azetidine-1-carboxylate; (+/-)-cis-3-Fluoro-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(1H -1,2,4-triazol-1-yl)azetidine-1-carboxylate; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 1-cyclopropyl-1,6-diazaspiro[3.3]heptane-6-carboxylate ; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 1-ethyl-1,6-diazaspiro[3.3]heptane-6-carboxylate ; 1-(3-(Methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 1-(2,2,2-trifluoroethyl)-1,6-diazaspiro [3.3]-heptane-6-carboxylate; (+/-)-trans-2-(Trifluoromethoxy)ethyl 3-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate; (+/-)-cis-2-(Trifluoromethoxy)ethyl 3-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (R)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; 2-(Trifluoromethoxy)ethyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; Tertbutyl 2,2-dimethyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; (S)-1-(Trifluoromethoxy)propan-2-yl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate ; (R)-1-(Trifluoromethoxy)propan-2-yl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate ; (S)-2-(Trifluoromethoxy)propyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; (R)-2-(Trifluoromethoxy)propyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; (S)-1-(Trifluoromethoxy)propan-2-yl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[ 3.3]-heptane-2-carboxylate; (S)-1-(Trifluoromethoxy)propan-2-yl (S)-3-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy )-pyrrolidine-1-carboxylate; (3S,4S)-3-Methyl-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate; (3R,4R)-3-Methyl-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(trifluoromethoxy)- azetidine-1-carboxylate; (S)-2-(Trifluoromethoxy)propyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate ; (R)-2-(Trifluoromethoxy)propyl (S)-3-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)pyrrolidine-1-carboxylate ; (S)-2-(Trifluoromethoxy)propyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)-2-azaspiro[3.3]-heptane -2-carboxylate; (R)-2-(Trifluoromethoxy)propyl 6-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]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-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; (3R,4S)-3-Methyl-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl isopropylcarbamate; (3R,4S)-3-Methyl-1-(3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)piperidin-4-yl 3-(trifluoromethoxy)- azetidine-1-carboxylate; (S)-1-Cyanopropan-2-yl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; (S)-1-Cyanopropan-2-yl (2R,4R)-2-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridine-5- yl)oxy)-piperidine-1-carboxylate; (S)-1-Cyclopropylethyl (2R,4R)-2-methyl-4-((6-methyl-3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl) hydroxy)-piperidine-1-carboxylate; 2-Hydroxy-2-methylpropyl (2R,4R)-2-methyl-4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy) -piperidine-1-carboxylate; 1-(2,2,2-Trifluoroethyl)pyrrolidin-3-yl 4-((3-(methyl-carbamoyl)-7-(trifluoromethyl)thieno[3,2-b]pyridin-5-yl)oxy)- piperidine-1-carboxylate; 2-(Fluoromethoxy)ethyl 4-((3-(methylcarbamoyl)-7-(trifluoromethyl)-thieno[3,2-b]pyridin-5-yl)oxy)piperidine-1-carboxylate; And (S)-1-(3-Fluoroazetidin-1-yl)propan-2-yl (2R,4R)-2-methyl-4-((3-(methylcarbamoyl)-7-(trifluoromethyl)thieno[3,2 -b]pyridin-5-yl)-oxy)piperidine-1-carboxylate. 19. A compound according to claim 1, selected from the group consisting of the following compounds: . 20. A compound according to claim 1, selected from the group consisting of the following compounds: . 21. A compound according to claim 1, selected from the group consisting of the following compounds: And . 22. A compound according to claim 1, selected from the group consisting of the following compounds: And . 23. A pharmaceutical composition for the treatment of lysosomal storage disease, comprising a pharmaceutically effective amount of a compound according to any one of paragraphs. 1-22 or a pharmaceutically acceptable salt thereof. 24. A method of treating a lysosomal storage disease, wherein the method comprises administering to a patient in need thereof a pharmaceutically effective amount of a compound according to any one of claims. 1-22 or compositions according to claim 23. 25. The method of claim 24, wherein the lysosomal storage disease is Krabbe disease (KD). 26. The method of claim 25, wherein the lysosomal storage disease is metachromatic leukodystrophy (MLD).