Compositions comprising USP1 inhibitors and methods of using the same

Abstract

The presently disclosed subject matter relates to compositions comprising Ubiquitin-Specific Protease 1 (USP1) inhibitors and methods of using the same.

Description

[0001] Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0002] COMPOSITIONS COMPRISING USP1 INHIBITORS AND METHODS OF USING THE SAME CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U. S. Provisional Patent Application Serial No. 63 / 720,168, filed on November 13, 2024, the contents of which are incorporated herein by reference in their entireties.

[0004] TECHNICAL FIELD

[0005] The subject matter described herein relates to compositions comprising Ubiquitin-Specific Protease 1 (USP1) inhibitors and methods of using the same.

[0006] BACKGROUND

[0007] The USP1 gene encodes a deubiquitinase that is directly involved in DNA damage repair by regulating the ubiquitination of key regulators like PCNA and FANCD2. Overexpression of USP1 is commonly observed in osteosarcoma, colorectal, non-small cell lung, and gastric cancers, and blockade of USP1 induces apoptosis in many cancers. Moreover, several USP1 inhibitors sensitize cancer cells to platinum-, DNA-damaging-, and radiation-induced death. Given the well-established role USP1 as a selective anti-cancer target for inhibition, there remains a need in the art for new USP1 inhibitors for use in the treatment of such cancers.

[0008] SUMMARY OF THE INVENTION

[0009] In certain aspects, the compositions and methods described herein relate to compositions comprising USP1 inhibitors and methods of their use in treating disease, e.g., cancer.

[0010] In certain embodiments, the compositions and methods described herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0011]

[0012] wherein

[0013] Active 126539678.1 1 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0014] X and Y are independently selected from C and N,

[0015] R is selected from C1-C3 alkyl, -CD3, -CHF2, and 3-, 4-, 5-, or 6- membered heterocyclyl,

[0016] R₁ is selected from H, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl,

[0017]

[0018] wherein ring C is selected from C3-C8 cycloalkyl ring, Ce-Cio aryl, 4-, 5-, 6-, or 7- membered heterocyclyl ring, and 4-, 5-, 6-, or 7- membered heteroaryl ring, wherein the C3-C8 cycloalkyl ring or 4-, 5-, 6-, or 7- membered heterocyclyl ring is optionally fused to a C3-C8 cycloalkyl ring, and wherein ring C is optionally substituted, wherein R₃ is selected from 3-8 membered heterocyclic group, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl, wherein the heterocyclic group comprises at least one atom selected from O and N, and wherein the C₁-C₆ alkyl is linear or branched,

[0019] wherein R3 optionally forms a bond with ring C to form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl, wherein the 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl is optionally substituted with one or more groups selected from C₁-C₆ alkyl, -OH, C₁-C₆ alkoxy, and halogen; and

[0020] wherein R₄ is selected from H, -OH, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, and C₁-C₆ haloalkyl, wherein the C₁-C₆ alkyl is linear or branched, and wherein the C₁-C₆ haloalkyl is linear or branched,

[0021] Rₐ and R_b are independently selected from -H, -D, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₂-C₆ alkynyl, optionally Rₐ or R_b forms a bond with ring C to form a 5-, 6-, or 7- membered carbocyclic group, and

[0022] Ring A is selected from a C4-C5 cycloalkyl and 5- or 6- membered heterocyclyl, wherein the 5-, or 6- membered heterocyclyl comprises one, two, or three heteroatoms selected from N and O,

[0023] Active 126539678.1 2 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0024] wherein when ring A is a 6-membered heterocyclyl, the 6-membered heterocyclyl is

[0025] selected from

[0026]

[0027] wherein when Y is C and ring A is a 5-membered heterocyclyl comprising three

[0028] N

[0029] R4 N

[0030] heteroatoms selected from N, R2 is selected from

[0031]

[0032] K3and

[0033]

[0034] R3

[0035] wherein ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)OR’, -C(O)NHR’, -C(O)NR’R”, -NH2, -NHR’, -NR’R”, =0, halogen, Ci-6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 nitrile, and C1-6 alkyl-epoxide; wherein R’ and R” are independently selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-8 membered saturated or unsaturated cycloalkyl, 5-6 membered saturated or unsaturated heterocyclyl, phenyl, and 5-6 membered heteroaryl.

[0036] In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof:

[0037] Active 126539678.1 3 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0038]

[0039] wherein

[0040] X and Y are independently selected from C and N;

[0041] R is selected from C1-C3 alkyl, -CD3, -CHF2, and 3-, 4-, 5-, or 6- membered heterocyclyl,

[0042] R₁ is selected from H, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl,

[0043]

[0044] wherein ring C is selected from C3-C8 cycloalkyl ring, Ce-Cio aryl, 4-, 5-, 6-, or 7- membered heterocyclyl ring, and 4-, 5-, 6-, or 7- membered heteroaryl ring, wherein the C3-C8 cycloalkyl ring or 4-, 5-, 6-, or 7- membered heterocyclyl ring is optionally fused to a C3-C8 cycloalkyl ring, and wherein ring C is optionally substituted, wherein R₃ is selected from 3-8 membered heterocyclic group, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl, wherein the heterocyclic group comprises at least one atom selected from O and N, and wherein the C₁-C₆ alkyl is linear or branched,

[0045] wherein R3 optionally forms a bond with ring C to form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl, wherein the 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl is optionally substituted with one or more groups selected from Ci-Ce alkyl, -OH, Ci-Ce alkoxy, and halogen, and

[0046] wherein R₄ is selected from H, -OH, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, and C₁-C₆ haloalkyl, wherein the C₁-C₆ alkyl is linear or branched, and wherein the C₁-C₆ haloalkyl is linear or branched,

[0047] Active 126539678.1 4 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0048] Rₐ and R_b are independently selected from -H, -D, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₂-C₆ alkynyl, optionally Rₐ or R_b forms a bond with ring C to form a 5-, 6-, or 7- membered carbocyclic group, and

[0049] Ring B is selected from C₄-C₈ cycloalkyl, C₆-C₁₀ aryl, and 4-, 5-, 6-, or 7- membered heterocyclyl, wherein the 4-, 5-, 6-, or 7- membered heterocyclyl comprises one, two, or three heteroatoms selected from N or O, and

[0050] wherein said ring B is optionally substituted with one or more groups selected from - OH, -COOH, -C(O)OR’, -C(O)NHR’, -C(O)NR’R”, -NH2, -NHR’, -NR’R”, =0, halogen, C1-6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 nitrile, and C1-6 alkyl-epoxide; wherein R’ and R” are independently selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-8 membered saturated or unsaturated cycloalkyl, 5-6 membered saturated or unsaturated heterocyclyl, phenyl, and 5-6 membered heteroaryl.

[0051] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein X is N and Y is C. In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein X is C and Y is N. In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein X is C and Y is C. In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein X is N and Y is N.

[0052] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein ring C is selected from

[0053]

[0054] wherein R₅ and R₆ are selected from -H, -OH, C₁-C₆ branched or linear alkyl, C₁-C₆ branched or linear haloalkyl, C₁-₆ alkoxy, 5-8 membered heteroaryl, C₃-₈ cycloalkyl, 3-8 membered heterocyclyl, -O-C₁-₆ alkyl, -O-C₁-₆ alkylene, -Cl, and -F; and wherein R₃ optionally forms a bond with R₅ to form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl, wherein the 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl is optionally substituted with one or more groups selected from C₁-C₆ alkyl, -OH, C₁-C₆ alkoxy, and halogen; or wherein Rₐ or R_b optionally forms a bond with R₆ to form a 5-, 6-, or 7-membered carbocyclic group.

[0055] Active 126539678.1 5 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0056] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein R₅ and R₆ are selected from -H, C₁-C₆ linear alkyl, and -F.

[0057] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein when R3 forms a bond

[0058]

[0059] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein R4 is selected from -CF3and -CHF2.

[0060] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein R3 is selected from

[0061]

[0062] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein R2 is selected from

[0063]

[0064] Active 126539678.1 6 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0065]

[0066] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein R is C1-C3 alkyl. In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein R is methyl. In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein Ra and Rb are each H.

[0067] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein ring A or ring B is

[0068] selected from

[0069]

[0070] 1,1wherein ring A or ring B is optionally substituted with one or more groups selected from - OH, -COOH, -C(O)OR’, -C(O)NHR’, -C(O)NR’R”, -NH2, -NHR’, -NR’R”, =0, halogen, Ci- 6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 nitrile, and C1-6 alkyl-epoxide; wherein R’ and R” are independently selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-8 membered saturated or unsaturated cycloalkyl, 5-6 membered saturated or unsaturated heterocyclyl, phenyl, and 5-6 membered heteroaryl. In

[0071] Active 126539678.1 7 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0072] particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein ring A or ring B is substituted with one or more groups selected from =0 and Ci-6 alkyl.

[0073] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein ring A is selected from

[0074]

[0075] In particular embodiments, the present disclosure provides a compound of formula (I)

[0076] or formula (II), or a pharmaceutically acceptable salt thereof, wherein ring B is [structure]. In particular embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein formula (I) is selected from

[0077]

[0078] Active 126539678.1 8 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0079]

[0080] Active 126539678.1 9 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0081]

[0082] In particular embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein formula (I) is

[0083]

[0084] Active 126539678.1 10 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0085] In particular embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein formula (II) is

[0086]

[0087] In certain embodiments, the compositions and methods described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof:

[0088]

[0089] (III) wherein:

[0090] X and Y are independently selected from C and N;

[0091] R1 is selected from C1-C6 branched and linear alkyl;

[0092] wherein ring A is selected from

[0093]

[0094]

[0095] I I I

[0096] wherein ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)OR’, -C(O)NHR’, -C(O)NR’R”, -NH2, -NHR’, -NR’R”, =0, halogen, Ci-6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 nitrile, and C1-6 alkyl-epoxide; wherein R’ and R” are independently selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-8 membered saturated or unsaturated cycloalkyl, 5-6 membered saturated or unsaturated heterocyclyl, phenyl, and 5-6 membered heteroaryl.

[0097] In particular embodiments, the present disclosure provides a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N and Y is C. In particular

[0098] Active 126539678.1 11 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0099] embodiments, the present disclosure provides a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein X is C and Y is C.

[0100] In particular embodiments, the present disclosure provides a compound of formula

[0101] (III), or a pharmaceutically acceptable salt thereof, wherein Ri is selected from

[0102]

[0103] andCH3

[0104] In particular embodiments, the present disclosure provides a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein formula (III) is selected from

[0105]

[0106] Active 126539678.1 12 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0107]

[0108] In particular embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein formula (I) is:

[0109]

[0110] In particular embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein formula (I) is:

[0111]

[0112] In particular embodiments, the present disclosure provides a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[0113]

[0114] Active 126539678.1 13 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0115]

[0116] Active 126539678.1 14 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0117]

[0118] Active 126539678.1 15 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0119]

[0120] Active 126539678.1 16 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0121]

[0122] Active 126539678.1 17 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0123]

[0124] Active 126539678.1 18 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0125]

[0126] In certain embodiments, the present disclosure is directed to a method of modulating USP1 activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0127] In certain embodiments, the present disclosure is directed to a method of inhibiting USP1 activity in a subject, wherein the method comprises administering to the subject a

[0128] Active 126539678.1 19 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0129] therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0130] In certain embodiments, the present disclosure is directed to a method of treating a disorder or disease with a USP1 inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0131] In certain embodiments, the present disclosure is directed to a method of treating cancer with a USP1 inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0132] In certain embodiments, the present disclosure is directed to a method of treating cancer with a USP1 inhibitor in a subject, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the cancer is characterized by over expression of USP1.

[0133] In certain embodiments, the present disclosure is directed to a method treating cancer with a USP1 inhibitor in a subject, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the cancer characterized by overexpression of USP1 is selected from prostate, breast, ovarian, non-small cell lung cancer, mesothelioma, Merkel cell carcinoma, synovial sarcoma, renal cell carcinoma, and osteosarcoma.

[0134] In certain embodiments, the present disclosure is directed to a use of a compound disclosed herein, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

[0135] In certain embodiments, the present disclosure is directed to a use of a compound disclosed herein, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, wherein the cancer is characterized by overexpression of USP1.

[0136] In certain embodiments, the present disclosure is directed to a process to manufacture a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0137] BRIEF DESCRIPTION OF THE DRAWINGS

[0138] The subject matter of the application will be more readily understood from the following detailed description when read in conjunction with the accompanying drawings, in which:

[0139] Active 126539678.1 20 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0140] FIG. 1 depicts the results of an experiment where MDA-MB-436 cells (2.5x106 cells / mouse in 50% Matrigel:50% HBSS) were injected subcutaneously into the right hind flank of female NOD / SCID mice at 7-9 weeks of age. Tumor length (L) and width (W) were measured twice weekly using digital calipers to calculate tumor volumes using the following formula: 0.5*L*W^2. Once tumor volumes reached an average of approximately 100 mm3, mice were randomly assigned (n=8) into treatment groups. Mice were treated daily by oral gavage (10 mL / kg). Animals were euthanized if body weight loss >20% was observed, tumor volume achieved >1500 mm3, or a humane endpoint was reached. Means with error bars representing s.e.m. were plotted. The treatment groups were as follows: (1) Vehicle (0.5% HPMC, 0.1% Tween 80); (2) Example 4 at 10 mg / kg; (3) Example 4 at 30 mg / kg; (4) Example 4 at 100 mg / kg.

[0141] FIG. 2 provides the body weight (means with error bars representing s.e.m.) of the mice described in FIG. 1.

[0142] FIG. 3 depicts the results of an experiment where MDA-MB-436 cells (2.5x106 cells / mouse in 50% Matrigel:50% HBSS) were injected subcutaneously into the right hind flank of female NOD / SCID mice at 7-9 weeks of age. Tumor length (L) and width (W) were measured twice weekly using digital calipers to calculate tumor volumes using the following formula: 0.5*L*W^2. Once tumor volumes reached an average of approximately 100 mm3, mice were randomly assigned (n=8) into treatment groups. Mice were treated daily by oral gavage (10 mL / kg). Animals were euthanized if body weight loss >20% was observed, tumor volume achieved >1500 mm3, or a humane endpoint was reached. Means with error bars representing s.e.m. were plotted. The treatment groups were as follows: (1) Vehicle (0.5% HPMC, 0.1% Tween 80); (2) Example 54 at 10 mg / kg; (3) Example 54 at 30 mg / kg; (4) Example 54 at 100 mg / kg.

[0143] FIG. 4 provides the body weight (means with error bars representing s.e.m.) of the mice described in FIG. 3.

[0144] FIG. 5 depicts the results of an experiment where MDA-MB-436 cells (2.5x106 cells / mouse in 50% Matrigel:50% HBSS) were injected subcutaneously into the right hind flank of female NOD / SCID mice at 7-9 weeks of age. Tumor length (L) and width (W) were measured twice weekly using digital calipers to calculate tumor volumes using the following formula: 0.5*L*W^2. Once tumor volumes reached an average of approximately 100 mm3, mice were randomly assigned (n=8) into treatment groups. Mice were treated daily by oral gavage (10 mL / kg). Animals were euthanized if body weight loss >20% was observed, tumor volume achieved >1500 mm3, or a humane endpoint was reached. Means with error bars

[0145] Active 126539678.1 21 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0146] representing s.e.m. were plotted. The treatment groups were as follows: (1) Vehicle (0.5% HPMC, 0.1% Tween 80); (2) Example 88 at 10 mg / kg; (3) Example 88 at 30 mg / kg; (4) Example 88 at 100 mg / kg.

[0147] FIG. 6 provides the body weight (means with error bars representing s.e.m.) of the mice described in FIG. 5.

[0148] DETAILED DESCRIPTION

[0149] The presently disclosed subject matter relates to compositions comprising USP1 inhibitors and methods of their use in treating cancer. For purposes of clarity of disclosure and not by way of limitation, the detailed description is divided into the following subsections:

[0150] 1. Definitions

[0151] 2. Compositions of Matter

[0152] 3. Methods of Use

[0153] 4. Examples

[0154] 1. Definitions

[0155] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the presently disclosed subject matter. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0156] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other instances “comprising,” “consisting of’, and “consisting essentially of,” the instances or elements presented herein, whether explicitly set forth or not.

[0157] For the recitation of numeric ranges herein, each intervening number within the range is explicitly contemplated with the same degree of precision. For example, for the range of

[0158] Active 126539678.1 22 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0159] 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

[0160] As used herein, the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.

[0161] As used herein, “modulate” or “modulating” refers to increasing or decreasing, e.g., modulation of the activity of an enzyme includes increasing the activity of the enzyme as well as decreasing the activity of the enzyme.

[0162] As used herein, “treat” or “treating” refers to an effort to alter the natural course of a disease, including prophylaxis of the disease, alleviation of symptoms and / or ameliorating pathology associated with the disease.

[0163] As used herein, “alkyl” includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and may be unsubstituted or substituted. Thus, Ci-Cnas in “Ci-Cnalkyl" is defined to include groups having 1, 2,...., n-1 or n carbons in a linear or branched arrangement. For example, Ci-Ce, as in “Ci-Ce alkyl” is defined to include groups having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pentyl, hexyl, and octyl.

[0164] As used herein, “alkenyl” refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non-aromatic carbon-carbon double bonds may be present, and may be unsubstituted or substituted. For example, “C2-C6 alkenyl” means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and up to 1, 2, 3, 4, or 5 carbon-carbon double bonds respectively. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.

[0165] The term “alkynyl” refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present, and may be unsubstituted or substituted. Thus, “C2-C6 alkynyl” means an alkynyl radical having 2 or 3 carbon atoms and 1 carbon-carbon

[0166] Active 126539678.1 23 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0167] triple bond, or having 4 or 5 carbon atoms and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms and up to 3 carbon-carbon triple bonds. Alkynyl groups include ethynyl, propynyl and butynyl.

[0168] As used herein, “heteroalkyl” includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and at least 1 heteroatom within the chain or branch.

[0169] As used herein, “cycloalkyl” shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).

[0170] As used herein, the term “heterocyclyl” or “heterocyclic” refers to a mono- or polycyclic ring system which can be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms. Preferred heteroatoms include N, O, and / or S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation. The heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed. Such rings may be optionally fused to one or more of another “heterocyclic” ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s). Examples of heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-di oxane, 1,3 -di oxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3- oxathiolane, and the like. The alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl substituents may be substituted or unsubstituted, unless specifically defined otherwise.

[0171] As used herein, “aryl” is intended to mean any stable monocyclic, bicyclic or polycyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted. Examples of such aryl elements include phenyl, p-toluenyl (4-methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is nonaromatic, it is understood that attachment is via the aromatic ring.

[0172] As used herein, the term “halogen” refers to F, Cl, Br, and I.

[0173] As used herein, the term “haloalkyl” means an alkyl group that is substituted with one or more fluorine, chlorine, bromine or iodine atoms. Examples of such haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1 -difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl groups.

[0174] Active 126539678.1 24 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0175] As used herein, the term “alkoxy” means an -O-alkyl group in which alkyl is defined herein. Preferably the alkoxy is a Ci-Ce alkoxy. Examples include, but are not limited to, methoxy and ethoxy. The group may be a terminal group or a bridging group.

[0176] The term “substitution,” “substituted” and “substituent” refers to a functional group as described above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Examples of substituent groups include the functional groups described herein, and halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, and trifluoromethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure result.

[0177] The compounds of the subject invention may have spontaneous tautomeric forms. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.

[0178] This invention also provides isotopic variants of the compounds disclosed herein, including wherein the isotopic atom is2H and / or wherein the isotopic atom13C. Accordingly, in the compounds provided herein hydrogen can be enriched in the deuterium isotope. It is to be understood that the invention encompasses all such isotopic forms.

[0179] In the compound structures depicted herein, hydrogen atoms are not shown for carbon atoms having less than four bonds to non-hydrogen atoms. However, it is understood that enough hydrogen atoms exist on said carbon atoms to satisfy the octet rule.

[0180] Active 126539678.1 25 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0181] Except where otherwise specified, if the structure of a compound of this invention includes an asymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, and isolated single enantiomer. All such isomeric forms of these compounds are expressly included in this invention. Except where otherwise specified, each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis.

[0182] The compounds of the present invention include all hydrates, solvates, and complexes of the compounds used by this invention. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. The compounds described in the present invention are in racemic form or as individual enantiomers.

[0183] In choosing the compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e., Ri, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity.

[0184] The compounds used in the method of the present invention may be in a salt form. As used herein, a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used to treat an infection or disease caused by a pathogen, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the alkali earth metal salts, sodium, potassium or lithium. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic

[0185] Active 126539678.1 26 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0186] or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.

[0187] The compounds used in the method of the present invention can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or in carriers such as the novel programmable sustained-release multi-compartmental nanospheres (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, nasal, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone or mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow- inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.

[0188] 2. Compositions of Matter

[0189] The presently disclosed subject matter relates to compositions comprising USP1 inhibitors and methods of using the same. For example, but not by way of limitation, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0190] Active 126539678.1 27 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0191]

[0192] In certain embodiments, the compositions and methods described herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0193] X and Y are independently selected from C and N,

[0194] R is selected from C1-C3 alkyl, -CD3, -CHF2, and 3-, 4-, 5-, or 6- membered heterocyclyl,

[0195] R₁ is selected from H, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl,

[0196]

[0197] wherein ring C is selected from C3-C8 cycloalkyl ring, Ce-Cio aryl, 4-, 5-, 6-, or 7- membered heterocyclyl ring, and 4-, 5-, 6-, or 7- membered heteroaryl ring, wherein the C3-C8 cycloalkyl ring or 4-, 5-, 6-, or 7- membered heterocyclyl ring is optionally fused to a C3-C8 cycloalkyl ring, and wherein ring C is optionally substituted,

[0198] wherein R3 is selected from 3-8 membered heterocyclic group, Ci-Ce alkyl, and C3- Ce cycloalkyl, wherein the heterocyclic group comprises at least one atom selected from O and N, and wherein the Ci-Ce alkyl is linear or branched,

[0199] wherein R3 optionally forms a bond with ring C to form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl, wherein the 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl is optionally substituted with one or more groups selected from C₁-C₆ alkyl, -OH, C₁-C₆ alkoxy, and halogen; and

[0200] wherein R₄ is selected from H, -OH, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, and C₁-C₆ haloalkyl, wherein the C₁-C₆ alkyl is linear or branched, and wherein the C₁-C₆ haloalkyl is linear or branched,

[0201] Active 126539678.1 28 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0202] Ra and Rb are independently selected from -H, -D, Ci-Ce alkyl, Ci-Cehaloalkyl, and C2-C6 alkynyl, optionally Ra or Rb forms a bond with ring C to form a 5-, 6-, or 7- membered carbocyclic group, and

[0203] Ring A is selected from a C4-C5 cycloalkyl and 5- or 6- membered heterocyclyl, wherein the 5-, or 6- membered heterocyclyl comprises one, two, or three heteroatoms selected from N and O,

[0204] wherein when ring A is a 6-membered heterocyclyl, the 6-membered heterocyclyl is

[0205]

[0206] wherein when Y is C and ring A is a 5-membered heterocyclyl comprising three

[0207] N

[0208] R4

[0209] N

[0210] heteroatoms selected from N, R2 is selected from

[0211]

[0212] K3and

[0213]

[0214] ■3

[0215] wherein ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)OR’, -C(O)NHR’, -C(O)NR’R”, -NH2, -NHR’, -NR’R”, =0, halogen, C1-6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 nitrile, and C1-6 alkyl-epoxide; wherein R’ and R” are independently selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-8

[0216] Active 126539678.1 29 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0217] membered saturated or unsaturated cycloalkyl, 5-6 membered saturated or unsaturated heterocyclyl, phenyl, and 5-6 membered heteroaryl.

[0218] For example, but not by way of limitation, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof:

[0219]

[0220] In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof:

[0221] wherein X and Y are independently selected from C and N;

[0222] R is selected from C1-C3 alkyl, -CD3, -CHF2, and 3-, 4-, 5-, or 6- membered heterocyclyl,

[0223] R₁ is selected from H, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl,

[0224]

[0225] wherein ring C is selected from Cs-Cs cycloalkyl ring, Ce-Cio aryl, 4-, 5-, 6-, or 7- membered heterocyclyl ring, and 4-, 5-, 6-, or 7- membered heteroaryl ring, wherein the C3-C8 cycloalkyl ring or 4-, 5-, 6-, or 7- membered heterocyclyl ring is optionally fused to a C3-C8 cycloalkyl ring, and wherein ring C is optionally substituted, wherein R₃ is selected from 3-8 membered heterocyclic group, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl, wherein the heterocyclic group comprises at least one atom selected from O and N, and wherein the C₁-C₆ alkyl is linear or branched,

[0226] wherein R3 optionally forms a bond with ring C to form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl, wherein the 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl is optionally substituted with one or more groups selected from Ci-Ce alkyl, -OH, Ci-Ce alkoxy, and halogen, and

[0227] Active 126539678.1 30 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0228] wherein R₄ is selected from H, -OH, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, and C₁-C₆ haloalkyl, wherein the C₁-C₆ alkyl is linear or branched, and wherein the C₁-C₆ haloalkyl is linear or branched,

[0229] Rₐ and R_b are independently selected from -H, -D, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₂-C₆ alkynyl, optionally Rₐ or R_b forms a bond with ring C to form a 5-, 6-, or 7- membered carbocyclic group, and

[0230] Ring B is selected from C4-C8 cycloalkyl, Ce-Cio aryl, and 4-, 5-, 6-, or 7- membered heterocyclyl, wherein the 4-, 5-, 6-, or 7- membered heterocyclyl comprises one, two, or three heteroatoms selected from N or O,

[0231] wherein said ring B is optionally substituted with one or more groups selected from - OH, -COOH, -C(O)OR’, -C(O)NHR’, -C(O)NR’R”, -NH2, -NHR’, -NR’R”, =0, halogen, C1-6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 nitrile, and C1-6 alkyl-epoxide; wherein R’ and R” are independently selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-8 membered saturated or unsaturated cycloalkyl, 5-6 membered saturated or unsaturated heterocyclyl, phenyl, and 5-6 membered heteroaryl.

[0232] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein X is N and Y is C. In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein X is C and Y is N. In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein X is C and Y is C. In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein X is N and Y is N.

[0233] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein ring C is selected from R6

[0234]

[0235] , r Nx IZJZ VNZ andwherein R5 and Re are selected from -H, -OH, Ci-Ce branched or linear alkyl, Ci-Ce branched or linear haloalkyl, C1-6 alkoxy, 5-8 membered heteroaryl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, -O-Cl-6 alkyl, -O-C1-6 alkylene, -Cl, and -F; and wherein R3 optionally forms a bond with R5 to form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl, wherein the 5-, 6-, 7-, 8-, 9-, 10-,

[0236] Active 126539678.1 31 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0237] 11-, or 12- membered heterocyclyl is optionally substituted with one or more groups selected from Ci-Ce alkyl, -OH, Ci-Ce alkoxy, and halogen; or wherein Raor Rb optionally forms a bond with Re to form a 5-, 6-, or 7-membered carbocyclic group.

[0238] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein R₅ and R₆ are selected from -H, C₁-C₆ linear alkyl, and -F.

[0239] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein when R3 forms a bond

[0240]

[0241] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein R4 is selected from -CF3and -CHF2.

[0242] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein R3 is selected from

[0243]

[0244] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein R2 is selected from

[0245]

[0246] Active 126539678.1 32 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0247]

[0248] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein R is C1-C3 alkyl. In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein R is methyl. In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein Ra and Rb are each H.

[0249] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein ring A or ring B is

[0250] selected from

[0251]

[0252] 1,1wherein ring A or ring B is optionally substituted with one or more groups selected from - OH, -COOH, -C(O)OR’, -C(O)NHR’, -C(O)NR’R”, -NH2, -NHR’, -NR’R”, =0, halogen, C1-6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 nitrile, and C1-6 alkyl-epoxide; wherein R’ and R” are independently selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-8 membered saturated or unsaturated cycloalkyl, 5-6 membered saturated or unsaturated heterocyclyl, phenyl, and 5-6 membered heteroaryl. In

[0253] Active 126539678.1 33 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0254] particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein ring A or ring B is substituted with one or more groups selected from =0 and Ci-6 alkyl.

[0255] In particular embodiments, the present disclosure provides a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein ring A is selected from

[0256]

[0257] In particular embodiments, the present disclosure provides a compound of formula (I)

[0258] or formula (II), or a pharmaceutically acceptable salt thereof, wherein ring B is

[0259]

[0260] In particular embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein formula (I) is selected from

[0261]

[0262] Active 126539678.1 34 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0263]

[0264] Active 126539678.1 35 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0265]

[0266] In particular embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein formula (I) is

[0267]

[0268] Active 126539678.1 36 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0269] In particular embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein formula (II) is

[0270]

[0271] For example, but not by way of limitation, the present disclosure is directed to a compound of formula (III), or a pharmaceutically acceptable salt thereof:

[0272]

[0273] In certain embodiments, the compositions and methods described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof:

[0274] wherein X and Y are independently selected from C and N;

[0275] R1 is selected from C1-C6 branched and linear alkyl;

[0276]

[0277] wherein ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)OR’, -C(O)NHR’, -C(O)NR’R”, -NH2, -NHR’, -NR’R”, =0, halogen, Ci-6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 nitrile, and C1-6 alkyl-epoxide; wherein R’ and R” are independently selected from Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-8 membered saturated or unsaturated cycloalkyl, 5-6 membered saturated or unsaturated heterocyclyl, phenyl, and 5-6 membered heteroaryl.

[0278] Active 126539678.1 37 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0279] In particular embodiments, the present disclosure provides a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N and Y is C. In particular embodiments, the present disclosure provides a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein X is C and Y is C.

[0280] In particular embodiments, the present disclosure provides a compound of formula

[0281] (III), or a pharmaceutically acceptable salt thereof, wherein Ri is selected from

[0282]

[0283] and 'CH3

[0284] In particular embodiments, the present disclosure provides a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein formula (III) is selected from

[0285]

[0286] Active 126539678.1 38 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0287]

[0288] In particular embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein formula (I) is:

[0289]

[0290] In particular embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein formula (I) is:

[0291]

[0292] In particular embodiments, the present disclosure provides a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[0293]

[0294] Active 126539678.1 39 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0295]

[0296] Active 126539678.1 40 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0297]

[0298] Active 126539678.1 41 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0299]

[0300] Active 126539678.1 42 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0301]

[0302] Active 126539678.1 43 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0303]

[0304] Active 126539678.1 44 Client Ref. No. EIK-0025-PCT Attorney Docket No. 092295.0194

[0305]

[0306] 45

[0307] Active 126539678.1 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0308] 3. Methods of Use

[0309] In certain embodiments, the present disclosure is directed to a method of modulating USP1 activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0310] In certain embodiments, the present disclosure is directed to a method of inhibiting USP1 activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0311] In certain embodiments, the present disclosure is directed to a method of treating a disorder or disease with a USP1 inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0312] In certain embodiments, the present disclosure is directed to a method of treating cancer with a USP1 inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0313] In certain embodiments, the present disclosure is directed to a method of treating cancer with a USP1 inhibitor in a subject, comprising administering a compound of disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the cancer is characterized by over expression of USP1.

[0314] In certain embodiments, the present disclosure is directed to a method treating cancer with a USP1 inhibitor in a subject, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the cancer characterized by overexpression of USP1 is selected from prostate, breast, ovarian, non-small cell lung cancer,

[0315] Active 126539678.1 46 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0316] mesothelioma, Merkel cell carcinoma, synovial sarcoma, renal cell carcinoma, and osteosarcoma.

[0317] In certain embodiments, the present disclosure is directed to a use of a compound disclosed herein, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

[0318] In certain embodiments, the present disclosure is directed to a use of a compound disclosed herein, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, wherein the cancer is characterized by overexpression of USP1.

[0319] In certain embodiments, the present disclosure is directed to a process to manufacture a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0320] 4. Examples

[0321] The following Examples are presented by way of illustration, not limitation. One skilled in the art can modify the procedures set forth in the illustrative examples to arrive at the desired products.

[0322] Table 1: Exemplary compounds.

[0323] EXAMP Structure MS1H NMR

[0324] LE [M +

[0325] H]+

[0326] 1 549.41H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.57 (s,

[0327] 1H), 8.15 (s, 1H), 8.11 (s, 1H), 7.59 - 7.49 (m, 5H), 6.34 (s, 1H), 4.73 (br s, 2H), 4.47-4.41 (m, 1H), 3.74 (s, 3H), 1.75 - 1.71 (m, 1H), 1.39 (d, J = 6.4 Hz, 6H), 0.96 - 0.91 (m, 2H), 0.74 -0.71 (m, 2H).

[0328] 2 550.21H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.57 (s,

[0329] 1H), 8.12 (s, 1H), 7.65 -7.53 (m, 5H), 6.33 (s, 1H), 4.75 - 4.69 (m, 3H), 3.74 (s, 3H), 1.75 - 1.73 (m, 1H), 1.43 (d, J = 6.4 Hz, 6H), 0.93 - 0.93 (m, 2H), 0.73 - 0.71 (m, 2H).

[0330] 3 521.31H NMR (400 MHz, DMSO-d6) δ 12.69 (br s, 1H), 8.57 (s,

[0331] 1H), 8.11 (s, 1H), 7.56 - 7.50 (m, 5H), 6.74 (s, 1H), 6.34 (s, 1H), 4.62 (br s, 2H), 3.75 (s, 3H), 2.31 (s, 3H), 1.75 - 1.72 (m, 1H), 0.92 - 0.94 (m, 2H), 0.76 - 0.74 (m, 2H).

[0332] 4 561.31H NMR (400 MHz, CD3OD) δ 9.02 (s, 1H), 8.87 (s, 1H),

[0333] 8.58 (s, 1H), 7.93 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 7.9 Hz, 2H), 6.79 (s, 1H), 4.81 (s, 2H), 4.56 (hept, J = 6.8 Hz, 1H), 3.87 (s, 3H), 1.78 (tt, J = 8.4, 4.7 Hz, 1H), 1.46 (d, J = 6.6 Hz, 6H), 1.15 - 1.04 (m, 2H), 0.89 - 0.76

[0334]

[0335] (m, 2H).

[0336] Active 126539678.1 47 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0337] 5 575.21H NMR (400 MHz, CD3OD) δ 9.00 (s, 1H), 8.85 (s, 1H),

[0338] Y N 8.56 (s, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, JUUL 2H), 6.98 (s, 1H), 6.71 (s, 1H), 4.84 (m, 2H), 4.80 (s, 2H), Ct / y 4.71 (t, J = 6.5 Hz, 2H), 4.37 (p, J = 7.7 Hz, 1H), 3.84 (s,

[0339] 1 '^'-CF33H), 1.74 (tt, J = 8.4, 4.8 Hz, 1H), 1.12 - 1.05 (m, 2H), O-J 0.87 - 0.78 (m, 2H).

[0340] 6 561.21H NMR (400 MHz, CD3OD) δ 9.01 (s, 1H), 8.85 (s, 1H),

[0341] 8.56 (s, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 6.74 (s, 1H), 6.62 (s, 1H), 4.81 (s, 2H), 3.85 (s, 3H), 3.02 (hept, J = 6.8 Hz, 1H), 1.75 (tt, J = 8.6, 4.8 Hz, 1H), 1.18 (d, J = 6.8 Hz, 6H), 1.12 - 1.06 (m, 2H), 0.86 - 0.80 (m, 2H).

[0342] 7 515.21H NMR (400 MHz, CD3OD) δ 9.00 (s, 1H), 8.85 (s, 1H),

[0343] Y N '^T

[0344] JUUL 8.56 (s, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.2 Hz,

[0345] 2H), 6.86 - 6.56 (m, 2H), 6.47 (s, 1H), 4.79 (s, 2H), 3.84 (s, 3H), 2.33 (s, 3H), 1.74 (tt, J = 8.5, 4.3 Hz, 1H), 1.12 -1V-^y / 1.04 (m, 2H), 0.86 - 0.76 (m, 2H).

[0346] 8 579.11H NMR (400 MHz, CD3OD) δ 9.03 (s, 1H), 8.87 (s, 1H),

[0347] Y ■^>r

[0348] JUUL 8.59 (s, 1H), 7.98 (s, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.44 (d, IL A J = 8.0 Hz, 1H), 7.38 (d, J = 10.7 Hz, 1H), 6.80 (s, 1H), o yO Oy 4.82 (s, 2H), 4.27 (hept, J = 6.6 Hz, 1H), 3.88 (s, 3H), 1.80 U

[0349] r y-CF’ (tt, J = 8.5, 4.7 Hz, 1H), 1.43 (d, J = 6.6 Hz, 6H), 1.15 - o o 1.09 (m, 2H), 0.88 -0.81 (m, 2H).

[0350] 9 562.21H NMR (400 MHz, CD3OD) δ 9.02 (s, 1H), 8.85 (s, 1H),

[0351] Y7 '^r 6z8.59 (s, 1H), 7.92 (s, 1H), 7.46 (s, 1H), 7.41 (d, J = 8.0 Hz, N JUUL NH 1H), 7.32 (d, J = 7.8 Hz, 1H), 6.81 (s, 1H), 4.76 (s, 2H), ’Ln" f / =Z Z— V ' jf 4.12 (hept, J = 6.3 Hz, 1H), 3.90 (s, 3H), 2.16 (s, 3H), 1.81 C LHA ^ / >"CF3(tt, J = 8.5, 4.7 Hz, 1H), 1.40 (d, J = 6.7 Hz, 6H), 1.17 - o O z / Z / — —— — 1.10 (m, 2H), 0.90 -0.82 (m, 2H).

[0352] 10 < > l> fAA-—

[0353] \ z= / — - / „ 1^

[0354] 10 562.21H NMR (400 MHz, CD3OD) δ 9.02 (s, 1H), 8.87 (s, 1H), 8.75 (s, 1H), 8.58 (s, 1H), 7.99 (s, 2H), 7.96 (s, 1H), 6.84 (s, 1H), 5.70 (hept, J = 6.7 Hz, 1H), 4.83 (s, 2H), 3.85 (s, 3H), 1.76 (tt, J = 8.5, 4.7 Hz, 1H), 1.50 (d, J = 6.7 Hz, 6H), 1.13 - 1.06 (m, 2H), 0.85 - 0.78 (m, 2H).

[0355] 11 575.21H NMR (400 MHz, CD3OD) δ 9.02 (s, 1H), 8.86 (s, 1H),

[0356] 8.58 (s, 1H), 8.29 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 6.75 (s, 1H), 5.55 (p, J = 7.0 Hz, 1H), 4.97 (t, J = 7.3 Hz, 2H), 4.85 (t, J = 6.7 Hz, 2H), 4.80 (s, 2H), 3.86 (s, 3H), 1.77 (tt, J = 8.4, 4.6 Hz, 1H), 1.15 - 1.06 (m, 2H), 0.88 - 0.79 (m, 2H).

[0357] 12 „ rci

[0358] \ 550.2 'H NMR (400 MHz, CD3OD) 5 9.02 (d, J = 1.7 Hz, 1H), Y7 A -N

[0359] 8.86 (d, J = 1.8 Hz, 1H), 8.59 (s, 1H), 7.62 (t, J = 8.1 Hz, N 1 '<< JUL NH F 1H), 7.43 (dd, J = 10.5, 2.0 Hz, 1H), 7.35 (dd, J = 8.3, 2.1 A Au Hz, 1H), 6.81 (s, 1H), 6.60 (s, 1H), 4.85 (s, 2H), 3.87 (s,

[0360] N X\—CF, 3H), 2.39 (s, 3H), 1.79 (tt, J = 8.5, 4.7 Hz, 1H), 1.16 - 1.08

[0361] (m, 2H), 0.90 -0.80 (m, 2H).

[0362] 13 _ 7 ^il

[0363] \7 ^N 532.2 'H NMR (400 MHz, CD3OD) 5 9.00 (d, J = 1.8 Hz, 1H), Y *'<r

[0364] 1 JUL 8.85 (d, J = 1.8 Hz, 1H), 8.56 (s, 1H), 7.60 (d, J = 8.2 Hz,

[0365] 2H), 7.49 (d, J = 8.2 Hz, 2H), 6.73 (s, 1H), 6.57 (s, 1H), A o 4.80 (s, 2H), 3.84 (s, 3H), 2.33 (s, 3H), 1.74 (tt, J = 8.6, 4.7

[0366] CF3Hz, 1H), 1.11 - 1.04 (m, 2H), 0.85 - 0.78 (m, 2H).

[0367] 14 „ fCl

[0368] \7 A ^N 532.2 'H NMR (400 MHz, CD3OD) 5 9.00 (d, J = 1.8 Hz, 1H), Y N "^T

[0369] JUUL 8.84 (d, J = 1.8 Hz, 1H), 8.56 (s, 1H), 7.68 (s, 1H), 7.64 (d, IL A Ux J = 8.1 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 6.74 (s, 1H), 4.78N° X 'AXIAX^N (s, 2H), 3.84 (s, 3H), 3.77 (s, 3H), 1.74 (tt, J = 8.3, 4.6 Hz, r 1H), 1.12 - 1.03 (m, 2H), 0.84 - 0.75 (m, 2H).

[0370]

[0371] Active 126539678.1 48 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0372] 15 546.21H NMR (400 MHz, CD3OD) δ 9.02 (d, J = 1.7 Hz, 1H),

[0373] 8.86 (d, J = 1.8 Hz, 1H), 8.58 (s, 1H), 7.79 (s, 1H), 7.60 (s, 4H), 6.76 (s, 1H), 4.80 (s, 2H), 4.12 (q, J = 7.3 Hz, 2H), Q 3.86 (s, 3H), 1.76 (tt, J = 8.7, 4.4 Hz, 1H), 1.38 (t, J = 7.4

[0374] Hz, 3H), 1.13 - 1.07 (m, 2H), 0.86 - 0.79 (m, 2H).

[0375] 16 559.11H NMR (400 MHz, CD3OD) δ 9.00 (s, 1H), 8.84 (s, 1H),

[0376] 8.56 (s, 1H), 7.74 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.45 (d, JLX J = 8.2 Hz, 1H), 7.43 (s, 1H), 6.74 (s, 1H), 4.75 (s, 2H), Vi 3.99 (t, J = 6.8 Hz, 2H), 3.84 (s, 3H), 2.71 (t, J = 7.1 Hz, Rs 2H), 2.34 (p, J = 6.9 Hz, 2H), 1.73 (tt, J = 8.2, 4.7 Hz, 1H),

[0377] 1.12 - 1.02 (m, 2H), 0.87 - 0.69 (m, 2H).

[0378] 17 601.31H NMR (400 MHz, CD3OD) δ 8.90 (d, J = 1.7 Hz, 1H),

[0379] 8.77 (d, J = 1.7 Hz, 1H), 8.61 (s, 1H), 7.73 (s, 1H), 6.96 (s, C 1H), 4.55 (s, 2H), 4.32 (t, J = 5.0 Hz, 3H), 4.24 - 4.10 (m,

[0380] J = 5.9, 5.1 Hz, 1H), 4.03 (t, J = 5.0 Hz, 3H), 3.93 (s, 3H), 3.44 (s, 3H), 1.85 (tt, J = 8.7, 4.8 Hz, 1H), 1.46 (d, J = 6.6 Hz, 6H), 1.17 (p, J = 4.0 Hz, 2H), 0.93 (dq, J = 7.3, 3.9 Hz, 2H).

[0381] 18 595.41H NMR (400 MHz, CD3OD) δ 8.98 (s, 1H), 8.80 (s, 1H),

[0382] 8.60 (s, 1H), 7.70 (s, 1H), 6.93 (s, 1H), 4.97 - 4.89 (m, 1H), A

[0383] iiX o> 4.25 (s, 2H), 3.94 (s, 3H), 3.44 (s, 2H), 2.36 - 2.23 (m, 2H),

[0384] X 2.19 - 2.03 (m, 4H), 1.93 - 1.78 (m, 3H), 1.45 (d, J = 6.5

[0385] Hz, 6H), 1.21 - 1.12 (m, 2H), 0.99 - 0.86 (m, 2H).

[0386] 19 549.61H NMR (400 MHz, CD3OD) δ 8.63 (s, 1H), 8.32 (s, 1H),

[0387] XA 8.12 (s, 1H), 7.98 (s, 1H), 7.69 - 7.59 (m, 4H), 6.83 (s, 1H),

[0388] 4.78 (s, 2H), 4.56 (p, J = 6.6 Hz, 1H), 3.89 (s, 3H), 1.92 - 1.83 (m, 1H), 1.47 (d, J = 6.6 Hz, 6H), 1.18 - 1.11 (m, 2H), 0.95 -0.87 (m, 2H).

[0389] 20 550.31H NMR (400 MHz, DMSO-d6) δ 9.23 (br s, 1H), 8.65 (s,

[0390] X 1H), 8.56 (s, 1H), 8.17 (s, 1H), 7.58 - 7.53 (m, 4H), 6.61

[0391] (s, 1H), 4.74 (s, 2H), 4.47-4.40 (m, 1H), 3.78 (s, 3H), 1.84 SQ - 1.80 (m, 1H), 1.38 (d, J = 6.8 Hz, 6H), 0.81- 0.81 (m, ^> 2H), 0.80 - 0.79 (m, 2H).

[0392] 21 522.31H NMR (400 MHz, DMSO-d6) δ 9.24 (t, J = 6.6 Hz, 1H),

[0393] IJL 8.65 (s, 1H), 8.57 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.55 (d,

[0394] J = 8.4 Hz, 2H), 6.75 (s, 1H), 6.63 (s, 1H), 4.75 (d, J = 6.8 xi Hz, 2H), 3.78 (s, 3H), 2.31 (s, 3H), 1.85 - 1.79 (m, 1H),

[0395] 1.01 - 0.98 (m, 2H), 0.84 - 0.80 (m, 2H).

[0396] 22 550.31H NMR (400 MHz, DMSO-d6) δ 8.71 (t, J = 6.0 Hz, 1H),

[0397] XJUL 8.66 (s, 1H), 8.51 (s, 1H), 8.16 (d, J = 0.8 Hz, 1H), 7.53 (s,

[0398] 4H), 6.53 (s, 1H), 4.69 (br s, 2H), 4.45 - 4.40 (m, 1H), 3.78 uu (s, 3H), 1.78 - 1.74 (m, 1H), 1.39 (d, J = 6.8 Hz, 6H), 1.01

[0399] - 0.98 (m, 2H), 0.82 - 0.80 (m, 2H).

[0400] 23 522.31H NMR (400 MHz, DMSO-d6): δ 8.71 (t, J = 6.0 Hz, 1H),

[0401] 8.67 (s, 1H), 8.51 (s, 1H), 7.59 - 7.52 (m, 4H), 6.75 (s, 1H), 6.54 (s, 1H), 4.70 (s, 2H), 3.79 (s, 3H), 2.31 (s, 3H), 1.78 - 1.72 (m, 1H), 1.01 - 0.99 (m, 2H), 0.84 - 0.82 (m, 2H).

[0402] 24 560.31H NMR (400 MHz, CD3OD) δ 8.86 (dd, J = 4.2, 1.6 Hz,

[0403] U 1H), 8.57 (s, 1H), 8.19 (dd, J = 8.6, 1.6 Hz, 1H), 7.92 - 7.88 (m, 1H), 7.74 (dd, J = 8.6, 4.2 Hz, 1H), 7.62 - 7.57 (m, 2H), 7.57 - 7.51 (m, 2H), 6.70 (s, 1H), 4.79 (s, 2H), L 4.54 (hept, J = 6.6 Hz, 1H), 3.86 (s, 3H), 1.74 - 1.64 (m,

[0404]

[0405] Active 126539678.1 49 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0406] 1H), 1.44 (d, J = 6.7 Hz, 6H), 1.13 - 1.02 (m, 2H), 0.87 - 0.74 (m, 2H).

[0407] 25 532.21H NMR (400 MHz, CD3OD) δ 8.84 (dd, J = 4.2, 1.6 Hz,

[0408] 1H), 8.56 (s, 1H), 8.19 (dd, J = 8.6, 1.6 Hz, 1H), 7.72 (dd, J = 8.5, 4.2 Hz, 1H), 7.62 - 7.57 (m, 2H), 7.52 - 7.44 (m, 2H), 6.64 (s, 1H), 6.57 (s, 1H), 4.78 (s, 2H), 3.85 (s, 3H), 2.33 (s, 3H), 1.71 - 1.61 (m, 1H), 1.15-0.99 (m, 2H), 0.88 J"" \i X. - 0.73 (m, 2H).

[0409] 26 561.41H NMR (400 MHz, CD3OD) δ 9.01 (d, J = 1.8 Hz, 1H),

[0410] XJJ 8.86 (d, J = 1.8 Hz, 1H), 8.57 (s, 1H), 7.91 (s, 1H), 7.60 (d, M

[0411] k J= 8.1 Hz, 2H), 7.54 (d, J= 8.1 Hz, 2H), 6.78 (s, 1H), 4.80

[0412] (s, 2H), 4.54 (hept, J = 6.7 Hz, 1H), 3.86 (s, 3H), 1.76 (tt, w

[0413] J

[0414] Y1 - J = 8.4, 4.6 Hz, 1H), 1.45 (d, J = 6.7 Hz, 6H), 1.16 - 1.04 CF3

[0415] C (m, 2H), 0.88 -0.75 (m, 2H).

[0416] 27 587.51H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 1.6 Hz, 1H),

[0417] 8.82 (d, J = 1.6 Hz, 1H), 8.68 (s, 1H), 8.05 (t, J = 6.4 Hz, 1H), 7.97 (s, 1H), 7.06 (s, 1H), 4.18 - 4.16 (m, 3H), 4.04 - 3.98 (m, 4H), 3.86 (s, 3H), 3.74 (d, J = 6.4 Hz, 2H), 1.89 - 1.84 (m, 1H), 1.38 (d, J = 6.4 Hz, 6H), 1.06-1.01 (m, 2H), 0.90 -0.87 (m, 2H).

[0418] 28 568.41H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 2.0 Hz, 1H),

[0419] N

[0420] J 8.81 (d, J = 2.0 Hz, 1H), 8.68 (s, 1H), 7.96 (t, J = 6.4 Hz,

[0421] 1H), 7.73 (d, J = 1.2 Hz, 1H), 6.94 (s, 1H), 4.37 - 4.34 (m, 1H), 3.87 (s, 3H), 3.37 - 3.35 (m, 2H), 2.75 - 2.72 (m, 2H), 2.51 - 2.49 (m, 2H), 1.91 - 1.46 (m, 4H), 1.46 - 1.38 (m, 2H), 1.34 (d, J = 6.4 Hz, 6H), 1.08 - 1.05 (m, 2H), 0.91 - 0.87 (m, 2H).

[0422] 29

[0423] ki?

[0424] t J,j

[0425] T ^YJT^ '

[0426] 30 o

[0427] \ / N X-A 575.51H NMR (400 MHz, DMSO-k) 59.06 (d, J = 2.0 Hz, 1H),

[0428] 8.87 (d, J = 1.6 Hz, 1H), 8.64 (s, 1H), 8.59 (t, J = 6.6 Hz, A 1H), 7.94 -7.94 (m, 1H), 7.52 (d, J = 8.0 Hz, lH), 7.19 (d,

[0429] J = 8.0 Hz, 1H), 7.15 (s, 1H), 6.80 (s, 1H), 4.65 (d, J = 6.4 JM Hz, 2H), 4.06 - 4.03 (m, 4H), 3.75 (s, 3H), 1.93 (br s, 2H), JJ 1.80 - 1.74 (m, 1H), 1.00 - 0.97 (m, 2H), 0.79 (d, J = 2.8

[0430] Hz, 2H).

[0431] 31 _ iki

[0432] VN589.4 'H NMR (400 MHz, DMSO-k) 59.06 (d, J = 1.6 Hz, 1H), k^N8.87 (d, J = 1.6 Hz, 1H), 8.64 (s, 1H), 8.50-8.70 (m, 1H),

[0433] 7.97 (br s, 1H), 7.30 - 7.40 (m, 2H), 7.20 (d, J = 8.0 Hz, 3 V 1H), 6.80 (s, 1H), 4.68 (d, J = 6.4 Hz, 2H), 4.17 (t, J = 5.0 J Hz, 2H), 3.76 (s, 3H), 3.60 - 3.70 (m, 2H), 1.80 - 1.90 (m, kJ 2H), 1.70 - 1.80 (m, 1H), 1.62 -1.69 (m, 2H), 0.96 - 1.08

[0434] (m, 2H), 0.75 - 0.85 (m, 2H).

[0435] 32 O

[0436] UU

[0437] X

[0438] 33 ^7 JL

[0439] JUUL

[0440] Vj k^i

[0441] 1UJ\

[0442] LACF!

[0443]

[0444] Active 126539678.1 50 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0445] 34

[0446] JO

[0447] H

[0448] ^N"? SQL

[0449] 35

[0450] N'A /

[0451] U A A A

[0452] uU b R K

[0453] 1ACF- 36

[0454] X X

[0455] 37

[0456] 38

[0457] 39 HN-Y

[0458] NXA'

[0459] J

[0460] Xc

[0461] A

[0462] 40

[0463] N N JU NH UA

[0464] p

[0465] 41

[0466] N AU

[0467] A1^lAXWX. N 42 ^. N XAA A AAX^N

[0468]

[0469] Active 126539678.1 51 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0470] 43

[0471] 44 573.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 1.6 Hz, 1H),

[0472] 8.87 (d, J = 1.6 Hz, 1H), 8.64 (s, 1H), 8.56 (t, J = 6.4 Hz, 1H), 7.95 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 6.0 Hz, 2H), 6.79 (s, 1H), 4.67 (d, J = 6.4 Hz, 2H), 4.03 - 3.98 3 M M r— (m, 1H), 3.75 (s, 3H), 2.72 - 2.71 (m, 1H), 2.51 - 2.44 (m, r y c / . _ 1H), 2.30 - 2.25 (m, 1H), 2.07 -2.00 (m, 1H), 1.80 - 1.76

[0473] (m, 1H), 1.45 (d, J = 6.8 Hz, 3H), 0.98 - 0.98 (m, 2H), 0.78 M - 0.77 (m, 2H).

[0474] 45

[0475] 46

[0476] U

[0477] N-~2 /

[0478] 47 597.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.09 (d, J = 2.0 Hz, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.77 (s, 1H), 8.75 (t, J = 6.6 Hz,

[0479] 1H), 8.16 (d, J = 1.2 Hz, 1H), 7.73 (t, J = 71.1 Hz, 1H), < X— 7.58 - 7.43 (m, 4H), 6.92 (s, 1H), 4.72 (d, J = 6.4 Hz, 2H), H 4.46 - 4.39 (m, 1H), 1.87 - 1.80 (m, 1H), 1.37 (d, J = 6.8

[0480] Hz, 6H), 1.06 - 1.04 (m, 2H), 0.87 - 0.85 (m, 2H).

[0481] 48 575.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 1H),

[0482] 8.87 (d, J = 2.0 Hz, 1H), 8.64 - 8.61 (m, 2H), 8.16 (d, J = 1.2 Hz, 1H), 7.55 - 7.50 (m, 4H), 6.80 (s, 1H), 7.50 (d, J = 2.8 Hz, 2H), 4.46 - 4.40 (m, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.83 - 1.76 (m, 1H), 1.38 (d, J = 6.4 Hz, 6H), 1.04 - 0.97 (m, 5H), 0.78 - 0.77 (m, 2H).

[0483] 49 603.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (d, J = 1.6 Hz, 1H),

[0484] L 8.88 (d, J = 1.6 Hz, 1H), 8.69 - 8.65 (m, 1H), 8.59 (s, 1H),

[0485] 8.15 - 8.14 (m, 2H), 7.58 - 7.51 (m, 4H), 6.96 (s, 1H), 4.74 - 4.70 (m, 4H), 4.47 - 4.40 (m, 1H), 4.29 - 4.25 (m, 2H), 0 1.91 - 1.82 (m, 1H), 1.38 (d, J = 6.4 Hz, 6H), 1.01 - 0.99

[0486] (m, 2H), 0.86 -0.78 (m, 2H).

[0487] 50

[0488] 51 563.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 1H),

[0489] 8.87 (d, J = 2.0 Hz, 1H), 8.64 (s, 1H), 8.61 (s, 1H), 8.16 (d, X J = 0.8 Hz, 1H), 7.60 - 7.42 (m, 4H), 6.81 (s, 1H), 4.47 - Mf 4.40 (m, 1H), 3.75 (s, 3H), 1.80 - 1.74 (m, 1H), 1.38 (d, J = 6.8 Hz, 6H), 1.10 - 0.90 (m, 2H), 0.84 - 0.70 (m, 2H).

[0490]

[0491] Active 126539678.1 52 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0492] 52

[0493] 53

[0494] N AJUL

[0495] “A

[0496] 1uu

[0497] Y^CF1

[0498] 54 559.3 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 1H),

[0499] AAA 8.87 (d, J = 2.0 Hz, 1H), 8.63 - 8.58 (m, 2H), 7.91 (d, J = H. A A 1.2 Hz, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz,1ULN 2H), 6.81 (s, 1H), 4.70 (d, J = 6.8 Hz, 2H), 3.75 (s, 3H),

[0500] 3.73 - 3.68 (m, 1H), 1.79 - 1.75 (m, 1H), 0.99 - 0.94 (m, 4H), 0.90 - 0.89 (m, 2H), 0.88 - 0.87 (m, 2H).

[0501] 55 575.4 ¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (d, J = 1.6 Hz, 1H),

[0502] 8.89 (d, J= 1.6 Hz, 1H), 8.63 - 8.63 (m, 1H), 8.16 - 8.15 XJOC (m, 1H), 8.13 (d, J= 8.0Hz, 1H), 7.63 (d,.7= 8.0 Hz, 2H), VA ^ 7.52 (d, J = 8.0 Hz, 2H), 6.71 (s, 1H), 5.04- 4.97 (m, 1H),1W r Z>—CF3 4.47- 4.40 (m, lH), 3.71 (s, 3H), 1.73 - 1.67 (m, 4H), 1.39

[0503] (d, J = 4.4 Hz, 6H), 0.98 (d, J = 4.8 Hz, 2H), 0.97 - 0.95 (m, 1H), 0.94 -0.93 (m, 1H).

[0504] 56 575.4 ¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (d, J = 1.6 Hz, 1H),

[0505] 8.89 (d, J= 1.6 Hz, 1H), 8.63 (s, 1H), 8.16 (s, 1H), 8.13 (d, LCC

[0506] ii A A ” J = 7.6 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.4 O Z / 1— — Hz, 2H), 6.71 (s, 1H), 5.04 - 4.99 (m, 1H), 4.47 - 4.41 (m, AA"

[0507] ^ r / >-*=. 1H), 3.71 (s, 3H), 1.60 - 1.80 (m, 4H), 1.30 - 1.50 (m, 6H),

[0508] 0.90 - 1.08 (m, 2H), 0.60 - 0.85 (m, 2H).

[0509] 57 631.4 ¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (d, J = 2.0 Hz, 1H),

[0510] 8.88 (d, J = 1.6 Hz, 1H), 8.62 - 8.61 (m, 2H), 8.15 (d, J = I AX 0.8 Hz, 1H), 7.52 - 7.52 (m, 4H), 6.83 (s, 1H), 5.20 (d, J =

[0511] 3.6 Hz, 1H), 4.72 (d, J = 6.4 Hz, 2H), 4.47 - 4.44 (m, 1H), 3.54 - 3.34 (m, 2H), 3.35 - 3.32 (m, 2H), 1.83 - 1.75 (m, A A 3H), 1.41 - 1.31 (m, 8H), 0.99 - 0.98 (m, 2H), 0.80 - 0.77

[0512] (m, 2H).

[0513] 58 589.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 1H),

[0514] 8.87 (d, J = 2.0 Hz, 1H), 8.65 (s, 1H), 8.52 (t, J = 6.6 Hz, XA 1H), 8.17 (d, J = 0.8 Hz, 1H), 7.21 (s, 2H), 6.83 (s, 1H), k NA o L r;^ Ax 4.62 (d, J = 6.4 Hz, 2H), 3.81 - 3.74 (m, 4H), 1.92 (s, 6H),1uu

[0515] 1 H / ACF>1.84 - 1.77 (m, 1H), 1.30 (d, J = 6.8 Hz, 6H), 1.02 - 0.99

[0516] (m, 2H), 0.81 -0.80 (m, 2H).

[0517] 59 589.4 ¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (d, J = 2.0 Hz, 1H),

[0518] 8.90 (d, J = 2.0 Hz, 1H), 8.62 (s, 1H), 8.14 (d, J = 0.8 Hz, N A XA NH I 1H), 8.06 (d, J= 7.2 Hz, 1H), 7.55 (d, J= 8.0 Hz, 1H), 7.40 I Aic (s, 1H), 7.32 (d, J= 8.0 Hz, 1H), 6.51 (s, 1H), 5.07 (t, J = _^N rA / )-CF3 6.8 Hz, 1H), 4.48 - 4.42 (m, 1H), 3.70 (s, 3H), 2.47 (s, 3H),

[0519] 1.78 - 1.77 (m, 1H), 1.75 (d, J = 4.0 Hz, 3H), 1.44 (d, J = 6.0 Hz, 6H), 0.99 - 0.93 (m, 2H), 0.81 - 0.80 (m, 1H), 0.79 - 0.77 (m, 1H).

[0520] 60 589.4 ¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (d, J = 1.6 Hz, 1H),

[0521] 8.90 (d, J= 2.0 Hz, 1H), 8.62 (s, 1H), 8.14 (d, J= 1.2 Hz, XA 1H), 8.06 (d, J= 12 Hz, 1H), 7.55 (d, J= 8.0 Hz, 1H), 7.40

[0522] (s, 1H), 7.32 (dd, J= 8.0, 1.6 Hz, 1H), 6.51 (s, 1H), 5.07 * A (t, J= 7.0 Hz, 1H), 4.48 - 4.42 (m, 1H), 3.70 (s, 3H), 2.47

[0523] (s, 3H), 1.78 - 1.74 (m, 1H), 1.64 (d, J= 6.8 Hz, 3H), 1.38

[0524]

[0525] Active 126539678.1 53 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0526] (d, J= 6.4 Hz, 6H), 0.99 - 0.98 (m, 2H), 0.98 - 0.96 (m, 1H), 0.95 - 0.93 (m, 1H).

[0527] 61 589.4 ¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (d, J = 2.0 Hz, 1H),

[0528] 8.90 (d, J= 2.0 Hz, 1H), 8.62 (s, 1H), 8.14 (d, J= 1.2 Hz, 1H), 8.06 (d, J= 12 Hz, 1H), 7.55 (d, J= 8.0 Hz, 1H), 7.33 (s, 1H), 7.31 (d, J= 1.2 Hz, 1H), 6.51 (s, 1H), 5.07 (t, J = 7.0 Hz, 1H), 4.48 - 4.42 (m, 1H), 3.70 (s, 3H), 2.47 (s, 3H), 1.78 - 1.74 (m, 1H), 1.64 (d, J = 6.8 Hz, 3H), 1.38 (d, J = y 6.4 Hz, 6H), 0.99 - 0.98 (m, 2H), 0.98 - 0.97 (m, 1H), 0.96

[0529] - 0.95 (m, 1H).

[0530] 62 573.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 1H),

[0531] 8.87 (d, J = 2.0 Hz, 1H), 8.72 - 8.70 (m, 2H), 8.27 (d, J = it XXXK Q 0.8 Hz, 1H), 7.59 - 7.50 (m, 4H), 6.80 (s, 1H), 4.72 (t, J = U 6.6 Hz, 3H), 3.75 (s, 3H), 2.51 - 2.49 (m, 4H), 1.79 - 1.71 uu (m, 3H), 1.00 - 0.96 (m, 2H), 0.78 -0.74 (m, 2H).

[0532] f

[0533] 63 573.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (d, J = 2.0 Hz, 1H),

[0534] XJOC 8.84 (d, J = 1.6 Hz, 1H), 8.55 (s, 1H), 7.69 (d, J = 8.0 Hz, A 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 0.8 Hz, 1H), 7.45

[0535] (s, 1H), 6.70 (s, 1H), 4.85 (s, 3H), 4.79 (d, J = 1.6 Hz, 1H), UU 3.82 (s, 3H), 2.81 -2.72 (m, 3H), 2.13 - 2.12 (m, 1H), 1.73

[0536] - 1.71 (m, 1H), 1.08 - 1.01 (m, 5H), 0.81 - 0.77 (m, 2H).

[0537] 64 573.4 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 1.6 Hz, 1H),

[0538] 8.87 (d, J = 1.6 Hz, 1H), 8.64 (s, 1H), 8.56 (t, J = 6.4 Hz, XjuC

[0539] it A 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.391(d, J = 6.0 Hz, 2H), 6.79 (s, 1H), 4.67 (d, J = 6.4 Hz, 2H), UULM. 4.02- 3.99 (m, 1H), 3.75 (s, 3H), 2.70 - 2.67 (m, 1H), 2.51

[0540] - 2.50 (m, 1H), 2.50 - 2.32 (m, 1H), 2.01 - 1.99 (m, 1H), 1.79 - 1.75 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H), 0.98 - 0.97 (m, 2H), 0.77 - 0.75 (m, 2H).

[0541] 65 573.4 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 1.6 Hz, 1H),

[0542] 8.87 (d, J = 1.6 Hz, 1H), 8.64 (s, 1H), 8.56 (t, J = 6.4 Hz, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 6.0 Hz, 2H), 6.79 (s, 1H), 4.67 (d, J = 6.4 Hz, 2H), 4.02- 3.99 (m, 1H), 3.75 (s, 3H), 2.70 - 2.67 (m, 1H), 2.51 - 2.50 (m, 1H), 2.50 - 2.32 (m, 1H), 2.01 - 1.99 (m, 1H), 1.79 - 1.75 (m, 1H), 1.45 (d, J = 6.8 Hz, 3H), 0.98 - 0.96 (m, 2H), 0.77 - 0.73 (m, 2H).

[0543] 66 573.4 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 1H),

[0544] 8.87 (d, J = 1.6 Hz, 1H), 8.63 (s, 1H), 8.58 - 8.58 (m, 1H), m

[0545] It A Ux 7.77 (d, J = 8.8 Hz, 1H), 7.62 (s, 1H), 7.38 (d, J = 7.2 Hz,

[0546] 2H), 6.74 (s, 1H), 4.68 - 4.63 (m, 3H), 3.73 (s, 3H), 2.86 - 2.81 (m, 1H), 2.74 - 2.71 (m, 1H), 2.51 - 2.49 (m, 1H),X— < CF32.05 - 2.04 (m, 1H), 1.76 - 1.73 (m, 1H), 1.01 - 0.96 (m,

[0547] 5H), 0.76 - 0.74 (m, 2H).

[0548] 67 573.4 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 1H),

[0549] AJOC 8.87 (d, J = 1.6 Hz, 1H), 8.63 (s, 1H), 8.58 - 8.58 (m, 1H),

[0550] 7.77 (d, J = 8.8 Hz, 1H), 7.62 (s, 1H), 7.38 (d, J = 7.2 Hz, vX S 2H), 6.74 (s, 1H), 4.68 - 4.63 (m, 3H), 3.73 (s, 3H), 2.86 - 2.81 (m, 1H), 2.74 - 2.71 (m, 1H), 2.51 - 2.49 (m, 1H), A 2.05 - 2.04 (m, 1H), 1.76 - 1.73 (m, 1H), 1.01 - 0.96 (m,

[0551] 5H), 0.76 - 0.74 (m, 2H).

[0552] 68 573.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 1H),

[0553] 8.87 (d, J= 2.0 Hz, 1H), 8.64 (s, 1H), 8.61 (d, J = 6.4 Hz, XjuC

[0554] t A k / x 1H), 8.01 (d, J= 1.2 Hz, 1H), 7.61 (d,.7 = 8.4 Hz, 2H), 7.53

[0555] (d, J= 8.4 Hz, 2H), 6.80 (s, 1H), 4.71 (d, J= 6.4 Hz, 2H),1UM

[0556] / .\_ / rN-M / V-^. 3.90 (d, J = 6.8 Hz, 2H), 3.75 (s, 3H), 1.79- 1.76 (m, 1H),

[0557] 1.10 - 1.08 (m, 1H), 0.99 - 0.97 (m, 2H), 0.77 - 0.75 (m,

[0558]

[0559] 2H), 0.50 - 0.45 (m, 2H), 0.28 - 0.25 (m, 2H).

[0560] Active 126539678.1 54 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0561] 69 589.6 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 1H),

[0562] 8.87 (d, J = 1.6 Hz, 1H), 8.64 (s, 1H), 8.62 (t, J = 6.2 Hz, 1H), 7.94 (d, J = 1.2 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 6.82 (s, 1H), 4.71 (d, J = 6.4 Hz, 2H), 4.56 - 4.52 (m, 2H), 4.40 (d, J = 7.6 Hz, 2H), 4.20 (t, J = 6.0 Hz, 2H), 3.75 (s, 3H), 3.30 - 3.28 (m, 1H), 1.80 - 1.76 (m, 1H), 1.00 - 0.97 (m, 2H), 0.80 - 0.76 (m, 2H).

[0563] 70 577.3 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 1H),

[0564] X 8.87 (d, J = 2.0 Hz, 1H), 8.64 (s, 1H), 8.61 (t, J = 6.6 Hz, ° — fi V* 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.53 00= (d, J = 8.4 Hz, 2H), 6.80 (s, 1H), 4.70 (d, J = 6.4 Hz, 2H),

[0565] 4.18 (t, J = 5.2 Hz, 2H), 3.75 (s, 3H), 3.61 (t, J = 5.2 Hz, 2H), 3.16 (s, 3H), 1.81 - 1.75 (m, 1H), 1.00-0.96 (m, 2H), 0

[0566] 0 0.80 - 0.77 (m, 2H).

[0567] 71 563.3 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 1H),

[0568] XAX 8.87 (d, J= 1.6 Hz, 1H), 8.64 (s, 1H), 8.33 - 8.27 (m, 1H),

[0569] 7.93 (s, 1H), 7.34 (d, J= 8.0 Hz, 1H), 7.29 (s, 1H), 7.22 (d,.7 = 7.6 Hz, 1H), 6.74 (s, 1H), 4.62 (d,.7 = 6.0 Hz, 2H), 3.88 UU0 V >-CF> (s, 3H), 3.76 (d, J= 6.0 Hz, 6H), 1.82 - 1.75 (m, 1H), 1.02

[0570] - 0.95 (m, 2H), 0.80 - 0.77 (m, 2H).

[0571] 72 561.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 1.6 Hz, 1H),

[0572] 8.87 (d, J = 2.0 Hz, 1H), 8.64 (s, 1H), 8.57 (t, J = 6.6 Hz, 1H), 8.00 (d, J = 0.8 Hz, 1H), 7.40 (s, 1H), 7.34 - 7.29 (m, 2H), 6.82 (s, 1H), 4.67 (d, J = 6.4 Hz, 2H), 3.79 - 3.73 (m, 5H), 2.08 (s, 3H), 1.82 - 1.76 (m, 1H), 1.18 (t, J = 3.6 Hz, 3H), 1.00 - 1.00 (m, 2H), 0.99 - 0.98 (m, 2H).

[0573] 73 591.4 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 1.6 Hz, 1H),

[0574] N 'Xr- t ''. J''''N H8.86 (d, J = 2.0 Hz, 1H), 8.64 (s, 1H), 8.56 (t, J = 6.6 Hz,

[0575] 1H), 7.94 (d, J= 1.2 Hz, 1H), 7.39 (s, 1H), 7.31 (t, J= 9.0 X _yO xc Hz, 2H), 6.82 (s, 1H), 4.66 (d, J= 6.4 Hz, 2H), 3.91 (t, J = 00X 0tAFi5.2 Hz, 2H), 3.77 (s, 3H), 3.47 (t, J= 5.2 Hz, 2H), 3.09 (s,

[0576] 3 H), 2.08 (s, 3H), 1.83 - 1.77 (m, 1H), 1.02-0.98 (m, 2H), 0.82 -0.82 (m, 2H).

[0577] 74 547.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 1H),

[0578] XJUC 8.87 (d, J= 1.6 Hz, 1H), 8.64 (s, 1H), 8.57 (t, J = 6.6 Hz,

[0579] 1H), 7.91 (d, J= 0.8 Hz, 1H), 7.40 (s, 1H), 7.33 (s, 2H),1ULN 6.81 (s, 1H), 4.66 (d, J= 6.4 Hz, 2H), 3.76 (s, 3H), 3.47 (s,

[0580] NX 3H), 2.12 (s, 3H), 1.81-1.75 (m, 1H), 1.01-0.98 (m, 2H),

[0581] 0.81-0.80 (m, 2H).

[0582] 75 603.6 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 2H),

[0583] 8.87 (d, J= 1.6 Hz, 2H), 8.64 (s, 1H), 8.56 (t, J = 6.4 Hz, XXX 1H), 7.96 (d, J= 0.8 Hz, 1H), 7.41 (s, 1H), 7.38 - 7.30 (m, ° So0Vc, 2H), 6.83 (d,.7= 5.2 Hz, 1H), 4.68 (d,.7 = 6.4 Hz, 2H), 4.51

[0584] (t, J= 3.8 Hz, 2H), 4.13 - 4.10 (m, 3H), 3.77 (s, 3H), 2.08 (s, 3H), 1.85 - 1.75 (m, 1H), 1.02 - 0.98 (m, 2H), 0.82 - 0.78 (m, 2H).

[0585] 76 577.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 1.6 Hz, 1H),

[0586] 8.87 (d, J = 1.6 Hz, 1H), 8.64 (s, 1H), 8.60 (t, J = 6.6 Hz, 1H), 7.93 (d, J = 1.2 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 6.81 (s, 1H), 5.09 (br s, 1H), 4.70 (d, J = 6.4 Hz, 2H), 3.99 - 3.85 (m, 3H), 3.75 (s, 3H), 1.82 - 1.75 (m, 1H), 1.00 - 0.97 (m, 5H), 0.80 - 0.76 (m, 2H).

[0587] 77 589.3 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 1H),

[0588] 8.87 (d, J = 2.0 Hz, 1H), 8.65 (s, 1H), 8.57 (t, J = 6.6 Hz, 1H), 8.48 (d, J= 1.2 Hz, 1H), 7.40 (s, 1H), 7.32 (d, J= 8.0 Hz, 1H), 7.20 (d, J= 8.0 Hz, 1H), 6.81 (s, 1H), 5.09 - 5.02 (m, 1H), 4.78 - 4.72 (m, 4H), 4.66 (d, J= 6.4 Hz, 2H), 3.77 (s, 3H), 2.01 (s, 3H), 1.82 - 1.75 (m, 1H), 1.02 - 0.98 (m,

[0589]

[0590] 2H), 0.82 -0.81 (m, 2H).

[0591] Active 126539678.1 55 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0592] 78 605.3 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 1.6 Hz, 1H),

[0593] X ''•>rXX 8.87 (d, J = 1.6 Hz, 1H), 8.64 (s, 1H), 8.54 (t, J = 6.4 Hz,

[0594] 2H), 7.83 (d, J = 1.2 Hz, 1H), 7.37 (s, 1H), 7.30 (t, J = 6.4 Hz, 1H), 6.81 (s, 1H), 4.84 (br s, 1H), 4.66 (d, J = 6.4 Hz, 2H), 3.77 (s, 3H), 3.73 (s, 2H), 2.09 (s, 3H), 1.83 - 1.77 (m, 1H), 1.01 - 0.99 (m, 2H), 0.85 (s, 6H), 0.82 - 0.79 (m, 2H).

[0595] 79 591.6 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 1H),

[0596] I XX 8.87 (d, J = 2.0 Hz, 1H), 8.64 (s, 1H), 8.60 (t, J = 6.4 Hz,NH1H), 7.84 (d, J = 0.8 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.51?(d, J = 8.0 Hz, 2H), 6.80 (s, 1H), 4.86 (br s, 1H), 4.70 (d, J ‘xx.

[0597] XXCF= 6.4 Hz, 2H), 3.98 (s, 2H), 3.76 (s, 3H), 1.82 - 1.75 (m,

[0598] 1H), 0.99 - 0.96 (m, 2H), 0.90 (s, 6H), 0.80 - 0.79 (m, 2H). HO zV \

[0599] 80 591.3 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (s, 1H), 8.87 (d, J XAX = 1.6 Hz, 1H), 8.64 (s, 1H), 8.55 (t, J= 6.2 Hz, 1H), 7.91

[0600] (s, 1H), 7.38 (s, 1H), 7.31 (s, 2H), 6.83 (s, 1H), 4.98 (br s, il X 0 1H), 4.66 (d, J= 6.4 Hz, 2H), 3.77 (s, 3H), 3.74 - 3.73 (m,

[0601] 1H), 3.71 -3.70 (m, 1H), 3.64 - 3.59 (m, 1H), 2.09 (s, 3H), 1.82 - 1.78 (m, 1H), 1.05 - 1.00 (m, 2H), 0.87 (d, J= 6.4 / Hz, 3H), 0.82 - 0.79 (m, 2H).

[0602] 81 601.3 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 1.6 Hz, 1H),

[0603] 8.87 (d, J = 1.6 Hz, 1H), 8.63 (s, 1H), 8.57 (t, J = 6.4 Hz, XXX 1H), 8.03 (d, J = 1.2 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.49

[0604] (d, J = 8.0 Hz, 2H), 6.78 (s, 1H), 5.97 (s, 1H), 4.69 (d, J =v?^0- 6.4 Hz, 2H), 4.11 (d, J = 2.4 Hz, 2H), 3.77 - 3.75 (m, 5H),

[0605] 0^ 2.32 - 2.30 (m, 2H), 1.80 - 1.74 (m, 1H), 0.99 - 0.96 (m,

[0606] 2H), 0.79 - 0.76 (m, 2H).

[0607] 82 587.3 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 1.6 Hz, 1H),

[0608] 8.87 (d, J = 1.6 Hz, 1H), 8.63 - 8.58 (m, 2H), 8.16 (d, J = XXl 1.2 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, kX

[0609] 1UL vN 2H), 6.79 (s, 1H), 6.04-6.03 (m, 1H), 4.71 -4.55 (m, 6H),

[0610] N-~y / XCF> 3.75 (s, 3H), 1.79 - 1.74 (m, 1H), 0.99 - 0.98 (m, 2H), 0.79

[0611] - 0.76 (m, 2H).

[0612] cr

[0613] 83 589.4 ¹H NMR (400 MHz, DMSO-d₆): δ 9.06 (d, J = 2.0 Hz, 1H),

[0614] X A 8.87 (d, J = 2.0 Hz, 1H), 8.64 - 8.61 (m, 2H), 7.87 (s, 1H),

[0615] 7.56 (s, 4H), 6.81 (s, 1H), 4.89 - 4.88 (m, 1H), 4.71 (d, J = X 6.4 Hz, 2H), 4.12 -4.09 (m, 1H), 3.90 - 3.86 (m, 1H), 3.83 NX / - 3.80 (m, 1H), 3.75 - 3.70 (m, 4H), 2.45 - 2.42 (m, 1H),

[0616] 2.07 - 2.07 (m, 1H), 1.24 - 1.21 (m, 1H), 1.00 - 0.78 (m, 2H), 0.77 - 0.75 (m, 2H).

[0617] 84 601.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (d, J = 1.6 Hz, 1H),

[0618] XJOC 8.87 (d, J = 2.0 Hz, 1H), 8.65 (s, 1H), 8.57 (t, J = 6.4 Hz,

[0619] 1H), 8.23 (d, J= 1.2 Hz, 1H), 7.39 (s, 1H), 7.33 (s, 2H), kX

[0620] 16.80 (s, 1H), 5.65 (t, J= 2.0 Hz, 1H), 4.75 - 4.65 (m, 2H), AV XXCF14.52 - 4.50 (m, 2H), 4.44 - 4.41 (m, 2H), 3.77 (s, 3H), 2.07

[0621] (s, 3H), 1.81 - 1.77 (m, 1H), 1.02 - 0.99 (m, 2H), 0.83 - O'"40.80 (m, 2H).

[0622] 85 617.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 1H),

[0623] XAX 8.87 (d, J = 2.0 Hz, 1H), 8.65 (s, 1H), 8.58 (t, J = 6.4 Hz,

[0624] 1H), 8.20 (s, 1H), 7.40 (s, 1H), 7.34 - 7.32 (m, 2H), 6.83 kf'V'

[0625] 1(s, 1H), 4.68 (d, J = 6.4 Hz, 2H), 3.85 - 3.78 (m, 6H), 3.21 XXx- 3.24 (m, 2H), 2.00 - 1.99 (m, 5H), 1.81 - 1.80 (m, 3H), ^TxCF" 1.00 (s, 2H), 0.81 - 0.80 (m, 2H).

[0626]

[0627] Active 126539678.1 56 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0628] 86 551.5 ¹H NMR (400 MHz, CD₃OD) δ 8.98 (d, J = 1.9 Hz, 1H),

[0629] 8.81 (d, J = 1.9 Hz, 1H), 8.54 (s, 1H), 7.73 - 7.67 (m, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.52 - 7.42 (m, 2H), 6.81 (s, 1H), 4.81 (s, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 1.78 (tt, J = 8.1, 4.7 Hz, 1H), 1.13 - 1.04 (m, 2H), 0.86 - 0.77 (m, 2H).

[0630] 87 561.3 ¹H NMR (400 MHz, CD₃OD) δ 8.99 (d, J = 1.9 Hz, 1H),

[0631] 8.81 (d, J = 1.9 Hz, 1H), 8.54 (s, 1H), 7.69 (q, J = 1.2 Hz, ^ / =1z

[0632] AAAA V v 1H), 7.29 (s, 1H), 7.19 (s, 1H), 6.74 (s, 1H), 4.66 (s, 2H),

[0633] 3.85 (s, 3H), 3.53 (s, 3H), 2.38 (s, 3H), 2.06 (s, 3H), 1.80 (tt, J = 8.0, 4.7 Hz, 1H), 1.18 - 1.03 (m, 2H), 0.90 - 0.77 40= (m, 2H).

[0634] 88 551.2 ¹H NMR (400 MHz, CD₃OD) δ 9.01 (d, J = 2.0 Hz, 1H),

[0635] 8.86 (d, J= 1.9 Hz, 1H), 8.57 (s, 1H), 7.74 (s, 1H), 7.53 (t, A J= 7.6 Hz, 1H), 7.44 - 7.33 (m, 2H), 6.78 (s, 1H), 4.80 (s,

[0636] 2H), 3.85 (s, 3H), 3.64 (s, 3H), 1.81 - 1.72 (m, 1H), 1.12 - 1.07 (m, 2H), 0.87 - 0.79 (m, 2H).

[0637] 89 607.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 1H),

[0638] 8.87 (d, J = 1.6 Hz, 1H), 8.64 (s, 1H), 8.39 (br s, 1H), 7.92 (d, J = 1.2 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 1.2 Hz, 1H), 7.23 (dd, J = 7.8 Hz, 1.4 Hz, 1H), 6.77 (s, 1H), 4.63 (d, J = 6.0 Hz, 2H), 4.22 - 4.20 (m, 2H), 3.76 (d, J = 4.0 Hz, 6H), 3.64 - 3.62 (m, 2H), 3.22 (s, 3H), 1.78 - 1.72 (m, 1H), 1.00 - 0.97 (m, 2H), 0.80 - 0.79 (m, 2H).

[0639] 90 563.4 ¹H NMR (400 MHz, DMSO-d₆): δ 9.12 (s, 1H), 8.96 (s,

[0640] 1H), 8.70 (s, 1H), 7.88 (d, J = 1.2 Hz, 1H), 7.32 - 7.29 (m, X Xx

[0641] ll A 2H), 7.11 - 6.95 (m, 3H), 4.76 (s, 2H), 3.80 (s, 3H), 3.77 " 1 (s, 3H), 3.46 (s, 3H), 1.81 - 1.79 (m, 1H), 1.02 - 0.80 (m, M C A oC

[0642] J J J)) A \ \\\ CKz z4H).

[0643] 91 594.7 ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (d, J = 2.0 Hz, 1H),

[0644] 1 v t jO

[0645] I ifr 8.80 (d, J = 2.0 Hz, 1H), 8.68 (s, 1H), 7.85 (t, J = 6.0 Hz, l A < A 1H), 7.66 - 7.66 (m, 1H), 6.90 (s, 1H), 4.43 - 4.40 (m, 1H), 1 VX> 3.87 (s, 3H), 3.78 - 3.76 (m, 2H), 3.32 - 3.25 (m, 2H), 2.50

[0646] - 2.49 (m, 1H), 2.07 - 1.97 (m, 2H), 1.88 - 1.85 (m, 1H), \ 1.69 - 1.51 (m, 6H), 1.36 (d, J = 6.4 Hz, 6H), 1.08 - 1.05

[0647] (m, 2H), 0.90 -0.86 (m, 2H).

[0648] 92 597.5 ¹H NMR (400 MHz, CD₃OD) δ 8.99 (d, J = 1.9 Hz, 1H),

[0649] 8.81 (d, J = 1.9 Hz, 1H), 8.62 (s, 1H), 7.99 - 7.94 (m, 1H), A LAA ci 7.34 - 7.25 (m, 2H), 7.01 (s, 1H), 4.83 (s, 2H), 4.58 (hept,1

[0650] F1A» J = 6.6 Hz, 1H), 3.92 (s, 3H), 1.83 (tt, J = 8.4, 4.7 Hz, 1H), v / CCF> 1.46 (d, J = 6.7 Hz, 6H), 1.19 - 1.12 (m, 2H), 0.94 - 0.86

[0651] (m, 2H).

[0652] 93 597.5 ¹H NMR (400 MHz, CD₃OD) δ 9.01 (d, J = 1.9 Hz, 1H), ii 8.85 (d, J = 1.9 Hz, 1H), 8.57 (s, 1H), 8.02 (d, J = 1.3 Hz,

[0653] 1H), 7.31 - 7.21 (m, 2H), 6.82 (s, 1H), 4.81 (s, 2H), 4.18NA I V TX V z>~ (hept, J = 6.7 Hz, 1H), 3.87 (s, 3H), 1.80 (tt, J = 8.1, 4.7

[0654] CFJ Hz, 1H), 1.42 (d, J = 6.7 Hz, 6H), 1.17- 1.07 (m, 2H), 0.89

[0655] - 0.78 (m, 2H).

[0656] 94 561.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 1.6 Hz, 1H),

[0657] 8.87 (d, J = 2.0 Hz, 1H), 8.64 (s, 1H), 8.58 (t, J = 6.4 Hz, 1H), 7.91 (d, J = 0.8 Hz, 1H), 7.43 (s, 1H), 7.35 - 7.33 (m, 2H), 6.82 (s, 1H), 4.68 (d, J = 6.4 Hz, 2H), 3.77 (s, 3H), 3.45 (s, 3H), 2.46 - 2.44 (m, 2H), 1.79 - 1.73 (m, 1H), 0.98

[0658]

[0659] - 0.99 (m, 2H), 0.98 - 0.95 (m, 3H), 0.93 - 0.92 (m, 2H).

[0660] Active 126539678.1 57 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0661] 95 613.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.20 (s, 1H), 9.10 (s,

[0662] 1H), 8.75 (s, 1H), 8.63 - 8.61 (m, 1H), 8.35 - 8.32 (m, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.22 - 6.97 (m, 2H), 4.90 (d, J = 5.6 Hz, 2H), 3.86 (s, 3H), 3.33 (d, J= 12.0 Hz, 2H), 3.09 - 3.04 (m, 2H), 1.84 - 1.78 (m, 5H), 1.26 - 0.82 (m, 4H).

[0663] 96 655.7 ¹H NMR (400 MHz, DMSO-d₆) δ 9.22 (d, J = 2.0 Hz, 1H),

[0664] AAA 9.14 (d, J = 2.0 Hz, 1H), 8.78 (s, 1H), 8.18 (d, J = 8.0 Hz, ll 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.49 N X 0 Ti

[0665] 1(d, J = 7.2 Hz, 2H), 7.30 (s, 1H), 4.95 (d, J = 6.4 Hz, 2H),

[0666] 4.46 - 4.34 (m, 2H), 3.79 (s, 4H), 2.96 - 2.95 (m, 2H), 2.50 - 2.34 (m, 1H), 2.01 (s, 3H), 1.86 - 1.70 (m, 4H), 1.55 - 1.51 (m, 1H), 1.06 -0.83 (m, 4H).

[0667] 97 547.3 ¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (d, J = 1.8 Hz, 1H),

[0668] 8.79 (d, J = 1.8 Hz, 1H), 8.67 (s, 1H), 7.93 (d, J = 1.4 Hz, 1H), 7.74 -7.62 (m, 2H), 7.50 -7.40 (m, 2H), 7.01 (s, 1H), 5.37 (s, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.30 (s, 3H), 1.91 - 1.79 (m, 1H), 1.06 - 0.99 (m, 2H), 0.92 - 0.80 (m, 2H).

[0669] 98 573.3 ¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (d, J = 1.8 Hz, 1H),

[0670] 8.83 (d, J = 1.8 Hz, 1H), 8.69 (s, 1H), 7.90 (d, J = 1.4 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.43 (s, 1H), 7.37 - 7.27 (m, 2H), 5.57 (s, 2H), 3.88 (s, 3H), 3.73 (s, 3H), 2.83 (dq, J = 6.7, o o u? uT

[0671] \ ° 1— 3.4 Hz, 1H), 1.93 (tt, J = 8.3, 4.6 Hz, 1H), 1.12 - 1.03 (m,

[0672] 2H), 0.98 - 0.86 (m, 4H), 0.73 - 0.62 (m, 2H).

[0673] QA

[0674] 99 617.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 1H),

[0675] \7

[0676] ^z_ / A. ■ 8.87 (d, J = 1.6 Hz, 1H), 8.64 (s, 1H), 8.57 (t, J = 6.6 Hz,

[0677] 1H), 7.93 (s, 1H), 7.56 (s, 1H), 7.37 - 7.32 (m, 2H), 6.86 O(

[0678] o Y 7 O z < z o Z JO— —— —— — _ / z HCMMZ zC~ C- (s, 1H), 4.69 (d, J = 6.4 Hz, 2H), 3.84 - 3.77 (m, 5H), 3.46

[0679] (s, 3H), 3.16 - 3.11 (m, 2H), 2.67 - 2.60 (m, 1H), 1.77 - JM [> M> > r Mz=

[0680] \ z - / iZM—- =x1.71 (m, 1H), 1.62 - 1.48 (m, 4H), 0.99 - 0.80 (m, 2H),

[0681] 0.79 - 0.77 (m, 2H).

[0682] 100 599.4 ¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (d, J = 1.6 Hz, 1H),

[0683] 8.89 (d, J = 1.6 Hz, 1H), 8.63 (s, 1H), 8.54 - 8.45 (m, 1H), N L vfXi NH 7.96 (s, 1H), 7.57 - 7.38 (m, 4H), 6.75 (s, 1H), 4.70 (d, J = N 0 F Af

[0684] 1F A 0! M T^-N6.4 Hz, 2H), 3.76 (d, J = 6.0 Hz, 6H), 1.83 - 1.81 (m, 1H),

[0685] CF

[0686] ’ / / 30.99 - 0.98 (m, 2H), 0.79 - 0.77 (m, 2H).

[0687] / A

[0688] 101 559.4 ¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.89 (s,

[0689] 1H), 8.72 (s, 1H), 7.74 (d, J = 1.2 Hz, 2H), 7.21 - 6.95 (m, N Y ''M? Ar.r" ''N H

[0690] I A i 1H), 4.22 (t, J = 5.0 Hz, 3H), 3.98 (t, J = 4.8 Hz, 3H), 3.88 1 PSAA (s, 3H), 3.80 (s, 2H), 3.55 (s, 3H), 1.91 - 1.90 (m, 1H), 1.24 / LMF’ - 1.09 (m, 2H), 0.93 - 0.89 (m, 2H).

[0691] 102 633.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 1H),

[0692] < o 8.86 (d, J = 2.0 Hz, 1H), 8.64 (s, 1H), 8.40 (t, J = 6.4 Hz,

[0693] 1H), 7.92 (d, J = 1.2 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.32 A X k A

[0694] 1(s, 1H), 7.20 - 7.18 (m, 1H), 6.78 (s, 1H), 4.77 - 4.75 (m, w

[0695] v zMCFa1H), 4.64 (d, J = 6.4 Hz, 2H), 3.80 (s, 4H), 3.79 (s, 4H),

[0696] 3.49 - 3.43 (m, 2H), 2.50 - 1.77 (m, 3H), 1.76 - 1.55 (m, 2H), 1.01 - 0.98 (m, 2H), 0.81 - 0.78 (m, 2H).

[0697] 103 607.4 ¹H NMR (400 MHz, DMSO-d₆) δ 10.36 (s, 1H), 9.21 (d, J v MN= 1.6 Hz, 1H), 9.11 (s, 1H), 8.95 (d, J = 133.6 Hz, 1H), N r ' k -Zi '' N H 8.05 (s, 1H), 7.31 (s, 2H), 7.21 -7.08 (m, 1H), 4.88 (d, J = Mo M-f6.0 Hz, 2H), 4.19 (t, J = 5.0 Hz, 2H), 3.73 (s, 3H), 3.52 - 0 1 N!'A / ^>— cf, 3.54 (m, 2H), 1.91 - 1.89 (m, 3H), 1.67 (s, 2H), 1.06- 1.09

[0698]

[0699] o (m, 2H), 0.87 -0.86 (m, 2H).

[0700] Active 126539678.1 58 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0701] 104 565.3 ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 1.9 Hz, 1H),

[0702] X NXX 8.88 (d, J= 1.9 Hz, 1H), 8.68 (t, J= 6.8 Hz, 1H), 8.65 (s,

[0703] 1H), 8.09 (s, 1H), 7.52 (t, J= 7.7 Hz, 1H), 7.47 - 7.37 (m, k X 01A u^ AuF2H), 6.85 (s, 1H), 4.72 (d, J= 6.7 Hz, 2H), 3.85 (q, J= 7.4 r 5-CF. Hz, 2H), 3.75 (s, 3H), 1.82 - 1.73 (m, 1H), 1.25 (t, J= 7.4

[0704] Hz, 3H), 1.01 - 0.95 (m, 2H), 0.82 - 0.75 (m, 2H).

[0705] 105 569.4 ¹H NMR (400 MHz, CD₃OD) δ 9.04 - 8.99 (m, 1H), 8.88

[0706] - 8.83 (m, 1H), 8.58 (s, 1H), 7.79 (s, 1H), 7.39 (t, J = 7.3 XXX F Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H), 6.86 (s, 1H), 3.87 (s, 3H), it X 3.68 (s, 3H), 2.82 -2.78 (m, 1H), 1.81 - 1.76 (m, 1H), 1.31

[0707] w r 7 Z>“CF3 - 1.27 (m, 1H), 1.16 - 1.08 (m, 2H), 0.93 - 0.82 (m, 2H).

[0708] 106 565.3 ¹H NMR (400 MHz, CD₃OD) δ 9.03 (d, J = 1.9 Hz, 1H),

[0709] XXX 8.87 (d, J = 1.9 Hz, 1H), 8.60 (s, 1H), 7.75 (s, 1H), 7.42 (t, vX, J = 7.6 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 6.87 (s, 1H), 4.85 AX (s, 2H), 3.90 (s, 3H), 3.56 (s, 3H), 2.14 (d, J = 2.5 Hz, 3H),1AL A«

[0710] u-f A / ". 1.82 (tt, J = 8.4, 4.6 Hz, 1H), 1.19 - 1.10 (m, 2H), 0.94 - 0.84 (m, 2H).

[0711] 107 611.4

[0712] A1H NMR (400 MHz, DMSO-A) 59.07 (d, J = 2.0 Hz, 1H),

[0713] 8.88 (d, J = 2.0 Hz, 1H), 8.66 (t, J = 6.0 Hz, 2H), 7.96 (s, XJAX 1H), 7.84 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 U. A A^A- Hz, 1H), 6.87 (s, 1H), 4.71 (d, J = 6.4 Hz, 2H), 3.78 (s, 3H),1UV

[0714] ;1XCF>3.47 (s, 3H), 1.82 - 1.75 (m, 1H), 1.02 - 0.99 (m, 2H), 0.82

[0715] - 0.79 (m, 2H).

[0716] 108 611.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (d, J = 1.6 Hz, 1H),

[0717] LA 8.82 (d, J = 1.6 Hz, 1H), 8.71 (s, 1H), 7.90 - 7.86 (m, 2H),

[0718] 7.66 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 5.48 - t X I

[0719] O 5.38 (m, 2H), 3.86 (s, 3H), 3.75 (s, 3H), 1.57 - 1.55 (m, NA A 1H), 1.09 - 1.01 (m, 4H).

[0720] 109 616.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.21 (d, J = 1.6 Hz, 1H),

[0721] 9.11 (s, 1H), 8.77 (s, 1H), 8.73 - 8.70 (m, 1H), 8.32 - 8.29 xXx (m, 1H), 7.98 (s, 1H), 7.45 (s, 1H), 7.41 - 7.35 (m, 2H), t X A^ 7.26 (Br s, 1H), 4.88 (d, J = 6.0 Hz, 2H), 4.07 - 4.02 (m,

[0722] 'AAA11H), 3.89 (s, 3H), 3.37 (d, J = 15.6 Hz, 2H), 2.93 - 2.91

[0723] (m, 2H), 2.12 - 2.05 (m, 7H), 1.91 -1.87 (m, 1H), 1.06 - 1.08 (m, 2H), 0.85 - 0.84 (m, 2H).

[0724] 110 658.3 ¹H NMR (400 MHz, CD₃OD) δ 9.00 (d, J = 1.9 Hz, 1H),

[0725] LA 8.84 (d, J = 1.8 Hz, 1H), 8.58 (s, 1H), 7.95 (s, 1H), 7.46 (s,

[0726] 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 6.81 it NX o A 77^ ^A /

[0727] 1(s, 1H), 4.75 (s, 2H), 4.62 (d, J = 13.9 Hz, 1H), 4.04 - 3.94 XX

[0728] X>CF1(m, 2H), 3.89 (s, 3H), 3.08 - 2.96 (m, 1H), 2.49 (dd, J =

[0729] 13.7, 11.0 Hz, 1H), 2.16 (s, 3H), 2.11 (s, 3H), 2.00 - 1.78 o^N-X (m, 5H), 1.16 - 1.08 (m, 2H), 0.86 (dq, J = 7.0, 3.7 Hz,

[0730] 2H).

[0731] 111 573.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.05 (d, J = 2.0 Hz, 1H),

[0732] 57 <kZ^N8.86 (d, J = 1.6 Hz, 1H), 8.66 (s, 1H), 8.55 (t, J = 6.6 Hz, XXX 1H), 8.45 (brs, 1H), 7.92 (s, 1H), 7.04 (s, 1H), 6.81 (s, 1H), GA AZ 6.66 (s, 1H), 4.63 (d, J = 6.8 Hz, 2H), 3.77 (s, 3H), 3.51 (s, r N-J >< -CF3 3H), 1.58 - 1.56 (m, 1H), 1.24 - 1.14 (m, 1H), 1.01 - 0.99

[0733] (m, 2H), 0.87 - 0.81 (m, 4H), 0.58 - 0.56 (m, 2H).

[0734] 112 568.2 ¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (d, J = 1.9 Hz, 1H),

[0735] L N A 8.88 (d, J = 1.9 Hz, 1H), 8.72 - 8.66 (m, 1H), 8.65 (s, 1H),

[0736] 7.97 (s, 1H), 7.69 (s, 1H), 7.51 (s, 2H), 6.86 (s, 1H), 4.71 AX 0 A X^ A °

[0737] 1(d, J = 6.6 Hz, 2H), 3.76 (s, 3H), 3.49 (s, 3H), 1.82 - 1.73 UXN JXCF' (m, 1H), 1.03 - 0.97 (m, 2H), 0.84 - 0.75 (m, 2H).

[0738]

[0739] Active 126539678.1 59 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0740] 113 575.6 ¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (d, J = 1.6 Hz, 1H),

[0741] 8.77 (d, J = 1.6 Hz, 1H), 8.69 (s, 1H), 8.14 (d, J = 0.8 Hz, XX? 1H), 7.59 - 7.47 (m, 4H), 5.32 - 5.21 (m, 2H), 4.47 - 4.40? SQL (m, 1H), 3.83 (s, 3H), 2.18 (s, 3H), 1.88 - 1.47 (m, 2H),

[0742] 1.45 (d, J = 4.4 Hz, 6H), 1.39 - 1.11 (m, 2H), 1.09 - 1.09 (m, 2H).

[0743] 114 575.5 ¹H NMR (400 MHz, DMSO-d₆) δ 8.95 (d, J = 2.0 Hz, 1H),

[0744] 8.78 (d, J = 2.0 Hz, 1H), 8.70 (s, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.60 - 7.58 (m, 1H), 7.50 - 7.50 (m, 4H), 5.27 (t, J = 6.0 Hz, 2H), 4.48-4.41 (m, 1H), 3.84 (s, 3H), 2.11 (s, 3H), 1.50 - 1.48 (m, 1H), 1.44 (d, J = 4.4 Hz, 6H), 1.24 - 0.94 (m, 2H), 0.84 -0.81 (m, 2H).

[0745] 115 575.5 ¹H NMR (400 MHz, DMSO-d₆) δ 8.95 (d, J = 2.0 Hz, 1H),

[0746] I??- 8.78 (d, J = 2.0 Hz, 1H), 8.70 (s, 1H), 8.15 (d, J = 1.6 Hz,

[0747] 1H), 7.60 - 7.58 (m, 1H), 7.50 - 7.50 (m, 4H), 5.27 (t, J = A 6.0 Hz, 2H), 4.48-4.41 (m, 1H), 3.84 (s, 3H), 2.11 (s, 3H), r>-CF* 1.50 - 1.48 (m, 1H), 1.44 (d, J = 4.4 Hz, 6H), 1.24 - 0.94

[0748] (m, 2H), 0.84 -0.81 (m, 2H).

[0749] 116 547.6 ¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (d, J = 1.2 Hz, 1H),

[0750] 8.77 (d, J = 1.2 Hz, 1H), 8.69 (s, 1H), 7.90 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 7.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 5.32 - 5.21 (m, 2H), 3.89 (s, 3H), 3.74 (s, 3H), 2.11 (s, 3H), 1.48 - 1.08 (m, 2H), 0.96 - 0.85 (m, 3H). o

[0751] 117 547.5 ¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (d, J = 1.6 Hz, 1H),

[0752] 8.78 (d, J = 1.6 Hz, 1H), 8.70 (s, 1H), 7.90 (d, J = 1.2 Hz, A XA 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.59-7.55 (m, 1H), 7.49 (d, J A = 8.0 Hz, 2H), 5.26 (t, J = 5.6 Hz, 2H), 3.90 (s, 3H), 3.75 _y\\z-~ O< (s, 3H), 2.11 (s, 3H), 1.49 - 1.45 (m, 1H), 1.24 - 1.10 (m,

[0753] 2H), 1.09 -0.97 (m, 2H).

[0754] 118 547.5 ¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (d, J = 1.6 Hz, 1H),

[0755] 8.78 (d, J = 1.6 Hz, 1H), 8.70 (s, 1H), 7.91 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.57 (t, J = 7.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 5.26 (t, J = 5.6 Hz, 2H), 3.84 (s, 3H), 3.75 (s, 3H), 2.11 (s, 3H), 1.49- 1.45 (m, 1H), 1.24- 1.10 (m, 2H),0.97 - 0.94 (m, 2H).

[0756] 119 569.4 ¹H NMR (400 MHz, CD₃OD) δ 9.02 (d, J = 1.9 Hz, 1H),

[0757] 8.87 (d, J = 1.9 Hz, 1H), 8.58 (s, 1H), 7.82 (s, 1H), 7.26 (d, xX J = 8.4 Hz, 2H), 6.82 (s, 1H), 4.81 (s, 2H), 3.87 (s, 3H),1w 3.62 (s, 3H), 1.79 (tt, J = 8.4, 4.7 Hz, 1H), 1.17 - 1.08 (m,

[0758] N-MZ?>--CF3 2H), 0.94 - 0.79 (m, 2H).

[0759] 120 583.5 ¹H NMR (400 MHz, CD₃OD) δ 9.02 (d, J = 1.9 Hz, 1H),

[0760] 8.87 (d, J = 1.9 Hz, 1H), 8.58 (s, 1H), 7.91 (s, 1H), 7.26 (d, XAI J = 8.3 Hz, 2H), 6.81 (s, 1H), 4.81 (s, 2H), 3.92 (q, J = 7.3 N Hz, 2H), 3.87 (s, 3H), 1.79 (tt, J = 8.4, 4.8 Hz, 1H), 1.33 (t, w

[0761] V J = 7.3 Hz, 3H), 1.15 - 1.07 (m, 2H), 0.90 - 0.80 (m, 2H). r

[0762] 121 573.5 ¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.89 (s,

[0763] NXJOQ 1H), 8.72 (s, 1H), 7.74 (d, J = 1.2 Hz, 2H), 7.21 - 6.95 (m,

[0764] 1H), 4.22 (t, J = 5.0 Hz, 3H), 3.98 (t, J = 4.8 Hz, 3H), 3.88 A XAA(s, 3H), 3.55 (s, 3H), 1.91 - 1.90 (m, 1H), 1.24 - 1.09 (m,

[0765] A 6H), 0.93 -0.89 (m, 2H).

[0766] 122 565.3 ¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (d, J = 2.0 Hz, 1H),

[0767] XXt 8.88 (d, J = 2.0 Hz, 1H), 8.65 (s, 1H), 8.49- 8.40 (m, 1H),

[0768] 7.95 (s, 1H), 7.40-7.31 (m, 2H), 6.84 (s, 1H), 4.70 (d, J =1xx» 6.3 Hz, 2H), 3.78 (s, 3H), 3.51 (s, 3H), 2.05 (s, 3H), 1.84 - 1.77 (m, 1H), 1.03 - 0.98 (m, 2H), 0.82 - 0.76 (m, 2H).

[0769]

[0770] Active 126539678.1 60 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0771] 123 569.31H NMR (400 MHz, DMSO-d6) 59.08 (d, J = 2.0 Hz, 1H),

[0772] 8.88 (d, J= 2.0 Hz, 1H), 8.66 (s, 1H), 8.51 - 8.46 (m, 1H), 8.02 (s, 1H), 7.54 (dd, J= 9.7, 5.9 Hz, 1H), 7.41 (dd, J = 10.2, 5.9 Hz, 1H), 6.89 (s, 1H), 4.74 (d, J = 6.3 Hz, 2H), 3.77 (s, 3H), 3.60 (s, 3H), 1.88 - 1.78 (m, 1H), 1.03 - 0.99 (m, 2H), 0.83 -0.79 (m, 2H).

[0773] 124 602.51H NMR (400 MHz, DMSO-d6) 59.06 (d, J = 1.6 Hz, 1H),

[0774] ^zf=8.87 (d, J = 2.0 Hz, 1H), 8.62 (t, J = 7.4 Hz, 2H), 8.11 (d, J = 0.8 Hz, 1H), 7.53 (s, 4H), 6.81 (s, 1H), 4.72 (d, J = 6.8 ° — Hz, 2H), 4.12-4.09 (m, 1H), 3.75 (s, 3H), 2.99 (d, J= 12.4

[0775] Hz, 2H), 2.45 - 2.39 (m, 2H), 1.82 - 1.77 (m, 5H), 0.98 - 0.96 (m, 2H), 0.78 - 0.74 (m, 2H).

[0776] 125 > y 577.51H NMR (400 MHz, DMSO-d6) 59.06 (d, J = 2.0 Hz, 1H),

[0777] 8.89 (d, J = 1.6 Hz, 1H), 8.64 (s, 1H), 7.96 (d, J = 1.2 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.39 (t, J = 10.0 Hz, 2H), 6.80 (s, 1H), 6.84- 6.82 (m, 1H),4.73 (s,2H), 3.77 (s, 3H), 3.44 - 3.40 (m, 1H), 1.78 - 1.74 (m, 1H), 0.99 (t, J = 3.6 Hz, 1H), 0.81 -0.78 (m, 6H).

[0778] 126 554.51H NMR (400 MHz, DMSO-d6) 5 9.07 (s, 1H), 8.86 (s,

[0779] XJOC 1H), 8.69 (s, 1H), 7.70 - 7.13 (m, 3H), 3.85 (s, 3H), 3.46 - 3.42 (m, 5H), 3.10 - 3.06 (m, 2H), 2.96 - 2.91 (m, 2H), X M / A 1.87- 1.69 (m, 3H), 1.47 (d, J = 13.2 Hz, 2H), 1.06 (s, 5H),

[0780] 0.89 -0.87 (m, 2H).

[0781] 127 573.51H NMR (400 MHz, DMSO-d6) 59.06 (d, J = 2.0 Hz, 1H),

[0782] 8.87 (d, J = 1.6 Hz, 1H), 8.64 (s, 1H), 8.58-8.55 (m, 1H), joX

[0783] X X 7.88-7.88 (m, 1H), 7.43-7.39 (m, 2H), 7.32 (d, J = 8.0 Hz, J CK 1H), 6.81 (s, 1H), 4.67 (d, J = 6.4 Hz, 2H), 3.77 (s, 3H), <\HMzC C- 3.33-3.28 (m, 1H), 2.14 (s, 3H), 1.82-1.76 (m, 1H), 1.01- 0.99 (m, 2H), 0.85-0.80 (m, 6H).

[0784] XXX MzX

[0785] 128 644.51H NMR (400 MHz, DMSO-d6): 5 9.10 (s, 1H), 8.94 (s,

[0786] 1H), 8.68 (s, 1H), 8.22 (s, 1H), 7.60 - 7.50 (m, 4H), 6.92 (s, 1H), 4.83 - 4.73 (m, 2H), 4.46 (d, J = 12.8 Hz, 1H), 4.40 - 4.35 (m, 1H), 3.87 (d, J = 13.6 Hz, 1H), 3.79 (s, 3H), 3.03 (t, J = 11.6 Hz, 1H), 2.50 - 2.40 (m, 1 H), 2.05 - 1.90 (m, 7H), 1.88 - 1.70 (m, 2H), 1.10 -0.90 (m, 2H), 0.30 - 0.20 (m, 2H).

[0787] 129 587.41H NMR (400 MHz, DMSO-d6) 59.09 (d, J = 1.6 Hz, 1H),

[0788] B 8.90 (d, J = 1.6 Hz, 1H), 8.76 (s, 2H), 7.98 (s, 1H), 7.55 - «XAANH7.50 (m, 2H), 7.44 - 7.39 (m, 2H), 6.95 (s, 1H), 4.73 (d, J N O = 6.4 Hz, 2H), 3.56 (s, 3H), 1.89 - 1.84 (m, 1H), 1.06 - ^ 0.90 (m, 2H), 0.88 - 0.87 (m, 2H).

[0789] 130 O 597.61H NMR (400 MHz, DMSO-d6) 59.09 (d, J = 2.0 Hz, 1H),

[0790] XAX 8.89 (d, J = 2.0 Hz, 1H), 8.78 (s, 1H), 8.69 (t, J = 6.6 Hz,

[0791] 1H), 8.44 (br s, 1H), 8.00 (d, J = 1.2 Hz, 1H),, 7.39 (s, 1H), 7.34 - 7.32 (m, 1H), 7.28 - 7.26 (m, 1H), 6.93 (s, 1H), 4.68 (d, J = 6.8 Hz, 2H), 3.77 - 3.72 (m, 2H), 2.07 (s, 3H), 1.86 - 1.83 (m, 1H), 1.18 (t, J = 7.4 Hz, 3H), 1.07 - 1.06 (m, 2H), 0.90 - 0.89 (m, 2H).

[0792] 131 669.51H NMR (400 MHz, DMSO-d6) 5 10.55 (s, 1H), 9.21 (d, J = 2.0 Hz, 1H), 9.13 (d, J = 2.0 Hz, 1H), 8.78 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.29 (s, 1H), 7.20 (d, J = 12.4 Hz, 1H), 4.90 (d, J = 5.6 Hz, 2H), 4.44 (d, J = 13.2 Hz, 1H), 3.89 (s, 3H), 3.89 - 3.79 (m, 1H), 3.43 (br s, 1H), 2.79 (d, J = 4.8 Hz, 1H), 0.23 (s, 1H), 1.97 (d, J = 14.0 Hz, 6H), 1.91 - 1.72 (m, 1H), 1.72 - 1.72 (m, 2H), 1.53 - 1.53 (m,

[0793]

[0794] 2H), 1.07 - 1.07 (m, 2H), 0.86 - 0.86 (m, 2H).

[0795] Active 126539678.1 61 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0796] 132 673.5 'H NMR (400 MHz, DMSO-A) 59.07 (d, J = 1.6 Hz, 1H),

[0797] 8.88 (d, J = 1.6 Hz, 1H), 8.64 (s, 2H), 8.20 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.0 Hz, 2H), 7.45 - 7.37 (m, 3H), 6.81 (s, 1H), 4.73 (d, J = 6.4 Hz, 2H), 3.76 (s, 3H), 2.89 - 2.83 (m, 1H), 2.71 -2.69 (m, 1H), 2.31 -2.28 (m, 1H), 1.99 (s, 3H), 1.83 - 1.77 (m, 1H), 1.65 - 1.52 (m, 4H), 1.01 - 0.98 (m, 4H).

[0798] 133 575.61H NMR (400 MHz, DMSO-A) 59.06 (d, J = 2.0 Hz, 1H),

[0799] 8.87 (d, J = 2.0 Hz, 1H), 8.64 (s, 1H), 8.57 (t, J = 6.6 Hz, 1H), 7.91 (d, J = 0.8 Hz, 1H), 7.54 (s, 1H), 7.33 - 7.26 (m, 2H), 6.84 (s, 1H), 4.69 (d, J = 6.4 Hz, 2H), 3.77 (s, 3H), 3.45 (s, 3H), 2.77 - 2.70 (m, 1H), 1.78- 1.71 (m, 1H), 1.04 - 0.98 (m, 8H), 0.81 - 0.79 (m, 2H),

[0800] 134 582.61H NMR (400 MHz, DMSO-A) 59.04 (d, J = 2.0 Hz, 1H),

[0801] 8.83 (d, J = 1.6 Hz, 1H), 8.68 (s, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.66 (t, J = 6.8 Hz, 1H), 7.08 (s, 1H), 4.37 - 4.31 (m, 1H), 3.84 (s, 3H), 3.39 (d, J = 7.2 Hz, 2H), 3.00 - 2.89 (m, 4H), 1.88 - 1.70 (m, 3H), 1.49 - 1.45 (m, 2H), 1.34 (d, J = 13.2 Hz, 6H), 1.07 (s, 5H), 0.89 - 0.86 (m, 2H).

[0802] 135 ^ 558.5 'H NMR (400 MHz, DMSO-A) 59.05 (d, J = 1.6 Hz, 1H),

[0803] 8.84 (d, J = 2.0 Hz, 1H), 8.68 (s, 1H), 8.82 (t, J = 6.8 Hz, XXx 1H), 7.54 (d, J = 1.2 Hz, 1H), 7.09 (s, 1H), 3.85 (s, 3H),

[0804] 3.73 (dd, J = 6.8 & 21.6 Hz, 2H), 3.49 (s, 3H), 3.20 - 3.10 (m, 2H), 3.05 - 2.97 (m, 2H), 2.00 - 1.84 (m, 5H), 1.24 - 1.06 (m, 2H), 0.89 - 0.88 (m, 2H).

[0805] 136 W 586.5 'H NMR (400 MHz, DMSO-A) 59.06 (d, J = 1.6 Hz, 1H),

[0806] IAX \7~ 8.85 (d, J = 1.6 Hz, 1H), 8.69 (s, 1H), 7.83 - 7.76 (m, 2H),

[0807] 7.11 (s, 1H), 4.42 - 4.35 (m, 1H), 3.86 (s, 3H), 3.77 - 3.70 < A o u

[0808] J<\z- (m, 2H), 3.05 - 2.97 (m, 4H), 2.00 - 1.84 (m, 5H), 1.35 (d,

[0809] J = 6.4 Hz, 6H), 1.24 - 1.06 (m, 2H), 0.89 - 0.88 (m, 2H).

[0810] M

[0811] 137 595.4 'H NMR (400 MHz, DMSO-A) 59.07 (d, J = 1.6 Hz, 1H),

[0812] XJOC 8.89 (d, J = 1.6 Hz, 1H), 8.68 - 8.66 (m, 2H), 8.05 (s, 1H),

[0813] 7.38 (d, J = 8.4 Hz, 2H), 6.88 (s, 1H), 4.73 (d, J = 6.4 Hz, 2H), 3.78 (s, 3H), 3.28 (s, 1H), 1.82 - 1.77 (m, 1H), 1.01 - U

[0814] Tp 0.94 (m, 2H), 0.87 -0.81 (m, 6H).

[0815] 138 579.51H NMR (400 MHz, DMSO-A) 59.07 (d, J = 2.0 Hz, 1H),

[0816] 8.87 (d, J = 2.0 Hz, 1H), 8.65 (s, 1H), 8.61 (t, J = 6.6 Hz, 1H), 8.09 (d, J = 1.2 Hz, 1H), 7.30 (s, 1H), 7.24 (d, J = 10.4 Hz, 1H), 6.85 (s, 1H), 4.67 (d, J = 6.4 Hz, 2H), 3.77 (s, 3H), 3.73 (d, J = 7.2 Hz, 2H), 2.07 (s, 3H), 1.83 - 1.77 (m, 1H), 1.20 (t, J = 7.2 Hz, 3H), 1.02 - 1.01 (m, 2H), 1.01 - 1.00 (m, 2H).

[0817] 139 623.4 'H NMR (400 MHz, DMSO-A) 59.07 (d, J = 1.6 Hz, 1H),

[0818] 8.88 (d, J = 2.0 Hz, 1H), 8.65 (s, 1H), 8.44 (t, J = 6.6 Hz, 1H), 7.99 (d, J = 0.8 Hz, 1H), 7.31 (d, J = 10.4 Hz, 1H), 6.84 (s, 1H), 6.78 (d, J = 5.6 Hz, 1H), 5.38 (t, J = 5.4 Hz, 1H), 4.86 (t, J = 6.8 Hz, 2H), 4.70 (d, J = 6.4 Hz, 2H), 4.54 - 4.51 (m, 2H), 3.78 (s, 3H), 3.55 (s, 3H), 1.81 - 1.77 (m, 1H), 1.02 - 0.99 (m, 2H), 0.82 - 0.82 (m, 2H).

[0819] 140 661.5 'H NMR (400 MHz, DMSO-A) 59.07 (d, J = 1.6 Hz, 1H),

[0820] 8.87 (d, J = 2.0 Hz, 1H), 8.65 (s, 1H), 8.42 (s, 1H), 7.99 (d, J = 0.8 Hz, 1H), 7.34 (d, J = 10.4 Hz, 1H), 7.23 (d, J = 6.0 Hz, 1H), 6.80 (s, 1H), 4.71 - 4.63 (m, 3H), 3.78 (s, 3H), 3.77 - 3.74 (m, 2H), 3.57 (s, 3H), 3.46-3.41 (m, 2H), 2.07 - 1.90 (m, 2H), 1.89 - 1.78 (m, 1H), 1.57 - 1.52 (m, 2H),

[0821]

[0822] 1.03 - 1.00 (m, 2H), 0.83 - 0.80 (m, 2H).

[0823] Active 126539678.1 62 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0824] 141 547.5 'H NMR (400 MHz, DMSO-A) 5 10.16 (s, 1H),9.21 (d, J IXX = 1.6 Hz, 1H), 9.12 (s, 1H), 8.78 (s, 1H), 7.94 (s, 1H), 7.71

[0825] (t, J = 9.2 Hz, 4H), 7.26 - 6.96 (m, 1H), 5.35 (s, 1H), 3.861uu (s, 3H), 3.79 (s, 3H), 1.75 (d, J = 6.8 Hz, 4H), 1.11 - 1.02

[0826] (m, 2H), 0.74 - 0.70 (m, 2H).

[0827] 142 637.51H NMR (400 MHz, DMSO-A) 59.07 (d, J = 2.0 Hz, 1H),

[0828] 8.87 (d, J = 2.0 Hz, 1H), 8.65 (s, 1H), 8.43 (t, J = 6.4 Hz, I Xl 1H), 7.98 (d, J = 0.8 Hz, 1H), 7.35 (d, J = 10.4 Hz, 1H), ru 6.81 (s, 1H), 6.56 (d, J = 5.6 Hz, 1H), 4.74 (d, J = 6.8 Hz, i r 2H), 4.63 (d, J = 6.4 Hz, 2H), 4.55 (d, J = 6.8 Hz, 2H), 3.78

[0829] (s, 3H), 3.55 (s, 3H), 1.81 - 1.77 (m, 1H), 1.58 (s, 3H), 1.01 (t, J = 3.6 Hz, 2H), 0.82 - 0.79 (m, 2H).

[0830] 143 565.51H NMR (400 MHz, DMSO-A) 59.07 (d, J = 2.0 Hz, 1H),

[0831] 8.89 (d, J = 2.0 Hz, 1H), 8.64 (s, 1H), 8.18 (d, J = 7.6 Hz, X iii & 1H), 7.98 (s, 1H), 7.60 - 7.49 (m, 3H), 6.77 (s, 1H), 5.07 - V 5.00 (m, 1H), 3.73 (s, 3H), 3.57 (s, 3H), 1.76 - 1.67 (m,

[0832] 4H), 0.98 (d, J = 4.4 Hz, 2H), 0.82 - 0.75 (m, 2H).

[0833] 144 637.5 'H NMR (400 MHz, DMSO-A) 59.01 (d, J = 2.0 Hz, 1H),

[0834] 8.89 (d, J = 2.0 Hz, 1H), 8.69 (s, 1H), 8.00 (d, J = 0.8 Hz, 1H), 7.75 (d, J = 10.0 Hz, 1H), 7.29 (s, 1H), 7.20 (d, J = 6.8 Hz, 1H), 5.22 (d, J = 14.8 Hz, 2H), 4.93 (t, J = 5.6 Hz, 1H), 4.83 (d, J = 14.8 Hz, 1H),, 3.79 (s, 3H), 3.61 (s, 3H), 3.43 (t, J = 5.2 Hz, 2H), 1.84 - 1.79 (m, 1H), 1.41 - 1.23 (m, 2H), 1.07 - 1.03 (m, 2H), 0.96 - 0.84 (m, 2H), 0.82 - b 0.81 (m, 2H).

[0835] 145 676.71H NMR (400 MHz, DMSO-A) 59.04 (d, J = 2.0 Hz, 1H),

[0836] A 8.82 (d, J = 2.0 Hz, 1H), 8.68 (s, 1H), 7.83 (d, J = 7.6 Hz, Jfy c= 1H), 7.65 (t, J = 6.8 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.06

[0837] (s, 1H), 4.52 (d, J = 12.8 Hz, 1H), 4.51 -3.41 (m, 1H), 3.39 H (s, 3H), 3.41 - 3.32 (m, 2H), 3.19 - 3.16 (m, 2H), 3.06 - 2.95 (m, 4H), 2.51 - 2.44 (m, 1H), 2.01 (s, 3H), 1.87 - 1.72 (m, 5H), 1.87 - 1.72 (m, 4H), 1.07 - 1.05 (m, 5H), 0.87 - 0.84 (m, 2H).

[0838] 146 680.61H NMR (400 MHz, DMSO-A) 59.07 (d, J = 2.0 Hz, 1H),

[0839] 8.86 (d, J = 1.6 Hz, 1H), 8.71 (s, 1H), 7.90 - 7.79 (m, 2H), XXx 7.45 (d, J = 7.6 Hz, 1H), 7.10 (s, 1H), 4.55 (d, J = 12.4 Hz,

[0840] 1H), 3.94 (d, J = 13.2 Hz, 1H), 3.85 (s, 3H), 3.79 - 3.72 < tu (m, 2H), 3.33 - 3.22 (m, 2H), 3.12 - 3.01 (m, 4H), 2.57 - 2.51 (m, 1H), 2.04 - 1.97 (m, 7H), 1.88 - 1.84 (m, 1H), 1.75 - 1.73 (m, 2H), 1.64 - 1.51 (m, 2H), 1.24 - 1.06 (m, 2H), 0.89 - 0.88 (m, 2H).

[0841] 147 607.5 'H NMR (400 MHz, DMSO-A) 58.98 (d, J = 1.2 Hz, 1H), y 8.85 (d, J = 1.2 Hz, 1H), 8.67 (s, 1H), 7.98 (s, 1H), 7.44 (d, A J = 10.4 Hz, 1H), 7.26 (d, J = 6.4 Hz, 1H), 7.10 (s, 1H), A o 5.33 (s, 2H), 4.36 (s, 2H), 4.20 (t, J = 5.4 Hz, 2H), 3.79 (s,

[0842] 3H), 3.57 (s, 3H), 2.10-2.07 (m, 2H), 1.83 - 1.77 (m, 1H), 1.03 - 1.02 (m, 2H), 0.84 - 0.83 (m, 2H).

[0843] 148 662.6 'H NMR (400 MHz, DMSO-A) 59.03 (d, J = 1.6 Hz, 1H),

[0844] 8.82 (d, J = 1.6 Hz, 1H), 8.68 (s, 1H),7.93 (t, J = 6.2 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 6.92 (s, 1H), 4.55 (d, J = 12.4 Hz, 1H), 3.95 - 3.87 (m, 4H), 3.38 - 3.32 (m, 4H), 3.11 - 2.99 (m, 2H), 2.77 (t, J = 12.0 Hz, 2H), 2.53 - 2.50 (m, 1H), 2.03 (s, 3H), 1.94 - 1.84 (m, 4H), 1.74 (t, J = 10.6 Hz, 2H), 1.64 - 1.63 (m, 1H), 1.50 - 1.44

[0845]

[0846] (m, 3H), 1.08 - 1.05 (m, 2H), 0.90 - 0.87 (m, 2H).

[0847] Active 126539678.1 63 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0848] 149 603.61H NMR (400 MHz, DMSO-d6) 59.09 (d, J = 1.6 Hz, 1H),

[0849] 8.91 (d, J = 2.0 Hz, 1H), 8.63 (s, 1H), 8.05 (d, J = 7.2 Hz, XAA 1H), 7.91 (d, J = 0.8 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.63 N O A (d, J = 8.4 Hz, 2H), 6.74 (s, 1H), 5.15 - 5.11 (m, 1H), 3.98 X V - 3.93 (m, 1H), 3.76 - 3.67 (m, 5H), 3.36 (s, 3H), 1.73 - 1.69 (m, 1H), 0.98 - 0.90 (m, 6H), 0.83 - 0.72 (m, 1H), 0.71 -0.62 (m, 1H).

[0850] 150 603.51H NMR (400 MHz, DMSO-d6) 59.09 (d, J = 2.0 Hz, 1H),

[0851] 8.92 (d, J = 2.0 Hz, 1H), 8.63 (s, 1H), 8.06 (d, J = 7.2 Hz, XXK 1H), 7.92 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 n Hz, 2H), 6.74 (s, 1H), 5.16 - 5.11 (m, 1H), 3.99 -3.94 (m, XZXA 1H), 3.77-3.71 (m, 5H), 3.36 (s, 3H), 1.73 - 1.69 (m, 1H),

[0852] 1.05 - 0.88 (m, 6H), 0.87 - 0.62 (m, 2H).

[0853] 151 603.51H NMR (400 MHz, DMSO-d6) 59.09 (d, J = 2.0 Hz, 1H),

[0854] 8.92 (d, J = 1.6 Hz, 1H), 8.63 (s, 1H), 8.06 (d, J = 7.6 Hz, XXX 1H), 7.92 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0

[0855] Hz, 2H), 6.74 (s, 1H), 5.16 - 5.11 (m, 1H), 3.99 -3.94 (m, J UCN 1H), 3.77 - 3.68 (m, 5H), 3.36 (s, 3H), 1.73 - 1.68 (m, 1H),

[0856] 1.05 - 0.88 (m, 6H), 0.83 - 0.73 (m, 1H), 0.71 - 0.62 (m, 1H).

[0857] 152 591.51H NMR (400 MHz, DMSO-d6): 5 9.06 (d, J = 2.0 Hz,

[0858] 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.63 (s, 1H), 7.95 (d, J = 8.0 XAc Hz, 1H), 7.90 (d, J = 0.8 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), v x

[0859] 0H7.59 (d, J = 8.4 Hz, 2H), 6.68 (s, 1H), 5.29 (s, 1H), 4.74 (d, XA> X_A

[0860] J = 8.0 Hz, 1H), 3.74 (s, 3H), 3.68 (s, 3H), 1.65 - 1.62 (m, 1H), 1.38 (s, 3H), 1.02 (s, 3H), 0.95 -0.93 (m, 2H), 0.75 - 0.73 (m, 2H).

[0861] 153 o 591.51H NMR (400 MHz, DMSO-d6): 5 9.06 (d, J = 2.0 Hz,

[0862] 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.63 (s, 1H), 7.95 (d, J = 8.0 XXX ''NH Hz, 1H), 7.90 (d, J = 1.2 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), vX 7.59 (d, J = 8.4 Hz, 2H), 6.68 (s, 1H), 5.29 (s, 1H), 4.74 (d, '0HATS^A^N

[0863] >~CF3 J = 8.4 Hz, 1H), 3.74 (s, 3H), 3.68 (s, 3H), 1.67 - 1.60 (m,

[0864] 1H), 1.38 (s, 3H), 1.02 (s, 3H), 0.95 -0.93 (m, 2H), 0.75 - 0.73 (m, 2H).

[0865] 154 617.51H NMR (400 MHz, DMSO-d6): 5 9.08 (d, J = 1.6 Hz,

[0866] 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.63 (s, 1H), 7.96 (d, J = 8.0 XXt NH Hz, 1H), 7.89 (d, J = 0.8 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), A Sn 7.58 (d, J = 8.4 Hz, 2H), 6.69 (s, 1H), 5.29 (s, 1H), 4.73 (d,

[0867] J = 8.4 Hz, 1H), 3.69 (s, 3H), 3.67 - 3.66 (m, 1H), 1.67 - 1.63 (m, 1H), 1.38 (s, 3H), 1.02 (s, 3H), 0.95 - 0.85 (m, 6H), 0.74 - 0.67 (m, 2H).

[0868] 155 X^JN 617.61H NMR (400 MHz, DMSO-d6): 5 9.08 (d, J = 1.6 Hz,

[0869] 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.63 (s, 1H), 7.96 (d, J = 8.0 I X AXX' ^NHHz, 1H), 7.89 (d, J = 0.8 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), X yU 7.58 (d, J = 8.4 Hz, 2H), 6.69 (s, 1H), 5.29 (s, 1H), 4.73 (d,

[0870] Z>~CF3 J = 8.4 Hz, 1H), 3.69 (s, 3H), 3.67 - 3.65 (m, 1H), 1.67 - 1.63 (m, 1H), 1.38 (s, 3H), 1.02 (s, 3H), 0.95 - 0.88 (m, 6H), 0.77 - 0.67 (m, 2H).

[0871] 156 o 589.5 'H NMR (400 MHz, CD3OD) 5 8.92 (d, J = 1.7 Hz, 1H),

[0872] 8.86 (d, J = 1.8 Hz, 1H), 8.59 (s, 1H), 7.67 (s, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.39 - 7.32 (m, 2H), 7.01 (s, 1H), 5.53 (s, 2H), 4.49 (t, J = 5.3 Hz, 2H), 4.29 (t, J = 5.6 Hz, 2H), 3.87 (s, 3H), 3.75 (s, 3H), 2.25 - 2.13 (m, 2H), 1.77 (It, J = 8.3, 4.6 Hz, 1H), 1.12 (dt, J = 6.3, 3.3 Hz, 2H), 0.86 (dq, J =

[0873]

[0874] 7.0, 3.8 Hz, 2H).

[0875] Active 126539678.1 64 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0876] 157 589.4 'H NMR (400 MHz, CD3OD) 5 8.93 (d, J = 1.8 Hz, 1H),

[0877] 8.83 (d, J = 1.8 Hz, 1H), 8.60 (s, 1H), 7.69 - 7.66 (m, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.32 (dd, J = 7.7, 1.8 Hz, 1H), 7.30 (d, J = 1.8 Hz, 1H), 7.13 (s, 1H), 5.56 (d, J= 15.7 Hz, 1H), 4.99 (d, J = 15.7 Hz, 1H), 4.95 - 4.91 (m, 1H), 4.60 - 4.49 (m, 1H), 4.10 (dd, J = 14.3, 9.6 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 1.81 - 1.74 (m, 1H), 1.46 (d, J= 6.3 Hz, 3H), 1.18 - 1.08 (m, 2H), 0.90 - 0.81 (m, 2H).

[0878] 158 X 619.5 'H NMR (400 MHz, CD3OD) 5 8.88 (d, J = 1.8 Hz, 1H),

[0879] X 8.83 (d, J = 1.7 Hz, 1H), 8.60 (s, 1H), 7.66 (q, J = 1.2 Hz,

[0880] 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.43 (s, 1H), 7.37 (d, J = 1.7 f Ny Hz, 1H), 7.25 (dd, J = 8.0, 1.7 Hz, 1H), 5.33 (s, 2H), 4.31 Qj - 4.23 (m, 2H), 4.17 - 4.10 (m, 2H), 4.10 - 4.04 (m, 2H),

[0881] 3.92 (s, 3H), 3.84 - 3.78 (m, 2H), 3.75 (s, 3H), 1.85 - 1.75 (m, 1H), 1.19 - 1.09 (m, 2H), 0.97 - 0.84 (m, 2H).

[0882] 159 575.3 'H NMR (400 MHz, CD3OD) 5 8.93 (d, J = 1.8 Hz, 1H),

[0883] 8.84 (d, J = 1.7 Hz, 1H), 8.59 (s, 1H), 7.67 (q, J = 1.2 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.32 (dd, J = 7.8, 1.8 Hz, 1H), 7.28 (d, J = 1.8 Hz, 1H), 7.12 (s, 1H), 5.35 (s, 2H), 4.56 (dd, J = 5.7, 3.3 Hz, 2H), 4.47 (dd, J = 5.7, 3.3 Hz, 2H), 3.87 (s, 3H), 3.77 (s, 3H), 1.77 (It, J = 8.0, 4.6 Hz, 1H), 1.19 - 1.08 (m, 2H), 0.92 - 0.80 (m, 2H).

[0884] 160 573.5 'H NMR (400 MHz, CD3OD) 5 8.75 (d, J = 1.8 Hz, 1H),

[0885] 8.72 (d, J = 1.8 Hz, 1H), 8.61 (s, 1H), 7.95 (d, J = 1.3 Hz, 1H), 7.53 (s, 1H), 7.50 (s, 2H), 6.80 (s, 1H), 5.45 - 4.94 (m, 4H), 4.63 (hept, J = 7.4 Hz, 1H), 3.92 (s, 3H), 1.89 (tt, X \ O

[0886] J = 8.1, 4.7 Hz, 1H), 1.49 (d, J = 6.7 Hz, 6H), 1.20 - 1.14 p r

[0887] . / X / “"”~ (m, 2H), 0.95 - 0.89 (m, 2H). 161 H C 587.7 'H NMR (400 MHz, CD3OD) 5 8.93 (d, J = 1.8 Hz, 1H),

[0888] 8.84 (d, J = 1.8 Hz, 1H), 8.61 (s, 1H), 7.91 (q, J = 1.3 Hz, x c

[0889] X MJ 1H), 7.42 (s, 1H), 7.37 (d, J = 1.2 Hz, 2H), 7.19 (s, 1H),

[0890] 5.05 (s, 2H), 4.58 (hept, J = 6.8 Hz, 1H), 4.30 (t, J = 5.7 Hz, 2H), 3.92 (s, 3H), 3.23 (t, J = 5.7 Hz, 2H), 1.85 (tt, J = 8.1, 4.6 Hz, 1H), 1.46 (d, J = 6.7 Hz, 6H), 1.19 - 1.13 (m, 2H), 0.94 - 0.87 (m, 2H).

[0891] 162 603.5 'H NMR (400 MHz, CD3OD) 5 8.91 (d, J = 1.7 Hz, 1H),

[0892] 8.80 (d, J = 1.8 Hz, 1H), 8.58 (s, 1H), 7.90 (d, J = 1.3 Hz, Y jo X

[0893] 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.22 (dd, J = 7.7, 1.8 Hz, w Q 1H), 7.17 (d, J = 1.7 Hz, 1H), 7.13 (s, 1H), 5.33 (s, 2H),

[0894] 4.61 - 4.50 (m, 3H), 4.49 - 4.42 (m, 2H), 3.87 (s, 3H), 1.79 ^ (tt, J = 8.0, 4.6 Hz, 1H), 1.43 (d, J = 6.7 Hz, 6H), 1.15 -

[0895]

[0896] 1.09 (m, 2H), 0.88 -0.81 (m, 2H).

[0897] Table 2: Abbreviations Used.

[0898] Abbreviation: Meaning:

[0899] DMSO DMSO

[0900] MeOH Methanol

[0901] NaBH4Sodium borohydride

[0902] LiAlH4Lithium aluminum hydride

[0903] DIBALH Diisobutylaluminum hydride

[0904] DCM Dichloromethane

[0905]

[0906] Active 126539678.1 65 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0907] DMF N,N-DMF

[0908] DME Dimethoxy ethane

[0909] MeCN Acetonitrile

[0910] EtOAc Ethyl acetate

[0911] NaH Sodium hydride

[0912] THF Tetrahydrofuran

[0913] CD3OD Deuterated methanol

[0914] CDCl3Deuterated chloroform

[0915] DIPEA N,N-Diisopropylethylamine cataCXium-A Di(1-adamantyl)-n-butylphosphine Boc Tert-butyloxycarbonyl NaOAc Sodium acetate

[0916] NH4OH Ammonium hydroxide

[0917] dppf 1,1'-Bis(diphenylphosphino)ferrocene XPhos 2-Dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl

[0918] TFA Trifluoroacetic acid

[0919]

[0920] Synthetic Examples

[0921] General Procedures

[0922] General Procedure A

[0923] Imidazole Formation

[0924] o

[0925]

[0926] To a stirred suspension of dibromoketone (1.40 equiv.) in water (1.05 M) was added NaOAc (1.60 equiv.) and the mixture was stirred at 100 °C for 1 h. The reaction was cooled to 23 °C and a solution of aldehyde (1.0 equiv.) in MeOH and 25% aqueous ammonia solution (1: 1, 0.4 M ) was added. The reaction mixture was stirred at room temperature for 1 h and then stirred at 100 °C for 2 h. The reaction was cooled to 23 °C and the MeOH was removed under reduced pressure. The aqueous phase was extracted with EtOAc and the

[0927] Active 126539678.1 66 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0928] organics were washed with sat. sodium bicarbonate, brine, dried over magnesium or sodium sulfate, filtered and concentrated.

[0929] General Procedure B

[0930] Imidazole Alkylation

[0931]

[0932] To a stirred solution of imidazole in MeCN or DMF (0.4 M) was added cesium carbonate (3.0 equiv.) at 0 °C followed by the alkyl halide (3.0 equiv.) and the mixture was heated at 90 °C for 24 h. The reaction was cooled to 23 °C and extracted with EtOAc. The organics were washed with sat. sodium bicarbonate, brine, dried over magnesium or sodium sulfate, filtered and concentrated.

[0933] General Procedure C

[0934] Reduction of Nitriles or Esters

[0935]

[0936] To a stirred solution of the benzonitrile (1.0 equiv.) in THF (0.3 M) was added H2(1.2 equiv, 2.0 M in THF) or diisobutyl aluminum hydride (1.0 M in hexane, 3.0 equiv.) at 0 °C and the reaction mixture was warmed to 23 °C and stirred for 1 - 4 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous sodium or magnesium sulfate, filtered, and concentrated under reduced pressure.

[0937] General Procedure D

[0938] Raney Ni Reduction of Nitriles

[0939]

[0940] To solution of the benzonitrile (1.0 equiv.) in EtOAc and 25% aq. ammonia solution (5:1, 0.3 M final concentration) stirring at 23 °C was added Raney nickel (85%, 5.0 equiv.) and the mixture was stirred under H2 (Parr reactor, 60 psi) for 8 - 16 h. The mixture was filtered through Celite and the bed was thoroughly washed with ethanol followed by EtOAc. The filtrate was evaporated under reduced pressure.

[0941] Synthesis of Intermediates:

[0942] Intermediate A

[0943] Active 126539678.1 67 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0944] Synthesis of (4-(l-methyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)phenyl)methanamine.

[0945] Intermediate A

[0946]

[0947] Step 1: Preparation of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile.

[0948] Intermediate A.1

[0949]

[0950] To a stirred suspension of 3, 3 -dibromo- 1,1,1 -trifluoropropan-2-one (173 g, 641 mmol) in water (600 mL) was added NaOAc (60.1 g, 732 mmol) and stirred at 100 °C for 1 h. The reaction mixture was cooled to 23 °C and a solution of 4-formylbenzonitrile (60.0 g, 457 mmol) in methanol (600 mL) and 25% aqueous ammonia solution (600 mL) was added. The resulting reaction mixture was stirred at room temperature for 1 h and then stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature and the methanol was removed under reduced pressure. The resulting solution was diluted with water (1000 mL) and extracted with EtOAc (2 x 1000 mL). The combined organic phases were washed with water (200 mL), brine (100 mL), dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue was purified via flash chromatography (30% EtOAc / petroleum ether eluent) to obtain 4-(4-(trifluoromethyl)- IT / -imidazol-2-yl)benzonitrile (51.0 g) as a pale yellow solid. LCMS observed m / z = 238.07 [M+H]+.

[0951] Step 2: Preparation of 4-(l-methyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)benzonitrile.

[0952] Intermediate A.1

[0953]

[0954] To a stirred solution of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (20 g, 84.32 mmol) in THF (200 mL) was added NaH (6.07 g, 252.97 mmol) at 0 °C and stirred for 15 minutes before adding methyl iodide (7.9 mL, 126.48 mmol). The reaction mixture was stirred at 0 °C for 5 h. After completion, the reaction mixture was quenched with cold water (50 mL), extracted with EtOAc (500 mL x 2). The combined organic layer was washed with

[0955] Active 126539678.1 68 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0956] water (200 mL), brine (100 mL), dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by flash column chromatography (30% EtOAc / petroleum ether eluent) to obtain 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (15.5 g, 73%) as a pale yellow solid. LCMS observed m / z = 252.15 [M+H]+.

[0957] Step 3: Preparation of (4-(l-methyl-4-(trifluoromethyl)- U / -imidazol-2-yl)phenyl)-methanamine.

[0958] Intermediate A

[0959] H2N^SjZ^|

[0960] r >-CF3

[0961]

[0962] ZN^

[0963] To a solution of 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (15.5 g, 61.70 mmol) in EtOAc (150 mL) and 25% aq. ammonia solution (30 mL) stirring at 23 °C was added Raney nickel (85%, 15 g) and the mixture was stirred under EE (Parr reactor, 60 psi) atmosphere for 16 h. Upon completion, the mixture was filtered through Celite. The cake was thoroughly washed with ethanol, followed by EtOAc. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography (10% MeOH / DCM eluent) to obtain (4-(l-methyl-4-(trifluoromethyl)- U / -imidazol-2-yl)phenyl)-m ethanamine (9.60 g) as a pale yellow solid. 'H NMR (DMSO-d6, 400 MHz) 87.92 (d, J = 0.8 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 3.82 (s, 2H), 3.77 (s, 3H). LCMS observed m / z = 256.06 [M+H]+.

[0964] Intermediate B

[0965] Synthesis of (4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[0966] Intermediate B

[0967]

[0968] The title compound was prepared using a similar procedure as Intermediate A, replacing methyl iodide with 2-iodopropane and using general procedure C to reduce the nitrile. 'HNMR (400 MHz, DMSO-t / 6) 88.17 (d, J = 1.2 Hz, 1H), 7.55 - 7.50 (m, 4H), 4.50 - 4.43 (m, 1H), 4.29 - 4.27 (m, 2H), 3.88 (s, 2H), 1.40 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 284.32 [M+H]+.

[0969] Active 126539678.1 69 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT Intermediate C

[0970] Synthesis of (4-(l-ethyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)phenyl)methanamine.

[0971] Intermediate C

[0972]

[0973] The title compound was prepared using a similar procedure as Intermediate A, replacing methyl iodide with ethyl iodide and using general procedure C to reduce the nitrile.

[0974] 1H NMR (400 MHz, DMSO-d6) 8 8.42 (bs, 2H), 8.06 (d, J = 0.8 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 4.13-4.08 (m, 4H), 1.32 (t, J = 7.2 Hz, 3H). LCMS observed m / z = 270.26 [M+H]+.

[0975] Intermediate D

[0976] Synthesis of (4-(l-(oxetan-3-yl)-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[0977] Intermediate D

[0978]

[0979] The title compound was prepared using a similar procedure as Intermediate A, replacing methyl iodide with 4-iodooxetane and using general procedure C to reduce the nitrile. 1H NMR (400 MHz, DMSO-d6) 8 8.42 (bs, 2H), 8.06 (d, J = 0.8 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 4.13-4.08 (m, 4H), 1.32 (t, J = 7.2 Hz, 3H). LCMS observed m / z = 298.19 [M+H]+.

[0980] Intermediate E

[0981] Synthesi s of (4-( 1 -isopropyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)-3 -methylphenyl)-methanamine*HCl.

[0982] Intermediate E

[0983]

[0984] Step 1: Preparation of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile.

[0985] Intermediate E.l

[0986] Active 126539678.1 70 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0987]

[0988] To a stirred solution of 4-bromo-3 -methylbenzonitrile (5.00 g, 25.5 mmol) in DMF (50.0 mL) was added bis(pinacolato)diboron (7.12 g, 28.1 mmol), followed by the addition of potassium acetate (5.00 g, 51.0 mmol) at 23 °C. The resultant suspension was purged with nitrogen gas for 20 min and subsequently Pd(dppf)Cl2(1.04 g, 1.27 mmol) was added. Then the reaction mixture was stirred at 100 °C for 16 h. The reaction was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (50 mL), brine (50.0 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified using flash chromatography (10% EtOAc / petroleum ether eluent) to afford 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (3.50 g) as a light green solid. 'H NMR (400 MHz, CDCl3) 8 7.81 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 3.0 Hz, 2H), 2.55 (s, 3H), 1.35 (s, 12H).

[0989] Step 2: Preparation of 4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)-3-methyl-benzonitrile.

[0990] Intermediate E.2

[0991]

[0992] To a stirred solution of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (LOO g, 4.11 mmol) in 1,4-dioxane (10.0 mL) and water (1.00 mL) was added 2-bromo-l-isopropyl-4-(trifluoromethyl)-U / -imidazole (1.16 g, 4.50 mmol), followed by the addition of potassium carbonate (1.13 g, 8.22 mmol) at 23 °C. The reaction mixture was then purged with nitrogen gas for 20 min. Subsequently Pd(dppf)Cl2(0.336 g, 0.411 mmol) was added and the resultant mixture was stirred at 90 °C for 6 h. The reaction mixture was quenched with cold-water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography (10-20% EtOAc / petroleum ether eluent) to afford 4-(l-isopropyl-4-(trifluoromethyl)- IT / -imidazol -2 -yl)-3 -methylbenzonitrile (1.10 g) as a brown solid. LCMS observed m / z = 294.26 [M+H]+.

[0993] Active 126539678.1 71 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[0994] Step 3: Preparation of (4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-methylphenyl)-methanamine*HCl.

[0995] Intermediate E

[0996]

[0997] To a stirred solution of 4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-methylbenzonitrile (1.10 g, 3.75 mmol) inTHF (17.0 mL) was added lithium aluminum hydride (15.0 mL, IM solution in THF, 15 mmol) at 0 °C. Then the reaction mixture was brought to 25 °C and stirred for 2 h. On completion, the reaction mixture was quenched with saturated NH4CI solution (10 mL) and extracted with EtOAc (2x 50 mL). The combined organic layer was washed with water (20 mL), brine (20 mL), dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue was dissolved in 4M hydrochloric acid solution in dioxane (10 mL). The mixture was stirred at 25 °C for 1 h and then concentrated under reduced pressure. Subsequently diethyl ether (5 mL) was added to the residue and the precipitated solid was filtered. The filtered residue was washed further with n-pentane (2 x 10 mL) and dried to afford (4-(l -isopropyl-4-(trifhioromethyl)- \H-imidazol-2-yl)-3-methylphenyl)methanamine,HCl (0.87 g) as an off-white solid.1H NMR (400 MHz, DMSO-de,) 8d 8.35 (br s, 3H), 8.18 (s, 1H), 7.50 (s, 1H), 7.45 - 7.40 (m, 2H), 4.08 (q, J = 5.7 Hz, 2H), 4.00 - 3.93 (m, 1H), 2.13 (s, 3H), 1.34 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 298.18 [M+H]+.

[0998] Intermediate F

[0999] Synthesis of l-4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)cuban-l-yl)-N-methylmethanamine*HCl.

[1000] Intermediate F

[1001]

[1002] Step 1: Preparation of methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-l-carb oxy late.

[1003] Intermediate F.l

[1004] Active 126539678.1 72 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1005]

[1006] A stirred solution of 3, 3 -dibromo- 1,1,1 -trifluoropropan-2-one (30.0 g, 110 mmol) in water (210 mL) was prepared and cooled to 0 °C. NaOAc (9.60 g, 118 mmol) was then added to the reaction mixture, which was subsequently stirred at 100 °C for 1 hour, then cooled to 0 °C. A solution of methyl 4-formylcubane-l -carboxylate (14.0 g, 73.6 mmol) in methanol (210 mL) and 25% aqueous ammonia solution (210 mL) was added to the reaction and the mixture was stirred at 0 °C for 1 hour. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove methanol. The material was then extracted with EtOAc (3 x 250 mL), and the combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with / / -pentane to afford methyl 4-(4-(trifluoromethyl)-IT / -imidazol-2-yl)cubane-l -carboxylate (12.0 g) as an off-white solid. LCMS observed m / z = 296.97 [M+H]+.

[1007] Step 2: Preparation of methyl 4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)cubane- 1 -carboxylate.

[1008] Intermediate F.2

[1009]

[1010] To a stirred solution of methyl 4-(4-(trifluoromethyl)- U / -imidazol-2-yl)cubane-l-carboxylate (12.0 g, 40.5 mmol) in DMF (120 mL) stirring at 0 °C were added cesium carbonate (39.6 g, 122 mmol) and 2-iodopropane (34.4 g, 203 mmol). The reaction mixture was then heated at 90 °C for 16 h. After completion, the reaction mixture was quenched with cold water (250 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to obtain a residue. The residue was purified by flash chromatography (10-20% EtOAc / petroleum ether eluent) to afford methyl 4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)cubane-l -carboxylate (5.50 g) as a pale brown solid. LCMS observed m / z = 339.62 [M+H]+.

[1011] Step 3: Preparation of 4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)cuban-l-yl)m ethanol.

[1012] Active 126539678.1 73 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1013] Intermediate F.3

[1014]

[1015] A solution of methyl 4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-l-carboxylate (2.00 g, 5.91 mmol) in THF (20 mL) and methanol (2.0 mL) was prepared at 0 °C. NaBH4 (0.670 g, 17.7 mmol) was then added to the solution, and the reaction mixture was stirred at 23 °C for 16 h. After completion, the reaction mixture was diluted with cold water (25 mL) and concentrated under reduced pressure to remove methanol. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (25 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (35-50% EtOAc / petroleum ether eluent) to afford (4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-l-yl) methanol (1.10 g) as a white solid.

[1016] 'H NMR (400 MHz, DMSO-d6) 8 7.99 (d, J = 1.2 Hz, 1H), 4.57 (t, J = 5.4 Hz, 1H), 4.16 (t, J = 5.0 Hz, 3H), 4.08 - 4.03 (m, 1H), 3.87 (t, J = 4.8 Hz, 3H), 3.57 (d, J = 5.2 Hz, 2H), 1.41 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 311.22 [M+H]+.

[1017] Step 4: Preparation of 4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1-carbaldehyde.

[1018] Intermediate F.4

[1019] o

[1020]

[1021] To a stirred solution of (4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl) methanol (1.90 g, 6.12 mmol) in DCM (40.0 mL) at 0 °C under a nitrogen atmosphere, Dess-Martin periodinane (0.957 g, 9.18 mmol) was added. The resulting reaction mixture was stirred at 23 °C for 2 hours. After completion, the reaction mixture was quenched with a saturated ammonium bicarbonate solution (20 mL). The product was extracted with DCM (50 mL x 2). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to obtain a residue. The residue was triturated with pentane to afford 4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-l-carbaldehyde (1.60 g) as an off-white solid. LCMS observed m / z = 309.0 [M+H]+.

[1022] Active 126539678.1 74 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1023] Step 5: Preparation of l-4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)cuban-1 -yl)-7V-methylmethanamine.

[1024] Intermediate F

[1025]

[1026] To a solution of 4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)cubane-l-carbaldehyde (1.60 g, 5.19 mmol) in methanol (40.0 mL) stirring at 0 °C was added methylamine hydrochloride (1.75 g, 26.0 mmol) and the mixture was stirred for 30 min. Sodium cyanoborohydride (10.2 g, 26.0 mmol) was added and the resulting reaction mixture was stirred at 23 °C for 16 h. Upon completion, the reaction mixture was quenched with cold water (25 ml) and evaporated under reduced pressure. The residue was extracted with EtOAc (2 x 50 mL) and the combined organic phases were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to get a residue. The residue was dissolved in 4 M HC1 in dioxane (5.0 ml) and the resulting reaction mixture was stirred at 23 °C for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified via reverse phase chromatography (0-100% MeCN / FLO w / 0.1% formic acid) to afford l-4-(l-isopropyl-4-(trifluoromethyl)-IT / -imidazol-2-yl)cuban-l-yl)-7V-methylmethanamine (0.19 g) as a brown gum.1H NMR (400 MHz, DMSO-d6) 57.98 (d, J = 0.8 Hz, 1H), 4.26-4.16 (m, 3H), 4.09-4.02 (m, 1H), 3.89-3.87 (m, 3H), 2.74 (s, 2H), 2.33 (s, 3H), 1.41 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 324.38 [M+H]+.

[1027] Intermediate G

[1028] Synthesis of (6-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)pyridin-3-yl)methanamine*HCl.

[1029] Intermediate G

[1030]

[1031] Stepl: Preparation of 5-bromo-2-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)pyridine.

[1032] Intermediate G.l

[1033] Active 126539678.1 75 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1034] CF3

[1035]

[1036] The title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with 5-bromo-2-pyridinecarboxaldehyde and following General Procedures A and B. LCMS observed m / z = 334.19 [M+H]+.

[1037] Step 2: Preparation of tert-butyl ((6-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)carbamate.

[1038] Intermediate G.2

[1039]

[1040] To a stirred solution of 5-bromo-2-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine (2.90 g, 8.68 mmol) in 1,4-dioxane (26.0 mL) and water (3.0 mL) was added potassium (((ter / -butoxycarbonyl)amino)methyl)trifluoroborate (2.47 g, 10.4 mmol), followed by the addition of cesium carbonate (7.07 g, 21.7 mmol) at 23 °C. The reaction mixture was purged with nitrogen gas for 30 min. Then cataCXium A Pd G3 (0.63 g, 0.87 mmol) was added under nitrogen atmosphere and the resulting reaction mixture was heated at 100 °C for 16 h. After completion, the reaction mixture quenched with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified via flash chromatography (60% EtOAc / petroleum ether eluent) to afford tert-butyl((6-(l-isopropyl-4-(trifluoromethyl)-lJT-imidazol-2-yl)pyridin-3-yl)methyl)carbamate (1.57 g) as a yellow solid. LCMS observed m / z = 385.5 [M+H]+.

[1041] Step 3: Preparation of (6-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3 -yl)methanamine*HCl.

[1042] Intermediate G

[1043]

[1044] To a stirred solution of tert-butyl ((6-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)pyridin-3-yl)methyl)carbamate (1.57 g, 4.08 mmol) inDCM (20 mL) was added 4M

[1045] Active 126539678.1 76 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1046] hydrochloric acid solution in 1,4-dioxane (2.0 mL, 8.00 mmol) at 0 °C. Subsequently the reaction mixture was brought to 23 °C and stirred for 2 h. After completion, the reaction mixture was concentrated under reduced pressure to afford product. The residue was triturated with pentane (5 mL) to obtain the desired product (6-(l-isopropyl-4-(trifluoromethyl)- 1H-imidazol -2 -yl)pyri din-3 -yl)methanamine hydrochloride (1.10 g, 95 %) as an off-white solid.

[1047] 1H NMR (400 MHz, DMSO-d6) 8 8.76 (d, J = 1.2 Hz, 1H), 8.45 (br s, 3H), 8.27 (d, J = 0.8 Hz, 1H), 8.13 - 8.06 (m, 2H), 5.77 - 5.71 (m, 1H), 4.17 - 4.13 (m, 2H), 1.46 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 285.23 [M+H]+Intermediate H

[1048] Synthesis of (4-(5-methyl-3-(trifluoromethyl)-U / -pyrazol-l-yl)phenyl)methanamine.

[1049] Intermediate H

[1050] HjN

[1051] CF3

[1052]

[1053] Step 1: Preparation of 4-(5-methyl-3-(trifluoromethyl)-U / -pyrazol-l-yl)benzonitrile.

[1054] Intermediate H.l

[1055]

[1056] To a stirred solution of 4-hydrazineylbenzonitrile (5 g, 37.55 mmol) and 1,1,1-trifluoropentane-2, 4-dione (8.67 g, 56.3 mmol) in Acetic acid (25 mL) was added NaO Ac anhydrous (6.16 g, 75.1 mmol) and the reaction mixture was stirred at 120 °C for 12 h. Upon completion, the reaction mixture was evaporated under reduced pressure and the residue was purified by flash column chromatography (20% EtOAc / hexanes eluent) to obtain 4-(5-methyl-3-(trifluoromethyl)- 17 / -pyrazol-l-yl (benzonitrile (3.5g) as an off white solid. LCMS observed m / z = 252.14 [M+H]+.

[1057] Step 2: Preparation of tert-butyl (4-(5-methyl-3-(trifluoromethyl)-IT / -pyrazol-l-yl)benzyl)carbamate.

[1058] Intermediate H.2

[1059] 3ocHN

[1060]

[1061] Active 126539678.1 77 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1062] To a stirred solution of 4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzonitrile (3 g, 12 mmol) in MeOH (30.0 mL) were added Nickel(II) chloride hexahydrate (0.56 g, 2.4 mmol) and NaBH4 (0.90 g, 24 mmol) at 0 °C. The reaction mixture was stirred at 23 °C for 10 min before adding Di-tert-butyl pyrocarbonate (2.86 g, 13.1 mmol) at 0°C and the reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered. The filtrate was evaporated under reduced pressure and the residue was purified by flash column chromatography (20% EtOAc / hexanes eluent) to obtain tert-butyl (4-(5-methyl-3 -(trifluoromethyl)- IT / -pyrazol- l-yl)benzyl)carbamate (2.6 g) as an off white solid. LCMS observed m / z = 356.30 [M+H]+.

[1063] Step 3: Preparation of (4-(5-methyl-3-(trifluoromethyl)-U / -pyrazol-l-yl)phenyl)methanamine.

[1064] Intermediate H

[1065] HjN

[1066] OF,

[1067]

[1068] To a stirred solution of tert-butyl (4-(5-methyl-3-(trifluoromethyl)-IT / -pyrazol-l-yl)benzyl)carbamate (2.6 g, 7.3 mmol) in DCM (25 mL) was added hydrogen chloride (4.95 mL, 4.0 M in 1,4-dioxane, 14.6 mmol) and the reaction mixture was stirred at 23 °C for 1 h. Upon completion, the reaction mixture was evaporated under reduced pressure and the residue was neutralized with saturated sodium bicarbonate solution (25 mL). The aqueous layer was extracted with EtOAc (3x100 mL). The combined organic layer was washed with brine (lOmL), dried over sodium sulfate, filtered and filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography (20% MeOH / DCM eluent) to obtain tert-butyl (4-(5-methyl-3-(trifluoromethyl)- IT / -pyrazol- l-yl)benzyl)carbamate (2.9 g) as a yellow liquid. Tf NMR (400 MHz, DMSO-d6): 8 7.55-7.18 (m, 4H), 6.75 (s, 1H), 3.85 (s, 2H), 2.33 (s, 3H). LCMS observed m / z = 256.1 [(M+H]+.

[1069] Intermediate I

[1070] Synthesi s of (4-(5 -(oxetan-3 -y 1) -3 -(trifluoromethyl)- 17 / -py razol - 1 -yl)phenyl)methanamine

[1071] Intermediate I

[1072] Active 126539678.1 78 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1073]

[1074] Step 1: Preparation of 5-(oxetan-3-yl)-3-(trifluoromethyl)-lrt-pyrazole Intermediate 1.1

[1075]

[1076] To a stirred solution of 2-bromo-3,3,3-trifluoroprop-l-ene (5 g, 28.58 mmol) and oxetane-3-carbaldehyde (4.92 g, 57.16 mmol in toluene (100 mL) were added 1,8-diazabicyclo[5.4.0]undec-7-ene (13.05 g, 85.74 mmol) followed by p-toluenesulfonyl hydrazine (7.83 g, 34.30 mmol) at 25 °C. The reaction mixture was stirred at 60 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure and diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered. The residue was purified by normal phase column chromatography (50-60% EtOAc / petroleum ether eluent) to afford 5-(oxetan-3 -yl)-3 -(trifluoromethyl)- Irt-pyrazolc (2 g, 36.42%) as a yellow solid. LCMS observed m / z = 193.24 [M+H]+

[1077] Step 2: Preparation of tert-butyl (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)- lrt-pyrazol- 1 -yl)benzyl)carbamate

[1078] Intermediate 1.2

[1079] BocHN

[1080]

[1081] To a stirred solution of 5 -(oxetan-3-yl)-3 -(trifluoromethyl)- 17 / -pyrazole (2.1 g, 10.93 mmol) and (4-(((ter / -butoxycarbonyl)amino)methyl)phenyl)boronic acid (4.11 g, 16.39 mmol) in 1,2-dichloroethane (50 mL)were added copper(II) acetate (2.98 g, 16.394 mmol) followed by pyridine (1.76 mL, 21.86 mmol) at 25° C. The reaction mixture was stirred at 25 °C for 6 h in air. Upon completion of reaction, the reaction mixture was fdtered through Celite and quenched with cold water (5 mL) and extracted with EtOAc (2x 5 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered. The filtrate was concentrated under reduced pressure. The residue purified by flash column chromatography (20% EtOAc / petroleum ether eluent) to obtain tert-butyl (4-(5-(oxetan-3-

[1082] Active 126539678.1 79 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1083] yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)carbamate (1.5 g, 34.54%) as an off-white solid. LCMS observed m / z = 398.24 [M+H]+.

[1084] Step 3: Preparation of (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-17 / -pyrazol-l-yl)phenyl)methanamine

[1085] Intermediate I

[1086]

[1087] To a stirred solution of tert-butyl (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-17 / -pyrazol-l-yl)benzyl)carbamate (1.5 g, 3.77 mmol) in DCM (20 mL) was added trifluoroacetic acid (15 mL, 37.74 mmol) at 0 °C and the reaction mixture was stirred at 25 °C for 3 h. Upon completion, reaction mixture was concentrated in vacuum to get the residue. The residue was triturated with pentane (50 mL) to obtain (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-17 / -pyrazol-l-yl)phenyl)methanamine (1 g, 89.12%) as an off white solid.1H NMR (400 MHz, DMSO-d6) 8 8.21 (br s, 2H), 7.63 (d, J= 8.4 Hz, 2H), 7.51 (d, J= 8.4 Hz, 2H), 7.25 (s, 1H), 4.77-4.73 (m, 2H), 4.68-4.64 (m, 2H), 4.39-4.31 (m, 1H), 4.15 (s, 2H). LCMS observed m / z = 298.32 [M+H]+.

[1088] Intermediate J

[1089] Synthesis of (4-(5-isopropyl-3-(trifluoromethyl)- l / 7-pyrazol- 1 -yl)phenyl)methanamine

[1090] Intermediate J

[1091]

[1092] Step 1: Preparation of 4-(5-bromo-3-(trifluoromethyl)-17 / -pyrazol-l-yl)benzonitrile Intermediate J.l

[1093]

[1094] To a stirred solution of (4-cyanophenyl)boronic acid (2.2 g, 14.97 mmol) and 5-bromo-3 -(trifluoromethyl)- l / 7-pyrazole (3.86 g, 17.96 mmol) in 1,2-dichloroethane (44 mL), copper(II) acetate (4.08 g, 22.46 mmol) was added, followed by pyridine (2.41 mL, 29.94 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 12 hours in air. Upon

[1095] Active 126539678.1 80 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1096] completion, the mixture was filtered through Celite, diluted with cold water (100 mL), and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by normal-phase column chromatography (20-30% EtOAc / hexanes eluent) to yield 4-(5-bromo-3 -(trifluoromethyl)- IJT-pyrazol-l-yl)benzonitrile (2.7 g) as an off-white solid.1H NMR (400 MHz, CDCl3): 87.84 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 6.82 (s, 1H). LCMS observed m / z = 315.9 [M+H]+.

[1097] Step 2: Preparation of 4-(5-(prop-l-en-2-yl)-3-(trifluoromethyl)-U / -pyrazol-l-yl)benzonitrile

[1098] Intermediate J.2

[1099] NC. / C

[1100]

[1101] To a stirred solution of 4-(5-bromo-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzonitrile (2.5 g, 7.91 mmol) in 1,4-dioxane (50.0 mL) and water (5.0 mL), 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (2.66 g, 15.82 mmol) and potassium carbonate (3.3 g, 23.73 mmol) were added. The reaction mixture was purged with nitrogen gas for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.91 g, 0.79 mmol) was then added, and the mixture was stirred at 110 °C for 16 hours. Upon completion, the reaction was quenched with cold water (25 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by normal-phase column chromatography (4-6% EtOAc / hexanes eluent) to yield 4-(5-(prop-l-en-2-yl)-3-(trifluoromethyl)-U / -pyrazol-l-yl)benzonitrile (1.8 g) as a pale brown solid. LCMS observed m / z = 278.15 [M+H]+

[1102] Step 3: Preparation of (4-(5-isopropyl-3-(trifluoromethyl)-U / -pyrazol-l-yl)phenyl)methanamine* TFA

[1103] Intermediate J

[1104]

[1105] To a stirred solution of 4-(5-(prop-l-en-2-yl)-3-(trifluoromethyl)-U / -pyrazol-l-yl)benzonitrile (1.8 g, 6.5 mmol) in EtOAc (50 mL), palladium on carbon (50% wet basis,

[1106] Active 126539678.1 81 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1107] 1.8 g), platinum(IV) oxide (0.2 g), and acetic acid (0.5 mL) were added. The reaction mixture was stirred in a Parr shaker under hydrogen atmosphere (85 psi) for 16 hours at 25 °C. Upon completion, as monitored by TLC (Rf: 0.6, mobile phase: 30% EtOAc in hexane), the mixture was filtered through a Buchner funnel. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (Mobile Phase A: 0.1% trifluoroacetic acid in H2O; Mobile Phase B: MeCN = 1:4) to yield (4-(5-isopropyl-3-(trifluoromethyl)-U / -pyrazol-l-yl) phenyl) methanamine (0.75 g) as a pale brown solid. The compound is in the form of a trifluoroacetic acid salt.1H NMR (400 MHz, DMSO-de) 88.22 (br s, 3H), 7.67-7.61 (m, 4H), 6.85 (s, 1H), 4.16 (d, J = 5.6 Hz, 2H), 3.01-2.94 (m, 1H), 1.15 (d, J = 6.8 Hz, 6H). LCMS observed m / z =284.38 [M+H]+

[1108] Intermediate K

[1109] Synthesis of (4-(l-isopropyl-3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)phenyl)methanamine

[1110] Intermediate K

[1111] HjN

[1112] \ y-cf’

[1113] ^N-N

[1114]

[1115] Step 1: Preparation of 5-bromo-l-isopropyl-3-(trifluoromethyl)-U / -l,2,4-triazole Intermediate K.1

[1116] Br> _ N

[1117] \ y-CFS

[1118] ^N-N

[1119]

[1120] To a stirred solution of 5-bromo-3-(trifluoromethyl)-U / -l,2,4-triazole (1.0 g, 4.63 mmol) in DMFDMF (DMF, 10 mL) was added NaH, 60% dispersion in mineral oil (333 mg, 13.9 mmol) at 0 °C and stirred for 15 minutes. Then 2-iodopropane (2.36 g, 13.9 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was quenched with cold water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (10-20% EtOAc / petroleum ether eluent) to obtain 5-bromo-l-isopropyl-3-(trifluoromethyl)-U / -l,2,4-triazole (800 mg). Note: The isomeric mixture was used moving forward. LCMS observed m / z = 257.87 [M+H]+.

[1121] Step 2: Preparation of 4-(l-isopropyl-3-(trifluoromethyl)-U / -l,2,4-triazol-5-yl)benzonitrile

[1122] Active 126539678.1 82 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT Intermediate K.2

[1123]

[1124] To a stirred solution of 5-bromo-l-isopropyl-3-(trifluoromethyl)-17 / -l,2,4-triazole (mixture of two regio-isomers) (800 mg, 3.10 mmol) in 1,4-dioxane (8 mL) and water (2 mL), (4-cyanophenyl) boronic acid (683 mg, 4.65 mmol) followed by potassium carbonate (1.28 g, 9.3 mmol) were added, and the mixture was purged with nitrogen gas for 30 min. Tetrakis(triphenylphosphine)palladium(0) (358 mg, 0.31 mmol) was added to the reaction mixture and stirred at 110 °C for 16 h. After completion, the reaction mixture was diluted with water (2 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (10-20% EtOAc / petroleum ether eluent) to obtain 4-(l-isopropyl-3-(trifluoromethyl)-17 / -l,2,4-triazol-5-yl)benzonitrile (600 mg) as a white solid. LCMS observed m / z = 281.31 [M+H]+.

[1125] Step 3: Preparation of (4-(l-isopropyl-3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)phenyl)methanamine

[1126] Intermediate K

[1127] . N

[1128]

[1129] To the stirred solution of 4-(l-isopropyl-3-(trifluoromethyl)-17 / -l,2,4-triazol-5-yl) benzonitrile (800 mg, 2.85 mmol) in THF (10 mL) was added LiAlH4powder (325 mg, 8.56 mmol) at 0 °C and stirred at room temperature for 16 h. After completion, the reaction mixture was quenched with saturated NH4C1 solution (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was evaporated under reduced pressure to obtain (4-(l-isopropyl-3-(trifluoromethyl)-17 / -l,2,4-triazol-5-yl) phenyl) methanamine (600 mg). 'HNMR (400 MHz, DMSO-d6) δ 8.37 (s, 3H), 7.75 (d, J= 8.4 Hz, 2H), 7.70 (d, J= 8.4 Hz, 2H), 4.69-4.75 (m, 1H), 4.15 (s, 2H), 1.48 (d, J = 12.0 Hz, 6H). LCMS observed m / z = 285.04 [M+H]+.

[1130] Intermediate L

[1131] Active 126539678.1 83 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1132] Synthesis (2-fluoro-4-(5-methyl-3-(trifluoromethyl)- 17 / -pyrazol-l-yl)phenyl)methanamine

[1133] Intermediate L

[1134]

[1135] The title compound was prepared using a similar procedure as Intermediate H, replacing 4-hydrazinylbenzonitrile with 2-fluoro-4-hydrazinylbenzonitrile. LCMS observed m / z 274.35 [M+H]+.

[1136] Intermediate M

[1137] Synthesi s of (3 -fluoro-4-( 1 -isopropyl-4-(trifluoromethyl)- lZZ-imidazol-2-yl)phenyl)methanamine

[1138] Intermediate M

[1139]

[1140] The title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with 3-fluoro-4-formylbenzonitrile and using general procedure C to reduce the nitrile. LCMS observed m / z = 302.17 [M+H]+.

[1141] Intermediate N

[1142] Synthesis of (4-(3-(difluoromethyl)-5-methyl-lJ / -pyrazol-l-yl)phenyl)methanamine Intermediate N

[1143] N

[1144]

[1145] Step 1: Preparation of 4-(3-(difluoromethyl)-5-methyl-17 / -pyrazol-l-yl)benzonitrile.

[1146] Intermediate N. I

[1147]

[1148] To a stirred solution of 3-(difluoromethyl)-5-methyl-IT / -pyrazole (5.0 g, 37.5 mmol) and (4-cyanophenyl)boronic acid (11.1 g, 76.0 mmol) in 1,2-di chloroethane (60.0 mL), pyridine (6.83 mL, 35.8 mmol) was added, followed by copper(II) acetate (10.2 g, 4.97 mmol)

[1149] Active 126539678.1 84 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1150] under an oxygen atmosphere. The reaction mixture was stirred at 60 °C for 16 h. Upon completion, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with ice-cold water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was evaporated under reduced pressure to obtain a residue which was purified by flash chromatography (25-30% EtOAc / petroleum ether eluent) to afford 4-(3-(difluoromethyl)-5-methyl- l / 7-pyrazol- l -yl)benzo nitrile (3.0 g) as an off-white solid. LCMS observed m / z = 232.10 [M-H]+.

[1151] Step 2: Preparation of (4-(3-(difluoromethyl)-5-methyl-lH-pyrazol-l-yl)phenyl)methanamine.

[1152] Intermediate N

[1153]

[1154] To a stirred solution of 4-(3-(difluoromethyl)-5-methyl-lJ / -pyrazol-l-yl)benzonitrile (0.6 g, 2.57 mmol) in THF (12.0 mL) cooled to 0 °C was added LiAlH4(0.29 g, 7.72 mmol) portion-wise over 10 min. The reaction mixture was warmed to 23 °C and stirred for 4 h. Upon completion, the mixture was slowly diluted with aq. 5M KOH solution (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by reverse-phase column chromatography using mobile phase-A: 0.1% trifluoroacetic acid in H2O and mobile phase-B: MeCN (1:4) to afford (4-(3-(difluoromethyl)-5-methyl-lJ / -pyrazol-l-yl)phenyl)methanamine (0.336 g) as a brown solid. 'H NMR (400 MHz, DMSO-de) 8 8.39 (br s, 3H), 7.67-7.57 (m, 4H), 7.19-6.87 (m, 1H), 6.58 (s, 1H), 4.12 (d, J = 4.8 Hz, 2H), 2.35 (s, 3H) LCMS observed m / z =238.33 [M+H]+.

[1155] Intermediate O

[1156] Synthesis of (2-(trifluoromethyl)-6,7-dihydro-5J / -benzo[c]imidazo[l,2-a]azepin-9-yl)m ethanamine.

[1157] Intermediate O

[1158]

[1159] Step 1: Preparation of 3-bromo-4-(4-(trifluoromethyl)-U / -imidazol-2-yl)benzonitrile.

[1160] Intermediate O.l

[1161] Active 126539678.1 85 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1162]

[1163] To a mixture of 3,3-dibromo-l,l,l-trifhioro-2-propanone (619 pL, 1.1 eq., 5.02 mmol) in water (2.13 mL, 118 mmol) was added potassium acetate (497 mg, 1.1 eq., 5.07 mmol) and the mixture was heated to 100 °C for 1 h. The mixture was cooled to 23 °C, then a solution of 3-bromo-4-formylbenzonitrile (950 mg, 4.52 mmol) in methanol (22.6 mL, 558 mmol) and NH4OH (5 mL, 128 mmol) (pre-stirred for 1 h) was added and stirred at 23 °C for 45 min, then warmed to 100 °C for 18 h. The reaction was cooled to 23 °C and diluted with water (75 mL) and EtOAc (50 mL). The mixture was filtered and the phases were separated. The organic was dried over MgSO4, filtered and concentrated to afford 3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile as a yellow solid (1.43 g). The material was used without purification. LCMS observed m / z =316.0 [M+H]+.

[1164] Step 2: Preparation of 4-(l-allyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)-3 -bromobenzonitrile.

[1165] Intermediate O.2

[1166]

[1167] To a solution of 3-bromo-4-[4-(trifluoromethyl)-2-imidazolyl]benzonitrile (1.43 g, 4.52 mmol) in DMF (9.04 mL, 117 mmol) was added dipotassium carbonate (1.25 g, 2 eq., 9.04 mmol) followed by 3 -bromopropene (586 pL, 1.5 eq., 6.78 mmol) and the mixture was stirred at 23 °C for 3 h. The reaction was poured into LiCl (20 mL, 10% aq) and extracted with EtOAc (2x 15 mL). The combined organics were washed with water (15 mL), brine (15 mL), dried over MgSO4, filtered and concentrated. The residue was purified via flash chromatography (10-25% EtOAc / hexanes eluent) to afford 4-(l -allyl -4-(trifluoromethyl)-1H-imidazol-2-yl)-3-bromobenzonitrile (0.78g) as an amber oil LCMS observed m / z = 357.1 [M+H]+.

[1168] Step 3: Preparation of 4-(l-allyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)-3-vinylbenzonitrile

[1169] Intermediate O.3

[1170] Active 126539678.1 86 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1171]

[1172] To a suspension of 4-(l-allyl-4-(trifluoromethyl)-U / -imidazol-2-yl)-3-bromobenzonitrile (356 mg, 1 mmol), dicesium carbonate (977 mg, 3 eq., 3 mmol), and 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (509 pL, 3 eq., 3 mmol) in 1,4-dioxane (4 mL, 46.9 mmol) and water (1 mL, 20 eq., 20 mmol) was added Pd(dppf)Cl2(81.7 mg, 0.1 eq., 0.1 mmol) and the mixture was degassed with N2 via vacuum / N2 backfill (5x). The vial was sealed and heated at 85 °C for 16 h. The reaction was not complete at this time. An additional 2.0 equiv. of the vinyl borane was added followed by Pd(dppf)Cl2(100 mg) and the reaction was heated to 100 °C for 24 h at which point the reaction was complete by LCMS. The reaction was diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic phases were dried over MgSCU, filtered and concentrated. The residue was purified via flash chromatography (10-20% EtOAc / hexanes eluent) to afford 4-(l-allyl-4-(trifluoromethyl)-U / -imidazol-2-yl)-3-vinylbenzonitrile (0.56 g) as a pale yellow oil. LCMS observed m / z =304.2 [M+H]+.

[1173] Step 4: Preparation of 2-(trifluoromethyl)-5J / -benzo[c]imidazo[l,2-a]azepine-9-carbonitrile

[1174] Intermediate O.4

[1175]

[1176] To a solution of 4-(l-allyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-vinylbenzonitrile (716.6 mg, 2.33 mmol) in DCM (3.22 mL, 50.3 mmol) was added ruthenium o-isopropoxymethanediidyltoluene l,3-bis(mesityl)-2,2-imidazolidinediide dichloride (74.0 mg, 0.05 eq., 118.1 pmol) and the mixture was stirred at 23 °C for 16 h. The reaction was filtered through a plug of SiO2, washing with 50% EtOAc / hexanes (5 mL) and the resulting solution was concentrated. The residue was purified via flash chromatography (80-90% EtOAc / hexanes eluent) to afford 2-(trifluoromethyl)-5J / -benzo[c]imidazo[l,2-a]azepine-9-carbonitrile (0.48g) as a yellow solid LCMS observed m / z =276.1 [M+H]+.

[1177] Step 5: Preparation of (2-(trifluoromethyl)-6,7-dihydro-5J / -benzo[c]imidazo[l,2-a]azepin-9-yl)m ethanamine

[1178] Intermediate O

[1179] Active 126539678.1 87 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1180]

[1181] To a solution of 2-(trifluoromethyl)-5J / -benzo[c]imidazo[l,2-a]azepine-9-carbonitrile (473 mg, 1.72 mmol) in THF (10 mL, 123 mmol) and methanol (10 mL, 247 mmol) at 0 °C was added nickel dichloride (81.8 mg, 0.2 eq., 344 pmol) followed by NaBH4(309 mg, 3 eq., 5.16 mmol). The mixture was warmed to 23 °C and stirred for 3 h at which point it was complete by LCMS. The reaction was quenched with water (10 mL) and stirred for 10 min. The mixture was extracted with EtOAc (2 x 10 mL) and the combined organics were washed with water (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified via flash chromatography (0-10% MeOH / DCM eluent) to afford (2-(trifluoromethyl)-6,7-dihydro-5J / -benzo[c]imidazo[l,2-a]azepin-9-yl)methanamine (243 mg) as an off white solid. LCMS observed m / z = 282.1 [M+H]+.

[1182] Intermediate P

[1183] Synthesis of ({4-[l-isopropyl-4-(trifluoromethyl)-2-imidazolyl]-2-oxabicyclo[2.2.2]oct-l-yl}methyl)amine *HC1.

[1184] Intermediate P

[1185] MCI

[1186] HaN

[1187]

[1188] Step 1: Preparation of tert-butyl ((4-formyl-2-oxabicyclo[2.2.2]octan-l-yl)methyl)carbamate

[1189] Intermediate P.l

[1190] .0.

[1191] BocHN

[1192]

[1193] To a solution of {4-(hydroxymethyl)-2-oxabicyclo[2.2.2]oct-l-yl (methyl 2-methyl-2-propanecarbamate (407 mg, 1.5 mmol) in DCM (15 mL, 234 mmol) stirring at 23 °C was added l,l-diacetoxy-3-oxo-l,3-dihydro-lX5,2-benziodaoxol-l-yl acetate (0.7 g, 1.1 eq., 1.65 mmol) and the reaction was stirred at 23 °C for 1 h. The reaction was quenched with sat. Na2S2O3 (5 mL) and stirred for 5 min. The mixture was diluted with DCM (10 mL) and the phases were separated. The organic was washed with water (10 mL), brine (10 mL), dried over MgSO4, filtered and was concentrated to afford the product as a colorless oil. The material was used without further purification LCMS observed m / z + Na = 292.2.

[1194] Active 126539678.1 88 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1195] Step 2: Preparation of tert-butyl ((4-(4-(trifluoromethyl)-U / -imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-l-yl)methyl)carbamate

[1196] Intermediate P.2

[1197] BocHN

[1198]

[1199] To a solution of 3, 3 -dibromo- 1,1,1 -trifluoro-2-propanone (206 pL, 1.1 equiv., 1.67 mmol) in water (869 pL, 48.2 mmol) was added NaOAc (138 mg, 1.1 eq., 1.68 mmol) and the mixture was heated to 100 °C for 1 h. The mixture was cooled to 23 °C and a solution of (4-formyl-2-oxabicyclo[2.2.2]oct-l-yl)methyl 2-methyl-2-propanecarbamate (404 mg, 1.5 mmol) in methanol (6.52 mL, 161 mmol) and NH4OH (1.5 mL) was added and the mixture was heated to 100 °C for 20 h. The reaction was cooled to 23 °C and the mixture was extracted with EtOAc (2 x 20 mL). The combined organics were washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated to afford the imidazole as a brown resin. The material was used in the next step without purification (370 mg). LCMS observed m / z = 376.2

[1200] Step 3: Preparation of tert-butyl ((4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-l-yl)methyl)carbamate

[1201] Intermediate P.3

[1202] > — ^.0.^

[1203]

[1204] To a suspension of tert-butyl ({4-[4-(trifluoromethyl)-2-imidazolyl]-2-oxabicyclo[2.2.2]oct-l-yl}methyl)carbamate (563 mg, 1.5 mmol) and dicaesium carbonate (1.47 g, 3 eq., 4.5 mmol) in MeCN (6 mL, 115 mmol) stirring at 23 °C was added 2-iodopropane (0.6 mL, 4 eq., 6 mmol) and the mixture was heated to 70 °C for 18 h. LCMS indicated conversion to the desired product. The reaction was cooled to 23 °C and filtered, washing with EtOAc (10 mL). The filtrate was concentrated and the residue was purified via flash chromatography (0-75% EtOAc / hexanes eluent) to afford the product (205 mg) as a pale yellow oil that solidified on standing. LCMS observed m / z = 418.3.

[1205] Step 4: Preparation of ({4-[l-isopropyl-4-(trifluoromethyl)-2-imidazolyl]-2-oxabicyclo[2.2.2]oct-l-yl}methyl)amine*HCl

[1206] Intermediate P

[1207] Active 126539678.1 89 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1208]

[1209] To a solution of tert-butyl ({4-[l-isopropyl-4-(trifluoromethyl)-2-imidazolyl]-2-oxabicyclo[2.2.2]oct-l-yl}methyl)carbamate (201 mg, 481 pmol) in 1,4-dioxane (481 pL, 5.64 mmol) stirring at 23 °C was added HC1 in 1,4-dioxane (4M, 3.0 mmol, 3.0 mL and the reaction was stirred at 23 °C for 1 h. The reaction was concentrated under reduced pressure, azeotroping with heptanes (5 mL) to afford the product as a white solid.1H NMR (CD3OD, 400 MHz): 8.04 (s, 1H), 5.00 (sept. J = 6.5 Hz, 1H), 4.26 (s, 2H), 2.38 - 2.30 (m, 2H), 2.20 - 2.12 (m, 2H), 2.09 - 1.99 (m, 2H), 1.89 - 1.80 (m, 2H), 1.49 (d, J = 6.5 Hz, 6H). LCMS observed m / z = 318.3.

[1210] Intermediate Q

[1211] Synthesis of 4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)cuban-l-yl)m ethanamine.

[1212] Intermediate Q

[1213]

[1214] Step 1: Preparation of 4-(4-(trifluoromethyl)- U / -imidazol-2-yl)cubane-l-carb oxami de.

[1215] Intermediate Q.l

[1216]

[1217] To a stirred solution of 3, 3 -dibromo- 1,1,1 -trifluoropropan-2-one (15.3 g, 56.8 mmol) in water (100 mL) was added NaO Ac (46.6 g, 56.8 mmol) at 0 °C. The reaction mixture was heated to 100 °C for 1 h. The reaction was cooled to 0 °C and a solution of methyl 4-formylcubane-l -carboxylate (9.00 g, 47.3 mmol) in MeOH (180 mL) and ammonia (180 mL, 25% in water) was added. The reaction mixture was stirred at 23 °C for 16 h. After completion, the precipitated solid was filtered and dried in a vacuum oven at 60 °C overnight to afford 4-(4-(trifluoromethyl)-1-imidazol-2-yl)cubane-1-carboxamide (4.50 g) as an off

[1218] Active 126539678.1 90 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1219] white solid. The compound was used in the next step without further purification. LCMS observed m / z = 280.19 [M-H]'.

[1220] Step 2: Preparation of 4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)cubane-1 -carboxamide.

[1221] Intermediate Q.2

[1222]

[1223] To a stirred solution of 4-(4-(trifluoromethyl)-U / -imidazol-2-yl)cubane-l-carboxamide (4.50 g, 16.0 mmol) in DMF (50.0 mL) were added cesium carbonate (7.82 g, 24.0 mmol) and 2-iodopropane (3.26 g, 19.2 mmol) at 0 °C. The reaction mixture was warmed to 60 °C and stirred for 12 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and the solids were collected via filtration. The solid was washed with / / -pentane and dried to obtain 4-(l-isopropyl-4-(trifluoromethyl)-IT / -imidazol-2-yl)cubane-l -carboxamide (2.80 g) as white solid. The material was used without further purification. LCMS observed m / z = 324.41 [M+H]+.

[1224] Step 3: Synthesis of 4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)cuban-l-yl)m ethanamine.

[1225] Intermediate Q

[1226]

[1227] To a stirred solution of 4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)cubane-1-carboxamide (2.80 g, 8.66 mmol) in DCM (30.0 mL) was added chlorotrimethylsilane (1.66 mL, 13.0 mmol) at 0 °C and the mixture was stirred for 10 min. LiAlH4(8.66 mL, 2.0 M solution in THF, 17.3 mmol) was added and the reaction mixture was warmed to 23 °C and stirred for 3 h. After completion, the reaction mixture was quenched with saturated aqueous sodium sulfate solution (25 mL) and diluted with DCM (100 mL). The resulting mixture was filtered through Celite, washing thoroughly with DCM (2 x 50 mL). The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (mobile phase: 20-100% acetonitrile in water w / 0.1% formic acid) to afford 4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-l-yl)methanamine (0.900 g of the formate salt) as an off white solid.1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.00

[1228] Active 126539678.1 91 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1229] (s, 1H), 3.70 - 3.21 (br s, 2H), 4.20 - 4.17 (m, 3H), 4.06 - 3.99 (m, 4H), 3.04 (s, 2H), 1.43 -1.41 (m, 6H). LCMS observed m / z = 310.32 [M+H]+.

[1230] Intermediate R

[1231] Synthesi s of ( 1 -( 1 -i sopropyl-4-(trifluoromethyl)- 1 J / -imidazol-2-yl)piperidin-4-yl)methanamine • TFA.

[1232] Intermediate R

[1233]

[1234] Step 1: Preparation of tert-butyl ((l-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methyl)carbamate.

[1235] Intermediate R.1

[1236] NHBoc

[1237]

[1238] A mixture of tert-butyl (piperidin-4-ylmethyl) carbamate (0.7 g, 3.26 mmol), 2-bromo-l-isopropyl-4-(trifluoromethyl)-lH-imidazole (2.52 g, 9.79 mmol) and potassium carbonate (2.71 g, 19.59mmol) was heated at 135 °C for 48 h in a sealed tube. After completion, the reaction mixture was adsorbed on silica gel. The residue was purified by flash column chromatography (40 % EtOAc / petroleum ether eluent) to obtain tert-butyl ((1-(1-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl) piperidin-4-yl) methyl) carbamate (0.237 g, 18%) as a white solid. LCMS observed m / z = 391.3 [M+H]+.

[1239] Step 2: Synthesis of (l-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)piperidin-4-yl)methanamine.

[1240] Intermediate R

[1241]

[1242] To a stirred solution of tert-butyl ((l-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl) piperidin-4-yl) methyl) carbamate (0.3 g, 0.76 mmol) in DCM (15 mL) at 0 °C was added trifluoroacetic acid (0.58 mL, 7.68 mmol). The reaction was stirred for 2 h at 0 °C.

[1243] Active 126539678.1 92 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1244] After completion, the reaction mixture was concentrated under reduced pressure, affording (l-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl) piperidin-4-yl) methanamine • TFA (0.22 g, 98%) as an off-white solid. The product was used without further purification. LCMS observed m / z = 291.2 [M+H]+.

[1245] Intermediate S

[1246] Synthesis of (2-(trifhioromethyl)-6,7-dihydro-5H-benzo[b]imidazo[2, 1-d] [ 1, 5]oxazocin- 10-yl)methanamine.

[1247] Intermediate S

[1248]

[1249] Step 1: Preparation of 2-(trifluoromethyl)-6,7-dihydro-5H-benzo[b]imidazo[2,l-d] [ 1, 5]oxazocine- 10-carbonitrile.

[1250] Intermediate S.l

[1251]

[1252] To a stirred solution of 3-fluoro-4-(4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile (2.0 g, 7.84 mmol) in DMF (20.0 mL) was added cesium carbonate (7.64 g, 23.51 mmol) followed by (3-bromopropoxy)(tert-butyl)dimethylsilane (2.38 g, 9.41 mmol). The reaction mixture was stirred at 60 °C for 16 h. Upon completion, the reaction mixture was diluted with ice cold water (80 mL), and the resultant slurry was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (30-35% EtOAc / petroleum ether eluent) to afford 2-(trifluoromethyl)-6,7-dihydro-5H-benzo[b]imidazo[2,l-d][l,5]oxazocine-10-carbonitrile (2.0 g, 87%) as an off white solid. LCMS observed m / z = 294.18 [M+H]+.

[1253] Step 2: Preparation of tert-butyl ((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[b]imidazo[2,l-d][l,5]oxazocin-10-yl)methyl)carbamate.

[1254] Intermediate S.l

[1255] Active 126539678.1 93 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1256] P L IT

[1257] a

[1258]

[1259] To a stirred solution of 2-(trifluoromethyl)-6,7-dihydro-5H-benzo[b]imidazo[2,l-d][l,5]oxazocine-10-carbonitrile (1.8 g, 6.14 mmol) in EtOAc (30 mL) and MeOH (30 mL) was added palladium on carbon (50% wet basis) (1.8 g) and di-tert-butyl dicarbonate (8.03 g, 36.83 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h under an atmosphere of H2gas (80 psi). Upon completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography ( 30% EtOAc / petroleum ether eluent) to afford tert-butyl ((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[b]imidazo[2,l-d][l,5]oxazocin-10-yl)methyl)carbamate (1.8 g, 74%) as an off white solid. LCMS observed m / z = 398.7 [M+H]+.

[1260] Step 3: Synthesis of (2-(trifluoromethyl)-6,7-dihydro-5H-benzo[b]imidazo[2,l-d] [ 1, 5]oxazocin- 10-yl)methanamine.

[1261] Intermediate S

[1262] NH2

[1263] || £

[1264] Y \ n

[1265]

[1266] The title compound was prepared using a similar procedure as Intermediate R, replacing tert-butyl ((l-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl) piperidin-4-yl) methyl) carbamate with tert-butyl ((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[b]imidazo[2,l-d][l,5]oxazocin-10-yl)methyl)carbamate. LCMS observed m / z = 298.6 [M+H]+.

[1267] Intermediate T

[1268] Synthesis of (2-(trifluoromethyl)-5,6,7,8-tetrahydrobenzo[Z»]imidazo[2, 1- ][l,5]oxazonin-l l-yl)methanamine • HC1.

[1269] Intermediate T

[1270]

[1271] Active 126539678.1 94 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1272] Step 1: Preparation of 3-fluoro-4-(l-(4-hydroxybutyl)-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile.

[1273] Intermediate T.l

[1274]

[1275] To a stirred solution of 3-fluoro-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (1 g, 3.91 mmol) in DMF (20 mL) was added cesium carbonate (3.83 g, 11.7 mmol) followed by (4-bromobutoxy)(tert-butyl)dimethylsilane (2.09 g, 7.83 mmol). The reaction mixture was stirred at 100 °C for 48 h. Upon consumption of starting material as indicated by TLC and LCMS, the reaction was quenched with water (500 mL), and the resultant slurry was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-fluoro-4-(l-(4-hydroxybutyl)-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile (1.2 g, 3.66 mmol) as a gum. The product was used without further purification. LCMS observed m / z = 328.2 [M+H]+.

[1276] Step 2: Preparation of 2-(trifluoromethyl)-5,6,7,8-tetrahydrobenzo[b]imidazo[2,l-d] [ 1, 5]oxazonine- 11 -carbonitrile

[1277] Intermediate T.l

[1278] . N

[1279]

[1280] To a stirred solution of 3-fluoro-4-(1-(4-hydroxybutyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (1.2 g, 3.66 mmol) in DMF (20 mL) was added cesium carbonate (3.58 g, 11.0 mmol). The reaction mixture was allowed to stir at 100° C for 16 h. Upon consumption of the starting material as indicated by TLC analysis, the reaction was quenched with water (500 mL), and the resultant slurry was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (50% EtOAc / petroleum ether eluent) to afford 2-(trifluoromethyl)-5,6,7,8-tetrahydrobenzo[b]imidazo[2,1-d][1,5]oxazonine-11-carbonitrile (0.700 g, 2.27 mmol) as a pale yellow solid. LCMS observed m / z = 308.7 [M+H]+.

[1281] Active 126539678.1 95 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1282] Step 3: Preparation of tert-butyl ((2-(trifluoromethyl)-5,6,7,8-tetrahydrobenzo[b]imidazo[2,l-d][l,5]oxazonin-ll-yl)methyl)carbamate

[1283] Intermediate T.3

[1284]

[1285] The title compound was prepared using a similar procedure as Intermediate S.2, replacing 2-(trifluoromethyl)-6,7-dihydro-5H-benzo[b]imidazo[2, 1 -d] [ 1, 5]oxazocine- 10-carbonitrile with 2-(trifluoromethyl)-5,6,7,8-tetrahydrobenzo[b]imidazo[2, 1-d][l,5]oxazonine-l 1 -carbonitrile. LCMS observed m / z = 412.2 [M+H]+.

[1286] Step 4: Synthesis of (2-(trifluoromethyl)-5,6,7,8-tetrahydrobenzo[b]imidazo[2,l-d][l,5]oxazonin-l l-yl)methanamine • HC1.

[1287] Intermediate T

[1288]

[1289] The title compound was prepared using a similar procedure as Intermediate R, replacing tert-butyl ((l-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl) piperidin-4-yl) methyl) carbamate with 2-(trifluoromethyl)-5,6,7,8-tetrahydrobenzo[b]imidazo[2,l-d][l,5]oxazonine-l 1 -carbonitrile and replacing trifluoroacetic acid with hydrochloric acid in 1,4-dioxane (4 M). 'H NMR (400 MHz, DMSO ) 8 8.39 (br s, 2H), 8.02 (d, J = 1.2 Hz, 1H), 7.51 (d, J = 1.2 Hz, 1H), 7.45-7.49 (m, 1H), 7.28-7.26 (m, 1H), 4.25 (t, J = 5.0 Hz, 2H), 4.10 (q, J = 5.7 Hz, 2H), 3.73-3.70 (m, 2H), 1.90-2.00 (m, 2H), 1.50-1.80 (m, 2H). LCMS observed m / z = 312.4 [M+H]+.

[1290] Intermediate U

[1291] Synthesis of (4-methyl-l-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)piperidin-4-yl)methanamine.

[1292] Intermediate U

[1293]

[1294] Active 126539678.1 96 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1295] The title compound was prepared using a similar procedure as Intermediate R, replacing tert-butyl (piperidin-4-ylmethyl) carbamate with tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate, and 2-bromo-l-isopropyl-4-(trifluoromethyl)-lH-imidazole with 2-bromo-l-methyl-4-(trifluoromethyl)-lH-imidazole. LCMS observed m / z = 277.6 [M+H]+.

[1296] Intermediate V

[1297] Synthesis of (l-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-4-methylpiperidin-4-yl) methanamine.

[1298] Intermediate V

[1299]

[1300] The title compound was prepared using a similar procedure as Intermediate R, replacing tert-butyl (piperidin-4-ylmethyl) carbamate with tert-butyl ((4-methylpiperidin-4-yl) methyl) carbamate. LCMS observed m / z = 305.4 [M+H]+.

[1301] Intermediate W

[1302] Synthesis of (4-fluoro-l-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl) piperidin-4-yl) methanamine.

[1303] Intermediate W

[1304]

[1305] The title compound was prepared using a similar procedure as Intermediate R, replacing tert-butyl (piperidin-4-ylmethyl) carbamate with tert-butyl ((4-fluoro-l-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl) piperidin-4-yl) methyl) carbamate, and 2-bromo-l-isopropyl-4-(trifluoromethyl)- IH-imidazole with 2-bromo- 1 -methyl-4-(trifluoromethyl)- 1H-imidazole. LCMS observed m / z = 309.4 [M+H]+.

[1306] Intermediate X

[1307] Synthesis of (4-fluoro-l-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl) piperidin-4-yl) methanamine.

[1308] Intermediate X

[1309] Active 126539678.1 97 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1310]

[1311] The title compound was prepared using a similar procedure as Intermediate R, replacing tert-butyl (piperidin-4-ylmethyl) carbamate with tert-butyl ((4-fluoropiperidin-4-yl) methyl) carbamate, and trifluoroacetic acid with hydrochloric acid in dioxane (4 M). LCMS observed m / z = 309.4 [M+H]+.

[1312] Intermediate Y

[1313] Synthesis of l-(4-(2-(4-(aminomethyl)-4-methylpiperidin-l-yl)-6- (trifluoromethyl)pyridin-3-yl)piperidin-l-yl)ethan-l-one.

[1314] Intermediate Y

[1315]

[1316] Step 1: Preparation of l-(2-chloro-6-(trifluoromethyl)-3',6'-dihydro-[3,4'-bipyridin]-l'(2'H)-yl) ethan-l-one.

[1317] Intermediate Y.l

[1318]

[1319] o

[1320] To a stirred solution of 3-bromo-2-chloro-6-(trifhioromethyl) pyridine (5 g, 19.19 mmol) and l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-l(2H)-yl) ethan-l-one (2.38 g, 19.19 mmol, 1 equiv.) in 1,4-dioxane (150 mL) and water (75 mL) was added tribasic potassium phosphate (12.21 g, 57.59 mmol, 3 equiv.). The solution was purged with N2gas by sparging for 10 minutes. To the reaction mixture was added Pd(dppf)Cl2(1.4 g, 1.92 mmol, 0.1 equiv.). The reaction mixture was stirred at 90 °C for 2 h. Upon consumption of the starting material as indicated by TLC and LCMS analysis, the reaction mixture was filtered through Celite. The filtrate was diluted with water (50 mL) and extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using flash column

[1321] Active 126539678.1 98 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1322] chromatography (40-50% EtOAc / petroleum ether eluent) to afford l-(2-chloro-6-(trifluoromethyl)-3',6'-dihydro-[3,4'-bipyridin]-T(2'H)-yl) ethan-l-one (4 g, yield: 68%) as a light brown solid. LCMS observed m / z = 305.0 [M+H]+.

[1323] Step 2: Preparation of tert-butyl ((l-(l'-acetyl-6-(trifluoromethyl)-T,2',3',6'-tetrahydro-[3,4'-bipyridin]-2-yl)-4-methylpiperidin-4-yl) methyl) carbamate.

[1324] Intermediate Y.2

[1325]

[1326] To a stirred solution of l-(2-chloro-6-(trifhioromethyl)-3',6'-dihydro-[3,4'-bipyridin]-l'(2'H)-yl) ethan-l-one (0.7 g, 2.29 mmol) inDMF (7 mL), was added tert-butyl ((4-methylpiperidin-4-yl) methyl) carbamate (1.04 g, 4.59 mmol, 2.0 equiv.) at 0 °C. K2CO3 (0.95 g, 6.89 mmol, 3 equiv.) was added at 0 °C. The reaction mixture was allowed to stir at 100 °C for 16 h. Upon consumption of the starting material as indicated by TLC and LCMS analysis, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (20 mL) and extracted with EtOAc (30 mL). The combined organic layers were dried over sodium sulfate, fdtered, and concentrated under reduced pressure. The residue was purified using flash column chromatography (40-50% EtOAc / petroleum ether eluent) to afford tert-butyl ((l-(l'-acetyl-6-(trifluoromethyl)-T,2',3',6'-tetrahydro-[3,4'-bipyridin]-2-yl)-4-methylpiperidin-4-yl) methyl) carbamate (0.6 g, 52%) as a light brown liquid. LCMS observed m / z = 497.3 [M+H]+.

[1327] Step 3: Preparation of tert-butyl ((l-(3-(l-acetylpiperidin-4-yl)-6-(trifluoromethyl) pyridin-2-yl)-4-methylpiperidin-4-yl) methyl) carbamate.

[1328] Intermediate Y.3

[1329]

[1330] To a stirred solution of tert-butyl ((l-(T-acetyl-6-(trifhioromethyl)-T,2',3',6'-tetrahydro-[3,4'-bipyridin]-2-yl)-4-methyl (0.6 g, 1.21 mmol) in ethanol (7 mL), EtOAc (7

[1331] Active 126539678.1 99 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1332] mL), andTHF (7 mL) was added Palladium on activated carbon, 10% Pd, (50% wet with water for safety) (0.644 g). The reaction mixture was hydrogenated at (80 psi) at 25°C for 16 h in Parr hydrogenation apparatus. Upon consumption of the starting material as indicated by TLC and LCMS analysis, the reaction mixture was filtered through Celite, washing with EtOAc (50 mL). The filtrate was diluted with water (30 mL) and extracted with EtOAc (2x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (50-60% EtOAc / petroleum ether eluent) to afford tert-butyl ((l-(3-(l-acetylpiperidin-4-yl)-6-(trifluoromethyl) pyridin-2-yl)-4-methylpiperidin-4-yl) methyl) carbamate (0.4 g, 66.32 %) as light-yellow gum. LCMS observed m / z = 499.4 [M+H]+.

[1333] Step 4: Synthesis of l-(4-(2-(4-(aminomethyl)-4-methylpiperidin-l-yl)-6-(trifluoromethyl) pyri din-3 -yl) piperidin-l-yl) ethan-l-one.

[1334] Intermediate Y

[1335]

[1336] To a stirred solution ofterLbutyl ((l-(3-(l-acetylpiperidin-4-yl)-6-(trifluoromethyl) pyridin-2-yl)-4-methylpiperidin-4-yl) methyl) carbamate (0.4 g, 0.8 mmol) inDCM (10 mL) at 0 °C was added trifluoroacetic acid (0.7 mL). The reaction mixture was stirred at 25°C for 2 h. Upon consumption of the starting material as indicated by TLC and LCMS analysis, the reaction was quenched with NaHCCb solution (30 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford l-(4-(2-(4-(aminomethyl)-4-methylpiperidin-l-yl)-6-(trifluoromethyl) pyridin-3-yl) piperidin-l-yl) ethan-l-one (0.250 g, 78%) as a light yellow gum. The product was used without further purification. LCMS observed m / z = 399.4 [M+H]+.

[1337] Intermediate Z

[1338] Synthesi s of 1 -(4-(2-(4-(aminomethyl)-4-fluoropiperidin- 1 -yl)-6-(trifluoromethyl) pyridin-3-yl) piperidin-l-yl) ethan-l-one.

[1339] Intermediate Z

[1340] Active 126539678.1 100 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1341]

[1342] The title compound was prepared using a similar procedure as Intermediate Y, replacing tert-butyl ((4-methylpiperidin-4-yl) methyl) carbamate with tert-butyl ((4-fluoropiperidin-4-yl) methyl) carbamate. LCMS observed m / z = 445.1 [M+H]+.

[1343] Intermediate AA

[1344] Synthesis of 1-(4-(2-(4-(aminomethyl) piperidin-1-yl)-6-(trifluoromethyl) pyridin-3-yl) piperidin-1-yl) ethan-1-one.

[1345] Intermediate AA

[1346]

[1347] The title compound was prepared using a similar procedure as Intermediate Y, replacing tert-butyl ((4-methylpiperidin-4-yl) methyl) carbamate with tert-butyl (piperidin-4-ylmethyl) carbamate. LCMS observed m / z = 385.3 [M+H]+.

[1348] Intermediate AB

[1349] Synthesis of tert-butyl 4-(2-(4-(aminomethyl)piperidin-l-yl)-6-(tri fluoromethyl)pyri din-3 -yl)piperi dine- 1 -carboxylate.

[1350] Intermediate AB

[1351]

[1352] Step 1: Preparation of tert-butyl 2-chloro-6-(trifluoromethyl)-3',6'-dihydro-[3,4'-bipyridine]- 1 '(2'H)-carboxylate.

[1353] Intermediate AB.l

[1354] Active 126539678.1 101 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1355]

[1356] The title compound was prepared using a similar procedure as Intermediate Y.l, replacing l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-l(2H)-yl) ethan-l-one with tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate. LCMS observed m / z = 363.2 [M+H]+.

[1357] Step 2: Preparation of 2-(4-(aminomethyl)phenyl)-6-(trifluoromethyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate.

[1358] Intermediate AB.2

[1359] CF3

[1360]

[1361] To a stirred solution of tert-butyl 2-chloro-6-(trifluoromethyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (3 g, 8.27 mmol) in 1,4 Dioxane (60 mL) and Water (15 mL)in a sealed tube at 25 °C was added potassium phosphate (4.388 g, 20.67 mmol) followed by (4-(aminomethyl)phenyl)boronic acid (1.873 g, 12.40 mmol). The reaction mixture was purged with argon gas for 10 minutes. Pd(dppf)Cl2(0.605 g, 0.82 mmol) was added, and the reaction mixture was stirred at 90 °C for 5 h. Upon consumption of the starting material as indicated by TLC analysis, the reaction was quenched with water (100 mL) and the resultant slurry was extracted with EtOAc (50mLx 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc eluent) to afford tert-butyl 2-(4-(aminomethyl)phenyl)-6-(trifluoromethyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (2 g, 56% yield) as a brown solid. LCMS observed m / z = 434.1 [M+H]+.

[1362] Step 3: Synthesis of tert-butyl 4-(2-(4-(aminomethyl)piperidin-l-yl)-6-(tri fluoromethyl)pyri din-3 -yl)piperi dine- 1 -carboxylate.

[1363] Intermediate AB

[1364] Active 126539678.1 102 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1365]

[1366] To a stirred solution of tert-butyl 2-(4-(aminomethyl)phenyl)-6-(trifluoromethyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (2 g, 4.61 mmol) in MeOH (20 mL) at 25 °C was added palladium 10% on carbon (2.0 g). The reaction mixture was stirred at 25 °C for 8 h under an atmosphere of hydrogen. Upon consumption of the starting material as indicated by TLC and LCMS analysis, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduce pressure, affording tert-butyl 4-(2-(4-(aminomethyl)piperidin-l-yl)-6-(trifluoromethyl)pyri din-3 -yl)piperi dine- 1 -carboxylate. The product was used without further purification. LCMS observed m / z = 436.24 [M+H]+.

[1367] Intermediate AC

[1368] Synthesis of l-(4-(2-(4-(aminomethyl)-2-methylphenyl)-6-(trifluoromethyl)pyridin-3-yl)piperidin-l-yl)ethan-l-one • TFA.

[1369] Intermediate AC

[1370]

[1371] Step 1: Preparation of 2-chloro-6-(trifluoromethyl)-1',2',3',6'-tetrahydro-3,4'-bipyridine.

[1372] Intermediate AC.l

[1373]

[1374] To a stirred solution of tert-butyl 2-chloro-6-(trifluoromethyl)-3',6'-dihydro-[3,4'-bipyridine]-l'(2'H)-carboxylate (Intermediate AB.l) (2.5 g, 6.89 mmol) in DCM (10 mL) at 0 °C under argon atmosphere was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at 25 °C for 1 h. Upon consumption of the starting material as indicated by TLC and LCMS analysis, the reaction mixture was concentrated under reduced pressure to afford

[1375] Active 126539678.1 103 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1376] 2-chloro-6-(trifluoromethyl)-1',2',3',6'-tetrahydro-3,4'-bipyridine (2.5 g, 75%) as a brown semi solid. The product was used without further purification. LCMS observed m / z = 263.6 [M+H]+.

[1377] Step 2: Preparation of l-(2-chloro-6-(trifluoromethyl)-3',6'-dihydro-[3,4'-bipyridin]-1 '(2'H)-yl)ethan- 1 -one.

[1378] Intermediate AC.2

[1379]

[1380] To a stirred solution of 2-chloro-6-(trifluoromethyl)-1',2',3',6'-tetrahydro-3,4'-bipyridine (2 g, 7.61 mmol) in DCM (20mL) at 0 °C under argon atmosphere was added pyridine (0.92 mL, 11.42 mmol) and acetic anhydride (2 mL). The reaction mixture was stirred at 25 °C for 2 h. Upon consumption of the starting material as indicated by TLC and LCMS analysis, the reaction mixture was filtered through Celite. The filtrate was dissolved in water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified using flash column chromatography (40-50% EtOAc / Petroleum ether eluent) to afford l-(2-chloro-6-(trifluoromethyl)-3',6'-dihydro-[3,4'-bipyridin]-r(2'H)-yl) ethan-l-one (1.8 g, 75 %) as a brown semi solid. LCMS observed m / z = 304.9 [M+H]+.

[1381] Step 3: Preparation of 4-(1'-acetyl-6-(trifluoromethyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridin]-2-yl)-3-methylbenzonitrile.

[1382] Intermediate AC.3

[1383]

[1384] o

[1385] To a stirred solution of 1-(2-chloro-6-(trifluoromethyl)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl) ethan-1-one (0.8 g, 2.626 mmol) and (4-cyano-2-methylphenyl) boronic acid (0.845 g, 5.251 mmol) in 1,4-dioxane (24 mL) and water (12 mL). was added tribasic potassium phosphate (1.39 g, 6.56 mmol). The reaction mixture was purged with N2 gas for 10 minutes. To the reaction mixture was added Pd(dppf)Cl2(0.184 g, 0.26 mmol). The reaction mixture was stirred at 100 °C for 16 h. Upon consumption of the starting material as

[1386] Active 126539678.1 104 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1387] indicated by TLC and LCMS analysis, the reaction mixture was filtered through Celite. The filtrate was dissolved in water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified using flash column chromatography (40-50% EtOAc / petroleum ether eluent) to afford 4-(1'-acetyl-6-(trifluoromethyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridin]-2-yl)-3-methylbenzonitrile (0.5 g, 49%) as a brown solid. LCMS observed m / z = 386.2 [M+H]+.

[1388] Step 4: Preparation of tert-butyl (4-(3-(1-acetylpiperidin-4-yl)-6-(trifluoromethyl)pyridin-2-yl)-3-methylbenzyl)carbamate.

[1389] Intermediate AC.4

[1390]

[1391] To a stirred solution of tert-butyl 4-(1'-acetyl-6-(trifluoromethyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridin]-2-yl)-3-methylbenzonitrile (0.5 g, 1.29 mmol, 1 equiv.)) in EtOAc (5 mL) was added palladium on carbon (10 w / w%, 0.413 g) and Boc anhydride (0.358 g, 2.59 mmol, 2 equiv.). The reaction was hydrogenated at (80 psi) at 25 °C for 16 h. Upon consumption of the starting material as indicated by TLC and LCMS analysis, the reaction mixture was filtered through Celite, and the cake was washed with EtOAc (10 mL). The filtrate was dried under reduced pressure to afford tert-butyl (4-(3-(1-acetylpiperidin-4-yl)-6-(trifluoromethyl)pyridin-2-yl)-3-methylbenzyl)carbamate. The product was used without further purification. LCMS observed m / z = 492.32 [M+H]+.

[1392] Step 5: Synthesis of l-(4-(2-(4-(aminomethyl)-2-methylphenyl)-6- (trifluoromethyl)pyridin-3-yl)piperidin-l-yl)ethan-l-one • TFA.

[1393] Intermediate AC

[1394]

[1395] o

[1396] To a stirred solution of tert-butyl (4-(3-(1-acetylpiperidin-4-yl)-6-(trifluoromethyl) pyridin-2-yl)-3-methylbenzyl) carbamate (0.5 g, 1.01 mmol, 1 equiv.) in DCM (10 mL) at 0

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[1398] °C under an atmosphere of argon was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 1 h. Upon consumption of the starting material as indicated by TLC and LCMS analysis, the reaction mixture was concentrated under reduced pressure, affording l-(4-(2-(4-(aminomethyl)-2-methylphenyl)-6-(trifluoromethyl) pyridin-3-yl) piperidin-l-yl) ethan-l-one TFA (0.3 g, 75%) as a brown semi solid. The product was used without further purification. LCMS observed m / z = 392.2 [M+H]+.

[1399] Intermediate AD

[1400] Synthesis of l-(4-(2-(4-(aminomethyl)-2-fluorophenyl)-6-(trifluoromethyl)pyri din-3 -yl)piperidin- 1 -yl)ethan- 1 -one.

[1401] Intermediate AD

[1402]

[1403] The title compound was prepared using a similar procedure as Intermediate AC, replacing (4-cyano-2-methylphenyl) boronic acid with (4-cyano-2-fluorophenyl)boronic acid. LCMS observed m / z = 396.3 [M+H]+.

[1404] Intermediate AE

[1405] Synthesis of tert-butyl 4-(2-(4-(aminom ethyl)phenyl)-4-(trifluoromethyl)- 1H-imidazol- 1 -yl)piperidine- 1 -carboxylate.

[1406] Intermediate AE

[1407]

[1408] Step 1: Preparation of tert-butyl 4-(2-(4-cyanophenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl) piperidine-1-carboxylate.

[1409] Intermediate AE.l

[1410] Active 126539678.1 106 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1411]

[1412] To a stirred solution of 4-(4-(trifluoromethyl)-lH-imidazol-2-yl) benzonitrile (Intermediate A.1) (1.6 g, 6.74 mmol) in DMF (16 mL) was added cesium carbonate (6.59 g, 20.2 mmol) and tert-butyl 4-(tosyloxy) piperidine- 1 -carboxylate (9.59 g, 26.9 mmol) at room temperature. Then the reaction mixture was heated at 100 °C for 16h. The reaction mixture was concentrated under reduced pressure, then diluted with water (150 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford tert-butyl 4-(2-(4-cyanophenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl) piperidine-1-carboxylate (0.5 g, 18 %). The product was used without further purification. LCMS observed m / z = 421.9 [M+H]+.

[1413] Step 2: Synthesis of tert-butyl 4-(2-(4-(aminom ethyl)phenyl)-4-(trifluoromethyl)- 1H-imidazol- 1 -yl)piperidine- 1 -carboxylate.

[1414] Intermediate AE

[1415]

[1416] To a solution of tert-butyl 4-(2-(4-cyanophenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl) piperidine-1-carboxylate (500 mg, 1.18 mmol,) in THF (10 mL) and MeOH (10 mL) was nickel chloride (0.028 g, 0.11 mmol) followed by NaBH₄ (0.22 g, 5.94 mmol at 0 °C. The reaction mixture was stirred at rt for 1 hr. The reaction mixture was then concentrated under reduced pressure, diluted with water (100 mL), and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford tert-butyl 4-(2-(4-(aminomethyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl) piperidine-1-carboxylate (0.32 g, 63.40 %). The product was used without further purification. LCMS observed m / z = 425.3 [M+H]+.

[1417] Intermediate AF

[1418] Synthesis of tert-butyl 4-(2-(4-(aminomethyl)-2-methylphenyl)-4-(trifluoromethyl)-IH-imidazol- 1 -yl)piperidine- 1 -carboxylate.

[1419] Active 126539678.1 107 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT Intermediate AF

[1420]

[1421] The title compound was prepared using a similar procedure as Intermediate AE, replacing 4-(4-(trifluoromethyl)-lH-imidazol-2-yl) benzonitrile (Intermediate A.1) with 3-methyl-4-(4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile (Intermediate BD.l). LCMS observed m / z = 439.3 [M+H]+.

[1422] Intermediate AG

[1423] Synthesis of (13-fluoro-2-(trifluoromethyl)-5,6,7,8-tetrahydrobenzo[b]imidazo[2,l-d] [ 1, 5]oxazonin- 11 -yl)methanamine.

[1424] Intermediate AG

[1425]

[1426] The title compound was prepared using a similar procedure as Intermediate T, replacing 3-fluoro-4-(4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile with 3,5-difluoro-4-(4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile, which was prepared according to General Procedure A using 3,5-difluoro-4-formylbenzonitrile as the aldehyde. LCMS observed m / z = 326.0 [M+H]+.

[1427] Intermediate AH

[1428] Synthesis of trans-8-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)methanamine.

[1429] Intermediate AH

[1430]

[1431] The title compound was prepared using a similar procedure as Intermediate R, replacing tert-butyl (piperidin-4-ylmethyl) carbamate with tert-butyl (((trans)-8-azabicyclo[3.2.1]octan-3-yl)methyl)carbamate. LCMS observed m / z = 317.2 [M+H]+.

[1432] Active 126539678.1 108 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1433] Intermediate Al

[1434] Synthesis of 6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-1,2,3,4-tetrahydroisoquinoline •HCl.

[1435] Intermediate AI

[1436] HCl HN'

[1437]

[1438] Step 1: Preparation of tert-butyl 6-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3,4-dihydroisoquinoline-2(lH)-carboxylate.

[1439] Intermediate AI.1

[1440]

[1441] To a solution of tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(lH)-carboxylate (147 mg, 0.471 mmol) in 1,4-dioxane (1.18 mL) was added potassium acetate (139 mg, 1.41 mmol), bis(pinacolato)diboron (132 mg, 0.518 mmol), and Pd(dppf)Cl2(17 mg, 0.024 mmol). The reaction mixture was heated to 80 °C and allowed to stir for 4 hours. Upon consumption of starting material as indicated by TLC analysis, 2-bromo-l-isopropyl-4-(trifluoromethyl)-IH-imidazole (182 mg, 0.706 mmol), Pd(dppf)Cl2(17 mg, 0.024 mmol), dipotassium carbonate (195 mg, 1.41 mmol), and water (0.060 mL) were added to the reaction vessel. The reaction mixture was allowed to stir overnight at 80 °C, then allowed to cool to room temperature. The cooled slurry was filtered through Celite, and the filtrate was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified via normal phase column chromatography (0-100% EtOAc / hexanes eluent), affording tert-butyl 6-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3,4-dihydroisoquinoline-2(lH)-carboxylate (142 mg, 74% yield). LCMS observed m / z = 410.5 [M+H]+.

[1442] Step 2: Synthesis of 6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-1,2,3,4-tetrahydroisoquinoline •HCl.

[1443] Intermediate AI

[1444] Active 126539678.1 109 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1445]

[1446] To a solution of tert-butyl 6-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3,4-dihydroisoquinoline-2(lH)-carboxylate in 1,4-dioxane (0.69 mL) was added hydrogen chloride in 1,4-dioxane (4 M, 0.86 mL). The reaction mixture was allowed to stir for 1 hour at room temperature, then concentrated under reduced pressure, affording 6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (148 mg, quantitative yield). The product was used without further purification.. LCMS observed m / z = 310.0 [M+H]+.

[1447] Intermediate AJ

[1448] Synthesis of 5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)isoindoline •HCl.

[1449] Intermediate AJ

[1450]

[1451] The title compound was prepared using a similar procedure as Intermediate AI, replacing tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate with tert-butyl 5-bromoisoindoline-2-carboxylate. LCMS observed m / z = 296.4 [M+H]+.

[1452] Intermediate AK

[1453] Synthesis of 8-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine.

[1454] Intermediate AK

[1455]

[1456] The title compound was prepared using a similar procedure as Intermediate AI, replacing tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate with tert-butyl 7-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate and using trifluoroacetic acid for removal of the tert-butyl carbamate group. LCMS observed m / z = 298.3 [M+H]+.

[1457] Intermediate AL

[1458] Synthesis of 1 l-bromo-2,3,5,6,7,8-hexahydrobenzo[i][l,4,7]dioxazecine.

[1459] Active 126539678.1 110 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1460] Intermediate AL

[1461]

[1462] Step 1: Preparation of methyl 4-bromo-2-(2-(2-((tert-butoxycarbonyl)amino)-ethoxy)ethoxy)benzoate.

[1463] Intermediate AL.l

[1464] o

[1465]

[1466] To a stirred solution of methyl 4-bromo-2-hydroxybenzoate (1.00 g, 4.33 mmol) in DMF (10.8 mL) was added dipotassium carbonate (897 mg, 6.49 mmol) and tert-butyl [2-(2-bromoethoxy)ethyl]carbamate (1.39 g, 5.19 mmol). The reaction mixture was heated to 80 °C for 2 hours, then cooled to room temperature. The slurry was decanted into a solution of aqueous lithium chloride (10 w / w%, 20 mL). The resulting mixture was extracted with EtOAc (40 mL). The combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via normal phase column chromatography (20-30% EtOAc / hexanes eluent), affording methyl 4-bromo-2-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)benzoate (1.76 g, 97% yield) as a colorless oil. LCMS observed m / z = 440.1 [M+H]+.

[1467] Step 2: Preparation of 4-bromo-2-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)benzoic acid.

[1468] Intermediate AL.l

[1469]

[1470] To a solution of methyl 4-bromo-2-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)benzoate (3.62 g, 8.65 mmol) in MeOH (17.3 mL) was added aqueous sodium hydroxide (1 M, 9.52 mL). The reaction mixture was allowed to stir at room temperature for 16 hours. Upon consumption of starting material as indicated by LCMS analysis, the reaction mixture was partially concentrated under reduced pressure to remove organic solvent. The pH of the concentrated slurry was adjusted to 2, as determined by litmus paper, by dropwise addition of aqueous hydrochloric acid (6 M). The acidified slurry was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure, affording

[1471] Active 126539678.1 111 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1472] 4-bromo-2-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)benzoic acid (4.00 g, quantitative yield) The product was used without further purification. LCMS observed m / z = 304.5 [M+H]+.

[1473] Step 3: Preparation of 2-(2-(2-aminoethoxy)ethoxy)-4-bromobenzoic acid trifluoroacetic acid (1 / 2).

[1474] Intermediate AL.3

[1475] o

[1476] H2N

[1477] O O

[1478]

[1479] F3C—OH

[1480] To a solution of 4-bromo-2-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)benzoic acid (4.00 g, 9.89 mmol) in DCM (7.1 mL) was added trifluoroacetic acid (6.00 mL, 78.4 mmol). The reaction mixture was allowed to stir at room temperature for 1 hour, then concentrated under reduced pressure, affording 2-(2-(2-aminoethoxy)ethoxy)-4-bromobenzoic acid trifluoroacetic acid (1 / 2) (5.96 g, quantitative yield). The product was used without further purification.. LCMS observed m / z = 304.3 [M+H]+.

[1481] Step 4: Preparation of 9-bromo-2,3,4,5-tetrahydro-6H-benzo[b][l,5]oxazocin-6-one.

[1482] Intermediate AL.4

[1483]

[1484] To a solution of 2-(2-(2-aminoethoxy)ethoxy)-4-bromobenzoic acid trifluoroacetic acid (1 / 2) (5.96 g, 11.2 mmol) in DMF (45 mL) was added DIPEA (9.75 mL, 56 mmol) and [dimethylamino-(3-oxidotriazolo[4,5-b]pyridin-3-ium-l-yl)methylidene]-dimethylazanium;hexafluorophosphate (4.30 g, 11.3 mmol). The reaction mixture was allowed to stir at room temperature for 16 hours, then partially concentrated to remove most of the DMF solvent. The concentrated slurry was washed with aqueous lithium chloride (2 M) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via flash column chromatography (0-100% EtOAc / DCM eluent), affording 9-bromo-2,3,4,5-tetrahydro-6H-benzo[b][l,5]oxazocin-6-one (2.77 g, 86% yield). LCMS observed m / z = 286.6 [M+H]+.

[1485] Active 126539678.1 112 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1486] Step 5: Synthesis of ll-bromo-2,3,5,6,7,8-hexahydrobenzo[i][l,4,7]dioxazecine.

[1487] Intermediate AL

[1488]

[1489] To a stirred solution of 9-bromo-2,3,4,5-tetrahydro-6H-benzo[b][l,5]oxazocin-6-one (200 mg, 0.700 mmol) in THF (2.9 mL) at 0 °C was added borane (1 M in THF, 3.50 mL). The reaction mixture was heated to 60 °C and allowed to stir at 60 °C for 1 hour. Upon consumption of starting material as indicated by LCMS analysis, the reaction mixture was allowed to cool to room temperature, then diluted with water (3 mL) and extracted with EtOAc (2 x 2 mL). The combined organic layers were washed with brine (2 x 3 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure, affording 11-bromo-2,3,5,6,7,8-hexahydrobenzo[i][1,4,7]dioxazecine (77 mg, 41% yield). The crude product was carried forward without further purification. LCMS observed m / z = 244.3 [M+H]+.

[1490] Intermediate AM

[1491] Synthesis of 9-bromo-3,4,5,6-tetrahydro-2H-benzo[b][l,5]oxazocine.

[1492] Intermediate AM

[1493]

[1494] The title compound was prepared using a similar procedure as Intermediate AL, replacing 1 l-bromo-2,3,6,7-tetrahydrobenzo[i][l,4,7]dioxazecin-8(5H)-one with 9-bromo-2,3,4,5-tetrahydro-6H-benzo[b][l,5]oxazocin-6-one. LCMS observed m / z = 244.4 [M+H]+.

[1495] Intermediate AN

[1496] Synthesis of 8-fluoro-9-(l -methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3, 4,5,6-tetrahy dro-2H-b enzo [b ] [ 1, 5 ] oxazocine.

[1497] Intermediate AN

[1498]

[1499] Step 1: Preparation of 2,5-difluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile.

[1500] Intermediate AN.l

[1501] Active 126539678.1 113 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1502]

[1503] The title compound was prepared using a similar procedure as Intermediate A.2, replacing 4-formylbenzonitrile with 2,5-difluoro-4-formylbenzonitrile. LCMS observed m / z = 288.16 [M+H]+.

[1504] Step 2: Preparation of 2-(3-(benzyloxy)propoxy)-5-fluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile.

[1505] Intermediate AN.2

[1506]

[1507] To a stirred solution of 3 -(benzyloxy) propan-l-ol (0.868 g, 5.22 mmol) in THF (15 mL) was added NaH (0.418 g, 10.45 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. 2,5-difhioro-4-(l-methyl-4-(trifhioromethyl)-lH-imidazol-2-yl) benzonitrile (1 g, 3.48 mmol) was added to the reaction, and the reaction mixture was stirred for 2 h at 25 °C. The reaction mixture was then diluted with water (60 mL) and extracted with EtOAc (2 x 60 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (20% EtOAc / hexanes eluent) to afford 2-(3 -(benzyloxy) propoxy)-5-fluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl) benzonitrile (1 g, 66%) as a yellow solid. LCMS observed m / z = 434.2 [M+H]+.

[1508] Step 3: Preparation of / c / 7-butyl (2-(3-(benzyloxy)propoxy)-5-fluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)carbamate.

[1509] Intermediate AN.3

[1510] NHBoc

[1511]

[1512] The title compound was prepared using a similar procedure as Intermediate AE, replacing Zc / V-butyl 4-(2-(4-cyanophenyl)-4-(trifluoromethyl)-lH-imidazol-l-yl) piperidine-1-carboxylate with 2-(3 -(benzyloxy) propoxy)-5-fluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl) benzonitrile. LCMS observed m / z = 538.2 [M+H]+.

[1513] Active 126539678.1 114 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1514] Step 4: Preparation of tert-butyl (5-fluoro-2-(3-hydroxypropoxy)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)carbamate.

[1515] Intermediate AN.4

[1516]

[1517] To a solution of 2-(3 -(benzyloxy) propoxy)-5-fluoro-4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl) benzonitrile (0.6 g, 1.38 mmol) in EtOAc (5 mL) and MeOH(5 mL) was added palladium 10% on carbon (wetted with ca. 55% water) (0.368 g). The reaction mixture was hydrogenated at 80 psi for 16 h at room temperature. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (20% EtOAc / hexanes eluent) to afford tert-butyl (5-fluoro-2-(3-hydroxypropoxy)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl) benzyl) carbamate (0.4 g, 80 %) as light brown gum. LCMS observed m / z = 448.1 [M+H]+.

[1518] Step 5: Preparation of 3-(2-(((tert-butoxycarbonyl)amino)methyl)-4-fluoro-5-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenoxy)propyl 4-methylbenzenesulfonate.

[1519] Intermediate AN.5

[1520]

[1521] To stirred solution of tert-butyl (5-fluoro-2-(3-hydroxypropoxy)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl) benzyl) carbamate (0.4 g, 0.89 mmol) in DCM (10 mL), was added tosyl chloride (0.34 g, 1.78mmol, 2 equiv.) at 0 °C followed by the addition of 4-dimethylaminopyridine (20 mg, 0.089 mmol, 0.1 equiv.) and triethylamine (0.346 g, 2.68 mmol, 3 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C and allowed to warm slowly to room temperature over a period of 3 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using flash column chromatography (40-50% EtOAc / petroleum ether eluent) to afford 3-(2-(((tert-butoxycarbonyl) amino) methyl)-4-fluoro-5-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl) phenoxy) propyl 4-methylbenzenesulfonate as a brown solid. LCMS observed m / z = 602.4 [M+H]+.

[1522] Active 126539678.1 115 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1523] Step 6: Preparation of 3-(2-(aminomethyl)-4-fluoro-5-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenoxy)propyl 4-methylbenzenesulfonate.

[1524] Intermediate AN.6

[1525] NH2

[1526] T

[1527]

[1528] The title compound was prepared using a similar procedure as Intermediate I, replacing tert-butyl (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-IT / -pyrazol-l-yl)benzyl)carbamate with afford 3-(2-(((tert-butoxycarbonyl) amino) methyl)-4-fluoro-5-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl) phenoxy) propyl 4-methylbenzenesulfonate. LCMS observed m / z = 502.4 [M+H]+.

[1529] Step 7: Synthesis of 8-fluoro-9-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3,4,5,6-tetrahydro-2H-benzo[b][l,5]oxazocine.

[1530] Intermediate AN

[1531]

[1532] To stirred solution of 3-(2-(aminomethyl)-3-fluoro-5-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl) phenoxy) propyl 4-methylbenzenesulfonate (0.4 g, 0.79 mmol) in DMF (4 mL), was added potassium carbonate (0.33 g, 2.39 mmol, 3 equiv.) at 0 °C. The reaction mixture was stirred at 110 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted in EtOAc (2x30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 7-fluoro-9-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3,4,5,6-tetrahydro-2H-benzo[b][l,5] oxazocine (0.12 g, 46%) as a white solid. The product was used without further purification. LCMS observed m / z = 330.3 [M+H]+.

[1533] Intermediate AO

[1534] Synthesi s of (S)- 1 -(4-( 1 -methyl-4-(trifluoromethyl)- lH-imidazol-2-yl)phenyl)ethan-1 -amine.

[1535] Intermediate AO

[1536] Active 126539678.1 116 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1537]

[1538] Step 1: Preparation of tert-butyl (S)-(l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate.

[1539] Intermediate AO.l

[1540] NHBoc

[1541]

[1542] The title compound was prepared using a similar procedure as Intermediate E.l, replacing 4-bromo-3 -methylbenzonitrile with tert-butyl (S)-(l-(4-bromophenyl)ethyl)carbamate. LCMS observed m / z = 292.4 [M+H]+.

[1543] Step 2: Preparation of tert-butyl (S)-(l-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)ethyl)carbamate.

[1544] Intermediate AO.2

[1545] NHBoc

[1546]

[1547] The title compound was prepared using a similar procedure as Intermediate E.2, replacing 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile with tertbutyl (S)-(l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate and 2-bromo-l-isopropyl-4-(trifluoromethyl)-1H-imidazole with 2-bromo-l-methyl-4-(trifluoromethyl)-lH-imidazole. LCMS observed m / z = 370.1 [M+H]+.

[1548] Step 3: Synthesis of (S)-l-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)ethan-l -amine.

[1549] Intermediate AO

[1550] NH2

[1551]

[1552] The title compound was prepared using a similar procedure as Intermediate I, replacing tert-butyl (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-lJ / -pyrazol-l-

[1553] Active 126539678.1 117 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1554] yl)benzyl)carbamate with tert-butyl (S)-(l-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)ethyl)carbamate. LCMS observed m / z = 270.2 [M+H]+.

[1555] Intermediate AP

[1556] Synthesis of (S)-l-(3-fluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)ethan-l -amine.

[1557] Intermediate AP

[1558]

[1559] The title compound was prepared using a similar procedure as Intermediate AO, replacing tert-butyl (S)-(l-(4-bromophenyl) ethyl) carbamate with tert-butyl (S)-(l-(4-bromo-3 -fluorophenyl)ethyl)carbamate and [1,1 'Bis(diphenylphosphino)ferrocene] dichloropalladium(II) with catacxium® A plus XPhos Pd G3. LCMS observed m / z = 288.5 [M+H]+.

[1560] Intermediate AQ

[1561] Synthesis of l-(4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-2-methoxyethan- 1 -amine.

[1562] Intermediate AQ

[1563]

[1564] Step 1: Preparation of methyl 2-((tert-butoxycarbonyl)amino)-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acetate.

[1565] Intermediate AQ.l

[1566] NHBoc

[1567]

[1568] The title compound was prepared using a similar procedure as Intermediate AO.l, replacing tert-butyl (S)-(l-(4-bromophenyl) ethyl) carbamate with methyl 2-(4-bromophenyl)-2-((tert-butoxycarbonyl) amino) acetate. LCMS observed m / z = 291.0 [M-C4H9O2]+.

[1569] Active 126539678.1 118 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1570] Step 2: Preparation of methyl 2-((tert-butoxycarbonyl)amino)-2-(4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)acetate.

[1571] Intermediate AQ.2

[1572]

[1573] The title compound was prepared using a similar procedure as Intermediate E.2, replacing 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile with methyl 2-((tert-butoxycarbonyl)amino)-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acetate, 2-bromo-l-isopropyl-4-(trifluoromethyl)-U / -imidazole with 2-bromo-l-cyclopropyl-4-(trifluoromethyl)-lH-imidazole, and Pd(dppf)Cl2with catacxium® A plus XPhos Pd G3. LCMS observed m / z = 440.1 [M+H]+.

[1574] Step 3: Preparation of tert-butyl (l-(4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-2-hydroxyethyl)carbamate.

[1575] Intermediate AQ.3

[1576]

[1577] To a stirred solution of methyl 2-((tert-butoxycarbonyl) amino)-2-(4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl) phenyl) acetate (0.3 g, 0.68 mmol) in THF (6 mL) at 0 °C under argon atmosphere, was added DIBALH (1.0 M in THF, 1.365 mL). The reaction was stirred at 25 °C for 4 h. Upon consumption of the starting material as indicated by TLC and LCMS analysis, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (50% EtOAc / petroleum ether eluent) to afford tertbutyl (l-(4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl) phenyl)-2-hydroxyethyl) carbamate (0.1 g, 35.60%) as a yellow solid. LCMS observed m / z = 412.3 [M+H]+.

[1578] Step 4: Preparation of tert-butyl (l-(4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-2-methoxyethyl)carbamate.

[1579] Intermediate AQ.4

[1580] Active 126539678.1 119 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1581]

[1582] To a stirred solution of tert-butyl (l-(4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl) phenyl)-2-hydroxyethyl) carbamate (0.75 g, 1.82 mmol) in THF (10 mL) at 0 °C under argon atmosphere was added NaH (0.088 g, 3.64 mmol) and iodomethane (0.259 g, 1.82 mmol). The reaction mixture was stirred at 25 ° C for 1 h. Upon consumption of the starting material as indicated by TLC and LCMS analysis, the reaction was quenched with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with ice cold water (50 mL), brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (50% EtOAc / petroleum ether eluent) to afford tert-butyl (l-(4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl) phenyl)-2-methoxyethyl) carbamate (0.6 g, 77%) as a pale-yellow semi solid. LCMS observed m / z = 426.4 [M+H]+.

[1583] Step 5: Synthesis of l-(4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-2-methoxy ethan- 1 -amine.

[1584] Intermediate AQ.5

[1585]

[1586] The title compound was prepared using a similar procedure as Intermediate I, replacing tert-butyl (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)carbamate with tert-butyl (l-(4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl) phenyl)-2-methoxyethyl) carbamate. LCMS observed m / z = 326.3 [M+H]+.

[1587] Intermediate AR

[1588] Synthesis of (4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methan-d2-amine.

[1589] Intermediate AR

[1590] NH2

[1591]

[1592] Active 126539678.1 120 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1593] Step 1: Preparation of 4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzamide.

[1594] Intermediate AR.1

[1595]

[1596] To a stirred solution of methyl 4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl) benzoate (0.9 g, 2.88 mmol) in MeOH (20 mL), was added saturated aqueous ammonia (20 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2 x 90 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl) benzamide (400 mg, 80%) as an off-white solid. The product was used without further purification. LCMS observed m / z = 298.4 [M+H]+.

[1597] Step 2: Synthesis of (4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methan-d2-amine.

[1598] Intermediate AR

[1599]

[1600] To a stirred solution of 4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl) benzamide (300 mg, 1.00 mmol) in THF (20.0 mL) was added lithium aluminum deuteride (339 mg, 8.07 mmol) at 0 °C. The reaction mixture was allowed to warm slowly to room temperature, then allowed to stir at room temperature for 16 hours. The reaction was quenched with saturated aqueous sodium sulfate, and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (8-10% MeOH / DCM eluent) to afford (4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl) phenyl)methan-d2-amine (80 mg, 27%) as a brown gummy solid. LCMS observed m / z = 286.2 [M+H]+.

[1601] Intermediate AS

[1602] Synthesis of (R)-l-(4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)ethan-l -amine.

[1603] Active 126539678.1 121 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1604] Intermediate AS

[1605] NH2

[1606] 1CF’

[1607]

[1608] The title compound was prepared using a similar procedure as Intermediate AO, replacing tert-butyl (S)-(l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate with (R)-(4-(l-((tert-butoxycarbonyl)amino)ethyl)phenyl)boronic acid, 2-bromo- 1 -methyl-4-(trifluoromethyl)-IH-imidazole with 2-bromo-l-isopropyl-4-(trifluoromethyl)-lH-imidazole, Pd(dppf)Cl2with XPhos Pd G3, and trifluoroacetic acid with 4 M hydrochloric acid in 1,4-dioxane. LCMS observed m / z = 298.4 [M+H]+.

[1609] Intermediate A T

[1610] Synthesi s of (S)- 1 -(4-( 1 -isopropyl-4-(trifluoromethyl)- lH-imidazol-2-yl)phenyl)ethan-l -amine.

[1611] Intermediate AT

[1612]

[1613] The title compound was prepared using a similar procedure as Intermediate AS, replacing (R)-(4-(l-((tert-butoxycarbonyl)amino)ethyl)phenyl)boronic acid with (S)-(4-(l-((tert-butoxycarbonyl) amino) ethyl) phenyl) boronic acid. LCMS observed m / z = 298.4 [M+H]+.

[1614] Intermediate A U

[1615] Synthesis of l-(4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-2-methylphenyl)ethan- 1 -amine.

[1616] Intermediate AU

[1617] NH3

[1618]

[1619] Step 1: Preparation of l-(2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)ethan-l-one.

[1620] Active 126539678.1 122 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT Intermediate AU.l

[1621]

[1622] The title compound was prepared using a similar procedure as Intermediate E.l, replacing 4-bromo-3 -methylbenzonitrile with l-(4-bromo-2-methylphenyl)ethan-l-one. LCMS observed m / z = 261.2 [M+H]+.

[1623] Step 2: Preparation of l-(4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-2-methylphenyl)ethan- 1 -one.

[1624] Intermediate AU.l

[1625]

[1626] The title compound was prepared using a similar procedure as Intermediate E.2, replacing 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile with l-(2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)ethan-l-one and Pd(dppf)Cl2with XPhosPdG2. LCMS observed m / z = 311.2 [M+H]+.

[1627] Step 3: Preparation of (Z)-l-(4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-2-methylphenyl)ethan- 1 -one oxime.

[1628] Intermediate AU.3

[1629]

[1630] To a stirred solution of l-(4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-2-methylphenyl) ethan-l-one (0.65 g, 2.095 mmol) in ethanol (5 mL) and water (5 mL) was added NaOAc (0.43 g, 5.23 mmol) followed by hydroxylamine hydrochloride (0.217 g, 3.142 mmol). The reaction mixture was allowed to stir at 90 °C for 2 h. Upon consumption of the starting material as indicated by TLC and LCMS analysis, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were concentrated under reduced pressure to afford (Z)-l-(4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-2-methylphenyl)ethan-l-one oxime (0.65 g, 95% yield).

[1631] Active 126539678.1 123 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1632] The crude product was used without further purification. LCMS observed m / z = 326.2 [M+H]+.

[1633] Step 4: Synthesis of l-(4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-2-methylphenyl)ethan- 1 -amine.

[1634] Intermediate AU

[1635]

[1636] To a stirred solution of(Z)-l-(4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-2-methylphenyl)ethan-l-one oxime (0.6 g, 18.443 mmol) in ethanol (5 mL) was added Raney nickel (0.5 g) at room temperature. The reaction mixture was stirred under an atmosphere of hydrogen (80 psi) in an autoclave at 70 °C for 16 h. Upon consumption of the starting material as indicated by TLC and LCMS analysis, the reaction mixture was filtered through Celite and washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (10% MeOH / DCM eluent) to afford 1-(4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-2-methylphenyl)ethan-l -amine (0.35 g, 60% yield). LCMS observed m / z = 312.5 [M+H]+.

[1637] Intermediate A V

[1638] Synthesis of 4-(l-cy cl opropyl-4-(trifluoromethyl)- lH-imidazol-2-yl)benzoic acid.

[1639] Intermediate AV

[1640]

[1641] Step 1: Preparation of methyl 4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzoate.

[1642] Intermediate AV.l

[1643]

[1644] To a stirred solution of methyl 4-(4-(trifluoromethyl)-lH-imidazol-2-yl) benzoate (2 g, 7.402 mmol) and cyclopropylboronic acid (3.179 g, 37.008 mmol) in DCE

[1645] Active 126539678.1 124 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1646] (50 mL) was added sodium carbonate (2.353 g, 22.205 mmol) and 2,2'-bipyridine (1.156 g, 7.402 mmol). The mixture was purged with oxygen gas for 5 minutes, then copper (II) acetate (1.479 g, 8.142 mmol) was added. The reaction mixture was stirred at 70 ° C for 48 h. Upon consumption of the starting material as indicated by TLC and LCMS analysis, the reaction was quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (50% EtOAc / petroleum ether eluent) to afford methyl 4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl) benzoate (1.2 g, 52%) as a brown liquid. LCMS observed m / z = 311.1 [M+H]+.

[1647] Step 2: Synthesis of 4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzoic acid.

[1648] Intermediate AV

[1649] o

[1650]

[1651] To a stirred solution of methyl 4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl) benzoate (0.9 g, 2.901 mmol) in THF (9 mL) and Water (3 mL) was added lithium hydroxide monohydrate (608.5 mg, 14.50 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for 16 h. Upon consumption of the starting material as indicated by TLC and LCMS analysis, the reaction was quenched with water (30 mL) and extracted with EtOAc (50 mL). The aqueous layer was acidified with IN HC1 (pH-adjusted to 4-5) and further extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with n-pentane (20 mL) to afford methyl 4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl) benzoic acid (0.7 g, 81%) as yellow solid. The product was used without further purification. LCMS observed m / z = 297.0 [M+H]+.

[1652] Intermediate A W

[1653] Synthesis of l-amino-2-methyl-l-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)propan-2-ol.

[1654] Intermediate AW

[1655] Active 126539678.1 125 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1656] NH2

[1657]

[1658] Step 1: Preparation of methyl 2-((ter / -butoxycarbonyl)amino)-2-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)acetate.

[1659] Intermediate AW.l

[1660]

[1661] The title compound was prepared using a similar procedure as Intermediate AQ.2, replacing 2-bromo-l-isopropyl-4-(trifluoromethyl)-1H-imidazole with 2-bromo-l-methyl-4-(trifluoromethyl)-lH-imidazole. LCMS observed m / z = 415.4 [M+H]+.

[1662] Step 2: Preparation of methyl 2-amino-2-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)acetate»HCl.

[1663] Intermediate AW.2

[1664]

[1665] The title compound was prepared using a similar procedure as Intermediate I, replacing tert-butyl (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-U / -pyrazol-l-yl)benzyl)carbamate with methyl 2-((tert-butoxycarbonyl)amino)-2-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)acetate and trifluoroacetic acid with 4 M hydrochloric acid in 1,4-dioxane. LCMS observed m / z = 314.7 [M+H]+.

[1666] Step 3: Synthesis of l-amino-2-methyl-l-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)propan-2-ol.

[1667] Intermediate AW

[1668] NH2

[1669]

[1670] To a stirred solution of methyl 2-amino-2-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl) phenyl) acetate hydrochloride (0.800 g, 1.935 mmol) in THF (18.0 mL) was added methylmagnesium bromide (1 M in THF, 8.70 mL) dropwise at 0 °C. The reaction

[1671] Active 126539678.1 126 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1672] mixture was allowed to stir at room temperature for 2 h. Upon consumption of the starting material as indicated by TLC and LCMS analysis, the reaction was quenched with saturated aqueous ammonium chloride, then partially concentrated under vacuum to remove organic solvent. The resultant slurry was extracted with 10% MeOH in DCM. The organic layer was concentrated under reduced pressure. The residue was purified by preparatory HPLC (mobile 0-70% MeCN in water with 0.1% formic acid) to afford l-amino-2-methyl-l-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl) phenyl) propan-2-ol (0.40 g, 66%) as off-white semi solid. 'H NMR (400 MHz,): 67.96 (s, 1H), 7.74 (d, J= 8.0 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H), 4.16 (s, 1H), 3.79 (s, 3H), 1.21 (s, 3H), 1.02 (s, 3H) ppm. LCMS observed m / z = 314.3 [M+H]+.

[1673] Intermediate AX

[1674] Synthesis of 1 -amino- l-(4-bromophenyl)-2-methylpropan-2-ol hydrochloride.

[1675] Intermediate AX

[1676] NH2HCI

[1677]

[1678] The title compound was prepared using a similar procedure as Intermediate AW.2, replacing methyl 2-((tert-butoxycarbonyl)amino)-2-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)acetate with tert-butyl (l-(4-bromophenyl)-2-hydroxy-2-methylpropyl)carbamate. LCMS observed m / z = 244.1 [M+H]+.

[1679] Intermediate A Y

[1680] Synthesis of (4-(l-cyclobutyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1681] Intermediate AY

[1682] NH2

[1683]

[1684] Step 1: Preparation of 4-(l-cyclobutyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile.

[1685] Intermediate AY.l

[1686] Active 126539678.1 127 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1687]

[1688] The title compound was prepared using a similar procedure as Intermediate A.2, replacing methyl iodide with bromocyclobutane and NaH with cesium carbonate. LCMS observed m / z = 292.1 [M+H]+.

[1689] Step 2: Preparation of tert-butyl (4-(l-cyclobutyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)carbamate.

[1690] Intermediate AY.2

[1691]

[1692] To a stirred solution of4-(l-cyclobutyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile (0.3 g, 1.03 mmol) inEtOAc (5 mL) and MeOH (5 mL) was added 10% palladium on carbon (0.3 g) followed by Boc anhydride (0.674 g, 3.090 mmol). The reaction mixture was allowed to stir at room temperature under an atmosphere of hydrogen (80 psi) in a Parr shaker apparatus for 8 h. Upon consumption of the starting material as indicated by TLC and LCMS analysis, the reaction mixture was filtered through Celite and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc / petroleum ether eluent) to afford tert-butyl (4-(l-cyclobutyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)carbamate (0.35 g, 85% yield). LCMS observed m / z = 396.3 [M+H]+.

[1693] Step 3: Synthesis of (4-(l-cyclobutyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1694] Intermediate AY

[1695]

[1696] The title compound was prepared using a similar procedure as Intermediate G, replacing tert-butyl ((6-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)pyridin-3-yl)methyl)carbamate with tert-butyl (4-(l-cyclobutyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)carbamate. LCMS observed m / z = 296.2 [M+H]+.

[1697] Active 126539678.1 128 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT Intermediate AZ

[1698] Synthesis of (4-(l-(oxetan-3-ylmethyl)-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1699] Intermediate AZ

[1700] NH2

[1701]

[1702] The title compound was prepared using a similar procedure as Intermediate A, replacing methyl iodide with 3-(bromomethyl)oxetane, NaH with cesium carbonate, and using General Procedure C for reduction of the nitrile. LCMS observed m / z = 312.1 [M+H]+.

[1703] Intermediate BA

[1704] Synthesi s of (4-( 1 -(2-methoxy ethyl)-4-(trifluoromethy 1)- 1 H-imidazol-2-yl)phenyl)methanamine.

[1705] Intermediate BA

[1706] NH2

[1707]

[1708] The title compound was prepared using a similar procedure as Intermediate A, replacing methyl iodide with l-bromo-2-methoxy ethane, NaH with cesium carbonate, and using General Procedure C for reduction of the nitrile. LCMS observed m / z = 300.4 [M+H]+.

[1709] Intermediate BB

[1710] Synthesis of l-(2-(4-(aminomethyl)phenyl)-4-(trifluoromethyl)-lH-imidazol-l-yl)-2-methylpropan-2-ol.

[1711] Intermediate BB

[1712]

[1713] Active 126539678.1 129 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1714] The title compound was prepared using a similar procedure as Intermediate A, replacing methyl iodide with l-bromo-2-methylpropan-2-ol, NaH with cesium carbonate, and using General Procedure C for reduction of the nitrile. LCMS observed m / z = 314.2 [M+H]+.

[1715] Intermediate BC

[1716] Synthesi s of 1 -(2-(4-(aminomethyl)phenyl)-4-(trifluoromethyl)- IH-imidazol- 1 -yl)propan-2-ol.

[1717]

[1718] Step 1: Preparation of 4-(l-(2-oxopropyl)-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile.

[1719] Intermediate BC.l

[1720]

[1721] The title compound was prepared using using a similar procedure as Intermediate A, replacing methyl iodide with l-bromopropan-2-one. LCMS observed m / z = 295.1 [M+H]+.

[1722] Step 2: Synthesis of l-(2-(4-(aminomethyl)phenyl)-4-(trifluoromethyl)-lH-imidazol-l-yl)propan-2-ol.

[1723] Intermediate BC

[1724]

[1725] The title compound was prepared using General Procedure C, with 4-(l-(2-oxopropyl)-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile (Intermediate BC.l) as the benzonitrile. Concomitant reduction of the carbonyl functional group was observed under these conditions. LCMS observed m / z = 300.0 [M+H]+.

[1726] Intermediate BD

[1727] Active 126539678.1 130 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1728] Synthesis of (3-methyl-4-(l -methyl-4-(trifluoromethyl)- lH-imidazol-2-yl)phenyl)methanamine.

[1729] Intermediate BD

[1730] NH2

[1731]

[1732] Step 1: Preparation of 3-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile.

[1733] Intermediate BD.l

[1734]

[1735] The title compound was prepared using General Procedure A, with 4-formyl-3-methylbenzonitrile as the aldehyde. LCMS observed m / z = 252.2 [M+H]+.

[1736] Step 2: Preparation of 3-methyl-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile.

[1737] Intermediate BD.l

[1738]

[1739] The title compound was prepared using General Procedure B, with 3-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile as the imidazole and methyl iodide as the alkyl halide. LCMS observed m / z = 266.0 [M+H]+.

[1740] Step 3: Synthesis of (3-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1741] Intermediate BD

[1742] NH2

[1743]

[1744] The title compound was prepared using General Procedure C, with 3-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile as the benzonitrile. LCMS observed m / z = 270.3 [M+H]+.

[1745] Intermediate BE

[1746] Active 126539678.1 131 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1747] Synthesis of (3-methyl-4-(l-(oxetan-3-ylmethyl)-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1748] Intermediate BE

[1749] NH2

[1750]

[1751] The title compound was prepared using a similar procedure as Intermediate BD, replacing methyl iodide with 3-(bromomethyl)oxetane. LCMS observed m / z = 326.3 [M+H]+.

[1752] Intermediate BF

[1753] Synthesis of (4-(l-(2-methoxyethyl)-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-methylphenyl)methanamine.

[1754] Intermediate BF

[1755]

[1756] The title compound was prepared using a similar procedure as Intermediate BD, replacing methyl iodide with l-bromo-2-methoxy ethane. LCMS observed m / z = 326.3 [M+H]+.

[1757] Intermediate BG

[1758] Synthesis of (4-(l-ethyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-methylphenyl)methanamine hydrochloride.

[1759] Intermediate BG

[1760]

[1761] The title compound was prepared using a similar procedure as Intermediate AY, replacing 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (Intermediate A.1) with 3-methyl-4-(4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile (Intermediate BD.l) and bromocyclobutane with ethyl iodide. LCMS observed m / z = 284.8 [M+H]+.

[1762] Active 126539678.1 132 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1763] Intermediate BH

[1764] Synthesis of (3-methyl-4-(l-(oxetan-3-yl)-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1765] Intermediate BH

[1766]

[1767] The title compound was prepared using a similar procedure as Intermediate BD, replacing methyl iodide with 3-iodooxetane. LCMS observed m / z = 312.0 [M+H]+.

[1768] Intermediate BI

[1769] Synthesis of l-(2-(4-(aminomethyl)-2-methylphenyl)-4-(trifluoromethyl)- 1H-imidazol- 1 -yl)-2-methylpropan-2-ol.

[1770] Intermediate BI

[1771]

[1772] The title compound was prepared using a similar procedure as Intermediate BD, replacing methyl iodide with l-bromo-2-methylpropan-2-ol. LCMS observed m / z = 328.2 [M+H]+.

[1773] Intermediate BJ

[1774] Synthesis of l-(2-(4-(aminomethyl)-2-methylphenyl)-4-(trifluoromethyl)- 1H-imidazol- 1 -yl)propan-2-ol.

[1775] Intermediate BJ

[1776]

[1777] The title compound was prepared using a similar procedure as Intermediate BC, replacing 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (Intermediate A.1) with 3-methyl-4-(4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile (Intermediate BD.l). LCMS observed m / z = 314.8 [M+H]+.

[1778] Active 126539678.1 133 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT Intermediate BK

[1779] Synthesis of (4-(l-methyl-4-(tri fluoromethyl)- IH-imidazol -2 -yl)cuban-l-yl)m ethanamine.

[1780] Intermediate BK

[1781]

[1782] Step 1: Preparation of 4-(4-(trifluoromethyl)-lH-imidazol-2-yl)cubane-l-carboxamide.

[1783] Intermediate BK.1

[1784]

[1785] The title compound was prepared using General Procedure A, with methyl-4-formylcubane-1 -carboxylate as the aldehyde. Conversion of the methyl ester to the carboxamide was observed under these conditions. LCMS observed m / z = 282.5 [M+H]+.

[1786] Step 2: Preparation of 4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)cubane-l-carboxamide.

[1787] Intermediate BK.2

[1788]

[1789] The title compound was prepared using General Procedure B, with methyl iodide as the alkyl halide. LCMS observed m / z = 296.3 [M+H]+.

[1790] Step 3: Synthesis of (4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)cuban-l-yl)m ethanamine.

[1791] Intermediate BK

[1792] NH2

[1793]

[1794] To a stirred solution of 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1-carboxamide (0.9 g, 3.04 mmol,) in DCM(10 mL)at 0 °C was added chlorotrimethylsilane (0.497 g, 4.57 mmol). The reaction mixture was allowed to stir at 0 °C for 10 minutes, then LiAlH4(2.0 M in THF, 3.04 mL) was added. The reaction mixture was allowed to warm

[1795] Active 126539678.1 134 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1796] slowly to room temperature, then allowed to stir at room temperature for 5 hours. Upon consumption of the starting material as indicated by TLC and LCMS analysis, the reaction was quenched with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford (4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)cuban-l-yl)m ethanamine (0.8 g, 93.31% yield) as a white solid. The product was used without further purification. LCMS observed m / z = 282.2 [M+H]+.

[1797] Intermediate BL

[1798] Synthesis of (4-(l-(2,5-dihydrofuran-3-yl)-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1799] Intermediate BL

[1800]

[1801] Step 1: Preparation of 4-(l-(2,5-dihydrofuran-3-yl)-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile.

[1802] Intermediate BL.l

[1803]

[1804] The title compound was prepared using a similar procedure as Intermediate AV.l, replacing methyl 4-(4-(trifluoromethyl)-lH-imidazol-2-yl) benzoate with 4-(4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile (Intermediate A.1), and cyclopropylboronic acid with 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane. LCMS observed m / z = 306.7 [M+H]+.

[1805] Step 2: Synthesis of (4-(l-(2,5-dihydrofuran-3-yl)-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1806] Intermediate BL

[1807] Active 126539678.1 135 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1808]

[1809] The title compound was prepared using General Procedure C, with 4-(l-(2,5-dihydrofuran-3-yl)-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile as the benzonitrile. LCMS observed m / z = 310.4 [M+H]+.

[1810] Intermediate BM

[1811] Synthesis of (4-(l-(2,5-dihydrofuran-3-yl)-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-methylphenyl)methanamine.

[1812] Intermediate BM

[1813]

[1814] The title compound was prepared using a similar procedure as Intermediate BL, replacing 4-(4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile (Intermediate A.1) with 3-methyl-4-(4-(trifluoromethyl)-l / 7-imidazol-2-yl)benzonitrile (Intermediate BD.l). LCMS observed m / z = 324.3 [M+H]+.

[1815] Intermediate BN

[1816] Synthesis of (4-(l-(3,6-dihydro-2H-pyran-4-yl)-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1817] Intermediate BN

[1818]

[1819] The title compound was prepared using a similar procedure as Intermediate BL, replacing 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane. LCMS observed m / z = 324.2 [M+H]+.

[1820] Intermediate BO

[1821] Active 126539678.1 136 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1822] Synthesi s of (3 -methyl-4-( 1 -(tetrahy dro-2H-pyran-4-yl)-4-(trifluoromethyl)- 1 H-imidazol-2-yl)phenyl)methanamine.

[1823] Intermediate BO

[1824]

[1825] Step 1: Preparation of 4-(l-(3,6-dihydro-2H-pyran-4-yl)-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-methylbenzonitrile.

[1826] Intermediate BO.l

[1827]

[1828] The title compound was prepared using a similar procedure as Intermediate AV.l, replacing methyl 4-(4-(trifluoromethyl)-lH-imidazol-2-yl) benzoate with 3-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile (Intermediate BD.l) and cyclopropylboronic acid with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane. LCMS observed m / z = 334.3 [M+H]+.

[1829] Step 2: Preparation of tert-butyl (3 -methyl-4-(l -(tetrahy dro-2H-pyran-4-yl)-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)carbamate.

[1830] Intermediate BO.l

[1831]

[1832] The title compound was prepared using a similar procedure as Intermediate AY.2, replacing 4-(l-cyclobutyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile with 4-(l-(3,6-dihydro-2H-pyran-4-yl)-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-methylbenzonitrile.

[1833] Concomitant reduction of the alkene was observed under these conditions. LCMS observed m / z = 440.2 [M+H]+.

[1834] Step 3: Synthesis of (3 -methyl-4-(l -(tetrahy dro-2H-pyran-4-yl)-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1835] Active 126539678.1 137 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1836] Intermediate BO

[1837]

[1838] The title compound was prepared using a similar procedure as Intermediate I, replacing tert-butyl (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-U / -pyrazol-l-yl)benzyl)carbamate with tert-butyl (3-methyl-4-(l-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)carbamate. LCMS observed m / z = 340.1 [M+H]+.

[1839] Intermediate BP

[1840] Synthesis of (2,6-difluoro-4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1841] Intermediate BP

[1842]

[1843] Step 1: Preparation of 2,6-difluoro-4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile.

[1844] Intermediate BP.l

[1845] p

[1846]

[1847] The title compound was prepared using a similar procedure as Intermediate E.l, replacing 4-bromo-3 -methylbenzonitrile with 4-bromo-2,6-difluorobenzonitrile. LCMS observed m / z = 316.6 [M+H]+.

[1848] Step 2: Preparation of tert-butyl (2,6-difluoro-4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)carbamate.

[1849] Intermediate BP.l

[1850] F

[1851]

[1852] Active 126539678.1 138 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1853] The title compound was prepared using a similar procedure as Intermediate AY.2, replacing 4-(l-cyclobutyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile with 2,6-difluoro-4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile. LCMS observed m / z = 420.6 [M+H]+.

[1854] Step 3: Synthesis of (2,6-difluoro-4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1855] Intermediate BP

[1856]

[1857] The title compound was prepared using a similar procedure as Intermediate G, replacing tert-butyl ((6-(l-isopropyl-4-(trifluoromethyl)-1-imidazol-2-yl)pyridin-3-yl)methyl)carbamate with tert-butyl (2,6-difluoro-4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)carbamate. LCMS observed m / z = 320.4 [M+H]+.

[1858] Intermediate BQ

[1859] Synthesis of (3,5-difluoro-4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1860] Intermediate BQ

[1861]

[1862] The title compound was prepared using a similar procedure as Intermediate AY, replacing 4-formylbenzonitrile with 3,5-difluoro-4-formylbenzonitrile and using General Procedure B for imidazole alkylation with 2-iodopropane as the alkyl halide. LCMS observed m / z = 320.4 [M+H]+.

[1863] Intermediate BR

[1864] Synthesis of (2-fluoro-4-(l -methyl-4-(trifluoromethyl)- lH-imidazol-2-yl)phenyl)methanamine.

[1865] Intermediate BR

[1866] Active 126539678.1 139 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1867]

[1868] The title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with 2-fluoro-4-formylbenzonitrile and using General Procedure C to reduce the nitrile. LCMS observed m / z = 274.3 [M+H]+.

[1869] Intermediate BS

[1870] Synthesis of (2,5-dimethyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1871] Intermediate BS

[1872]

[1873] The title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with 4-formyl-2,5-dimethylbenzonitrile and using General Procedure C to reduce the nitrile. LCMS observed m / z = 283.9 [M+H]+.

[1874] Intermediate BT

[1875] Synthesis

[1876]

[1877] (3-fluoro-4-(l -methyl-4-(tri fluoromethyl)- lH-imidazol-2-yl)phenyl)methanamine.

[1878] Intermediate BT

[1879]

[1880] The title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with 3-fluoro-4-formylbenzonitrile and using General Procedure C to reduce the nitrile. LCMS observed m / z = 274.2 [M+H]+.

[1881] Intermediate BU

[1882] Synthesis of (3-methoxy-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1883] Intermediate BU

[1884]

[1885] Active 126539678.1 140 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1886] The title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with 4-formyl-3 -methoxybenzonitrile and using General Procedure C to reduce the nitrile. LCMS observed m / z = 286.3 [M+H]+.

[1887] Intermediate BV

[1888] Synthesis of (3-bromo-4-(l -methyl-4-(trifluoromethyl)- lH-imidazol-2-yl)phenyl)methanamine.

[1889] Intermediate BV

[1890]

[1891] The title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with 4-formyl-3 -bromobenzonitrile and using General Procedure C to reduce the nitrile. LCMS observed m / z = 334.2 [M+H]+.

[1892] Intermediate BW

[1893] Synthesis of (4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)phenyl)methanamine.

[1894] Intermediate BW

[1895]

[1896] Step 1: Preparation of 3-(3,6-dihydro-2H-pyran-4-yl)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile.

[1897] Intermediate BW.l

[1898]

[1899] To a stirred solution of 3-bromo-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl) benzonitrile (Intermediate BV) (500 mg, 1.51 mmol) and (3,6-dihydro-2H-pyran-4-yl) boronic acid (387 mg, 3.03 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was added potassium phosphate tribasic (964 mg, 4.54 mmol). The mixture was purged with N2 gas for 10 minutes. Bis(di- / c / 7-butyl(4-dimethylaminophenyl) phosphine) di chloropalladium (II)

[1900] Active 126539678.1 141 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1901] (107 mg, 0.15 mmol) was added to the reaction mixture, then the reaction mixture was stirred at 100 °C for 2 h in a sealed tube. The reaction mixture was cooled to room temperature, diluted with EtOAc (30 mL), and fdtered through Celite. The filtrate was washed with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (40-50% EtOAc / petroleum ether eluent) to afford 3 -(3,6-dihydro-2H-pyran-4-yl)-4-( 1 -methyl-4-(trifluoromethyl)- 1 H-imidazol-2-yl) benzonitrile (500 mg, 98 %) as a yellow solid. LCMS observed m / z = 334.0 [M+H]+.

[1902] Step 2: Preparation of tert-butyl (4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)benzyl)carbamate.

[1903] Intermediate BW.2

[1904]

[1905] The title compound was prepared using a similar procedure as Intermediate BO.2, replacing 4-(l-(3,6-dihydro-2H-pyran-4-yl)-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-methylbenzonitrile with 3-(3,6-dihydro-2H-pyran-4-yl)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl) benzonitrile. LCMS observed m / z = 440.2 [M+H]+.

[1906] Step 3: Synthesis of (4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)phenyl)methanamine.

[1907] Intermediate BW

[1908]

[1909] The title compound was prepared using a similar procedure as Intermediate I, replacing tert-butyl (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-177-pyrazol-l-yl)benzyl)carbamate with tert-butyl (4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)benzyl)carbamate.1H NMR (400 MHz, DMSO-de) 8 8.21 (br s, 2H), 7.63 (d, J= 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.25 (s, 1H), 4.77-4.73 (m, 2H), 4.68-4.64 (m, 2H), 4.39-4.31 (m, 1H), 4.15 (s, 2H). LCMS observed m / z = 298.3 [M+H]+.

[1910] Intermediate BX

[1911] Active 126539678.1 142 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1912] Synthesis of (3-ethyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1913] Intermediate BX

[1914]

[1915] Step 1: Preparation of 4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-viny lb enzonitril e.

[1916] Intermediate BX.l

[1917] V

[1918]

[1919] The title compound was prepared using a similar procedure as Intermediate BW.l, replacing (3,6-dihydro-2H-pyran-4-yl) boronic acid with ethenylboronic acid. LCMS observed m / z = 278.5 [M+H]+.

[1920] Step 2: Preparation of 3-ethyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile.

[1921] Intermediate BX.l

[1922]

[1923] To a stirred solution of 4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-vinylbenzonitrile (0.2 g, 0.722 mmol) in EtOAc (10 mL) and ethanol (10 mL) was added palladium on carbon (10 w / w%) (0.23 g, 2.16 mmol). The reaction mixture was stirred under an atmosphere of hydrogen (50 psi) for 1 h at room temperature in a Parr shaker apparatus. Upon consumption of the starting material as indicated by TLC and LCMS analysis, the reaction mixture was filtered through Celite and the cake was washed with EtOAc (40 mL). The filtrate was concentrated under reduced pressure to afford 3-ethyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl) benzonitrile (0.17 g, 84%) as a white semisolid. The product was used without further purification. LCMS observed m / z = 280.6 [M+H]+.

[1924] Active 126539678.1 143 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1925] Step 3: Synthesis of (3-ethyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1926] Intermediate BX

[1927]

[1928] The title compound was prepared using General Procedure C, with 3-ethyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile as the benzonitrile. LCMS observed m / z = 284.0 [M+H]+.

[1929] Intermediate BY

[1930] Synthesis of (3-isopropyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1931] Intermediate BY

[1932]

[1933] The title compound was prepared using a similar procedure as Intermediate BX, replacing ethenylboronic acid with potassium isopropenyltrifluoroborate. LCMS observed m / z = 298.1 [M+H]+.

[1934] Intermediate BZ

[1935] Synthesis of (2,3-difluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1936]

[1937] The title compound was prepared using a similar procedure as Intermediate E, replacing 4-bromo-3 -methylbenzonitrile with 4-bromo-2,3-difluorobenzonitrile and 2-

[1938] Active 126539678.1 144 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1939] bromo-l-isopropyl-4-(trifluoromethyl)-lJ7-imidazole with 2-bromo-l-methyl-4-(trifluoromethyl)-lH-imidazole. LCMS observed m / z = 292.3 [M+H]+.

[1940] Intermediate CA

[1941] Synthesis of (2-fluoro-3-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1942] Intermediate CA

[1943]

[1944] The title compound was prepared using a similar procedure as Intermediate E, replacing 4-bromo-3 -methylbenzonitrile with 6-bromo-2-fluoro-3-toluonitrile. LCMS observed m / z = 288.2 [M+H]+.

[1945] Intermediate CB

[1946] Synthesis of (3,5-difluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1947] Intermediate CB

[1948]

[1949] The title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with 3,5-difluoro-4-formylbenzonitrile and using general procedure C to reduce the nitrile. LCMS observed m / z = 292.6 [M+H]+.

[1950] Intermediate CC

[1951] Synthesis of (2-fluoro-5-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1952] Intermediate CC

[1953]

[1954] Active 126539678.1 145 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1955] The title compound was prepared using a similar procedure as Intermediate E, replacing 4-bromo-3-methylbenzonitrile with 4-bromo-2-fluoro-5-methylbenzonitrile and 2-bromo-l-isopropyl-4-(trifluoromethyl)-1H-imidazole with 2-bromo-l-methyl-4-(trifluoromethyl)-lH-imidazole. LCMS observed m / z = 288.2 [M+H]+.

[1956] Intermediate CD

[1957] Synthesis of (2,5-difluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[1958] Intermediate CD

[1959]

[1960] The title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with 2,5-difluoro-4-formylbenzonitrile and using general procedure C to reduce the nitrile. LCMS observed m / z = 292.1 [M+H]+.

[1961] Intermediate CE

[1962] Synthesis of (4-(l-ethyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-fluorophenyl)methanamine.

[1963] Intermediate CE

[1964]

[1965] The title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with 3-fluoro-4-formylbenzonitrile, methyl iodide with ethyl iodide, and using general procedure C to reduce the nitrile. LCMS observed m / z = 288.2 [M+H]+.

[1966] Intermediate CF

[1967] Synthesis of (4-(l-ethyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3,5-difluorophenyl)methanamine.

[1968] Intermediate CF

[1969] Active 126539678.1 146 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1970]

[1971] The title compound was prepared using a similar procedure as Intermediate CB, replacing methyl iodide with ethyl iodide. LCMS observed m / z = 306.6 [M+H]+.

[1972] Intermediate CG

[1973] Synthesis of (4-(l-ethyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-fluoro-5-methylphenyl)methanamine.

[1974] Intermediate CG

[1975]

[1976] The title compound was prepared using a similar procedure as Intermediate G, replacing 5-bromo-2-pyridinecarboxaldehyde with 4-bromo-2-fluoro-6-methylbenzaldehyde, isopropyl iodide with ethyl iodide, and 4 M hydrochloric acid in 1,4-dioxane with trifluoroacetic acid. LCMS observed m / z = 302.0 [M+H]+.

[1977] Intermediate CH

[1978] Synthesis of (4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-fluorophenyl)methanamine.

[1979] Intermediate CH

[1980]

[1981] Step 1: Preparation of 4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-fluorobenzonitrile.

[1982] Intermediate CH.l

[1983] Active 126539678.1 147 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1984]

[1985] The title compound was prepared using a similar procedure as Intermediate AV.l, replacing methyl 4-(4-(trifluoromethyl)-lH-imidazol-2-yl) benzoate with 3-fluoro-4-(4-(trifluoromethyl)-lH-imidazol-2-yl) benzonitrile. LCMS observed m / z = 296.6 [M+H]+.

[1986] Step 2: Preparation of tert-butyl (4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-fluorobenzyl)carbamate.

[1987] Intermediate CH.2

[1988]

[1989] The title compound was prepared using a similar procedure as Intermediate S.2, replacing 2-(trifluoromethyl)-6,7-dihydro-5H-benzo[b]imidazo[2, 1 -d] [ 1, 5]oxazocine- 10-carbonitrile with 4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-fluorobenzonitrile. LCMS observed m / z = 400.3 [M+H]+.

[1990] Step 3: Synthesis of (4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-fluorophenyl)methanamine.

[1991] Intermediate CH

[1992]

[1993] The title compound was prepared using a similar procedure as Intermediate I, replacing tert-butyl (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-lrt-pyrazol-l-yl)benzyl)carbamate with tert-butyl (4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-fluorobenzyl)carbamate. LCMS observed m / z = 300.1 [M+H]+.

[1994] Intermediate CI

[1995] Active 126539678.1 148 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[1996] Synthesis of (4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-methylphenyl)methanamine.

[1997] Intermediate CI

[1998]

[1999] The title compound was prepared using a similar procedure as Intermediate CH, replacing 3-fluoro-4-(4-(trifluoromethyl)-lH-imidazol-2-yl) benzonitrile with 3-methyl-4-(4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile (Intermediate BD.l). LCMS observed m / z = 296.7 [M+H]+.

[2000] Intermediate CJ

[2001] Synthesis of (4-(l-cyclopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3,5-difluorophenyl)methanamine.

[2002] Intermediate CJ

[2003]

[2004] The title compound was prepared using a similar procedure as Intermediate CH, replacing 3-fluoro-4-(4-(trifluoromethyl)-lH-imidazol-2-yl) benzonitrile with 3,5-difluoro-4-(4-(trifluoromethyl)-lH-imidazol-2-yl) benzonitrile. LCMS observed m / z = 318.0 [M+H]+.

[2005] Intermediate CK

[2006] Synthesis of (4-(l -cy cl opropyl-4-(tri fluoromethyl)- IH-imidazol -2-yl)phenyl)methanamine.

[2007] Intermediate CK

[2008]

[2009] Active 126539678.1 149 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2010] The title compound was prepared using a similar procedure as Intermediate CH, replacing 3-fluoro-4-(4-(trifluoromethyl)-lH-imidazol-2-yl) benzonitrile with 4-(4-(trifluoromethyl)-U / -imidazol-2-yl)benzonitrile (Intermediate A.1) and using General Procedure C for reduction of the nitrile. LCMS observed m / z = 282.2 [M+H]+.

[2011] Intermediate CL

[2012] Synthesi s of (4-( 1 -i sopropyl-4-(trifluoromethyl)- 1 H-imidazol-2-yl)-3, 5 -dimethylphenyl)methanamine.

[2013] Intermediate CL

[2014]

[2015] Step 1: Preparation of 4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3,5-dimethylbenzonitrile.

[2016]

[2017] The title compound was prepared using a similar procedure as Intermediate E.2, replacing 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile with (4-cyano-2,6-dimethylphenyl) boronic acid and Pd(dppf)Cl2with XPhos Pd G2. LCMS observed m / z = 308.3 [M+H]+.

[2018] Step 2: Preparation of tert-butyl (4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3,5-dimethylbenzyl)carbamate.

[2019] Intermediate CL.2

[2020]

[2021] Active 126539678.1 150 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2022] The title compound was prepared using a similar procedure as Intermediate AY.2, replacing 4-(l-cyclobutyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile with 4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3,5-dimethylbenzonitrile. LCMS observed m / z = 412.3 [M+H]+.

[2023] Step 3: Synthesis of (4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3,5-dimethylphenyl)methanamine.

[2024] Intermediate CL

[2025]

[2026] The title compound was prepared using a similar procedure as Intermediate I, replacing tert-butyl (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-U / -pyrazol-l-yl)benzyl)carbamate with tert-butyl (4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3,5-dimethylbenzyl)carbamate. LCMS observed m / z = 312.2 [M+H]+.

[2027] Intermediate CM

[2028] Synthesis of (2-methoxy-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[2029]

[2030] The title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with 4-formyl-2-methoxybenzonitrile and using General Procedure C to reduce the nitrile. LCMS observed m / z = 285.2 [M+H]+.

[2031] Intermediate CN

[2032] Synthesis of (2-(2 -methoxy ethoxy)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[2033] Intermediate CN

[2034] Active 126539678.1 151 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2035]

[2036] Step 1: Preparation of 2-methoxy-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile.

[2037]

[2038] The title compound was prepared using a similar procedure as Intermediate A.2, replacing 4-formylbenzonitrile with 4-formyl-2-methoxybenzonitrile. LCMS observed m / z = 282.2 [M+H]+.

[2039] Step 2: Preparation of 2-hydroxy-4-(l -methyl -4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile.

[2040] Intermediate CN.2

[2041]

[2042] To a stirred solution of 2-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (0.5 g, 1.778 mmol) in DMF (0.5 mL) was added lithium chloride (0.75 g, 17.778 mmol). The reaction mixture was allowed to stir at 120 °C for 24 h. The reaction was cooled to 23 °C, diluted with water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (40% EtOAc / petroleum ether eluent) to afford 3-hydroxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (0.2 g, 42% yield) as a yellow solid. LCMS observed m / z = 268.0 [M+H]+.

[2043] Step 3: Preparation of 2-(2-methoxyethoxy)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile.

[2044] Active 126539678.1 152 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2045]

[2046] To a stirred solution of 3-hydroxy-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile (0.2 g, 0.748 mmol) in DMF (2 mL) was added cesium carbonate (0.73 g, 2.245 mmol) followed by l-Bromo-2-methoxyethane (0.31 g, 2.245 mmol). The reaction mixture was allowed to stir at 90 °C for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to afford 3-(2-methoxyethoxy)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile (0.18 g, 74%). The product was used without further purification. LCMS observed m / z = 326.2 [M+H]+.

[2047] Step 4: Synthesis of (2-(2-methoxyethoxy)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[2048]

[2049] The title compound was prepared using General Procedure C, with 2-(2-methoxyethoxy)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile as the nitrile. LCMS observed m / z = 330.3 [M+H]+.

[2050] Intermediate CO

[2051] Synthesis of (4-(l-methyl-4-(trifluoromethyl)- lH-imidazol-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)methanamine.

[2052] Intermediate CO

[2053] Active 126539678.1 153 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2054]

[2055] The title compound was prepared using a similar procedure as Intermediate CN, replacing l-Bromo-2-m ethoxy ethane with 4-Bromotetrahydro-2H-pyran. LCMS observed m / z = 356.1 [M+H]+.

[2056] Intermediate CP

[2057] Synthesi s of (2-(difluoromethoxy)-4-( 1 -methyl-4-(trifluoromethyl)- 1 H-imidazol-2-yl)phenyl)methanamine.

[2058]

[2059] Step 1: Preparation of 2-(difluoromethoxy)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile.

[2060]

[2061] To a stirred solution of potassium hydroxide (0.315 g, 3.742 mmol) in water (1 mL) at 0 °C was added 3-hydroxy-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile (Intermediate CN.2, 0.1 g, 0.374 mmol). The reaction mixture was stirred for 15 min, then diethyl (bromodifluoromethyl)phosphonate (0.3 g, 1.123 mmol) was added at 0 °C. The reaction mixture was allowed to stir at 25 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to afford 3-(difluoromethoxy)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile (0.1 g,

[2062] Active 126539678.1 154 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2063] 84%). The product was used without further purification. LCMS observed m / z = 318.6 [M+H]+.

[2064] Step 2: Synthesis of (2-(difluoromethoxy)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanamine.

[2065]

[2066] The title compound was prepared using General Procedure C, with 2-(difluoromethoxy)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile as the nitrile. LCMS observed m / z = 322.3 [M+H]+.

[2067] Intermediate CQ

[2068] Synthesis of (5-fluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-2-(oxetan-3-yloxy)phenyl)methanamine.

[2069] Intermediate CQ

[2070]

[2071] Step 1: Preparation of 5-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-(oxetan-3-yloxy)benzonitrile.

[2072] Intermediate CQ.l

[2073]

[2074] To a stirred solution of oxetan-3-ol (0.387 g, 5.22 mmol, 1.5 equiv.) in THF (10 mL), was added NaH (24 g, 10.44 mmol, 3 equiv.) at 0 °C, followed by 2,5 -difluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl) benzonitrile (Intermediate AN.l) (1.0 g, 3.48 mmol). The reaction mixture was stirred at 23 °C for 5 h. The reaction mixture was diluted

[2075] Active 126539678.1 155 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2076] with water (50 mL) and extracted with DCM (2 x30 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (40-50% EtOAc / petroleum ether eluent) to afford 5-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-(oxetan-3-yloxy)benzonitrile (0.6 g, 50%) as a light-yellow solid. LCMS observed m / z = 342.22 [M+H]+.

[2077] Step 2: Synthesis of (5-fluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-2-(oxetan-3 -y 1 oxy )pheny l)methanami ne.

[2078] Intermediate CQ

[2079]

[2080] The title compound was prepared using a similar procedure as Intermediate O, replacing 2-(trifluoromethyl)-5H-benzo[c]imidazo[1,2-a]azepine-9-carbonitrile with 5-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-(oxetan-3-yloxy)benzonitrile. LCMS observed m / z = 346.2 [M+H]+.

[2081] Intermediate CR

[2082] Synthesis of (5-fluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)methanamine.

[2083]

[2084] Step 1: Preparation of 5-fluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile.

[2085] Intermediate CR.1

[2086] Active 126539678.1 156 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2087]

[2088] The title compound was prepared using a similar procedure as Intermediate CQ.l, replacing oxetan-3-ol with tetrahydro-2H-pyran-4-ol. LCMS observed m / z = 370.1 [M+H]+.

[2089] Step 2: Preparation of tert-butyl (5-fluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)carbamate.

[2090] Intermediate CR.2

[2091]

[2092] The title compound was prepared using a similar procedure as Intermediate AY.2, replacing 4-(l-cyclobutyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile with 5-fluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. LCMS observed m / z = 474.4 [M+H]+.

[2093] Step 3: Synthesis of (5-fluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)methanamine.

[2094]

[2095] The title compound was prepared using a similar procedure as Intermediate I, replacing tert-butyl (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-U / -pyrazol-l-yl)benzyl)carbamate with tert-butyl (5-fluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)carbamate. LCMS observed m / z = 374.1 [M+H]+.

[2096] Active 126539678.1 157 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2097] Intermediate CS

[2098] Synthesis of (5-fluoro-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-2-((3-methyloxetan-3-yl)oxy)phenyl)methanamine.

[2099] Intermediate CS

[2100] N

[2101] N.

[2102]

[2103] The title compound was prepared using a similar procedure as Intermediate CQ.l, replacing oxetan-3-ol with 3-methyloxetan-3-ol. LCMS observed m / z = 360.3 [M+H]+.

[2104] Intermediate CT

[2105] Synthesis of 2-(4-(chloromethyl)phenyl)- 1 -isopropyl-4-(trifluoromethyl)- 1H-imidazole.

[2106] Intermediate CT

[2107]

[2108] Step 1: Preparation of (4-(l-methyl-4-(trifluoromethyl)- lJT-imidazol-2-yl)phenyl)methanol.

[2109] Intermediate CT.l

[2110]

[2111] The title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with methyl 4-formylbenzoate, 2-iodopropane with methyliodide, and using General Procedure C (diisobutyl aluminum hydride) to reduce the ester. LCMS (ESI) m / z = 257.1 [M+H]+.

[2112] Step 2: Preparation of 2-(4-(chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole.

[2113] Intermediate CT

[2114]

[2115] Active 126539678.1 158 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2116] To a stirred solution of (4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)methanol (12.0 g, 46.8 mmol) in 1,2-Dichloroethane (240 mL) was added thionyl chloride (16.7 g, 141 mmol) and the mixture was heated at 50 °C for 1 h. The reaction mixture concentrated, quenched with cold-water (100 mL) and extracted with DCM (2x 100 mL). The combined organic phases were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4and filtered. The filtrate was evaporated under reduced pressure and the residue was triturated with diethyl ether to afford 2-(4-(chloromethyl)phenyl)-l-methyl-4-(trifluoromethyl)-lH-imidazole (10.1 g) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.95 (d, J = 0.8 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 4.85 (s, 2H), 3.80 (s, 3H). LCMS (ESI) m / z = 275.2 [M+H]+.

[2117] Intermediate CU

[2118] Synthesis of 2-(4-(chloromethyl)phenyl)- 1 -isopropyl-4-(trifluoromethyl)- 1H-imidazole.

[2119] Intermediate CU

[2120]

[2121] The title compound was prepared using a similar procedure as Intermediate CT, replacing methyl iodide with 2-iodopropane. ¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (d, J = 1.2 Hz, 1H), 7.59 (s, 4H), 4.86 (s, 2H), 4.52 – 4.45 (m, 1H), 1.41 (d, J = 6.4 Hz, 6H). LCMS (ESI) m / z = 303.2 [M+H]+.

[2122] Intermediate CV

[2123] Synthesis of 4-cyclopropyl-6-ethoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine.

[2124] Intermediate CV

[2125]

[2126] Step 1: Preparation of 5-bromo-4-cyclopropyl-6-ethoxypyrimidine.

[2127] Intermediate CV.l

[2128]

[2129] Active 126539678.1 159 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2130] A solution of sodium hydride (0.257 g, 60% dispersion in mineral oil, 6.42 mmol) in ethanol (50 mL) was stirred at 23 °C for 20 min. The mixture was cooled to -20 °C and 5-bromo-4-chloro-6-cyclopropylpyrimidine (1.00 g, 4.28 mmol) was added. The reaction was warmed to 23 °C and stirred for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (50 mL) and extracted with EtOAc (30 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to afford 5-bromo-4-cyclopropyl-6-ethoxypyrimidine (1.0 g) as a colorless liquid. LCMS (ESI) m / z = 243.0 [M+H]+.

[2131] Step 2: Preparation of 4-cyclopropyl-6-ethoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine.

[2132] Intermediate CV

[2133]

[2134] To a solution of 5-bromo-4-cyclopropyl-6-ethoxypyrimidine (0.80 g, 3.29 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.918 g, 4.94 mmol) in THF (10 mL) cooled at -78 °C under nitrogen was added n-BuLi (2.63 mL, 2.5 M in hexanes, 6.58 mmol) dropwise and the reaction was stirred at -78 °C for 3 h. The reaction was quenched with sat. NH4CI solution (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 4-cyclopropyl-6-ethoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (0.8 g) which was used without purification. LCMS (ESI) m / z = 209.1 [M+H]+.

[2135] Intermediate CW

[2136] Synthesis of 4-cyclopropyl-6-(oxetan-3-yloxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine.

[2137] Intermediate CW

[2138]

[2139] 6 o

[2140] The title compound was prepared using a similar procedure to Intermediate CV, replacing ethanol with oxetan-3-ol and using THF as the solvent in the first step. LCMS (ESI) m / z = 319.2 [M+H]+.

[2141] Intermediate CX

[2142] Active 126539678.1 160 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2143] Synthesis of (4-cyclopropyl-6-((tetrahydro-2J / -pyran-4-yl)oxy)pyrimidin-5-yl)boronic acid.

[2144] Intermediate CX

[2145]

[2146] The title compound was prepared using a similar procedure to Intermediate CV, replacing ethanol with tetrahydro-2H-pyran-4-ol and using THF as the solvent in the first step and replacing 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane with triisopropyl borate in step 2. LCMS (ESI) m / z = 265.2 [M+H]+.

[2147] Intermediate CY

[2148] Synthesis of (5-methyl-2-(trifluoromethyl)-6,7-dihydro-5J / -benzo[c]imidazo[l,2-a]azepin-9-yl)methanamine and (5-methyl-3-(trifluoromethyl)-6,7-dihydro-5J / -benzo[c]imidazo[l,2-a]azepin-9-yl)methanamine.

[2149] Intermediate CY

[2150]

[2151] Step 1: Preparation of 4-(l-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-bromobenzonitrile.

[2152] Intermediate CY.l

[2153]

[2154] The title compound was prepared using a similar procedure as Intermediate 0.2, replacing 3 -bromopropene with benzylbromide. LCMS (ESI) m / z = 406.3 [M+H]+.

[2155] Step 2: Preparation of 4-(l-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-(3-hydroxybut- 1 -yn- 1 -yl)benzonitrile.

[2156] Intermediate CY.2

[2157]

[2158] Active 126539678.1 161 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2159] To a stirred solution of 4-(l-benzyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-bromobenzonitrile (4.7 g, 11.6 mmol) in pyridine (30 mL) and triethylamine (10mL) was added copper iodide (2.2 g, 11.6 mmol) followed by but-3-yn-2-ol (1.62 g, 23.1 mmol) and the reaction mixture was purged with nitrogen gas for 10 min. Bis(triphenylphosphine)palladium(II)Dichloride (0.812 g, 1.16 mmol) was added and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 120 mL). The combined organic phases were dried over Na₂SO₄, filtered, concentrated under reduced pressure and purified by silica gel chromatography (40% EtOAc / petroleum ether eluent) to afford 4-(1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-bromobenzonitrile (2.6 g) as a light brown solid. LCMS (ESI) m / z = 396.5 [M+H]+.

[2160] Step 3: Preparation of tert-butyl (3-(3-hydroxybutyl)-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)carbamate.

[2161] Intermediate CY.3

[2162]

[2163] To a stirred solution of 4-(l-benzyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-3-(3-hydroxybut-l-yn-l-yl)benzonitrile (2.00 g, 5.06 mmol) in ethyl acetate (100 mL), methanol (100 mL) and THF (100 mL) was added palladium (wetted with ca. 55% Water) (1.62 g, 10% on Carbon wt. w / 55% water, 15.2 mmol) followed by di-tert-butyl dicarbonate (3.49 mL, 15.2 mmol) and the reaction mixture was stirred at 23 °C in a par shaker under hydrogen atmosphere (80 psi) for 24 h. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (70% EtOAc / petroleum ether eluent) to afford tert-butyl (3-(3-hydroxybutyl)-4-(5-(trifluoromethyl)-lH-imidazol-2-yl)benzyl)carbamate (1.8 g) as an off white solid.

[2164] LCMS (ESI) m / z 414.3 [M+H]+.

[2165] Step 4: Preparation of tert-butyl ((5-methyl-2-(trifluoromethyl)-6,7-dihydro-57 / -benzo[c]imidazo[l,2-a]azepin-9-yl)methyl)carbamate and tert-butyl ((5-methyl-3-(trifhioromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)carbamate.

[2166] Intermediate CY.4

[2167] Active 126539678.1 162 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2168]

[2169] To a stirred solution of tert-butyl (3 -(3 -hydroxybutyl)-4-(5 -(trifluoromethyl)- 1H-imidazol-2-yl)benzyl)carbamate (1.5 g, 3.6 mmol) in Toluene (10 mL). was added 2-(Tributyl-phosphoranylidene)acetonitrile (1.7 g, 7.2 mmol) and the reaction was heated at 110 °C for 16 h. The reaction mixture was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure and the crude material was purified by silica gel chromatography (20-25% EtOAc / petroleum ether eluent) to afford tert-butyl ((5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[l,2-a]azepin-9-yl)methyl)carbamate and ((5-methyl-3-(trifluoromethyl)-6,7-dihydro-57 / -benzo[c]imidazo[l,2-a]azepin-9-yl)methyl)carbamate as a mixture (1.3 g, 90% yield). LCMS (ESI) m / z 396.2 [M+H]+.

[2170] Step 5: Preparation of (5-methyl-2-(trifluoromethyl)-6,7-dihydro-5 / 7-benzo[c]imidazo[l,2-a]azepin-9-yl)methanamine and (5-methyl-3-(trifluoromethyl)-6,7-dihydro-57 / -benzo[c]imidazo[l,2-a]azepin-9-yl)methanamine.

[2171] Intermediate CY

[2172]

[2173] To a stirred solution tert-butyl ((5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[l,2-a]azepin-9-yl)methyl)carbamate and ((5-methyl-3-(trifluoromethyl)-6,7-dihydro-57 / -benzo[c]imidazo[l,2-a]azepin-9-yl)methyl)carbamate (0.80 g, 2.02 mmol) in DCM (15 mL) was added trifluoroacetic acid (3.2 mL) at 0 °C and the reaction was warmed to 23 °C and stirred for 2 h. The reaction mixture was evaporated to dryness and the crude residue was triturated diethyl ether and pentane to afford (5-methyl-2-(trifluoromethyl)-6,7-dihydro-57 / -benzo[c]imidazo[l,2-a]azepin-9-yl)methanamine and (5-methyl-3-(trifluoromethyl)-6,7-dihydro-57 / -benzo[c]imidazo[l,2-a]azepin-9-yl)methanamine (0.5 g) as a mixture. LCMS (ESI) m / z 296.1 [M+H]+.

[2174] Synthesis of Exemplified Compounds:

[2175] 1.1 EXAMPLE 1

[2176] Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-A-(4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-17 / -imidazo[4,5-b]pyridin-7-amine.

[2177] Compound 1

[2178] Active 126539678.1 163 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2179]

[2180] Step 1: Preparation of 5-chloro-7V-(4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-l#-imidazo[4,5-b]pyridin-7-amine.

[2181] Compound 1.1

[2182]

[2183] To a stirred solution of 5,7-dichloro-U / -imidazo[4,5-b] pyridine (300 mg, 1.59 mmol) in ethanol (15 mL) in a sealed tube, was DIPEA (1.36 mL, 7.97 mmol) at 25°C followed by the addition of 4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl) phenyl) methanamine (452 mg, 1.59 mmol) at the same temperature. The reaction mixture was stirred at 120 °C for 7 days. The reaction mixture was then concentrated under reduced pressure. The residue was purified by prep. HPLC to afford 5-chloro-N-(4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl) benzyl)- U / -imidazo[4,5-b] pyridin-7-amine (35 mg) as a white solid. LCMS observed m / z = 435.2 [M+H]+.

[2184] Step 2: Preparation of 5-chloro-7V-(4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-l-(tetrahydro-2J / -pyran-2-yl)-U / -imidazo[4,5-b]pyridin-7-amine.

[2185] Compound 1.2

[2186]

[2187] To a stirred solution of 5-chloro-A-(4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl) benzyl)- lJ / -imidazo[4,5-b] pyridin-7-amine (0.2 g, 0.46 mmol) in toluene (2 mL) was

[2188] Active 126539678.1 164 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2189] added 3, 4-Dihydro-27 / -pyran (0.077 g, 0.92 mmol) and p-toluenesulfonic acid monohydrate (9 mg, 0.046 mmol) at 25 °C. The reaction mixture was stirred at 100 °C for 16h. On completion, the reaction mixture was diluted with water (20 mL) and product was extracted with EtOAc (2 X 20 mL). Combined organic layer was washed with water (20 mL) and brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (40-50% EtOAc / petroleum ether eluent) to afford 5-chloro-A-(4-(l-isopropyl-4-(trifluoromethyl)-177-imidazol-2-yl) benzyl)-l-(fetrahydro-2Z7-pyran-2-yl)-177-imidazo[4,5-b] pyridin-7-amine (0.125 g) as a white solid. LCMS observed m / z = 519.3 [M+H]+.

[2190] Step 3: Preparation of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-A-(4-(l-isopropyl-4-(trifluoromethyl)-lZ7-imidazol-2-yl)benzyl)-l-(tetrahydro-2Z7-pyran-2-yl)-lZ7-imidazo[4,5-b]pyridin-7-amine.

[2191] Compound 1.3

[2192]

[2193] To a stirred solution of 5-chloro-7V-(4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-l -(tetrahydro-27 / -pyran-2-yl)-l7 / -imidazo[4,5-b]pyridin-7-aminc (115 mg, 0.22 mmol) in 1,4-dioxane (8 mL) and water (2mL) in a sealed tube, was added (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (85 mg, 0.44 mmol) at 25 °C followed by the addition of potassium carbonate (152 mg, 1.108 mmol) at the same temperature. The reaction mixture was purged with nitrogen gas for 30 min and X-phosPd-G2 (34 mg, 0.044 mmol) was added to the reaction and stirred at 80°C for 16 h. On completion (monitored by TLC, Rf: 0.30, mobile phase: 30% EtOAc in hexane), the reaction mixture was diluted with water (2.0 mL) and product was extracted with EtOAc (2 x 20 mL). Combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via flash chromatography (15% EtOAc / petroleum ether eluent) to obtain 5-(4-cy cl opropyl-6-methoxypyrimidin-5-yl)-7V-(4-(l-isopropyl-4-(tri fluoromethyl)- 1H-imidazol-2-yl) benzyl)-l-(tetrahydro-2J / -pyran-2-yl)-lJ / -imidazo[4,5-b] pyridin-7-amine (0.065 g) as a white semi-solid. LCMS observed m / z = 634.1 [M+H]+.

[2194] Step 4: Preparation of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-A-(4-(l-isopropyl-4-(trifluoromethyl)-lZ7-imidazol-2-yl)benzyl)-l / 7-imidazo[4,5-b]pyridin-7-amine.

[2195] Active 126539678.1 165 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2196] Compound 1

[2197]

[2198] To a stirred solution of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7V-(4-(l-isopropyl-4-(trifluoromethyl)- U / -imidazol-2-yl) benzyl)- 1 -(tetrahydro-27 / -pyran-2-yl)- 1H-imidazo[4,5-b] pyridin-7-amine (100 mg, 0.16 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.5 mL) at 0°C. The reaction mixture was stirred for 5 hat 0°C. On completion, the reaction mixture was concentrated under reduced pressure to afford material which was purified by prep HPLC by following the below mentioned condition to afford 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7V-(4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl) benzyl)- U / -imidazo[4,5-b] pyridin-7-amine (14.95 mg) as a white solid.1H NMR (400 MHz, DMSO-d6) 8 12.69 (s, 1H), 8.57 (s, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 7.59-7.49 (m, 5H), 6.34 (s, 1H), 4.73 (br s, 2H), 4.47-4.41 (m, 1H), 3.74 (s, 3H), 1.75-1.71 (m, 1H), 1.39 (d, J = 6.4 Hz, 6H), 0.96-0.91 (m, 2H), 0.74-0.71 (m, 2H). LCMS observed m / z = 549.4 [M+H]+.

[2199] 2.1 EXAMPLE 2

[2200] Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(l-isopropyl-3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl)benzyl)-lH-imidazo[4,5-b]pyridin-7-amine.

[2201] Compound 2

[2202]

[2203] The title compound was prepared using a similar procedure as EXAMPLE 1, replacing 4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl) phenyl)methanamine (Intermediate B) with (4-(l-isopropyl-3-(trifluoromethyl)-U / -l,2,4-triazol-5-yl) phenyl)methanamine (Intermediate K).1H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.57 (s, 1H), 8.12 (s, 1H), 7.65-7.53 (m, 5H), 6.33 (s, 1H), 4.75-4.69 (m, 3H), 3.74 (s, 3H), 1.75-

[2204] Active 126539678.1 166 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2205] 1.73 (m, 1H), 1.43 (d, J= 6.4 Hz, 6H), 0.93-0.93 (m, 2H), 0.73-0.71 (m, 2H). LCMS observed m / z = 550.2 [M+H]+.

[2206] 3.1 EXAMPLE 3

[2207] Preparation of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7V-(4-(5-methyl-3-(trifluoromethyl)-U / -pyrazol-l-yl)benzyl)-U / -imidazo[4,5-b]pyridin-7-amine.

[2208] Compound 3

[2209]

[2210] The title compound was prepared using a similar procedure as Compound 1, replacing 4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl) phenyl)methanamine (Intermediate B) with (4-(5-methyl-3 -(trifluoromethyl)- 17 / -pyrazol - 1 -yl)phenyl)m ethanamine (Intermediate H)1H NMR (400 MHz, DMSO-d6) δ 12.69 (br s, 1H), 8.57 (s, 1H), 8.11 (s, 1H), 7.56-7.50 (m, 5H), 6.74 (s, 1H), 6.34 (s, 1H), 4.62 (br s, 2H), 3.75 (s, 3H), 2.31 (s, 3H), 1.75-1.72 (m, 1H), 0.92-0.94 (m, 2H), 0.76-0.74 (m, 2H). LCMS observed m / z = 521.3 [M+H]+.

[2211] 4.1 EXAMPLE 4

[2212] Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7V-(4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)benzyl)pyrido[2,3-b]pyrazin-8-amine.

[2213] Compound 4

[2214]

[2215] Step 1: Preparation of 8-chloro-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-b]pyrazine.

[2216] Compound 4.1

[2217]

[2218] Active 126539678.1 167 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2219] To a suspension of 6,8-dichloro-l,4,5-triazanaphthalene (21.9 g, 109 mmol) and (4-cyclopropyl-6-methoxy-5-pyrimidinyl)boranediol (22.3 g, 1.1 eq., 115 mmol) in 1,4-dioxane (274 mL, 3.21 mol) was added water (54.7 mL, 3.04 mol) followed by dicaesium carbonate (89.2 g, 2.5 eq., 274 mmol). Pd(dppf)Cl2(8.01 g, 0.1 eq., 10.9 mmol) was added and the reaction was stirred under nitrogen at 70 °C for 5h. Reaction was quenched with lOOmL EtOAc and lOOmL H2O, the aqueous layer was removed, and the organic layer was washed with 500 mL 10% N-Ac-L-Cys (neutralized to 7-8 pH with NaHCO3). The mixture was washed in 4 batches with a total of 3L brine solution, and the organics were collected, concentrated in vacuo, and purified via flash chromatography (0-100% EtOAc / DCM eluent) to give 8-chloro-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-b]pyrazine (16.0 g) as a pale yellow solid. LCMS observed m / z = 314.0 [M+H]+.

[2220] Step 2: Preparation of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-A-(4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)benzyl)pyrido[2,3-b]pyrazin-8-amine.

[2221] Compound 4

[2222]

[2223] To a 250ml round bottom flash, 8-chloro-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrido[2,3-b]pyrazine (3.87 g, 12.3 mmol) and (4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (5.24 g, 1.5 eq., 18.5 mmol) was dissolved in ethanol (30.8 mL, 528 mmol), followed by the addition of N-ethyldiisopropylamine (6.45 mL, 3 eq., 37 mmol) and was then allowed to stir for 16 h at reflux. The mixture was concentrated in vacuo, taken up in 200mL DCM, washed with 200mL saturated sodium chloride solution, and the organic layer was dried on sodium sulfate and concentrated in vacuo. The residue was purified via flash chromatography (0-6% MeOH / DCM eluent) to afford 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-A-(4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)benzyl)pyrido[2,3-b]pyrazin-8-amine as a beige solid. 'H NMR. (400 MHz, CD3OD) 88.99 (s, 1H), 8.83 (s, 1H), 8.56 (s, 1H), 7.90 (s, 1H), 7.59 (d, 2H), 7.54 (d, J = 1.7 Hz, 2H), 6.76 (s, 1H), 4.79 (s, 2H), 4.54 (hept, J = 6.8 Hz, 1H), 3.84 (s, 3H), 1.75 (tt, J = 7.7, 4.1 Hz, 1H), 1.44 (d, J = 1.7 Hz, 6H), 1.14 - 1.02 (m, 2H), 0.89 - 0.72 (m, 2H). NH not detected in CD3OD. LCMS observed m / z = 561.4 [M+H]+.

[2224] Active 126539678.1 168 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2225] 5.1 EXAMPLE 5

[2226] Preparation of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7V-(4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-17 / -pyrazol-l-yl)benzyl)pyrido[2,3-b]pyrazin-8-amine.

[2227] Compound 5

[2228] r ii

[2229]

[2230] The title compound was prepared using a similar procedure as Compound 4, replacing (4-(l-isopropyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)phenyl)methanamine with (4-(5-(oxetan-3-yl)-3 -(trifluoromethyl)- 17 / -pyrazol-l-yl)phenyl)m ethanamine (Intermediate I).1H NMR (400 MHz, CD3OD) 89.00 (s, 1H), 8.85 (s, 1H), 8.56 (s, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 6.98 (s, 1H), 6.71 (s, 1H), 4.84 (dd, J = 8.6, 6.0 Hz, 4H), 4.80 (s, 2H), 4.71 (t, J = 6.5 Hz, 2H), 4.37 (p, J = 7.7 Hz, 1H), 3.84 (s, 3H), 1.74 (tt, J = 8.4, 4.8 Hz, 1H), 1.12 - 1.05 (m, 2H), 0.87 - 0.78 (m, 2H). LCMS observed m / z = 575.2 [M+H]+.

[2231] 6.1 EXAMPLE 6

[2232] Preparation of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7V-(4-(5-isopropyl-3-(trifluoromethyl)-17 / -pyrazol-l-yl)benzyl)pyrido[2,3-b]pyrazin-8-amine.

[2233] Compound 6

[2234] r H

[2235] V-CF3

[2236]

[2237] The title compound was prepared using a similar procedure as Compound 4, replacing (4-(l-isopropyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)phenyl)methanamine with (4-(5-isopropyl-3-(trifluoromethyl)-IT / -pyrazol-l-yl)phenyl)methanamine (Intermediate J). 'H NMR (400 MHz, CD3OD) 89.01 (s, 1H), 8.85 (s, 1H), 8.56 (s, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 6.74 (s, 1H), 6.62 (s, 1H), 4.81 (s, 2H), 3.85 (s, 3H), 3.02 (hept, J = 6.8 Hz, 1H), 1.75 (tt, J = 8.6, 4.8 Hz, 1H), 1.18 (d, J = 6.8 Hz, 6H), 1.12 - 1.06 (m, 2H), 0.86 - 0.80 (m, 2H). LCMS observed m / z = 561.2 [M+H]+.

[2238] 7.1 EXAMPLE 7

[2239] Active 126539678.1 169 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2240] Preparation of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7V-(4-(3-(difluoromethyl)-5-methyl-U / -pyrazol-l-yl)benzyl)pyrido[2,3-b]pyrazin-8-amine.

[2241] Compound 7

[2242]

[2243] The title compound was prepared using a similar procedure as Compound 4, replacing (4-(l-isopropyl-4-(trifluoromethyl)- U / -imidazol-2-yl)phenyl)methanamine with (4-(3-(difluoromethyl)-5-methyl-U / -pyrazol-l-yl)phenyl)methanamine (Intermediate N).1H NMR (400 MHz, CD3OD) δ 9.00 (s, 1H), 8.85 (s, 1H), 8.56 (s, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 6.86 - 6.56 (m, 2H), 6.47 (s, 1H), 4.79 (s, 2H), 3.84 (s, 3H), 2.33 (s, 3H), 1.74 (tt, J = 8.5, 4.3 Hz, 1H), 1.12 - 1.04 (m, 2H), 0.86 - 0.76 (m, 2H). LCMS observed m / z = 515.2 [M+H]+.

[2244] 8.1 EXAMPLE 8

[2245] Preparation of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7V-(3-fluoro-4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)benzyl)pyrido[2,3-b]pyrazin-8-amine.

[2246] Compound 8

[2247]

[2248] The title compound was prepared using a similar procedure as Compound 4, replacing (4-(l-isopropyl-4-(trifluoromethyl)- U / -imidazol-2-yl)phenyl)methanamine with (3-fluoro-4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)phenyl)methanamine (Intermediate M).1H NMR (400 MHz, CD3OD) 89.03 (s, 1H), 8.87 (s, 1H), 8.59 (s, 1H), 7.98 (s, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 10.7 Hz, 1H), 6.80 (s, 1H), 4.82 (s, 2H), 4.27 (hept, J = 6.6 Hz, 1H), 3.88 (s, 3H), 1.80 (tt, J = 8.5, 4.7 Hz, 1H), 1.43 (d, J = 6.6 Hz, 6H), 1.15 - 1.09 (m, 2H), 0.88 - 0.81 (m, 2H). LCMS observed m / z = 579.1 [M+H]+.

[2249] 9.1 EXAMPLE 9

[2250] Active 126539678.1 170 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2251] Preparation of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7V-(4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)-3-methylbenzyl)pyrido[2,3-b]pyrazin-8-amine.

[2252] Compound 9

[2253]

[2254] The title compound was prepared using a similar procedure as Compound 4, replacing (4-(l-isopropyl-4-(trifluoromethyl)- U / -imidazol-2-yl)phenyl)methanamine with (4-(l -isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)-3-methylphenyl)methanamine (Intermediate E).1H NMR (400 MHz, CD3OD) δ 9.02 (s, 1H), 8.85 (s, 1H), 8.59 (s, 1H), 7.92 (s, 1H), 7.46 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 6.81 (s, 1H), 4.76 (s, 2H), 4.12 (hept, J = 6.3 Hz, 1H), 3.90 (s, 3H), 2.16 (s, 3H), 1.81 (tt, J = 8.5, 4.7 Hz, 1H), 1.40 (d, J = 6.7 Hz, 6H), 1.17 - 1.10 (m, 2H), 0.90 - 0.82 (m, 2H). LCMS observed m / z = 562.2 [M+H]+.

[2255] 10.1 EXAMPLE 10

[2256] Preparation of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7V-((6-(l-isopropyl-4-(trifluoromethyl)-l -imidazol-2-yl)pyridin-3-yl)methyl)pyrido[2,3-b]pyrazin-8-amine.

[2257] Compound 10

[2258]

[2259] The title compound was prepared using a similar procedure as Compound 4, replacing (4-(l-isopropyl-4-(trifluoromethyl)- U / -imidazol-2-yl)phenyl)methanamine with (6-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)pyridin-3-yl)methanamine (Intermediate G). 'HNMR (400 MHz, CD3OD) 89.02 (s, 1H), 8.87 (s, 1H), 8.75 (s, 1H), 8.58 (s, 1H), 7.99 (s, 2H), 7.96 (s, 1H), 6.84 (s, 1H), 5.70 (hept, J = 6.7 Hz, 1H), 4.83 (s, 2H), 3.85 (s, 3H), 1.76 (tt, J = 8.5, 4.7 Hz, 1H), 1.50 (d, J = 6.7 Hz, 6H), 1.13 - 1.06 (m, 2H), 0.85 - 0.78 (m, 2H). LCMS observed m / z = 562.2 [M+H]+.

[2260] 11.1 EXAMPLE 11

[2261] Active 126539678.1 171 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2262] Preparation of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7V-(4-(l-(oxetan-3-yl)-4-(trifluoromethyl)-U / -imidazol-2-yl)benzyl)pyrido[2,3-b]pyrazin-8-amine.

[2263] Compound 11

[2264]

[2265] The title compound was prepared using a similar procedure as Compound 4, replacing (4-(l-isopropyl-4-(trifluoromethyl)- U / -imidazol-2-yl)phenyl)methanamine with (4-(l -(oxetan-3-yl)-4-(trifluoromethyl)- IJT-imidazol -2 -yl)phenyl)m ethanamine (Intermediate D) and using DMSO as solvent.1H NMR (400 MHz, CD3OD) δ 9.02 (s, 1H), 8.86 (s, 1H), 8.58 (s, 1H), 8.29 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 6.75 (s, 1H), 5.55 (p, J = 7.0 Hz, 1H), 4.97 (t, J = 7.3 Hz, 2H), 4.85 (t, J = 6.7 Hz, 2H), 4.80 (s, 2H), 3.86 (s, 3H), 1.77 (tt, J = 8.4, 4.6 Hz, 1H), 1.15 - 1.06 (m, 2H), 0.88 - 0.79 (m, 2H). LCMS observed m / z = 575.2 [M+H]+.

[2266] 12.1 EXAMPLE 12

[2267] Preparation of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(2-fluoro-4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzyl)pyrido[2,3-b]pyrazin-8-amine.

[2268] Compound 12

[2269]

[2270] The title compound was prepared using a similar procedure as Compound 4, replacing (4-(l-isopropyl-4-(trifluoromethyl)- U / -imidazol-2-yl)phenyl)methanamine with (2-fluoro-4-(5-methyl-3-(trifluoromethyl)-U / -pyrazol-l-yl)phenyl)methanamine (Intermediate L). ¹H NMR (400 MHz, CD₃OD) δ 9.02 (d, J = 1.7 Hz, 1H), 8.86 (d, J = 1.8 Hz, 1H), 8.59 (s, 1H), 7.62 (t, J = 8.1 Hz, 1H), 7.43 (dd, J = 10.5, 2.0 Hz, 1H), 7.35 (dd, J = 8.3, 2.1 Hz, 1H), 6.81 (s, 1H), 6.60 (s, 1H), 4.85 (s, 2H), 3.87 (s, 3H), 2.39 (s, 3H), 1.79 (tt, J = 8.5, 4.7 Hz, 1H), 1.16 - 1.08 (m, 2H), 0.90 - 0.80 (m, 2H). LCMS observed m / z = 550.2 [M+H]+.

[2271] 13.1 EXAMPLE 13

[2272] Active 126539678.1 172 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2273] Preparation of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7V-(4-(5-methyl-3-(trifluoromethyl)-U / -pyrazol-l-yl)benzyl)pyrido[2,3-b]pyrazin-8-amine.

[2274] Compound 13

[2275]

[2276] The title compound was prepared using a similar procedure as Compound 4, replacing (4-(l-isopropyl-4-(trifluoromethyl)- U / -imidazol-2-yl)phenyl)methanamine with (4-(5-methyl-3 -(trifluoromethyl)- IT / -pyrazol-l-yl)phenyl)methanamine (Intermediate H).1H NMR (400 MHz, CD3OD) 89.00 (d, J = 1.8 Hz, 1H), 8.85 (d, J = 1.8 Hz, 1H), 8.56 (s, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 6.73 (s, 1H), 6.57 (s, 1H), 4.80 (s, 2H), 3.84 (s, 3H), 2.33 (s, 3H), 1.74 (tt, J = 8.6, 4.7 Hz, 1H), 1.11 - 1.04 (m, 2H), 0.85 - 0.78 (m, 2H). LCMS observed m / z = 532.2 [M+H]+.

[2277] 14.1 EXAMPLE 14

[2278] Preparation of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7V-(4-(l-methyl-4-(trifluoromethyl)-U / -imidazol-2-yl)benzyl)pyrido[2,3-Z>]pyrazin-8-amine.

[2279] Compound 14

[2280]

[2281] The title compound was prepared using a similar procedure as Compound 4, replacing (4-(l-isopropyl-4-(trifluoromethyl)- U / -imidazol-2-yl)phenyl)methanamine with (4-(l-methyl-4-(trifluoromethyl)-U / -imidazol-2-yl)phenyl)methanamine (Intermediate A). 'H NMR (400 MHz, CD3OD) 89.00 (d, J = 1.8 Hz, 1H), 8.84 (d, J = 1.8 Hz, 1H), 8.56 (s, 1H), 7.68 (s, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 6.74 (s, 1H), 4.78 (s, 2H), 3.84 (s, 3H), 3.77 (s, 3H), 1.74 (tt, J = 8.3, 4.6 Hz, 1H), 1.12 - 1.03 (m, 2H), 0.84 - 0.75 (m, 2H). LCMS observed m / z = 533.1 [M+H]+.

[2282] 15.1 EXAMPLE 15

[2283] Preparation of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7V-(4-(l-ethyl-4-(trifluoromethyl)-U / -imidazol-2-yl)benzyl)pyrido[2,3-b]pyrazin-8-amine.

[2284] Active 126539678.1 173 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2285] Compound 15

[2286]

[2287] The title compound was prepared using a similar procedure as Compound 4, replacing (4-(l-isopropyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)phenyl)methanamine with (4-(l-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (Intermediate C).1H NMR (400 MHz, CD3OD) 89.02 (d, J = 1.7 Hz, 1H), 8.86 (d, J = 1.8 Hz, 1H), 8.58 (s, 1H), 7.79 (s, 1H), 7.60 (s, 4H), 6.76 (s, 1H), 4.80 (s, 2H), 4.12 (q, J = 7.3 Hz, 2H), 3.86 (s, 3H), 1.76 (tt, J = 8.7, 4.4 Hz, 1H), 1.38 (t, J = 7.4 Hz, 3H), 1.13 - 1.07 (m, 2H), 0.86 - 0.79 (m, 2H). LCMS observed m / z = 546.2 [M+H]+.

[2288] 16.1 EXAMPLE 16

[2289] Preparation of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7V-((2-(trifluoromethyl)-6,7-dihydro-57 / -benzo[c]imidazo[l,2-a]azepin-9-yl)methyl)pyrido[2,3-b]pyrazin-8-amine.

[2290] Compound 16

[2291]

[2292] The title compound was prepared using a similar procedure as Compound 4, replacing (4-(l-isopropyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)phenyl)methanamine with (2- (trifluoromethyl)-6,7-dihydro-57 / -benzo[c]imidazo[l,2-a]azepin-9-yl)methanamine (Intermediate O). 'H NMR (400 MHz, CD3OD) 8 9.00 (s, 1H), 8.84 (s, 1H), 8.56 (s, 1H), 7.74 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.43 (s, 1H), 6.74 (s, 1H), 4.75 (s, 2H), 3.99 (t, J = 6.8 Hz, 2H), 3.84 (s, 3H), 2.71 (t, J = 7.1 Hz, 2H), 2.34 (p, J = 6.9 Hz, 2H), 1.73 (tt, J = 8.2, 4.7 Hz, 1H), 1.12 - 1.02 (m, 2H), 0.87 - 0.69 (m, 2H).

[2293] LCMS observed m / z = 559.1 [M+H]+.

[2294] 17.1 EXAMPLE 17

[2295] Preparation of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7V- (((ls,2R,3s,4r,5S,6r,7R,8S)-4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-l-yl)methyl)-7V-methylpyrido[2,3-b]pyrazin-8-amine.

[2296] Compound 17

[2297] Active 126539678.1 174 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2298]

[2299] The title compound was prepared using a similar procedure as Compound 4, replacing (4-(l-isopropyl-4-(trifluoromethyl)- U / -imidazol-2-yl)phenyl)methanamine with 1-((ls,2R,3s,4r,5S,6r,7R,8S)-4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)cuban-l-yl)-7V-methylmethanamine (Intermediate F).1H NMR (400 MHz, CD3OD) 88.90 (d, J = 1.7 Hz, 1H), 8.77 (d, J = 1.7 Hz, 1H), 8.61 (s, 1H), 7.73 (s, 1H), 6.96 (s, 1H), 4.55 (s, 2H), 4.32 (t, J = 5.0 Hz, 3H), 4.24 - 4.10 (m, J = 5.9, 5.1 Hz, 1H), 4.03 (t, J = 5.0 Hz, 3H), 3.93 (s, 3H), 3.44 (s, 3H), 1.85 (tt, J = 8.7, 4.8 Hz, 1H), 1.46 (d, J = 6.6 Hz, 6H), 1.17 (p, J = 4.0 Hz, 2H), 0.93 (dq, J = 7.3, 3.9 Hz, 2H). LCMS observed m / z = 601.3 [M+H]+.

[2300] 18.1 EXAMPLE 18

[2301] Preparation of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7V-((4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-l-yl)methyl)pyrido[2,3-b ] py razin- 8 -amine.

[2302] Compound 18

[2303]

[2304] The title compound was prepared using a similar procedure as Compound 4, replacing (4-(l-isopropyl-4-(trifluoromethyl)- U / -imidazol-2-yl)phenyl)methanamine with (4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-l-yl)methanamine (Intermediate P). 'HNMR (400 MHz, CD3OD) 88.98 (s, 1H), 8.80 (s, 1H), 8.60 (s, 1H), 7.70 (s, 1H), 6.93 (s, 1H), 4.97 - 4.89 (m, 1H), 4.25 (s, 2H), 3.94 (s, 3H), 3.44 (s, 2H), 2.36 - 2.23 (m, 2H), 2.19 - 2.03 (m, 4H), 1.93 - 1.78 (m, 3H), 1.45 (d, J = 6.5 Hz, 6H), 1.21 - 1.12 (m, 2H), 0.99 - 0.86 (m, 2H). LCMS observed m / z = 595.4 [M+H]+.

[2305] 19.1 EXAMPLE 19

[2306] Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7V-(4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)benzyl)imidazo[l,2-b]pyridazin-8-amine.

[2307] Active 126539678.1 175 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2308]

[2309] Step 1: Preparation of 6-chloro-N-(4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)imidazo[l,2-b]pyridazin-8-amine.

[2310] Compound 19.1

[2311]

[2312] To a stirred solution of (4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (54 mg, 0.168 mmol, Intermediate B) in DMF (0.3 mL) were added DIPEA (52 mg, 0.40 mmol) followed by 6,8-dichloroimidazo[l,2-b]pyridazine (30 mg, 0.160 mmol) at room temperature and the reaction mixture was stirred at 80 °C for 16 hours in a sealed tube. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (0-100% EtOAc / hexanes eluent) to afford 6-chloro-N-(4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)benzyl)imidazo[l,2-b]pyridazin-8-amine (46 mg). LCMS observed m / z = 435.3 [M+H]+.

[2313] Step 2: Preparation of tert-butyl (6-chloroimidazo[l,2-b]pyridazin-8-yl)(4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)benzyl)carbamate.

[2314] Compound 19.2

[2315]

[2316] To a stirred solution of 6-chloro-A-(4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)imidazo[l,2-b]pyridazin-8-amine ( 46 mg, O.lOmmol) in THF (0.26 mL) at room temperature was added tert-butoxycarbonyl -tert-butyl carbonate ( 69 mg, 0.31 mmol). To

[2317] Active 126539678.1 176 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2318] this mixture N, N-dimethyl-4-pyridylamine (13 mg, 0. lOmmol) was added and allowed to stir for 30min. Upon completion, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (0-100% EtOAc / hexanes eluent) to afford tert-butyl (5-chloro-l,3a,4-triaza-7 -indenyl)( { p- [ 1 -i sopropyl-4-(trifluoromethyl)-2-imidazolyl]phenyl } methyl)carbamate (49mg). LCMS observed m / z = 535.5 [M+H]+.

[2319] Step 3: Preparation of tert-butyl (6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)imidazo[l,2-b]pyridazin-8-yl)(4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)carbamate.

[2320] Compound 19.3

[2321]

[2322] To a suspension of tert-butyl (5-chloro-l,3a,4-triaza-7-indenyl)({p-[l-isopropyl-4-(trifluoromethyl)-2-imidazolyl]phenyl}methyl)carbamate (49mg, 0.91 mmol) and (4-cyclopropyl-6-methoxy-5-pyrimidinyl)boranediol (39.1mg, 0.20 mmol) in 1,4-dioxane (0.450 mL) was added water (0.1 mL) followed by dicaesium carbonate (89.5 mg, 0.275 mmol). Iron bi s [ 1 -(diphenylphosphino)-2,4-cyclopentadien- 1 -ide] — dichloro-palladamethane (11.2 mg, 0.013 mmol) was added and the reaction was stirred under nitrogen at 120 °C for 2h. Upon completion, the reaction mixture was purified by flash chromatography (0-100% EtOAc / hexanes eluent) to afford tert-butyl (6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)imidazo[l,2-b]pyridazin-8-yl)(4-(l-isopropyl-4-(tri fluoromethyl)-U / -imidazol-2-yl)benzyl)carbamate (12mg) as a solid. LCMS observed m / z = 649.6 [M+H]+.

[2323] Step 4: Preparation of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-A-(4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)benzyl)imidazo[l,2-b]pyridazin-8-amine.

[2324] Compound 19

[2325]

[2326] Active 126539678.1 177 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2327] To a reaction vial charged with tert-butyl (6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)imidazo[l,2-b]pyridazin-8-yl)(4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)benzyl)carbamate (12 mg, 0.018 mmol) was added 4N Hydrochloric Acid in 1,4-Dioxanes (1.5mL) and was allowed to stir at room temperature for Ih. Upon completion, the residue was purified by preparatory HPLC (mobile 10-70% MeCN in water with 0.1% formic acid) to afford 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-A-(4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)benzyl)imidazo[l,2-b]pyridazin-8-amine (1.4mg) as a solid.1H NMR (400 MHz, CD3OD) δ 8.63 (s, 1H), 8.32 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.69 - 7.59 (m, 4H), 6.83 (s, 1H), 4.78 (s, 2H), 4.56 (p, J = 6.6 Hz, 1H), 3.89 (s, 3H), 1.92 - 1.83 (m, 1H), 1.47 (d, J = 6.6 Hz, 6H), 1.18 - 1.11 (m, 2H), 0.95 - 0.87 (m, 2H). LCMS observed m / z = 549.6 [M+H]+.

[2328] 20.1 EXAMPLE 20

[2329] Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-A-(4-(l-isopropyl-4-(trifluoromethyl)-l -imidazol-2-yl)benzyl)-[l, 2, 4]tri azolof l,5-a]pyrimidin-7-amine.

[2330] Compound 20

[2331]

[2332] Step 1: Preparation of 5-chloro-A-(4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)benzyl)-[ 1, 2, 4]tri azolof 1, 5-a]pyrimidin-7-amine.

[2333] Compound 20.1

[2334]

[2335] To a stirred solution of 5,7-dichloro-[l,2,4]triazolo[l,5-a]pyrimidine (200 mg, 1.05 mmol )in ethanol (6.0 mL) was added (4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)phenyl)methanamine (329 mg, 1.16 mmol, Intermediate B)at 25 °C followed by the addition of potassium carbonate (292 mg, 2.11 mmol). The reaction mixture was stirred at 25 °C for 16 h. On completion, the reaction mixture was diluted with water (4 mL) and product

[2336] Active 126539678.1 178 Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT

[2337] was extracted with EtOAc (2 x 40 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (40-45% EtOAc / petroleum ether eluent) to afford 5-chloro-N-(4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl) benzyl)-[l,2,4]triazolo[l,5-a]pyrimidin-7-amine (180 mg) as an off white solid. LCMS observed m / z = 436.3 [M+H]+.

[2338] Step 2: Preparation of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-A-(4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl)benzyl)-[l,2,4]triazolo[l,5-a]pyrimidin-7-amine.

[2339] Compound 20

[2340]

[2341] To a stirred solution of 5-chloro-N-(4-(l-isopropyl-4-(trifluoromethyl)-lH-imidazol-2-yl) benzyl)-[l,2,4]triazolo[l,5-a]pyrimidin-7-amine (100 mg, 0.23 mmol) in 1,4-dioxane (4.0 mL) and water (0.5 mL) was added (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (89.0 mg, 0.46 mmol) followed by the addition of potassium carbonate (158 mg, 1.14 mmol). The reaction mixture was purged with nitrogen gas for 10 min and then XPhos-Pd-G2 (36.0 mg, 46.0 umol) was added to the reaction mixture. The reaction was carried out in microwave for 7 hat 125°C. On completion, the reaction mixture was diluted with water (2 mL) and extracted with EtOAc (2 X 10 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by Prep-HPLC by following the below mentioned condition to afford 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(l-isopropyl-4-(trifluoromethyl)-U / -imidazol-2-yl) benzyl)-[l,2,4]triazolo[l,5-a]pyrimidin-7-amine (60.0 mg) as white solid.1H NMR (400 MHz, DMSO-de) 9.23 (br s, 1H), 8.65 (s, 1H), 8.56 (s, 1H), 8.17 (s, 1H), 7.58-7.53 (m, 4H), 6.61 (s, 1H), 4.74 (s, 2H), 4.47-4.40 (m, 1H), 3.78 (s, 3H), 1.84-1.80 (m, 1H), 1.38 (d, J = 6.8 Hz, 6H), 0.81-0.81 (m, 2H), 0.80-0.79 (m, 2H). LCMS observed m / z = 550.3 [M+H]+.

[2342] 21.1 EXAMPLE 21

[2343] Preparation of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-A-(4-(5-methyl-3-(trifluoromethyl)-U / -pyrazol-l-yl)benzyl)-[l,2,4]triazolo[l,5-a]pyrimidin-7-amine.

[2344] Active 1265...

Claims

Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCTCLAIMS1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:X and Y are independently selected from C and N;R is selected from C1-C3 alkyl, -CD3, -CHF2, and 3-, 4-, 5-, or 6- membered heterocyclyl;Ri is selected from H, Ci-Ce alkyl, and C3-C6 cycloalkyl;wherein ring C is selected from C3-C8 cycloalkyl ring, Ce-Cio aryl, 4-, 5-, 6-, or 7- membered heterocyclyl ring, and 4-, 5-, 6-, or 7- membered heteroaryl ring, wherein the C3-C8 cycloalkyl ring or 4-, 5-, 6-, or 7- membered heterocyclyl ring is optionally fused to a C3-C8 cycloalkyl ring, and wherein ring C is optionally substituted;wherein R3 is selected from 3-8 membered heterocyclic group, Ci-Ce alkyl, and C3-C6 cycloalkyl, wherein the heterocyclic group comprises at least one atom selected from O and N, and wherein the Ci-Ce alkyl is linear or branched; wherein R3 optionally forms abond with ring C to form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl, wherein the 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl is optionally substituted with one or more groups selected from C₁-C₆ alkyl, -OH, C₁-C₆ alkoxy, and halogen; and wherein R4 is selected from H, -OH, Ci-Ce alkyl, C3-C6 cycloalkyl, and Ci-Ce haloalkyl, wherein the Ci-Ce alkyl is linear or branched, and wherein the Ci- Ce haloalkyl is linear or branched;Active 126539678.1 272Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCTRa and Rb are independently selected from -H, -D, Ci-Ce alkyl, Ci-Ce haloalkyl, and C2-C6 alkynyl, optionally Ra or Rb forms a bond with ring C to form a 5-, 6-, or 7-membered carbocyclic group; andRing A is selected from a C4-C5 cycloalkyl and 5- or 6- membered heterocyclyl, wherein the 5-, or 6- membered heterocyclyl comprises one, two, or three heteroatoms selected from N and O;wherein when ring A is a 6-membered heterocyclyl, the 6-memberedheterocyclyl is selected fromwherein when Y is C and ring A is a 5-membered heterocyclyl comprisingthree heteroatoms selected from N, R2 is selected fromwherein ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)OR’, -C(O)NHR’, -C(O)NR’R”, -NH2, -NHR’, -NR’R”, =0, halogen, C1-6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 nitrile, and C1-6 alkyl-epoxide;wherein R’ and R” are independently selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-8 membered saturated or unsaturated cycloalkyl, 5-6 membered saturated or unsaturated heterocyclyl, phenyl, and 5-6 membered heteroaryl.Active 126539678.1 273Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT2. A compound of formula (II), or a pharmaceutically acceptable salt thereof:(II)wherein:X and Y are independently selected from C and N;R is selected from C1-C3 alkyl, -CD3, -CHF2, and 3-, 4-, 5-, or 6- membered heterocyclyl;Ri is selected from H, Ci-Ce alkyl, and C3-C6 cycloalkyl;wherein ring C is selected from C3-C8 cycloalkyl ring, Ce-Cio aryl, 4-, 5-, 6-, or 7- membered heterocyclyl ring, and 4-, 5-, 6-, or 7- membered heteroaryl ring, wherein the C3-C8 cycloalkyl ring or 4-, 5-, 6-, or 7- membered heterocyclyl ring is optionally fused to a C3-C8 cycloalkyl ring, and wherein ring C is optionally substituted;wherein R3 is selected from 3-8 membered heterocyclic group, Ci-Ce alkyl, and C3-C6 cycloalkyl, wherein the heterocyclic group comprises at least one atom selected from O and N, and wherein the Ci-Ce alkyl is linear or branched; wherein R3 optionally forms abond with ring C to form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl, wherein the 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl is optionally substituted with one or more groups selected from C₁-C₆ alkyl, -OH, C₁-C₆ alkoxy, and halogen; and wherein R4 is selected from H, -OH, Ci-Ce alkyl, C3-C6 cycloalkyl, and Ci-Ce haloalkyl, wherein the Ci-Ce alkyl is linear or branched, and wherein the Ci- Ce haloalkyl is linear or branched;Ra and Rb are independently selected from -H, -D, Ci-Ce alkyl, C1-C6 haloalkyl, and C2-C6 alkynyl, optionally Ra or Rb forms a bond with ring C to form a 5-, 6-, or 7- membered carbocyclic group; andActive 126539678.1 274Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCTRing B is selected from C4-C8 cycloalkyl, Ce-Cio aryl, and 4-, 5-, 6-, or 7- membered heterocyclyl, wherein the 4-, 5-, 6-, or 7- membered heterocyclyl comprises one, two, or three heteroatoms selected from N or O;wherein ring B is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)OR’, -C(O)NHR’, -C(O)NR’R”, -NH2, -NHR’, -NR’R”, =0, halogen, C1-6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 nitrile, and C1-6 alkyl-epoxide; wherein R’ and R” are independently selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-8 membered saturated or unsaturated cycloalkyl, 5-6 membered saturated or unsaturated heterocyclyl, phenyl, and 5-6 membered heteroaryl.

3. The compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, according to claims 1-2, wherein X is N and Y is C.

4. The compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, according to claims 1-2, wherein X is C and Y is N.

5. The compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, according to claims 1-2, wherein X is C and Y is C.

6. The compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, according to claims 1-2, wherein X is N and Y is N.

7. The compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, according to claims 1 and 2, wherein ring C is selected fromR6wherein Rs and Re are selected from -H, -OH, Ci-Ce branched or linear alkyl, Ci-Ce branched or linear haloalkyl, Ci-6 alkoxy, 5-8 membered heteroaryl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, -O-Cl-6 alkyl, -O-C1-6 alkylene, -Cl, and -F; and wherein R3 optionally forms abond with Rs to form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl, wherein the 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl is optionally substituted with one or more groups selected from Ci-Ce alkyl, -OH, Ci-Ce alkoxy, and halogen; orwherein Ra or Rb optionally forms a bond with Re to form a 5-, 6-, or 7-membered carbocyclic group.

8. The compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, according to any claims 1-7, wherein R₅ and R₆ are selected from -H, C₁-C₆ linear alkyl, and -F.Active 126539678.1 275Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT9. The compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, according to claim 7, wherein when R3 forms a bond with R5, R2 is selected10. The compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, according to any of claims 1-9, wherein R4 is selected from -CF3 and -CHF2.

11. The compound of formula (I) or formula (II), or a pharmaceutically acceptable salt / ■" O I thereof, according to any of claims 1-10 wherein R3 is selected from* i,, ^CH312. The compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, according to any of claims 1-11, wherein R2 is selected fromActive 126539678.1 276Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT13. The compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, according to any of claims 1-12, wherein R is C1-C3 alkyl.

14. The compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, according to any of claims 1-13, wherein R is methyl.

15. The compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, according to any of claims 1-14, wherein Ra and Rb are each H.

16. The compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, according to any of claims 1-15, wherein ring A or ring B is selected fromwherein ring A or ring B is optionally substituted with one or more groups selected from -OH, -C00H, -C(O)OR’, -C(0)NHR’, -C(0)NR’R”, -NH2, -NHR’, -NR’R”, =0, halogen, C1-6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, Ci- 6 hydroxyalkyl, C1-6 nitrile, and C1-6 alkyl-epoxide;wherein R’ and R” are independently selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-8 membered saturated or unsaturated cycloalkyl, 5-6 membered saturated or unsaturated heterocyclyl, phenyl, and 5-6 membered heteroaryl.

17. The compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, according to claim 16, wherein ring A or ring B is substituted with one or more groups selected from =0 and C1-6 alkyl.

18. The compound of formula (I), or a pharmaceutically acceptable salt thereof, accordingto any of claims 1, and 3-17, wherein ring A is selected fromActive 126539678.1 277Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT19. The compound of formula (II), or a pharmaceutically acceptable salt thereof,according to any of claims 2-17, wherein ring B is20. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1, 4, 5, and 7-16, and 18, wherein formula (I) is selectedActive 126539678.1 278Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCTActive 126539678.1 279Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT21. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1, 5, 7, 8, 10-16, 18 and 20, wherein formula (I) is:

22. The compound of formula (II), or a pharmaceutically acceptable salt thereof, according to any of claims 2-16, and 18, wherein formula (II) is:

23. A compound of formula (III), or a pharmaceutically acceptable salt thereof:Active 126539678.1 280Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCTwherein:X and Y are independently selected from C and N;R1 is selected from C1-C6 branched and linear alkyl;wherein ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)OR’, -C(O)NHR’, -C(O)NR’R”, -NH2, -NHR’, -NR’R”, =0, halogen, C1-6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 nitrile, and C1-6 alkyl-epoxide;wherein R’ and R” are independently selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-8 membered saturated or unsaturated cycloalkyl, 5-6 membered saturated or unsaturated heterocyclyl, phenyl, and 5-6 membered heteroaryl.

24. The compound of formula (III), or a pharmaceutically acceptable salt thereof, according to claim 23, wherein X is N and Y is C.

25. The compound of formula (III), or a pharmaceutically acceptable salt thereof, according to claim 23, wherein X is C and Y is C.

26. The compound of formula (III), or a pharmaceutically acceptable salt thereof,according to claims 23-25, wherein Ri is selected fromActive 126539678.1 281Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT27. The compound of formula (III), or a pharmaceutically acceptable salt thereof, according to any of claims 23-26, wherein formula (III) is selected from28. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1, 5, 7, 8, 10-16, 18 and 20, wherein formula (I) is:Active 126539678.1 282Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT29. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1, 5, 7, 8, 10-16, and 18, wherein formula (I) is:

30. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:Active 126539678.1 283Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCTActive 126539678.1 284Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCTActive 126539678.1 285Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCTActive 126539678.1 286Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCTActive 126539678.1 287Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCTActive 126539678.1 288Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCTActive 126539678.1 289Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT31. A method of modulating USP1 activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of formula (I), formula (II), or formula (III) according to any one of claims 1-29 or a therapeutically effective amount of the compound of claim 30, or a pharmaceutically acceptable salt thereof,.

32. A method of inhibiting USP1 activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of formula (I), formula (II), or formula (III) according to any one of claims 1-29 or a therapeutically effective amount of the compound of claim 30, or a pharmaceutically acceptable salt thereof,.

33. A method of treating a disorder or disease with a USP1 inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), formula (II), or formula (III) according to any one of claims 1-29 or a therapeutically effective amount of the compound of claim 30, or a pharmaceutically acceptable salt thereof.

34. A method of treating cancer with a USP1 inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound formula (I), formula (II), or formula (III) according to any one of claims 1-29 or a therapeutically effective amount of the compound of claim 30, or a pharmaceutically acceptable salt thereof.

35. A method of treating cancer with a USP1 inhibitor in a subject, comprising administering a compound of formula (I), formula (II), or formula (III) according to any one of claims 1-29 or a therapeutically effective amount of the compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein the cancer is characterized by over expression of USP1.

36. The method according to claim 35, wherein the cancer characterized by overexpression of USP1 is selected from prostate, breast, ovarian, non-small cell lung cancer, mesothelioma, Merkel cell carcinoma, synovial sarcoma, renal cell carcinoma, and osteosarcoma.

37. The use of a compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-31, in the manufacture of a medicament for the treatment of cancer.

38. The use according to claim 37, of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-31, wherein the cancer is characterized by overexpression of USP1.Active 126539678.1 290Attorney Docket No. 092295.0194 Client Ref. No. EIK-0025-PCT39. A process to manufacture a compound according to any one of claims 1-31, or a pharmaceutically acceptable salt thereof.Active 126539678.1 291

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