EA045362B1 - CARDIAC SARCOMER INHIBITORS - Google Patents

Description

This patent application claims benefit from U.S. Provisional Application No. 62/726162, filed August 31, 2018, entitled CARDIAC SARCOMERE INHIBITORS, the contents of which are incorporated herein by reference in their entirety in all respects.

Field of technology

Provided herein are heterocyclic compounds, pharmaceutical compositions containing such compounds, and methods of treating various cardiac diseases and conditions with such compounds.

State of the art

The disclosure relates to certain chemicals that selectively modulate cardiac sarcomeres, and in particular to certain chemicals, pharmaceutical compositions and methods for treating various cardiac diseases and conditions. The cardiac sarcomere consists of a network of contractile and structural proteins that regulate the function of the heart muscle. Cardiac sarcomere components represent targets for the treatment of various cardiac diseases and pathological conditions, for example by increasing contractility or promoting complete relaxation to modulate systolic and diastolic function, respectively. The strength and speed of cardiac muscle contraction is a major determinant of organ function and is modulated by cyclic interactions between actin and myosin. The regulation of actin and myosin binding is determined by the network of myofilament regulatory proteins and the level of intracellular Ca ²⁺ . Troponin complex and tropomyosin are thin filamentous proteins that determine the accessibility of actin binding sites and essential and regulatory light chains, and myosin binding protein C modulates the position and mechanical properties of myosin, cardiac sarcomere abnormalities have been identified as a major cause of various diseases and pathological heart conditions such as hypertrophic cardiomyopathy (HCM) and heart failure with preserved ejection fraction (HFpEF), mutations in sarcomere proteins cause the disease by making the heart muscle either hyper or hypo contractile.

Cardiac sarcomere modulators can be used to restore contractility balance and stop or reverse the disease. Current agents that target the cardiac sarcomere, such as inotropes (drugs that increase cardiac contractility), are poorly selective for cardiac tissue, resulting in recognized side effects that limit their use. These adverse effects include cellular damage caused by increased energy expenditure, exacerbation of impaired relaxation, and potential arrhythmogenic side effects that may result from increased cytosolic Ca ²⁺ and cyclic AMP concentrations in inotropically stimulated myocardium. Given the limitations of current agents, new approaches are needed to improve cardiac function in SUI and HFpEF. There continues to be a pressing need for agents that utilize novel mechanisms of action and may have better outcomes in terms of symptom relief, safety, and patient mortality, both short-term and long-term. New agents with improved therapeutic index compared to current agents will provide the means to achieve these clinical outcomes. Selectivity of agents targeting cardiac sarcomeres (eg, by targeting cardiac myosin) has been identified as an important means to achieve this improved therapeutic index. The present disclosure provides such agents (in particular, cardiac sarcomere inhibitors) and methods of using them. These agents are allosteric inhibitors of cardiac myosin. The advantages of these compounds include a broader therapeutic index, less impact on cardiac relaxation, better pharmacokinetics, and better safety.

The present disclosure provides chemicals, pharmaceutical compositions and methods for the treatment of heart failure, including SUI and HFpEF. The compositions are cardiac sarcomere inhibitors, for example, cardiac myosin inhibitors.

The essence of the invention

In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided:

where R ¹ is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted pyridyl;

R ^2a , R ^2b and R ³ are defined by any of (i)-(iii):

(i) R ^2a represents H or substituted or unsubstituted alkyl;

R ^2B is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cyclo

- 1 045362 alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; And

R ³ represents substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; or (ii) R ^2A represents H or substituted or unsubstituted alkyl;

R ^2B represents substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; And

R ³ represents substituted or unsubstituted alkyl; or (iii) R ^2A and R ^2B are taken together with the carbon atom to which they are attached to form G ¹ , where G ¹ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, or substituted or unsubstituted heterocyclyl a ring, each of which is optionally fused to a phenyl ring; And

R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted ar sludge and replaced or unsubstituted heteroaryl;

R ⁴ represents H or substituted or unsubstituted alkyl; And

R ⁵ represents H or substituted or unsubstituted alkyl; wherein, when one or more provisions (a)-(c) are used, R ¹ represents substituted or unsubstituted pyridyl or phenyl substituted with at least one substituent other than methyl or methoxy:

(a) R ^2A and R ^2B are as defined in (i), and R ³ is substituted or unsubstituted phenyl;

(b) R ^2A and R ³ are as defined in (ii), and R ^2B is 4-methoxyphenyl;

(c) R ^2A and R ^2B are as defined in (iii), and R ³ is 4methoxyphenylmethyl.

In another aspect, a compound of formula (Ia) or a pharmaceutically acceptable salt thereof is provided: O R ⁵ λΛR ³ YR ^2B O (la) where R ¹ is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted pyridyl;

R ^2A represents H or substituted or unsubstituted alkyl;

R ^2B is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted puppy Aril and substituted or unsubstituted heteroaryl;

R ³ represents substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl;

R ⁴ represents H or substituted or unsubstituted alkyl; And

R ⁵ represents H or substituted or unsubstituted alkyl;

wherein R ³ is substituted or unsubstituted phenyl, R ¹ is substituted or unsubstituted pyridyl or phenyl substituted with at least one substituent other than methyl or methoxy.

In another aspect, a compound of formula (Ib) or a pharmaceutically acceptable salt thereof is provided: O R ⁵

YA /1%YR ^2A

R ³ YR ^2B

O (lb) where R ¹ is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted pyridyl;

R ^2A represents H or substituted or unsubstituted alkyl;

R ^2B represents substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl;

R ³ represents substituted or unsubstituted alkyl;

R ⁴ represents H or substituted or unsubstituted alkyl; And

R ⁵ represents H or substituted or unsubstituted alkyl;

- 2 045362 wherein R ^2B is 4-methoxyphenyl, R ¹ is substituted or unsubstituted pyridyl or phenyl substituted with at least one substituent other than methyl or methoxy.

In another aspect, a compound of formula (Ic) or a pharmaceutically acceptable salt thereof is provided:

⁰ (ic) where R ¹ is selected from the group consisting of substituted or unsubstituted pyridyl and substituted or unsubstituted pyridyl;

R ^2a and R ^2b are taken together with the carbon atom to which they are attached to form G ¹ , where G ¹ represents a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl or substituted or unsubstituted heterocyclyl ring, each of which optionally fused to a phenyl ring;

R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted ar sludge and replaced or unsubstituted heteroaryl;

R ⁴ represents H or substituted or unsubstituted alkyl; And

R ⁵ represents H or substituted or unsubstituted alkyl;

wherein R ³ is 4-methoxyphenylmethyl, R ¹ is substituted or unsubstituted pyridyl or phenyl substituted with at least one substituent other than methyl or methoxy.

In another aspect, a compound of formula (Id) or a pharmaceutically acceptable salt thereof is provided:

where R ^2a represents H or substituted or unsubstituted alkyl;

R ^2B is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted puppy Aril and substituted or unsubstituted heteroaryl;

n is 0, 1 or 2;

R ^3a is selected from the group consisting of halogen and cyano; And

R ⁴ represents H.

In another aspect, a compound of formula (Ie) or a pharmaceutically acceptable salt thereof is provided:

1e) where R ¹ is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted pyridyl;

R ^2A represents H or substituted or unsubstituted alkyl;

R ^2B represents substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; And

R ⁴ represents H;

wherein R ^2B is 4-methoxyphenyl, R ¹ is substituted or unsubstituted pyridyl or phenyl substituted with at least one substituent other than methyl or methoxy. In another aspect, a compound of formula (If) or a pharmaceutically acceptable salt thereof is provided:

- 3 045362

wherein G ¹ is selected from the group consisting of a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl and a substituted or unsubstituted heterocyclyl ring, each of which is optionally fused to a phenyl ring;

R ^1a is selected from the group consisting of cyano, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl and substituted or unsubstituted diazirinyl;

R ^2a is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino and substituted unsubstituted or unsubstituted alkyl;

n is 0, 1, 2 or 3;

R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted aryl; And

R ⁴ represents H;

moreover, when R ³ represents 4-methoxyphenylmethyl, R ^1a does not represent methyl or methoxy.

In another aspect, a compound of formula (Ig) or a pharmaceutically acceptable salt thereof is provided:

where R ^1a is selected from the group consisting of cyano, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl and substituted or unsubstituted diazirinyl;

R ^2a is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino and substituted unsubstituted or unsubstituted alkyl;

n is 0, 1, 2 or 3;

R ^3a is selected from the group consisting of halogen and cyano; And

R ⁴ represents H.

In another aspect, there is provided a compound of formula (In) or a pharmaceutically acceptable salt thereof:

where R ^1a is selected from the group consisting of cyano, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl and substituted or unsubstituted diazirinyl;

R ^2a is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino and substituted unsubstituted or unsubstituted alkyl;

R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or

- 4 045362 unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted aryl; And

R ⁴ represents H;

moreover, when R ³ represents 4-methoxyphenylmethyl, R ^1a does not represent methyl or methoxy.

In another aspect, there is provided a compound of formula (Ii), or a pharmaceutically acceptable salt thereof:

where R ^1a is selected from the group consisting of cyano, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl and substituted or unsubstituted diazirinyl;

R ^2a is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino and substituted alkyl or unsubstituted alkyl:

R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted aryl;

R ⁴ represents H;

R ⁵ represents H or substituted or unsubstituted alkyl; And

X represents -CH ₂ - or -C(O)-;

moreover, when R ³ represents 4-methoxyphenylmethyl, R ^1a does not represent methyl or methoxy.

In another aspect, a compound of formula (Ij) or a pharmaceutically acceptable salt thereof is provided:

where R ¹ represents substituted or unsubstituted phenyl;

each R ^2b independently represents substituted or unsubstituted alkyl;

R ³ represents substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl;

R ⁴ represents H;

R ⁵ represents H or substituted or unsubstituted alkyl;

n is 0, 1 or 2; and q is 0 or 1, wherein when R ³ is substituted or unsubstituted phenyl, then R ¹ is phenyl substituted with at least one substituent other than methyl or methoxy.

In another aspect, a compound of formula (Ik-1) or a pharmaceutically acceptable salt thereof is provided:

where R ^2a represents H or substituted or unsubstituted alkyl;

R ^2b is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;

m is 0, 1 or 2;

p is 0, 1 or 2;

each R ^1a is independently selected from the group consisting of halogen and substituted or unsubstituted

- 5 045362 alkyl;

each R ^3a is independently selected from the group consisting of halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkoxy; And

R ⁴ represents H.

In another aspect, a compound of formula (Ik-2) or a pharmaceutically acceptable salt thereof is provided:

'P (Ik-2) where G ¹ is selected from the group consisting of substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclyl;

each R ^1a is independently selected from the group consisting of halogen and substituted or unsubstituted alkyl;

each R ^2a is independently selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminothionyl, substituted or unsubstituted aminocarbonylamino, and substituted substituted or unsubstituted alkyl;

each R ^3a is independently selected from the group consisting of halogen, cyano and substituted or unsubstituted alkyl,

R ⁴ represents H;

R ⁵ represents H or substituted or unsubstituted alkyl;

m is 0, 1 or 2;

n is 0, 1 or 2; and p is 0, 1 or 2.

In another aspect, a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided:

where R ^2A represents H or substituted or unsubstituted alkyl;

R ^2b is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl and hydroxy;

m is 0, 1 or 2;

p is 0, 1 or 2;

each R ^1a is independently selected from the group consisting of halogen and substituted or unsubstituted alkyl;

each R ^3a is independently halogen; And

R ⁴ represents H.

In another aspect, a compound of formula (Im) or a pharmaceutically acceptable salt thereof is provided:

where Q represents -O- or -N(R ^2b )-;

R ^2b is selected from the group consisting of H and substituted or unsubstituted acyl;

m is 0, 1 or 2;

p is 0, 1 or 2;

each R ^1a is independently selected from the group consisting of halogen and substituted or unsubstituted

- 6 045362 th alkyl;

each R ^3a is independently halogen; And

R ⁴ represents H.

In another aspect, a compound of formula (In-1) or a pharmaceutically acceptable salt thereof is provided:

where R ¹ is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted pyridyl;

r ^2A , r ^2B and R ³ are defined by any of (i)-(iii):

(i) R ^2a represents H or substituted or unsubstituted alkyl;

R ^2B is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted puppy Aril and substituted or unsubstituted heteroaryl; And

R ³ represents substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; or (ii) R ^2A represents H or substituted or unsubstituted alkyl;

R ^2B represents substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; And

R ³ represents substituted or unsubstituted alkyl; or (iii) R ^2a and R ^2B are taken together with the carbon atom to which they are attached to form G ¹ , where G ¹ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, or substituted or unsubstituted heterocyclyl a ring, each of which is optionally fused to a phenyl ring; And

R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted ar sludge and replaced or unsubstituted heteroaryl;

R ⁴ represents H or substituted or unsubstituted alkyl; And

R ⁵ represents H or substituted or unsubstituted alkyl;

wherein, when one or more provisions (a)-(c) are used, R ¹ represents substituted or unsubstituted pyridyl or phenyl substituted with at least one substituent other than methyl or methoxy:

(a) R ^2a and R ^2B are as defined in (i), and R ³ is substituted or unsubstituted phenyl;

(b) R ^2a and R ³ are as defined in (ii), and R ^2B is 4-methoxyphenyl;

(c) R ^2a and R ^2B are as defined in (iii), and R ³ is 4methoxyphenylmethyl.

In another aspect, a compound of formula (In-2) or a pharmaceutically acceptable salt thereof is provided:

-2) where R ¹ is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted pyridyl;

R ^2A , r ^2B and R ³ are defined by any of (i)-(iii):

(i) R ^2a represents H or substituted or unsubstituted alkyl;

R ^2B is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted puppy Aril and substituted or unsubstituted heteroaryl; And

- 7 045362

R ³ represents substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; or (ii) R ^2A represents H or substituted or unsubstituted alkyl;

R ^2b represents substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; And

R ³ represents substituted or unsubstituted alkyl; or (iii) R ^2a and R ^2b are taken together with the carbon atom to which they are attached to form G ¹ , where G ¹ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, or substituted or unsubstituted heterocyclyl a ring, each of which is optionally fused to a phenyl ring; And

R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted ar sludge and replaced or unsubstituted heteroaryl;

R ⁴ represents H or substituted or unsubstituted alkyl; And

R ⁵ represents H or substituted or unsubstituted alkyl;

wherein, when one or more provisions (a)-(c) are used, R ¹ represents substituted or unsubstituted pyridyl or phenyl substituted with at least one substituent other than methyl or methoxy:

(a) R ^2a and R ^2b are as defined in (i), and R ³ is substituted or unsubstituted phenyl;

(b) R ^2a and R ³ are as defined in (ii), and R ^2B is 4-methoxyphenyl;

(c) R ^2a and R ^2b are as defined in (iii), and R ³ is 4methoxyphenylmethyl.

In some cases, compounds selected from the group consisting of compounds in Table 1 are provided. 1 or their pharmaceutically acceptable salts. In some aspects, a pharmaceutical composition is provided comprising a compound of formula (I) or any pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In some aspects, methods are provided for treating heart disease in a subject in need thereof, the method comprising administering to the subject a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of formula (I) or any variation thereof , or a pharmaceutically acceptable salt thereof. In some embodiments, the heart disease is hypertrophic cardiomyopathy (HCM). In some embodiments, NSM is obstructive or non-obstructive or caused by sarcomeric and/or non-sarcomeric mutations. In some embodiments, the heart disease is heart failure with preserved ejection fraction (HFpEF). In some embodiments, the heart disease is selected from the group consisting of diastolic dysfunction, primary or secondary restrictive cardiomyopathy, myocardial infarction, angina, and left ventricular outflow tract obstruction. In some embodiments, the heart disease is hypertensive heart disease, congenital heart disease, cardiac ischemia, coronary artery disease, diabetic heart disease, congestive heart failure, right-sided heart failure, cardiorenal syndrome, or infiltrative cardiomyopathy. In some embodiments, the heart disease is a pathological condition that represents or is associated with cardiac aging and/or diastolic dysfunction due to aging. In some embodiments, the heart disease is a pathological condition that represents or is associated with left ventricular hypertrophy and/or concentric left ventricular remodeling.

In other aspects, methods are provided for treating a disease or condition associated with SUI in a subject in need thereof, the method comprising administering to the subject a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of formula ( I) or any variation thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is selected from the group consisting of Fabry disease, Danon disease, mitochondrial cardiomyopathy, and Noonan syndrome.

In some aspects, methods are provided for treating a disease or condition that is associated with left ventricular wall thickening in a subject in need thereof, the method comprising administering to the subject a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, containing a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is selected from the group consisting of hypertension,

- 8 045362 heart defects (such as aortic stenosis and mitral valve regurgitation), metabolic syndromes (such as diabetes and obesity), end-stage renal failure, scleroderma, sleep apnea, amyloidosis, Fabry disease, Friedreich disease, Friedreich ataxia, Danon disease , Noonan syndrome and Pompe disease.

In other aspects, methods are provided for treating a disease or condition that is associated with left ventricular small cavity and cavity obliteration, left ventricular hyperdynamic contraction, myocardial ischemia, or cardiac fibrosis. Methods for treating muscular dystrophy (eg, Duchenne muscular dystrophy) or glycogen storage disease are also provided.

Methods of inhibiting cardiac sarcomeres are also provided, the method comprising contacting the cardiac sarcomere with a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt, or a pharmaceutical composition containing a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof .

Detailed description of the invention

Definitions.

As used herein, the following words and phrases generally have the meanings set forth below, except that the context in which they are used indicates otherwise.

Throughout this application, unless the context otherwise indicates, references to a compound of formula (I) include all subgroups of formula (I) defined herein, such as formulas (Ia), (Ib), (Ic), (Id) , (Ie), (If), (Ig), (Ih), (Il), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1) and (In-2), including all substructures, subgenera, preferences, embodiments, examples and specific compounds defined and/or described herein. References to a compound of formula (I) and subgroups thereof, such as formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1) and (In-2) include ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, cocrystals, chelates, isomers, tautomers, oxides (eg N-oxides, S-oxides), esters, prodrugs, isotopes and/or protected forms thereof. In some embodiments, references to a compound of formula (I) and subgroups thereof, such as formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) , (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1) and (In-2) include their polymorphs, solvates, cocrystals, isomers, tautomers and/or oxides. In some embodiments, references to a compound of formula (I) and subgroups thereof, such as formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) , (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1) and (In-2) include their polymorphs, solvates and/or cocrystals. In some embodiments, references to a compound of formula (I) and subgroups thereof, such as formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) , (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1) and (In-2) include their isomers, tautomers and/or oxides In some embodiments, references to a compound of formula (I) and subgroups thereof, such as formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) , (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1) and (In-2) include their solvates.

Alkyl covers straight and branched carbon chains having a specified number of carbon atoms, for example, from 1 to 20 carbon atoms, or from 1 to 8 carbon atoms, or from 1 to 6 carbon atoms. For example, C ₁ . ₆ alkyl covers both linear and branched alkyl with 1-6 carbon atoms. When an alkyl moiety having a certain number of carbon atoms is named, all branched and straight chain versions having that number of carbon atoms are to be covered; thus, for example, propyl includes n-propyl and isopropyl; and butyl includes n-butyl, sec-butyl, isobutyl and t-butyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. When a range of values is specified (for example, C ₁ . ₆ alkyl), every value within the range is included, as well as all ranges in between. For example, C1.6alkyl includes _CbC2 , C3, C4, C5, _C6 , C^, _CM , C3.6, C«, C5.6, C1-5, C2-5, C3-5, C4. 5, C _M , C2.4, C3.4, C1-3, C ₂ - ₃ and C ₁ . ₂ alkil.

Alkenyl refers to an unsaturated branched or linear alkyl group having a specified number of carbon atoms (eg, 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon double bond. The group may be in cis or trans configuration (Z or E configuration) relative to the double bond(s). Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop2-en-2-yl) and butenyl (e.g. but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2 -en-1-yl, but2-en-1-yl, buta-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl). Alkynyl refers to an unsaturated branched or linear alkyl group having a specified number of carbon atoms (eg, 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond. Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1yl, prop-2-yn-1-yl), and butynyl (e.g., but-1-yn-1-yl, but- 1-in-3-yl, but-3-in-1-yl).

Cycloalkyl means a non-aromatic, fully saturated carbocyclic ring having a specified number of carbon atoms, for example, from 3 to 10, or from 3 to 8, or from 3 to 6 carbon atoms in the ring. Cycloalkyl groups can be monocyclic or polycyclic

- 9 045362 (for example, bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, as well as bridging and backbone ring groups (eg, norbornane, bicyclo[2.2.2]octane). In addition, one ring of a polycyclic cycloalkyl group may be aromatic, provided that the polycyclic cycloalkyl group is linked to the parent structure through a non-aromatic carbon. For example, the 1,2,3,4-tetrahydronaphthalene-1-yl group (where the moiety is linked to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group, whereas 1,2,3,4-tetrahydronaphthalene-5-yl (where fragment linked to the original structure via an aromatic carbon atom) is not considered a cycloalkyl group. Examples of polycyclic cycloalkyl groups consisting of a cycloalkyl group fused to an aromatic ring are described below.

Cycloalkenyl refers to a non-aromatic carbocyclic ring containing a specified number of carbon atoms (for example, 3 to 10 or 3 to 8 or 3 to 6 carbon atoms per ring) and at least one carbon-carbon double bond. Cycloalkenyl groups can be monocyclic or polycyclic (eg, bicyclic, tricyclic). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl, as well as bridging and backbone ring groups (eg, bicyclo[2,2.2]octene). In addition, one ring of a polycyclic cycloalkenyl group may be aromatic, provided that the polycyclic alkenyl group is bonded to the parent structure through a non-aromatic carbon atom. For example, inden-1-yl (where the moiety is linked to the parent structure via a non-aromatic carbon atom) is considered a cycloalkenyl group, whereas inden-4-yl (where the moiety is linked to the parent structure via an aromatic carbon atom) is not considered a cycloalkenyl group. Examples of polycyclic cycloalkenyl groups consisting of a cycloalkenyl group fused to an aromatic ring are described below.

Cycloalkynyl refers to an unsaturated hydrocarbon group in cycloalkyl having at least one site of acetylene unsaturation (ie, having at least one moiety of the formula C=C). The cycloalkynyl may consist of a single ring, such as cyclooctyne, or multiple rings. One cycloalkynyl fragment is an unsaturated cyclic hydrocarbon containing from 5 to 10 ring carbon atoms (C ₅ -C ₁₀ -cycloalkynyl). Examples include cyclopentine, cyclohexine, cycloheptine, cyclooctine, cyclononine and the like.

Aryl refers to an aromatic carbocyclic ring having a specified number of carbon atoms, for example 6 to 12 or 6 to 10 carbon atoms. Aryl groups may be monocyclic or polycyclic (eg, bicyclic, tricyclic). In some cases, both rings of a polycyclic aryl group are aromatic (eg naphthyl). In other cases, polycyclic aryl groups may include a non-aromatic ring fused to an aromatic ring, provided that the polycyclic aryl group is linked to the parent structure through an atom on the aromatic ring. Thus, the 1,2,3,4-tetrahydronaphthalene-5-yl group (where the moiety is linked to the parent structure via an aromatic carbon atom) is considered an aryl group, while the 1,2,3,4-tetrahydronaphthalene-1-yl group (where the moiety is linked with the original structure via a non-aromatic carbon atom) is not considered an aryl group. Similarly, a 1,2,3,4-tetrahydroquinolin-8yl group (where the moiety is linked to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydroquinolin-1-yl (where the moiety is linked to the parent structure structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term aryl does not encompass or overlap heteroaryl as defined herein, regardless of the point of attachment (eg, both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some cases, aryl is phenyl or naphthyl. In some cases, aryl is phenyl. Additional examples of aryl groups including an aromatic carbon ring fused to a non-aromatic ring are described below. Heteroaryl means an aromatic ring containing a specified number of atoms (for example, from 5 to 12 or from 5 to 10 membered heteroaryl), consisting of one or more heteroatoms (for example, 1, 2, 3 or 4 heteroatoms) selected from N, O and S and the rest of the ring atoms, which are carbon. Heteroaryl groups do not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group is no more than 2. In some embodiments, the total number of S and O atoms in the heteroaryl group is no more than 1. If not otherwise stated, heteroaryl groups may be linked to the parent structure by a carbon or nitrogen atom if valence permits. For example, pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl groups, and pyrrolyl includes 1-pyrrol, 2-pyrrol and 3-pyrrol. In some cases, the heteroaryl group is monocyclic.

Examples include pyrrole, pyrazole, imidazole, triazole (e.g. 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g. 1 ,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g. 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (eg 1,2,4-triazine, 1,3,5-triazine) and tetrazine.

- 10 045362

In some cases, both rings of a polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzoimidazole, benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4- b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H[1,2,3]triazolo[4,5-b]pyridine, N-pyrrolo[3,2b]pyridine, 1H-pyrazolo[4, 3-b]pyridine, 1H-imidazo[4,5b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo [3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c] pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, furo[2,3b]pyridine , oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2b]pyridine, oxazolo[4, 5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine, oxazopo[5,4-c ]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4c]pyridine, furo[3,2-c]pyridine. oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine,

[1,2,3]ok sadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4b]pyridine, [1,2 ,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3] thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3]thiadiazolo[5 ,4-c]pyridine, thieno[3,2-c]pyridine, thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5- c]pyridine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (for example, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2, 6-naphthyridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-0]thiazole, 1Hpyrazolo[4,3-0]thiazole and imidazo[2,1-b]thiazole.

In other cases, polycyclic heteroaryl groups may include a non-aromatic ring (eg, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, provided that the polycyclic heteroaryl group is linked to the parent structure through an atom on the aromatic ring. For example, a 4,5,6,7-tetrahydrobenzo[0]thiazol-2-yl group (where the moiety is linked to the parent structure via an aromatic carbon atom) is considered a heteroaryl group, whereas a 4,5,6,7-tetrahydrobenzo[d] thiazol-5-yl (where the moiety is linked to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl group. Examples of polycyclic heteroaryl groups consisting of a heteroaryl ring fused to a non-aromatic ring are described below.

Heterocycloalkyl means a non-aromatic, fully substituted ring having a specified number of atoms (for example, 3 to 10 or 3 to 7 membered heterocycloalkyl), consisting of one or more heteroatoms (for example, 1, 2, 3 or 4 heteroatoms) selected from N , O and S and the remaining atoms of the ring, representing carbon. Heterocycloalkyl groups can be monocyclic or polycyclic (eg, bicyclic, tricyclic). Examples of heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. Examples include thiomorpholine Soxide and thiomorpholine S,S dioxide. In addition, one ring of a polycyclic heterocycloalkyl group may be aromatic (eg, aryl or heteroaryl), as long as the polycyclic heterocycloalkyl group is bonded to the parent structure through a non-aromatic carbon or nitrogen atom. For example, a 1,2,3,4-tetrahydroquinolin-1-yl group (where the moiety is linked to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, whereas a 1,2,3,4-tetrahydroquinolin-8-yl group (where the moiety is linked with the original structure via an aromatic carbon atom) is not considered a heterocycloalkyl group. Examples of polycyclic heterocycloalkyl groups consisting of a heterocycloalkyl group fused to an aromatic ring are described below.

Heterocycloalkenyl means a non-aromatic ring having a specified number of atoms (for example, 3 to 10 or 3 to 7 membered heterocycloalkyl) consisting of one or more heteroatoms (for example, 1, 2, 3 or 4 heteroatoms) selected from N, O and S and the remaining ring atoms representing carbon, and at least one double bond obtained by removing one hydrogen molecule from adjacent carbon atoms, adjacent nitrogen atoms, or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl. Heterocycloalkenyl groups may be monocyclic or polycyclic (eg, bicyclic, tricyclic). Examples of heterocycloalkenyl groups include dihydrofuranyl (for example, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (for example, 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (for example, 2,3-dihydro-1H- pyrrolyl, 2,5-dihydro-1H-pyrrolyl), dihydroimidazoyl (e.g. 2,3-dihydro-1H-imidazoyl, 4,5-dihydro-1H-imidazoyl), pyranyl, dihydropyranyl (e.g. 3,4dihydro-2H- pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g. 1,2,3,4tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl) and dihydropyridine (e.g. 1,2-dihydropyridine, 1,4- dihydropyridine). In addition, one ring of a polycyclic heterocycloalkenyl group may be aromatic (eg, aryl or heteroaryl), as long as the polycyclic heterocycloalkenyl group is bonded to the parent structure through a non-aromatic carbon or nitrogen atom. For example, a 1,2-dihydroquinolin-1-yl group (where the fragment is linked to the original structure through

- 11 045362 non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, whereas a 1,2-dihydroquinolin-8-yl group (where the moiety is linked to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkenyl group. Examples of polycyclic heterocycloalkenyl groups consisting of a heterocycloalkenyl group fused to an aromatic ring are described below.

Examples of polycyclic rings consisting of an aromatic ring (eg, aryl or heteroaryl) fused to a non-aromatic ring (eg, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl, 2,3-dihydro-1H-indenyl, 1,2 ,3,4tetrahydronaphthalenyl, benzo[1,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxynyl, indolinyl, isoindolinyl, 2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo [d]imidazoylyl, 2,3dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 1,3-dihydrobenzo[c]isoxazolyl, 2,3dihydrobenzo[d]isoxazolyl, 2,3-dihydrobenzo[0]oxazolyl, 2,3-dihydrobenzo[b ]thiophenyl, 1,3dihydrobenzo[c]thiophenyl, 1,3-dihydrobenzo[c]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl, 2,3dihydrobenzo[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d ]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, 5,6-dihydro-4H-pyrrolo[3,4-0]thiazolyl, 4,5,6,7-tetrahydrothiazolo[5,4-c ]pyridinyl, indolin-2-one, indolin-3-one, isoindolin-1-one, 1,2-dihydroindazol-3-one, 1H-benzo[0]imidazoyl-2(3H)-one, benzofuran2(3H) -one, benzofuran-3(2H)-one, isobenzofuran-1(3H)-one, benzo[c]isoxazol-3(1H)-one, benzo[d]isoxazol3(2H)-one, benzo[0]oxazole -2(3H)-one, benzo[b]thiophen-2(3H)-one, benzo[b]thiophen-3(2H)-one, benzo[c]thiophen1(3H)-one, benzo[c]isothiazole -3(1H)-one, benzo[0]isothiazol-3(2H)-one, benzo[d]thiazol-2(3H)-one, 4,5dihydropyrrolo[3,4-0]thiazol-6-one, 1,2-dihydropyrazolo[3,4-0]thiazol-3-one, quinolin-4(3H)-one, quinazolin-4(3H)-one, quinazolin-2,4(1H,3H)-dione, quinoxaline -2(1H)-one, quinoxalin-2,3(1H,4H)-dione, cinnolin-4(3H)-one, pyridin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin- 4(3H)-one, pyridazin-3(2H)-one, 1Hpyrrolo[3,2b]pyridin-2(3H)-one, 1H-pyrrolo[3,2-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-c]pyridin-2(3H)one, 1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 1,2-dihydropyrazolo[3,4-0]thiazole -3-one and 4,5dihydropyrrolo[3,4-d]thiazol-6-one. As discussed herein, whether each ring is considered an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group through which the moiety is linked to the parent structure.

The term heterocycle, heterocyclyl or heterocyclic refers to a saturated, partially unsaturated or unsaturated 4-12 membered ring containing at least one heteroatom independently selected from nitrogen, oxygen and sulfur. Unless otherwise specified, the heteroatom may be bonded to carbon or nitrogen, the -CH ₂ - group may optionally be replaced by -C(O)-, and the ring sulfur atom may optionally be oxidized to form a sulfinyl or sulfonyl group. Heterocycles can be aromatic (heteroaryls) or non-aromatic. In addition, not all rings of a polycyclic heterocyclyl group may be aromatic (eg, aryl or heteroaryl). For example, a 1,2,3,4-tetrahydroquinolin-1-yl group and a 1,2,3,4-tetrahydroquinolin-8yl group are both considered a heterocyclyl group.

Heterocyclyl, heterocyclyl or heterocyclic also includes bicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic rings is fused with one or two rings independently selected from aryls, cycloalkyls and heterocycles. Examples of heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothi azolidinyl, isoxazolidinyl, isothiazolyl , isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxa loyl, tetrahydrofuryl , tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranyl and triazolyl. Halogen refers to fluorine, chlorine, bromine or iodine.

Unless otherwise indicated, the compounds disclosed and/or described herein include all possible enantiomers, diastereomers, mesoisomers and other stereoisomeric forms, including racemic mixtures, optically pure forms and mixtures of intermediates thereof. Enantiomers, diastereomers, mesoisomers and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents or separated using conventional techniques. Unless otherwise indicated, when the compounds disclosed and/or described herein contain olefinic double bonds or other centers of geometric asymmetry, the compounds are intended to include both E and Z isomers. When compounds described herein contain moieties capable of tautomerization, and unless otherwise indicated, the compounds are intended to include all possible tautomers.

A protecting group has the meaning usually associated with it in organic synthesis, i.e. a group that selectively blocks one or more reactive sites in a multifunctional compound so that a chemical reaction can be carried out selectively at another unprotected reactive site, and such that the group can be easily removed after the reaction is complete

- 12 045362 on. Various protecting groups are described, for example, in T.N. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, the hydroxyl-protected form contains at least one hydroxy group protected by a hydroxyl protecting group. Likewise, amines and other reactive groups may be similarly protected.

The term pharmaceutically acceptable salt refers to a salt of any of the compounds described herein that are known to be non-toxic and commonly used in the pharmaceutical literature. In some embodiments, the pharmaceutically acceptable salt of the compound retains the biological effectiveness of the compounds described herein and is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be prepared include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Organic acids from which salts can be prepared include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be prepared include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum. Organic bases from which salts can be prepared include, for example, primary, secondary and tertiary amines; substituted amines, including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts. If the compound described herein is prepared as an acid addition salt, the free base can be prepared by making the acid salt solution alkaline. Conversely, if the compound is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating with an acid solution in accordance with conventional techniques for preparing acid addition salts from basic compounds (see, for example, Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19). Various synthetic procedures are known to those skilled in the art that can be used to prepare pharmaceutically acceptable addition salts.

The solvate is formed by the interaction of a solvent and a compound. Suitable solvents include, for example, water and alcohols (eg ethanol). Solvates include hydrates having any ratio of compound to water, such as monohydrates, dihydrates and hemihydrates.

The term substituted means that the specified group or fragment contains one or more substituents, including, but not limited to, substituents such as alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, amino, aminoacyl, alkoxycarbonyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halogen, hydroxyl, nitro, carboxyl, thiol, thioalkyl, alkyl, alkenyl, alkynyl, heterocyclyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo and the like. The term unsubstituted means that the specified group has no substituents. Where the term substituted is used to describe a structural system, substitution is meant at any position of acceptable valence in the system. When a group or moiety has more than one substituent, it is intended that the substituents may be the same or different from each other. In some embodiments, the substituted group or moiety contains one to five substituents. In some embodiments, the substituted group or moiety has one substituent. In some embodiments, the substituted group or moiety has two substituents. In some embodiments, the substituted group or moiety contains three substituents. In some embodiments, the substituted group or moiety contains four substituents. In some embodiments, the substituted group or moiety contains five substituents.

Optional or optional means that the subsequently described event or circumstance may or may not occur, and that the description includes cases in which the event or circumstance occurs and cases in which it does not occur. For example, optionally substituted alkyl includes both alkyl and substituted alkyl as defined herein. Spezia

- 13 045362 sheets in the art will understand that with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or replacement structures that are sterically impractical, synthetically impractical and/or inherently unstable . It should also be understood that when a group or moiety is optionally substituted, the disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.

The compounds disclosed and/or described herein may be enriched in isotopic forms, such as enriched in ^2H , ^3H , ^11C , ^13C and/or ^14C . In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be obtained, for example, using the procedure described in US patents No. 5846514 and 6334997.

Such deuterated compounds may improve the potency and increase the duration of action of the compounds disclosed and/or described herein. Deuterium-substituted compounds can be synthesized using a variety of methods, such as those described in: Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000; 6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

The term pharmaceutically acceptable carrier or pharmaceutically acceptable excipient includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption retarding agents, and the like. The use of such media and agents in relation to pharmaceutically active substances is well known in the art. Unless any conventional carrier or agent is incompatible with the active ingredient, it is intended for use in pharmaceutical compositions. Additional active ingredients may also be included in pharmaceutical compositions.

The terms patient, individual and subject refer to an animal such as a mammal, bird or fish. In some embodiments of the invention, the patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows and humans. In some embodiments, the patient or subject is a human, such as a human who has been or will be the subject of treatment, observation, or experiment. The compounds, compositions and methods described herein may be useful in both human and veterinary medicine.

As used herein, the term therapeutic refers to the ability to modulate the cardiac sarcomere. As used herein, the term modulation refers to a change in activity as a direct or indirect response to the presence of a chemical entity, as described herein, relative to activity in the absence of a chemical entity. The change may be an increase in activity or a decrease in activity, and may be due to the direct interaction of the chemical entity with the target or due to the interaction of the chemical entity with one or more other factors that in turn influence the target of the activity. For example, the presence of a chemical entity may, for example, increase or decrease a target activity by directly binding to the target, causing (directly or indirectly) another factor to increase or decrease the target activity, or (directly or indirectly) increase or decrease the amount of target present in the cell or organism .

The term therapeutically effective amount or effective amount refers to that amount of a compound as disclosed and/or described herein that is sufficient to effect a treatment as defined herein when administered to a patient in need of such treatment. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease sensitive to cardiac sarcomere modulation. The therapeutically effective amount will vary depending on, for example, the subject and the disease being treated, the weight and age of the subject, the severity of the disease state, the particular compound, the dosage regimen to be followed, the time of administration, the route of administration, which can be readily determined by one skilled in the art. this area. The therapeutically effective amount can be determined experimentally, for example, by analyzing the concentration of the chemical in the blood, or theoretically, by calculating bioavailability.

Treatment (and related terms such as treat, cured, treating) includes one or more of: inhibiting a disease or disorder; slowing or stopping the development of clinical symptoms of a disease or disorder; and/or alleviation of a disease or disorder (ie, alleviation or regression of clinical symptoms). The term covers both complete and partial reduction of a pathological condition or disorder, as well as complete or partial reduction of the clinical symptoms of a disease or disorder. Thus, the compounds described and/or disclosed herein may prevent the worsening of an existing disease or disorder, help treat a disease or disorder, or reduce or eliminate a disease or disorder.

- 14 045362

ATPase refers to an enzyme that hydrolyzes ATP. ATPases include proteins containing molecular motors such as myosins. As used herein, the term selective binding or selectively binding refers to preferential binding to a target protein in one type of muscle or muscle fiber as opposed to other types. For example, a compound selectively binds to fast skeletal troponin C if the compound preferentially binds troponin C in the fast skeletal muscle fiber or sarcomere troponin complex over troponin C in the slow muscle fiber or sarcomere troponin complex or to troponin C in the cardiac sarcomere troponin complex .

It will be understood that embodiments described herein as comprising include embodiments consisting of and consisting essentially of embodiments.

Connections.

The compounds and their salts (such as pharmaceutically acceptable salts) are described in detail herein, including in the summary and in the accompanying claims. Also provided is the use of all compounds described herein, including any and all stereoisomers, including geometric isomers (cis/trans), E/Z isomers, enantiomers, diastereomers and mixtures thereof in any ratio, including racemic mixtures, salts and solvates described compounds described herein, as well as methods for preparing such compounds. Any compound described herein may also be referred to as a drug.

In one aspect, compounds of formula (I) or pharmaceutically acceptable salts thereof are provided:

where R ¹ is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted pyridyl;

R ^2a , R ^2b and R ³ are defined by any of (i)-(iii):

(i) R ^2a represents H or substituted or unsubstituted alkyl;

R ^2b is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted puppy Aril and substituted or unsubstituted heteroaryl; And

R ³ represents substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; or (ii) R ^2a represents H or substituted or unsubstituted alkyl;

R ^2b represents substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; And

R ³ represents substituted or unsubstituted alkyl; or (iii) R ^2a and R ^2b are taken together with the carbon atom to which they are attached to form G ¹ , where G ¹ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, or substituted or unsubstituted heterocyclyl a ring, each of which is optionally fused to a phenyl ring; And

R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted ar sludge and replaced or unsubstituted heteroaryl;

R ⁴ represents H or substituted or unsubstituted alkyl; And

R ⁵ represents H or substituted or unsubstituted alkyl;

wherein, when one or more provisions (a)-(c) are used, R ¹ represents substituted or unsubstituted pyridyl or phenyl substituted with at least one substituent other than methyl or methoxy:

(a) R ^2a and R ^2b are as defined in (i), and R ³ is substituted or unsubstituted phenyl;

(b) R ^2a and R ³ are as defined in (ii), and R ^2b is 4-methoxyphenyl;

(c) R ^2a and R ^2b are as defined in (iii), and R ³ is 4methoxyphenylmethyl.

In some embodiments of Formula (I), R ⁴ and R ⁵ are each independently H. In some embodiments of Formula (I), at least one of R ⁴ and R ⁵ is different from H. In some embodiments of Formula (I) (I), R ⁴ represents a substituted or non-substituted

- 15 045362 substituted alkyl. In some embodiments of Formula (I), R ⁴ is methyl. In some embodiments of Formula (I), R ⁴ is alkyl substituted with alkoxy. In some embodiments of Formula (I), R ⁴ is methoxymethyl. In some embodiments of Formula (I), R ⁵ is a substituted or unsubstituted alkyl. In some embodiments of Formula (I), R ⁵ is methyl. In some embodiments of Formula (I), R ⁵ is alkyl. In some embodiments of Formula (I), R ⁵ is hydroxymethyl.

In some embodiments of Formula (I), R ¹ is unsubstituted pyridyl or unsubstituted phenyl. In some embodiments of Formula (I), R ¹ is 2pyridyl. In some embodiments of Formula (I), R ¹ is phenyl or pyridinyl, each of which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents independently selected from the group consisting of cyano, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl and substituted or unsubstituted diazirinyl. In some embodiments of Formula (I), R ¹ is pyridyl substituted with one or two halogens selected from the group consisting of F and Cl. In some embodiments of Formula (I), R ¹ is pyridyl substituted with -CF3. In some embodiments of Formula (I), R ¹ is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halogens selected from the group consisting of F and Cl. In some embodiments of Formula (I), R ¹ is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) methyls. In some embodiments of Formula (I), R ¹ is phenyl substituted with one or more (eg, 1 or 2 or 3 or 14 or 1-3 or 2-4) cyano. In some embodiments of formula (I), R ¹ is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) -CF3. In some embodiments of Formula (I), R ¹ is phenyl substituted with one halogen and one cyano. In some embodiments of Formula (I), R ¹ is phenyl substituted with one Cl and one F. In some embodiments of Formula (I), R ¹ is phenyl substituted with one halogen and one -CF ₃ . In some embodiments of Formula (I), R ¹ is phenyl substituted with diazirinyl. In some embodiments of Formula (I), R ¹ is phenyl, substituted diazirinyl, substituted trifluoromethyl.

In some embodiments of formula (I), the carbon bearing the R ^2A and R ^2B moieties is in the S stereochemical configuration. In some embodiments of formula (I), the carbon bearing the R ^2A and R ^2B moieties is in the R stereochemical configuration. It is understood that for any of the embodiments of formula (I) and its subformulas proposed herein, the description includes embodiments in which the carbon bearing the R ^2A and R ^2B moieties is in the stereochemical S configuration and embodiments in which the carbon, carrying fragments R ^2a and R ^2b is in the stereochemical R configuration.

It is understood that each of the variables described herein may be combined with other variables in the same manner as if each combination were specifically and individually stated. For example, each R ¹ of formula (I) can be combined with each of R ^2A , R ^2B , R ³ , R ⁴ and R ⁵ , either individually or collectively. It will also be understood that this applies to formula (I) and each of the subgroups: Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), ( Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1) and (In-2) described in this document.

In another aspect, a compound of formula (I) is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

where R ¹ is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted pyridyl; R ^2A represents H or substituted or unsubstituted alkyl; R ^2B is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted puppy Aril and substituted or unsubstituted heteroaryl; R ³ represents substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; R ⁴ represents H or substituted or unsubstituted alkyl; and R ⁵ represents H or substituted or unsubstituted alkyl; wherein R ³ is substituted or unsubstituted phenyl, R ¹ is substituted or unsubstituted pyridyl or phenyl substituted with at least one substituent other than methyl or methoxy.

In some embodiments, formula (Ia), R ⁴ and R ⁵ each independently represent

- 16 045362 is H. In some embodiments of formula (Ia), at least one of R ⁴ and R ⁵ is different from H. In some embodiments of formula (Ia), R ³ is substituted or unsubstituted pyridyl. In some embodiments of formula (Ia), R ³ is 2pyridyl. In some embodiments of Formula (Ia), R ³ is unsubstituted phenyl. In some embodiments of Formula (Ia), R ³ is phenyl or pyridyl, each of which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halogen substituents selected from group consisting of F and Cl. In some embodiments of Formula (Ia), R ³ is phenyl or pyridyl, each of which is substituted with two halogen substituents selected from the group consisting of F and Cl. In some embodiments of formula (Ia), R ³ is phenyl or pyridyl, each of which is substituted with two F. In some embodiments of formula (Ia), R ³ is phenyl or pyridyl, each of which is substituted with two Cl. In some embodiments of Formula (Ia), R ³ is phenyl or pyridyl, each of which is substituted with one F and one Cl. In some embodiments of Formula (Ia), R ³ is phenyl or pyridyl, each of which is substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) CN substituents. In some embodiments of Formula (Ia), R ³ is phenyl or pyridyl, each of which is substituted with two CN substituents. In some embodiments of formula (Ia), R ³ is phenyl or pyridyl, each of which is substituted with one halogen and one CN substituent. In some embodiments of Formula (Ia), R ³ is phenyl or pyridyl, each of which is substituted with one Cl and one CN. In some embodiments of formula (Ia), R ³ is phenyl or pyridyl, each of which is substituted with one F and one CN.

In some embodiments of formula (Ia), R ^2A is H. In some embodiments of formula (Ia), R ^2A is substituted or unsubstituted alkyl. In some embodiments of Formula (Ia), R ^2A is substituted or unsubstituted methyl. In some embodiments of Formula (Ia), R ^2A is methyl.

In some embodiments of formula (Ia), R ^2B is H. In some embodiments of formula (Ia), R ^2B is substituted or unsubstituted alkyl. In some embodiments of formula (Ia), R ^2B is selected from the group consisting of methyl, isopropyl and propyl. In some embodiments of formula (Ia), R ^2B is alkyl substituted with hydroxyl, or substituted or unsubstituted alkoxy. In some embodiments of Formula (Ia), R ^2B is hydroxymethyl. In some embodiments of Formula (Ia), R ^2B is a substituted alkoxyalkyl. In some embodiments of Formula (Ia), R ^2B is trifluoromethoxymethyl. In some embodiments of Formula (Ia), R ^2B is a substituted or unsubstituted cycloalkyl. In some embodiments of Formula (Ia), R ^2B is substituted or unsubstituted C3-C7 cycloalkyl. In some embodiments of Formula (Ia), R ^2B is cyclobutanyl. In some embodiments of Formula (Ia), R ^2B is a substituted or unsubstituted heterocyclyl. In some embodiments of formula (Ia), R ^2B is a substituted or unsubstituted C3-C ₇ heterocyclyl. In some embodiments of formula (Ia), R ^2B is a substituted or unsubstituted C ₃ -C ₇ heterocyclyl that contains one or more (for example, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) ring N or O ring atoms. In some embodiments of formula (Ia), R ^2B is oxetanyl. In some embodiments of Formula (Ia), R ^2B is 3-oxetanyl.

In some embodiments of Formula (Ia), R ¹ is substituted or unsubstituted pyridyl. In some embodiments of Formula (Ia), R ¹ is 2pyridyl. In some embodiments of Formula (Ia), R ¹ is unsubstituted phenyl. In some embodiments of Formula (Ia), R ¹ is phenyl or pyridyl, each of which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents independently selected from group consisting of cyano, halogen, alkoxy, -CF3, alkyl and diazirinyl. In some embodiments of Formula (Ia), R ¹ is phenyl or pyridyl, each of which is substituted with a substituted alkyl. In some embodiments of Formula (Ia), R ¹ is phenyl or pyridyl, each of which is substituted with -CF3. In some embodiments of Formula (Ia), R ¹ is phenyl substituted with 4-CF3. In some embodiments of Formula (Ia), R ¹ is phenyl substituted with -CF3 and R ³ is phenyl substituted with two halogen substituents. In some embodiments of Formula (Ia), R ¹ is phenyl substituted with -CF3, and R ³ is phenyl substituted with one halogen and one CN. In some embodiments of Formula (Ia), R ¹ is substituted or unsubstituted pyridyl, and R ³ is phenyl substituted with two halogens. In some embodiments of Formula (Ia), R ¹ is substituted or unsubstituted pyridyl, and R ³ is phenyl substituted with one halogen and one CN. In some embodiments of Formula (Ia), R ¹ is 2-pyridyl, and R ³ is phenyl substituted with two halogens. In some embodiments of formula (Ia), R ¹

- 17 045362 is 2-pyridyl and R ³ is phenyl substituted with one halogen and one CN. In some embodiments of Formula (Ia), R ¹ is phenyl substituted with CF ₃ and R ³ is phenyl.

In some embodiments of formula (Ia), R ¹ is phenyl substituted with CF3, R ^2a is H, R ^2B is 3-oxetanyl, R ³ is phenyl substituted with one or more substituents selected from the group consisting of F and Cl, R ⁴ is H and R ⁵ is H. In some embodiments of formula (Ia), R ¹ is phenyl substituted -CF3, R ^2a is H, R ^2b is 3-oxetanyl, R ³ is pyridyl substituted with one or more substituents selected from the group consisting of F and Cl, R ⁴ is H, and R ⁵ is H. In some embodiments of formula (Ia), R ¹ is phenyl, substituted -CF3, R ^2a is H, R ^2b is isopropyl, R ³ is phenyl substituted with one or more substituents selected from the group consisting of F and Cl, R ⁴ is H, and R ⁵ is H. In some embodiments of formula (Ia), R ¹ is phenyl substituted with -CF3, R ^2a is H, R ^2b is isopropyl, R ³ is pyridyl substituted with one or more substituents selected from the group consisting of F and Cl, R ⁴ is H and R ⁵ is H.

In some embodiments of formula (Ia): R ⁴ and R ⁵ are each independently H; R ³ represents phenyl or pyridyl, each of which is substituted with two halogen substituents selected from the group consisting of F and Cl; R ^2a is H or methyl; R ^2b is selected from the group consisting of methyl, isopropyl, propyl, hydroxymethyl, trifluoromethoxymethyl, cyclobutanyl and 3-oxetanyl; and R ¹ is phenyl or pyridyl, each of which is substituted with -CF ₃ .

In another aspect, a compound of formula (I) is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof:

where R ¹ is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted pyridyl; R ^2a represents H or substituted or unsubstituted alkyl; R ^2b represents substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; R ³ represents substituted or unsubstituted alkyl; R ⁴ represents H or substituted or unsubstituted alkyl; and R ⁵ represents H or substituted or unsubstituted alkyl; wherein R ^2b is 4-methoxyphenyl, R ¹ is substituted or unsubstituted pyridyl or phenyl substituted with at least one substituent other than methyl or methoxy.

In some embodiments of Formula (Ib), R ⁴ and R ⁵ are each independently H. In some embodiments of Formula (Ib), at least one of R 4 and R 5 is different from H. In some embodiments of Formula (Ib), at least one of R ⁴ and R ⁵ is different from H. In some embodiments of Formula (Ib), (Ib), R ^2a is H. In some embodiments of formula (Ib), R ^2a is substituted or unsubstituted alkyl. In some embodiments of Formula (Ib), R ^2a is substituted or unsubstituted methyl. In some embodiments of formula (Ia), R ^2a is methyl.

In some embodiments of Formula (Ib), R ^2b is substituted or unsubstituted pyridyl. In some embodiments of formula (Ib), R ^2b is 2pyridyl. In some embodiments, R ^2b is substituted or unsubstituted phenyl. In some embodiments of Formula (Ib), R ^2b is phenyl or pyridyl, each of which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents independently selected from a group consisting of halogen, substituted or unsubstituted alkoxy and substituted or unsubstituted alkyl. In some embodiments of formula (Ib), R ^2b is pyridyl substituted with one or more substituents (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) selected from the group consisting of halogen and substituted or unsubstituted alkyl. In some embodiments of formula (Ib), R ^2b is pyridyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halogens. In some embodiments of formula (Ib), R ^2b is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halogens. In some embodiments of formula (Ib), R ^2b is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) -CF ₃ . In some embodiments of Formula (Ib), R ^2b is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) alkoxy. In some embodiments of Formula (Ib), R ^2b is phenyl substituted with one or

- 18 045362 more (for example, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) methoxy.

In some embodiments of Formula (Ib), R ³ is substituted or unsubstituted Q-Ciu-alkyl. In some embodiments of Formula (Ib), R ³ is unsubstituted Q-Ciu-alkyl. In some embodiments of Formula (Ib), R ³ is unsubstituted C2-C6 alkyl. In some embodiments of Formula (Ib), R ³ is unsubstituted C3-C ₅ alkyl. In some embodiments of Formula (Ib), R ³ is unsubstituted C ₃ -alkyl. In some embodiments of Formula (Ib), R ³ is unsubstituted isopropyl.

In some embodiments of Formula (Ib), R ¹ is substituted or unsubstituted pyridyl. In some embodiments of Formula (Ib), R ¹ is 2pyridyl. In some embodiments of Formula (Ib), R ¹ is substituted or unsubstituted phenyl. In some embodiments of Formula (Ib), R ¹ is phenyl or pyridinyl, each of which is substituted with one or more substituents (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) independently selected from the group consisting of cyano, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl and substituted or unsubstituted diazirinyl. In some embodiments of Formula (Ib), R ¹ is pyridyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halogens. In some embodiments of formula (Ib), R ¹ is pyridyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) -CF3. In some embodiments of Formula (Ib), R ¹ is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halogens. In some embodiments of formula (Ib), R ¹ is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) -CF3. In some embodiments of Formula (Ib), R ¹ is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) -CN. In some embodiments of Formula (Ib), R ¹ is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) methyls. In some embodiments of formula (Ib), R ^2B is 4-methoxyphenyl, and R ¹ is substituted or unsubstituted pyridyl. In some embodiments of formula (Ib), R ^2B is 4-methoxyphenyl, and R ¹ is 2-pyridyl. In some embodiments of Formula (Ib), R ^2B is 4methoxyphenyl, and R ¹ is 2-pyridyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halogens . In some embodiments of Formula (Ib), R ^2B is 4-methoxyphenyl, and R ¹ is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halogens . In some embodiments of formula (Ib), R ^2b is 4-methoxyphenyl, and R ¹ is phenyl substituted with 4-Cl.

In some embodiments of formula (Ib), R ¹ is pyridyl substituted with one or more substituents independently selected from the group consisting of halogen and -CF3, R ^2A is H, R ^2B is pyridyl substituted with one or more substituents selected from the group consisting of F and Cl, R ³ is isopropyl, R ⁴ is H, and R ⁵ is H. In some embodiments of formula (Ib), R ¹ is phenyl substituted with one or more substituents , independently selected from the group consisting of halogen, -CF3, -CN and methyl, R ^2A is H, R ^2B is pyridyl. substituted with one or more substituents selected from the group consisting of F and Cl, R ³ is isopropyl, R ⁴ is H, and R ⁵ is H. In some embodiments of formula (Ib), R ¹ is pyridyl, substituted with one or more substituents independently selected from the group consisting of halogen and -CF3, R ^2A is methyl, R ^2B is pyridyl substituted with one or more substituents selected from the group consisting of F and Cl, R ³ is isopropyl, R ⁴ is H, and R ⁵ is H. In some embodiments of formula (Ib), R ¹ is phenyl substituted with one or more substituents independently selected from the group consisting of halogen, -CF3, -CN and methyl, R ^2A is methyl, R ^2B is pyridyl substituted with one or more substituents selected from the group consisting of F and Cl, R ³ is isopropyl, R ⁴ is H, and R ⁵ is H.

In another aspect, a compound of formula (I) is a compound of formula (Ic) or a pharmaceutically acceptable salt thereof:

where R ¹ is selected from the group consisting of substituted or unsubstituted pyridyl and substituted or unsubstituted phenyl; R ^2A and R ^2B are taken together with the carbon atom to which they are attached, with

- 19 045362 by the formation of G ¹ , where G ¹ represents a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, or a substituted or unsubstituted heterocyclyl ring, each of which is optionally fused to a phenyl ring; R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted ar sludge and replaced or unsubstituted heteroaryl; R ⁴ represents H or substituted or unsubstituted alkyl; and R ⁵ represents H or substituted or unsubstituted alkyl; wherein R ³ is 4-methoxyphenylmethyl, R ¹ is substituted or unsubstituted pyridyl or phenyl substituted with at least one substituent other than methyl or methoxy.

In some embodiments of Formula (Ic), R ⁴ and R ⁵ are each independently H. In some embodiments of Formula (Ic), at least one of R 4 and R 5 is different from H. In some embodiments of Formula (Ic), at least one of R ⁴ and R ⁵ is different from H. In some embodiments of Formula (Ic), (Ic), R ⁴ represents substituted or unsubstituted alkyl. In some embodiments of formula (Ic), R ⁴ is methyl. In some embodiments of formula (Ic), R ⁴ is alkyl substituted with alkoxy. In some embodiments of formula (Ic), R ⁴ is methoxymethyl. In some embodiments of Formula (Ic), R ⁵ is substituted or unsubstituted alkyl. In some embodiments of formula (Ic), R ⁵ is methyl. In some embodiments of formula (Ic), R ⁵ is alkyl. In some embodiments of formula (Ic), R ⁵ is hydroxymethyl.

In some embodiments of formula (Ic), G ¹ is selected from the group consisting of substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted 2,3-dihydro-1H-indene. In some embodiments of formula (Ic), G ¹ is a substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments of formula (Ic), G ¹ is a substituted or unsubstituted C3-C ₆ heterocyclyl. In some embodiments of formula (Ic), G ¹ is substituted or unsubstituted cyclopropyl. In some embodiments of formula (Ic), G ¹ is substituted or unsubstituted cyclobutanyl. In some embodiments of formula (Ic), G ¹ is substituted or unsubstituted azetidinyl. In some embodiments of formula (Ic), G ¹ is substituted or unsubstituted tetrahydrofuranyl. In some embodiments of formula (Ic), G ¹ is substituted or unsubstituted pyrrolidinyl. In some embodiments of formula (Ic), G ¹ is substituted or unsubstituted pyrrolidin-2-on-yl.

In some embodiments of formula (Ic), G ¹ is heterocyclyl or cycloalkyl, each of which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminothionyl, substituted or unsubstituted aminocarbonylamino and substituted or unsubstituted alkyl In some embodiments of formula (Ic), G ¹ is heterocyclyl substituted with substituted or unsubstituted phenyl. In some embodiments of formula (Ic), G ¹ is heterocyclyl substituted with phenyl, which is substituted with halogen. In some embodiments of formula (Ic), G ¹ is heterocyclyl, substituted or unsubstituted heteroaryl. In some embodiments of formula (Ic), G ¹ is heterocyclyl, substituted or unsubstituted pyridyl. In some embodiments of formula (Ic), G ¹ is a heterocyclyl substituted with pyridyl that is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group, consisting of alkyl, CN, hydroxyl, alkoxycarbonyl, methoxycarbonyl, alkoxy, carboxyl, cycloalkyl, halogen and aminoacyl. In some embodiments of formula (Ic), G ¹ is heterocyclyl, substituted or unsubstituted with pyrimidyl. In some embodiments of formula (Ic), G ¹ is heterocyclyl, substituted or unsubstituted pyrazolyl. In some embodiments of formula (Ic), G ¹ is heterocyclyl, substituted pyrazolyl, which is substituted with alkyl. In some embodiments of formula (Ic), G ¹ is heterocyclyl substituted with a substituted or unsubstituted thiazolyl. In some embodiments of formula (Ic), G ¹ is a heterocyclyl substituted with a thiazolyl which is substituted with an aminoacyl. In some embodiments of formula (Ic), G ¹ is heterocyclyl substituted with substituted or unsubstituted alkoxycarbonyl. In some embodiments of formula (Ic), G ¹ is heterocyclyl substituted with methoxycarbonyl. In some embodiments of formula (Ic), G ¹ is a heterocyclyl substituted with a substituted or unsubstituted aminoacyl. In some embodiments

- 20 045362 formula (Ic), G ¹ represents heterocyclyl substituted with methylomanoacyl. In some embodiments of formula (Ic), the G ¹ heterocyclyl is substituted with an aminoacyl that is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of aryl , cycloalkyl, pyridyl, pyrazolyl and alkoxyalkyl. In some embodiments of formula (Ic), G ¹ is heterocyclyl substituted with substituted or unsubstituted pyridin-on-yl. In some embodiments of formula (Ic), G ¹ is heterocyclyl substituted with pyridin-on-yl, which is substituted with alkyl. In some embodiments of formula (Ic), G ¹ is heterocyclyl substituted with substituted or unsubstituted oxadiazolyl. In some embodiments of formula (Ic), G ¹ is an oxadiazolyl-substituted heterocyclyl that is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group, consisting of alkyl and phenyl. In some embodiments of formula (Ic), G ¹ is a heterocyclyl substituted with a substituted or unsubstituted 9-membered bicyclic heterocyclyl. In some embodiments of formula (Ic), G ¹ is heterocyclyl substituted with -C(O)H. In some embodiments of formula (Ic), G ¹ is heterocyclyl substituted with substituted or unsubstituted pyridazinyl. In some embodiments of formula (Ic), G ¹ is a heterocyclyl substituted with pyridazinyl that is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group, consisting of halogen, alkoxy, alkyl and aminoacyl. In some embodiments of formula (Ic), G ¹ is heterocyclyl substituted with substituted or unsubstituted aminothionyl. In some embodiments of formula (Ic), G ¹ is heterocyclyl substituted with aminothionyl, which is substituted with alkyl. In some embodiments of formula (Ic), G ¹ is heterocyclyl substituted with a substituted or unsubstituted acyl. In some embodiments of formula (Ic), G ¹ is an acyl-substituted heterocyclyl that is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group, consisting of cycloalkyl, alkyl and heterocyclyl. In some embodiments of formula (Ic), G ¹ is an acyl-substituted heterocyclyl that is substituted with morpholinyl. In some embodiments of formula (Ic), G ¹ is heterocyclyl, substituted or unsubstituted aminocarbonylamino. In some embodiments of formula (Ic), G ¹ is an aminocarbonylamino-substituted heterocyclyl that is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group, consisting of cycloalkyl and heterocyclyl.

In some embodiments of formula (Ic), G ¹ is cycloalkyl substituted with substituted or unsubstituted phenyl. In some embodiments of formula (Ic), G ¹ is a cycloalkyl substituted with a substituted or unsubstituted thiazolyl. In some embodiments of formula (Ic), G ¹ is cycloalkyl substituted with thiazolyl, which is substituted with alkyl. In some embodiments of formula (Ic), G ¹ is cycloalkyl substituted with substituted or unsubstituted oxazolyl. In some embodiments of formula (Ic), G ¹ is cycloalkyl substituted with oxazolyl, which is substituted with alkyl. In some embodiments of formula (Ic), G ¹ is a cycloalkyl substituted with a substituted or unsubstituted aminoacyl. In some embodiments of formula (Ic), G ¹ is a cycloalkyl substituted with an aminoacyl that is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group, consisting of alkyl, heterocyclyl and cycloalkyl. In some embodiments of formula (Ic), G ¹ is cycloalkyl substituted with substituted or unsubstituted oxadiazolyl. In some embodiments of formula (Ic), G ¹ is a cycloalkyl substituted with oxadiazolyl that is substituted with one or more substituents (e.g., 1 or 2 or 3 or 1-4 or 13 or 2-4) selected from the group consisting of cycloalkyl and alkyl. In some embodiments of formula (Ic), G ¹ is a cycloalkyl substituted with a substituted or unsubstituted acyl. In some embodiments of formula (Ic), G ¹ is a cycloalkyl substituted with an acyl that is substituted with a heterocyclyl. In some embodiments of formula (Ic), G ¹ is cycloalkyl substituted with substituted or unsubstituted aminocarbonylamino. In some embodiments of formula (Ic), G ¹ is a cycloalkyl substituted with aminocarbonylamino that is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group, consisting of alkyl, cycloalkyl and heterocyclyl. In some embodiments of formula (Ic), G ¹ is cycloalkyl substituted with substituted or unsubstituted alkoxycarbonyl. In some embodiments of formula (Ic), G ¹ is cycloalkyl substituted with alkoxycarbonyl, which is substituted with alkyl. In some embodiments of formula (Ic), G ¹ is cycloalkyl substituted with substituted or unsubstituted alkyl. In some embodiments of formula (Ic), G ¹ is cycloalkyl, substituted with alkyl, which is substituted with hydroxyl. In some embodiments of formula (Ic), G ¹ is cycloalkyl substituted with hydroxyl.

- 21 045362

In some embodiments of formula (Ic), R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl. In some embodiments of formula (Ic), R ³ is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of nitro, alkoxy, halogen, cycloalkyl, cyano, alkenyl, alkoxycarbonyl, phenylcarbonyl and alkyl. In some embodiments of formula (Ic), R ³ is cycloalkyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, cyano and halogen. In some embodiments of Formula (Ic), R ³ is alkyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkoxy, cyano and halogen. In some embodiments of Formula (Ic), R ¹ is substituted or unsubstituted pyridyl. In some embodiments of formula (Ic), R ¹ is 2-pyridyl. In some embodiments of formula (Ic), R ¹ is substituted or unsubstituted phenyl. In some embodiments of formula (Ic), R ¹ is phenyl or pyridinyl, each of which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents independently selected from the group consisting of cyano, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl and substituted or unsubstituted diazirinyl. In some embodiments of Formula (Ic), R ¹ is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halogens. In some embodiments of formula (Ic), R ¹ is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 24) -CF ₃ . In some embodiments of formula (Ic), R ¹ is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) methyls. In some embodiments of formula (Ic), R ¹ is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) diazirinyls. In some embodiments, formula (Ic). R ¹ is phenyl substituted with trifluoromethyldiazirinyl.

In some embodiments of formula (Ic), R ¹ is phenyl substituted with Cl, and R ³ is substituted with 4-methoxyphenylmethyl. In some embodiments of formula (Ic), R ¹ is phenyl substituted with F, and R ³ is substituted with 4-methoxyphenylmethyl. In some embodiments of formula (Ic), R ¹ is phenyl substituted with -CF ₃ and R ³ is substituted with 4methoxyphenylmethyl. In some embodiments of formula (Ic), R ¹ is phenyl substituted with trifluoromethyldiazirinyl, and R ³ is substituted with 4-methoxyphenylmethyl. In another aspect, a compound of formula (I) is a compound of formula (Id) or a pharmaceutically acceptable salt thereof:

where R ^2a represents H or substituted or unsubstituted alkyl; R ^2B is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted puppy Aril and substituted or unsubstituted heteroaryl; n is 0, 1 or 2; each R ^3a is independently selected from the group consisting of halogen and cyano; and R ⁴ is H.

In some embodiments of Formula (Id), R ^2a is H. In some embodiments of Formula (Id), R ^2A is substituted or unsubstituted alkyl. In some embodiments of Formula (Id), R ^2a is substituted or unsubstituted methyl. In some embodiments of formula (Id), R ^2a is methyl.

In some embodiments of formula (Id), R ^2B is H. In some embodiments of formula (Id), R ^2B is substituted or unsubstituted alkyl. In some embodiments of formula (Id), R ^2B is selected from the group consisting of methyl, isopropyl and propyl. In some embodiments of formula (Id), R ^2B is alkyl substituted with hydroxyl, or substituted or unsubstituted alkoxy. In some embodiments of Formula (Id), R ^2B is hydroxymethyl. In some embodiments of Formula (Id), R ^2B is a substituted alkoxyalkyl. In some embodiments of Formula (Id), R ^2B is trifluoromethoxymethyl. In some embodiments,

- 22 045362 formula (Id), R ^2b represents a substituted or unsubstituted cycloalkyl. In some embodiments of formula (Id), R ^2b is substituted or unsubstituted C3-C7 cycloalkyl. In some embodiments of Formula (Id), R ^2b is cyclobutanyl. In some embodiments of Formula (Id), R ^2b is a substituted or unsubstituted heterocyclyl. In some embodiments of Formula (Id), R ^2b is a substituted or unsubstituted C3-C ₇ heterocyclyl. In some embodiments of formula (Id), R ^2b is a substituted or unsubstituted C ₃ -C ₇ heterocyclyl that contains one or more (for example, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) S, N, or O atoms. In some embodiments of Formula (Id), R ^2b is oxetanyl. In some embodiments of Formula (Id), R ^2b is 3-oxetanyl.

In some embodiments of Formula (Id), n is 0. In some embodiments of Formula (Id), n is 1. In some embodiments of Formula (Id), n is 2. In some embodiments of Formula (Id), each R ^3a is a halogen, such as Cl or F. In some embodiments of formula (Id), each R ^3a is cyano. In some embodiments of formula (Id), n is 2, one R ^3a is halogen, and one R ^3a is cyano. In some embodiments of formula (Id), n is 2 and both R ^3a are halogen. In some embodiments of formula (Id), n is 2 and both R ^3a are cyano. In some embodiments of Formula (Id), n is 2, and R ^3a is 2-F and 4-F. In some embodiments of Formula (Id), n is 2, and R ^3a is 2-Cl and 4-Cl. In some embodiments of Formula (Id), n is 2, and R ^3a is 2-F and 4-Cl. In some embodiments of Formula (Id), n is 2, and R ^3a is 2-F and 4-CN. In some embodiments of Formula (Id), n is 2, and R ^3a is 2-Cl and 4-CN. In some embodiments of Formula (Id), n is 2, and R ^3a is 2-CN and 4-Cl. In some embodiments of Formula (Id), n is 2, and R ^3a is 2-CN and 4-F. In some embodiments of Formula (Id), n is 2, and R ^3a is 2-CN and 4-CN. In some embodiments of Formula (Id), R ^2a is H, R ^2b is trifluoromethoxymethyl, n is 1, and R ^3a is cyano or halogen. In some embodiments of Formula (Id), R ^2a is H, R ^2b is 3-oxetanyl, n is 1, and R ^3a is cyano or halogen. In some embodiments of Formula (Id), R ^2a is H, R ^2b is cyclobutanyl, n is 1, and R ^3a is cyano or halogen. In some embodiments of formula (Id), R ^2a is H, R ^2b is trifluoromethoxymethyl, n is 2, and each R ^3a is independently cyano or halogen. In some embodiments of Formula (Id), R ^2a is H, R ^2b is 3-oxetanyl, n is 2, and each R ^3a is independently cyano or halogen. In some embodiments of formula (Id), R ^2a is H, R ^2b is cyclobutanyl, n is 2, and each R ^3a is independently cyano or halogen.

In another aspect, the compound of formula (I) is a compound of formula (Ie) or a pharmaceutically acceptable salt thereof:

where R ¹ is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted pyridyl; R ^2a represents H or substituted or unsubstituted alkyl; R ^2b represents substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; and R ⁴ represents H; wherein R ^2b is 4-methoxyphenyl, R ¹ is substituted or unsubstituted pyridyl or phenyl substituted with at least one substituent other than methyl or methoxy.

In some embodiments of formula (Ie), R ^2a is H. In some embodiments of formula (Ie), R ^2a is substituted or unsubstituted alkyl. In some embodiments of Formula (Ie), R ^2a is substituted or unsubstituted methyl. In some embodiments of formula (Ie), R ^2a is methyl.

In some embodiments of Formula (Ie), R ^2b is substituted or unsubstituted pyridyl. In some embodiments of Formula (Ie), R ^2b is 2pyridyl. In some embodiments, R ^2b is substituted or unsubstituted phenyl. In some embodiments of formula (Ie), R ^2b is phenyl or pyridyl, each of which is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents independently selected from a group consisting of halogen, substituted or unsubstituted alkoxy, and substituted or unsubstituted alkyl. In some embodiments, formula

- 23 045362 (Ie), R ^2B is pyridyl substituted with one or more (for example 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of halogen and substituted or unsubstituted alkyl. In some embodiments of formula (Ie), R ^2B is pyridyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halogens. In some embodiments of formula (Ie), R ^2B is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halogens. In some embodiments of formula (Ie), R ^2B is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) -CF ₃ . In some embodiments of formula (Ie), R ^2B is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) alkoxy. In some embodiments of formula (Ie), R ^2B is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) methoxy.

In some embodiments of Formula (Ie), R ¹ is substituted or unsubstituted pyridyl. In some embodiments of Formula (Ie), R ¹ is 2pyridyl. In some embodiments of formula (Ie), R ¹ is unsubstituted phenyl. In some embodiments of Formula (Ie), R ¹ is phenyl or pyridinyl, each of which is substituted with one or more substituents independently selected from the group consisting of cyano, halogen, and substituted or unsubstituted alkyl. In some embodiments of Formula (Ie), R ¹ is pyridyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halogens. In some embodiments of Formula (Ie), R ¹ is pyridyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) -CF3. In some embodiments of Formula (Ie), R ¹ is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halogens. In some embodiments of Formula (Ie), R ¹ is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) -CF3. In some embodiments of formula (Ie), R ¹ is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 24) CN. In some embodiments of Formula (Ie), R ¹ is phenyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) methyls. In some embodiments of formula (Ie), R ^2B is 4-methoxyphenyl and R ¹ is substituted or unsubstituted pyridyl. In some embodiments of formula (Ie). R ^2B is 4-methoxyphenyl and R ¹ is 2-pyridyl. In some embodiments of formula (Ie), R ^2B is 4-methoxyphenyl, and R ¹ is 2-pyridyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4 ) halogens. In some embodiments of Formula (Ie), R ^2B is 4-methoxyphenyl, and R ¹ is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) halogens . In some embodiments of formula (Ie), R ^2B is 4-methoxyphenyl, and R ¹ is phenyl substituted with 4-Cl.

In another aspect, a compound of formula (I) is a compound of formula (If) or a pharmaceutically acceptable salt thereof:

where G ¹ is selected from the group consisting of a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl and a substituted or unsubstituted heterocyclyl ring, each of which is optionally fused to a phenyl ring; R ^1a is selected from the group consisting of cyano, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl and substituted or unsubstituted diazirinyl; each R ^2a is independently selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino, and substituted or unsubstituted alkyl; n is 0, 1, 2 or 3; R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted aryl; and R ⁴ represents H; moreover, when R ³ represents 4-methoxyphenylmethyl, R ^1a does not represent methyl or methoxy.

It is clear that the G ¹ group is a ring containing a carbon atom, which it shares with the piperazinedione ring.

- 24 045362

In some embodiments of formula (If), G ¹ is selected from the group consisting of substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted 2,3-dihydro-1H-indene. In some embodiments of formula (Ic), G ¹ is a substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments of formula (Ic), G ¹ is a substituted or unsubstituted C3-C ₆ heterocyclyl. In some embodiments of formula (Ic), G ¹ is substituted or unsubstituted cyclopropyl. In some embodiments of formula (Ic), G ¹ is substituted or unsubstituted cyclobutanyl. In some embodiments of formula (Ic), G ¹ is substituted or unsubstituted azetidinyl. In some embodiments of formula (Ic), G ¹ is substituted or unsubstituted tetrahydrofuranyl. In some embodiments of formula (Ic), G ¹ is substituted or unsubstituted pyrrolidinyl. In some embodiments of formula (Ic), G ¹ is substituted or unsubstituted pyrrolidin-2-on-yl.

In some embodiments of formula (If), G ¹ is heterocyclyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) R ^2a . Each R ^2a is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminothionyl, substituted or unsubstituted aminocarbonylamino, and substituted alkyl or unsubstituted alkyl. In some embodiments of formula (If), R ^2a is substituted or unsubstituted phenyl. In some embodiments of formula (If), R ^2a is phenyl substituted with halogen. In some embodiments of formula (If), R ^2a is substituted or unsubstituted heteroaryl. In some embodiments of formula (If), R ^2a is substituted or unsubstituted pyridyl. In some embodiments of formula (If), R ^2a is pyridyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, CN, hydroxyl, alkoxycarbonyl, methoxycarbonyl, alkoxy, carboxyl, cycloalkyl, halogen and aminoacyl. In some embodiments of formula (If), R ^2a is substituted or unsubstituted pyrimidyl. In some embodiments of formula (If), R ^2a is substituted or unsubstituted pyrazolyl. In some embodiments of formula (If), R ^2a is pyrazolyl substituted with alkyl. In some embodiments of formula (If), R ^2a is a substituted or unsubstituted thiazolyl. In some embodiments of formula (If), R ^2a is a thiazolyl substituted with an aminoacyl. In some embodiments of formula (If), R ^2a is a substituted or unsubstituted alkoxycarbonyl. In some embodiments of formula (If), R ^2a is methoxycarbonyl. In some embodiments of formula (If), R ^2a is a substituted or unsubstituted aminoacyl. In some embodiments of formula (If), R ^2a is methylaminoacyl. In some embodiments of formula (If), R ^2a is aminoacyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of aryl, cycloalkyl, pyridyl, pyrazolyl and alkoxyalkyl. In some embodiments of formula (If), R ^2a is a substituted or unsubstituted pyridin-on-yl. In some embodiments of formula (If), R ^2a is pyridin-on-yl substituted with alkyl. In some embodiments of formula (If), R ^2a is substituted or unsubstituted oxadiazolyl. In some embodiments of formula (If), R ^2a is oxadiazolyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl and phenyl In some embodiments of formula (If), R ^2a is a substituted or unsubstituted 9-membered bicyclic heterocyclyl. In some embodiments of formula (If), R ^2a is -C(O)H. In some embodiments of formula (If), R ^2a is substituted or unsubstituted pyridazinyl. In some embodiments of formula (If), R ^2a is pyridazinyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of halogen, alkoxy, alkyl and aminoacyl. In some embodiments of formula (If), R ^2a is substituted or unsubstituted aminothionyl. In some embodiments of formula (If), R ^2a is aminothionyl substituted with alkyl. In some embodiments of formula (If), R ^2a is a substituted or unsubstituted acyl. In some embodiments of formula (If), R ^2a is acyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of cycloalkyl, alkyl and heterocyclyl. In some embodiments of formula (If), R ^2a is acyl substituted with morpholinyl. In some embodiments of formula (If), R ^2a is substituted or unsubstituted aminocarbonylamino. In some embodiments of formula (If), R ^2a is aminocarbonylamino substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting

- 25 045362 cabbage soup from cycloalkyl and heterocyclyl.

In some embodiments of formula (If), G ¹ is cycloalkyl substituted with one or more (eg, 1 or 2 or 3 or 1-4 or 1-3 or 2-4) R ^2a . In some embodiments of formula (If), R ^2a is substituted or unsubstituted phenyl. In some embodiments of formula (If), R ^2a is a substituted or unsubstituted thiazolyl. In some embodiments of formula (If), R ^2a is thiazolyl substituted with alkyl. In some embodiments of formula (If), R ^2a is a substituted or unsubstituted oxazolyl. In some embodiments of formula (If), R ^2a is oxazolyl substituted with alkyl. In some embodiments of formula (If), R ^2a is a substituted or unsubstituted aminoacyl. In some embodiments of formula (If), R ^2a is aminoacyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 13 or 2-4) substituents selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl. In some embodiments of formula (If), R ^2a is substituted or unsubstituted oxadiazolyl. In some embodiments of formula (If), R ^2a is oxadiazolyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of cycloalkyl and alkyl In some embodiments of formula (If), R ^2a is a substituted or unsubstituted acyl. In some embodiments of formula (If), R ^2a is acyl substituted with heterocyclyl. In some embodiments of formula (If), R ^2a is substituted or unsubstituted aminocarbonylamino. In some embodiments of formula (If), R ^2a is aminocarbonylamino substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, cycloalkyl and heterocyclyl. In some embodiments of formula (If), R ^2a is a substituted or unsubstituted alkoxycarbonyl. In some embodiments of formula (If), R ^2a is alkoxy carbonyl substituted with alkyl. In some embodiments of formula (If), R ^2a is substituted or unsubstituted alkyl. In some embodiments of formula (If), R ^2a is alkyl substituted with hydroxyl. In some embodiments of formula (If), R ^2a is hydroxyl.

In some embodiments of formula (If), R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl. In some embodiments of formula (If), R ³ is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of nitro, alkoxy, halogen, cycloalkyl, cyano, alkenyl, alkoxycarbonyl, phenylcarbonyl and alkyl. In some embodiments of formula (If), R ³ is cycloalkyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, cyano and halogen. In some embodiments of formula (If), R ³ is alkyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkoxy, cyano and halogen. In some embodiments of formula (If), R ^1a is selected from the group consisting of cyano, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted diazirinyl. In some embodiments of formula (If), R ^1a is halogen. In some embodiments of formula (If), R ^1a is -CF3. In some embodiments of formula (If), R ^1a is methyl. In some embodiments of formula (If), R ^1a is diazirinyl. In some embodiments of formula (If), R ^1a is trifluoromethyldiazirinyl. In some embodiments of formula (If), R ^1a is Cl, and R ³ is substituted with 4-methoxyphenylmethyl. In some embodiments of formula (If), R ^1a is F, and R ³ is substituted with 4-methoxyphenylmethyl. In some embodiments of formula (If), R ^1a is -CF3, and R ³ is substituted with 4-methoxyphenylmethyl. In some embodiments of Formula (If), R ^1a is trifluoromethyldiazirinyl, and R ³ is substituted with 4methoxyphenylmethyl.

In some embodiments of Formula (I), Formula (Ic), and Formula (If), G ¹ is selected from the group consisting of:

- 26 045362

where * indicates the point of attachment to the original structure.

R ^2a is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino and substituted unsubstituted or unsubstituted alkyl; and n is 0, 1, 2 or 3.

In some embodiments of Formula (I), Formula (Ic), and Formula (If), G ¹ is substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) R ^2a independently selected from the group consisting of:

where n is 0-3 and each X is independently selected from the group consisting of H, halogen, alkyl, cyano, hydroxyl, cycloalkyl, alkoxycarbonyl, carboxyl, aminoacyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, aminothionyl and heterocyclyl.

In another aspect, a compound of formula (Ig) or a pharmaceutically acceptable salt thereof is provided:

where R ^1a is selected from the group consisting of cyano, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl and substituted or unsubstituted diazirinyl; R ^2a is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl,

- 27 045362 substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino and substituted or unsubstituted alkyl; n is 0, 1,2, or 3; each R ^3a is independently selected from the group consisting of substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, halogen, nitro and cyano; and R ⁴ is H. In some embodiments of formula (Ig), R ^1a is selected from the group consisting of cyano, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted diazirinyl. In some embodiments of formula (Ig), R ^1a is halogen. In some embodiments of formula (Ig), R ^1a is -CF ₃ . In some embodiments of formula (Ig), R ^1a is methyl. In some embodiments of Formula (Ig), R ^1a is diazirinyl. In some embodiments of Formula (Ig), R ^1a is trifluoromethyldiazirinyl. In some embodiments of Formula (Ig), n is 0. In some embodiments of Formula (Ig), n is 1. In some embodiments of Formula (Ig), n is 2. In some embodiments of Formula (Ig), each R ^3a is a halogen, such as Cl or F. In some embodiments of formula (Ig), each R ^3a is cyano. In some embodiments of formula (Ig), n is 2, one R ^3a is halogen, and one R ^3a is cyano. In some embodiments of formula (If), n is 2 and both R ^3a are halogen. In some embodiments of formula (If), n is 2 and both R ^3a are cyano. In some embodiments of formula (If), n is 2, and R ^3a are 2-F and 4-F. In some embodiments of Formula (Ig), n is 2, and R ^3a is 2-Cl and 4-Cl. In some embodiments of Formula (Ig), n is 2, and R ^3a is 2-F and 4-Cl. In some embodiments of Formula (Ig), n is 2, and R ^3a is 3-F and 4-Cl. In some embodiments of Formula (Ig), n is 2, and R ^3a is 3-F and 4-CN. In some embodiments of Formula (Ig), n is 2, and R ^3a is 4-F and 3-Cl. In some embodiments of Formula (Ig), n is 2, and R ^3a is 2-F and 4-CN. In some embodiments of Formula (Ig), n is 2, and R ^3a is 2-Cl and 4-CN. In some embodiments of Formula (Ig), n is 2, and R ^3a is 2-CN and 4-Cl. In some embodiments of Formula (Ig), n is 2, and R ^3a is 2-CN and 4-F. In some embodiments of Formula (Ig), n is 2, and R ^3a is 2-CN and 4-CN. In some embodiments of formula (Ig), R ^3a is nitro. In some embodiments of Formula (Ig), n is 1 and R ^3a is 4-nitro. In some embodiments of formula (Ig), n is 1 and R ^3a is 4Cl or 3-Cl. In some embodiments of Formula (Ig), n is 1 and R ^3a is 4-F or 3-F. In some embodiments of formula (Ig), n is 1 and R ^3a is 4-CN or 3-CN. In some embodiments of Formula (Ig), R ^3a is difluoromethoxy. In some embodiments of Formula (Ig), R ^3a is propenyl. In some embodiments of formula (Ig), R ^3a is methyl. In some embodiments of Formula (Ig), n is 2, and R ^3a is 3-methyl and 4-Cl. In some embodiments of Formula (Ig), n is 2, and R ^3a is 3-methyl and 4-CN. In some embodiments of Formula (Ig), n is 2, and R ^3a is 3-F and 4-difluoromethoxy.

In some embodiments of Formula (Ig), R ^2a is substituted or unsubstituted phenyl. In some embodiments of Formula (Ig), R ^2a is a substituted or unsubstituted aminoacyl. In some embodiments of formula (Ig), R ^2a is aminoacyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, heterocyclyl and cycloalkyl. In some embodiments of Formula (Ig), R ^2a is substituted or unsubstituted oxadiazolyl. In some embodiments of formula (Ig), R ^2a is oxadiazolyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of cycloalkyl and alkyl In some embodiments of Formula (Ig), R ^2a is a substituted or unsubstituted acyl. In some embodiments of formula (Ig), R ^2a is acyl substituted with heterocyclyl. In some embodiments of Formula (Ig), R ^2a is acyl substituted with aryl. In some embodiments of formula (Ig), R ^2a is acyl substituted with phenyl. In some embodiments of Formula (Ig), R ^2a is acyl substituted with alkyl. In some embodiments of Formula (Ig), R ^2a is substituted or unsubstituted pyridyl. In some embodiments of formula (Ig), R ^2a is pyridyl substituted with CN or halogen. In some embodiments of Formula (Ig), R ^2a is substituted or unsubstituted aminocarbonylamino. In some embodiments of formula (Ig), R ^2a is aminocarbonylamino substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, cycloalkyl and heterocyclyl. In some embodiments of Formula (Ig), R ^2a is a substituted or unsubstituted alkoxycarbonyl. In some embodiments of formula (Ig), R ^2a

- 28 045362 is alkoxy carbonyl substituted with alkyl. In some embodiments of Formula (Ig), R ^2a is substituted or unsubstituted alkyl. In some embodiments of formula (Ig), R ^2a is alkyl substituted with hydroxyl. In some embodiments of formula (Ig), R ^2a is alkyl substituted with halogen. In some embodiments of formula (Ig), R ^2a is hydroxyl. In some embodiments of Formula (Ig), R ^2a is substituted or unsubstituted aminosulfonyl. In some embodiments of Formula (Ig), R ^2a is aminosulfonyl substituted with alkyl. In another aspect, a compound of formula (Ih) or a pharmaceutically acceptable salt thereof is provided:

where R ^1a is selected from the group consisting of cyano, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl and substituted or unsubstituted diazirinyl; R ^2a is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino and substituted unsubstituted or unsubstituted alkyl; R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted aryl; and R ⁴ represents H; moreover, when R ³ represents 4-methoxyphenylmethyl, R ^1a does not represent methyl or methoxy.

In some embodiments of formula (Ih), R ^1a is selected from the group consisting of cyano, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted diazirinyl. In some embodiments of formula (Ih), R ^1a is halogen. In some embodiments of formula (Ih), R ^1a is CF ₃ . In some embodiments of formula (Ih), R ^1a is methyl. In some embodiments of formula (Ih), R ^1a is diazirinyl. In some embodiments of Formula (Ih), R ^1a is trifluoromethyldiazirinyl. In some embodiments of Formula (Ih), R ^2a is substituted or unsubstituted phenyl. In some embodiments of Formula (Ih), R ^2a is a substituted or unsubstituted aminoacyl. In some embodiments of formula (Ih), R ^2a is aminoacyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, heterocyclyl and cycloalkyl. In some embodiments of Formula (Ih), R ^2a is substituted or unsubstituted oxadiazolyl. In some embodiments of formula (Ih), R ^2a is oxadiazolyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of cycloalkyl and alkyl In some embodiments of formula (Ih), R ^2a is a substituted or unsubstituted acyl. In some embodiments of formula (Ih), R ^2a is acyl substituted with heterocyclyl. In some embodiments of Formula (Ih), R ^2a is acyl substituted with aryl. In some embodiments of formula (Ih), R ^2a is acyl substituted with phenyl. In some embodiments of formula (Ih), R ^2a is acyl substituted with alkyl. In some embodiments of Formula (Ih), R ^2a is substituted or unsubstituted pyridyl. In some embodiments of formula (Ih), R ^2a is pyridyl substituted with CN or halogen. In some embodiments of Formula (Ih), R ^2a is substituted or unsubstituted aminocarbonylamino. In some embodiments of formula (Ih), R ^2a is aminocarbonylamino substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, cycloalkyl and heterocyclyl. In some embodiments of Formula (Ih), R ^2a is a substituted or unsubstituted alkoxycarbonyl. In some embodiments of Formula (Ih), R ^2a is alkoxycarbonyl substituted with alkyl. In some embodiments of Formula (Ih), R ^2a is substituted or unsubstituted alkyl. In some embodiments of Formula (In), R ^2a is alkyl substituted with hydroxyl. In some embodiments of formula (In), R ^2a is alkyl substituted with halogen. In some embodiments of Formula (In), R ^2a is hydroxyl. In some embodiments of Formula (In), R ^2a is substituted or unsubstituted aminosulfonyl. In some embodiments

- 29 045362 formula (Ih), R ^2a represents aminosulfonyl substituted with alkyl. In some embodiments of Formula (Ih), R ^2a is a substituted or unsubstituted thiazolyl. In some embodiments of formula (Ih), R ^2a is thiazolyl substituted with alkyl. In some embodiments of Formula (Ih), R ^2a is a substituted or unsubstituted oxazolyl. In some embodiments of formula (Ih), R ^2a is oxazolyl substituted with alkyl.

In some embodiments of formula (Ih), R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl. In some embodiments of formula (Ih), R ³ is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of nitro, alkoxy, halogen, cycloalkyl, cyano, alkenyl, alkoxycarbonyl, phenylcarbonyl and alkyl. In some embodiments, R ³ is phenyl substituted with CN and F. In some embodiments of formula (Ih), R ³ is alkyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkoxy, cyano and halogen. In some embodiments, R ³ is isopropyl. In another aspect, there is provided a compound of formula (Ii), or a pharmaceutically acceptable salt thereof:

where R ^1a is selected from the group consisting of cyano, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl and substituted or unsubstituted diazirinyl; R ^2a is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino and substituted unsubstituted or unsubstituted alkyl; R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted aryl; R ⁴ represents H; R ⁵ represents H or substituted or unsubstituted alkyl; and X and Y are independently -CH2- or -C(O)-; moreover, when R ³ represents 4methoxyphenylmethyl, R ^1a does not represent methyl or methoxy. In some embodiments of formula (Ii), R ^1a is selected from the group consisting of cyano, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted diazirinyl. In some embodiments of formula (Ii), R ^1a is halogen. In some embodiments of formula (Ii), R ^1a is -CF3. In some embodiments of formula (Ii), R ^1a is methyl. In some embodiments of formula (Ii), R ^1a is Cl. In some embodiments of Formula (Ih), R ^1a is trifluoromethyldiazirinyl.

In some embodiments of Formula (Ii), R ^2a is substituted or unsubstituted phenyl. In some embodiments of Formula (Ii), R ^2a is substituted or unsubstituted pyridyl. In some embodiments of Formula (Ii), R ^2a is pyridyl substituted with alkyl, CN, or halogen. In some embodiments of Formula (Ii), R ^2a is substituted or unsubstituted pyrimidyl. In some embodiments of Formula (Ii), R ^2a is substituted or unsubstituted pyridazinyl. In some embodiments of Formula (Ii), R ^2a is pyridazinyl. substituted with one or more (eg 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of halogen, alkoxy, alkyl and aminoacyl. In some embodiments of Formula (Ii), R ^2a is a substituted or unsubstituted aminoacyl. In some embodiments of formula (Ii), R ^2a is aminoacyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, heterocyclyl, aryl, heteroaryl and cycloalkyl. In some embodiments of Formula (Ii), R ^2a is substituted or unsubstituted pyrazolyl. In some embodiments of Formula (Ii), R ^2a is pyrazolyl substituted with alkyl. In some embodiments of Formula (Ii), R ^2a is substituted or unsubstituted oxadiazolyl. In some embodiments of Formula (Ii), R ^2a is oxadiazolyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of cycloalkyl and alkyl In some embodiments of formula (Ii), R ^2a

- 30 045362 is a substituted or unsubstituted acyl. In some embodiments of Formula (Ii), R ^2a is acyl substituted with heterocyclyl. In some embodiments of formula (Ii), R ^2a is acyl substituted with aryl. In some embodiments of formula (Ii), R ^2a is acyl substituted with phenyl. In some embodiments of Formula (Ii), R ^2a is acyl substituted with alkyl. In some embodiments of Formula (Ii), R ^2a is substituted or unsubstituted aminocarbonylamino. In some embodiments of Formula (Ii), R ^2a is aminocarbonylamino substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, cycloalkyl and heterocyclyl. In some embodiments of Formula (Ii), R ^2a is a substituted or unsubstituted alkoxycarbonyl. In some embodiments of Formula (Ii), R ^2a is alkoxycarbonyl substituted with alkyl. In some embodiments of Formula (Ii), R ^2a is substituted or unsubstituted alkyl. In some embodiments of Formula (Ii), R ^2a is alkyl substituted with hydroxyl. In some embodiments of Formula (Ii), R ^2a is alkyl substituted with halogen. In some embodiments of formula (Ii), R ^2a is hydroxyl. In some embodiments of Formula (Ii), R ^2a is substituted or unsubstituted aminosulfonyl. In some embodiments of Formula (Ii), R ^2a is aminosulfonyl substituted with alkyl. In some embodiments of formula (Ii), R ^2a is a substituted or unsubstituted thiazolyl. In some embodiments of Formula (Ii), R ^2a is thiazolyl substituted with alkyl. In some embodiments of Formula (Ii), R ^2a is a substituted or unsubstituted oxazolyl. In some embodiments of formula (ii), R ^2a is oxazolyl substituted with alkyl.

In some embodiments of formula (Ii), R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted aryl. In some embodiments of Formula (Ii), R ³ is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of nitro, alkoxy, halogen, cycloalkyl, cyano, alkenyl, alkoxycarbonyl, phenylcarbonyl and alkyl. In some embodiments of Formula (Ii), R ³ is phenyl substituted with CN and F. In some embodiments of Formula (Ii), R ³ is phenyl substituted with CN or Cl. In some embodiments of Formula (Ii), R ³ is cycloalkyl. substituted with one or more (eg 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkyl, cyano and halogen. In some embodiments of formula (Ii), R ³ is cyclopropyl substituted with alkyl. In some embodiments of Formula (Ii), R ³ is alkyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of alkoxy, cyano and halogen. In some embodiments of formula (Ii), R ³ is isopropyl, methyl or ethyl. In some embodiments of Formula (Ii), R ³ is a substituted or unsubstituted heterocyclyl. In some embodiments of formula (Ii), R ³ is furanyl. In some embodiments of Formula (Ii), R ⁵ is substituted or unsubstituted alkyl. In some embodiments of formula (Ii), R ⁵ is methyl. In some embodiments of Formula (Ii), R ⁵ is alkyl. In some embodiments of Formula (Ii), R ⁵ is hydroxymethyl. In some embodiments of Formula (Ii), R ⁵ is H. In some embodiments of Formula (Ii), X and Y are independently -CH ₂ - or -C(O)-. In some embodiments of formula (Ii), both X and Y are -CH2-. In some embodiments of Formula (Ii), X is -CH2- and Y is -C(O)-. In some embodiments of formula (Ii), Y is CH ₂ - and X is -C(O)-.

In another aspect, the compound of formula (I) is a compound of formula (Ij) or a pharmaceutically acceptable salt thereof:

where R ¹ represents substituted or unsubstituted phenyl; each R ^2b independently represents substituted or unsubstituted alkyl; R ³ represents substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; R ⁴ represents H; R ⁵ represents H or substituted or unsubstituted alkyl; n is 0, 1 or 2; and q is 0 or 1; and when

- 31 045362

R ³ is substituted or unsubstituted phenyl, then R ¹ is substituted or unsubstituted pyridyl or phenyl substituted with at least one substituent other than methyl or methoxy.

In some embodiments of formula (Ij), R ¹ is substituted or unsubstituted phenyl. In some embodiments of formula (Ij), R ¹ is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of halogen, unsubstituted alkyl and alkyl substituted with one or more halogen groups. In some embodiments of formula (Ij), R ¹ is phenyl substituted with halogen. In some embodiments of formula (Ij), R ¹ is phenyl substituted with F or Cl. In some embodiments of formula (Ij), R ¹ is phenyl substituted with unsubstituted alkyl. In some embodiments of formula (Ij), R ¹ is phenyl substituted with methyl or ethyl. In some embodiments of Formula (Ij), R ¹ is phenyl, substituted alkyl, substituted with one or more halogen groups. In some embodiments of formula (Ij), R ¹ is phenyl substituted with -CHF2 or -CF3. In some embodiments of Formula (Ij), R ¹ is phenyl substituted with 4-Cl. In some embodiments of Formula (Ij), R ¹ is phenyl substituted with 4-CF3. In some embodiments of formula (Ij), R ¹ is phenyl substituted with two or more groups selected from the group consisting of F, Cl, methyl and -CF3. In some embodiments of formula (Ij), R ¹ is phenyl substituted with two F groups. In some embodiments of formula (Ij), R ¹ is phenyl substituted with F and Cl. In some embodiments of formula (Ij), R ¹ is phenyl substituted with F and methyl. In some embodiments of formula (Ij), R ¹ is phenyl substituted with F and -CF3. In some embodiments of formula (Ij), n is 0, 1, or 2. In some embodiments of formula (Ij), n is 0. In some embodiments of formula (Ij), n is 1. In some embodiments of formula (Ij ), n is 1, and R ^2b is substituted or unsubstituted alkyl. In some embodiments of Formula (Ij), n is 1 and R ^2b is unsubstituted alkyl. In some embodiments of formula (Ij), n is 1 and R ^2b is methyl. In some embodiments of Formula (Ij), R ³ is substituted or unsubstituted phenyl. In some embodiments of formula (Ij), R ³ is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of halogen and cyano. In some embodiments of formula (Ij), R ³ is phenyl substituted with halogen. In some embodiments of formula (Ij), R ³ is phenyl substituted with F, Cl or Br. In some embodiments of Formula (Ij), R ³ is phenyl substituted with cyano. In some embodiments of Formula (Ij), R ³ is phenyl substituted with two or more groups selected from the group consisting of F, Cl, Br and cyano. In some embodiments of Formula (Ij), R ³ is phenyl substituted with F and Cl. In some embodiments of Formula (Ij), R ³ is phenyl substituted with F and Br. In some embodiments of Formula (Ij), R ³ is phenyl substituted with F and cyano. In some embodiments of Formula (Ij), R ³ is substituted or unsubstituted pyridinyl. In some embodiments of formula (Ij), R ³ is pyridinyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl and substituted or unsubstituted alkoxy. In some embodiments of formula (Ij), R ³ is pyridinyl substituted with halogen. In some embodiments of Formula (Ij), R ³ is pyridinyl substituted with F or Cl. In some embodiments of formula (ij), R ³ is pyridinyl substituted with unsubstituted alkyl. In some embodiments of Formula (Ij), R ³ is pyridinyl substituted with methyl. In some embodiments of Formula (Ij), R ³ is pyridinyl substituted with unsubstituted alkenyl. In some embodiments of Formula (Ij), R ³ is pyridinyl substituted with -CH=CH2. In some embodiments of formula (Ij), R ³ is pyridinyl substituted with alkoxy, optionally substituted with halogen. In some embodiments of Formula (Ij), R ³ is pyridinyl substituted with methoxy or -OCHF2. In some embodiments of formula (Ij), R ³ is pyridinyl substituted with two or more groups selected from the group consisting of halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkoxy. In some embodiments of Formula (Ij), R ³ is pyridinyl substituted with F and Cl. In some embodiments of formula (Ij), R ³ is pyridinyl substituted with Cl and methyl. In some embodiments of Formula (Ij), R ³ is pyridinyl substituted with F and methoxy. In some embodiments of Formula (Ij), R ³ is pyridinyl substituted with F and -OCHF2. In some embodiments of Formula (Ij), R ³ is pyridinyl substituted with F and -CH=CH ₂ . In some embodiments of formula (Ij), R ³

- 32 045362 is a substituted or unsubstituted pyridin-2-yl. In some embodiments of Formula (Ij), R ⁵ is H. In some embodiments of Formula (Ij), R ⁵ is substituted or unsubstituted alkyl. In some embodiments of formula (Ij), R ⁵ is methyl.

In some embodiments of formula (Ij), q is 0. In some embodiments of formula (Ij), q is 1.

In some embodiments of formula (Ij), R ¹ is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CHF2 and -CF3, n is 0, R ³ is pyridinyl, substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CH=CH2, methoxy and -OCHF2, R ⁵ is H, and q is 0. In some embodiments of formula (Ij), R ¹ is is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CHF2 and -CF3, n is 0, R ³ is phenyl substituted with one or more substituents selected from the group consisting of F , Cl, Br and cyano, R ⁵ is H, and q is 0. In some embodiments of formula (Ij), R ¹ is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl , -CHF2 and -CF3, n is 1, R ^2b is methyl, R ³ is pyridinyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CH=CH2, methoxy and -OCHF2 , R ⁵ is H, and q is 0. In some embodiments of formula (Ij), R ¹ is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CHF2 and -CF3 , n is 1, R ^2b is methyl, R ³ is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, Br and cyano, R ⁵ is H, and q is 0. In some In embodiments of formula (Ij), R ¹ is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CHF2 and -CF3, n is 0, R ³ is pyridinyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CH=CH2, methoxy and -OCHF ₂ , R ⁵ is H, and q is 1. In some embodiments of formula (Ij), R ¹ is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CHF2 and -CF3, n is 0, R ³ is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, Br and cyano, R ⁵ is H, and q is 1. In some embodiments of formula (Ij), R ¹ is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CHF2 and -CF3, n is 1, R ^2b is methyl, R ³ is pyridinyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CH=CH2, methoxy and -OCHF2, R ⁵ is H and q is 1. In some embodiments of formula (Ij), R ¹ is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, methyl, -CHF2 and -CF ₃ , n is 1, R ^2b is methyl, R ³ is phenyl substituted with one or more substituents selected from the group consisting of F, Cl, Br and cyano, R ⁵ is H, and q is 1.

In some embodiments of Formula (Ij): R ¹ is phenyl substituted with one substituent selected from the group consisting of F, Cl, methyl, ethyl, -CHF2 or -CF3; n is 0 or n is 1, and R ^2b is methyl; R ³ is pyridinyl substituted with two substituents selected from the group consisting of F, Cl, methyl, -CH=CH2, methoxy and -OCHF ₂ ; R ⁵ represents H; and q is 0 or 1.

In another aspect, the compound of formula (I) is a compound of formula (Ik-1) or a pharmaceutically acceptable salt thereof:

where R ^2a represents H or substituted or unsubstituted alkyl; R ^2B is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclyl; m is 0, 1 or 2; p is 0, 1 or 2; each R ^1a is independently selected from the group consisting of halogen and substituted or unsubstituted alkyl; each R ^3a is independently selected from the group consisting of halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkoxy; and R ⁴ is H. In some embodiments of formula (Ik-1), R ^2A is H. In some embodiments of formula (Ik-1), R ^2A is substituted or unsubstituted alkyl. In some embodiments, formula (Ik-1). R ^2A is substituted or

- 33 045362 unsubstituted methyl. In some embodiments of Formula (Ik-1), R ^2A is methyl.

In some embodiments of Formula (Ik-1), R ^2B is substituted or unsubstituted alkyl. In some embodiments of formula (Ik-1), R ^2B is isopropyl. In some embodiments of Formula (Ik-1), R ^2B is alkyl. In some embodiments of formula (Ik-1), R ^2B is alkyl substituted with halogen. In some embodiments of Formula (Ik-1), R ^2B is -CHF2. In some embodiments of Formula (Ik-1), R ^2B is alkyl substituted with -OH. In some embodiments of Formula (Ik-1), R ^2B is -CH(OH)CH3. In some embodiments of Formula (Ik-1), R ^2B is -CH2OH. In some embodiments of Formula (Ik-1), R ^2b is -CH2CH ₂ SCH ₃ . In some embodiments of formula (Ik-1), R ^2b is -CH2CH2S(O)2CH3. In some embodiments of Formula (Ik-1), R ^2b is -CH2N(H)C(O)CH ₃ . In some embodiments of formula (Ik-1), R ^2B is -CH2CH2C(O)NH2. In some embodiments of Formula (Ik-1), R ^2B is alkyl substituted with heterocyclyl. In some embodiments of Formula (Ik-1), R ^2b is C1-C2 alkyl substituted with heterocyclyl. In some embodiments of formula (Ik-1), R ^2B is methyl substituted with oxetanyl. In some embodiments of Formula (Ik-1), R ^2B is methyl substituted with azetidinyl.

In some embodiments of formula (Ik-1), R ^2B is a substituted or unsubstituted cycloalkyl. In some embodiments of Formula (Ik-1), R ^2B is substituted or unsubstituted C ₃ -C ₅ -cycloalkyl. In some embodiments of Formula (Ik-1), R ^2B is unsubstituted cyclopropyl. In some embodiments of formula (Ik-1), R ^2B is unsubstituted cyclobutyl. In some embodiments of formula (Ik-1), R ^2B is cyclobutyl substituted with hydroxyl. In some embodiments of formula (Ik-1), R ^2B is cyclobutyl substituted with methoxy. In some embodiments of Formula (Ik-1), R ^2B is a polycyclic cycloalkyl. In some embodiments of Formula (Ik-1), R ^2B is substituted or unsubstituted bicyclo[1.1.1]pentanyl. In some embodiments of Formula (Ik-1), R ^2B is bicyclo[1.1.1]pentanyl substituted with a group selected from the group consisting of hydroxy, alkoxycarbonyl, carbamoyl, and hydroxymethyl.

In some embodiments of Formula (Ik-1), R ^2B is a substituted or unsubstituted heterocyclyl. In some embodiments of formula (Ik-1), R ^2B is a substituted or unsubstituted 4-membered to 7-membered heterocyclyl. In some embodiments of Formula (Ik-1), R ^2B is a substituted or unsubstituted 4- to 7-membered heterocyclyl that contains one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2- 4) N, O or S atoms. In some embodiments of formula (Ik-1), R ^2B is a substituted or unsubstituted 4-6 membered heterocyclyl containing one nitrogen atom. In some embodiments of Formula (Ik-1), R ^2B is substituted or unsubstituted azetidinyl. In some embodiments of formula (Ik-1), R ^2B is 3-azetidinyl substituted with aminoacyl or acyl. In some embodiments of formula (Ik-1), R ^2B is a substituted or unsubstituted 4-6 membered heterocyclyl containing one O atom. In some embodiments of formula (Ik-1), R ^2B is a substituted or unsubstituted oxetanyl. In some embodiments of Formula (Ik-1), R ^2B is unsubstituted 3-oxetanyl. In some embodiments of Formula (Ik-1), R ^2B is 3-oxetanyl substituted with methyl. In some embodiments of Formula (Ik-1), R ^2B is substituted or unsubstituted tetrahydro-2H-pyranyl. In some embodiments of Formula (Ik-1), R ^2B is unsubstituted tetrahydro-2Hpyranyl. In some embodiments of formula (Ik-1), R ^2B is a substituted or unsubstituted 4-6 membered heterocyclyl containing one S atom. In some embodiments of formula (Ik-1), R ^2B is a substituted or unsubstituted 4- tetrahydro-2Hthiopyranyl.

In some embodiments of formula (Ik-1), both R ^2A and R ^2B are methyl. In some embodiments of formula (Ik-1), R ^2A is methyl, and R ^2B is substituted methyl. In some embodiments of Formula (Ik-1), R ^2A is methyl and R ^2B is -CH2OH. In some embodiments of formula (Ik-1), R ^2A is methyl, and R ^2B is -CH2N(H)C(O)CH3. In some embodiments of formula (Ik-1), R ^2A is methyl and R ^2B is -CHF2.

In some embodiments of formula (Ik-1), m is 0. In some embodiments of formula (Ik-1), m is 1. In some embodiments of formula (Ik-1), m is 2. In some embodiments of formula (Ik-1), each R ^1a is independently selected from the group consisting of halogen and substituted or unsubstituted alkyl. In some embodiments of formula (Ik-1), m is 1 and R ^1a is at the 4th position of the phenyl moiety. In some

- 34 045362 embodiments of formula (Ik-1), m is 1, and R ^1a is halogen. In some embodiments of Formula (Ik-1), m is 1 and R ^1a is 4-F. In some embodiments of Formula (Ik-1), m is 1 and R ^1a is 4-Cl. In some embodiments of Formula (Ik-1), m is 1 and R ^1a is substituted or unsubstituted C1-C3 alkyl. In some embodiments of formula (Ik-1), m is 1 and R ^1a is 4methyl. In some embodiments of formula (Ik-1), m is 1 and R ^1a is 4ethyl. In some embodiments of formula (Ik-1), m is 1 and R ^1a is 4CHF2. In some embodiments of Formula (Ik-1), m is 1 and R ^1a is 4-CF3. In some embodiments of formula (Ik-1), m is 2, and two R ^1a groups are at the 3rd and 4th positions of the phenyl moiety. In some embodiments of formula (Ik-1), m is 2, and R ^1a are 3-F and 4-F. In some embodiments of Formula (Ik-1), m is 2, and R ^1a is 3-F and 4-Cl. In some embodiments of formula (Ik-1), m is 2 and R ^1a is 3-F and 4-methyl. In some embodiments of Formula (Ik-1), m is 2, and R ^1a is 3-F and 4-CF3. In some embodiments of Formula (Ik-1), m is 2, and R ^1a is 3-Cl and 4-F. In some embodiments of formula (Ik-1), m is 2, and R ^1a is 3-methyl and 4-F.

In some embodiments of formula (Ik-1), p is 0. In some embodiments of formula (Ik-1), p is 1. In some embodiments of formula (Ik-1), p is 2. In some embodiments of formula (Ik-1), p is 2, and each R ^3a is independently selected from the group consisting of halogen, cyano, substituted or unsubstituted C1-C3-alkyl, substituted or unsubstituted C2-C3 alkenyl, and substituted or unsubstituted C1-C3 -alkoxy. In some embodiments of formula (Ik-1), p is 2, and each R ^3a is independently F, Cl, Br, cyano, methyl, -CH=CH2, -OCH3 _, or -OCHF2. In some embodiments of Formula (Ik-1), p is 2, and at least one R ^3a is F. In some embodiments of Formula (Ik-1), p is 2, and at least one R ^3a is 3-F. In some embodiments of formula (Ik-1), p is 2 and one R ^3a is 3-F and one R ^3a is at the 5th position of the pyridinyl moiety and is selected from the group consisting of halogen, cyano, unsubstituted C ₁ -C ₃ -alkyl, unsubstituted C ₂ -C ₃ -alkenyl and substituted or unsubstituted C1-C ₃ -alkoxy. In some embodiments of formula (Ik-1), p is 2, and R ^3a is 3-F and 5-Cl. In some embodiments of Formula (Ik-1), p is 2, and R ^3a is 3-F and 5-Br. In some embodiments of formula (Ik-1), p is 2, and R ^3a is 3-F and 5-cyano. In some embodiments of formula (Ik-1), p is 2, and R ^3a is 3-F and 5-methyl. In some embodiments of Formula (Ik-1), p is 2, and R ^3a is 3-F and 5-ethenyl. In some embodiments of formula (Ik-1), p is 2, and R ^3a is 3-F and 5-methoxy. In some embodiments of formula (Ik-1), p is 2, and R ^3a is 3-F and 5-OCH3. In some embodiments of Formula (Ik-1), p is 2, and R ^3a is 3-F and 5-OCHF2. In some embodiments of formula (Ik1), p is 2, and R ^3a is 3-methyl and 5-Cl.

In some embodiments of formula (Ik-1), R ^2A is H, R ^2B is isopropyl, m is 1, R ^1a is selected from the group consisting of F, Cl, and -CF3, p is 1, and R ^3a is selected from the group consisting of F, Cl and cyano. In some embodiments of formula (Ik-1), R ^2A is H, R ^2b is 3-oxetanyl, m is 1, R ^1a is selected from the group consisting of F, Cl and -CF3, p is 1, and R ^3a is selected from the group consisting of F, Cl and cyano. In some embodiments of formula (Ik-1), R ^2A is methyl, R ^2B is methyl, m is 1, R ^1a is selected from the group consisting of F, Cl, and -CF ₃ , p is 1, and R ^3a selected from the group consisting of F, Cl and cyano.

In some embodiments of formula (Ik-1), R ^2A is H, R ^2B is isopropyl, m is 1, R ^1a is selected from the group consisting of F, Cl, and -CF3, p is 2, and each R ^3a is independently selected from the group consisting of F, Cl and cyano. In some embodiments of formula (Ik-1), R ^2A is H, R ^2B is 3-oxetanyl, m is 1, R ^1a is selected from the group consisting of F, Cl and -CF3, p is 2, and each R ^3a is independently selected from the group consisting of F, Cl and cyano. In some embodiments of formula (Ik-1), R ^2A is methyl, R ^2B is methyl, m is 1, R ^1a is selected from the group consisting of F, Cl, and -CF ₃ , p is 2, and each R ^3a is independently selected from the group consisting of F, Cl and cyano.

In some embodiments of formula (Ik-1), R ^2A is H, R ^2B is isopropyl, m is 2, each R ^1a is independently selected from the group consisting of F, Cl, and -CF3, p is 1, and R ^3a is selected from the group consisting of F, Cl and cyano. In some embodiments of formula (Ik-1), R ^2a is H, R ^2B is 3-oxetanyl, m is 2, each R ^1a is independently selected from the group consisting of F, Cl and -CF3, p is 1, and R ^3a is selected from the group consisting of F, Cl and cyano. In some embodiments of formula (Ik-1), R ^2A is methyl, R ^2B is methyl, m is 2, each R ^1a is independently selected from the group consisting of F, Cl, and

- 35 045362

CF ₃ , p is 1, and R ^3a is selected from the group consisting of F, Cl and cyano.

In some embodiments of formula (Ik-1), R ^2A is H, R ^2B is isopropyl, m is 2, each R ^1a is independently selected from the group consisting of F, Cl, and -CF3, p is 2, and each R ^3a is independently selected from the group consisting of F, Cl and cyano. In some embodiments of formula (Ik-1), R ^2A is H, R ^2B is 3oxetanyl, m is 2, each R ^1a is independently selected from the group consisting of F, Cl and -CF3, p is 2, and each R ^3a is independently selected from the group consisting of F, Cl and cyano. In some embodiments of formula (Ik-1), R ^2A is methyl, R ^2B is methyl, m is 2, each R ^1a is independently selected from the group consisting of F, Cl, and -CF3, p is 2, and each R ^3a is independently selected from the group consisting of F, Cl and cyano. In some embodiments of Formula (Ik-1): R ^2A is H or methyl; R ^2B is selected from the group consisting of isopropyl, -CHF2, -CH(OH)CH3, -CH2OH, -CH2CH2SCH3, -CH2CH2S(O)2CH3, -CH2N(H)C(O)CH3, CH2CH ₂ C(O) NH ₂ , methyl substituted with oxetanyl or azetidinyl, cyclopropyl, cyclobutyl, 3-azetidinyl substituted with aminoacyl or acyl, 3-oxetanyl, 3-oxetanyl substituted with methyl, tetrahydro-2H-pyranyl and 4-tetrahydro-2H-thiopyranyl; m is 1; R ^1a is 4-F, 4-Cl, 4methyl, 4-CHF2 and 4-CF3; p equals 2; and the two R ^3a groups are selected from the group consisting of 3-F and 5-Cl, 3-F and 5Br, 3-F and 5-cyano, 3-F and 5-methyl, 3-F and 5-ethenyl, 3 -F and 5-methoxy, 3-F and 5-OCH3, 3-F and 5-OCHF2, and 3methyl and 5-Cl. In another aspect, the compound of formula (I) is a compound of formula (Ik-2) or a pharmaceutically acceptable salt thereof:

where G ¹ is selected from the group consisting of substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclyl; each R ^1a is independently selected from the group consisting of halogen and substituted or unsubstituted alkyl; each R ^2a is independently selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted aminothionyl, substituted or unsubstituted aminocarbonylamino, and substituted substituted or unsubstituted alkyl; each R ^3a is independently selected from the group consisting of halogen, cyano and substituted or unsubstituted alkyl; R ⁴ represents H; R ⁵ represents H or substituted or unsubstituted alkyl; m is 0, 1 or 2; n is 0, 1 or 2; and p is 0, 1 or 2.

In some embodiments of formula (Ik-2), G ¹ is a substituted or unsubstituted cycloalkyl. In some embodiments of formula (Ik-2), G ¹ is substituted or unsubstituted cyclopropyl. In some embodiments of formula (Ik2), G ¹ is substituted or unsubstituted cyclobutanyl. In some embodiments of formula (Ik-2), G ¹ is a substituted or unsubstituted 4-membered to 6-membered heterocyclyl that contains one or more (for example, 1 or 2 or 3 or 1-4 or 1-3 or 2- 4) N or O atoms. In some embodiments of formula (Ik-2), G ¹ is a substituted or unsubstituted 4-membered to 6-membered heterocyclyl that contains one N atom. In some embodiments of formula (Ik-2 ), G ¹ represents substituted or unsubstituted azetidinyl. In some embodiments of Formula (Ik-2), G ¹ is substituted or unsubstituted piperidinyl. In some embodiments of formula (Ik-2), G ¹ is a substituted or unsubstituted 4-membered to 6-membered heterocyclyl that contains one O atom. In some embodiments of formula (Ik-2), G ¹ is a substituted or unsubstituted oxetanil. In some embodiments of formula (Ik2), G ¹ is substituted or unsubstituted tetrahydrofuranyl.

In some embodiments of Formula (Ik-2), m is O. In some embodiments of Formula (Ik-2), m is 1, and R ^1a is selected from the group consisting of halogen and substituted or unsubstituted alkyl. In some embodiments of formula (Ik-2), m is 1 and R ^1a is at the 4th position of the phenyl moiety. In some embodiments of formula (Ik2), m is 1 and R ^1a is 4-F. In some embodiments of Formula (Ik-2), m is 1 and R ^1a is 4-Cl. In some embodiments of formula (Ik-2), m is 1 and R ^1a is C1- _C3 alkyl, optionally substituted with halogen. In some embodiments of formula (Ik-2), m is 1 and R ^1a is 4-methyl. In some embodiments of formula (Ik-2), m is 1 and R ^1a is 4-CHF2. In some embodiments of Formula (Ik-2), m is 1 and R ^1a is 4-CF3.

In some embodiments of formula (Ik-2), n is 0. In some embodiments,

- 36 045362 implementation of formula (Ik-2), n is 1. In some embodiments of formula (Ik-2), n is 2.

In some embodiments of formula (Ik-2), each R ^2a is independently selected from the group consisting of halogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, and hydroxy. In some embodiments of formula (Ik-2), R ^2a is a halogen, such as fluorine. In some embodiments of Formula (Ik-2), R ^2a is substituted or unsubstituted aryl. In some embodiments of formula (Ik-2), R ^2a is substituted or unsubstituted phenyl. In some embodiments of formula (Ik-2), R ^2a is phenyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of halogen, alkoxycarbonyl, substituted or unsubstituted amino and substituted or unsubstituted aminoacyl. In some embodiments of formula (Ik-2), R ^2a is phenyl substituted with halogen. In some embodiments of formula (Ik-2), R ^2a is phenyl substituted with alkoxy carbonyl. In some embodiments of formula (Ik-2), R ^2a is phenyl substituted with methoxycarbonyl. In some embodiments of formula (Ik-2), R ^2a is phenyl substituted with substituted or unsubstituted amino. In some embodiments of Formula (Ik-2), R ^2a is phenyl substituted with methylamino. In some embodiments of Formula (Ik-2), R ^2a is phenyl substituted with a substituted or unsubstituted aminoacyl. In some embodiments of formula (Ik-2), R ^2a is phenyl substituted with methylaminoacyl. In some embodiments of formula (Ik-2), R ^2a is phenyl substituted with two substituents selected from the group consisting of methoxycarbonyl, methylamino and methylaminoacyl. In some embodiments of Formula (Ik-2), R ^2a is substituted or unsubstituted heteroaryl. In some embodiments of Formula (Ik-2), R ^2a is substituted or unsubstituted oxadiazolyl. In some embodiments of formula (Ik2), R ^2a is unsubstituted oxadiazolyl. In some embodiments of Formula (Ik-2), R ^2a is oxadiazolyl substituted with cycloalkyl. In some embodiments of Formula (Ik-2), R ^2a is oxadiazolyl substituted with cyclopropyl. In some embodiments of Formula (Ik-2), R ^2a is substituted or unsubstituted pyridinyl. In some embodiments of Formula (Ik-2), R ^2a is unsubstituted pyridinyl. In some embodiments of formula (Ik-2), R ^2a is pyridinyl substituted with a halogen, such as F. In some embodiments of formula (Ik-2), R ^2a is pyridinyl substituted with cyano. In some embodiments of Formula (Ik-2), R ^2a is substituted or unsubstituted pyridin-2-yl. In some embodiments of Formula (Ik-2), R ^2a is a substituted or unsubstituted alkoxycarbonyl. In some embodiments of Formula (Ik-2), R ^2a is methoxycarbonyl. In some embodiments of Formula (Ik-2), R ^2a is ethoxycarbonyl. In some embodiments of Formula (Ik-2), R ^2a is a substituted or unsubstituted aminoacyl. In some embodiments of Formula (Ik-2), R ^2a is unsubstituted aminoacyl. In some embodiments of formula (Ik-2), R ^2a is an aminoacyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of C1-C3 alkyl, C3-C6 cycloalkyl and 4-membered to 7-membered heterocyclyl. In some embodiments of Formula (Ik-2), R ^2a is aminoacyl substituted with C1-C3 alkyl. In some embodiments of Formula (Ik-2), R ^2a is methylaminoacyl, ethylaminoacyl, or isopropylaminoacyl. In some embodiments of formula (Ik-2), R ^2a is dimethylaminoacyl. In some embodiments of Formula (Ik-2), R ^2a is cyclopropylaminoacyl. In some embodiments of formula (Ik-2), R ^2a is tetrahydropyranyl aminoacyl. In some embodiments of Formula (Ik-2), R ^2a is a substituted or unsubstituted acyl. In some embodiments of formula (Ik-2), R ^2a is an unsubstituted acyl. In some embodiments of formula (Ik-2), R ^2a is an acyl substituted with one or more (e.g., 1 or 2 or 3 or 1-4 or 1-3 or 2-4) substituents selected from the group consisting of substituted or unsubstituted alkyl and substituted or unsubstituted aryl. In some embodiments of formula (Ik-2), R ^2a is acyl substituted with methyl. In some embodiments of formula (Ik-2), R ^2a is acyl substituted with phenyl, wherein the phenyl is optionally substituted with amino. In some embodiments of Formula (Ik-2), R ^2a is substituted or unsubstituted alkyl. In some embodiments of Formula (Ik-2), R ^2a is a C1-C3 alkyl substituted with halogen. In some embodiments of formula (Ik-2), R ^2a is ethyl substituted with two fluorine groups, such as -CH2CHF ₂ . In some embodiments of formula (Ik-2), R ^2a is hydroxy.

In some embodiments of formula (Ik-2), p is 0. In some embodiments of formula (Ik-2), p is 1. In some embodiments of formula (Ik-2), p is 1.

- 37 045362 and R ^3a represents halogen. In some embodiments of formula (Ik-2), p is 1 and R ^3a is 5-Cl. In some embodiments of formula (Ik-2), p is 2. In some embodiments of formula (Ik-2), p is 2, and each R ^3a is independently halogen, cyano, or substituted or unsubstituted C1-C3- αlkyl. In some embodiments of formula (Ik-2), p is 2, and each R ^3a is independently F, Cl, Br, cyano, or methyl. In some embodiments of formula (Ik-2), p is 2, and at least one R ^3a is F or methyl. In some embodiments of formula (Ik-2), p is 2, and at least one R ^3a is 3-F or 3-methyl. In some embodiments of formula (Ik-2), p is 2, and the one R ^3a is at the 3-position of the pyridinyl moiety and is selected from the group consisting of F and methyl, and the one R ^3a is at the 5-position of the pyridinyl moiety and is selected from group consisting of halogen, cyano and unsubstituted C1-C ₃ -αalkyl. In some embodiments of formula (Ik-2), p is 2, and R ^3a is 3-F and 5-Cl. In some embodiments of formula (Ik-2), p is 2, and R ^3a is 3-F and 5-Br. In some embodiments of formula (Ik-1), p is 2, and R ^3a is 3-F and 5-cyano. In some embodiments of formula (Ik-2), p is 2, and R ^3a is 3-methyl and 5-Cl. In some embodiments of formula (Ik-2), p is 2, and R ^3a is 3-methyl and 5-cyano.

In some embodiments of formula (Ik-2), R ⁵ is H. In some embodiments of formula (Ik-2), R ⁵ is substituted or unsubstituted alkyl. In some embodiments of formula (Ik-2), R ⁵ is methyl. In some embodiments of formula (Ik-2), G ¹ is cyclobutanyl, m is 1, R ^1a is selected from the group consisting of F, Cl, and -GF3, n is 0, p is 1, R ^3a is selected from the group consisting of F, Cl and cyano, and R ⁵ is H. In some embodiments of formula (Ik-2), G ¹ is azetidinyl, m is 1, R ^1a is selected from the group consisting of F, Cl and -CF3 , n is 0, p is 1, R ^3a is selected from the group consisting of F, Cl and cyano, and R ⁵ is H. In some embodiments of formula (Ik-2), G ¹ is oxetanyl, m is 1 , R ^1a is selected from the group consisting of F, Cl and -CF3, n is 0, p is 1, R ^3a is selected from the group consisting of F, Cl and cyano, and R ⁵ is H. In some embodiments of the formula (Ik-2), G ¹ is cyclobutanyl, m is 1, R ^1a is selected from the group consisting of F, Cl and -CF3, n is 0, p is 1, R ^3a is selected from the group consisting of F, Cl both cyano and R ⁵ is methyl. In some embodiments of formula (Ik-2), G ¹ is azetidinyl, m is 1, R ^1a is selected from the group consisting of F, Cl, and -CF3, n is 0, p is 1, R ^3a is selected from the group consisting of F, Cl and cyano, and R ⁵ represents methyl. In some embodiments of Formula (Ik-2), G ¹ is oxetanyl, m is 1, R ^1a is selected from the group consisting of F, Cl, and -CF3, n is 0, p is 1, R ^3a is selected from the group consisting of F, Cl and cyano, and R ⁵ represents methyl. In some embodiments of formula (Ik-2), G ¹ is cyclobutanyl, m is 1, R ^1a is selected from the group consisting of F, Cl, and -CF3, n is 0, p is 2, each R ^3a is independently selected from the group consisting of F, Cl and cyano and R ⁵ is H. In some embodiments of formula (Ik-2), G ¹ is azetidinyl, m is 1, R ^1a is selected from the group consisting of F, CI and - CF3, n is 0, p is 2, each R ^3a is independently selected from the group consisting of F, Cl and cyano and R ⁵ is H. In some embodiments of formula (Ik-2), G ¹ is oxetanyl, m is 1, R ^1a is selected from the group consisting of F, Cl and -CF3, n is 0, p is 2, each R ^3a is independently selected from the group consisting of F, Cl and cyano and R ⁵ is H. In some In embodiments of formula (Ik-2), G ¹ is cyclobutanyl, m is 1, R ^1a is selected from the group consisting of F, Cl and -CF3, n is 0, p is 2, each R ^3a is independently selected from the group, consisting of F, Cl and cyano and R ⁵ represents methyl. In some embodiments of Formula (Ik-2), G ¹ is azetidinyl, m is 1, R ^1a is selected from the group consisting of F, Cl, and -GF3, n is 0, p is 2, each R ^3a is independently selected from group consisting of F, Cl and cyano and R ⁵ represents methyl. In some embodiments of formula (Ik-2), G ¹ is oxetanyl, m is 1, R ^1a is selected from the group consisting of F, Cl and CF3, n is 0, p is 2, each R ^3a is independently selected from the group , consisting of F, Cl and cyano and R ⁵ represents methyl.

In some embodiments of formula (Ik-2), G ¹ is cyclobutanyl, m is 2, each R ^1a is independently selected from the group consisting of F, Cl and -CF3, n is 0, p is 1, R ^3a is selected from the group consisting of F, Cl and cyano and R ⁵ is H. In some embodiments of formula (Ik-2), G ¹ is azetidinyl, m is 2, each R ^1a is independently selected from the group consisting of F, Cl and -CF3, n is 0, p is 1, R ^3a is selected from the group consisting of F, Cl and cyano and R ⁵ is H. In some embodiments of formula (Ik-2), G ¹ is oxetanyl, m is 2, each R ^1a is independently selected from the group consisting of F, Cl and -CF3, n is 0, p is 1, R ^3a is selected from the group consisting of F, Cl and cyano and R ⁵ is H. In some In embodiments of formula (Ik-2), G ¹ is cyclobutanyl, m is 2, each R ^1a is independently selected from the group consisting of F, Cl and -CF ₃ , n is 0, p is 1, R ^3a is selected from the group , consisting of F, Cl and cyano and R ⁵ represents methyl. In some embodiments,

- 38 045362 formula (Ik-2), G ¹ is azetidinyl, m is 2, each R ^1a is independently selected from the group consisting of F, Cl and -CF3, n is 0, p is 1, R ^3a is selected from group consisting of F, Cl and cyano and R ⁵ represents methyl. In some embodiments of formula (Ik-2), G ¹ is oxetanyl, m is 2, each R ^1a is independently selected from the group consisting of F, Cl and -CF3, n is 0, p is 1, R ^3a is selected from group consisting of F, Cl and cyano and R ⁵ represents methyl.

In some embodiments of Formula (Ik-2), G ¹ is cyclobutanyl, m is 2, each R ^1a is independently selected from the group consisting of F, Cl, and -CF3, n is 0, p is 2, each R ^3a is independently is selected from the group consisting of F, Cl and cyano and R ⁵ is H. In some embodiments of formula (Ik-2), G ¹ is azetidinyl, m is 2, each R ^1a is independently selected from the group consisting of F , Cl and -CF3, n is 0, p is 2, each R ^3a is independently selected from the group consisting of F, Cl and cyano and R ⁵ is H. In some embodiments of formula (Ik-2), G ¹ is is oxetanyl, m is 2, each R ^1a is independently selected from the group consisting of F, Cl and -CF3, n is 0, p is 2, each R ^3a is independently selected from the group consisting of F, Cl and cyano and R ⁵ is H. In some embodiments of formula (Ik-2), G ¹ is cyclobutanyl, m is 2, each R ^1a is independently selected from the group consisting of F, Cl and -CF3, n is 0, p is 2, each R ^3a is independently selected from the group consisting of F, Cl and cyano and R ⁵ is methyl. In some embodiments of formula (Ik-2), G ¹ is azetidinyl, m is 2, each R ^1a is independently selected from the group consisting of F, Cl and CF3, n is 0, p is 2, each R ^3a is independently selected from the group consisting of F, Cl and cyano and R ⁵ represents methyl. In some embodiments of formula (Ik-2), G ¹ is oxetanyl, m is 2, each R ^1a is independently selected from the group consisting of F, Cl, and -CF3, n is 0, p is 2, each R ^3a is independently selected from the group consisting of F, Cl and cyano and R ⁵ represents methyl. In another aspect, the compound of formula (I) is a compound of formula (Il) or a pharmaceutically acceptable salt thereof:

where R ^2A represents H or substituted or unsubstituted alkyl; R ^2b is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl and hydroxy; m is 0, 1 or 2; p is 0, 1 or 2; each R ^1a is independently selected from the group consisting of halogen and substituted or unsubstituted alkyl; each R ^3a is independently halogen; and R ⁴ is H.

In some embodiments of formula (Il), R ^2A is H.

In some embodiments of formula (Il), R ^2b is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, and hydroxy. In some embodiments of formula (Il), R ^2b is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, and hydroxy. In some embodiments of formula (Il), R ^2b is selected from the group consisting of substituted C1-C3 alkyl, unsubstituted C1-C3 alkoxycarbonyl, unsubstituted aminoacyl, and hydroxy. In some embodiments of Formula (Il), R ^2b is C1- _C3 alkyl substituted with hydroxy. In some embodiments of Formula (Il), R ^2b is -CH ₂ OH. In some embodiments of Formula (Il), R ^2b is methoxycarbonyl. In some embodiments of Formula (Il), R ^2b is ethoxycarbonyl. In some embodiments of Formula (Il), R ^2b is unsubstituted aminoacyl. In some embodiments of Formula (Il), R ^2b is hydroxy.

In some embodiments of formula (Il), m is 1, and R ^1a is selected from the group consisting of halogen and substituted or unsubstituted alkyl. In some embodiments of formula (Il), m is 1 and R ^1a is at the 4th position of the phenyl moiety. In some embodiments of formula (Il), m is 1 and R ^1a is 4-F. In some embodiments of Formula (Il), m is 1 and R ^1a is 4-Cl. In some embodiments of formula (Il), m is 1 and R ^1a is C ₁ -C ₃ alkyl, optionally substituted with halogen. In some embodiments of formula (Il), m is 1 and R ^1a is 4-methyl. In some embodiments of formula (Il), m is 1 and R ^1a is 4-CHF2. In some embodiments of formula (Il), m is 1 and R ^1a is 4-CF3.

In some embodiments of formula (Il), p is 2, and each R ^3a is independently halogen. In some embodiments of formula (Il), p is

- 39 045362 is 2, and each R ^3a is independently F or Cl. In some embodiments of Formula (Il), p is 2, and one R ^3a is 3-halogen, and one R ^3a is 5-halogen. In some embodiments of formula (Il), p is 2, and R ^3a is 3-F and 5-Cl.

In another aspect, a compound of formula (I) is a compound of formula (Im) or a pharmaceutically acceptable salt thereof:

-уУ where Q represents -O- or -N(R ^2b )-; R ^2b is selected from the group consisting of H and substituted or unsubstituted acyl; m is 0, 1 or 2; p is 0, 1 or 2; each R ^1a is independently selected from the group consisting of halogen and substituted or unsubstituted alkyl; each R ^3a is independently halogen; and R ⁴ is H.

In some embodiments of formula (Im), Q is -O-. In some embodiments of formula (Im), Q is -N(R ^2b )-.

In some embodiments of formula (Im), R ^2b is a substituted or unsubstituted acyl. In some embodiments of formula (Im), R ^2b is unsubstituted acyl. In some embodiments of formula (Im), R ^2b is acyl substituted with alkyl. In some embodiments of formula (Im), R ^2b is acyl substituted with methyl.

In some embodiments of formula (Im), m is 1, and R ^1a is selected from the group consisting of halogen and substituted or unsubstituted alkyl. In some embodiments of formula (Im), m is 1 and R ^1a is at the 4th position of the phenyl moiety. In some embodiments of formula (Im), m is 1 and R ^1a is 4-F. In some embodiments of formula (Im), m is 1 and R ^1a is 4-Cl. In some embodiments of formula (Im), m is 1, and R ^1a is C ₁ -C ₃ alkyl, optionally substituted with halogen. In some embodiments of formula (Im), m is 1 and R ^1a is 4methyl. In some embodiments of formula (Im), m is 1 and R ^1a is 4CHF2. In some embodiments of formula (Im), m is 1 and R ^1a is 4-CF3.

In some embodiments of formula (Im), p is 2, and each R ^3a is independently halogen. In some embodiments of formula (Im), p is 2, and each R ^3a is independently F or Cl. In some embodiments of formula (Im), p is 2, and one R ^3a is 3-halogen, and one R ^3a is 5-halogen. In some embodiments of Formula (Im), p is 2, and R ^3a is 3-F and 5-Cl. In another aspect, the compound of formula (I) is a compound of formula (In1) or formula (In-2) or a pharmaceutically acceptable salt thereof:

where R ¹ is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted pyridyl;

r ² a, R2B and r ³ are defined by any of (i)-(iii):

(i) R ^2A represents H or substituted or unsubstituted alkyl;

R ^2B is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted puppy Aril and substituted or unsubstituted heteroaryl; And

R ³ represents substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; or (ii) R ^2A represents H or substituted or unsubstituted alkyl;

R ^2B represents substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; And

R ³ represents substituted or unsubstituted alkyl; or (iii) R ^2A and R ^2B are taken together with the carbon atom to which they are attached to form G ¹ , where G ¹ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted

- 40 045362 cycloalkenyl, substituted or unsubstituted cycloalkynyl, or substituted or unsubstituted heterocyclyl ring, each of which is optionally fused to a phenyl ring; And

R ³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted ar sludge and replaced or unsubstituted heteroaryl;

R ⁴ represents H or substituted or unsubstituted alkyl; and R ⁵ represents H or substituted or unsubstituted alkyl; wherein, when one or more provisions (a)-(c) are used, R ¹ represents substituted or unsubstituted pyridyl or phenyl substituted with at least one substituent other than methyl or methoxy:

(a) R ^2A and R ^2B are as defined in (i), and R ³ is substituted or unsubstituted phenyl;

(b) R ^2A and R ³ are as defined in (i), and R ^2B is 4-methoxyphenyl;

(c) R ^2A and R ^2B are as defined in (iii), and R ³ is 4methoxyphenylmethyl.

In some embodiments, the invention provides the compounds and their salts described in Table 1. 1.

Table 1

No. Structure Name 1 tι t /7^ N-cyclobutyl-E- isopropyl-7,10-dioxo-6- (4-(trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-2- carboxamide 2 ud s o 5-(4-chlorobenzyl}-8- isoprot and l-2-phen and l-2 5. rho[3.5] non a n -6,9- dione 3 4 V H ^Λ · U g 5- (4-chloro rbe nzyl)-2- (4- fluorophenyl) -8- isol rop IL- 2,5,8- triaeaspi ro[3.5] non a n -6,9- dione 5-(4-chlorobenzyl)-2-(4chlorophenyl)-8-isoprolyl - 2.5,8- triazaspiro[3.5] non a n -6,9dione

-41 045362

5 Z-V/ /..... 5-{4-chlorobenzyl)-2-(3chlorphen1ll)-8-topropyl2,5,8- triazaspiro[3 5]nonam-6,9DIONE 6 i \ And Ψ Ό’ ' r if/)! 5-(4-chlorobenzyl)-visopropyl-2-{lyridine-2- il)-2.5,v- triazaspiro[3.5]nonane-6,9- DION 7 y ../ c./· 5-(4-chlorobenzyl)-8isopropyl-2-(pyridin-3yl)-2,5,8- triazaspiro[3.5]nonane-6,9dione 8 χϊ-y ---- v...^ T:· \ 5-(4-chlorobenzyl)-8- isopropyl-2-(pyridine-4- il)-2,5,8- triazaspiro[3.5]nonane-6,9dione 9 TX X; -A X .·-· X /' y 5-(4-chlorobenzyl)-8isopropyl-2-(5methylpyridin-2-yl)-2,5,8triazaspiro[3.5]nonane-6,9dione 10 /7 Z ⁴ - \ 5-(4-chlorobenzyl)-8isopropyl-2-(2methylpyridin-4-yl)-2,5,8triazaspiro[3.5]nonane-6,9dione eleven C. / 5-(4-chlorobenzyl)-8isopropyl-2-(pyrimidin-2yl)-2,5,8- triazaspiro[3.5]nonane-6,9dione

-42 045362

12 'Y/ Α'4,· Ar k YY''AAk 7 A-Aa a “—a 5-(4-chlorobenzyl)-8isopropyl-2-(pyrazine-2- il)-2,5,8- triazaspiro[3.5]nonane-6,9- DION 13 5-(4-chlorobenzyl)-8- isopropyl-2-(2- methylpyridin-3-yl)-2,5,8triazaspiro[3.5]nonane-6,9dione 14 /4..7 A 5-(4-chlorobenzyl)-8- isopropyl-2-(6- methylpyridin-3-yl)-2,5,8- triazaspiro[3.5]nonane-6,9dione 15 /a // Χ.7· ^: \ \ ''\'x._A/ 5-(4-chlorobenzyl)-8isopropyl-2-(4methylpyridin-2-yl)-2,5,8triazaspiro[3.5]nonane-6,9dione 16 X \ . Ϋ 7 . : 5-(4-chlorobenzyl)-8isopropyl-2-(5methylpyridin-3-yl)-2,5,8triazaspiro[3.5]nonane-6,9dione

- 43 045362

17 5-(4-chlorobenzyl)-2-(5fluoropyridin-2-yl)-8isopropyl-2,5,8- triazaspiro[3.5]nonane-6,9DIONE 18 . /X” 5-(4-chlorobenzyl)-2-(5- fluoropyridin-3-yl)-8- isopropyl-2,5,8- triazaspiro[3.5]nonane-6,9- dione 19 5-(4-chlorobenzyl)-8- isopropyl-2-(pyrimidine-4- il)-2,5,8- triazaspiro[3.5]nonane-6,9- dione 20 > —X r _: · χ—У 'Υ— 5-(4-chlorobenzyl)-2-(4fluorophenyl)-8-isopropyl7-methyl-2,5,8- triazaspiro[3.5]nonane-6,9dione 21 \ χ y----« ./ \ / \ ιθ>··~-- d > >"X\- -X 5-(4-chlorobenzyl)-8isopropyl-2-(1-methyl-1 Npyrazol-4-yl)-2,5,8triazaspiro[3.5]nonane-6,9dione

- 44 045362

22 χθ ΌΟ i 5-(4-chlorobenzyl)-8isopropyl-2-(thiazol-2-yl)- 2,5,8- triazaspiro[3.5]nonane-6,9- DION 23 yO 0, ..0% 0 ' ' O 5-(4-chlorobenzyl)-8isopropyl-2-(pyridazin-3yl)-2,5,8- triazaspiro[3.5]nonane-6,9dione 24 ?<< , _ O Ο .0····Ο X . > χ/ O 5-(4-chlorobenzyl)-8isopropyl-2-(pyridazin-4yl)-2,5,8- triazaspiro[3.5]nonane-6,9dione 25 X., O\χ.______.χ\··%J ’ / /.··.....- ·α 5-(4-chlorobenzyl)-8isopropyl-2-(pyrimidin-5yl)-2.5,8- triazaspiro[3.5]nonane-6,9dione 26 V <5 \...... . W ΟΟΛ......../ 0' ^g '~0 A ^ν! ό%Γ ' 5-(4-chlorobenzyl)-8isopropyl-2-(5-methyl-1 Npyrazol-3-yl)-2,5,8triazaspiro[3.5]nonane-6,9dione

- 45 045362

27 ⁴ x\\ 4-(5-(4-chlorobenzyl)-8isopropyl-6,9-dioxo- 2,5,8- triazaspiro[3.5]nonan-2yl)picolinonitrile 28 R% /-· /X 5-(4-chlorobenzyl)-2-(2- hydroxypyridin-4-yl)-8- isopropyl-2,5,8- triazaspiro[3.5]nonane-6,9- dione 29 5-(4-chlorobenzyl)-2-(2(difluorometal)pyridin-4yl)-8-isopropyl-2,5,8triazaspiro[3.5]nonane-6,9dione thirty _th X : >— — /..... s. + Z- ^S >\ 8-isopropyl-5-(4methylbenzyl)-2-(2methylpyridin-4-yl)-2,5,8triazaspiro[3.5]nonane-6,9dione 31 IX. ° z\ Z. jO z 8-isopropyl-2-(2methylpyridin-4-yl)-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-6,9dione

- 46 045362

32 I o from 5-(4-chlorobenzyl)-8isopropyl-2-(thiazol-4-yl)- 2,5,8- triazaspiro[3.5]nonane-6,9- DION 33 And T ' ^z -т χ / ,,ΤόΟΧΤ ·...........< 5-(4-chlorobenzyl)-8- isopropyl-2-(thiazol-5-yl)- 2,5,8- triazaspiro[3.5]nonane-6,9dione 34 .-g O x \> \ \D T? 5-(4-chlorobenzyl)-2-(2cyclopropylpyridin-4yl)-8-isopropyl-2,5,8triazaspiro[3.5]nonane-6,9dione 35 -L—'' ’ O—'r ' .-.у— methyl-4-(5-(4-chlorobenzyl)- 8-isopropyl-6,9-dioxo- 2,5,8- triazaspiro[3.5]nonan-2yl)picolinate 36 4-(5-(4-chlorobenzyl)-8isopropyl-6,9-dioxo- 2,5,8- triazaspiro[3.5]nonan-2yl)picolinic acid

- 47 045362

37 /P \ 0 U- ( ⁰ Q C! 4-(5-(4-chlorobenzyl)-8isopropyl-6,9-dioxo- 2,5,8- triazaspiro[3.5]nonan-2yl)picolinamide 38 X' Р 5>о$5 ΗΝ-Ζ a )— ^z O / 4-(5-(4-chlorobenzyl)-8- isopropyl-6,9-dioxo- 2,5,8- triazaspiro[3.5]nonan-2yl)-M-methylpicolinamide 39 ' A ---X :( --u.u, / 5-(4-chlorobenzyl)-8- isopropyl-2-(4- (trifluoromethyl)thiazole-2- il)-2,5,8- triazaspiro[3.5]nonane-6,9dione 40 R . R- ]b>.....<rr S+.ί,! .A',,,·' V V ? 'Y r-'r / L δ \р.х/ 2-(5-(4-chlorobenzyl)-8- isopropyl-6,9-dioxo- 2,5,8- triazaspiro[3.5]nonan-2yl)thiazol-4-carboxamide 41 _o V. ν....../ ¥ ?' / .. / \ *'</__________ Χζ 5-(4-chlorobenzyl)-8isopropyl-2-(1 Η-pyrazol4-yl)-2,5,8- triazaspiro[3.5]nonane-6,9dione

- 48 045362

42 th O )- 5-(4-chlorobenzyl)-8isopropyl-2-(1-methyl-2oxo-1,2-dihydropyridine- 4-yl)-2,5,8- triazaspiro[3.5]nonane-6,9dione 43 h 1 jrh. from I < >... G. ;-·.Ό ί 5-(4-chlorobenzyl)-8isopropyl-2-(4methyltaazol-2-yl)-2,5,8triazaspiro[3.5]nonane-6,9dione 44 t >— '% o“ ........o....... ⁷ ' ⁷ 5-(4-chlorobenzyl)-8isopropyl-2-(5methyltaazol-2-yl)-2,5,8triazaspiro[3.5]nonane-6,9dione 45 _x VZ........ OhOo 5-(4-chlorobenzyl)-8- isopropyl-2-(5-methyl- 1,3,4-oxadiazol-2-yl)- 2,5,8- triazaspiro[3.5]nonane-6,9- dione 46 I F F 8-isopropyl-2-(pyridin-2yl)-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-6,9dione

- 49 045362

47 'V> \\ ⁴ 7......A /z \ / y 5-(4-chlorobenzyl)-2-(6,7dihydro-4H-pyrano[4,3c1]thiazol-2-yl)-8isopropyl-2,5,8triazaspiro[3.5]nonane-6,9dione 4§ l> o\° 4, F F 8-isopropyl-2-(2-oxo-1,2dihyde ropyridin-4-yl)-5-(4(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonane-6,9dione 49 \ U Ci 5-(4-chlorobenzyl)-2-(2,6- dimethylpyridin-4-yl)-8- isopropyl-2,5,8- triazaspiro[3.5]nonane-6,9- dione 50 φ o 5-(4-chlorobenzyl)-2-(6chloropyridazin-3-yl)-8isopropyl-2,5,8- triazaspiro[3.5]nonane-6,9dione 51 'Oh ά fUo' 5-(4-chlorobenzyl)-8isopropyl-2-(6methoxypyridazin-3-yl)2,5,8- triazaspiro[3.5]nonane-6,9dione

- 50 045362

52 Cl I HN-N . NM οχ An У ) 0=/ ^V VN 0 — 5-(4-chlorobenzyl)-8isopropyl-2-(6-oxo-1,6dihydropyridazin-3-yl)- 2,5,8- triazaspiro[3.5]nonane-6,9dione 53 A i/o X 5-(4-chlorobenzyl)-8isopropyl-2-(6(trifluoromethyl)pyridazin3-yl)-2,5,8- triazaspiro[3.5]nonane-6,9dione 54 o )— h ₂ n nn y-n A Q Cl 6-(5-(4-chlorobenzyl)-8isopropyl-6,9-dioxo- 2,5,8- triazaspiro[3.5]nonan-2yl)pyridazine-3carboxamide 55 .....<00 N-N NM U Cl 5-(4-chlorobenzyl)-8- isopropyl-2-(6- methylpyridazin-3-yl)- 2,5,8- triazaspiro[3.5]nonane-6,9- dione 56 _N=x ,yh “HMA/ Y Cl 5-(4-chlorobenzyl)-2-(5chloropyrazin-2-yl)-8isopropyl-2,5,8- triazaspiro[3.5]nonane-6,9dione

- 51 045362

57 O /- γ F F 6-(8-ethyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonan-2yl)nicotinonitrile 58 A' ......Y °b 6-(8-cyclopentyl-6,9- dioxo-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-2yl)nicotinonitrile 59 V .........Y b- 6-(8-isobutyl-6,9-d ioxo-5(4-(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonan-2yl)nicotinonitrile 60 Cl o - Ύ4 Q Cl 5-(4-chlorobenzyl)-2-(5chloropyridazin-3-yl)-8isopropyl-2,5,8- triazaspiro[3.5]nonane-6,9dione 61 Cl 0 U- i>f U Cl 5-(4-chlorobenzyl)-2-(6chloropyridazin-4-yl)-8isopropyl-2,5,8triazac™ro[3.5]nonane-6,9dione

- 52 045362

62 “ Ο 6-(8-cyclohexyl-6,9- dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-2yl)nicotinonitrile 63 ο — -047 Q C.I. 6-(5-(4-chlorobenzyl)-8- isopropyl-6,9-dioxo- 2,5,8- triazaspiro[3.5]nonan-2yl)nicotinonitrile 64 CI β θ, Λ Ν-χ 0 )— methyl-5-(4-chlorobenzyl)-8isopropyl-6,9-dioxo- 2,5,8- triazaspiro[3.5]nonane-2carboxylate 65 0 ο — 5-(4-chlorobenzyl)-8isopropyl-N-methyl-6,9dioxo-2,5,8triazaspiro[3.5]nonane-2carboxamide 66 ....../' β 5-(4-chlorobenzyl)-8isopropyl-N-(1-methyl-1Hpyrazol-4-yl)-6,9-dioxo2,5,8- triazaspiro[3.5]nonane-2carboxamide

- 53 045362

67 1 i gyhu. I 1 Ή 8-Η3θπροπππ-Ν-ΜθΤΗΠ-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 6§ o - H,N _l y-n <нОх ) O N-H h, FF 8-isopropyl-6,9-dioxo-5(4-(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2- carboxamide 69 \ Q, : ^---^ '>-------< L 7 _E ________' \ X /x^\\ / \ -------/ S 8-isopropyl-6, E-dioxo-5(4-(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2- carbaldehyde 70 1 xy° V-' -п 8-cyclopentyl-M-methyl- 6,9-dioxo-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 71 6-(4-chlorobenzyl)-9- isopropyl-2-(pyrimidine-4- il)-2.6,9- triazaspiro[4.5]decane- 7,10-dione

- 54 045362

72 o\Υα-ΌΑ) 2 4 ^f 9-isopropyl-2-(2methylpyridin-4-ip)-6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane- 7,10-dione 73 ao _y . 9-isopropyl-2-(pyridazine- 3-yl)-6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane- 7,10-dione 74 6-(4-chlorobenzyl)-9isopropyl-2-(pyrazine-2- il)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 75 x \______Ϊ ”' 4;. ^-.-0 6-(4-chlorobenzyl)-9isopropyl-2-(5methylpyridin-2-ip)-2,6,9triazaspiro[4.5]decane7,10-dione 76 ^ΗΝ νΎ / ^N 'Z i O X 9-isopropyl-2-(2-oxo-1,2dihyde ropyridin-4-yl)-6-(4(trifluoromethyl)benzyl)2,6,9- triazaspiro[4.5]decane- 7,10-dione

- 55 045362

77 -To °U 2-(2,6-dimethylpyridin-4yl)-9-isopropyl-6-(4(trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane- 7,10-dione 78 /y 6-(4-chlorobenzyl)-9isopropyl-2-(1-methyl-1 Npyrazol-4-yl)-2,6,9triazaspiro[4.5]decane7,10-dione 79 ο\ X^SlU Hu 6-(4-chlorobenzyl)-9isopropyl-2-(pyridazine-3- il)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 80 _Χχ /¼¾ y. A··U _ch l //U X.U·'' ⁴ .: 6-(4-chlorobenzyl)-9- isopropyl-2-(1-methyl-2- oxo-1,2-dihydropyridine- 4-yl)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 81 \..-- ίΆ.. xO'' ⁴ ) HuXu y 6-(4-chlorobenzyl)-9isopropyl-2-(2-oxo-1,2dihydropyridin-4-yl)- 2,6,9- triazaspiro[4.5]decane- 7,10-dione

- 56 045362

82 6-(4-chlorobenzyl)-9-ethyl-2- (pirzzin-2-yl)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 83 „..Χχ. . \..... 6-(4-chlorobenzyl)-9cyclopentyl-2-(pyridin-2yl)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 84 /УЧл У-^'\ . / Uh ·χ 6-(4-chlorobenzyl)-9isobutyl-2-(pyridin-2-yl)- 2,6,9- triazaspiro[4.5]decane- 7,10-dione 85 L U .L' ¹ '···...,·'··'''\ ^: ' . / : ^H '' \. .. . / \ ·'^ χ УУ.У/: 6-(4-chlorobenzyl)-9-(1methylcyclopropyl)-2(pyridin-2-yl)-2,6,9triazaspiro[4.5]decane7,10-dione 86 ,y. _v . 6-(4-chlorobenzyl)-9-(1methoxypropan-2-yl)-2(pyridin-2-yl)-2,6,9triazaspiro[4.5]decane7,10-dione

- 57 045362

87 6-(4-chlorobenzyl)-9isopropyl-2-(2methoxypyridin-4-yl)- 2,6,9- triazaspiro[4.5]decane- 7,10-dione 88 M \ St. 'Uh? F F 2-(9-isopropyl-7,10dioxo-6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-2yl)isonicotinonitrile 89 Ο _Ν __/ Ν-Λθ h ₂ n^2J Vs 'Λ·.-* FF 2-(9-isopropyl-7,10dioxo-6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-2yl)isonicotinamide 90 V'S·'·?'-. y< 6-(6-(3,4-dichlorobenzyl)-9- isopropyl-7,10-dioxo- 2,6,9- triazaspiro[4.5]decane-2yl)nicotinonitrile 91 6-(6-(3,4-dichlorobenzyl)-9isopropyl-7,10-d ioxo- 2,6,9- triazaspiro[4.5]decane-2yl)nicotinamide

- 58 045362

92 τ / o a b Cl 6-(4-chlorobenzyl)-2-(5fluoropyridin-2-yl)-9isopropyl-2,6,9- triazaspiro[4.5]decane7,10-dione 93 Cl _l A CL o gu o 6-(4-chlorobenzyl)-2- (pyridin-2-yl)-9-((P)tetrahydrofuran-3-yl)- 2,6,9- triazaspiro[4.5]decane- 7,10-dione 94 A X G O ^OLA 6-(4-chlorobenzyl)-2- (pyridin-2-yl)-9-((8)- tetrahydrofuran-3-yl)- 2,6,9- triazaspiro[4.5]decane- 7,10-dione 95 \,χ-···' ^: Ο' V: '^; \ Τ< ⁴ ·Ό 'Ό Ό -ί ΤΟ υ\ \ 2-(6-(4-chlorobenzyl)-9- isopropyl-7,10-dioxo- 2,6,9- triazaspiro[4.5]decane-2yl)isonicotinonitrile 96 ^4Χ -> ⁴ \X. 'Ο'Οχ b-(6-(4-chlorobenzyl)-9- isopropyl-7,10-d ioxo- 2,6,9- triazaspiro[4.5]decane-2yl)nicotinonitrile

- 59 045362

97 :· L ’L v< 2-(6-(4-chlorobenzyl)-9isopropyl-7,10-d ioxo- 2,6,9- triazaspiro[4.5]decane-2yl)isonicotinamide 98 L ‘ L X L 'L' β !' “Lch? 7 6-(6-(4-chlorobenzyl)-9isopropyl-7,10-d ioxo- 2,6,9- triazaspiro[4.5]decane-2yl)nicotinamide 99 <' '7 m,..... / 1 (5)-6-(4-chlorobenzyl)-9isopropyl-2-(pyrimidin-4yl)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 100 0 ^Г \ \:::^ - ·' Y (8)-6-(4-chlorobenzyl)-9isopropyl-2-(pyrazin-2yl)-2.6,9- triazaspiro[4.5]decane7,10-dione 101 ' 5 ?β f ' Q c~i \ (3)-6-(4-chlorobenzyl)-9- isopropyl-2-(5- methylpyridin-2-yl)-2,6,9triazaspiro[4.5]decane- 7,10-dione

- 60 045362

102 I Y YjY ’ γ ABOUT (5)-6-(4-chlorobenzyl)-2-(5fluoropyridin-2-yl)-9isopropyl-2,6,9triazaspiro[4.5]decane7,10-dione 103 rYY Αν ΥΥ and C γ> (5)-6-(4-chlorobenzyl)-9- isopropyl-2-(pyridazine-3- il)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 104 ν.Υ Ο *q (8)-6-(4-chlorobenzyl)-9isopropyl-2-(1-methyl-2oxo-1,2-dihydropyridin4-yl)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 105 ν.... . Γ;7 5 £ϊ “Ρ ίQ, U (B)-6-(4-chlorobenzyl)-9isopropyl-2-(2-oxo-1,2dihydropyridin-4-yl)2,6,9- triazaspiro[4.5]decane7,10-dione 106 γΗ γ .. , Υ γ (3)-6-(4-chlorobenzyl)-9isopropyl-2-(1-methyl-1 Npyrazol-4-yl)-2,6,9triazaspiro[4.5]decane7,10-dione

- 61 045362

107 y С Η ₂ Ν F F ^F 9-isopropyl-7,10-d ionso-6(4-(trifluoromethyl)benzyl)2,6,9- triazaspiro[4.5]decane-2carboxamide 108 A Ά 9-isopropyl-M-methyl-7,10dioxo-6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-2carboxamide 109 ABOUT U Τ’ °аа с 9-isopropyl-7,10-d ioxoM-phenyl-6-(4(trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-2carboxamide 110 A methyl-9-isopropyl-7,10dioxo-6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-2carboxylate 111 U Cha d Wed Αν-^ ^ν Α ⁰ λ- 9-isopropyl-7,10-d ioxo- M-(pyridin-4-yl)-6-(4(trifluoromethyl)benzyl)2,6,9- triazaspiro[4.5]decane-2carboxamide

- 62 045362

112 N ryO ^! Oh oh... M-(tert-butyl)-9isopropyl-7,10-d ioxo-6(4-(trifluoromethyl)benzyl)2,6,9triazaspiro[4.5]decane-2carboxamide 113 0/R 0\A O / 9-isopropyl-7,10-d ioxoM-(pyridin-3-yl)-6-(4(trifluoromethyl)benzyl)2,6,9- triazaspiro[4.5]decane-2carboxamide 114 Of t n '— P o / 9-isopropyl-M-(1-methyl1H-pyrazol-4-yl)-7,10dioxo-6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-2carboxamide 115 And. ^0-¾ ⁰ оХ ZT Р Ν-(4-φτορφβΗΗπ)-9isopropyl-7,10-dioxo-6(4-(trifluoromethyl)benzyl)2,6,9triazaspiro[4.5]decane-2carboxamide 116 F.F 8 -l< M-ethal-9-isopropyl-7,10dioxo-6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-2carboxamide

- 63 045362

117 A H ryO ^! o o 2— M,9-diisopropyl-7,10- dioxo-6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-2carboxamide 118 th ΟΥν o / N-cyclopropyl-Eisopropyl-7,10-d ioxo-6(4-(trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-2carboxamide 119 γ.Υ ......... x / Υ,.^· ^Xch -x 4Υ ^-'Ύ. G 6-(4-chlorobenzyl)-1\1-ethyl-9isopropyl-7,10-d ioxo- 2,6,9- triazaspiro[4.5]decane-2carboxamide 120 Cl % jY h ₂ n-^ o I 'o 6-(4-chlorobenzyl)-9- isopropyl-7,10-d ioxo- 2,6,9- triazaspiro[4.5]decane-2carboxamide 121 >Όχ χ A A _ ko ·γ γ...·- 6-(4-chlorobenzyl)-9Μ3θπροπΐΛΠ-Ν-ινΐθΤΗΠ-7,10dioxo-2,6,9- triazaspiro[4.5]decane-2carboxamide

- 64 045362

122 V-X, XY'X\·: 6-(4-chlorobenzyl)-Mcyclopropyl-9-isopropyl- 7,10-dioxo-2,6,9- triazaspiro[4.5]decane-2carboxamide 123 %···'ii . 6-(4-chlorobenzyl)-9- isopropyl-7,10-d ioxo-Nphenyl-2,6,9- triazaspiro[4.5]decane-2carboxamide 124 G%) ъ WITH!' (5)-6-(4-chlorobenzyl)-9- isopropyl-7,10-d ioxo- 2,6,9- triazaspiro[4.5]decane-2- carboxamide 125 υ χΧ _χ -.4 > Ύ /P. g?^1 V + f h.b (S)-6-(4-xnop6eH3nr)-Ncyclopropyl-9-isopropyl7,1 O-dioxo-2,6,9triazaspiro[4.5]decane-2carboxamide 126 \ .-.’K A.. A 7 /I p X -1 d (8)-6-(4-chlorobenzyl)-9isopropyl-7,10-d ioxo-Nphenyl-2,6,9triazaspiro[4.5]decane-2carboxamide

- 65 045362

127 G/ -D Υ' \....../ ¥ x ⁴ ' 6-(4-chlorobenzyl)-9- isopropyl-2-phenyl-2,6,9- triazaspiro[4.5]decane- 7,10-dione 128 RACHA ‘r._ \ / X·* ' Hh Urrrgh. Ru...R U 6-(4-chlorobenzyl)-9- isopropyl-2-(pyridine-2- il)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 129 ^: x... ^... r r 6-(4-chlorobenzyl)-9isopropyl-2-(2methylpyridin-4-yl)-2,6,9triazaspiro[4.5]decane7,10-dione 130 GCHI , 1 l) SAL W b (8)-6-(4-chlorobenzyl)-9isopropyl-2-(pyridin-2yl)-2.6,9- triazaspiro[4.5]decane- 7,10-dione 131 <? ----- district 1 A / X ^g “~1? ъ (3)-6-(4-chlorobenzyl)-9isopropyl-2-phenyl-2,6,9triazaspiro[4.5]decane7,10-dione

- 66 045362

132 „ ν G U ( /l x^· (B)-6-(4-chlorobenzyl)-9isopropyl-2-(2methylpyridin-4-yl)-2,6,9triazaspiro[4.5]decane7,10-dione 133 O class ⁵ h X\ ' / (5)-6-(4-chlorobenzyl)-9isopropyl-M-methyl-7,10dioxo-2,6,9- triazaspiro[4.5]decane-2carboxamide 134 ABOUT + > (5)-6-(4-chlorobenzyl)-Methyl-9-isopropyl-7,10dioxo-2,6,9- triazaspiro[4.5]decane-2carboxamide 135 XXX about X- (8)-6-(4-chlorobenzyl)-M,9diisopropyl-7,10-dioxo2,6,9- triazaspiro[4.5]decane-2carboxamide 136 bX _x s\UQ\SG (8)-6-(4-chlorobenzyl)-9isopropyl-7,10-d ioxo-N(pyridin-2-yl)-2,6,9triazaspiro[4.5]decane-2carboxamide

- 67 045362

137 h./ J/:/Ό (8)-6-(4-chlorobenzyl)-9- Μ3θπροπΜΓ-Ν-(2- methoxyethyl)-7,10-d ioxo- 2,6,9- triazaspiro[4.5]decane-2carboxamide 138 ζ ύ 8-isopropyl-2-(pyridin-2yl)-5-(1-(4- (trifluoromethyl)phenyl)these l)-2,5,8- triazaspiro[3.5]nonane-6,9dione 139 1 ' ΊΊ 8-isopropyl-M-methyl-6,9dioxo-5-(1-(4- (trifluoromethyl)phenyl)ethyl)-2,5,8- triazaspiro[3.5]nonane-2carboxamide 140 .....g 8-isopropyl-2-phenyl-5-(1(4- (trifluoromethyl)phenyl)ethyl)-2,5,8- triazaspiro[3.5]nonane-6,9dione 141 Λ-/ ^- + 2v ^F FF (B)-8-isopropyl-2-phenyl- 5-(1-(4- (trifluoromethyl)phenyl)these l)-2,5,8- triazaspiro[3.5]nonane-6,9dione

- 68 045362

142 ό (8)-8-isopropyl-2-phenip- 5-(1-(4- (trifluoromethyl)phenyl)these l)-2,5,8- triazaspiro[3.5]nonane-6,9dione 143 Q'h /D ₍ S)-6-((S)-1-(4chlorophenyl)ethyl)-9isopropyl-2-(pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane-7,10-dione 144 oA ABOUT (R)-6-((S)-1-(4chlorophenyl)ethal)-9isopropyl-2-(pyridine-2- il)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 145 -X% ABOUT- 8-(4-methoxyphenyl)-Mmethyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonane-2carboxamide 146 ί ΗΝ^ο N Sk\Z γ 1 L 1 ί 7 F 8-(4-cyanophenyl)-N- methyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide

- 69 045362

147 u. u ¢0 z 8-(6-cyanopyridin-3-yl)~ Ν-μθτμπ-6,9-αμοκοο-5-(4(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonane-2carboxamide 148 I HN^O N oJJ γ MMM methyl-4-(2- (methylcarbamoyl)-6,9- dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-8yl)benzoate 149 I HN^ON CK >< /x ,x /VA M ^F _F MP 8-(4-fluorophenyl)-1M-methyl- 6,9-diszhso-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 150 HN^O N cr 8-(4-chlorophenyl)-N-methyl- 6,9-dioxo-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 151 I ΗΝ^,ο N । ιΎΊ ^%,n. A 0 A _c π T ' o 00 0 ^F F M-methyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)-8(4-(trifluoromethyl)phenyl)2,5,8triazaspiro[3.5]nonane-2carboxamide

- 70 045362

152 I N ,ΓΥ ^Ν Χ UL₽ ^F VA F 8-(3,4-difluorophenyl)-Mmethyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 153 p<H У “П τι ^methyl-6,9-dioxo-8-(ptolyl)-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 154 IHN^O N GG ° O ·- I 8-(6-methoxypyridin-3-yl)Ν-μθτηπ-6,9-αηοκοο-5-(4(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonane-2carboxamide 155 Kommersant 8-(4-chloro-3-fluorophenyl)-Mmethyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 156 LL IX Y _>Υ y O 8-(5-chloropyridin-2-yl)-M- methyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide

- 71 045362

157 U 8-(4- (difluoromethyl)phenyl)-1Hmethyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonane-2carboxamide 158 IX LL at Mi H 8-(4-cyclopropylphenyl)M-methyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonane-2carboxamide 159 N o.// χχΉ ХУ Д F ^F 8-(4- (difluoromethoxy)phenyl)-14methyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 160 ^HN yo A θΑ2 _ / ⁴ %\ <, fV ^N A y\ Ο У FF M-methyl-6,9-dioxo-8-(4(trifluoromethoxy)phenyl)5-(4(trifluoromethyl)benzyl)2,5,8triazaspiro[3.5]nonane-2carboxamide

- 72 045362

161 -H -Π -Π M-methyl-6,9-dioxo-8-(4- (prop-1-en-2-yl)phenyl)-5(4-(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 162 / ΗΝ^Ο Ν 0^44 ΤΉ'\ ₌ -ίΚ GUUKA, _F % 8-(4-cyano-3-fluorophenyl)M-methyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonane-2carboxamide 163 '-ъ ^>-1- Ώ\Ο % 8-(3-chlorophenyl)-M-me™l- 6,9-dioxo-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 164 / Ν 5-(4-chlorobenzyl)-8-(4cyanophenyl)-1H-methyl-6,9dioxo-2,5,8- triazaspiro[3.5]nonane-2carboxamide 165 IX IX ί < % ο X 8-(4-(5-(difluoromethyl)- 1,2,4-oxadiazol-Zyl)phenyl)-N-me™l-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide

- 73 045362

166 I HN^o N Ο.χ,Χ „ _ । GU? A UH _c fY -% Cl^№^ F I 8-(4-chloro-3-methylphenyl)~ ^methyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 167 HN^GN ο. XT ^F 8-(4-cyano-3-methylphenyl)M-methyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 168 x< Y Ύ| *P 8-(4-chloro-2-fluorophenyl)-Nmethyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonane-2carboxamide 169 U.L.L. Г >x X X 8-(4-cyano-2-fluorophenyl)N-weTnn-6,9-flHOKCO-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 170 I HN^o N О _%х S< _l T Ν'^γί^Χ fy-\ 4^ _{F ?} VX 8-(3-fluoro-4methoxyphenyl)-1Хmethyl6,9-dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide

- 74 045362

171 I HN^ _O N guU LI II I O Ji F ^f ^ ^{f f} 8-(4-(difluoromethoxy)-3φτορφθΗππ)-Ν-Μθ™π-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 172 N HDU _Λ /Η-'Χ.^χ <V ^N x -A / «\U AF chu 8-(4-benzoylphenyl)-Nmethyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonane-2carboxamide 173 HN^ON F _FF AhUA X Ji / ^F 8-(4-cyano-2-fluorophenyl)Ν-Μβτππ-6,9-ΑΜθκοο-5-(4-(3(trifluoromethyl)-3H- diazirin-3-yl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 174 xL^o y y y 1 _s Г /[ --0 V< _v F / ^F 3-fluoro-4-(2-isobutyryl- 6,9-diszhso-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.53nonan-8yl)benzonitrile 175 νθ F // N'Vxx yy-R 1 g y ,1 F U> hL 4-(2-acetyl-5-(4- chlorobenzyl)-6,9-dioxo- 2,5,8- triazaspiro[3.53nonan-8yl)-3-fluorobenzonitrile

- 75 045362

176 Ъл 0 4-(2-acetyl-5-(4- fluorobenzyl)-6,9-dioxo- 2,5,8- triazaspiro[3.5]nonan-8yl)-3-fluorobenzonitrile 177 N.H. F F ^methyl-6,9-dioxo-8-(2oxo-2H-chromen-6-yl)-5-(4(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonane-2carboxamide 178 I HN^ON fS0Г VWf /y^O νψ n ⁿ 8-(4-ethynyl-2-fluorophenyl)N-methyl-6,9-dioxo-5-(4-(3(trifluoromethyl)-3Hdiazirin-3-yl)benzyl)2,5,8- triazaspiro[3.5]nonane-2carboxamide 179 9 oYl ό 3-fluoro-4-(2-formyl-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-8yl)benzonitrile 180 □ o«^~ Ny V-/ ^F \ /^Och\ O W^N F~7( FV 4-(2-(cyclobutanecarbonyl)- 6,9-dioxo-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-8yl)-3-fluorobenzonitrile

- 76 045362

181 \ N.H. M b/o n-n M-methyl-6,9-dioxo-8-(2- oxo-2H-chromen-6-yl)-5-(4(3-(trifluoromethyl)-3Hdiazirin-3-yl)benzyl)2,5,8- triazaspiro[3.5]nonane-2carboxamide 182 N S-Λ ₀ Λ _ζ ν 2-acetyl-8-(5-chloro-3fluoropyridin-2-yl)-5-(4chlorobenzyl)-2,5,8triazaspiro[3.5]nonane-6,9dione 183 \n o=CH N-d Ull *νΛ li y ^F S 9-(4-cyanophenyl)-Nmethyl-7,10-dioxo-6-(4(trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-2carboxamide 184 LL LL s E-(b-cyanopyridin-3-yl)N-methyl-7,10-d ioxo-6-(4(trifluoromethyl)benzyl)2,6,9triazaspiro[4.5]decane-2carboxamide 185 X ί 'U'-y 6-(4-chlorobenzyl)-9-(4cyanophenyl)-1M-methyl7,10-dioxo-2,6,9triazaspiro[4.5]decane-2carboxamide

- 77 045362

186 b/l l ΤΙ Π 4-(2-acetyl-6,9-dioxo-5(4-(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-8yl)benzonitrile 187 G Ν ο _χ Τ Ν'\ΧΧ xy-^o ρ F 4-(6,9-dioxo-2-propionyl- 5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-8yl)benzonitrile 188 >γ 4 ζ methyl-8-(4-cyanophenyl)- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxylate 189 HN^S N ο. χ. τ γγγ Γγ aa^f F 8-(4-4Μ3ΗθφθΗΜπ)-Νmethyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonane-2carbothioamide 190 О riTwYA γ< ° ' ^N FF О 4-(2-formyl-6,9-dioxo-5(4-(trifluoromethyl)benzyl)~ 2,5,8- triazaspiro[3.5]nonan-8yl)benzonitrile

- 78 045362

191 4-(2-(2,2-difluoroethal)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-8yl)benzonitrile 192 d >—ζ oC Wo 4-<>Υ q h 6-(8-(4-cyanophenyl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-2yl)nicotinonitrile 193 f4—/Л—\ ,o F ^N ~4 y ⁿ /~L Y N 4-(2-(2,2-difluoroethyl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-8yl)-2-fluorobenzonitrile 194 τΥΥγ 4' N 2-fluoro-4-(2-formyl-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-8yl)benzonitrile 195 HN^S Tqwq]yWW |Ύ T F 8-(4-cyano-3-fluorophenyl)M-methyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carbothioamide

- 79 045362

196 + , F + η Ή methyl-8-(4-cyano-3- fluorophenyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxylate 197 “Π “Π 4-(2-acetyl-6,9-d ioxo-5(4-(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonan-8yl)-2-fluorobenzonitrile 198 +, ++ + “Π -π 8-(4-cyano-3-fluorophenyl)- 6,9-dioxo-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 199 Υ ΗΝ^Ο ά Ν< τ 8-(4-cyano-3-fluorophenyl)M-cyclopropyl-6,9-dioxo5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 200 +" ΗΝ--Υ ζιτθ+ ο=γ >=ο g 8-(4-cyano-3-fluorophenyl)M-(1-methyl-1H-pyrazop-4yl)-6,9-dioxo-5-(4(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonane-2carboxamide

- 80 045362

201 χ' τ ΊΠ ΊΊ 8-(4-cyano-3-fluorophenyl)- M,M-dimethyl-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)~ 2,5,8- triazaspiro[3.5]nonane-2carboxamide 202 Ν 4-(2-acetyl-6,9-d ioxo-5(4-(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonan-8yl)-3-fluorobenzonitrile 203 Ν Χ&Χχ JU with nU 4-(2- (cyclopropanecarbonyl)- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-8yl)-3-fluorobenzonitrile 204 n ₂ m^o Ν Xm A j< A. U ,f XT _N u 8-(4-cyano-2-fluorophenyl)- 6,9-dioxo-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 205 ©Y N— i Dhch 4-(2-acetyl-6-(4chlorobenzyl)-7,10-d ioxo- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile

- 81 045362

206 A - N N—\ X--ΞΝ cHr N Co (8)-4-(2-acetyl-6-(4- chlorobenzyl)-?, 10-d ioxo- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 207 b V. —\ GL FA x- NN—f V—ΞΝ A ⁰¹ ·'” o ^L? O tert-butyl-(S)-6-(4chlorobenzyl)-9-(4-cyano-2fluorophenyl)-?, 10-d ioxo- 2,6,9- triazaspiro[4.5]decane-2carboxylate 208 E F fV X-N N-# \—ΞΞΞΝ / ) '6 F N o^o tert-butyl-(8)-9-(4-cyano2-fluorophenyl)-7,10-d ioxo6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-2carboxylate 209 Z d A U. (8)-4-(2-acetyl-7,10- dioxo-6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 210 ΧΑΆ °5e -a (8)-4-(6-(4-chlorobenzyl)-2(oxetane-3-carbonyl)-7,10dioxo-2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile

- 82 045362

211 ^C )x o M b _N /V ^N \—N / ^N \=/ Г; ⁰ f O^° methyl-(8)-6-(4- chlorobenzyl)-9-(4-cyano-2fluorophenyl)-?, 10-d ioxo- 2,6,9- triazaspiro[4.5]decane-2carboxylate 212 4 O °U XU Q (8)-4-(6-(4-chlorobenzyl)-2(cyclobutanecarbonyl)7,10-dioxo-2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 213 ^y=o r\ Xf° Fy ABOUT Cl (8)-4-(6-(4-chlorobenzyl)-2(cyclopropanecarbonyl)7,10-dioxo-2,6,9triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 214 <4 N—·j A4.D L ji (8)-4-(6-(4-chlorobenzyl)- 7,10-d ioxo-2-propionyl- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 215 4 Y *X. A (8)-3-fluoro-4-(2-(oxetane-3carbonyl)-7,10-dioxo-6(4-(trifluoromethyl)benzyl)2,6,9- triazaspiro[4.5]decane-9yl)benzonitrile

- 83 045362

216 7%~A metal-(5)-9-(4-cyano-2- fluorophenyl)-7,10-d ioxo-6- (4-(trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-2- carboxylate 217 u. g z (8)-4-(2- (cyclobutanecarbonyl)- 7,10-dioxo-6-(4(trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 218 LL LL J* A (S)-4-(7,10-d ioxo-2propionyl-6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 219 1a F z (5)-4-(2- (cyclopropanecarbonyl)- 7,10-dioxo-6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 220 OL ^LJnaS Cf ⁷ Ι-^Άν cr (8)-4-(6-(4-chlorobenzyl)-2formyl-7,10-dioxo-2,6,9triazaspiro[4.5]decan-9yl)-3-fluorobenzonitrile

- 84 045362

221 Cl (5)-4-(6-(4-chlorobenzyl)-2isobutyryl-7,10-d ioxo- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 222 r\ n Sy ^f \ Ο N FF (5)-3-fluoro-4-(2-formyl- 7,10-dioxo-6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-9yl)benzonitrile 223 οΛ У F °VO-X Αντί SO Au ο %--V. f Y _F (8)-3-fluoro-4-(2- isobutyryl-7,10-d ioxo-6(4-(trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-9yl)benzonitrile 224 ^C '0a Y ^f ^Υ ^ν ΛΥ° C / ° N Lo (3)-2-acetal-6-(4chlorobenzyl)-9-(4(difluoromethoxy)phenyl)- 2,6,9- triazaspiro[4.5]decane- 7,10-dione 225 /A ..Ύ' yY4 0\ O (5)-2-acetyl-6-(4- chlorobenzyl)-9-(5- methoxypyridin-2-yl)- 2,6,9- triazaspiro[4.5]decane- 7,10-dione

- 85 045362

226 αΛ f ¹ I tert-butyl-(2h,4h)-8-(4cyano-2-fluorophenyl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxylate 227 I γγχ A L J.....’ 1 χ" tert-butyl-(2g,4g)-8-(4cyano-2-fluorophenyl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxylate 228 i ^f H '^x; y S / А А γ,γ ' Ύ - 4-((25,43)-2-(1D4oxadiazol-2-yl)-6,9dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)-3-fluorobenzonitrile 229 J...LALA i '.''\ I, .„.g -: I '—Cha ^! 3-fluoro-4-((2h,4h)-2-(3methyl-1,2,4-oxadiazol-5yl)-6,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[ 3.5]nonan8-yl)benzonitrile 230 FF CHH/A. jM G no. X ,0 1 ^N 3-φτορ-4-((2ε,45)-2-(3-(1- hydroxyethyl)-1,2,4oxadiazol-5-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)benzonitrile

- 86 045362

231 F. F A Ύ -M _N _/, \\— .% ..... 3-φτορ-4-((2δ,48)-2-(5methyloxazol-2-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 232 To Z^O uch oO A UL 4-((2s,4s)-2-(3- cyclopropyl-1,2,4oxadiazol-5-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)-3-fluorobenzonitrile 233 I I Λ N '^ ^S N' 3-fluoro-4-((23,45)-2-(5methyl-1,3,4-oxadiazol-2yl)-6,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[ 3.5]nonan8-yl)benzonitrile 234 Т\ Я1 FW ⁴ — NN—e ^x )—==N o/ ^1f O ^N Ύ 3-fluoro-4-((28.43)-2-(4metaloxazol-2-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 235 Oo 4Z^ oZ ^OF 0 3-fluoro-4-((23,45)-2(morpholine-4-carbonyl)6,9-dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)benzonitrip

- 87 045362

236 U LL 4-((2h,4a)-2-(azetidin-1carbonyl)-b,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)-3-fluorobenzonitrile 237 A (28.45)-8-(4-cyano-2fluorophenyl)-N- cyclopropyl-b!-metal-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 238 pF ό ^L A _F 0 ^<N OH 3-$Top-4-((2s,4s)-2-(4hydroxypiperidin-1carbonyl)-6,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 239 NHsi (2s,4s)-8-(4-nnaHO-2-fluorophenyl)-Н-(oxetan-3yl)-6 _! 9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 240 » _s j00 ^a i .1 4 pl IX N\ to r 4-((2s,4s)-2-(5- (difluoromethyl)-1,3,4oxadiazol-2-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan8-yl)-3-fluorobenzonitrile

- 88 045362

241 \-Ν Ν-ί у-—=Ν АЧ Μ 0 0 F to and y N F 4-((2s,4s)-2-(3- (difluoromethyl)-1,2,4oxadiazol-5-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)-3-fluorobenzonitrile 242 ^F \/ ^F H > ίΧ· 0' NH 4 (23,43)-8-(4-cyano-2fluorophenyl)-Ncyclopropyl-6,9-dioxo-5(4-(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 243 I X (2h,43)-8-(4-cyano-2fluorophenyl)-M-((1h,38)-3hydroxycyclobutyl)-6,9dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2 -carboxamide 244 mm* ? ’ But' (23,48)-8-(4-cyano-2fluorophenyl)-M-((1 r,3R)-3hydroxycyclobutyl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide

- 89 045362

245 Ta. , dL (Υχ 1-((2h,45)-8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan2-yl)-3-methylurea 246 EF Qkn NN—C 7 АЧ )=/ О P 0 ^F vy unС 1-((2h,4h)-8-(4-cyano-2fluorophenyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)~ 5,8-diazaspiro[3.5]nonan- 2-yl)-3- cyclopropylurea 247 Q _ zrP^ ^N O _v P ° ^F y-NH _O A—NH 1-((2h,45)-8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan2-yl)-3-(oxetan-3yl)urea 248 z lil A rY Cm U- (2h,4c)-8-(4-cyano-2fluorophenyl)-M-(2hydroxyethyl)-6,9-dioxo5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 249 4^ N.H. (2s,4s)-8-(4-pnaHO-2φτορφθΗπη)-Νcyclobutyl-6,9-dioxo-5(4-(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide

- 90 045362

250 P III (2s,4s)-8-(4-pnaHO-2φτορφθΗππ)-Ν-(3,3difluorocyclobutyl)-6,9dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 251 - LHU11. ' , ^; ' - 3-fluoro-4-((2h,4h)-2(hydroxymetal)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 252 ABOUT--* (2s,4s)-8-(4-L|naHO-2fluorophenyl)-M-methyl-M(oxetan-3-yl)-6,9-dioxo5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[ 3.5]nonane2-carboxamide 253 O Λ L 4-У 5 C< '4 3-fluoro-4-((23,45)-2-(2hydroxypropan-2-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 254 ψ 0 0 MS L (2s,4s)-8-(4-xrop-2fluorophenyl)-2-(2hydroxypropan-2-yl)-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane6,9-dione

- 91 045362

255 (U 1. L. r J ] i (2s,4s)-8-(4-xnop-2fluorophenyl)-2-hydroxy-5(4-(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane6,9-dione 256 Ύ i 3-fluoro-4-((28.4z)-2- hydroxy-6,9-d and oxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 257 ό AL 4 / 1 (2g,4g)-8-(4-chloro-2fluorophenyl)-2-hydroxy-5(4-(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane6,9-dione 258 c. yS j i LU 3-fluoro-4-((2g,4g)-2hydroxy-6,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 259 x ⁵³ ί·Ύ ϊ·Χ Ά ” ' ⁵ X ⁴ HH, X (2g,4g)-8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 2-carboxamide

- 92 045362

260 oooh U; (25,4h)-8-(4-cyano-2fluorophenium)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 261 ', ' , · g '' ”· V ' _{h h} (23,45)-8-(4-cyano-2fluorophenyl)-M-methyl-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 262 ... O' Ϋ, 'G U ί J J (2g,4g)-8-(4-cyano-2fluorophenyl)-N,N-dimethyl6,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 263 O. DJU 1 1. (2g,4g)-8-(4-cyano-2- fluorophenyl)-b1-methyl-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane2-carboxamide 264 η '1 ''Uts (2h,4h)-8-(4-cyano-2fluorophenyl)^^-dimethyl6,9-disso-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide

- 93 045362

265 A HJ L 1 I., ' Λ. Me™n-(2s,4s)-5-(4chlorobenzyl)-8-(4-cyano-2fluorophenyl)-6,9-dioxo5,8-diazaspiro[3.5]nonane2-carboxylate 266 C V ϊ Jy y s Λ (2h,4h)-5-(4-chlorobenzyl)-8(4-cyano-2-fluorophenyl)6,9-disso-5,8- diazaspiro[3.5]nonane-2carboxamide 267 ό _β Upk 4-((2s, 4s)-5-(4- chlorobenzyl)-2-(4hydroxypiperidin-1carbonyl)-6,9-dioxo-5,8diazaspiro[3.5]nonan-8yl)-3-fluorobenzonitrile 268 ά 1D , , Λ- Ο (2s,4s)-8-(4-xnop-2- fluorophenyl)-5-(4chlorobenzyl)-2-(4hydroxypiperidine-1carbonyl)-5,8- diazaspiro[3.5]nonane-6,9dione 269 ' * < Λ ^Λ 3-fluoro-4-(3(hydroxymethyl)-3-methyl2,5-dioxo-4-(4- (trifluoromethyl)benzyl)pipe erazin-1-yl)benzonitrile

- 94 045362

270 Ι· Ύ·''·' ⁴ 1-(4-chloro-2-fluorophenyl)-3(hydroxymethyl)-3-metal4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 271 XX 7-(4-chloro-2-fluorophenyl)-4- (4-(trifluoromethyl)benzyl)- 4,7-diazaspiro[2.5]octane- 5,8-dione 272 < χ ) γ/ 8-(4-chloro-2-fluorophenyl)-5(4-(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane6,9-dione 273 IX y 1 / / 77 ^: 1-(4-chloro-2-fluorophenyl)- 3,3-dimethyl-4-(4(trifluoromethyl)benzyl)pipe erazine-2,5-dione 274 X. W ^v, Yd χ /χ \ '·.·. //'SV / y / Χ-Χ' / 8-(4-chloro-2-fluorophenyl)-5(4-(trifluoromethyl)benzyl)2-oxa-5,8- diazaspiro[3.5]nonane-6,9dione

- 95 045362

275 It I I (R)-1-(4-xnop-2- fluorophenyl)-3-methyl-4-(4(trifluoromethyl)benzyl)pipe erazine-2,5-dione 276 A...-0. ,.-'x T Y Y'Yi (S)-1-(4-xnop-2fluorophenyl)-3-methyl-4-(4(trifluoromethyl)benzyl)pipe erazine-2,5-dione 277 γΥγ Y А 'Y*'' 1-(4-chloro-2-fluorophenyl)-4- (4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 278 O ^yjOOv-^Q, ^F N 4-(5,8-dioxo-4-(4(trifluoromethyl)benzyl)4,7-diazaspiro[2.5]octan7-yl)-3-fluorobenzonitrile 279 --4. .Υ' I Y X\ ..··’ .i 4-(3,3-dimethyl-2,5-dioxo- 4-(4- (trifluoromethyl)benzyl)pipe erazin-1-yl)-3fluorobenzonitrile 2§0 EF b>y A — NN—4 0— o ^z 4-(6,9-dioxo-5-(4- (trifluoromethyl)benzyl)-2- oxa-5,8- diazaspiro[3.5]nonan-8yl)-3-fluorobenzonitrile

- 96 045362

281 J.. JT ... f T JyC _k Y Ύ 1-(4-chloro-2-fluorophenyl)-3- (oxetan-3-yl)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 282 'Ά . . . L\ .·- .·. . ll Ά 3-fluoro-4-(3-(oxetan-3-yl)- 2,5-dioxo-4-(4- (trifluoromethyl)benzyl)pipe erazin-1-yl)benzonitrile 283 ⁴ X (5)-3-fluoro-4-(3-isopropyl- 2,5-dioxo-4-(4- (trifluoromethyl)benzyl)pipe erazin-1-yl)benzonitrile 284 fAf ό q YfT _No. JX^ (8)-4-(3-cyclobutyl-2,5- dioxo-4-(4- (trifluoromethyl)benzyl)pipe erazin-1-yl)-3fluorobenzonitrile 285 % y.......... ABOUT (8)-4-(3-(tert- butoxymethyl)-2,5-dioxo- 4.(4- (trifluoromethyl)benzyl)pipe erazin-1-yl)-3fluorobenzonitrile

- 97 045362

286 To Τΐ “Π 4-(7,10-d ioxo-6-(4- (trifluoromethyl)benzyl)-2- oxa-6,9- diazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 287 (5)-3-fluoro-4-(3- (hydroxymethyl)-2,5- dioxo-4-(4- (trifluoromethyl)benzyl)pipe erazin-1-yl)benzonitrile 288 '>· ν' 4-(4-chlorobenzyl)-3-(4- chlorophenyl)-1isopropylpiperazine-2,5dione 289 _νΑ . _ν (8)-4-(4-chlorobenzyl)-3-(4- chlorophenyl)-1- isopropylpiperazine-2,5dione 290 .- j y -., (C)-4-(4-chlorobenzyl)-3-(4chlorophenyl)-1isopropylpiperazine-2,5dione

- 98 045362

291 (8)-3-(4-chlorophenyl)-4-((5- chlorpyridin-2-yl)methyl)1-isopropylpiperazine-2,5dione 292 CC's (C)-3-(4-chlorophenyl)-4-((5chloropyridin-2-yl)methyl)1-isopropylpiperazine-2,5dione 293 : ,.D·. A'Αχ 3-(4-chlorophenyl)-4-((5chloropyridin-2-yl)methyl)1-isopropylpiperazine-2,5dione 294 IkUZJ A ''' ^Χ ·Ά 4-benzyl-3-(4-chlorophenyl)~ 1-isopropylpiperazine-2,5dione 295 X. A (^-4-(4-chlorobenzyl)-3-(5chloropyridin-2-yl)-1isopropylpiperazine-2,5dione

- 99 045362

296 (8)-4-(4-chlorobenzyl)-3-(5chloropyridin-2-yl)-1isopropylpiperazine-2,5dione 297 4-(4-chlorobenzyl)-3-(5- chlorpyridin-2-yl)-1isopropylpiperazine-2,5dione 298 TSH 1 -H. J ..•Gch . ' ' 4-(3-chlorobenzyl)-3-(4- chlorophenyl)-1isopropylpiperazine-2,5- DION 299 Or TV. 3-(4-chlorophenyl)-4-(3fluorobenzyl)-1isopropylpiperazine-2,5dione 300 3-(4-chlorophenyl)-1isopropyl-4-(2methylbenzyl)piperazine2,5-dione

- 100 045362

301 ..” . i 1 .... 2-((2-(4-chlorophenyl)-4isopropyl-3,6dioxopiperazin-1yl)methyl)benzonitrile 302 1 J Ν ₄ УХ : x''' ⁴ ·.. : .-'''''X 4-(2-chlorobenzyl)-3-(4- chlorophenyl)-1- isopropylpiperazine-2,5dione 303 Hch.H 3-(4-chlorophenyl)-4-(4- fluorobenzyl)-1isopropylpiperazine-2,5DIONE 304 GPU ,./Χ ...X „XX ,.,-..., 3-(4-chlorophenyl)-1isopropyl-4-(3methylbenzyl)piperazine- 2.5-dione 305 ...xyi 3-(4-chlorophenyl)-1isopropyl-4-(4methylbenzyl)piperazine2,5-dione

- 101 045362

306 7' D J - L 3-((2-(4-chlorophenyl)-4isopropyl-3,6dioxopiperazin-1yl)methyl)benzonitrile 307 4-((2-(4-chlorophenyl)-4isopropyl-3,6dioxopiperazin-1yl)methyl)benzonitrile 308 C—x _o / 7= _o k.....A O “Π “P 3-(4-chlorophenyl)-1isopropyl-4-(3(trifluoromethyl)benzyl)piperazine-2,5-dione 309 fAf o o Ά A ha _a 3-(4-chlorophenyl)-1isopropyl-4-(4(trifluoromethyl)benzyl)piperazine-2,5-dione 310 Ζ · «· A _h · . ..·.··\ _h; ...·Ά. 4-(4-chlorobenzyl)-3-(2- chlorophenyl)-1isopropylpiperazine-2,5dione

- 102 045362

311 . \........ . _X N : : ⁴ v·'·· ' -F 4-(4-chlorobenzyl)-3-(4- fluorophenyl)-1isopropylpiperazine-2,5dione 312 %'Af T T''CF 4-(4-chlorobenzyl)-3-(3- chlorophenyl)-1- isopropylpiperazine-2,5dione 313 _h .a _x ..-% 4-(4-chlorobenzyl)-1isopropyl-3-(4methoxyphenyl)piperazine- 2.5-dione 314 Cl A Af Π Съ F ^F 4-(4-chlorobenzyl)-1- isopropyl-3-(4- (trifluoromethyl)phenyl)pipe erazine-2,5-dione 315 fAf T t G Ta 3-(4-chlorophenyl)-1isopropyl-4-((5(trifluoromethyl)pyridin-2yl)methyl)piperazine-2,5dione

- 103 045362

316 i 4 Υ'ΑΑ A l γ,.·Υ τ τ Ύ' ^ν γ·' 4-(4-chlorobenzyl)-3-(4chlorophenyl)-1-isopropyl3-methylpiperazine-2,5dione 317 γ-Ύ V”' Ύ Ύ 1'-(4-chlorobenzyl)-4'- isoprolyl-1,3- Dihydrospiro[indene-2,2'perazine]-3',6'-dione 318 \\ 4#..... ^: \ Αχ / V 5-(4-chlorobenzyl)-8isopropyl-2-phenyl-5,8diazaspiro[3.5]nonane-6,9dione 319 -Χ ^γ 4'-isopropyl-T-(4- (trifluoromethyl)benzyl)- 2,3-dihydrospiro[indene1,2'-piperazine]-3',6'-dione 320 κψ,Γ ο f ο ° _ν 4^ ^Ν γ'χ 1 ο ¹ ^.ΝΗ 8-(1-cyanopropan-2-yl)-1+ methyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonane-2carboxamide

- 104 045362

321 d'wd—NH VN. ⁰ SE 8-((1 S, 3R)-3cyanocyclopentyl)-Mmethyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonane-2carboxamide 322 O^z N α^° Л^-Ό. 2-acetyl-8-((1g,4g)-4methylcyclohexyl)-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-6,9dione 323 \^O N Arn 2-acetyl-8-(4ethylcyclohexyl)-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-6,9dione 324 \^ON Yfn _Ργ α F 2-acetyl-8-(4- (difluoromethyl)cyclohexyl)-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-6,9dione

- 105 045362

325 \^.ΟΝ nX (1 g,4 g)-4-(2-acetal-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-8yl)cyclohexane-1carbonitrile 326 Ύ° Ν ^F 2-acetyl-8-cycloheptal-5(4-(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonane-6,9dione 327 0 f.....on o=4 A ⁰ N—' \ 9-isopropyl-2-phenyl-6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane- 1,7,10-trione 328 “P 71 i Y>o '—( \£ (8)-9-imino-8-isopropyl-2phenyl-5-(1-(4- (trifluoromethyl)phenyl)these l)-2,5,8- triazaspiro[3.5]nonane-6- He 329 . Ζ-·'··\\ 5-(4-chlorobenzyl)-8isopropyl-7-methyl-2phenyl-2,5,8- triazaspiro[3.5]nonane-6,9dione

- 106 045362

330 '' C ' '0\ \ 6-(4-chlorobenzyl)-9isopropyl-2-(1-methyl-1 Npyrazol-4-yl)-2,6,9triazaspiro[4.5]decane1,7,10-trione 331 ϊ V /A : Am / / 0--· m. _? v.”—.nV < \v : X? A 6-(4-chlorobenzyl)-9- isopropyl-2-phenyl-2,6,9triazaspiro[4.5]decane3,7,10-trione 332 6-(4-chlorobenzyl)-9isopropyl-2-(pyridine-2- il)-2,6,9- triazaspiro[4.5]decane- 3,7,10-trione 333 A-' 6-(4-chlorobenzyl)-9isopropyl-2-(2methylpyridin-4-yl)-2,6,9triazaspiro[4.5]decane1,7,10-trione 334 I y ' μ····· ' ^χ '-·4. ,m ^: ·;, // ^: 6-(4-chlorobenzyl)-9-(4methoxybenzyl)-M-methyl7,10-dioxo-2,6,9triazaspiro[4.5]decane-2carboxamide

- 107 045362

335 8 ν<Κ5 -NH У-N /=\ F ⁰ M-methip-6,9-dioxo-5,8bis(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 336 T - X Ό;. 8-(4-cyanobenzyl)-Mmethyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 337 /4 X......·-' < \ 8-(4-χπορ6θΗ3ππ)-Ν-ΜθΤΗΓ- 6,9-dioxo-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 338 F, F P —NH /- N /=\ °' ZiO ^N 8-(1-(4-cyanophenyl)ethyl)N-weTnn-6,9-flHOKCO-5-(4(trifluoromethyl)benzyl) 2,5,8- triazaspiro[3.5]nonane-2carboxamide 339 LL LL X o '4 (3)-4-(2-acetyl-6,9-dioxo- 5-(1-(4- (trifluoromethyl)phenyl)these l)-2,5,8- triazaspiro[3.5]nonan-8yl)-3-fluorobenzonitrile

- 108 045362

340 Ν Гх^гП. .v, A. Muku u (8)-2-acetal-8-(4-chloro-2- fluorophenyl)-5-(1-(4- (trifluoromethyl)phenyl)these l)-2,5,8- triazaspiro[3.5]nonane-6,9dione 341 Ύ° Ν уХу _C i ^F 2-acetyl-8-(4-chloro-2fluorophenyl)-7-methyl-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-6,9dione 342 /Y MtL ν fJU X % (2g,4g)-8-isopropyl-2-(5methyltaazol-2-yl)-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane6,9-dione 343 °<r ^F M^ Г- (2s,4s)-8-H3onponnn-Nmethyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 344 °Ycco iF (2s,4s)-2-(4,5- dimethyloxazol-2-yl)-8isopropyl-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane6,9-dione

- 109 045362

345 itoH V-N 0 — (2s,4s)-8-M3onponwn-2-(4methyloxazol-2-yl)-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane6,9-dione 346 I am λΑγΡχ Η α 6-((S)-6-((R)-1-(4- chlorophenyl)-2- hydroxyethyl)-9isopropyl-7,10-d ioxo- 2,6,9- triazaspiro[4.5]decane-2yl)nicotinonitrile 347 . )Ζ-·Ζ ζ .Ρ-··4 6-(5-(4-chlorobenzyl)-8- isopropyl-7- (methoxymethyl)-6,9-dioxo- 2,5,8- triazaspiro[3.5]nonan-2yl)nicotinonitrile 348 CI ° ΑΑ _ν+ οπ 0 6-(6-(4-chlorobenzyl)-9-(4nitrophenyl)-7,10-d ioxo- 2,6,9- triazaspiro[4.5]decane-2yl)nicotinonitrile 349 y r ^b 6-(4-chlorobenzyl)-N-methyl9-(4-nitrophenyl)-7,10dioxo-2,6,9- triazaspiro[4.5]decane-2carboxamide

- 110 045362

350 5. A if OH YES fA 6-(6,9-d ioxo-8-phenyl-5(4-(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-2yl)nicotinonitrile 351 °Ά Cl 6-(4-chlorobenzyl)-9isopropyl-2-(pyrimidin-4yl)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 352 _g lU D'' Λ ' s A.. (K)-6-(4-chlorobenzyl)-9isopropyl-2-(pyrimidin-4yl)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 353 OU C| 6-(4-chlorobenzyl)-9isopropyl-2-(pyrazine-2- il)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 354 \ A l,i _h A-.U \ / O p ' Q <? (P)-6-(4-chlorobenzyl)-9- isopropyl-2-(pyrazine-2- il)-2,6,9- triazaspiro[4.5]decane- 7,10-dione

- 111 045362

355 Clά O / 6-(4-chlorobenzyl)-9isopropip-2-(5me™lpyridin-2-yl)-2,6,9triazaspiro[4.5]decane7,10-dione 356 ult......7 ABOUT \ (C)-6-(4-chlorobenzyl)-9isopropyl-2-(5methylpyridin-2-yl)-2,6,9triazaspiro[4.5]decane7,10-dione 357 O. / X 6-(4-chlorobenzyl)-2-(5fluoropyridin-2-yl)-9isopropyl-2,6,9- triazaspiro[4.5]decane7,10-dione 358 5. \ _Λ ζ [ - _h X ' /l \y (E?)-6-(4-chlorobenzyl)-2-(5fluoropyridin-2-yl)-9isopropyl-2,6,9triazaspiro[4.5]decane7,10-dione 359 ©y 6-(4-chlorobenzyl)-9isopropyl-2-(pyridazin-3yl)-2 _: 6,9-triazaspiro[4.5]decane-7,10-dione

- 112 045362

360 _€ y. g x ) /h y/ (R)-6-(4-xnop6eH3wn)-9isopropyl-2-(pyridazine-3- il)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 361 .US d 6-(4-chlorobenzyl)-9isopropyl-2-(1-methyl-2oxo-1,2-dihydropyridine- 4-yl)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 362 GLUL ,νΥ 1 y < * T Uch. (C)-6-(4-chlorobenzyl)-9isopropyl-2-(1-methyl-2oxo-1,2-dihydropyridine- 4-yl)-2,6,9- triazaspiro[4.5]decane- 7,10-dione 363 CHUA °h TO X Ch. O 6-(4-chlorobenzyl)-9isopropyl-2-(2-oxo-1,2dihydropyridin-4-yl)- 2,6,9- triazaspiro[4.5]decane- 7,10-dione 364 _g -\%, HH XJ < ° ⁵ O o (K)-6-(4-chlorobenzyl)-9isopropyl-2-(2-oxo-1,2dihydropyridin-4-yl)2,6,9- triazaspiro[4.5]decane7,10-dione

- 113 045362

365 M 6-(4-chlorobenzyl)-9isopropyl-2-(1-methyl-1 Ηpyrazol-4-yl)-2,6,9triazaspiro[4.5]decane7,10-dione 366 \ . / ΓΥΥ A- ⁷ w η (K)-6-(4-chlorobenzyl)-9- isopropyl-2-(1-methyl-1 Npyrazol-4-yl)-2,6,9triazaspiro[4.5]decane7,10-dione 367 ΌΙ 6-(4-chlorobenzyl)-9isopropyl-7,10-d ioxo- 2,6,9- triazaspiro[4.5]decane-2carboxamide 368 La>^s> $/$L (C)-6-(4-chlorobenzyl)-9isopropyl-7,10-d ioxo2,6,9- triazaspiro[4.5]decane-2carboxamide 369 ο. ο 6-(4-chlorobenzyl)-Mcyclopropyl-9-isopropyl7,10-dioxo-2,6,9triazaspiro[4.5]decane-2carboxamide

- 114 045362

370 l) \ (R)-6-(4-xnop6eH3wn)-Ncyclopropyl-9-isopropyl- 7,10-dioxo-2,6,9- triazaspiro[4.5]decane-2carboxamide 371 Ο-λΥΧ Y 6-(4-chlorobenzyl)-9- isopropyl-7,10-d ioxo-Nphenyl-2,6,9- triazaspiro[4.5]decane-2carboxamide 372 ohf ΓΥχγ* '< iY—< Y/4 < .?·;:* .. About Q (^-6-(4-chlorobenzyl)-9isopropyl-7,10-d ioxo-Nphenyl-2,6,9triazaspiro[4.5]decane-2carboxamide 373 I Ω 6-(4-chlorobenzyl)-9isopropyl-2-(pyridin-2yl)-2.b,9- triazaspiro[4.5]decane- 7,10-dione 374 ^-Χγ ^υ Η (R)-6-(4-xnop6eH3wn)-9isopropyl-2-(pyridin-2yl)-2D9- triazaspiro[4.5]decane- 7,10-dione

- 115 045362

375 did you eat? χΑ H 6-(4-chlorobenzyl)-9- isopropyl-2-phenyl-2,6,9- triazaspiro[4.5]decane- 7,10-dione 376 с ^/ОО L S < ' Q (C)-6-(4-chlorobenzyl)-9isopropyl-2-phenyl-2,6,9triazaspiro[4.5]decane7,10-dione 377 With Cl 6-(4-chlorobenzyl)-9isopropyl-2-(2methylpyridin-4-yl)-2,6,9triazaspiro[4.5]decane7,10-dione 378 _v >..... .... nt) KJ ( ⁴ (C)-6-(4-chlorobenzyl)-9isopropyl-2-(2methylpyridin-4-yl)-2,6,9triazaspiro[4.5]decane7,10-dione 379 ό CVy ^z 6-(4-chlorobenzyl)-9isopropyl-LKmethyl-7,10dioxo-2,6,9- triazaspiro[4.5]decane-2carboxamide

- 116 045362

380 O .. X γ ' γ “ / (B)-6-(4-chlorobenzyl)-9μ3Οπροπηπ-Ν-μθτμπ-7, 10dioxo-2,6,9- triazaspiro[4.5]decane-2carboxamide 381 'ύ _o q < 6-(4-chlorobenzyl)-1M-ethyl-9isopropyl-7,10-d ioxo2,6,9- triazaspiro[4.5]decane-2carboxamide 382 Μ V/ < H K ' /~ ί ' (R)-6-(4-xnop6eH3nn)-Nethyl-9-isopropyl-7,10dioxo-2,6,9- triazaspiro[4.5]decane-2carboxamide 383 I X w/X) i T /y 6-(4-chlorobenzyl)-Н,9- diisopropyl-7,10-dioxo- 2,6,9- triazaspiro[4.5]decane-2carboxamide 384 R GH'YA Ύ' A. (B)-6-(4-chlorobenzyl)-N,9diisopropyl-7,10-dioxo2,6,9- triazaspiro[4.5]decane-2carboxamide

- 117 045362

385 ©+o+ 6-(4-chlorobenzyl)-9isopropyl-7,10-d ioxo-N- (pirzzin-2-yl)-2,6,9- triazaspiro[4.5]decane-2carboxamide 386 ΐt (C)-6-(4-chlorobenzyl)-9isopropyl-7,10-d ioxo-N(pyridin-2-yl)-2,6,9triazaspiro[4.5]decane-2carboxamide 387 0 Λ +4 OO/ 1 - 6-(4-chlorobenzyl)-9- isopropyl-N-(2methoxyethyl)-7,10-d ioxo- 2,6,9- triazaspiro[4.5]decane-2carboxamide 388 I +0 X/“Y G (E)-6-(4-chlorobenzyl)-9- Η3θπροπππ-Ν-(2- methoxyethyl)-7,10-d ioxo- 2,6,9- triazaspiro[4.5]decane-2carboxamide 389 cm/ ΌΙ 6-((S)-1-(4- chlorophenyl)ethyl)-9isopropyl-2-(pyridine-2- il)-2,6,9- triazaspiro[4.5]decane- 7,10-dione

- 118 045362

390 ό (B)-4-(2-acetyl-6-(4chlorobenzyl)-7,10-d ioxo- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 391 ASAO tert-butyl-6-(4- chlorobenzyl)-9-(4-cyano-2fluorophenyl)-7,10-d ioxo2,6,9- triazaspiro[4.5]decane-2carboxylate 392 A Аα'° tert-butyl-(K)-6-(4chlorobenzyl)-9-(4-cyano-2fluorophenyl)-7,10-d ioxo2,6,9- triazaspiro[4.5]decane-2carboxylate 393 Λ οΑ F / Τ N-^s^sSx Α-ν : / ) ΑΑρ tert-butyl-9-(4-cyano-2fluorophenyl)-7,10-d ioxo-6(4-(trifluoromethyl)benzyl)2,6,9- triazaspiro[4.5]decane-2carboxylate 394 οΑ° Ο F Ϋνν· _Ί ΑζΑ 1 π ί f ο AA^f νΑΑ> F tert-butyl-(^-9-(4-cyano- 2-fluorophenyl)-7,10-d ioxo- 6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-2carboxylate

- 119 045362

395 F, F ^V -N NL >-= _N 4-(2-acetyl-7,10-dioxo-6(4-(trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 396 Qv 4V-fU _N Xo (E)-4-(2-acetyl-7,10- dioxo-6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 397 T o 4-(6-(4-chlorobenzyl)-2(oxetane-3-carbonyl)-7,10dioxo-2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 398 o oJ/ \ _ ^y Ν'Λ V/ V QW=n Cl· (I)-4-(6-(4-chlorobenzyl)-2(oxetane-3-carbonyl)-7,10dioxo-2,6,9triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 399 Cl Q ^OF oX 1 methyl 6-(4-chlorobenzyl)-9(4-cyano-2-fluorophenyl)7,10-dioxo-2,6,9triazaspiro[4.5]decane-2carboxylate

- 120 045362

400 \ °=< ^Ο Pj Near BH Cl metal-(P)-6-(4- chlorobenzyl)-9-(4-cyano-2fluorophenyl)-?, 10-d ioxo2,6,9- triazaspiro[4.5]decane-2carboxylate 401 Y y>p— £7^° 4-(6-(4-chlorobenzyl)-2- (cyclobutanecarbonyl)7,10-dioxo-2,6,9triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 402 O y·· α (E)-4-(6-(4-chlorobenzyl)-2(cyclobutanecarbonyl)7,10-dioxo-2,6,9triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 403 1 y δ 4-(6-(4-chlorobenzyl)-2(cyclopropanecarbonyl)7,10-dioxo-2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 404 bdu w° Cl (E)-4-(6-(4-chlorobenzyl)-2(cyclopropanecarbonyl)7,10~dioxo-2,6,9triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile

- 121 045362

405 WITH!. '^-Ν Ν—/X—== _Ν AA 4-(6-(4-chlorobenzyl)-7,10dioxo-2-propionyl-2,6,9triazaspiro[4.5]decan-9yl)-3-fluorobenzonitrile 406 '9 III ζ (C)-4-(6-(4-chlorobenzyl)- 7,10-d ioxo-2-propionyl- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 407 τ ΙΤΠ χτ AT ° ϊ ? ζ 3- fluoro p-4- (2- (o xeta n-3carbonyl)-7,10-dioxo-6- (4-(trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-9yl)benzonitrile 408 F _x F ¥~ΐ F /Λ VN^O (B)-3-fluoro-4-(2-(oxetane-3carbonyl)-7,10-dioxo-6(4-(trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-9yl)benzonitrile 409 RF Τα λλ Τ _{Ν Ν} _Τ υ,—= _Ν Αο methyl-9-(4-cyano-2- fluorophenyl)-7,10-d ioxo-6(4-(trifluoromethyl)benzyl)2,6,9- triazaspiro[4.5]decane-2carboxylate

- 122 045362

410 EF X ^λ —Ν N—C V-~NX ^OF ” 0^0 metal-(P)-9-(4-cyano-2- fluorophenyl)-7,10-d ioxo-6- (4-(trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-2carboxylate 411 EF x—nn—ep— ° _r X 7 4-(2-(cyclobutanecarbonyl)- 7,10-dioxo-6-(4(trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 412 z-\ /“O ^- ^FF (R)-4-(2- (cyclobutanecarbonyl)- 7,10-dioxo-6-(4(trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 413 lx XA Ao i 4-(7,10-d ioxo-2propionyl-6-(4(trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 414 F, F ъ. . A _N N—AZ— ^Ξ Ν X ^f ” zA 1 (E?)-4-(7,10-dioxo-2- propionyl-6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile

- 123 045362

415 F, F N 4 }—=N ^A° 4-(2- (cyclopropanecarbonyl)- 7,10-dioxo-6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 416 O 4¾°v cfr^ (R)-4-(2- (cyclopropanecarbonyl)- 7,10-dioxo-6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 417 ^c \ 4-(6-(4-chlorobenzyl)-2formyl-7,10-dioxo-2,6,9triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 418 O^'N-'X w> ^F \/X Υ/Υ Cl (B)-4-(6-(4-chlorobenzyl)-2formyl-7,10-dioxo-2,6,9triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 419 K Ad N _Ν γ y-= _N / > O F 1 Y^Q 4-(6-(4-chlorobenzyl)-2isobutyryl-7,10-d ioxo- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile

- 124 045362

420 Ar '-N _N _^ λ—ΞΞ _Ν \/A ₀ (E?)-4-(6-(4-chlorobenzyl)-2isobutyryl-7,10-d ioxo- 2,6,9- triazaspiro[4.5]decane-9yl)-3-fluorobenzonitrile 421 w (UoG Ν 3-fluoro-4-(2-formyl-7,10dioxo-6-(4- (trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-9yl)benzonitrile 422 > l (P1)-3-fluoro-4-(2-formyl7,10-dioxo-6-(4(trifluoromethyl)benzyl)2,6,9- triazaspiro[4.5]decane-9yl)benzonitrile 423 T_>l -<y^ _N o ⁴ - \χΆ _ο 3-fluoro-4-(2-isobutyryl- 7,10-dioxo-6-(4(trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-9yl)benzonitrile 424 ^O SG Z ¥ z (P)-3-fluoro-4-(2- isobutyryl-7,10-d ioxo-6(4-(trifluoromethyl)benzyl)- 2,6,9- triazaspiro[4.5]decane-9- yl)benzonitrile

- 125 045362

425 A- M S '—Ν Ν—d D—0 SL Ν U'O 2-acetyl-6-(4-chlorobenzyl)- 9-(4- (difluoromethoxy)phenyl)- 2,6,9- triazaspiro[4.5]decane- 7,10-dione 426 ci.._„ ^F \-f UL Qv Λ\-θ L> ° (K)-2-acetyl-6-(4chlorobenzyl)-9-(4(difluoromethoxy)phenyl)- 2,6,9- triazaspiro[4.5]decane- 7,10-dione 427 Py.^ DM n-A Ο θ Ν 1 Ao 2-acetyl-6-(4-chlorobenzyl)9-(5-methoxypyridin-2-yl)2,6,9- triazaspiro[4.5]decane- 7,10-dione 428 -/ MD sO° rru _l (K)-2-acetyl-6-(4- chlorobenzyl)-9-(5- methoxypyridin-2-yl)- 2,6,9- triazaspiro[4.5]decane- 7,10-dione 429 .S _K1 _ /A\ /M ) ΝΞΞ-# y- Ν N— A /l O D tert-butyl-8-(4-cyano-2fluorophenyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxylate

- 126 045362

430 / l y—\ 1рХч > Udu/L 4-(2-(1,3,4-oxadiazop-2- yl)-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan8-yl)-3-fluorobenzonitrile 431 ...χ .0 * · * ^! L ^: Ks.jS :W' 4-((2g,4g)-2-(1,3,4- oxadiazol-2-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)-3-fluorobenzonitrile 432 MX Xt 3-fluoro-4-(2-(3-methyl-1,2,4oxadiazol-5-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 433 ..-X to XU'Xl y И X x JI g 1 ^Г G x -X 3-fluoro-4-((2g,4g)-2-(3methyl-1,2,4-oxadiazol-5yl)-6,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[ 3.5]nonan8-yl)benzonitrile 434 Cha. 3-fluoro-4-(2-(3-(1- hydroxyethyl)-1,2,4oxadiazol-5-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)benzonitrile

- 127 045362

435 K YES 7 3-fluoro-4-((2g, 4r)-2-(3-(1hydroxyethyl)-1,2,4oxadiazol-5-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 436 V Ά y YES ~P ΊΊ 3-fluoro-4-(2-(5methyloxazol-2-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 437 Ύ 9 4 1 ί ' V 3-fluoro-4-((2g,40-2-(5- methyloxazol-2-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 438 qN AA o A —<1 У AA ΓΓ ^{Ν 1} '-'ΓΙ ';—/ I 4-(2-(3-cyclopropyl-1,2,4- oxadiazol-5-yl)-6,9- dioxo-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan8-yl)-3-fluorobenzonitrile 439 fAf O A N-O F A 4-((2g,40-2-(3-cyclopropyl1,2,4-oxadiazol-5-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)-3-fluorobenzonitrile

- 128 045362

440 N=/ ΝγΟ U' 3-fluoro-4-(2-(5-methyl-1,3,4oxadiazol-2-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 441 'O ν l Ch/A-/ ACh A U o F _N 3-fluoro-4-((2g,4g)-2-(5- methyl-1,3,4-oxadiazol-2yl)-6,9-dioxo-5-(4(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 442 ^p ^hO~\ / y 3-fluoro-4-(2-(4methyloxazol-2-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 443 oh/nr-^ Oof OU An \ 3-fluoro-4-((2g,4g)-2-(4methyloxazol-2-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 444 b> < l A Ch m -p 3-fluoro-4-(2-(morpholin-4carbonyl)-8,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)benzonitrile

- 129 045362

445 ....... _o y D 3-fluoro-4-((2g,4g)-2(morpholine-4-carbonyl)6,9-dioxo-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 446 A. '.....f/ P A U ΤΊ ΊΠ 4-(2-(azetadine-1carbonyl)-6,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)-3-fluorobenzonitrile 447 K F M.Y. o=K 4-((2g,4g)-2-(azetidin-1carbonyl)-6,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)-3-fluorobenzonitrile 448 Y χΝγΟ _F У К X, Uky JU U ^F A 8-(4-cyano-2-fluorophenyl)N-cycloπpoπyl-N-methyl6,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 449 fXf ABOUT V 9 CHA °v tKk (2g,4g)-8-(4-cyano-2fluorophenyl)-МμΜκποπροππη-Ν-ΜβΤΜΠ-δ,θdioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide

- 130 045362

450 l \ P no-h N—\ _s b Χ- _Ν \=/ _F o=( )=o i N 3-φτορ-4-(2-(4- Hydroxypiperidine-1- carbonyl)-6,9-dioxo-5-(4(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 451 Μ-ζΛ-ξ F X"O"YA 0=4 )=o V N 3-fluoro-4-((2g,4g)-2-(4hydroxypiperidin-1carbonyl)-b,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 452 I J Sn ^x = ^z f 0=( J=o V g 8-(4-cyano-2-fluorophenyl)M-(oxetan-3-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 453 i/-2. IL O=X Uo L-O-U? _t ° l (2g,4g)-8-(4-cyano-2- fluorophenyl)-M-(oxetan-3yl)-6,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 454 1 \ ,οχ/ϊ f 1 F ^f X _n 4-(2-(5-(difluoromethyl)- 1 D4-oxadiazol-2-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)-3-fluorobenzonitrile

- 131 045362

455 .. U Π ) · - n-'-y ' $ -у .-X'Sx Q * ⁴ 4-((2r,4r)-2-(5- (difluoromethyl)-1,3,4oxadiazol-2-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)-3-fluorobenzonitrile 456 X O^N X^o 4-(2-(3-(difluoromethyl)- 1,2,4-oxadiazol-5-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)-3-fluorobenzonitrile 457 fV -~N N—/ S UU N=\ U' 4-((2g,4g)-2-(3- (difluoromethyl)-1,2,4oxadiazol-5-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)-3-fluorobenzonitrile 458 /K k 8-(4-cyano-2-fluorophenyl)N-cyclopropyl-6,9-dioxo5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 459 to ν...... '^-Ν Ν-ΖΥ-ΐΞΞΞΝ -Μ g' M ΝΗ (2g,4g)-8-(4-cyano-2fluorophenyl)-Mcyclopropyl-6,9-dioxo-5(4-(trifluorometal)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide

- 132 045362

460 3 mA ¹ 40 h (2g,4E?)-8-(4-cyano-2φτορφθΗππ)-Ν-((ΐ5,35)-3hydroxycyclobutyl)-6,9dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5] nonane2-carboxamide 461 h N-4. HN—0>UN < hmm. oM ° U (2g,4C)-8-(4-cyano-2fluorophenyl)-N-((1g,3C)-3hydroxycyclobutyl)-6,9dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2 -carboxamide 462 to MM” p M\g F 8-(4-cyano-2-fluorophenyl)M-(3-hydroxycyclobutyl)6,9-disso-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 463 m„ — N N0 ^{Z x} )—ΞΝ 0-ΝΗ —NH 1-(8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 2-yl)-3-methylurea 464 Ϋ o.. A _k mt '«· I: ^V ' 1-((2g,4g)-8-(4-cyano-2fluorophenyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan2-yl)-3-methylurea

- 133 045362

465 Ау N—ЛУ—== ^N _o ΔΛ F ~ V-NH 4 ^NH 1-(8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 2-yl)-3- cyclopropylurea 466 A' ⁷ C-U U 1-((2g,4g)-8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan2-yl)-3- cyclopropylurea 467 ό O Al TX a y4 ^N 4 ηη ΪΧΚ 1-(8-(4-cyano-2fluorophenyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan2-yl)-3-(oxetan-3yl)urea 468 d cl °h a ..4γ ^N 4 » >g A k k X 1-((2g,4g)-8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan2-yl)-3-(oxetan-3yl)urea 469 h o 'H „-O-Xi-.. 8-(4-cyano-2-fluorophenyl)M-(2-hydroxyethyl)-6,9dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide

- 134 045362

470 γ,...... '-Ν Ν-Υ Υξν d'/ / ο=< ΝΗ HQ ^Z (2g,4g)-8-(4-cyano-2φτορφθΗππ)-Ν-(2hydroxyethyl)-6,9-dioxo5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 471 Ε F ,Α / ^ΝΗ 8-(4-cyano-2-fluorophenyl)M-cyclobutyl-6,9-dioxo5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 472 R F ΝΥ 7—=Ν oW (2g,4g)-8-(4-cyano-2- fluorophenyl)-Mcyclobutyl-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 473 RF Ν—χ ⁴ )—ΞΝ A..... 8-(4-cyano-2-fluorophenyl)M-(3,3-difluorocyclobutyl)6,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 474 X § Υ ^ζ γ° ill 2: (2g,4g)-8-(4-cyano-2fluorophenyl)-M-(3,3difluorocyclobutyl)-6,9dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide

- 135 045362

475 ABOUT 3-fluoro-4-(2- (hydroxymethyl)-6,9- dioxo-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 476 Cl X X_____ _{__} _ / / 3-fluoro-4-((2g,4g)-2(hydroxymethyl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 477 F f p O F 0=^ c 8-(4-cyano-2-fluorophenyl)^methyl-N-(oxetan-3-yl)6,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 478 £& AX “ ^v ° (2g,4g)-8-(4-cyano-2- fluorophenyl)-M-methyl-N(oxetan-3-yl)-6,9-dioxo5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 479 E F C S-N Ν-γ 0>—ΞΝ Oof hqY 3-fluoro-4-(2-(2hydroxypropan-2-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonan8-yl)benzonitrip

- 136 045362

480 Yj 411 3-fluoro-4-((2g,4g)-2-(2hydroxypropan-2-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan8-yl)benzonitrile 481 0+ -V NN—С y—Cl HO ⁴ 8-(4-chloro-2-fluorophenyl)-2(2-hydroxypropan-2-yl)-5(4-(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane6,9-dione 482 \J...... (2g,4g)-8-(4-chloro-2fluorophenyl)-2-(2hydroxypropan-2-yl)-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane6,9-dione 483 Cl 8-(4-chloro-2-fluorophenyl)-2hydroxy-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane6,9-dione 484 ⁷ Yai Ο ^λ hi 3-fluoro-4-(2-hydroxy-6,9- dioxo-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan8-yl)benzonitrile

- 137 045362

485 A b to _ _n _z 4—=n Oof oO NH ₂ 8-(4-cyano-2-fluorophenyl)- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane2-carboxamide 486 F F N N—AA—=N Mr 0=7 NH/ 8-(4-cyano-2-fluorophenyl)M-methyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 487 F.F A. p, N N—7 V—ΞΞΝ Mr o=( N— / 8-(4-cyano-2-fluorophenyl)N^-dimethyl-6,9-dioxo-5(4-(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 488 ^c \ Cy \_ _NN # —=N Oof o=7 o / metal-5-(4-chlorobenzyl)-8(4-cyano-2-fluorophenyl)6,9-dioxo-5,8- diazaspiro[3.5]nonane-2carboxylate 489 CS _'s I me™l-(2g,4g)-5-(4chlorobenzyl)-8-(4-cyano-2fluorophenyl)-6,9-dioxo5,8-diazaspiro[3.5]nonane2-carboxylate

- 138 045362

490 h ₂ n To Cl 5-(4-chlorobenzyl)-8-(4cyano-2-fluorophenyl)-6,9dioxo-5,8- diazaspiro[3.5]nonane-2carboxamide 491 to y, _ν Υ/ Μ A O=< νη ₂ (2g,4g)-5-(4-chlorobenzyl)-8(4-cyano-2-fluorophenyl)6,9-dioxo-5,8- diazaspiro[3.5]nonane-2carboxamide 492 but ъ υΥ ⁴ Q Ci 4-(5-(4-chlorobenzyl)-2-(4hydroxypiperidine-1carbonyl)-6,9-dioxo-5,8diazaspiro[3.5]nonan-8yl)-3-fluorobenzonitrile 493 A (J Ύ - ' '7 ABOUT * Y 4-((2g,4g)-5-(4-chlorobenzyl)2-(4-hydroxypiperidine-1carbonyl)-6,9-dioxo-5,8diazaspiro[3.5]nonan-8yl)-3-fluorobenzonitrile 494 wY Ύ 8-(4-chloro-2-fluorophenyl)-5(4-chlorobenzyl)-2-(4- Hydroxypiperidine-1- carbonyl)-5,8diazaspiro[3.5]nonane-6,9dione

- 139 045362

495 ίΤ V . ό (2r,4r)-8-(4-xnop-2fluorophenyl)-5-(4chlorobenzyl)-2-(4hydroxypiperidine-1carbonyl)-5,8- diazaspiro[3.5]nonane-6,9dione 496 X X ΊοχΟ HYny F '------< 8-isopropyl-2-(5methyltaazol-2-yl)-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane6,9-dione 497 X ,---Ν 9 (2s,4s)-8-M3onponnn-2-(5- methyltaazol-2-yl)-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 6,9-dione 498 ΗΝ-/ _F Ъ O>^ ^F MN F oX )=o N— ⁷ 8-isopropyl-M-methyl-6,9dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 499 T yU (2g,4g)-8-isopropyl-M- methyl 6,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide

- 140 045362

500 Q οΑχΟ-γ F 2-(4,5-dimethyloxazol-2yl)-8-isopropyl-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane6,9-dione 501 Q J (2g,4g)-2-(4.5- dimethyloxazole-2-ip)-8- isopropyl-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 6,9-dione 502 \X y F' 8-isopropyl-2-(4methyloxazol-2-yl)-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane6,9-dione 503 r^/L-l */ \ / \ O O - (2g,4g)-8-isopropyl-2-(4methyloxazol-2-yl)-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane6,9-dione 504 / kF (WITH )\ I/O CX A 6-(6-(1 -(4-chlorophenyl)-2hydroxyethyl)-9- isopropyl-7,10-d ioxo- 2,6,9- triazaspiro[4.5]decane-2yl)nicotinonitrile

- 141 045362

505 ft 6-((R)-6-((R)-1-(4chlorophenyl)-2hydroxyethyl)-9isopropyl-7,10-d ioxo2,6,9- triazaspiro[4.5]decane-2yl)nicotinonitrile 506 G! X _; °W _O 6-(4-chlorobenzyl)-2(pyridin-2-yl)-9(tetrahydrofuran-3-yl)- 2,6,9- triazaspiro[4.5]decane- 7,10-dione 507 l o 1-(4-chloro-2-fluorophenyl)-3methyl-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 508 E F z sG l A- 3-fluoro-4-(3-isopropyl-2,5dioxo-4-(4- (trifluoromethyl)benzyl)pipe erazin-1-yl)benzonitrile 509 E F Ν=Ξ—ί) V-Ν L Ay (R)-3-φτop-4-(3-isoπpopyl- 2,5-dioxo-4-(4- (trifluoromethyl)benzyl)pipe erazin-1-yl)benzonitrile

- 142 045362

510 .......... _ΝΞΞ —# _NN y F 4-(3-cyclobutyl-2,5- dioxo-4-(4- (trifluoromethyl)benzyl)pipe erazin-1-yl)-3fluorobenzonitrile 511 E F ........... ΝΞ—f y—N N-U (A)-4-(3-cyclobutyp-2,5- dioxo-4-(4- (trifluoromethyl)benzyl)pipe erazin-1-yl)-3fluorobenzonitrile 512 F.F h/ X 4-(3-(tert-butoxymetal)- 2,5-diszhso-4-(4(trifluoromethyl)benzyl)piperazin-1-yl)-3fluorobenzonitrile 513 FF to ! ^F Q Д _F X- NN—4 у—ΞΞΝ (I)-4-(3-(tert- butoxymethyl)-2,5-dioxo- 4-(4- (trifluoromethyl)benzyl)pipe erazin-1-yl)-3fluorobenzonitrile 514 X An ^/4 Ai rrX D'Ur o OH F 3-fluoro-4-(3- (hydroxymethyl)-2,5- dioxo-4-(4- (trifluoromethyl)benzyl)pipe erazin-1-yl)benzonitrile

- 143 045362

515 0 guFLA,L\D _R 0 OH F U (R)-3-φτop-4-(3- (hydroxymethyl)-2,5- dioxo-4-(4- (trifluoromethyl)benzyl)pipe erazin-1-yl)benzonitrile 516 F F °l 2-acetyl-8-(4- methylcyclohexyl)-5-(4(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonane-6,9dione 517 And And -η 2-acetyl-8-((13,45)-4methylcyclohexyl)-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-6,9dione 518 '—Ν N-D I ί^ ⁰ oC ΝΗ / 8-(3-cyanocyclopentyl)-M- methyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 519 E F λΑ ^Ν Ν Ν D I o=( ΝΗ / 8-((1 R,3R)-3- cyanocyclopental)-Mmethyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide

- 144 045362

520 _F v Q к ,...... ^V ~NN —< )—ΞΝ °x 4-(2-acetyl-6,9-dioxo-5(4-(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonan-8yl)cyclohexane-1carbonitrile 521 F, F -l °+ (1h,48)-4-(2-acetyl-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-8yl)cyclohexane-1carbonitrile 522 qa ^f wVa ^f HN^ N—' 9-imino-8-isopropyl-2- phenyl-5-(1-(4- (trifluoromethyl)phenyl)these l)-2,5,8- triazaspiro[3.5]nonane-6- He 523 p F N-V 0=( pNH X-N (K)-9-imino-8-isopropyl2-phenyl-5-(1-(4- (trifluoromethyl)phenyl)ethyl)-2,5,8- triazaspiro[3.5]nonane-6- He 524 FF _F _v pN N—У—ΞΝ AnX^ °X 4-(2-acetyl-6,9-dioxo-5(1-(4- (trifluoromethyl)phenyl)ethyl)-2,5,8- triazaspiro[3.5]nonan-8yl)-3-fluorobenzonitrile

- 145 045362

525 EF b·>. >-Ν Ν-ΥΛ—ΞΝ gM N ^J Ο F °4 (I)-4-(2-acetyl-6,9-dioxo- 5-(1-(4- (trifluoromethyl)phenyl)these l)-2,5,8- triazaspiro[3.5]nonane-8- yl)-3-fluorobenzonitrile 526 Ε F °4 2-acetyl-8-(4-chloro-2fluorophenyl)-5-(1-(4(trifluoromethyl)phenyl)ethyl)-2,5,8- triazaspiro[3.5]nonane-6,9dione 527 Ε F Α ν ν—ci Ά (I)-2-acetyl-8-(4-chloro-2- fluorophenyl)-5-(1-(4(trifluoromethyl)phenyl)these l)-2,5,8- triazaspiro[3.5]nonane-6,9- dione 528 FFΆ,. _Ύ F °4 2-acetyl-8-(5-chloro-3fluoropyridin-2-yl)-5-(4(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-6,9dione 529 Ε F Υ ο ΧΑά=~ ΑοΗ °4 6-(2-acetyl-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)~ 2,5,8- triazaspiro[3.5)nonan-8yl)-5- methylnicotinonitrile

- 146 045362

530 RF 'bx _o ....... 6-(2-acetyl-6,9-d ioxo-5(4-(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonan-8yl)-5-fluoronicotinonitrile 531 “Π Ka K z 3-fluoro-4-(2-(2(methylamino)benzoyl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.51nonan-8yl)benzonitrile 532 IEF fir methyl 4-(8-(2-cyano-2fluorophenyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-2yl)benzoate 533 A Qy, mA A g methyl 4-(8-(3-cyano-2fluorophenyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonan-2yl)benzoate 534 A^A X-N N—'( Y-=N M.A. 6 °5 methyl-4-(8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2- yl)benzoate

- 147 045362

535 F F F-V Zu —N n—e p— cA 3-fluoro-4-(2-(2(methylamino)phenyl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-8yl)benzonitrile 536 D/ by -a \—N N—E—=N a 3-fluoro-4-(2-(3(methylamino)phenyl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-8yl)benzonitrile 537 QyXp _X NH A fi GP AzXA„ ХА/ JU A ^F FA 2-(8-(4-cyano-2fluorophenyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)~ 2,5,8- triazaspiro[3.5]nonan-2yl)-N-methylbenzamide 538 ^NH? lYHЪ _n -a 3-fluoro-4-(2-(4- (methylamino)phenyl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-8yl)benzonitrile

- 148 045362

539 Wh °^0 N A/A Wf/J F ' N' 3-(8-(4-cyano-2fluorophenyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-2yl)-M-methylbenzamide 540 HNyO Φ N Υ<ΤΤ /X 4-(8-(4-cyano-2fluorophenyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-2yl)-M-methylbenzamide 541 Ν methyl 4-(8-(4-cyano-2fluorophenyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonan-2yl)-2-(methylamino)benzoate 542 iw δ A -and “And 4-(8-(4-cyano-2fluorophenyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-2yl)-^methyl-2- (methylamino)benzamide 543 L.L. u. S' X methyl-4-(8-(5-cyano-2- fluorophenyl)-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2- yl)-2-(methylamino)benzoate

- 149 045362

544 w i “P “P methyl-4-(8-(2-cyano-2- fluorophenyl)-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2- yl)-6-(methylamino)benzoate 545 4%/ ? N 5-(8-(4-cyano-2fluorophenyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonan-2yl)-M-methyl-2- (methylamino)benzamide 546 XX gС n Ci 'ΥΎ O ΗΝ^ [ сА<$ methyl-4-(8-(3-cyano-2- fluorophenyl)-6,9-dioxo-5- (4-(trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2- yl)-2-(methylamino)benzoate 547 \ ζτ to %Chu -P 41 3-(8-(4-cyano-2- fluorophenyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonan-2yl)-M-methyl-2- (methylamino)benzamide 548 WITH! 4 O /\---/ 8-(5-chloro-3-fluoropyridine- 2-yl)-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonan- 6,9-dione

- 150 045362

549 У Αδ У oto Θ 1-(5-chloro-3-fluoropyridin2-yl)-3,3-dimethyl-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 550 g o Yes Jo. f'^ci 7-(5-chloro-3-fluoropyridine- 2-yl )-4-(4- (trifluoromethyl)benzyl)4,7-diazaspiro[2.5]octane5,8-dione 551 Ci che oq k......o....... ^/h 8-(5-chloro-3-fluoropyridine- 2-yl)-5-(4- (trifluoromethyl)benzyl)-2- oxa-5,8- diazaspiro[3.5]nonane-6,9- dione 552 ί ->< δ 8-(5-chloro-3-fluoropyridin2-yl)-N-methyl-6,9-d ioxo5-(4- (trifluoromethyl)benzyl)- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 553 \—ν γ-α O O F o 9-(5-chloro-3-fluoropyridine- 2-yl)-6-(4- (trifluoromethyl)benzyl)-2- oxa-6,9- diazaspiro[4.5]decane-7,10dione

- 151 045362

554 _r , <0 ' Cl—0 У—NN—/ F cCC” (S)-1-(5-xnop-3- fluoropyridin-2-yl)-3- isopropyl-4-(4(trifluoromethyl)benzyl)pipe erazine-2,5-dione 555 EF _a ......<+' 0—0 VN N— f P. (8)-1-(5-chloro-3fluoropyridin-2-yl)-3cyclobutyl-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 556 Q Yak A o\° WITH/ Q (8)-2-acetyl-8-(5-chloro-3fluoropyridin-2-yl)-5-(1-(4chlorophenyl)ethyl)-2,5,8triazaspiro[3.5]nonane-6,9dione 557 F, F A Ov y-d N-^ \-NN—0 Cl M + 0=0 MH ₂ (2g,4g)-8-(5-chloro-3- fluoropyridin-2-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 558 mm/ o U—N 'ABOUT (8)-8-(5-chloro-3fluoropyridin-2-yl)-5-(1-(4chlorophenyl)ethyl)-2-oxa5,8-diazaspiro[3.5]nonane6,9-dione

- 152 045362

559 (S)-&-(5-xnop-3- fluoropyridin-2-yl)-5-(1-(4- chlorophenyl)ethyl)-Ycyclopropyl-6,9-dioxo2,5,8- triazaspiro[3.5]nonane-2carboxamide 560 .....00 c (S)-8-(5-xnop-3fluoropyridin-2-yl)-5-(1-(4chlorophenyl)ethyl)-N-ethal6,9-dioxo-2,5,8triazaspiro[3.5]nonane-2carboxamide 561 I U X! (S)-8-(5-xnop-3- fluoropyridin-2-yl)-5-(1-(4- chlorophenyl)ethyl)-Misopropyl-6,9-dioxo- 2,5,8- triazaspiro[3.5]nonane-2carboxamide 562 WITH! A 0*ΝΗ %ό1 _α (8)-8-(5-chloro-3fluoropyridin-2-yl)-5-(1-(4chlorophenyl)ethyl)-6,9dioxo-Ntetrahydro-2Hpyran-4-yl)-2,5,8triazaspiro[3.5] nonane-2carboxamide

- 153 045362

563 1 HN^ON f X\L.L I D i II ⁰ aAzN (S)-8-(5-xnop-3fluoropyridin-2-yl)-5-(1-(4chlorophenyl)ztyl)-LGmethyl6,9-dioxo-2,5,8triazaspiro[3.5]nonane-2carboxamide 564 ^C bv x ~v_/ y—NN—/ 2--\ XX _F “ ^F °x (3)-2-acetal-5-(1-(4chlorophenyl)ethyl)-8-(5(difluoromethyl)-Zfluoropyridin-2-yl)-2,5,8triazaspiro[3.5]nonane-6,9dione 565 l (5)-2-acetal-5-(1-(4chlorophenyl)ethal)-8-(3fluoro-5- (trifluoromethyl)pyridin-2yl)-2,5,8- triazaspiro[3.5]nonane-6,9dione 566 st. (S)-8-(5-xnop-3- fluoropyridin-2-yl)-5-(1-(4chlorophenyl)ethyl)-2-(2,2difluoroethyl)-2,5,8- triazaspiro[3.5]nonane-6,9dione 567 OU. X Gn ° O methyl-(5)-8-(5-chloro-3fluoropyridin-2-yl)-5-(1-(4chlorophenyl)ztyl)-6,9- dioxo-2,5,8- triazaspiro[3.5]nonane-2carboxylate

- 154 045362

568 Μ Ά (S)-8-(5-xnop-3fluoropyridin-2-yl)-5-(1-(4chlorophenyl)ethyl)-6,9dioxo-2,5,8triazaspiro[3.5]nonane-2carbaldehyde 569 Cl h _a /x/> _F 2,2-difluoroe™l-(3)-8-(5chloro-3-fluoropyridin-2-yl)5-(1-(4-chlorophenyl)ethyl)6,9-dioxo-2,5,8triazaspiro[3.5 ]nonane-2carboxylate 570 FF ^F \ Ο θν '—( M\ У-NN—V MCI A (5)-2-acetal-8-(5-chloro-3fluoropyridin-2-yl)-5-(1-(4(trifluoromethyl)phenyl)ethyl)-2,5,8- triazaspiro[3.5]nonane-6,9dione 571 FF ^Р ^Л 0 vJ Μ N-0 _N _0 y_ _Br f °л (8)-2-acetyl-8-(5-bromo-3fluoropyridin-2-yl)-5-(1-(4(trifluoromethyl)phenyl)ethyl)-2,5,8- triazaspiro[3.5]nonane-6,9dione 572 Ti o rr·· ¹ Qy ° 1 '0 Ω 9-acetyl-4-(5-chloro-3fluoropyridin-2-yl)-1-(4(trifluoromethyl)benzyl)- 1,4,9- triazaspiro[5,5]undecane2,5-dione

- 155 045362

573 Ch U _l Τι 1 O F Ch%G' o 1-(5-chloro-3-fluoropyridin2-yl)-3-(hydroxymethyl)-3methyl-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 574 o CHA\ _N PgCHH ^h F 8-(5-chloro-3-fluoropyridin2-yl)-2-fluoro-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane6,9-dione 575 0 χΛ Ν _α 0 _ο ^ ^Ν 0 _α Cl ^u ο ^Ci 8-(5-chloro-3-fluoropyridin2-yl)-5-(4-chlorobenzyl)-2oxa-5,8- diazaspiro[3.5]nonane-6,9dione 576 XHL/ SrXX 0 1-(5-chloro-3-fluoropyridin2-yl)-4-(4-chlorobenzyl)-3,3dimethylpiperazine-2,5dione 577 aUUrCh ό _R Ach _a 7-(5-chloro-3-fluoropyridin2-yl)-4-(4-chlorobenzyl)-4,7diazaspiro[2.5]octane-5,8dione 578 O -L O / ^z Zh y (8)-1-(5-chloro-3- fluoropyridin-2-yl)-3-((8)1-hydroxyethyl)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione

- 156 045362

579 . ABOUT? ' <: T τι (S)-1-(5-xnop-3- φτopπpyridin-2-yl)-3-((R)1-hydroxyethyl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 580 A D ^h ° ¹ o (R)-1-(5-xnop-3- fluoropyridin-2-yl)-3-((8)1-hydroxyethyl)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 581 SK VNF F _o y min _ns y\ (R)-1-(5-xnop-3- φτopπpyridin-2-yl)-3-((R)1-hydroxyethyl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 582 C X O OH F (S)-1-(5-xnop-3- fluoropyridin-2-yl)-3(hydroxymethyl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 583 About X ,N. A hA >F ί Υ Π Ί Y _F □Μ O OH F (R)-1-(5-xnop-3- fluoropyridin-2-yl)-3(hydroxymethyl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 584 Oh ψργ, LA° he (8)-1-(5-chloro-3- fluoropyridin-2-yl)-4-(4- chlorobenzyl)-3- ίhydroxymethyl)piperazine- 2 5-dion

- 157 045362

585 cr O ότ T - aX-Za. oh he ^Cl (R)-1-(5-xrop-3fluoropyridin-2-yl)-4-(4xporbenzyl)-3- (hydroxymethyl)piperazine2,5-dione 586 ST Cl 4 OfrV (S)-1-(5-xnop-3- fluoropyridin-2-yl)-4-(4- chlorobenzyl)-3- isopropylpiperazine-2,5- dione 587 or Ci 0 ' A ,N, .bk J·., s OCTT T _F (I)-1-(5-chloro-3- fluoropyridin-2-yl)-4-(4- chlorobenzyl)-3- isopropylpiperazine-2,5dione 588 Cl- O i ^F J (S)-1-(5-xnop-3fluoropyridin-2-yl)-3(hydroxymethyl)-3-methyl4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 589 Cl- W ^F O HJX ? he Τ' γ o F ^f J ^F (R)-1-(5-xnop-3- fluoropyridin-2-yl)-3(hydroxymethyl)-3-methyl4.(4. (trifluoromethyl)benzyl)pipe erazine-2,5-dione

- 158 045362

590 LL LL X X o (S)-1-(5-xnop-3- fluoropyridin-2-yl)-3isopropyl-4-((5)-1-(4(trifluoromethyl)phenyl)ethyl)piperazine-2,5-dione 591 ^ci >Xn k ^F Ai ^f _Ο Χ ^Ν Ά^ (R)-1-(5-xnop-3- fluoropyridin-2-yl)-3isopropyl-4-((5)-1-(4(trifluoromethyl)phenyl)ethyl)piperazine-2,5-dione 592 Ϋ. X ./1 Y-N N—C V-Ci X NH/ (S)-8-(5-xnop-3- fluoropyridin-2-yl)-Nmethyl-6,9-dioxo-5-(1-(4(trifluoromethyl)phenyl)ethyl)-2,5,8- triazaspiro[3.5]nonane-2carboxamide 593 ΑΟχ F---( \ы x (S)-8-(5-xnop-3fluoropyridin-2-yl)-2-(2,2difluoroethyl)-5-(1-(4(trifluoromethyl)phenyl)ethyl)-2,5,8- triazaspiro[3.5]nonane-6,9dione 594 X., ^x —Ν Ν—v V—Cl dl/ ( ethyl-(2g,4g)-8-(5-chloro-3fluoropyridin-2-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxylate

- 159 045362

595 <3ίΑ IL ethyl-(25.4h)-8-(5-chloro-3fluoropyridin-2-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane2-carboxylate 596 Ci \_ _N N—V 7—Cl AC VJ 0 F o=< \ ethyl-(2g,4g)-8-(5-chloro-3- fluoropyridin-2-yl)-5-(4- chlorobenzyl)-6,9-dioxo- 5,8-diazaspiro[3.5]nonane2-carboxylate 597 A 7 _Ύ γΑ ethyl-(2h,4h)-8-(5-chloro-3fluoropyridin-2-yl)-5-(4chlorobenzyl)-6,9-dioxo5,8-diazaspiro[3.5]nonane2-carboxylate 598 Cl NHj ^C ' (2g,4g)-8-(5-chloro-3fluoropyridin-2-yl)-5-(4chlorobenzyl)-6,9-dioxo5,8-diazaspiro[3.5]nonane2-carboxamide 599 F. F FY 4A _Jv MF' °M NH / (2g,4g)-8-(5-chloro-3fluoropyridin-2-yl)-Mmethyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide

- 160 045362

600 U l N N—7---01 M X 0=7 N— / (2r,4r)-8-(5-xnop-3fluoropyridin-2-yl)-M^dimethyl-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane2-carboxamide 601 F ^F Uh-huh O x oX nh ₂ (2s,4s)-8-(5-xnop-3fluoropyridin-2-yl)6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 602 EF ^F \ Q Ύ — NN—V '>-CI NH (2s,4s)-8-(5-xnop-3fluoropyridin-2-yl)-Mmethyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 603 V ^F X M Vy jy У N— / (2s,4s)-8-(5-xnop-3- fluoropyridin-2-yl)-M,Mdimethyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 604 b K Ny 0=7 nh ₂ (2s,4s)-8-(5-xnop-3fluoropyridin-2-yl)-5-(4chlorobenzyl)-6,9-dioxo5,8-diazaspiro[3.5]nonane2-carboxamide

- 161 045362

605 b k -ν ^v N Ν—V y—Cl J ^A NH / (2s, 4s)-δ·-(5-ΧΠ o p-3fluoropyridin-2-yl)-5-(4chlorobenzyl)-^methyl-6,9dioxo-5,8- diazaspiro[3.5]nonane-2carboxamide 606 X Chl N— / (2s,4s)-8-(5-xnop-3fluoropyridin-2-yl)5-(4chlorobenzyl)-N,M-dimethyl6,9-dioxo-5,8diazaspiro[3.5]nonane-2carboxamide 607 Xu Ν Ν—V у—Cl dL/ 0=( NH/ (2g,4g)-8-(5-chloro-3fluoropyridin-2-yl)-5-(4chlorobenzyl)-M-methyl-6,9dioxo-5,8diazaspiro[3.5]nonane-2carboxamide 608 Yi υ _Ν N-/ V-CI ό Г F o=< N— / (2g,4g)-8-(5-chloro-3- fluoropyridin-2-yl)-5-(4chlorobenzyl)-M,Ndimethyl6,9-dioxo-5,8diazaspiro[3.5]nonane-2carboxamide 609 \Z XV P Ci—£>-n N- ^{7 F} ° Q (R)-1-(5-xnop-3fluoropyridin-2-yl)-3(oxetan-3-yl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione

- 162 045362

610 V / f-Ύ s hL ^V -NN—DO D- ⁷ N-^ O 1-(5-chloro-3-fluoropyridine- 2-yl)-3-(2-(methylthio)ethyl)- 4-(4. (trifluoromethyl)benzyl)pipe erazine-2,5-dione 611 ^WITH! \Li >7 _F DL o ⁷ (S)-1-(5-xnop-3fluoropyridin-2-yl)-3(oxetan-3-yl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 612 o D\ /D _NN _// \D _S | L l ur 1-(5-chloro-3-fluoropyridine- 2-yl)-3-(2- (methyl sulfone yl)ethyl)-4- (4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 613 o D\ NA _N MD A—Q Q\ ^M ° ^F ~” m >ζ FF ' ^J (8)-1-(5-chloro-3fluoropyridin-2-yl)-3-(2(methyl sulfonyl)ethyl)-4(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 614 O DD bD Ν ΝΜ ^Х Д Cl ,< - FF / ⁰ (R)-1-(5-xnop-3fluoropyridin-2-yl)-3-(2(methyl sulfonyl)ethyl)-4(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione

- 163 045362

615 F, F St. \N-Λ )—Ν ν-Α y-Cl A / metal-(5)-8-(5-chloro-3fluoropyridin-2-yl)-6,9dioxo-5-(1-(4- (trifluoromethyl)phenyl)these l)-2,5,8- triazaspiro[3.5]nonane-2carboxylate 616 i ⁰ Yu F^ A _C | (R)-7-(5-xnop-3- fluoropyridin-2-yl)-4-(1-(4chlorophenyl)ethyl)-4,7diazaspiro[2.5]octane-5,8dione 617 xn nA ⁴ > -ci AC /Ά A o ^z oC nh ₂ (2g,4g)-8-(5-chloro-3- methylpyridin-2-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 618 Άλ An nA V _C! OD nh ₂ (2g,4g)-8-(5-chloropyridine-2- yl)-6,9-dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 619 a O 4 k / Y'A-ri An n—c Aci ho—ν-Ύβ / ⁷ V o ^F A (C)-2-acetyl-8-(5-chloro-3fluoropyridin-2-yl)-5-(1-(4chlorophenyl)-2hydroxyethyl)-2,5,8triazaspiro[3.5]nonane-6,9dione

- 164 045362

620 YOH," AR a WITH! (S)-&-(5-xnop-3- fluoropyridin-2-yl)-6,9- dioxo-5-(1-(4- (trifluoromethyl)phenyl)these l)-2,5,8- triazaspiro[3.5]nonane-2carbaldehyde 621 u----Z U. (38.65)-1-(5-chloro-3fluoropyridin-2-yl)-3(hydroxymethyl)-b-methyl4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 622 (3R,6R)-1-(5-xnop-3fluoropyridin-2-yl)-3(hydroxymethyl)-b-methyl4.(4. (trifluoromethyl)benzyl)pipe erazine-2,5-dione 623 to “ΠΤΊ 1-(5-chloro-3-fluoropyridin2-yl)-3-(3-methyloxetan-3yl)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 624 4 1-(5-chloro-3-fluoropyridin2-yl)-4-(4-chlorobenzyl)-3(3-methyloxetane-Zyl)piperazine-2,5-dione

- 165 045362

625 RF / ру_°У Ay NH Ra a _{n Ν} „_ς Aci (S)-N-((4-(5-xnop-3fluoropyridin-2-yl)-3,6d ioxo-1-(4- (trifluoromethyl)benzyl)pipe erazin-2- yl)methyl)acetamide 626 RF / A°=J A\ NH O ^f \ \_ _N N^ \ Q \J _N A O (R)-N-((4-(5-xnop-3- fluoropyridin-2-yl)-3,6- dioxo-1-(4- (trifluoromethyl)benzyl)pipe erazin-2- yl)methyl)acetamide 627 FF / fAJ o=J Ay NH Qr. _ann _^\ _Clϋ (S)-N-((4-(5-xnop-3- fluoropyridin-2-yl)-2methyl l-3,6-d ioxo-1 -(4(trifluoromethyl)benzyl)pip erazin-2- yl)methyl)acetamide 628 EF / FV O=J Ay NH RW A a _n n~у Aa (/ / (R)-N-((4-(5-xnop-3fluoropyridin-2-yl)-2methyl l-3,6-d ioxo-1 -(4(trifluoromethyl)benzyl)piperazin-2yl)methyl)acetamide 629 E F / F-CH °U Ay N.H. Rwa An nA\ //-^ M-((4-(5-chloro-3fluoropyridin-2-yl)-3,6dioxo-1-(4(trifluoromethyl)benzyl)piperazin-2yl)methyl)acetamide

- 166 045362

630 E F / fV o=U 2=x NH J A N N—b—Cl /—i N-M q' N-((4-(5-xrop-3fluoropyridin-2-yl)-2methyl l-3,6-d ioxo-1 -(4(trifluoromethyl)benzyl)piperazin-2yl)methyl)acetamide 631 Cl oj X\NH H^X n n—у λ—ci Ν-((4-(5-χπορ-3- fluoropyridin-2-yl)-1-(4- chlorobenzyl)-2-methyl-3,6- dioxopiperazin-2yl)methyl)acetamide 632 Cl oZ N.H. 44k —N N—(\ M-((4-(5-chloro-3- fluoropyridin-2-yl)-1-(4chlorobenzyl)-3,6dioxopiperazin-2yl)methyl)acetamide 633 Cl a/ or XX \ _{F ;} 1-(5-chloro-3-fluoropyridin2-yl)-4-(4-chlorobenzyl)-3(oxetan-3-yl)piperazine2,5-dione 634 Cl X 4 Λύ (S)-1-(5-xnop-3- fluoropyridin-2-yl)-4-(4chlorobenzyl)-3-(oxetan-3yl)piperazin-2,5-dione

- 167 045362

635 j yy (R)-1-(5-xnop-3- fluoropyridin-2-yl)-4-(4chlorobenzyl)-3-(oxetan-3yl)piperazin-2,5-dione 636 W Cl 1-(5-chloro-3-fluoropyridine- 2-yl)-4-(4-chlorobenzyl)-3(difluoromethyl)-3- methylpiperazine-2,5-dione 637 Cl U, wy (S)-1-(5-xnop-3- fluoropyridin-2-yl)-4-(4- chlorobenzyl)-3- (difluoromethyl)-3- methylpiperazine-2,5-dione 638 Cl'k, WkS ' 'A (R)-1-(5-xrop-3fluoropyridin-2-yl)-4-(4chlorobenzyl)-3(difluoromethyl)-3methylpiperazine-2,5-dione 639 LL C\4 w % F y-u. V o 1-(5-chloro-3-fluoropyridin2-yl)-3-(oxetan-3ylmethyl)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione

- 168 045362

640 .7 1-(5-chloro-3-fluoropyridine- 2-yl)-4-(4-chlorobenzyl)-3(oxetane-3- ylmethyl)piperazine-2,5dione 641 Ε F „ g d Cl—e >-NN—F ϋ A, YNH 0 ^x 3-(4-(5-chloro-3- fluoropyridin-2-yl)-3,6dioxo-1-(4- (trifluoromethyl)benzyl)pip erazin-2-yl)-Mmethylazetidine-1carboxamide 642 3-(4-(5-chloro-3- fluoropyridin-2-yl)-1-(4- chlorobenzyl)-3,6- dioxopiperazin-2-yl)-Nmetalazetidin-1carboxamide 643 // f£ nY- _C! 3-(1-acetylazetidin-3-yl)- 1-(5-chloro-3-fluoropyridine- 2-yl)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 644 Ύ° V XX ci ^/ ^ 3-(1-acetylazetidin-3-yl)- 1-(5-chloro-3-fluoropyridine- 2-yl)-4-(4- chlorobenzyl)piperazine-2,5dione

- 169 045362

645 ,,,.....A' Cl—0 y~N N- ⁷ ' ϋ +d 1-(5-chloro-3-methylpyridin2-yl)-3-(oxetan-3-yl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 646 1-(5-chloro-3-fluoropyridine- 2-yl)-4-(4-fluorobenzyl)-3(oxetan-3-yl)piperazin- 2.5-dione 647 1-(5-chloro-3-fluoropyridine- 2-yl)-4-(3,4- difluorobenzyl)-3-(oxetan3-yl)piperazine-2,5-dione 648 A aJ ©A a-(^-chloro-3-fluorobenzyl)-1(5-chloro-3-fluoropyridine-2- yl)-3-(oxetane-3- yl)piperazine-2,5-dione 649 E ^F 0 1-(5-chloro-3-fluoropyridin2-yl)-4-(3-fluoro-4- (trifluoromethyl)benzyl)-3(oxetan-3-yl)piperazine2,5-dione

- 170 045362

650 /V C|—I n—/ FQ L _o 1-(5-chloro-3-fluoropyridin2-yl)-4-(4- (difluorometal)benzyl)-3(oxetan-3-yl)piperazine2,5-dione 651 o 4 y T ^m 1-(5-chloro-3-methylpyridin- 2-yl)-3-(oxetane-3- yl methyl )-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 652 LL LL 1 ill 'X, f-Ο D ° X o 1-(5-chloro-3-methylpyridin2-yl)-3-(3-methyloxetan-3yl)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 653 EF Cl—VN ^- ^{7 4} O /- 3-(1-acetylazetidin-3-yl)1-(5-chloro-3-methylpyridin2-yl)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 654 Cl , ~ ,...... «° 0 _C |--(/ y_ _NN _/ ^A o 1-(5-chloro-3-methylpyridin2-yl)-4-(4-chlorobenzyl)-3(oxetan-3-yl)piperazine2,5-dione

- 171 045362

655 Cl y, l ci—e Vn n— ⁷ \ _o ^x \-H _o 1-(5~chloro-3-methylpyridin2-yl)-4-(4-chlorobenzyl)-3(oxetane-3- ylmethyl)piperazine-2,5- dione 656 o Al Ch _N N—C V-CI . : ^: ·' FF NH ₂ 3-(4-(5-chloro-3- fluoropyridin-2-yl)-2- methyl l-3,6-d ioxo-1 -(4(trifluoromethyl)benzyl)pip erazin-2-yl)propanamide 657 4F f ci-A^n 7f 1-(5-chloro-3-fluoropyridin2-yl)-3-(difluorometal)-3methyl-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 658 Q A n-Tl (S)-1-(5-xnop-3- fluoropyridin-2-yl)-3(difluoromethyl)-3-methyl-4(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 659 φ У Tf n (R)-1-(5-xnop-3fluoropyridin-2-yl)-3- (difluoromethyl)-3-methyl-4- (4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione

- 172 045362

660 Cl Dp (S)-1-(5-xnop-3- methylpyridin-2-yl)-4-(4- chlorobenzyl)-3- isopropylpiperazine-2,5dione 661 α^ _Ν Yf 3-((1-acetyl azetide in-3yl)methyl)-1-(5-chloro-3fluoropyridin-2-yl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 662 Xts Y O 3-((1-acetyl azetide in-3yl)methyl)-1-(5-chloro-3fluoropyridin-2-yl)-4-(4chlorobenzyl)piperazine-2,5dione 663 Cl /Ν Ν /\ 1-(5-chloro-3-methylpyridin2-yl)-4-(4-chlorobenzyl)-3(3-methyloxetane-Zyl)piperazine-2,5-dione 664 Ω th..... Ύ У° YQ 1-(5-chloro-3-fluoropyridin2-yl)-4-(3-fluoro-4methylbenzyl)-3-(oxetan3-yl)piperazin-2,5-dione

- 173 045362

665 0 X X jOC ϊυ cr Χ·' γ 1-(5-chloro-3-fluoropyridin2-yl)-4-(4-ethylbenzyl)-3(oxetan-3-yl)piperazine2,5-dione 666 on 1-(5-chloro-3-fluoropyridin2-yl)-4-(4-methylbenzyl)-3(oxetan-3-yl)piperazine2,5-dione 667 .0' A ,χγ>υ 1-(5-chloro-3-fluoropyridin2-yl)-4-(4-fluoro-3methylbenzyl)-3-(oxetan3-yl)piperazin-2,5-dione 668 /χγ Μ ο 1-(5-chloro-3-fluoropyridine- 2-yl)-4-(3-chloro-4fluorobenzyl)-3-(oxetan-3yl)piperazine-2,5-dione 669 F °Ύ8 _χ ο /X ^f γχχγ £ J Η (8)-1-(5-chloro-3- fluoropyridin-2-yl)-4-(4(difluoromethyl)benzyl)-3(oxetan-3-yl)piperazine2,5-dione

- 174 045362

670 Ck ^F οΑ ^Ν AU ^F (R)-1-(5-xrop-3fluoropyridin-2-yl)-4-(4(difluorome™l)benzyl)-3(oxetan-3-yl)piperazine2,5-dione 671 . '·' (S)-1-(5-xnop-3- methylpyridin-2-yl)-4-(4chlorobenzyl)-3-(oxetan-3yl)piperazin-2,5-dione 672 Dgo (I)-1-(5-chloro-3- methylpyridin-2-yl)-4-(4chlorobenzyl)-3-(oxetan-3yl)piperazin-2,5-dione 673 C1\>TT Lf k K /A a / f γ n I Uo (S)-1-(5-xnop-3fluoropyridin-2-yl)-3(oxetan-3-ylmethyl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 674 S K'G? Τ..Α ,γΤ ο (R)-1-(5-xnop-3fluoropyridin-2-yl)-3(oxetan-3-ylmethyl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione

- 175 045362

675 ABOUT (S)-1-(5-chloro-3fluoropyridin-2-yl)-4-(4chlorobenzyl)-3-(oxetan-3ylmethyl)piperazin-2,5dione 676 Cl MV l°p Cl—C y-N N—' f g—/X (R)-1-(5-xnop-3fluoropyridin-2-yl)-4-(4chlorobenzyl)-3-(oxetan-3ylmethyl)piperazine-2,5dione 677 FO ^Z (8)-3-(1-acetylazetidin-3yl)-1-(5-chloro-3- fluoropyridin-2-yl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 678 C! 0 Qj NX fV ^N \A a (8)-3-(1-acetylazetidin-3yl)-1-(5-chloro-3- fluoropyridin-2-yl)-4-(4chlorobenzyl)piperazine-2,5dione 679 EF l Cl-# ⁴ }-NN— ⁷ A ~0 (8)-1-(5-chloro-3- fluoropyridin-2-yl)-4-(3fluoro-4- (trifluoromethyl)benzyl)-3(oxetan-3-yl)piperazine2,5-dione

- 176 045362

680 F. F 01-( ⁷ y—N N- ⁷ xA ⁷ (R)-1-(5-xnop-3- fluoropyridin-2-yl)-4-(3- fluorine-4- (trifluoromethyl)benzyl)-3(oxetan-3-yl)piperazine2,5-dione 681 F _o (“YF _N /—<a—# VN n— ⁷ F (/ Y^ (S)-1-(5-xnop-3- fluoropyridin-2-yl)-4-(3,4difluorobenzyl)-3-(oxetan3-yl)piperazin-2,5-dione 682 F a O- ^f _N MA a—с Vn n— ⁷ F Ό (R)-1-(5-xnop-3fluoropyridin-2-yl)-4-(3,4difluorobenzyl)-3-(oxetan3-yl)piperazin-2,5-dione 683 F _N a—7 v—nn— ⁷ <- _o (S)-1-(5-xnop-3- fluoropyridin-2-yl)-4-(4fluorobenzyl)-3-(oxetan-3yl)piperazin-2,5-dione 684 F a—# ^- ⁷ F (R)-1-(5-xnop-3fluoropyridin-2-yl)-4-(4fluorobenzyl)-3-(oxetan-3yl)piperazin-2,5-dione

- 177 045362

685 Cl X 0” ^F Cl—/ U-NN— ⁷ X (S)-4-(4-xnop-3- fluorobenzyl)-1-(5-chloro-3fluoropyridin-2-yl)-3(oxetan-3-yl)piperazine2,5-dione 686 a / O~ ^F Cl~X XN N— ⁷ F (/ X X (R)-4-(4-xnop-3- fluorobenzyl)-1-(5-chloro-3fluoropyridin-2-yl)-3(oxetan-3-yl)piperazine2,5-dione 687 F F ^.x F ϋ 2--< 1-(5-chloro-3-fluoropyridin2-yl)-3-(tetrahydro-2Hthiopyran-4-yl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 688 F. F FQ 2—4 x _o ^z 1-(5-chloro-3-fluoropyridin2-yl)-3-(tetrahydro-2Hpyran-4-yl)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 689 F F ' Q 1-(5-chloro-3-fluoropyridin2-yl)-3-(1,1- dioxidotetrahydro-2Nthiopyran-4-yl)-4-(4(trifluoromethyl)benzyl)piperazin-2,5-dione

- 178 045362

690 A' D—N 4 χ/ Chi (S)-1-(5-xnop-3- methylpyridin-2-yl)-3(oxetan-3-yl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 691 FF ^F 1-(3-fluoro-5-methylpyridin2-yl)-3-(oxetan-3-yl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 692 F.F—? y—N N- ⁷ (5)-1-(3-fluoro-5- methylpyridin-2-yl)-3- (oxetan-3-yl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 693 Yi ΤΊ (K)-1-(3-fluoro-5- methylpyridin-2-yl)-3(oxetan-3-yl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 694 /P O~ ^F _G N U- ⁷ ci—xr ^N ^- ⁷ 4n, (S)-1-(5-xnop-3fluoropyridin-2-yl)-4-(3fluoro-4-methylbenzyl)-3(oxetan-3-yl)piperazine2,5-dione

- 179 045362

695 / O λ~Ν U ⁷ S1D DY Ν- ⁷ “f/ ⁴ D (R)-1-(5-xnop-3- fluoropyridin-2-yl)-4-(3- fluoro-4-methylbenzyl)-3(oxetan-3-yl)piperazine2,5-dione 696 F /Р SU~ _N /D D ⁷ s—e D ν ν— ⁷ F s/ (S)-1-(5-xnop-3fluoropyridin-2-yl)-4-(4fluoro-3-methylbenzyl)-3(oxetan-3-yl)piperazine2,5-dione 697 XXY o qK S' (R)-1-(5-xnop-3fluoropyridin-2-yl)-4-(4fluoro-3-methylbenzyl)-3(oxetan-3-yl)piperazine2,5-dione 698 Near LA (S)-1-(5-xnop-3- fluoropyridin-2-yl)-4-(3chloro-4-fluorobenzyl)-3(oxetan-3-yl)piperazine2,5-dione 699 Mind ° C<LL d (R)-1-(5-xnop-3- fluoropyridin-2-yl)-4-(3- chloro-4-fluorobenzyl)-3(oxetan-3-yl)piperazine2,5-dione

- 180 045362

700 M V<00 Μ 1-(4-bromo-2-fluorophenyl)-4- (4-fluorobenzyl)-3-(oxetane- 3-yl)piperazine-2,5-dione 701 Μ \ A x-N Ν-0 UM 1 AM Nm A ^0F °H 2-acetyl-8-(2-fluoro-4(1,2,4-oxadiazol-Zyl)phenyl)-5-(4(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonane-6,9dione 702 E F ^F J o H X—N Nf X)—ζ 1 AM Im A ^{0 F} °H 2-acetyl-8-(2-fluoro-4-(5methyl-1,2,4-oxadiazol-Zyl)phenyl)-5-(4(trifluoromethyl)benzyl)2,5,8- triazaspiro[3.5]nonane-6,9dione 703 F _F ^F “-q-AP M, oh 1-(3-fluoro-5- methoxypyridin-2-yl)-3(oxetan-3-yl)-4-(4(trifluoromethyl)benzyl)pipe erazine-2,5-dione 704 j ZhTA (Shch-1-(5-chloro-3- fluoropyridin-2-yl)-4-(4methylbenzyl)-3-(oxetan3-yl)piperazin-2,5-dione

- 181 045362

705 A° Lae u (S)-1-(5-xnop-3- fluoropyridin-2-yl)-4-(4- methylbenzyl)-3-(oxetane- 3-yl)piperazine-2,5-dione 706 3-fluoro-4-(4-(4- fluorobenzyl)-3-(oxetan-3yl)-2,5-dioxopiperazin-1yl)benzonitrile 707 ώ y ,U 1-(5-bromo-3-fluoropyridin2-yl)-4-(4-fluorobenzyl)-3(oxetan-3-yl)piperazine2,5-dione 708 y. A XX U B<XY>: 1-(5-bromo-3-fluoropyridin2-yl)-4-(4-chlorobenzyl)-3(oxetan-3-yl)piperazine2,5-dione 709 o— yS yG UM · (8)-1-(3-fluoro-5- methoxypyridin-2-yl)-3(oxetan-3-yl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione

- 182 045362

710 O- ΊΊ “Π (R)-1-(3-0Top-5- methoxypyridin-2-yl)-3(oxetan-3-yl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 711 _Fy F θΧΝ V ^F V ν CT J 1-(5-(difluoromethoxy)-3fluoropyridin-2-yl)-3(oxetan-3-yl)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 712 Ti and VQ. P (8)-1-(5-(difluoromethoxy)3-fluoropyridin-2-yl)-3(oxetan-3-yl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 713 F^ ^F V XT ^F WNI 1-/ \ X _Z ^N U F (B)-1-(5-(difluoromethoxy)3-fluoropyridin-2-yl)-3(oxetan-3-yl)-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione 714 A δ 1-(5-chloro-3-methylpyridin- 2-yl)-4-(4-fluorobenzyl)-3(oxetan-3-yl)piperazine2,5-dione

- 183 045362

715 J χά ά u 1¼ (S)-1-(5-xnop-3- methylpyridin-2-yl)-4-(4fluorobenzyl)-3-(oxetan-3yl)piperazin-2,5-dione 716 g or\ Λα (R)-1-(5-xnop-3- methylpyridin-2-yl)-4-(4fluorobenzyl)-3-(oxetan-3yl)piperazin-2,5-dione 717 cr\+\ 1-(5-chloro-3-methylpyridin- 2-yl)-4-(3-chloro-4- fluorobenzyl)-3-(oxetane-3- yl)piperazine-2,5-dione 718 ^.N И JL^ К ) I Η \——о ⁰ cr M (8)-1-(5-chloro-3methylpyridin-2-yl)-4-(3chloro-4-fluorobenzyl)-3(oxetan-3-yl)piperazine2,5-dione 719 (C)-1-(5-chloro-3methylpyridin-2-yl)-4-(3chloro-4-fluorobenzyl)-3(oxetan-3-yl)piperazine2,5-dione

- 184 045362

720 F XL/ ¹ JYf vr μ 1-(5-chloro-3-methylpyridin- 2-yl)-4-(3,4- difluorobenzyl)-3-(oxetan3-yl)piperazine-2,5-dione 721 F CI-^N 0 W v-M У '4 (S)-1-(5-xnop-3- methylpyridin-2-yl)-4-(3,4difluorobenzyl)-3-(oxetan3-yl)piperazin-2,5-dione 722 Ts. 4 MX k O (R)-1-(5-xnop-3- methylpyridin-2-yl)-4-(3,4difluorobenzyl)-3-(oxetan3-yl)piperazin-2,5-dione 723 WITH! ϋ 0 Ж α 4-(4-chlorobenzyl)-1-(3fluoro-5-vinylpyridin-2yl)-3-(oxetan-3yl)piperazine-2,5-dione 724 C. X 4Ύθ° ζΆ X ο 1-(5-chloro-3-methylpyridin- 2-yl)-4-(3-fluoro-4methylbenzyl)-3-(oxetan3-yl)piperazine-2,5-dione 725 Ts u ο (S)-1-(5-xnop-3- methylpyridin-2-yl)-4-(3- fluoro-4-methylbenzyl)-3- (oxetan-Z-yl)piperazine- 2.5-dione

- 185 045362

726 Al x° CL ^X θΎ (R)-1-(5-xnop-3methylpyridin-2-yl)-4-(3fluoro-4-methylbenzyl)-3(oxetan-3-yl)piperazine2,5-dione 727 Ω ft OD TO A 1-(5-chloro-3-methylpyridin2-yl)-4-(4-fluoro-3- methylbenzyl)-3-(oxetan3-yl)piperazine-2,5-dione 728 Αχχχ (R)-1-(5-xnop-3methylpyridin-2-yl)-4-(4fluoro-3-methylbenzyl)-3(oxetan-3-yl)piperazine2,5-dione 729 ..“A (8)-1-(5-chloro-3methylpyridin-2-yl)-4-(4fluoro-3-metalbenzyl)-3(oxetan-3-yl)piperazine2,5-dione 730 Y' AI J J. XX Yu SG Ά A 4-(4-chloro-3-fluorobenzyl)-1(5-chloro-3-methylpyridin-2yl)-3-(oxetan-3yl)piperazine-2,5-dione

- 186 045362

731 Cl Yes (S)-4-(4-xnop-3- fluorobenzyl)-1-(5-chloro-3methylpyridin-2-yl)-3(oxetan-3-yl)piperazine2,5-dione 732 Cl (WITH' J or χ (R)-4-(4-xnop-3fluorobenzyl)-1-(5-chloro-3methylpyridin-2-yl)-3(oxetan-3-yl)piperazine2,5-dione 733 L? θ H·· ⁰ сг А А 1-(5-chloro-3-methylpyridin2-yl)-4-(4-methylbenzyl)-3(oxetan-3-yl)piperazine2,5-dione 734 (8)-1-(5-chloro-3- methylpyridin-2-yl)-4-(4methylbenzyl)-3-(oxetan3-yl)piperazin-2,5-dione 735 j cr AY\ (R)-1-(5-xnop-3- methylpyridin-2-yl)-4-(4methylbenzyl)-3-(oxetan3-yl)piperazin-2,5-dione

- 187 045362

736 EF _N =—// \V_ _NN _/ ...... ⁽ .....00 5-fluoro-6-(3-(oxetan-3-yl)- 2,5-dioxo-4-(4- (trifluoromethyl)benzyl)pipe erazin-1- yl)nicotinonitrile 737 o I _/~N /~L Br—fy—NN—' ^f °d 1-(5-bromo-3-fluoropyridine2-mi)-3-((1s,3s)-3- methoxycyclobutyl)-4-(4(trifluoromethyl)benzyl)pipe erazine-2,5-dione 738 F^F 0 1-(5-bromo-3-fluoropyridine- 2-yl)-3-((1g,3g)-3- methoxycyclobutyl)-4-(4(trifluoromethyl)benzyl)pipe erazine-2,5-dione 739 4 z—Z U. O=Y Ao AL /=ξ Z—( b o I 1-(5-chloro-3-fluoropyridine- 2-nn)-3-((1s,3s)-3- Hydroxycyclobutyl)-4-(4(trifluoromethyl)benzyl)pipe erazine-2,5-dione 740 LU LL. Y U ^g o 1-(5-chloro-3-fluoropyridine- 2-yl)-3-(3- Hydroxycyclobutyl)-4-(4(trifluoromethyl)benzyl)pipe erazine-2,5-dione

- 188 045362

741 To? 1-(5-chloro-3-fluoropyridin2-yl)-4-(4-fluorobenzyl)-3((1s,3s)-3- methoxycyclobutyl)piper zine-2,5-dione 742 F Ϋ .ίΧ 1-(5-chloro-3-fluoropyridine- 2-yl)-4-(4-fluorobenzyl)-3- ((1 g,3g)-3- methoxycyclobutyl)piper zine-2,5-dione 743 A oAa c>U ''o 1-(5-chloro-3-fluoropyridine- 2-yl)-4-(4- (difluoromethyl)benzyl)-3- ((1s,3s)-3- methoxycyclobutyl)piper zine-2,5-dione 744 ό O x' /y _C XX _F ° 1-(5-chloro-3-fluoropyridine- 2-yl)-4-(4- (difluoromethyl)benzyl)-3- ((1g,3g)-3- methoxycyclobutyl)piper zin-2,5-dione 745 E F , α—f y—Ν Ν' ⁷ FQ (8)-1-(4-chloro-2- fluorophenyl)-3-(oxetane-3- silt)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione

- 189 045362

746 FF _Λ ,<Υ ci—/ V-м N— “ F (R)-1-(4-xrop-2- fluorophenyl)-3-(oxetane-3- silt)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 747 F F Y Cl—4 Λ N N—' ¢/ Y, ^o' 1-(4-chloro-3-fluorophenyl)-3- (oxetan-3-yl)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 748 y _F y yP ci—(\ Yn n- ⁷ θχ ~o (S)-1-(4-xnop-3- fluorophenyl)-3-(oxetane-3- silt)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 749 FF Jk ci—4 Y n— ^j A (R)-1-(4-xnop-3- fluorophenyl)-3-(oxetane-3- silt)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 750 ^F Y ^F «< Y ' α—£ YN n— ⁷ (5)-1-(5-chloro-3fluoropyridin-2-yl)-3cyclopropyl-4-(4(trifluoromethyl)benzyl)pipe erazin-2,5-dione

- 190 045362

751 AV m°_0 Cl—C ΑΝ N—' F (S)-1-(5-xnop-3fluoropyridin-2-yl)-3cyclopropyl-4-(4fluorobenzyl)piperazine2,5-dione 752 7 '—N ΝΑ Ή Cl dlu nh ₂ (2g,4g)-8-(5-chloro-3fluoropyridin-2-yl)-5-(4(difluoromethyl)benzyl)-6,9dioxo-5,8- diazaspiro[3.5]nonane-2carboxamide 753 X NN—C Cl JrtA nh ₂ (2s,4s)-8-(5-xnop-3- fluoropyridin-2-yl)-5-(4(difluorometal)benzyl)-6,9dioxo-5,8- diazaspiro[3.5]nonane-2carboxamide 754 A N NA y—Cl Hr Oy nh ₂ (2g,4g)-8-(5-chloro-3fluoropyridin-2-yl)-5-(4fluorobenzyl)-6,9-dioxo5,8-diazaspiro[3.5]nonane2-carboxamide 755 N NA V-CI .ΰ ^r nh ₂ (2s,4s)-8-(5-xnop-3fluoropyridin-2-yl)-5-(4fluorobenzyl)-6,9-dioxo5,8-diazaspiro[3.5]nonane2-carboxamide

- 191 045362

756 0 Cha N-y /—N N“V ChS1 0 Λ - F 8-(5-chloro-3-fluoropyridin2-yl)-5-(4-fluorobenzyl)-2oxa-5,8- diazaspiro[3.5]nonane-6,9dione 757 O H Ν-Λ _N N“7 ^_ _C | 0A° % 8-(5-chloro-3-fluoropyridin2-yl)-5-(4-methylbenzyl)-2oxa-5,8- diazaspiro[3.5]nonane-6,9dione 758 XX U/O 1-(3-fluoro-5- methoxypyridin-2-yl)-4-(4methylbenzyl)-3-(oxetan3-yl)piperazin-2,5-dione 759 o-^ \ Р ^F \ /~N N0 0 ° 0Г ' (8)-1-(3-fluoro-5- methoxypyridin-2-yl)-4-(4methylbenzyl)-3-(oxetane3 1L)piperazine-2,5-dione 760 o-^ /—N NyX-O 0> “ (K)-1-(3-fluoro-5- methoxypyridin-2-yl)-4-(4methylbenzyl)-3-(oxetan3-yl)piperazin-2,5-dione

- 192 045362

761 A A LTP 4-(3-fluoro-4-methylbenzyl)1-(3-fluoro-5- methoxypyridin-2-yl)-3(oxetan-3-yl)piperazine2,5-dione 762 b -π 2-----, 0==/ S=o d Ύ (8)-4-(3-fluoro-4- methylbenzyl)-1-(3-fluoro-5methoxypyridin-2-yl)-3(oxetan-3-yl)piperazine2,5-dione 763 X.....7 (R)-4-(3-φτop-4- methylbenzyl)-1-(3-fluoro-5- methoxypyridin-2-yl)-3(oxetan-3-yl)piperazine2,5-dione 764 ”~~T% f V.. γ Ci 8-(5-chloro-3-fluoropyridin2-yl)-5-(4-fluorobenzyl)-2hydroxy-5,8- diazaspiro[3.5]nonane-6,9dione 765 .....0 .....ok (2g,4g)-8-(5-chloro-3fluoropyridin-2-yl)-5-(4fluorobenzyl)-2-hydroxy5,8-diazaspiro[3.5]nonane6,9-dione

- 193 045362

766 0 _r DgTh (2s,4s)-8-(5-xnop-3fluoropyridin-2-yl)-2hydroxy-5-(4methylbenzyl)-5,8diazaspiro[3.5]nonane-6,9dione 767 X X >— ......about ⁷ % (2g,4g)-8-(5-chloro-3- fluoropyridin-2-yl)-2hydroxy-5-(4methylbenzyl)-5,8diazaspiro[3.5]nonane-6,9dione 768 ''S/ '.....i 8-(5-chloro-3-fluoropyridine- 2-yl)-5-(4- (difluorometal)benzyl)-2- oxa-5,8- diazaspiro[3.5]nonane-6,9- dione 769 Xυ/χΎ 4-(4-chlorobenzyl)-1-(3fluoro-5-methoxypyridin-2yl)-3-(oxetan-3yl)piperazine-2,5-dione 770 it .......<Ύ (8)-4-(4-chlorobenzyl)-1-(3fluoro-5-methoxypyridin-2yl)-3-(oxetan-3yl)piperazine-2,5-dione

- 194 045362

771 Cl ,φ (I)-4-(4-chlorobenzyl)-1-(3- fluoro-5-methoxypyridin-2yl)-3-(oxetane-3- yl)piperazine-2,5-dione 772 Cl .Αχ, g m-'- 4-(4-chloro-3-fluorobenzyl)-1(3-fluoro-5-methoxypyridin2-yl)-3-(oxetan-3yl)piperazine-2,5-dione 773 C.I. A (S)-4-(4-xnop-3fluorobenzyl)-1-(3-fluoro-5methoxypyridin-2-yl)-3(oxetan-3-yl)piperazine2,5-dione 774 (R)-4-(4-xrop-3fluorobenzyl)-1-(3-fluoro-5methoxypyridin-2-yl)-3(oxetan-3-yl)piperazine2,5-dione 775 / l U==O 0 zhu 4-(3-chloro-4-fluorobenzyl)-1(3-fluoro p-5-meto xip iridin 2-yl)-3-(oxetan-3yl)piperazine-2,5-dione

- 195 045362

776 Λ (S)-4-(3-xnop-4- fluorobenzyl)-1-(3-fluoro-5methoxypyridin-2-yl)-3(oxetan-3-yl)piperazine2,5-dione 777 UHLa (R)-4-(3-xnop-4- fluorobenzyl)-1-(3-fluoro-5methoxypyridin-2-yl)-3(oxetan-3-yl)piperazine2,5-dione 778 km methyl-3-(4-(5-chloro-3fluoropyridin-2-yl)-3,6dioxo-1-(4- (trifluoromethyl)benzyl)pipe erazin-2- yl)bicyclo[1.1.1]pentane-1carboxylate 779 iA^F ό, Au methyl 3-(4-(5-chloro-3fluoropyridin-2-yl)-1-(4(difluorometal)benzyl)-3,6dioxopiperazin-2yl)bicyclo[1,1.1]pentane-1carboxylate 780 F and yAA methyl-3-(4-(5-chloro-3fluoropyridin-2-yl)-1-(4fluorobenzyl)-3,6- dioxopiperazin-2yl)bicyclo[1.1.1]pentane-1carboxylate

- 196 045362

781 ,-Υ\ζ ^! \ζ4, methyl-3-(4-(5-chloro-3- fluoropyridin-2-yl)-1-(4methylbenzyl)-3,6- dioxopiperazin-2yl)bicyclo[1.1. 1]pentane-1carboxylate 782 Φ A. γΥ ethyl-3-(4-(5-chloro-3fluoropyridin-2-yl)-3,6dioxo-1-(4- (trifluoromethyl)benzyl)pipe erazin-2- yl)bicyclo[1.1.1]pentane-1carboxylate 783 F ₅ ,Av ⁿ vA 3-(4-(5-chloro-3fluoropyridin-2-yl)-3,6dioxo-1-(4- (trifluoromethyl)benzyl)pipe erazin-2- yl)bicyclo[1.1.1]pentane-1carboxamide 784 F v> _P yAAX 1-(5-chloro-3-fluoropyridin2-yl)-3-(3- (hydroxymethyl)bicyclo[1. 1,1 ]pentan-1 -yl)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 785 Ai A 2-acetyl-8-(4-chloro-2fluorophenyl)-5-(4fluorobenzyl)-2,5,8triazaspiro[3.5]nonane-6,9dione

- 197 045362

786 Ί\γπ s X' y ABOUT (S)-1-(5-xnop-3- fluoropyridin-2-yl)-3- ((1s,3R)-3- Hydroxycyclobutyl)-4-(4(trifluoromethyl)benzyl)pipe erazine-2,5-dione 787 D 0 Luu But (S)-1-(5-xnop-3- fluoropyridin-2-yl)-3- ((1r,3S)-3- Hydroxycyclobutyl)-4-(4(trifluoromethyl)benzyl)pipe erazine-2,5-dione 788 F.F HO (R)-1-(5-xnop-3- fluoropyridin-2-yl)-3- ((1s,3S)-3- Hydroxycyclobutyl)-4-(4(trifluoromethyl)benzyl)pipe erazine-2,5-dione 789 F. F D % . \—/ 2 ₄ V_ _N N—^ V-CI 4) F HO (R)-1-(5-xnop-3- fluoropyridin-2-yl)-3- ((1r,3R)-3- Hydroxycyclobutyl)-4-(4(trifluoromethyl)benzyl)pipe erazine-2,5-dione 790 ό % i 3-(4-(5-chloro-3fluoropyridin-2-yl)-1-(4(difluoromethyl)benzyl)-3,6dioxopiperazine-2- yl)bicyclo[1.1.1]pentane-1carboxamide

- 198 045362

791 F A , U L _ci 3-(4-(5-chloro-3- fluoropyridin-2-yl)-1-(4- fluorobenzyl)-3,6- dioxopiperazin-2yl)bicyclo[1.1. 1]pentane-1carboxamide 792 _H2N 3-(4-(5-chloro-3fluoropyridin-2-yl)-1-(4methylbenzyl)-3,6dioxopiperazin-2yl)bicyclo[1.1.1]pentane-1carboxamide 793 (S)-1-(4-xnop-2- fluorophenyl)-4-(4- fluorobenzyl)-3-((13,3R)-3hydroxycyclobutyl)piper azine-2,5-dione 794 ΗΟ^°LA. _0! (R)-1-(4-xnop-2- fluorophenyl)-4-(4fluorobenzyl)-3-((13,35)-3hydroxycyclobutyl)piper azine-2,5-dione 795 mrtx (S)-1-(4-xnop-2fluorophenyl)-4-(4fluorobenzyl)-3-((1 r,3S)-3hydroxycyclobutyl)piper azine-2,5-dione

- 199 045362

796 /Η М0 IT Til but* ^v (R)-1-(4-xnop-2- fluorophenyl)-4-(4- fluorobenzyl)-3-((1 r,3R)-3hydroxycyclobutyl)piper azine-2,5-dione 797 -Q ^ο== Τ Τ° ......0......0 (2s,4s)-8-(4-xnop-2- fluorophenyl)-5-(4fluorobenzyl)-2-hydroxy5,8-diazaspiro[3.5]nonane6,9-dione 798 φ. XD, Aril (2g,4g)-8-(4-chloro-2fluorophenyl)-5-(4fluorobenzyl)-2-hydroxy5,8-diazaspiro[3.5]nonane6,9-dione 799 Ά 4 8-(4-chloro-2-fluorophenyl)-5(4-fluoro rb en z i l)-2-o xa-5,8diazaspiro[3.5]nonane-6,9dione 800 F 0 Q 4α A? ττχ Η0 \Ζ\, (S)-1-(5-xnop-3- fluoropyridin-2-yl)-4-(4- fluorobenzyl)-3-((1e,3R)-3hydroxycyclobutyl)piper azine-2,5-dione

- 200 045362

801 rrVrS but "' ' ° Ch+Uya (S)-1-(5-xnop-3- fluoropyridin-2-yl)-4-(4- fluorobenzyl)-3-((1 g,33)-3hydroxycyclobutyl)piper azine-2,5-dione 802 (R)-1-(5-xnop-3- fluoropyridin-2-yl)-4-(4fluorobenzyl)-3-((18,33)-3hydroxycyclobutyl)piper azine-2,5-dione 803 τ TH ......°.....t (R)-1-(5-xnop-3fluoropyridin-2-yl)-4-(4fluorobenzyl)-3-((1 r,3R)-3hydroxycyclobutyl)piper azin-2,5-dione 804 Ci zrVrS O N.. Vi (S)-1-(5-xnop-3- fluoropyridin-2-yl)-4-(4xnop6eH3Mn)-3-((1s,3R)-3hydroxycyclobutyl)piper azin-2,5-dione 805 (S)-1-(5-xnop-3fluoropyridin-2-yl)-4-(4chlorobenzyl)-3-((1 r,3S)-3hydroxycyclobutylfiper azin-2,5-dione

- 201 045362

806 ^X C1 (R)-1-(5-xnop-3- fluoropyridin-2-yl)-4-(4chlorobenzyl)-3-((1h, 35)-3hydroxycyclobutyl)piper azin-2,5-dione But" JbiX Χι OK -, 807 Chl. ϊ 1 1 χΊΓΊι at (R)-1-(5-xnop-3- fluoropyridin-2-yl)-4-(4chlorobenzyl)-3-((1 r,3R)-3hydroxycyclobutyl)piper azin-2,5-dione 808 at Λα (2s,4s)-8-(5-xnop-3fluoropyridin-2-yl)-5-(4fluorobenzyl)-2-hydroxy5,8-diazaspiro[3.5]nonane6,9-dione 809 Λ Yes At >3 (R)-1-(5-xnop-3- fluoropyridin-2-yl)-3- ((1s,3S)-3- Hydroxycyclobutyl)-4-(4methylbenzyl)piperazine2,5-dione 810 y . -rA. ^.ν / Т 1 ° ^N x XI (R)-1-(5-xnop-3- fluoropyridin-2-yl)-3- ((1r,3R)-3- Hydroxycyclobutyl)-4-(4methylbenzyl)piperazine2,5-dione

- 202 045362

811 W 0=/ (S)-1-(5-xnop-3- fluoropyridin-2-yl)-3- ((1s,3R)-3- Hydroxycyclobutyl)-4-(4methylbenzyl)piperazine2,5-dione 812 Y Ai. (S)-1-(5-chloro-3fluoropyridin-2-yl)-3((1r,3S)-3- Hydroxycyclobutyl)-4-(4methylbenzyl)piperazine2,5-dione 813 , in' /-4 y—' ^Ci \ A ^NN ” ⁴² % 10-(5-chloro-3-fluoropyridine- 2-yl)-7-(4- (trifluoromethyl)benzyl)-2- oxa-7,10- diazad ispiro[3.1.56.14]do decan-8,11-dione 814 /d Y Ci—7 y—N N- ⁷ F 10-(5-chloro-3-fluoropyridine- 2-yl)-7-(4- (difluoromethyl)benzyl)-2- oxa-7,10- diazad ispiro[3.1.56.14]do decan-8,11-dione 815 F _JV <'0 a—7 Vn n— ⁷ A ~o 10-(5-chloro-3-fluoropyridin2-yl)-7-(4-fluorobenzyl)-2oxa-7,10- diazad ispiro[3.1.56.14]do decane-8,11-dione

- 203 045362

816 У V ci—С γ-N ν— ⁷ f ο с 10-(5-chloro-3-fluoropyridin2-yl)-7-(4-methylbenzyl)-2oxa-7,10- diazad ispiro[3.1.56.14]do decane-8,11-dione 817 FF^Yf VA o Ln ₂ (8)-3-(4-(5-chloro-3- fluoropyridin-2-yl)-3,6- dioxo-1-(4- (trifluoromethyl)benzyl)pipe erazin-2- yl)bicyclo[1.1.1]pentane-1- carboxamide 818 O. Unn ₂ FF (R)-3-(4-(5-xnop-3fluoropyridin-2-yl)-3,6dioxo-1-(4- (trifluoromethyl)benzyl)pipe erazin-2- yl)bicyclo[1.1.1]pentane-1carboxamide 819 F ХД F ^¥А nh ₂ (S)-3-(4-(5-xnop-3- fluoropyridin-2-yl)-3,6- dioxo-1-(4- fluorobenzyl)piperazin-2yl)bicyclo[1.1.1]pentane-1carboxamide 820 o U-in ₂ F O Cl—4 J—N Ν—\ ''U F (R)-3-(4-(5-xnop-3fluoropyridin-2-yl)-3,6dioxo-1-(4fluorobenzyl)piperazin-2yl)bicyclo[1.1.1]pentan-1carboxamide

- 204 045362

821 nh ₂ (S)-3-(4-(5-xnop-3- fluoropyridin-2-yl)-3,6- d ioxo-1-(4- (difluoromethyl)benzyl)pipe erazin-2- yl)bicyclo[1.1. 1]pentane-1carboxamide 822 Ynh ₂ ci—An ν-λ u hA ° / ^F F (C)-3-(4-(5-chloro-3fluoropyridin-2-yl)-3,6d ioxo-1 -(4- (difluoromethyl)benzyl)pipe erazin-2- yl)bicyclo[1.1.1]pentane-1carboxamide 823 A γΥζ nh ₂ (S)-3-(4-(5-xnop-3fluoropyridin-2-yl)-1-(4methylbenzyl)-3,6dioxopiperazin-2yl)bicyclo[1.1.1]pentan-1carboxamide 824 0 JAnh ₂ _A Ά < (R)-3-(4-(5-xrop-3fluoropyridin-2-yl)-1-(4metalbenzyl)-3,6dioxopiperazin-2yl)bicyclo[1.1.1]pentane-1carboxamide 825 .0 fX )=/ ciA An n^ A yo 2-acetyl-10-(5-chloro-3fluoropyridin-2-yl)-7-(4(trifluoromethyl)benzyl)- 2,7,10- triazadispiro[3.1.56.14]d decane-8,11-dione

- 205 045362

826 G 2-acetyl-10-(5-chl op-3- fluoropyridin-2-yl)-7-(4- (difluoromethyl)benzyl)- 2,7,10- triazad ispiro[3.1.56.14]d decane-8,11-dione 827 ° 2-acetyl-10-(5-chloro-3fluoropyridin-2-yl)-7-(4fluorobenzyl)-2,7,10- triazad ispiro[3. 1.56.14]d decane-8,11-dione 828 10-(5-chloro-3-fluoropyridin2-yl)-7-(4-fluorobenzyl)- 8,11-dioxo-2,7,10triazad ispiro[3.1.56.14]d decane-2-carbaldehyde 829 2-acetyl-10-(5-chloro-3fluoropyridin-2-yl)-7-(4methylbenzyl)-2,7,10- triazad ispiro[3.1.56.14]d decane-8,11-dione 830 10-(5-chloro-3-fluoropyridin2-yl)-7-(4-methylbenzyl)- 8,11-dioxo-2,7,10triazad ispiro[3. 1.56.14]d decane-2-carbaldehyde

- 206 045362

831 X 2-acetyl-10-(5-chloro-3fluoropyridin-2-yl)-7-(4chlorobenzyl)-2,7,10- triazad ispiro[3. 1.56.14]d decane-8,11-dione 832 O 10-(5-chloro-3-fluoropyridin2-yl)-7-(4-chlorobenzyl)- 8,11-dioxo-2,7,10triazad ispiro[3.1.56.14]d decane-2-carbaldehyde 833 X/ O (2s,4s)-8-(5-xnop-3fluoropyridin-2-yl)-5-(4- chlorobenzyl)-2-hydroxy- 5,8-diazaspiro[3.5]nonan- 6,9-dione 834 ^сн Оу Η0'·<Α/ аЦ (2g,4g)-8-(5-chloro-3- fluoropyridin-2-yl)-5-(4chlorobenzyl)-2-hydroxy5,8-diazaspiro[3.5]nonane6,9-dione 835 Cl XX νη ₂ 3-(4-(5-chloro-3fluoropyridin-2-yl)-1-(4chlorobenzyl)-3,6dioxopiperazin-2yl)bicyclo[1.1.1]pentane-1carboxamide

- 207 045362

836 X νη ₂ (S)-3-(4-(5-xnop-3fluoropyridin-2-yl)-1-(4chlorobenzyl)-3,6dioxopiperazin-2yl)bicyclo[1.1. 1]pentane-1carboxamide 837 O _h Ανη ₂ ХН ° w Cl (I)-3-(4-(5-chloro-3fluoropyridin-2-yl)-1-(4chlorobenzyl)-3,6dioxopiperazin-2yl)bicyclo[1.1.1]pentane-1carboxamide 838 fA-F uv j 1-(5-chloro-3-fluoropyridine- 2-yl)-3-(3- hydroxybicyclo[1.1.1]pent an-1-yl)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 839 fAf γΊ X aVR (S) -1 - (5-chloro p-3fluoropyridin-2-yl)-3-(3hydroxybicyclo[1.1.1]pentan-1-yl)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 840 OH X X • Xq, F F (R)-1-(5-xnop-3- fluoropyridin-2-yl)-3-(3hydroxybicyclo[1.1.1]pentan-1-yl)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione

- 208 045362

841 Uh, 1-(5-chloro-3-fluoropyridine- 2-yl)-4-(4-chlorobenzyl)-3- (3- Hydroxybicyclo[1.1.1]pentan-1-yl)piperazine-2,5dione 842 CI Ha LtU (3)-1-(5-chloro-3fluoropyridin-2-yl)4-(4chlorobenzyl)-3-(3hydroxybicyclo[1.1.1]pentan-1-yl)piperazine-2,5dione 843 HE F % H CI (R)-1-(5-xnop-3fluoropyridin-2-yl)-4-(4chlorobenzyl)-3-(3hydroxybicyclo[1.1.1]pentan-1-yl)piperazine-2,5dione 844 F 'Z Q yA I nsg^$ | ,[ 1-(5-chloro-3-fluoropyridin2-yl)-4-(4-fluorobenzyl)-3(3- Hydroxybicyclo[1.1.1]pentan-1-yl)piperazine-2,5dione 845 Xi! (S)-1-(5-xnop-3fluoropyridin-2-yl)-4-(4fluorobenzyl)-3-(3hydroxybicyclo[1.1.1]pentan-1-yl)piperazine-2,5dione

- 209 045362

846 HE ......Α-γ F (R)-1-(5-xnop-3fluoropyridin-2-yl)-4-(4- fluorobenzyl)-3-(3- hydroxybicyclo[1.1. 1]pentan-1-yl)piperazine-2,5dione 847 O f ό g (2h,45)-8-(5-chloropyridin-2yl)-2-(5-cyclopropyl- 1,3,4-oxadiazol-2-yl)-5(4-fluorobenzyl)-5,8diazaspiro[3.5]nonane-6,9dione 848 Y ₀ >-ϋ ^α ί<ι. (2g,4g)-8-(5-chloropyridin-2yl)-2-(5-cyclopropyl- 1,3,4-oxadiazol-2-yl)-5(4-fluorobenzyl)-5,8diazaspiro[3.5]nonane-6,9dione 849 ^F \/ ^F ό YF ^HO ° 1-(5-chloro-3-fluoropyridine- 2-yl)-4-(4- (difluoromethyl)benzyl)-3- (3- Hydroxybicyclo[1.1.1]pentan-1-yl)piperazine-2,5dione 850 o Y F -°Ύό, (S)-1-(5-xnop-3- fluoropyridin-2-yl)-4-(4(difluoromethyl)benzyl)-3(3- Hydroxybicyclo[1.1.1]pentan-1-yl)piperazine-2,5dione

- 210 045362

851 χ, —ζΎ YXci Π ο But (R)-1-(5-xnop-3fluoropyridin-2-yl)-4-(4(difluoromethyl)benzyl)-3- (3- hydroxybicyclo[1.1. 1]pentan-1-yl)piperazine-2,5dione 852 ό 1-(5-chloro-3-fluoropyridine- 2-yl)-3-(3- hydroxybicyclo[1.1.1]pent an-1-yl)-4-(4- methylbenzyl)piperazine- 2.5-dione 853 To 1 Ίχ (S)-1-(5-xnop-3- fluoropyridin-2-yl)-3-(3- ™droxybicyclo[1.1.1]pent an-1-yl)-4-(4- methylbenzyl)piperazine- 2.5-dione 854 by.....,y _v 0- nn—e χσ ^F HO (R)-1-(5-xnop-3- fluoropyridin-2-yl)-3-(3hydroxybicyclo[1.1.1]pentan-1-yl)-4-(4- methylbenzyl)piperazine2,5-dione 855 Q ό ΧΥΧ (28.4h)-8-(5-chloropyridine-2- yl)-5-(4-fluorobenzyl)-2- (1,3,4-oxadiazol-2-yl)- 5,8-diazaspiro[3.5]nonan- 6,9-dione

- 211 045362

856 F (2g,4g)-8-(5-chloropyridin-2yl)-5-(4-fluorobenzyl)-2(1,3,4-oxadiazol-2-yl)5,8-diazaspiro[3.5]nonane6,9- dione 857 U 4 c ^X ------Z IL ft o 1-(5-chloro-3-fluoropyridin2-yl)-3-(hydroxymethyl)-4(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 858 F Rd/ A XM 1-(5-chloro-3-fluoropyridin2-yl)-3-(1-hydroxyethyl)-4<4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 859 4. CA mMtS i| 0 ό " ethyl-8-(5-chloro-3fluoropyridin-2-yl)-6,9dioxo-5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxylate 860 C UmChZh O==/ R' ethyl 8-(5-chloro-3fluoropyridin-2-yl)-5-(4chlorobenzyl)-6,9-dioxo5,8-diazaspiro[3.5]nonane2-carboxylate

- 212 045362

861 1-(5-chloro-3-fluoropyridine- 2-yl)-3-(oxetan-3-yl)-4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione 862 Ann £ΥΆ A. x oh he Ci F 1-(5-chloro-3-fluoropyridin2-yl)-4-(4-chlorobenzyl)-3(hydroxymethyl)piperazine2,5-dione 863 Ω b A y XX 1-(5-chloro-3-fluoropyridin2-yl)-4-(4-chlorobenzyl)-3isopropylpiperazine-2,5dione 864 0 DP XX 1-(5-chloro-3-fluoropyridin-2-yl)-3-isopropyl-4-((5)-1 ₍₄ _ (trifluoromethyl)phenyl)ethyl)piperazine-2,5-dione 865 about liXrV F OH O X D G (63)-1 -(5-chloro-3fluoropyridin-2-yl)-3(hydroxymethyl)-b-methyl4-(4- (trifluoromethyl)benzyl)pipe erazine-2,5-dione

- 213 045362

866 Г i fl V о i il ^N 1 Λ Ш /% X 14 1-(4-chloro-2-fluorophenyl)-4(4-fluorobenzyl)-3-(3hydroxycyclobutyl)piper azine-2,5-dione 8S7 —\ i χί ^f ~a Cl 8-(4-chloro-2-fluorophenyl)-5(4-fluorobenzyl)-2- guide roxy-5.8- diazaspiro[3.5]nonane-6,9- dione 868 yy ,° -X 0 >=N Cl 8-(5-chloro-3-fluoropyridin2-yl)-2-hydroxy-5-(4methylbenzyl)-5,8- diazaspiro[3.5]nonane-6,9dione 869 Cl--/ 4--p Xb ) l < Ci 8-(5-chloro-3-fluoropyridin2-yl)-5-(4-chlorobenzyl)-2hydroxy-5,8- diazaspiro[3.5]nonane-6,9dione 870 at •ΊΊ z—< at 8-(5-chloro-3-fluoropyridin2-yl)-N-methyl-6,9-d ioxo5-(4- (trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide

- 214 045362

871 F A A." 8-(5-chloro-3-fluoropyridin2-yl)-MA-dimethyl-6,9dioxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 872 Cl 'Μ o Chl °γ^I II NH ₂ F'^^CI 8-(5-chloro-3-fluoropyridin2-yl)-5-(4~chlorobenzyl)-6,9~ dioxo-5,8- diazaspiro[3.5]nonane-2carboxamide 873 Cl + f γ© XX Ah ^{f Ci} 8-(5-chloro-3-fluoropyridin2-yl)-5-(4-chlorobenzyl)-Namethi l-6,9-d ioxo-5,8diazaspiro[3.5]nonane-2caeboxamide 874 Cl 0 Ts 0Sh 8-(5-chloro-3-fluoropyridin2-yl)-5-(4-chlorobenzyl)- M,M-dimethyl-6,9-dioxo- 5,8-diazaspiro[3.5]nonane2-carboxamide 875 ©A. 8-(5-chloro-3-fluoropyridine- 2-yl)-5-(4- (difluoromethyl)benzyl)-6,9- dioxo-5,8- diazaspiro[3.5]nonane-2- carboxamide

- 215 045362

876 F ό A. „ “γ^ϊ χχ nh ₂ ^{f Ci} 8-(5-chloro-3-fluoropyridin2-yl)-5-(4-fluorobenzyl)~ 6,9-dioxo-5,8- diazaspiro[3.5]nonane-2carboxamide 877 _Ρ χρ C n o U 1 । o AL nh ₂ ^{g Ci} 8-(5-chloro-3-fluoropyridin2-yl)-6,9-dioxo-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane2-carboxamide 878 X kA| οΛγνι ι!ιη ₂ ° 8-(5-chloro-3-methylpyridin2- and l)-6,9-d and oxo-5-(4(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane2-carboxamide 879 _F F V ΑϊΑ 1 0 nh ₂ ^Ci 8-(5-chloropyridin-2-yl)- 6,9-dioxo-5-(4- (trifluoromethyl)benzyl)- 5,8-diazaspiro[3.5]nonane2-carboxamide 880 A F—/ \\ o 'L.U-=-\-Z ^LH' X 8-(5-chloropyridin-2-yl)-2(5-cyclopropyl-1,3,4oxadiazol-2-yl)-5-(4fluorobenzyl)-5,8- diazaspiro[3.5]nonane-6,9dione

- 216 045362

881 Μ τ ΥίΤ 8-(5-chloropyridin-2-yl)-5(4-fluorobenzyl)-2-(1,3,4oxadiazol-2-yl)-5,8diazaspiro[3.5]nonane-b,9dione 882 Ο X-sN / Ν Οχ JK I i ^f 0'0\ MM L // _α Α<Ν ° ^Ci 8-(5-chloro-3-methylpyridin- 2-yl)-5-(4-chlorobenzyl)-2(pyridin-2-yl)-2,5,8triazaspiro[3.5]nonane-6,9dione 883 4 D-ο 0 8-(5-chloro-3-methylpyridin2-yl)-5-(4-fluorobenzyl)-2(pyridin-2-yl)-2,5,8- triazaspiro[3.5]nonane-6,9dione 884 AMM ρ F 8-(5-chloro-3-methylpyridin2-yl)-5-(4-chlorobenzyl)-2(5-fluoropyridin-2-yl)- 2,5,8- triazaspiro[3.5]nonane-6,9dione 885 Τ ΗΤΧυΊ ί Ύ 0 ,ζ0- _! 8-(5-chloro-3-methylpyridin~2-yl)-5-(4-fluorobenzyl)-2(5-fluoropyridin-2-yl)2,5,8- triazaspiro[3.5]nonane-6,9dione

- 217 045362

886 A W/V A d 6-(8-(5-chloro-3methylpyridin-2-ip)-5-(4chlorobenzyl)-6,9-dioxo- 2,5,8- triazaspiro[3.5]nonan-2yl)nicotinonitrile 887 ....... _O J X—N У-N 0 )=NA 6-(8-(5-chloro-3methylpyridin-2-yl)-5-(4fluorobenzyl)-6,9-dioxo- 2,5,8- triazaspiro[3.5]nonan-2yl)nicotinonitrile 888 Αγ F Ci (6R)-1-(5-xnop-3- fluoropyridin-2-yl)-3- (hydroxymethyl)-b-methyl- 4.(4. (trifluoromethyl)benzyl)pipe erazine-2,5-dione 889 F £ jY Br F ^υ 1-(5-bromo-3-fluoropyridine- 2-yl)-3-(3- methoxyci|{lobutyl)-4-(4(trifluoromethyl)benzyl)pipe erazine-2,5-dione 890 O b -n z—v pAY 1-(5-chloro-3-fluoropyridine- 2-yl)-4-(4-fluorobenzyl)-3- (3- methoxycyclobutyl)piper zine-2,5-dione

- 218 045362

1-(5-chloro-3-fluoropyridin2-yl)-4-(4(difluoromethyl)benzyl)-3(3methoxycyclobutyl)piper zin-2,5-dione

1-(5-chloro-3-fluoropyridin2-yl)-4-(4-fluorobenzyl)-3(3hydroxycyclobutyl)piper azin-2,5-dione

1-(5-chloro-3-fluoropyridin2-yl)-4-(4-chlorobenzyl)-3(3hydroxycyclobutyl)piper azin-2,5-dione

1-(5-chloro-3-fluoropyridin2-yl)-3-(3hydroxycyclobutyl)-4-(4methylbenzyl)piperazine2,5-dione

In some variations, any of the compounds described herein, such as a compound of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) , (li), (Ij), (Ik-1), (Ik-2), (II), (Im), (In-1) or (In-2), or any variation thereof, or compounds of Table. 1 can be deuterated (for example, the hydrogen atom is replaced by a deuterium atom). In some of these variations, the compound is deuterated at one location. In other embodiments, the compound is deuterated at multiple locations. Deuterated compounds can be prepared from deuterated starting materials in a manner similar to the preparation of the corresponding non-deuterated compounds. Hydrogen atoms can also be replaced by deuterium atoms using another method known in the art. Any formula provided herein, such as formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1) or (In-2) is intended to represent compounds having the structures depicted by the structural formula, as well as defined variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of compounds of the general formula and their mixtures in any ratio are considered within the framework of the formula. Thus, any formula provided herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. When the connection table 1 is depicted with a specific stereochemical configuration, any alternative stereochemical configuration of a compound, as well as a mixture of stereoisomers of a compound in any ratio, are also provided herein. For example, when the connection from the table. 1 has a stereocenter that has the stereochemical configuration S, an enantiomer of the compound is also provided herein, this stereocenter being in the stereochemical configuration R. Likewise, when the compound of Table. 1 has a stereocenter that is in the R configuration, the enantiomer of the compound in the S stereochemical configuration is also provided herein. Mixtures of compounds with stereochemical configurations S and R are also proposed. In addition, if the compound from the table. 1 has two or more stereocenters, and any enantiomers or diastereomers of the compound are also provided. For example, if the connection from the table. 1 contains a first stereocenter and a second stereocenter with stereochemical configurations R and R, respectively, stereoisomers of a compound having first and second stereocenters with S and S stereochemical configurations, respectively, S and R stereochemical configurations, respectively, and R and S stereochemical configurations are also provided. respectively. If the connection from the table 1 contains a first stereocenter and a second stereocenter with stereochemical configurations S and S, respectively, stereoisomers of a compound having first and second stereocenters with R and R stereochemical configurations, respectively, S and R stereochemical configurations, respectively, and R and S are also provided.

- 219 045362

S stereochemical configurations, respectively. If the connection from the table 1 contains a first stereocenter and a second stereocenter with stereochemical configurations S and R, respectively, stereoisomers of a compound having first and second stereocenters with R and S stereochemical configurations, respectively, R and R stereochemical configurations, respectively, and S and S stereochemical configurations are also provided. respectively. Similarly, if the connection from the table. 1 contains a first stereocenter and a second stereocenter with stereochemical configurations R and S, respectively, stereoisomers of a compound having first and second stereocenters with S and R stereochemical configurations, respectively, R and R stereochemical configurations, respectively, and S and S stereochemical configurations are also provided. respectively. In addition, some structures may exist as geometric isomers (ie, cis and trans isomers), tautomers, or atropisomers. In addition, any formula set forth herein is also intended to refer to any one of the hydrates, solvates, and amorphous and polymorphic forms of such compounds and mixtures thereof, even if such forms are not expressly stated. In some embodiments, the solvent is water and the solvates are hydrates.

Illustrative examples of the connections described in detail herein, including intermediate connections and final connections, are depicted in the tables and elsewhere in this document. It is understood that, in one aspect, any of the compounds can be used in the methods described in detail herein, including, where applicable, intermediate compounds that can be isolated and administered to an individual or subject. The compounds depicted herein may be present in the form of salts, even if salts are not depicted, and it is understood that the compositions and methods provided herein cover all salts and solvates of the compounds depicted herein, as well as non-salt and non-solvate forms. connections, as understood by one skilled in the art. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

In one variation, the compounds of this invention are synthetic compounds prepared for administration to an individual or subject. In another variation, compositions are provided containing the compound in substantially pure form. In another variation, pharmaceutical compositions are provided containing a compound described in detail herein and a pharmaceutically acceptable carrier. Another variation provides methods for administering the compound. Purified forms, pharmaceutical compositions and methods of administration of the compounds are suitable for any compound or form thereof described in detail herein.

Any variation or embodiment of the invention G ¹ , R ¹ , R ^2A , R ^2B , R ³ , R ⁴ and R ⁵ proposed herein may be combined with any other variation or embodiment of the invention G ¹ , R ¹ , R ^2A , R ^2B R ³ , R ⁴ , and R ⁵ as if each combination were individually and specifically described. Any variation or embodiment of the invention G ¹ , R ¹ , R ^2A , R ^2B , R ³ , R ⁴ , R ⁵ , R ^1a , R ^2a , R ^2b , R ^3a , m, n, p, q, X and Q proposed herein may be combined with any other variation or embodiment of the invention ^G1 , ^R1 , ^R2A , ^R2B , ^R3 , ^R4 , ^R5 , ^R1a , ^R2a , ^R2b , ^R3a , m, n, p, q, X and Q as if each combination were individually and specifically described. For the purposes of this document, when any variable appears more than once in a chemical formula, its definition in each instance is independent of its definition in each in another case.

Formula (I) includes all its subformulas. For example, formula (I) includes compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), ( Ik-1), (Ik-2), (Il), (Im), (In-1) and (In-2).

Specific names of compounds presented in this document, including in Table. 1, provided by ChemBioDraw Professional 15.0.0.106. One skilled in the art will appreciate that compounds may be named or identified using various generally accepted nomenclature systems and symbols. By way of example, compounds may be named or identified by common names, systematic names, or non-systematic names. Nomenclature systems and symbols that are widely known in the field of chemistry include, for example, the Chemical Abstract Service (CAS), ChemBioDraw Ultra, and the International Union of Pure and Applied Chemistry (IUPAC).

Compositions.

Also provided are compositions, such as pharmaceutical compositions, which include a compound disclosed and/or described herein and one or more additional drugs, pharmaceutical agents, adjuvants, carriers, excipients and the like. Suitable medicinal and pharmaceutical agents include those described herein. In some embodiments, the pharmaceutical composition includes a pharmaceutically acceptable excipient or adjuvant and at least one chemical component, as described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose and magnesium carbonate. In some embodiments, the invention provides compositions, such as pharmaceutical compositions, that

- 220 045362 contain one or more of the compounds described herein, or pharmaceutically acceptable salts thereof.

In some embodiments, the invention provides a pharmaceutically acceptable composition containing a compound of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), ( li), (Ij), (Ik-1), (Ik2), (Il), (Im), (In-1) or (In-2), or a compound from table. 1, or a pharmaceutically acceptable salt thereof. In some aspects, the composition may contain a synthetic intermediate that can be used in the preparation of the compound described herein. The compositions described herein may contain any other suitable active or inactive agents. Any of the compositions described herein may be sterile or contain components that are sterile. Sterilization can be achieved by methods known in the art. Any of the compositions described herein may contain one or more compounds or conjugates that are substantially pure. Also provided are packaged pharmaceutical compositions containing a pharmaceutical composition as described herein and instructions for use of the composition to treat a patient suffering from a disease or condition described herein.

Methods of application.

The compounds and pharmaceutical compositions herein can be used to treat or prevent a disease or condition in an individual or subject.

When used prophylactically, the compounds disclosed and/or described herein may prevent the development of a disease or disorder or reduce the extent of a disease or disorder that may develop in a person or subject at risk of developing a disease or disorder.

Without being limited by any theory, the compounds and pharmaceutical compositions disclosed herein are believed to act by inhibiting myosin. This inhibition potentially reduces the number of independent myosin heads interacting with actin filaments, reducing the extent of contraction. Reducing the contraction of the heart muscle may be important in treating heart conditions in which excessive contraction is a problem. In some embodiments, the invention provides methods for treating or preventing heart disease in an individual or subject, comprising administering to the individual or subject in need thereof a compound of formula (I), (Ia), (Ib), (Ic), (Id), ( Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1) or ( In-2), or connection from table. 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the invention provides methods for treating or preventing heart disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one chemical agent as described herein. In some embodiments, the invention provides methods for treating heart disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one chemical agent as described herein. In some embodiments, the invention provides methods for treating established or diagnosed heart disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one chemical agent as described herein. In some embodiments, the invention provides methods for preventing heart disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one chemical agent as described herein. Also provided herein is the use of a compound of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij ), (Ik1), (Ik-2), (Il), (Im), (In-1) or (In-2), or compounds from table. 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a heart condition in a subject. In some aspects, a compound or composition as described herein is provided for use in a method of treating a human or animal body through therapy. In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) are provided herein. , (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1) or (In-2), or a compound from table. 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating a human or animal body with a therapy. In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) are provided herein. , (Ij), (Ik-1) or (Ik-2), or a compound from table. 1, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of heart disease. In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) are provided herein. , (Ij), (Ik-1) or (Ik-2), or a compound from table. 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of heart disease. In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) are provided herein. , (Ij), (Ik-1) or (Ik-2), or a compound from table. 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of established or diagnosed heart disease. In other embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) are provided herein. , (Ij), (Ik-1) or (Ik-2), or a combination of

- 221 045362 table. 1, or a pharmaceutically acceptable salt thereof, for use in the prevention of heart disease. In some embodiments, provided herein are compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (li) , (Ij), (Ik-1). or (Ik-2), or compound from table. 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition associated with SUI. In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) are provided herein. , (Ij), (Ik-1) or (Ik-2), or a compound from table. 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition associated with secondary thickening of the left ventricular wall. In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) are provided herein. , (Ij), (Ik-1) or (Ik-2), or a compound from table. 1, or a pharmaceutically acceptable salt thereof, for use in alleviating a symptom associated with heart disease. In other embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) are provided herein. , (Ij), (Ik-1) or (Ik-2), or a compound from table. 1, or a pharmaceutically acceptable salt thereof, for use in reducing the risk of symptoms associated with heart disease. In other embodiments, provided herein are compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1) or (Ik-2), or a compound from table. 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or pathological condition associated with a small left ventricular cavity, cavity obliteration, hyperdynamic contraction of the left ventricle, obstruction of left ventricular blood flow, cardiac hypertrophy, small stroke volume, impaired relaxation of the left ventricle, high left ventricular filling pressure, myocardial ischemia or cardiac fibrosis. In certain embodiments of the invention, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) are provided herein. , (Ij), (Ik-1) or (Ik-2), or a compound from table. 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition associated with left ventricular small cavity and cavity obliteration, left ventricular hyperdynamic contraction, myocardial ischemia, or cardiac fibrosis. In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) are provided herein. , (Ij), (Ik-1) or (Ik-2), or a compound from table. 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of muscular dystrophy. In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) are provided herein. , (Ij), (Ik-1) or (Ik-2), or a compound from table. 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of glycogen storage disease. In other embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) are provided herein. , (Ij), (Ik-1) or (Ik-2), or a compound from table. 1, or a pharmaceutically acceptable salt thereof, for use in cardiac sarcomere modulation, eg, cardiac sarcomere inhibition. In other embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii) are provided herein. , (Ij), (Ik-1) or (Ik-2), or a compound from table. 1, or a pharmaceutically acceptable salt thereof for use in potentiating cardiac myosin. In some embodiments, the subject is a mammal. In some embodiments, the subject is a mouse, rat, dog, cat, pig, sheep, horse, cow, or human. In some embodiments, the subject is a human. In some embodiments, the subject has established or diagnosed heart disease. In some embodiments, the subject has been diagnosed with hypertrophic cardiomyopathy (HCM). In some embodiments, the subject is at risk for developing cardiovascular disease. In some embodiments, the subject has a mutation that increases the risk of heart disease. In some embodiments, the subject has a mutation that increases the risk of developing hypertrophic cardiomyopathy (HCM). In some embodiments, the mutation is a sarcomeric mutation. In some embodiments, the mutation is a mutation in myosin heavy chain β (MHC-β), cardiac troponin T (cTnT), tropomyosin alpha 1 chain (TPM1), cardiac type myosin binding protein C (MYBPC3), cardiac troponin I (cTnI), myosin essential light chain (ELC), titin (TTN), ventricular/cardiac muscle regulatory myosin light chain isoform 2 (MLC-2), cardiac alpha actin, muscle LIM protein (MLP) or activated protein -AMP kinase subunit gamma 2 (PRKAG2). In some embodiments, the mutation is a mutation in MHC-β. In some embodiments, the subject has been diagnosed with hypertrophic cardiomyopathy without a proven genetic etiology.

In some embodiments, the subject is at high risk for progressive symptoms. In some embodiments, the subject is at high risk for atrial fibrillation, ventricular tachyarrhythmias, stroke, and/or sudden death. In some embodiments, the subject has reduced physical activity. In some variants

- 222 045362 implementation of the invention, the reduced physical activity is compared with a control group of the corresponding age. In some embodiments, the subject is eligible for surgery or percutaneous ablation to treat heart disease.

In some embodiments, the heart disease is hypertrophic cardiomyopathy (HCM). In some embodiments, the heart disease is obstructive SUI. In some embodiments, the heart disease is non-obstructive SUI. In some embodiments, SCI is associated with a sarcomeric mutation. In some embodiments, NSM is associated with a nonsarcomeric mutation. In some embodiments, the heart disease is obstructive or non-obstructive SUI or is caused by sarcomeric and/or non-sarcomeric mutations. In some embodiments, the sarcomeric mutation is a mutation in myosin heavy chain β (MHC-β), cardiac troponin T (cTnT), tropomyosin alpha 1 chain (TPM1), cardiac type myosin binding protein C (MYBPC3), troponin I cardiac (cTnl), myosin essential light chain (ELC), titin (TTN), ventricular/cardiac muscle regulatory myosin light chain isoform 2 (MLC-2), cardiac alpha actin, or muscle LIM protein (MLP). In some embodiments, the sarcomeric mutation is a mutation in MHC-β. In some embodiments, the nonsarcomeric mutation is a mutation in the protein kinase AMP-activated noncatalytic subunit gamma 2 (PRKAG2). In some embodiments, provided herein are methods of treating a disease or condition associated with SUI, comprising administering to an individual or subject in need thereof a compound of formula (I), (Ia), (Ib), (Ic), (Id ), (Ie), (If), (Ig), (Ih), (li), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1 ) or (In-2), or a compound from table. 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is Fabry disease, Danon disease, mitochondrial cardiomyopathy, or Noonan syndrome.

Also provided herein is the use of a compound of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij ), (Ik-1), (Ik-2), (Il), (Im), (In-1) or (In-2), or compounds from table. 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or condition associated with SUI.

In some embodiments, the heart disease is heart failure with preserved ejection fraction (HFpEF). In some embodiments, the heart disease is diastolic dysfunction. In some embodiments, the heart disease is cardiomyopathy. In some embodiments, the heart disease is a primary or secondary restrictive cardiomyopathy. In some embodiments, the heart disease is a pathological condition or symptoms caused by coronary artery disease. In some embodiments, the heart disease is myocardial infarction or angina. In some embodiments, the heart disease is left ventricular tract obstruction. In some embodiments, the heart disease is hypertensive heart disease. In some embodiments, the heart disease is a congenital heart defect. In some embodiments, the heart disease is cardiac ischemia and/or coronary artery disease. In some embodiments, the heart disease is diabetic heart disease. In other embodiments, the heart disease is chronic heart failure. In some embodiments, the heart disease is right ventricular failure. In other embodiments, the heart disease is cardiorenal syndrome. In some embodiments, the heart disease is infiltrative cardiomyopathy. In some embodiments, the heart disease is a pathological condition that represents or is associated with cardiac aging or diastolic dysfunction due to aging. In some embodiments, the heart disease is a pathological condition that represents or is associated with left ventricular hypertrophy and/or concentric left ventricular remodeling.

Some embodiments of the invention provide methods for treating a disease or condition associated with secondary left ventricular wall thickening in an individual or subject, comprising administering to the individual or subject in need thereof a compound of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im ), (In-1) or (In-2), or compounds from table. 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is hypertension, heart disease (aortic stenosis, mitral valve regurgitation), metabolic syndromes (diabetes, obesity), end-stage renal disease

- 223 045362 insufficiency, scleroderma, sleep apnea, amyloidosis, Fabry disease, Friedreich disease, Friedreich ataxia, Danon disease, Noonan syndrome and Pompe disease.

Also provided herein is the use of a compound of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij ), (Ik-1), (Ik-2), (Il), (Im), (In-1) or (In-2), or compounds from table. 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or condition, is associated with secondary thickening of the left ventricular wall. Some embodiments of the invention provide methods for alleviating symptoms associated with heart disease in a subject, comprising administering to an individual or subject in need thereof a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1) or (Ik-2), or a compound from table. 1, or a pharmaceutically acceptable salt thereof, wherein the symptom is selected from one or more of poor or decreased cardiac elasticity, poor or decreased left ventricular diastolic relaxation, abnormal left atrial pressure (eg, abnormally high left atrial pressure), paroxysmal or persistent atrial fibrillation , increased left atrial pressure and pulmonary artery capillary wedge pressure, increased left ventricular diastolic pressure, syncope, ventricular relaxation during diastole, ventricular fibrosis, left ventricular hypertrophy, left ventricular mass, increased left ventricular wall thickness, left ventricular middle cavity obstruction, increased systolic anterior motion of the mitral valve, left ventricular outflow obstruction, chest pain, dyspnea on exertion, presyncope, abnormal exertion, and fatigue.

Some embodiments of the invention provide methods for reducing the risk of a symptom associated with heart disease in a subject, comprising administering to an individual or subject in need thereof a compound of formula (I), (Ia), (Ib), (Ic), (Id) , (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1) or (Ik-2), or a compound from table. 1, or a pharmaceutically acceptable salt thereof, wherein the symptom is selected from one or more of sudden cardiac death, poor or decreased cardiac elasticity, poor or decreased left ventricular diastolic relaxation, abnormal left atrial pressure (eg, abnormally high left atrial pressure), paroxysmal or persistent atrial fibrillation, increased left atrial pressure and pulmonary capillary wedge pressure, increased left ventricular diastolic pressure, syncope, ventricular relaxation during diastole, ventricular fibrosis, left ventricular hypertrophy, left ventricular mass, increased left ventricular wall thickness, middle obstruction left ventricular cavity, increased systolic anterior motion of the mitral valve, left ventricular outflow obstruction, chest pain, dyspnea on exertion, presyncope, abnormal exertion, and fatigue. In some embodiments, the invention provides methods for treating a disease or condition associated with a small left ventricular cavity, cavity obliteration, hyperdynamic left ventricular contraction, obstruction of blood flow from the left ventricle, cardiac hypertrophy, small stroke volume, impaired left ventricular relaxation, high filling pressure left ventricular ischemia, myocardial ischemia or cardiac fibrosis in an individual or subject, comprising administering to the individual or subject in need thereof a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), ( If), (Ig), (Ih), (Ii), (Ij), (Ik-1) or (Ik-2), or compounds from table. 1, or a pharmaceutically acceptable salt thereof.

In some embodiments, the invention provides methods for treating a disease or condition associated with left ventricular small cavity and cavity obliteration, left ventricular hyperdynamic contraction, myocardial ischemia, or cardiac fibrosis in an individual or subject, comprising administering to the individual or subject in need thereof a compound of the formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1) or (In-2) or compounds from table. 1, or a pharmaceutically acceptable salt thereof.

Also provided herein is the use of a compound of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij ), (Ik-1), (Ik-2), (Il), (Im), (In-1) or (In-2), or compounds from table. 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or pathological condition associated with left ventricular small cavity and cavity obliteration, left ventricular hyperdynamic contraction, myocardial ischemia or cardiac fibrosis.

Some embodiments of the invention provide methods for treating muscular dystrophy in an individual or subject (e.g., Duchenne muscular dystrophy), comprising administering to the individual or subject in need thereof a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In -1) or (In-2), or connection from table. 1, or a pharmaceutically acceptable salt thereof. Also provided herein is the use of a compound of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij ), (Ik-1), (Ik-2), (Il), (Im), (In-1) or (In-2), or compounds from table. 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of muscular dystrophies (eg, Duchenne muscular dystrophy). In some embodiments, the invention provides methods for treating or preventing glycogen storage disease in an individual or subject, comprising administering to the individual or subject in need thereof a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1) or

- 224 045362 (In-2), or connection from table. 1, or a pharmaceutically acceptable salt thereof. Also provided herein is the use of a compound of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (li), (Ij ), (Ik1), (Ik-2), (Il), (Im), (In-1) or (In-2), or compounds from table. 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of glycogen storage disease.

Also provided are methods of modulating a cardiac sarcomere in an individual or subject, the method comprising administering to the individual or subject in need thereof a therapeutically effective amount of at least one chemical as described herein. In some embodiments, the invention provides methods for inhibiting a cardiac sarcomere, comprising contacting the cardiac sarcomere with at least one chemical as described herein, such as a compound of formulas (I), (Ia), (Ib), (Ic) , (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), ( In-1) or (In-2), or a compound from table. 1 or a pharmaceutically acceptable salt thereof. Further provided herein is the use of at least one chemical as described herein, such as a compound of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), ( If), (Ig), (Ih), (Il), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1) or (In-2) , or compounds from the table. 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting a human or subject cardiac sarcomere. Also provided are methods of potentiating cardiac myosin in an individual or subject, the method comprising administering to the individual or subject in need thereof a therapeutically effective amount of at least one chemical as described herein, such as a compound of formula (I), (Ia ), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1) or (In-2), or compounds from table. 1, or a pharmaceutically acceptable salt thereof. Further provided herein is the use of at least one chemical as described herein, such as a compound of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), ( If), (Ig), (Ih), (Il), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1) or (In-2) , or compounds from the table. 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for potentiating cardiac myosin in a human or subject. In some embodiments, the methods provided herein further include monitoring the effectiveness of the treatment. Examples of indicators include, but are not limited to, improvement in one or more of the following: New York Heart Association (NYHA) functional classification, exercise, cardiac elasticity, left ventricular diastolic relaxation, left atrial pressure, paroxysmal or persistent atrial fibrillation, left atrial pressure and pulmonary artery capillary wedge pressure, left ventricular diastolic pressure, syncope, ventricular relaxation during diastole, ventricular fibrosis, left ventricular hypertrophy, left ventricular mass, left ventricular wall thickness, left ventricular mid-cavity obstruction, systolic anterior motion of the mitral valve, obstruction left ventricular outflow tract, chest pain, shortness of breath on exertion, lightheadedness, impaired physical performance and fatigue. These indicators can be monitored by methods known in the art, including self-reporting; ECG, including ambulatory ECG; echocardiography; MRI of the heart; CT; biopsy; cardiopulmonary exercise tests (CPET); and actigraphy.

In some embodiments of the invention, the compound reduces the contractility of the cardiomyocyte. In some embodiments, the compound reduces cardiomyocyte contractility by more than 40%, such as by more than 45, 50, 60, 70, 80, or 90%. In some embodiments, the compound reduced cardiomyocyte contractility by 40-90%, such as 40-80, 40-70, 50-90, 50-80, or 50-70%. In some embodiments, the compound does not significantly alter calcium transients in the cardiomyocyte. In some embodiments, the compound reduces ATPase activity in the cardiomyocyte. Methods for measuring contractility, ATPase activity and calcium transients are known in the art, for example, from calcium tracers, electrophysiological recordings and microscopic images. In some embodiments, the compound does not significantly inhibit or induce cytochrome P450 protein (CYP).

Without being limited by theory, it is believed that a stereoisomer of a compound of formula (I) or any variant thereof in which the carbon bearing the R ^2A and R ^2B moieties is in the stereochemical configuration S is more active, as measured by a myofibril assay (such as an described in Example B-1) than the corresponding stereoisomer in which the carbon bearing the R ^2A and R ^2B moieties is in the stereochemical configuration R. A crystal structure was obtained for a representative compound of formula (I), demonstrating that between the S isomer and the The R more active stereoisomer, as measured by the myofibril assay described in Example B-1, is a stereoisomer in which the carbon bearing the R ^2A and R ^2B moieties is in the stereochemical S configuration.

In some embodiments, the subject has a left ventricular wall that is thicker than normal before treatment. In some embodiments, the subject has a left ventricular wall thickness greater than 15 mm, such as greater than 18 mm, 20 mm, 22 mm, 25 mm, or 30 mm, before treatment. In some embodiments, the left ventricular wall thickness

- 225 045362 decreases by more than 5%, for example more than 8, 10, 12, 15, 20 or 30% after treatment. Left ventricular wall thickness can be measured by methods known in the art, such as echocardiography, computed tomography, or cardiac MRI.

In some embodiments, the subject has abnormal cardiac fibrosis prior to treatment. In some embodiments, abnormal cardiac fibrosis is reduced by more than 5%, such as by more than 8, 10, 12, 15, 20, or 30%, after treatment. Cardiac fibrosis can be measured by methods known in the art, such as cardiac biopsy or MRI.

In some embodiments, the subject has reduced physical activity prior to treatment. In some embodiments, the subject's exercise capacity increases by more than 5%, such as by more than 8, 10, 12, 15, 20, or 30%, after treatment. In some embodiments, exercise is measured using cardiopulmonary exercise testing (CPET). CPET measures changes in oxygen consumption (VO ₂ max). Methods for measuring CPET and VO ₂ max. are well known in the field (Malhotra et al., JACC: Heart Failure, 2016, 4(8): 607-616; Guazzi et al., J Amer College Cardiol, 2017, 70(13): 1618-1636; Rowin et al., JACC: Cariovasc Imaging, 2017, 10(11):1374-1386). In some embodiments, VO ₂ max. improves by more than 1 ml/kg/ ^m2 , for example, more than 1.2 ml/kg/ ^m2 , 1.4 ml/kg/ ^m2 , 1.5 ml/kg/ ^m2 , 1.7 ml /kg/ ^m2 , 2 ml/kg/ ^m2 , 2.2 ml/kg/ ^m2 , 2.5 ml/kg/ ^m2 , 3 ml/kg/ ^m2 , 3.2 ml/kg/m ² or 3.5 ml/kg/ ^m2 after treatment.

In some embodiments, the subject has a New York Heart Association (NYHA) functional classification II, III, or IV prior to initiation of treatment. In some embodiments, the subject has a New York Heart Association (NYHA) functional classification III or IV prior to initiation of treatment. In some embodiments, the subject has a New York Heart Association (NYHA) functional classification IV prior to initiation of treatment. In some embodiments, the subject remains in the same NYHA functional class or has a reduced NYHA functional class after treatment.

In some embodiments, VO2 max. improves by more than 1 ml/kg/ ^m2 , for example, more than 1.2 ml/kg/ ^m2 , 1.4 ml/kg/ ^m2 , 1.5 ml/kg/ ^m2 , 1.7 ml /kg/m ² or 2 ml/kg/m ² and the subject has a reduced NYHA functional class after treatment. In some embodiments, VO ₂ max. improves by more than 2.5 ml/kg/m ² , 3 ml/kg/m ² , 3.2 ml/kg/m ² or 3.5 ml/kg/m ² and the subject remains in the same NYHA functional class or has a reduced NYHA functional class after treatment.

In some embodiments, the subject's daily activities and/or activity level improve after treatment. Improved daily activities and/or activity level can be measured, for example, using logging or actigraphy, such as FitBit or FitBit-like observations.

In some embodiments, the subject experiences one or more of the following: shortness of breath, chest pain, decreased arrhythmic burden such as atrial fibrillation and ventricular arrhythmia, decreased incidence of heart failure, and decreased ventricular outflow obstruction following treatment.

Doses.

The compounds and compositions disclosed and/or described herein are administered at a therapeutically effective dose, for example, a dose sufficient to treat a disease. Although human dose levels have yet to be optimized for the chemicals described herein, a typical daily dose ranges from 0.01 to 100 mg/kg body weight; In some cases, from about 0.05 to 10.0 mg/kg body weight, and in some embodiments, the invention provides a release of from about 0.10 to 1.4 mg/kg body weight. Thus, for administration to a 70 kg person, in some embodiments the dosage range may be from 0.7 to 7000 mg per day; in some embodiments, from about 3.5 to 700.0 mg per day, and in some embodiments, from about 7 to 100.0 mg per day. The amount of chemical administered will depend, for example, on the subject and disease state being treated, the severity of the disease, the route and schedule of administration, and the discretion of the prescribing physician. For example, an illustrative dosage range for oral administration is from about 5 mg to about 500 mg per day, and an illustrative dosage range for intravenous administration is from about 5 mg to about 500 mg per day, each depending on the pharmacokinetics of the compound. The daily dose is the total amount administered in a day. The daily dose may be administered, but not limited to, every day, every other day, every week, every 2 weeks, every month, or at various intervals. In some embodiments, the daily dose is administered over a period of one day for the life of the subject. In some embodiments, the daily dose is administered once daily. In some embodiments, the daily dose is administered in multiple divided doses, for example, 2, 3 or 4 divided doses. In some embodiments, the daily dose is administered in 2 divided doses.

Administration of the compounds and compositions disclosed and/or described herein may

- 226 045362 be any acceptable route of administration of therapeutic agents, including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal or intraocular administration. In some embodiments, the compound or composition is administered orally or intravenously. In some embodiments, a compound or composition disclosed and/or described herein is administered orally. Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms such as tablets, capsules, powder, liquid, suspension, suppository and aerosol forms. The compounds disclosed and/or described herein may also be administered in sustained or controlled release dosage forms (e.g., controlled/sustained release tablets, sustained release injection, osmotic pump, or transdermal (including electrotransport) patches) over long periods of time. time and/or pulsed administration at a given speed. In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.

The compounds disclosed and/or described herein may be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition may also contain minor amounts of non-toxic excipients such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (for example, sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate ). Typically, depending on the intended route of administration, the pharmaceutical composition will contain from about 0.005% to 95%, or from about 0.5% to 50%, by weight of a compound disclosed and/or described herein. Actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. In some embodiments, the compositions will take the form of a pill or tablet, and thus the composition may contain, in addition to the compounds disclosed and/or described herein, one or more diluents (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g. , magnesium stearate) and/or binder (for example, starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives). Other solid dosage forms include powder, marume, solution or suspension (eg in propylene carbonate, vegetable oils or triglycerides) enclosed in a gelatin capsule.

Liquid pharmaceutically administered compositions can, for example, be prepared by dissolving, dispersing or suspending, etc. a compound disclosed and/or described herein and optional pharmaceutical additives in a carrier (eg, water, saline, aqueous dextrose, glycerin, glycols, ethanol, or the like) to form a solution or suspension. Injectable preparations may be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of compound contained in such parenteral compositions depends, for example, on the physical nature of the compound, the activity of the compound, and the needs of the subject. However, a percentage of active ingredient of 0.01% to 10% in solution is applicable and may be higher if the composition is a solid that will subsequently be diluted to a different concentration. In some embodiments, the composition will be from about 0.2 to 2% of the compound disclosed and/or described herein in solution. Pharmaceutical compositions of the compounds disclosed and/or described herein can also be administered to the respiratory tract as an aerosol or nebulizer solution or as a finely ground powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the pharmaceutical composition may have diameters less than 50 microns or, in some embodiments, less than 10 microns. In addition, pharmaceutical compositions may include a compound disclosed and/or described herein and one or more additional drugs, pharmaceutical agents, adjuvants, and the like. Suitable medicinal and pharmaceutical agents include those described herein.

Sets.

Also provided are products and kits containing any of the compounds or pharmaceutical compositions provided herein. The product may contain a container with a label. Suitable containers include, for example, bottles, vials and tubes. Containers can be made from various materials such as glass or plastic. The container may contain a pharmaceutical composition provided herein. The label on the container may indicate that the pharmaceutical composition is used to prevent, treat, or suppress a condition described in

- 227 045362 this document, and may also indicate directions for in vivo or in vitro use. In one aspect, provided herein are kits containing a compound or composition described herein and instructions for use. The kits may contain instructions for use in the treatment of heart disease in an individual or subject in need thereof. The kit may further contain any materials or equipment that may be used in administering the compound or composition, such as vials, syringes, or intravenous bags. The kit may also contain sterile packaging.

Combinations.

The compounds and compositions described and/or disclosed herein may be administered alone or in combination with other therapies and/or therapeutic agents useful for treating the aforementioned disorders, diseases or conditions.

The compounds and compositions described and/or disclosed herein may be combined with one or more other therapies for the treatment of heart diseases such as SUI or HFpEF. In some embodiments, the one or more treatment methods include treatments that slow the progression of heart failure by inhibiting neurohormonal stimulation of the heart and attempting to prevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), beta blockers, aldosterone receptor antagonists, or neuronal endopeptidase inhibitors). In some embodiments, the one or more therapies include therapies that improve cardiac function by stimulating cardiac contractility (eg, positive inotropic agents such as the β-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone). In other embodiments, the one or more therapies include therapies that reduce cardiac preload (eg, diuretics such as furosemide) or afterload (vasodilators of any class, including, but not limited to, calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists , renin inhibitors or smooth muscle myosin modulators). The compounds and compositions described and/or disclosed herein may be combined with one or more other therapies for the treatment of SUI or HFpEF. In some embodiments, the compounds and/compositions may be combined with a β-blocker, verapamil and/or disopyramide.

General synthetic methods.

Compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1 ), (Ik-2), (II), (Im), (In-1) and (In-2) will now be described with reference to illustrative synthesis schemes to depict their general preparation method below and specific examples that follow. Those skilled in the art will appreciate that for the preparation of the various compounds provided herein, starting materials can be suitably selected so that the final desired substituents are carried through the reaction scheme with or without protection, as appropriate, to obtain the desired product. Alternatively, it may be necessary or desirable to use a suitable group in place of the final desired substituent, which can be carried around the reaction scheme and replaced with the desired substituent as appropriate. In addition, one skilled in the art will appreciate that protecting groups can be used to protect certain functional groups (amino, carboxy or side chains) from reaction conditions and that such groups are removed under standard conditions when necessary. Unless otherwise stated, the variables are as defined above with respect to formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) , (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1) and (In-2).

Where it is desired to obtain a particular enantiomer of a compound, this can be accomplished from an appropriate mixture of enantiomers using any suitable conventional technique for separating or separating enantiomers. Thus, for example, diastereomeric derivatives can be prepared by reacting a mixture of enantiomers, for example, a racemate and the corresponding chiral compound. The diastereomers can then be separated by any convenient method, such as crystallization, and the desired enantiomer can be recovered. In another separation method, the racemate can be separated using chiral high performance liquid chromatography. Alternatively, if desired, the specific enantiomer can be obtained using a suitable chiral intermediate in one of the described processes. Chromatography, recrystallization, and other conventional separation techniques may also be used with intermediates or end products where it is desired to obtain a specific isomer of a compound or otherwise purify the reaction product.

General methods for preparing the compounds described herein are depicted below as examples of methods. Groups of variables in the schemes proposed in this document are defined as for formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik-1), (Ik-2), (Il), (Im), (In-1) and (In-2) or any variation thereof. Other compounds described herein can be prepared by similar methods.

In some embodiments, the compounds provided herein

- 228 045362 can be synthesized in accordance with Scheme 1.

Scheme 1 _r sa A

R ¹

R ^s

R ¹

ABOUT

A

R ⁴

R ¹ R-4 RA r ^2B (\ ^α

_CO2Ak

Ri _Η Λ

R» ¹ ?

ABOUT

J-L A o

wherein R ¹ , R ^2a , R ^2b , R ³ , R ⁴ and R ⁵ are as defined for formula (I), or any variations thereof as detailed herein.

An illustrative example of the option is shown in Scheme 1a.

implementation of the preparative method in Scheme 1 is illustrated R ^1a

Scheme 1a

R ^la , NH, ^R Hh RZsrCOMk

THF DCE, AcOH

STAB. RT, 15 h _R 2b'''COjAIK

R ^1a

R'

Aik ₂ NH ₂ , MeCN

Et ₃ N, 80 °C, 15 h

N I

R4J J

R ^?e ί About where R ^2a and R ^2b are as defined for formula (I), or any variations thereof described in detail herein; and wherein R ^1a is as defined for formula (If), or any variations thereof detailed herein.

Another illustrative example of an embodiment of the preparative method in Scheme 1 is illustrated in Scheme 1b.

Scheme 1b

AM ^Γ< ·Ά ta v /

_R3.NH2 . MsCbi Ri O u D

EiM 8iiC. F, G

TFU.DHM

R.T-US and

R-o

-U A

N'A

ΗΜψ}Y

wherein R ¹ , R ³ , R ⁴ and R ⁵ are as defined for formula (I), or any variations thereof detailed herein, and where R ^2a is as defined for formula (If), or any variations thereof described in detail in this document.

Another illustrative example of an embodiment of the preparative method in Scheme 1 is illustrated in Scheme 1c.

- 229 045362

Scheme 1s

where R ^1a and R ^2a are as defined for formula (If), or any variations thereof described in detail herein.

In some embodiments, the compounds provided herein can be synthesized according to Scheme 2.

Scheme 2

wherein R ¹ , R ^2A , R ^2B , R ³ , R ⁴ and R ⁵ are as defined for formula (I), or any variations thereof as described in detail herein.

Another illustrative example of an embodiment of the preparative method in Scheme 2 is illustrated in Scheme 2a.

Scheme 2a

where R ^2A and R ^2B are as defined for formula (I), or any variations thereof described in detail herein; and wherein R ^1a is as defined for formula (If), or any variations thereof detailed herein.

Another illustrative example of an embodiment of the preparative method in Scheme 2 is illustrated in Scheme 2b.

- 230 045362

Scheme 2b

TW DXM

Y? . 45

PA Μ

where R ¹ , R ³ , R ⁴ and R ⁵ are as defined for formula (I), or any variations thereof detailed herein, where R ^2a is as defined for formula (If), or any variations thereof are described in detail herein, and where X represents a halogen.

Another illustrative example of an embodiment (eg, the preparative method in Scheme 2) is illustrated in Scheme 2c.

Scheme 2c

-T .2,·. ·>.· ГЧ·.· ^к у t у „а

------------ „“MAm ¹ ---------rYY δ

where R ¹ , R ³ , R ⁴ and R ⁵ are as defined for formula (I), or any variations thereof as described in detail herein.

Another illustrative example of the preparative method embodiment in Scheme 2 is illustrated in Scheme 2d.

2d diagram

R ^1a

TFA. DCM.

R.T., 45 m

R^X

E1 ₃ N, DCM, RT. 15 m

-231 045362 where R ^1a and R ^2a are as defined for formula (If), or any variations thereof detailed herein.

Another illustrative example of an embodiment (eg, the preparative method in Scheme 2) is illustrated in Scheme 2e.

Scheme 2e

Another illustrative example of an embodiment (eg, the preparative method in Scheme 2) is illustrated in Scheme 2f.

Scheme 2f

Another illustrative example of the preparative method embodiment in Scheme 2 is illustrated in Scheme 2g.

Scheme 2g

where X represents a halide; where R ^2A and R ³ are as defined for formula (I), or any variations thereof described in detail herein; and where R ^1a and m are such,

- 232 045362 as defined for formula (Ik-1), or any variations thereof detailed herein.

In some embodiments, the compounds provided herein can be synthesized according to Scheme 3.

Scheme 3

wherein R ¹ , R ^2A , R ^2B , R ³ , R ⁴ and R ⁵ are as defined for formula (I), or any variations thereof as described in detail herein.

Another illustrative example of an embodiment of the preparative method in Scheme 3 is illustrated in Scheme 3 a.

Scheme 3a

where R ^1a is as defined for formula (If), or any variations thereof detailed herein; and wherein R ^a and R ^b are independently H or C1- _C6 alkyl.

Another illustrative example of an embodiment of the preparative method in Scheme 3 is illustrated in Scheme 3b-1.

- 233 045362

Scheme 3b-l

where X represents CH or N; and where R ^la is as defined for formula (If), or any variations thereof detailed herein.

Another illustrative example of an embodiment of the preparative method in Scheme 3 is illustrated in Scheme 3b-2.

Scheme Zb-2

where X represents CH or N; and where R ^la is as defined for formula (If), or any variations thereof detailed herein.

Another illustrative example of an embodiment of the preparative method in Scheme 3 is illustrated in Scheme 3c.

Scheme Zs

where R ^la is as defined for formula (If), or any variations thereof detailed herein.

Another illustrative example of the preparative method embodiment in Scheme 3 is illustrated in Scheme 3d.

-234045362

3d diagram

where R ^2A is as defined for formula (I), or any variations thereof detailed herein; and where R ^1a is selected from the group consisting of cyano, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl and substituted or unsubstituted diazirinyl.

Another illustrative example of the preparative method embodiment in Scheme 3 is illustrated in Scheme 3e.

Scheme 3e

where R ^1a is selected from the group consisting of cyano, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl and substituted or unsubstituted diazirinyl.

Another illustrative example of the preparative method embodiment in Scheme 3 is illustrated in Scheme 3f.

Scheme 3f

ci

Cl

Pd(OH) ₂ /C

MeOH/THF where R ^1a is selected from the group consisting of halogen and substituted or unsubstituted alkyl; and where m is 0, 1 or 2.

Another illustrative example of the preparative method embodiment in Scheme 3 is illustrated in Scheme 3g.

- 235 045362

3g circuit

where R ^la and m are as defined for formula (Ik-I), or any variations thereof as detailed herein.

Another illustrative example of a preparative method is illustrated in Scheme 4.

Scheme 4

where R ^la , R ^3a , dash are as defined for formula (Ik-Ι), or any variations thereof as detailed herein.

Specific non-limiting examples are offered in the Examples section below.

Examples

The following examples are offered to illustrate, and not to limit, the compositions, uses and methods proposed herein. Compounds are prepared using the general methods described above. In the following examples, the designation of a compound using a compound number followed by a specific letter indicates the stereoisomeric form or mixture of stereoisomers of such compound, as will be apparent from the context of the particular example. Thus, it will be appreciated that if a compound, such as compound 288, can exist as two separate stereoisomeric forms, the two-letter designations, 288A and 288B, may be used herein to designate the individual stereoisomeric forms. Likewise, individual diastereomers or mixtures thereof, as will be clear from the examples below, can be designated 858A, 858B, 858C and 858D. It is clear that the data tables presented in this document, for example, table. And, where applicable, data associated with a specific stereoisomer will be provided using the notation specified in these examples. Due to the terminology used in this document, it should also be understood that certain compounds indicated in specific stereoisomeric forms in these examples by letter designation may find analogues in table. 1, where such compounds are indicated by structure and name.

The following abbreviations are used in the examples: TEA (trimethylamine), DCM (dichloromethane), (Boc) _2O (di-tert-butyl dicarbonate), EA (ethyl acetate), PE (petroleum ether, DMF (Ν,Ν

-236 045362 dimethylformamide), DIEA (Aethyl-X-isopropylpropan-2-amine), HATU (1-[bis(dimethylamino)methylene]1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HOAt (1-hydroxy-7-azabenzotriazole), HOBt (hydroxybenzotriazole), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), MeOH (methanol), EtOH (ethanol), IPA (iPrOH; propane -2-ol), NMP (1-methylpyrrolidin-2-one), STAB (sodium triacetoxyhydroborate), ACN (acetonitrile), TFA (trifluoroacetic acid), DPPA (diphenylphosphoryl azide), DBU (1,8-diazabicyclo(5,4 ,0)undec-7-ene), THF (tetrahydrofuran), PPh ₃ (triphenylphosphane), SM (starting material), Hex (hexane), NCS (N-chlorosuccinimide), room. pace. (room temperature), DCE (dichloroethane), FA (formic acid), CHCl ₃ (chloroform), BnBr (benzyl bromide), HCl (hydrogen chloride), eq. (equivalent), RT (retention time), SFC (supercritical liquid chromatography) and DSC (bis(2,5-dioxopyrrolidin-1-yl)carbonate).

Example 1. Synthesis of compound 288.

1. Synthesis of intermediate 1-2:

_m E2

To a solution of methyl 2-amino-2-(4-chlorophenyl)acetate (1.5 g, 7.51 mmol, 1.0 eq.) in DCE (20 ml) at room. pace. add 4-chlorobenzaldehyde (1.05 g, 7.47 mmol, 1.00 eq), acetic acid (900 mg, 14.99 mmol, 2.00 eq) and STAB (2.4 g, 11.32 mmol, 1.50 eq.). The mixture was stirred at room. pace. for 2 hours, diluted with EA (100 ml), washed twice with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2.4 g (99%) methyl-2(4-chlorophenyl)- 2-[[(4-chlorophenyl)methyl]amino]acetate as a brown oil.

2. Synthesis of intermediate 1-3:

To a solution of methyl 2-(4-chlorophenyl)-2-[[(4-chlorophenyl)methyl]amino]acetate (2.4 g, 7.40 mmol, 1.00 eq.) in DCM (30 ml) at room pace. TEA (1.5 g, 14.82 mmol, 2.00 eq) and 2-chloroacetyl chloride (1 g, 8.85 mmol, 1.20 eq) were added dropwise. The mixture was stirred at room. pace. for 2 h, diluted with DCM (50 ml), washed twice with brine (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified on a silica gel column with ACN and water (3:1) to give 2 g (67%) methyl 2-[2-chloro-N-[(4-chlorophenyl)methyl]acetamido]-2-(4chlorophenyl)acetate as a brown oil.

3. Synthesis of compound 288:

same

To a solution of methyl 2-[2-chloro-N-[(4-chlorophenyl)methyl]acetamido]-2-(4-chlorophenyl)acetate (150 mg, 0.37 mmol, 1.0 eq.) in ACN ( 10 ml) at room. pace. propan-2-amine (66.5 mg, 1.1 mmol, 3.0 eq.) and TEA (115 mg, 1.1 mmol, 3.0 eq.) were added. The mixture was stirred at room. pace. for 1 h and at 80°C for 2 h, concentrated under reduced pressure and purified by preparative HPLC under the following conditions (2#-Analyse HPLC-SHIMADZU(HPLC-10)): Column, XBridge Shield RP18 OBD column, 5 µm , 19x150 mm; mobile phase, water (0.05% NH ₃ H ₂ O) and ACN (48.0% ACN to 68.0% in 8 min); detector, UV 220 nm) to obtain 100 mg of 3-(4-chlorophenyl)-4-[(4-chlorophenyl)methyl]-1-(propan-2-yl)piperazin2,5-dione. HPMS (ES) m/z 391 (M+H).

1H NMR (DMSO- _d6 , 300 MHz) δ 7.44-7.33 (m, 2H), 7.36-7.22 (m, 4H), 7.22-7.13 (m, 2H) , 4.95 (s, 1H), 4.88 (d, J=15.1 Hz, 1H), 4.40 (g, J=6.9 Hz, 1H), 4.15 (d, J= 17.7 Hz, 1H), 3.98 (d, J=17.8 Hz, 1H), 3.86 (d, J=15.1 Hz, 1H), 1.07 (d, J=6, 8 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H).

The following compounds were prepared by methods similar to those described for compound 288:

- 237 045362

Connection No. HPMS (ES) m/z 293 M+H=392 294 M+H=357 297 M+H=392 298 M+H=391 299 M+H=375 300 M+H=371 301 M+H=382 302 M+H=391 303 M+H=375 304 M+H=371 305 M+H=371 306 M+H=382 307 M+H=382 308 M+H=425 309 M+H=425 310 M+H=391 311 M+H=375 312 M+H=391 313 M+H=387 314 M+H=425 315 M+H=426 316 M+H=405 317 M+H=383 318 M+H=397.2 319 M+H=417.1

4. Separation of enantiomers of compound 288.

Enantiomers 288A and 288B

238A G Enantiomer 2S8S

Connection 283

The racemic compound 3-(4-chlorophenyl)-4-[(4-chlorophenyl)methyl]-1-cyclopentylpiperazine-2,5dione (80 mg, 0.19 mmol, 1.0 eq.) was separated by chiral HPLC under the following conditions ( Column: CHIRAL ART Cellulose-SB, 2x25 cm, 5 µm; mobile phase A: Hex-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 ml/min; gradient: 30 V to 30 V over 10 min; 220/254 nm) to obtain 25.4 mg (first eluting peak) of enantiomer 288A and 32 mg (second eluting peak) of enantiomer 288B. Chiral analytical data (Column: CHIRAL Cellulose-SB; 0.46 cm x 15 cm; 5 microns; Hex (0.2% isopropylamine): EtOH=70:30 at 1 ml/min) illustrates that enantiomer 288A is the first eluting peak (RT 3.3 min) and enantiomer 288B represents the second eluting peak (RT 4.0 min).

Enantiomer 288A: HPMC (ES) m/z 391 (M+H).

1H NMR (300 MHz, DMSO) δ 7.44-7.34 (m, 2H), 7.39-7.22 (m, 4H), 7.27-7.13 (m, 2H), 4, 95 (s, 1H), 4.87 (d, J=15.1 Hz, 1H), 4.39 (g, J=6.8 Hz, 1H), 4.15 (d, J=17.7 Hz, 1H), 3.97 (d, J=17.8 Hz, 1H), 3.86 (d, J=15.1 Hz, 1H), 1.07 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.9 Hz, 3H).

Enantiomer 288B: HPMC (ES) m/z 391 (M+H).

1H NMR (300 MHz, DMSO- _d6 ) δ 7.44-7.33 (m, 2H), 7.36-7.22 (m, 4H), 7.22-7.13 (m, 2H) , 4.95 (s, 1H), 4.87 (d, J=15.1 Hz, 1H), 4.41 (p, J=6.8 Hz, 1H), 4.15 (d, J= 17.7 Hz, 1H), 3.97 (d, J=17.8 Hz, 1H), 3.86 (d, J=15.1 Hz, 1H), 1.07 (d, J=6, 8 Hz, 3H), 0.96 (d, J=6.9 Hz, 3H).

The following compounds were prepared by methods similar to those described for enantiomers 288A and 288B:

- 238 045362

Enantiomer No. HPLC RT (min) HPMS (ES) m/z HPLC separation conditions 293A 2.1 M+N-392 CHIRALPAK LA-3; 0.46 cm x 5 cm; 3 microns; Hex(0.1%OEA)GYN=50:50 at 1 ml/min 293V 2.5 M+H=392 297A 1.7 M+H=392 297V 2.3 M+H=392 629A 1.48 M+N-473 CHIRALPAK IE-3; 0.46 cm x 5 cm; 3 microns; Hex(0.1% DEA):EtOH=50:50 at 1 ml/min 629V 1.90 M+H =473

Example 2 Synthesis of Compound 20

2-1 Connection 20

To a solution of 5-(4-chlorobenzyl)-2-(4-fluorophenyl)-8-isopropyl-2,5,8-triazaspiro[3,5]nonane-6,9-dione (20.5 mg, 0.049 mmol, 1.0 eq.) in dry THF (2 ml) at -78°C, LHMDS (1 M in THF, 54 μl, 0.054 mmol, 1.1 eq.) was added. The mixture was stirred at -78°C for 2 min, MeI (2 M in ether, 30 µl, 0.059 mmol, 1.2 eq.) was added to the mixture, stirred at -78°C for 5 min, warmed slowly to room temperature. . pace. and diluted with water and EA. The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified by silica gel chromatography (40 g column, 0-60% EtOAc in hexanes) to give 9.9 mg (47%) 5-(4-chlorobenzyl)-2- (4-fluorophenyl)-8-isopropyl-7-methyl-2,5,8-triazaspiro[3.5]nonane-6,9dione as a white solid. HPMS (ES) m/z 430.1 (M+H).

1H NMR (methylene chloride-d ₂ , 400 MHz, ppm) δ 7.40-7.28 (m, 2H), 7.24-7.13 (m, 2H), 7.06-6.91 (m, 2H), 6.46-6.37 (m, 2H), 5.29 (d, J=16.2 Hz, 1H), 4.87 (d, J=16.3 Hz, 1H) , 4.72 (d, J=8.6 Hz, 1H), 4.44 (hept, J=6.8 Hz, 1H), 4.28-4.14 (m, 2H), 4.03 ( dd, J=9.8, 8.2 Hz, 2H), 1.49 (d, J=7.0 Hz, 3H), 1.33 (dd, J=6.9, 5.0 Hz, 6H ).

The following compound was prepared using methods similar to the method described for compound 20:

Compound No. HPMS (ES) m/z

329

Example 3. Synthesis of compound 65.

1. Synthesis of intermediate 3-2

M+H=412.1

To a solution of 1-(tert-butyl)-3-methyl-3-aminoazetidine-1,3-dicarboxylate (5.0 g, 21.7 mmol, 1.0 eq.) in MeOH (50 ml) was added 4-chlorobenzaldehyde (4.5 g, 32.6 mmol, 1.5 eq.). The mixture was stirred for 1 hour at room. pace. NaCNBH ₃ (1.4 g, 21.7 mmol, 1.0 eq.) and AcOH (1 ml) were added to this mixture. This mixture was continued to stir for 4 hours, concentrated under reduced pressure and diluted with DCM (60 ml) and saturated aqueous sodium hydrogen carbonate (60 ml). The aqueous layer was extracted with DCM (25 ml). The combined organic layers were dried over sodium sulfate, filtered through celite, concentrated under reduced pressure and purified by silica gel chromatography (80 g column, 0-100% EtOAc in hexanes) to give 6.0 g (78%) 1-(t-butyl )-3-methyl-3-((4chlorobenzyl)amino)azetidine-1,3-dicarboxylate. HPMS (ES) m/z 355.2 (M+H).

1H NMR (methylene chloride-0 ₂ , 400 MHz, ppm) δ 7.35 (s, 4H), 4.19 (d, J=8.8 Hz, 2H), 3.86 (d, J= 8.8 Hz, 2H), 3.82 (s, 3H), 3.68 (s, 2H), 1.46 (s, 9H).

- 239 045362

2. Synthesis of intermediate 3-3

To a solution of 1-(tert-butyl)-3-methyl-3-((4-chlorobenzyl)amino)azetidine-1,3-dicarboxylate (6.0 g, 16.9 mmol, 1.0 eq.) in DCM (50 ml), cooled to 0°C, TEA (7.1 ml, 50.7 mmol, 3.0 eq.) and chloroacetyl chloride (2.7 ml, 33.8 mmol, 2.0 eq.) were added. The ice bath was removed and the mixture was stirred for 3 hours at room temperature. pace. before pouring into saturated aqueous NH ₄ Cl (200 ml). The aqueous layer was extracted three times with DCM (100 ml). The combined organic layers were dried over MgSO ₄ and concentrated to give the intermediate, 1-(tert-butyl)-3-methyl-3-(2-chloro-N-(4chlorobenzyl)acetamido)azetidine-1,3-dicarboxylate. HPMC (ES) m/z 431.1 (M+H).

3. Synthesis of intermediate 3-4

3-3 3-4

To a solution of 1-(tert-butyl)-3-methyl-3-(2-chloro-N-(4-chlorobenzyl)acetamido)azetidine-1,3dicarboxylate (16.9 mmol, 1.0 eq., assuming a yield of 100 %) in ACN (300 ml) was added isopropylamine (2.9 ml, 33.9 mmol, 2.0 eq.) and TEA (7.1 ml, 50.8 mmol, 3.0 eq.). The mixture was heated to 80°C for 15 hours, concentrated and purified by chromatography on silica gel (80 g, 0-100% EtOAc in hexanes) to give 6.5 g (91%) tert-butyl-5-(4-chlorobenzyl) -8-isopropyl-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane2-carboxylate as a colored solid. HPMS (ES) m/z 366.1 (M+H-tBu).

4. Synthesis of intermediate 3-5

3-4 ³ ' ⁵

To a solution of tert-butyl 5-(4-chlorobenzyl)-8-isopropyl-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2carboxylate (6.5 g, 15.4 mmol, 1. 0 eq.) in DCM (40 ml) was added TFA (12 ml). The mixture was stirred for 1 hour at room. pace. concentrated, diluted with saturated aqueous NaHCO ₃ (200 ml) and extracted three times with DCM. The combined organic layers were dried over MgSO ₄ , concentrated and purified by silica gel chromatography (40 g column, 0-50% MeOH in DCM) to give 4.1 g (83%) 5(4-chlorobenzyl)-8-isopropyl-2, 5,8-triazaspiro[3.5]nonane-6,9-dione as a white solid with a metallic tint. HPMS (ES) m/z 322.1 (M+H).

1H NMR (dichloromethane-d ₂ , 400 MHz, ppm) δ 7.36-7.32 (m, 2H), 7.28-7.24 (m, 2H), 5.16 (s, 2H ), 4.85 (p, J=6.9 Hz, 1H), 4.30-4.19 (m, 4H), 4.00 (s, 2H), 1.24 (d, J=6, 8 Hz, 6H).

5. Synthesis of compound 65

3-5 85

To a solution of 5-(4-chlorobenzyl)-8-isopropyl-2,5,8-triazaspiro[3.5]nonane-6,9-dione (20 mg, 0.062 mmol, 1.0 eq.) in DCM (0.2 mL) DIEA (22 μL, 0.12 mmol, 2.0 eq.) and methyl isocyanate (5.0 mg, 0.093 mmol, 1.5 eq.) were added. The mixture was stirred for 15 hours at room. temp., concentrated, and purified by reverse phase HPLC (Phenomenex, dimer 5 micron C18 150x21.2 mm, gradient 10-70% acetonitrile in water with 0.1% formic acid over 25 min) to obtain 8.6 mg ( 37%) 5-(4-chlorobenzyl)8-isopropyl-N-methyl-6,9-dioxo-2,5,8-triazaspiro[3,5]nonane-2-carboxamide as white foam

- 240 045362 solids. HPMS (ES) m/z 379.1 (M+H).

^1H NMR (methanol^, 400 MHz, ppm) δ 7.39-7.34 (m, 2H), 7.32-7.27 (m, 2H), 4.98 (s, 2H) , 4.75 (hept, J=6.9 Hz, 1H), 4.41-4.37 (m, 2H), 4.08 (s, 2H), 4.07-4.04 (m, 2H ), 2.69 (s, 3H), 1.24 (d, J=6.8 Hz, 6H).

The following compounds were prepared by methods similar to those described for compound 65:

Connection No. HPMS (ES) m/z 64 M+N-380.1 66 M+H=445.2 67 M+N-413.1 68 M+N^ZEED 69 M+H=384.1 70 M+H=439.2

Example 4. Synthesis of compound 373.

1. Synthesis of intermediate 4-2

To a solution of 1-tert-butyl-3-methyl-3-aminopyrrolidine-1,3-dicarboxylate (1.9 g, 7.78 mmol, 1.0 eq.) in DCE (30 ml) at room. pace. 4-chlorobenzaldehyde (1.1 g, 7.83 mmol, 1.0 eq.) and acetic acid (934 mg, 15.55 mmol, 2.0 eq.) were added. The mixture was stirred for 10 minutes at room. pace. STAB (2.5 g, 11.80 mmol, 1.50 eq.) was added to this mixture in portions. The mixture was stirred for 1.5 hours, quenched with water (20 ml) and extracted twice with DCM (20 ml). The combined organic layers were washed with aqueous NaHCO ₃ (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by reverse phase HPLC under the following conditions: (column, silica gel C18; mobile phase, A : water (10 mmol/l NH4HCO3), B: ACN, 65% B to 75% B gradient over 20 min; detector, UV 210/254 nm) to give 2.2 g (77%) 1-tert- butyl 3-methyl-3-[[(4-chlorophenyl)methyl]amino]pyrrolidine-1,3-dicarboxylate as a brown oil. HPMS (ES) m/z 313 (M+H-56).

2. Synthesis of intermediate 4-3

To a solution of 1-tert-butyl-3-methyl-3-[[(4-chlorophenyl)methyl]amino]pyrrolidine-1,3-dicarboxylate (2.28 g, 6.18 mmol, 1.0 eq.) in DCM (30 ml) was cooled to 0°C and 2-chloroacetyl chloride (3.12 g, 27.62 mmol, 4.50 eq) and TEA (5.63 g, 55.64 mmol, 9.00 eq) were added. . The mixture was stirred overnight at room. temp., quenched with water (20 ml) and extracted twice with DCM (20 ml). The combined organic layers were washed twice with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2.9 g of 1-tert-butyl-3-methyl-3-[2-chloro-N-[(4chlorophenyl )methyl]acetamido]pyrrolidine-1,3-dicarboxylate as a brown oil. HPMS (ES) m/z 389 (M+H-56).

3. Synthesis of intermediate 4-4

To a solution of 1-tert-butyl-3-methyl-3-[2-chloro-N-[(4-chlorophenyl)methyl]acetamido]pyrrolidine-1,3dicarboxylate (2.9 g, 6.51 mmol, 1.0 eq.) in ACN (30 ml) at room. pace. propan-2-amine was added

- 241 045362 (1.9 g, 32.14 mmol, 5.00 eq.) and TEA (5.3 g, 8.00 eq.). The mixture was stirred for 1 hour at room temperature and then heated to 80°C overnight. The next day the mixture was cooled to room. temp, concentrated under reduced pressure, purified by reverse phase HPLC under the following conditions: column, silica gel C18; mobile phase, A: water (10 mmol/l NH ₄ HCO ₃ ), B: ACN, 20% B to 25% B gradient over 20 min; detector, UV 210/254 nm to obtain 2.4 g (85%) tert-butyl-6-[(4chlorophenyl)methyl]-7,10-dioxo-9-(propan-2-yl)-2,6, 9-triazaspiro[4.5]decane-2-carboxylate as a brown solid. HPMS (ES) m/z 380 (M+H-56).

4. Synthesis of intermediate 4-5 ^C1

G ™ g, ^N O ¹ HN^ A I

Vos

4-4 4-5

To a solution of tert-butyl-6-[(4-chlorophenyl)methyl]-7,10-dioxo-9-(propan-2-yl)-2,6,9triazaspiro[4.5]decane-2-carboxylate (2.4 g, 5.51 mmol, 1.0 eq.) in DCM (30 ml) at room. temp, TFA (8 ml) was added. The mixture was stirred for 1 hour at room. pace. The pH of the solution was adjusted to 9 with sodium hydroxide (6N, ~3 ml). The mixture was diluted with water and extracted twice with DCM (20 ml). The combined organic layers were washed twice with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.7 g (92%) 6-[(4chlorophenyl)methyl]-9-(propan-2-yl) -2,6,9-triazaspiro[4.5]decane-7,10-dione as a brown solid. HPMS (ES) m/z 336 (M+H).

5. Synthesis of compound 373

To a solution of 2-bromopyridine (200 mg 1.27 mmol, 1.0 eq.) in dioxane (5 ml) was added 6-[(4chlorophenyl)methyl]-9-(propan-2-yl)-2,6,9 -triazaspiro[4.5]decane-7,10-dione (94 mg, 0.28 mmol, 1.0 eq.), Pd ₂ (dba) ₃ CHCl ₃ (62 mg, 0.06 mmol, 0.10 eq. ), Xphos (57 mg, 0.12 mmol, 0.20 eq.) and Cs ₂ CO ₃ (389 mg, 1.19 mmol, 2.0 eq.) under nitrogen. The mixture was stirred at 90°C overnight, cooled to room temp. Filtered to remove solids and purified by preparative HPLC under the following conditions (2#-Analyse HPLC-8N1MAE2i(HPLC-10)): Column, XBridge Prep C18 OBD column, 5 µm, 19x150 mm; mobile phase, water (10 mmol/L NH ₄ HCO ₃ ) and ACN (39.0% ACN to 53.0% gradient over 8 min); detector, UV 254 nm to obtain 15 mg (6%) 6-[(4-chlorophenyl)methyl]-9-(propan-2-yl)-2(pyridin-2-yl)-2,6,9-triazaspiro [4.5]decane-7,10-dione as a white solid. HPMS (ES) m/z 413 (M+H).

Ή NMR (300 MHz, methanol-a ₄ , ppm): δ 8.01-7.93 (m, 1H), 7.50 (ddd, J=8.9, 7.2, 1.9 Hz, 1H), 7.287.19 (m, 2H), 7.10 (d, J=8.4 Hz, 2H), 6.61 (dd, J=6.9, 5.2 Hz, W), 6.41 (d, J=8.6 Hz, 1H), 4.76-4.54 (m, ZN), 4.16 (s, 2H), 3.97 (d, J=11.9 Hz , 1H), 3.75 (d, J=11.8 Hz, 1H), 3.66-3.42 (m, 2H), 2.62-2.38 (m, 2H), 1.20 ( dd, J=6.8, 1.4 Hz, 6H).

6. Separation of enantiomers of compound 373

Racemic compound 6-[(4-chlorophenyl)methyl]-9-(propan-2-yl)-2-(pyridin-2-yl)-2,6,9triazaspiro[4.5]decane-7,10-dione (80 mg, 0.19 mmol, 1.0 eq.) were separated by chiral HPLC under the following conditions (preparative HPLC-009): Column: Chiralpak IC, 2x25 cm, 5 µm; mobile phase A: Hex-HPLC, mobile phase B: EtOH-HPLC; flow rate: 15 ml/min; isocratic dilution for 21 min; 220/254 nm) yielding 28.7 mg (36%, first eluted peak) of enantiomer 373A and 29 mg

-242045362 (second eluting peak) of enantiomer 373B as white solids. Chiral analytical data (CHIRALPAK IC-3; 0.46 cm x 5 cm; 3 µm; Hex (0.1% DEA): EtOH=55:45 at 1 ml/min) illustrates that enantiomer 373A represents the first eluting peak (RT 2.2 min) and enantiomer 373B represents the second eluted peak (RT 3.2 min).

Enantiomer 373A: HPMC (ES) m/z 413 (M+H).

1H NMR (300 MHz, methanol-d ₄ , ppm) δ 7.97 (ddd, J=5.2, 1.9, 0.9 Hz, 1H), 7.50 (ddd, J=8 ,8, 7.1, 1.9 Hz, 1H), 7.28-7.18 (m, 2H), 7.10 (d, J=8.4 Hz, 2H), 6.61 (ddd, J=7.2, 5.1, 0.9 Hz, 1H), 6.41 (d, J=8.6 Hz, 1H), 4.86 (s, 1H), 4.76-4.54 (m, 2H). 4.15 (s, 2H), 3.97 (d, J=11.8 Hz, 1H), 3.75 (d, J=11.8 Hz, 1H), 3.66-3.42 (m , 2H), 2.62-2.38 (m, 2H), 1.20 (dd, J=6.8, 1.4 Hz, 6H).

Enantiomer 373B: HPMC (ES) m/z 413 (M+H).

1H NMR (300 MHz, methanol-th ₄ ) δ 8.01-7.93 (m, 1H), 7.50 (ddd, J=8.8, 7.2, 1.9 Hz, 1H), 7 ,28-7.18 (m, 2H), 7.10 (d, J=8.3 Hz, 2H), 6.61 (dd, J=6.9, 5.4 Hz, 1H), 6, 41 (d, J=8.5 Hz, 1H), 4.76-4.54 (m, 2H), 4.16 (s, 2H), 3.97 (d, J=11.8 Hz, 1H ), 3.75 (d, J=11.8 Hz, 1H), 3.66-3.42 (m, 2H), 2.62-2.38 (m, 2H), 1.20 (dd, J=6.9, 1.4 Hz, 6H).

The following compounds were prepared by methods similar to those described for compound 373:

HPLC separation conditions

Symbol HPLC CONDITIONS A Regenerated Chiral ΙΑ; 0.46 cm x 10 cm; 5 microns ;Hex:EUN=50:50 at 1 ml/min IN Regenerated IA; 0.46 cm x 10 cm; 5 microns; (Hex:DCM=3:1)(0.1% DEA):EtOH=50:50 at 1 ml/min WITH CHIRALPAK IA-3; 0.46 cm x 5 cm; 3 microns; Hex(0.1% DEA):EtOH=50:50 at 1 ml/min D CHIRALPAK IC-3; 0.46 cm x 5 cm; 3 micro; Hex(0.1% DEA):EtOH=55:45 at 1 ml/min E CHIRALPAK IC-3; 0.46 cm x 5 cm; 3 microns; Hex(0.1% DEA):EtOH=50:50 at 1 ml/min F CHIRALPAK IC-3; 0.46 cm x 5 cm; 3 micro; Hex(0.1% DEA):EtOH=70:30 at 1 ml/min G CHIRALART Cellulose-SB; 0.46 cm x 10 cm; 3 microns; Hex (0.1% DEA):E1OH = 50:50 at 1 ml/min N CHIRALPAK IE-3: 0.46 cm x 10 cm; 3 microns; (Hex:flXM=3:1)(0.1%DEA):EtOH=50:50 at 1 ml/min

Enantiomer No. HPMS (ES) m/z Retention time (min) HPLC separation conditions 375A M+H=412 3.4 A 375V M+H=412 4.1 377A M+H=427 2.9 D 377V M+H=427 3.7 351A M+H=414 3.0 WITH 351B M+H=414 4.9 353A M+H=414 3.8 WITH 353B M+H=414 5.0 355A M+H=427 2.0 E 355V M+H=427 4.0 357A M+H=431 1.7 D 357V M+H=431 2.3 359A M+H=414 2.6 WITH 359V M+H=414 3.9 361A M+H=443 3.8 IN 361B M+H=443 5.5 363A M+H=429 2.6 WITH

- 243 045362

363V M+H=429 3.6 365A M+H=416 2.4 IN 365V M+H=416 3.8 379A M+H=393 2.4 E 379V M+N-393 2.9 381A M+H=407 2.1 E 381B M+H=407 2.5 383A M+H=421 3.0 F 383V M+H=421 3.6 369A M+H=419 2.7 D 369V M+H=419 3.4 371A M+H=455 2.8 G 371B M+H=455 3.7 385A M+H=456 1.6 E 385V M+H=456 3.1 387A M+H=437 3.3 N 387V M+H=437 4.8

Example 5. Synthesis of compound 108.

1. Synthesis of intermediate 5-2

4-(Trifluoromethyl)benzaldehyde ( 5.6 g, 31.9 mmol, 1.05 eq.). The mixture was stirred for 1 hour at room. temp., NaCNBH ₃ (2.9 g, 45.6 mmol, 1.5 eq.) and AcOH (0.5 ml) were added and stirred for 2 hours. A mixture containing 1-(tert-butoxycarbonyl)-3 -((4(trifluoromethyl)benzyl)amino)pyrrolidine-3-carboxylic acid was used directly in the next step. HPMS (ES) m/z 389.2 (M+H).

2. Synthesis of intermediate 5-3

DCM ( 100 ml) and (trimethylsilyl)diazomethane (2 M in hexanes, 45.6 ml,

91.1 mmol, 3.0 eq.). The mixture was stirred for 3 hours at room. temp., add AcOH (5.0 g), concentrate on silica gel (30 g) and purify by chromatography on silica gel (120 g, 0-100% EtOAc in hexanes) to give 7.4 g (61% per step) 1- (tert-butyl)-3-methyl-3-((4(trifluoromethyl)benzyl)amino)pyrrolidine-1,3-dicarboxylate as a white solid. HPMS (ES) m/z 403.2 (M+H).

3. Synthesis of intermediate 5-4

To a solution of 1-(tert-butyl)-3-methyl-3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-1,3dicarboxylate (7.4 g, 18.4 mmol, 1.0 eq.) in DCM (50 ml), cooled to 0°C, added TEA (7.7

- 244 045362 ml, 84.9 mmol, 3.0 eq.) and chloroacetyl chloride (2.9 ml, 36.8 mmol, 2.0 eq.). The ice bath was removed and the mixture was stirred for 3 hours at room temperature. pace. before pouring into saturated aqueous NH ₄ Cl (200 ml). The aqueous layer was extracted three times with DCM (100 ml). The combined organic layers were dried over MgSO ₄ and concentrated to give the intermediate, 1-(tert-butyl)-3-methyl3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)pyrrolidine-1,3-dicarboxylate . HPMS (ES) m/z 379.1 (M+H-Boc).

4. Synthesis of intermediate 5-5

To a solution of 1-(tert-butyl)-3-methyl-3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)pyrrolidine 1,3-dicarboxylate (18.4 mmol, 1.0 eq., assuming 100% yield, isopropylamine (4.7 mL, 55.1 mmol, 3.0 eq) and TEA (7.7 mL, 55.1 mmol, 3.0 eq) were added to ACN (300 mL). The mixture was heated at 80°C for 15 hours, concentrated and purified by chromatography on silica gel (80 g, 0-100% EtOAc in hexanes) to obtain a mixture of intermediates containing tert-butyl-9-isopropyl-7,10-dioxo6- (4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-2-carboxylate. HPMS (ES) m/z 414.2 (M+HtBu).

5. Synthesis of intermediate 5-6

solution of tert-butyl-9-isopropyl-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9 triazaspiro[4.5]decane-2-carbokeylate (18.4 mmol, 1.0 equiv .) TFA (20 ml) was added to DCM (40 ml). The mixture was stirred for 1 hour at room. pace. concentrated, diluted with saturated aqueous NaHCO ₃ (200 ml) and extracted three times with DCM. The combined organic layers were dried over MgSO ₄ , filtered, concentrated and purified by silica gel chromatography (40 g column, 0-50% MeOH in DCM with 1% TEA) to give 2.8 g (41% in 3 steps) 9-isopropyl- 6-(4-(trifluoromethyl)benzyl)-2,6,9triazaspiro[4.5]decane-7,10-dione as a solid. HPMS (ES) m/z 370.2 (M+H).

1H NMR (dichloromethane-d ₂ , 400 MHz, ppm) δ 7.65-7.60 (m, 2H), 7.39-7.33 (m, 2H), 4.93-4.65 (m, 3H), 4.02 (s, 2H), 3.46-3.40 (m, 1H), 3.16 (ddd, J=11.3, 8.2, 5.3 Hz, 1H ), 3.00 (dd, J=11.3, 8.1, 6.7 Hz, 1H), 2.92 (d, J=12.1 Hz, 1H), 2.45 (dd, J= 13.6, 8.3, 6.7 Hz, 1H), 1.98 (ddd, J=13.5, 8.0, 5.2 Hz, 1H), 1.23 (d, J=6, 8 Hz, 6H).

6. Synthesis of compound 108

To a solution of 9-isopropyl-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-7,10-dione (50 mg, 0.14 mmol, 1.0 eq.) in DCM (2 ml) was added with TEA (27 mg, 0.27 mmol, 2.0 eq.) and methyl isocyanate (15 mg, 0.27 mmol, 2.0 eq.). The mixture was stirred for 30 minutes at room. temp., concentrated and purified by reverse phase HPLC (Phenomenex, dimer 5 micron C18 150x21.2 mm, gradient 10-100% acetonitrile in water with 0.1% formic acid over 40 min) to obtain 49 mg (85% ) 9-isopropylN-methyl-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-2-carboxamide as a white foamy solid. HPMS (ES) m/z 327.2 (M+H).

1H NMR (methanol- _d4 , 400 MHz, ppm) δ 7.67-7.62 (m, 2H), 7.43-7.36 (m, 2H), 4.95 (d, J =17.0 Hz, 1H), 4.79-4.65 (m, 2H), 4.18 (d, J=2.1 Hz, 2H), 3.95 (d, J=11.7 Hz , 1H), 3.59 (d, J=11.7 Hz, 1H), 3.52-3.43 (m, 2H), 2.69 (s, 3H), 2.49-2.33 ( m, 2H), 1.24 (dd, J=6.8, 1.3 Hz, 6H).

The following compounds were prepared by methods similar to those described for compound 108:

- 245 045362

Connection No. HPMS (ES) m/z 107 M+H=413.2 109 M+H=489.2 1 M+H=467.2 110 M+H=428.2 111 M+H=490.2 112 M+H=469.2 113 M+H=490.2 114 M+H=493.2 115 M+H=507.2 116 M+H=441.2 117 M+H=455.2 118 M+H=453.2 119 M+H=407 120 M+H=379 121 M+H=393 122 M+H=419 123 M+H=455

Example 6. Synthesis of compound 76.

1. Synthesis of intermediate 6-2

4-(Trifluoromethyl)benzaldehyde ( 5.6 g, 31.9 mmol, 1.05 eq.), and the mixture was stirred for 1 hour at room temperature. pace. NaCNBH ₃ (2.9 g, 45.6 mmol, 1.5 eq.) and AcOH (0.5 ml) were added to this mixture. The mixture was stirred for 2 hours at room. pace. to obtain a solution containing 1 -(tert-butoxycarbonyl)-3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-3-carboxylic acid, which was used for the next reaction without treatment. HPMS (ES) m/z 389.2 (M+H).

2. Synthesis of intermediate 6-3

To the solution containing 1-(tert-butoxycarbonyl)-3-((4(trifluoromethyl)benzyl)amino)pyrrolidine-3-carboxylic acid (30.4 mmol, 1.0 eq.) from the previous step was added DCM (100 ml ) and (trimethylsilyl)diazomethane (2 M in hexanes, 45.6 mL, 91.1 mmol, 3.0 eq). The mixture was stirred for 3 hours at room. temp., quenched AcOH (5 g), concentrated on 30 g SiO ₂ and purified by chromatography on silica gel (120 g, 0-100% EtOAc in hexanes) to obtain 7.4 g (61% in 2 steps) 1-(tert -butyl)-3-methyl-3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-1,3-dicarboxylate

as a white solid. HPMS (ES) m/z 403.15 (M+H). 3. Synthesis of intermediate 6-4 p "X C NK TEA. DH^ Ί /A o.. Zch /'CH V'r Vos' Vos az R §4

- 246 045362

To a solution of 1-(tert-butyl)-3-methyl-3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-1,3dicarboxylate (7.4 g, 18.4 mmol, 1.0 eq.) in With DCM (50 mL) at 0°C, TEA (7.7 mL, 84.9 mmol, 3.0 eq.) and chloroacetyl chloride (2.9 mL, 36.8 mmol, 2.0 eq.) were added. The ice bath was removed and the mixture was stirred for 3 hours at room temperature. pace. The reaction mixture was poured into saturated aqueous NH ₄ Cl (200 ml) and the layers were separated. The aqueous layer was extracted three times with DCM (100 ml). The combined organic layers were dried over MgSO ₄ and concentrated to give the intermediate, 1-(tert-butyl)-3-methyl-3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetαamido)pyrrolidine-1,3-dicarboxylate . HPMS (ES) m/z 379.1 (M+H-Boc).

4. Synthesis of intermediate 6-5

S-4 U

To a solution of 1-(tert-butyl)-3-methyl-3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)pyrrolidine 1,3-dicarboxylate (18.4 mmol, 1.0 eq., assuming 100% yield, isopropylamine (4.7 mL, 55.1 mmol, 3.0 eq) and TEA (7.7 mL, 55.1 mmol, 3.0 eq) were added to ACN (300 mL). The mixture was heated at 80°C for 15 h, concentrated and purified by chromatography on silica gel (80 g, 0-100% EtOAc in hexanes) to give the intermediate, tert-butyl-9-isopropyl-7,10-dioxo-6- (4(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-2-carboxylate as a colored solid. HPMS (ES) m/z 414.15 (M+H-tBu).

5. Synthesis of intermediate 6-6

S-S

To a solution of tert-butyl-9-isopropyl-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9triazaspiro[4.5]decane-2-carboxylate (18.4 mmol, 1.0 eq. .) from the previous step TFA (20 ml) was added to DCM (40 ml). The mixture was stirred for 1 hour at room. temp., concentrated, diluted with saturated NaHCO3 (200 ml) and extracted three times with DCM. The combined organic layers were dried over MgSO ₄ , filtered, concentrated and purified by silica gel chromatography (40 g column, 0-50% MeOH in DCM with 1% TEA) to give 2.8 g (41% in 3 steps) 9-isopropyl- 6-(4(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-7,10-dione as a dark sticky solid. HPMS (ES) m/z 370.2 (M+H).

1H NMR (dichloromethane-d2, 400 MHz, ppm) δ 7.65-7.60 (m, 2H), 7.39-7.33 (m, 2H), 4.93-4.65 ( m, 3H), 4.02 (s, 2H), 3.46-3.40 (m, 1H), 3.16 (ddd, J=11.3, 8.2, 5.3 Hz, 1H) , 3.00 (dd, J=11.3, 8.1, 6.7 Hz, 1H), 2.92 (d, J=12.1 Hz, 1H), 2.45 (dd, J=13 ,6, 8.3, 6.7 Hz, 1H), 1.98 (ddd, J=13.5, 8.0, 5.2 Hz, 1H), 1.23 (d, J=6.8 Hz, 6H).

6. Synthesis of compound 76

To a mixture of 9-isopropyl-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-7,10-dione (50 mg, 0.14 mmol, 1.0 eq.), Potassium tert-butoxide (61 mg, 0.54 mmol, 4.0 eq.), Pd ₂ (dba) ₃ (12 mg, 0.014 mmol, 0.1 eq.) and xantphos (16 mg, 0.027 mmol, 0.0 eq.) 2 eq.) were combined in a 5 ml microwave vessel (5 ml) 4-bromopyrudin-2(1H)-one (47 mg, 0.27 mmol, 2.0 eq.) and dioxane (2 ml) were added. The mixture was sealed and heated at 150°C in a microwave reactor for 30 min, filtered and purified by reverse phase HPLC (Phenomenex, dimeric 5 μm C18 150x21.2 mm, gradient 10-100% acetonitrile in water with 0.1% formic acid in for 40 min) to obtain 4.8 mg (8%) 9-isopropyl-2-(2-oxo-1,2dihydropyridin-4-yl)-6-(4-(trifluoromethyl)benzyl)-2,6,9 -triazaspiro[4.5]decane-7,10-dione as a foamy solid. HPMS (ES) m/z 463.2 (M+H).

1H NMR (methanol-d4, 400 MHz, ppm) δ 8.18 (s, 1H), 7.62 (d, J=8.1 Hz, 2H), 7.41-7.36 (m , 2H), 7.20 (d,

- 247 045362

J=7.4 Hz, 1H), 5.88 (dd, J=7.4, 2.4 Hz, 1H), 5.30 (d, J=2.4 Hz, 1H), 4.99 ( d, J=16.9 Hz, 1H), 4.79-4.68 (m, 2H), 4.23 (d, J=2.0 Hz, 2H), 3.88 (d, J=11 .8 Hz, 1H), 3.66 (d, J=11.7 Hz, 1H), 3.57-3.49 (m, 2H), 2.67-2.46 (m, 2H), 1 .26 (d, J=6.8 Hz, 6H).

The following compounds were prepared by methods similar to those described for compound 76:

Connection No. HPMS (ES) m/z 127 M+H=412 128 M+H=413 129 M+N-427 71 M+H=414 72 M+H=461.2 73 M+H=448.2 74 M+H=414 75 M+H=427 92 M+H=431 77 M+H=475.2 78 M+H=416 79 M+H=414 80 M+H=443 81 M+H=429 82 M+H=399.1 83 M+H=439.2 84 M+H=427.2 85 M+H=425.2 86 M+H=443.2 93 M+H=441.2 94 M+H=441.1 87 M+H=443.2 95 M+H=438.2 96 M+H=438.2 97 M+H=456.1 98 M+H=456.2 88 M+H=472.2 89 M+H=490.2 90 M+H=472.1 91 M+H=490.1

Example 7. Synthesis of compound 49.

1. Synthesis of intermediate 7-2

C.I.

To a solution of 1-(tert-butyl)-3-methyl-3-aminoazetidine-1,3-dicarboxylate (5.0 g, 21.7 mmol, 1.0 eq.) in MeOH (50 ml) was added 4-chlorobenzaldehyde (4.5 g, 32.6 mmol, 1.5 eq.). The mixture was stirred for 1 hour at room. pace. NaCNBH ₃ (1.4 g, 21.7 mmol, 1.0 eq.) and AcOH (1 ml) were added to this mixture. The mixture was continued to stir for 4 hours, concentrated under reduced pressure and partitioned between DCM (60 ml) and saturated sodium hydrogen carbonate solution (60 ml). The layers were separated and the aqueous phase was extracted with DCM (25 ml). The combined organic layers were dried over sodium sulfate, filtered through celite, concentrated under reduced pressure and purified by silica gel chromatography (80 g column, 0-100% EA Ac in hexanes) to give 6.0 g (78%) 1-(tert- butyl)3-methyl-3-((4-chlorobenzyl)amino)azetidine-1,3-dicarboxylate. HPMS (ES) m/z 355.2 (M+H).

NMR (methylene chloride-(1 ₂ , 400 MHz, ppm) δ 7.35 (s, 4H), 4.19 (d, J=8.8 Hz, 2H), 3.86 (d, J =8.8 Hz,

-248 045362

2H), 3.82 (s, 3H), 3.68 (s, 2H), 1.46 (s, 9H).

2. Synthesis of intermediate 7-3

7-2 7-3

To a solution of 1-(tert-butyl)-3-methyl-3-((4-chlorobenzyl)amino)azetidine-1,3-dicarboxylate (6.0 g, 16.9 mmol, 1.0 eq.) in DCM (50 ml), cooled to 0°C. TEA (7.1 mL, 50.7 mmol, 3.0 eq.) and chloroacetyl chloride (2.7 mL, 33.8 mmol, 2.0 eq.) were added. The mixture was stirred for 3 hours at room. temp, and poured into a saturated aqueous solution of NH ₄ C1 (200 ml). The aqueous layer was extracted three times with DCM (100 ml). The combined organic layers were dried over MgSO ₄ and concentrated to give the intermediate, 1-(tert-butyl)-3-methyl-3-(2-chloro-X-(4-chlorobenzyl)acetamido)azetidine-1,3-dicarboxylate. HPMS (ES) m/z 431.1 (M+H).

3. Synthesis of intermediate 7-4

To a solution of 1-(tert-butyl)-3-methyl-3-(2-chloro-X-(4-chlorobenzyl)acetamido)azetidine-1,3dicarboxylate (16.9 mmol, 1.0 eq.) in ACN ( 300 ml) isopropylamine (2.9 ml, 33.9 mmol, 2.0 eq) and TEA (7.1 ml, 50.8 mmol, 3.0 eq) were added. The mixture was heated at 80°C for 15 hours, cooled to room temperature, concentrated and purified by chromatography on silica gel (80 g, 0-100% EtOAc in hexanes) to give 6.5 g (91%) tert-butyl- 5-(4-chlorobenzyl)-8-isopropyl-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane2-carboxylate as a colored solid. HPMS (ES) m/z 366.1 (M+H- ^l Bu).

4. Synthesis of intermediate 7-5

To a solution of tert-butyl 5-(4-chlorobenzyl)-8-isopropyl-6.9-dioxo-2,5,8-triazaspiro[3.5]nonane-2carboxylate (6.5 g, 15.4 mmol, 1.0 equiv .) TFA (12 ml) was added to DCM (40 ml). The mixture was stirred for 1 hour at room temperature, concentrated, diluted with saturated NaHCO ₃ (200 ml) and extracted three times with DCM. The combined organic washes were dried over MgSO ₄ , filtered, concentrated and purified by silica gel chromatography (40 g column, 0-50% MeOH in DCM) to give 4.1 g (83%) 5-(4-chlorobenzyl)-8-isopropyl -2,5,8-triazaspiro[3.5]nonane-6,9-dione as a white solid with a metallic tint. HPMS (ES) m/z 322.1 (M+H).

*H NMR (dichloromethane-b ₂ , 400 MHz, ppm) δ 7.36-7.32 (m, 2H), 7.28-7.24 (m, 2H), 5.16 (s, 2H), 4.85 (p, J=6.9 Hz, 1H), 4.30-4.19 (m, 4H), 4.00 (s, 2H), 1.24 (d, J=6 ,8 Hz, 6H).

5. Synthesis of compound 49

Compound 49

To a mixture of 5-(4-chlorobenzyl)-8-isopropyl-2,5,8-triazaspiro[3.5]nonane-6,9-dione (50 mg, 0.16 mmol, 1.0 eq.), tert-butoxide potassium (70 mg, 0.62 mmol, 4.0 eq.), Pd ₂ (dba) ₃ (7 mg, 0.008 mmol, 0.05 eq.) and xantphos (9 mg, 0.016 mmol, 0.1 eq. ), combined in a microwave vessel (5 ml), 4-bromo2,6-dimethylpyridine (58 mg, 0.31 mmol, 2.0 eq.) and dioxane (2 ml) were added. The mixture was hermetically sealed and heated

-249045362 soaked at 150°C in a microwave reactor for 10 min, filtered, and purified by reverse phase HPLC (Phenomenex, dimeric 5 μm C18 150x21.2 mm, gradient 10-100% acetonitrile in water with 0.1% formic acid for 40 min) to give 7.1 mg (10%) 5-(4-chlorobenzyl)-2-(2,6dimethylpyridin-4-yl)-8-isopropyl-2,5,8-triazaspiro[3.5]nonane -6,9-dione as a white foamy solid. HPMS (ES) m/z 427.15 (M+H).

1H NMR (methylene chloride-a ₂ , 400 MHz, ppm) δ 7.42-7.33 (m, 2H), 7.24-7.17 (m, 2H), 6.07 (s, 2H ), 4.95 (s, 2H), 4.84 (p, J=6.9 Hz, 1H), 4.62 (dd, J=9.5, 1.1 Hz, 2H), 4.25 (dd, J=9.5, 1.1 Hz, 2H), 4.06 (s, 2H), 2.57 (s, 6H), 1.25 (d, J=6.8 Hz, 6H) .

The following compounds were prepared by methods similar to those described for compound 49:

Connection No. HPMS (ES) m/z 2 M+N-398 3 M+HM16 4 M+H=432 5 M+N-432 6 M+N-399.1 7 M+H=399 8 M+H=399 9 M+H=413 10 M+H=413 eleven M+H=400 12 M+H=400 13 M+H=413.1 14 M+H=413.1 15 M+H=413.1 16 M+H=413 17 M+H=417 18 M+H=417 19 M+H=400 21 M+H=402.2 22 M+H=405.1 23 M+H=400 24 M+H=400 25 M+H=400 26 M+H=402.2 27 M+H=424.1 28 M+H=415.1 29 M+H=449.1 thirty M+H=393.2 31 M+H=447.2 32 M+H=405.1 33 M+H=405.1 34 M+H=439.1 35 M+H=457.2 36 M+H=443.1 37 M+H=442.1 38 M+H=456.2 39 M+H=473.1 40 M+H=448.1 41 M+H=388.1 42 M+H=429.3 43 M+H=419.1 44 M+H=419.1 45 M+H=404.1 46 M+H=433.2 47 M+H=461.1 48 M+N-449.1

- 250 045362

50 M+H=434.1 51 M+H=430.2 52 M+H=416.1 53 M+H=468.1 54 M+H=443.1 55 M+H=414.2 56 M+H=434.1 57 M+H=444.1 58 M+H=484.2 59 M+H=472.2 60 M+H=434.1 61 M+H=434.1 62 M+H=498.2 63 M+H=424.2

Example 8. Synthesis of compound 142.

1. Synthesis of intermediate 8-2 hedgehog

A mixture of azetin-3-ol hydrochloride (1.3 g, 11.9 mmol, 1.0 eq.), E(-)-proline (0.55 g, 4.8 mmol, 0.4 eq.), iodide copper(1) (0.45 g, 2.4 mmol, 0.2 eq.) and cesium carbonate (9.7 g, 29.7 mmol, 2.5 eq.) were combined in a septum flask, evacuated and purged nitrogen 3 times. Iodobenzene (2.0 ml, 18 mmol, 1.5 eq) and dry DMSO (30 ml) were added to this container. The mixture was heated at 90°C for 15 h, diluted with water and extracted three times with EA. The combined organic layers were dried over magnesium sulfate, filtered, evaporated and purified by silica gel chromatography (40 g, 60 5 μm, 00% ethyl acetate in hexanes gradient over 14 min) to give 1.6 g (90%) 1-phenylazetidine- 3-ol in the form of a clear, colorless oil. HPMS (ES) m/z 150 (M+H).

A NMR (400 MHz, methylene chloride-ph) δ 7.27-7.20 (m, 2H), 6.81-6.74 (m, 1H), 6.55-6.49 (m, 2H), 4.80

4.72 (m, 1H), 4.23-4.16 (m, 2H), 3.71-3.65 (m, 2H).

2. Synthesis of intermediate 8-3 he

S3 №0 TEA

To a solution of oxalyl chloride (1.5 mL, 17 mmol, 1.7 eq.) in dry DCM (15 mL) was added DMSO (2.4 mL, 34 mmol, 3.3 eq.) dropwise at -78°C. The mixture was stirred for 10 min at -78°C followed by the addition of 1-phenylazetidin-3-ol (1.5 g, 10.3 mmol, 1.0 eq.) in dry DCM (15 ml) dropwise and stirred for 1 hour. TEA (10.0 mL, 71.9 mmol, 7.0 eq.) was added to this mixture at -78°C. The mixture was continued to stir for 1 hour at -78°C, diluted with saturated sodium hydrogen carbonate solution and extracted three times with DCM. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, evaporated and purified by chromatography on silica gel (40 g, 60 μm, 0-10% ethyl acetate in hexanes, gradient over 28 min) to give 0.96 g (63% ) 1-phenylazetidin-3-one as a clear yellow oil. HPMS (ES) m/z 148 (M+H).

'n NMR (400 MHz, methylene chloride-a ₂ ) δ 7.36-7.29 (m, 2H), 6.92-6.87 (m, 1H), 6.69-6.63 (m, 2H ), 4.70 (s, 4H).

3. Synthesis of intermediate 8-4

1. (1S)-1-[4-(trifluoromethyl)phenyl]ethan-1-amine, MeOH

2. Acetic acid, NaCN

8-3

1-Phenylazetidin-3-one (0.31 g, 2.1 mmol, 1.0 eq.) and (18)-1-[4-(trifluoromethyl)phenyl]ethan-1-amine (0.44 g, 2.3 mmol, 1.1 eq) were combined in dry MeOH (3 ml) and the mixture was heated at 60°C for 1 hour.

-251 045362

To this mixture, cooled to 0°C, acetic acid (0.13 ml, 2.3 mmol, 1.1 eq.) and sodium cyanide (0.11 g, 2.3 mmol, 1.1 eq.) were successively added. ). The mixture was heated at 60°C for 15 hours, diluted with water and extracted three times with EA. The combined organic washes were dried over magnesium sulfate, filtered, evaporated and purified by chromatography on silica gel (12 g, 60 μm, 020% ethyl acetate in hexanes, gradient over 22 min) to give 0.46 g (62%) (S)-1 -phenyl-3-((1-(4(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carbonitrile in the form of a clear, colorless oil. HPMS (ES) m/z 346 (M+H).

'n NMR (400 MHz, methylene chloride-ph) δ 7.69-7.65 (m, 2H), 7.64-7.59 (m, 2H), 7.26-7.19 (m, 2H) , 6.856.79 (m, 1H), 6.42-6.38 (m, 2H), 4.38-4.35 (m, 1H), 4.26 (k, J=6.6 Hz, 1H ), 3.92-3.88 (m, 1H), 3.83-3.79 (m, 1H), 3.38-3.34 (m, 1H), 1.48 (d, J=6 ,6 Hz, ZN).

4. Synthesis of intermediate 8-5

8-4 8-5

To a solution of (S)-l-phenyl-3-((G(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carbonitrile (0.20 g, 0.58 mmol, 1.0 eq.) in dry MeOH (2 ml) was added aqueous sodium hydroxide (1N, 1.2 ml, 1.2 mmol, 2.0 eq.). The mixture was heated at 100°C for 15 h, cooled to room temperature, neutralized with HC1 (1 M, 1.2 ml, 1.2 mmol, 2.0 eq.) and extracted twice with EA. The combined organic washes were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 89 mg (42%) (S)-l-phenyl-3-((G(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3 -carboxylic acid as a pale yellow solid.

5. Synthesis of intermediate 8-6

8-5 8-6

To a solution of (S)-l-phenyl-3-((G(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carboxylic acid (89 mg, 0.24 mmol, 1.0 eq.) in a mixture DCM (1 ml) and methanol (1 ml) were added dropwise with (trimethylsilyl)diazomethane in hexanes (2 M, 0.37 ml, 0.74 mmol, 3.0 eq.). The mixture was stirred at room. temp. over 2 hours, concentrated and purified by silica gel chromatography (12 g, 60 microns, 0-30% ethyl acetate in hexanes, gradient over 22 minutes) to give 79 mg (86%) methyl-(8)-1- phenyl 3-((1-(4(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carboxylate as a clear, colorless oil. HPMS (ES) m/z 379 (M+H).

6. Synthesis of intermediate 8-7

To a solution of methyl (8)-1-phenyl-3-((1 -(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carboxylate (79 mg, 0.21 mmol, 1.0 eq.) in DCM (1 ml), TEA (0.18 ml, 1.2 mmol, 6.0 eq.) and chloroacetyl chloride (0.067 ml, 0.84 mmol, 4.0 eq.) were added dropwise. The mixture was stirred for 30 minutes at room temperature, diluted with saturated sodium hydrogen carbonate solution and extracted with DCM. The organic layer was dried over magnesium sulfate, filtered and concentrated to obtain 140 mg of methyl (8)-3-(2chloro-K-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamido)-1-phenylazetidine-3-carboxylate in the form of red oil. HPMS (ES) m/z 455 (M+H).

-252 045362

7. Synthesis of compound 142

To a solution of methyl (8)-3-(2-chloro-M-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamido)-1-phenylazetidine-3carboxylate (0.21 mmol, 1.0 eq.) in dry ACN (7.5 mL), triethylamine (0.13 mL, 0.94 mmol, 4.5 eq.) and isopropylamine (0.053 mL, 0.62 mmol, 3.0 eq.) were added. The mixture was heated at 80°C for 15 h, concentrated and purified by reverse phase HPLC (Phenomenex, dimeric 5 µm C18 150x21.2 mm, gradient 10-100% acetonitrile in water with 0.1% formic acid for 25 min) yielding 19 mg (20% in 2 steps) (8)-8-isopropyl-2-phenyl-5-(1-(4-(trifluoromethyl)phenyl)ethyl)-2,5,8triazaspiro[3.5]nonane-6 ,9-dione. HPMS (ES) m/z 446 (M+H).

Ή NMR (400 MHz, methanol-b ₄ ) δ 7.67-7.62 (m, 2H), 7.60-7.55 (m, 2H), 7.22-7.16 (m, 2H) , 6.79-6.73 (m, 1H), 6.49-6.44 (m, 2H), 5.74-5.65 (m, 1H), 4.73 (hept, >6.8 Hz, 1H), 4.46-4.41 (m, 1H), 4.37-4.32 (m, 1H), 4.274.21 (m, 1H), 4.13-4.09 (m, 1H), 4.07-3.96 (m, 2H), 2.01 (d, >7.0 Hz, ZN), 1.23 (d, >6.8 Hz, 6H).

The following compounds were prepared by methods similar to those described for compound 142:

Connection No. HPMS (ES) m/z 138 M+H=447.2 139 M+H=427.2 140 M+H=446.2 141 M+H=446.2

Example 9. Synthesis of compound 327.

1. Synthesis of intermediate 9-2

9-1 9-2

To a solution of 1-phenyl-2-oxo-3-pyrrolidinecarboxylic acid (0.95 g, 4.6 mmol, 1.0 eq.) in a mixture of DCM (10 ml) and MeOH (10 ml), cooled to 0°C , (trimethylsilyl)diazomethane in hexanes (2 M, 7.0 mL, 14 mmol, 3.0 eq.) was added dropwise. The mixture was stirred for 30 min at room temperature, concentrated and purified by chromatography on silica gel (24 g, 0-10% ethyl acetate in hexanes, gradient over 11.5 min) to give 1.02 g (100%) methyl- 2-oxo-1-phenylpyrrolidine-3-carboxylate as a white solid. HPMS (ES) m/z 220 (M+H).

A NMR (400 MHz, methylene chloride-a ₂ ) δ 7.66-7.61 (m, 2H), 7.45-7.38 (m, 2H), 7.25-7.19 (m, 1H) , 4.023.95 (m, 1H), 3.91-3.84 (m, 1H), 3.81 (s, ZN), 3.68-3.63 (m, 1H), 2.59-2 .50 (m, 1H), 2.48-2.38 (m, 1H).

2. Synthesis of intermediate 9-3

9-2 9-3

To a mixture of methyl 2-oxo-1-phenylpyrrolidine-3-carboxylate (0.30 g, 1.4 mmol, 1.0 eq.) and ytterbium(III) trifluoromethanesulfonate (0.255 g, 0.41 mmol, 0.30 eq.) in EA (9 ml) was added NBS (0.244 g, 1.4 mmol, 1.0 eq.). The mixture was stirred for 30 minutes at room temperature, concentrated and purified by chromatography on silica gel (24 g, 0-30% ethyl acetate in hexanes, gradient over 11.5 minutes) to obtain 408 mg (100%) 3-bromo- 2-oxo-1-phenylpyrrolidine-3-carboxylate as a white solid. HPMS (ES) m/z 298 (M+H).

A NMR (400 MHz, methylene chloride-a ₂ ) δ 7.68-7.62 (m, 2H), 7.48-7.42 (m, 2H), 7.30-7.24 (m, 1H) , 4.043.97 (m, 1H), 3.94-3.88 (m, 4H), 3.19-3.10 (m, 1H), 2.72-2.64 (m, 1H).

-253 045362

3. Synthesis of intermediate 9-4

9-3 9-4

To a solution of 3-bromo-2-oxo-1-phenylpyrrolidine-3-carboxylate (0.113 g, 0.38 mmol, 1.0 eq.) in DMF (1 ml) was added TEA (0.21 ml, 1.5 mmol , 4.0 eq.) and 4-(trifluoromethyl)benzylamine (0.11 ml, 0.76 mmol, 2.0 eq.). The mixture was stirred for 15 minutes at room temperature, heated at 50°C for 1 hour, diluted with water and extracted three times with EA. The combined organic extracts were washed once with brine, dried over magnesium sulfate, filtered, concentrated, purified by silica gel chromatography (12 g, 60 μm, 0-40% ethyl acetate in hexanes, gradient over 22 min) and purified again by silica gel chromatography ( 12 g, 60 µM, 0-30% ethyl acetate in hexanes, gradient over 22 min) to give 24 mg (16%) methyl-2-oxo-1-phenyl-3-((4(trifluoromethyl)benzyl)amino) pyrrolidine-3-carboxylate in the form of a clear, colorless oil. HPMS (ES) m/z 393 (M+H).

'H NMR (400 MHz, methylene chloride- _c12 ) δ 7.59-7.54 (m, 2H), 7.54-7.49 (m, 2H), 7.49-7.44 (m, 2H ), 7.357.29 (m, 2H), 7.15-7.09 (m, 1H), 3.95-3.84 (m, 2H), 3.81-3.69 (m, 5H), 2.68-2.61 (m, 1H), 2.24-2.14 (m, 1H).

4. Synthesis of intermediate 9-5

9-4 9-5

To a solution of methyl 2-oxo-1-phenyl-3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-3-carboxylate (0.024 g, 0.061 mmol, 1.0 eq.) in DCM (1 ml) was added TEA (0.051 ml, 0.36 mmol, 6.0 eq.) and chloroacetyl chloride (0.022 ml, 0.24 mmol, 4.0 eq.). This mixture was stirred for 15 minutes. To this mixture was added an additional portion of TEA (0.051 ml, 0.36 mmol, 6.0 eq.) and twice chloroacetyl chloride (0.022 ml, 0.24 mmol, 4.0 eq.). The mixture was stirred for 15 min, diluted with dichloroethane (2 ml), heated at 83°C overnight, cooled to room temperature, diluted with saturated sodium hydrogen carbonate solution and extracted with DCM three times. The combined organic extracts were then washed once with brine, dried over magnesium sulfate, filtered and concentrated to give 29 mg (quantitative) methyl-3-(2-chloro-X-(4-(trifluoromethyl)benzyl)acetamido)-2oxo-1 -phenylpyrrolidine-3-carboxylate as a brown solid. HPMS (ES) m/z 469 (M+H).

5. Synthesis of compound 327

S-S 32?

To a solution of methyl 3-(2-chloro-X-(4-(trifluoromethyl)benzyl)acetamido)-2-oxo-1-phenylpyrrolidine-3carboxylate (29 mg, 0.079 mmol, 1.0 eq.) in ACN (4 mL) TEA (0.067 mL, 0.48 mmol, 7.8 eq.) and isopropylamine (0.027 mL, 0.32 mmol, 6.3 eq.) were added. The mixture was heated at 80°C for 1 h, concentrated, and purified by reverse phase HPLC (Phenomenex, dimeric 5 μm C18 150x21.2 mm, gradient ΙΟΙ 00% acetonitrile in water with 0.1% formic acid for 25 min) to obtain 15 mg (20%) of 9-isopropyl-2-phenyl-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-1,7,10-trio as a clear colorless oil . HPMS (ES) m/z 460 (M+H).

'H NMR (400 MHz, methanol-sc) δ 7.64-7.59 (m, 2H), 7.57-7.53 (m, 2H), 7.53-7.49 (m, 2H) , 7.42-7.36 (m, 2H), 7.27-7.21 (m, 1H), 4.99-4.92 (m, 1H), 4.76-4.67 (m, 2H), 4.33-4.16 (m, 2H), 4.16-4.08 (m, 1H), 3.87-3.78

-254 045362 (m, IH), 2.86-2.77 (μ, 1Η), 2.59-2.48 (μ, 1Η), 1.28-1.20 (m, 6Η).

Example 10. Synthesis of compound 328.

1. Synthesis of the intermediate

10-2

L(-)-proline Cui CS2OO3 DMSO iodobenzene

He

10-1

Azetin-Z-ol hydrochloride (1.3 g, 11.9 mmol, 1.0 eq.), C-)-proline (0.55 g, 4.8 mmol, 0.4 eq.), copper iodide ( 1) (0.45 g, 2.4 mmol, 0.2 eq.) and cesium carbonate (9.7 g, 29.7 mmol, 2.5 eq.) were combined in a septum flask, which was then evacuated and purged nitrogen 3 times. Iodobenzene (2.0 ml, 18 mmol, 1.5 eq) and dry dimethyl sulfoxide (30 ml) were added to this container. The mixture was heated at 90°C for 15 h, diluted with water and extracted three times with EA. The combined organic layers were dried over magnesium sulfate, filtered, evaporated and purified by silica gel chromatography (40 g, 60 μm, 0-100% ethyl acetate in hexanes gradient over 14 min) to give 1.6 g (90%) 1-phenylazetidine-3- ol in the form of a clear, colorless oil. HPMS (ES) m/z 150 (M+H).

'Η NMR (400 MHz, methylene chloride-b ₂ ) δ 7.27-7.20 (m, 2H), 6.81-6.74 (m, 1H), 6.55-6.49 (m, 2H ), 4.804.72 (m, 1H), 4.23-4.16 (m, 2H), 3.71-3.65 (m, 2H).

2. Synthesis of intermediate 10-3

To a solution of oxalyl chloride (1.5 mL, 17 mmol, 1.7 eq.) in dry DCM (15 mL) was added DMSO (2.4 mL, 34 mmol, 3.3 eq.) dropwise at -78°C. The mixture was stirred for 10 min at -78°C and 1-phenylazetidin-3-ol (1.5 g, 10.3 mmol, 1.0 eq.) in dry DCM (15 ml) was added dropwise, stirred for 1 hour, add TEA (10.0 ml, 71.9 mmol, 7.0 eq.), continue stirring for 1 hour at -78°C, dilute with saturated sodium hydrogen carbonate solution and extract three times with DCM. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, evaporated and purified by chromatography on silica gel (40 g, 60 μm, 0-10% ethyl acetate in hexanes, gradient over 28 min) to give 0.96 g (63% ) 1-phenylazetidin-3-one as a clear yellow oil. HPMS (ES) m/z 148 (M+H).

'H NMR (400 MHz, methylene chloride-b ₂ ) δ 7.36-7.29 (m, 2H), 6.92-6.87 (m, 1H), 6.69-6.63 (m, 2H ), 4.70 (s, 4H).

3. Synthesis of intermediate 10-4

F nA 1. {1S)-1-[4-(trinuoromethyl}phenyl]ethan-1-amine, MeOH

2. Acetic acid, NaCN

10-3 Yu-4

1-Phenylazetidin-3-one (0.31 g, 2.1 mmol, 1.0 eq.) and (18)-1-[4-(trifluoromethyl)phenyl]ethane-Namine (0.44 g, 2.0 eq.) 3 mmol, 1.1 eq.) were combined in dry MeOH (3 ml), and the mixture was heated at 60°C for 1 hour. To this mixture, cooled to 0°C, acetic acid (0.13 ml, 2.3 mmol, 1.1 eq.) and sodium cyanide (0.11 g, 2.3 mmol, 1.1 eq.). The mixture was heated at 60°C for 15 hours, diluted with water and extracted three times with EA. The combined organic washes were dried over magnesium sulfate, filtered, evaporated and purified by chromatography on silica gel (12 g, 60 µm, 020% ethyl acetate in hexanes, gradient over 22 min) to give 0.46 g (62%) (8)-1 -phenyl-3-((1-(4(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carbonitrile in the form of a clear, colorless oil. HPMS (ES) m/z 346 (M+H).

Y NMR (400 MHz, methylene chloride-<1 ₂ ) δ 7.69-7.65 (m, 2H), 7.64-7.59 (m, 2H), 7.26-7.19 (m, 2H ), 6.856.79 (m, 1H), 6.42-6.38 (m, 2H), 4.38-4.35 (m, 1H), 4.26 (k, J=6.6 Hz, 1H), 3.92-3.88 (m, 1H), 3.83-3.79 (m, 1H), 3.38-3.34 (m, 1H), 1.48 (d, J= 6.6 Hz, ZN).

-255 045362

4. Synthesis of intermediate 10-5

To a solution of (S)-l-phenyl-3-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)azetidine-3-carbonitrile (0.272 g, 0.787 mmol, 1.0 eq.) in DCM (3 mL), TEA (0.33 mL, 2.4 mmol, 3.0 eq.) and chloroacetyl chloride (0.12 mL, 1.6 mmol, 2.0 eq.) were added dropwise. The mixture was stirred for 15 minutes. TEA (0.33 mL, 2.4 mmol, 3.0 eq.) and chloroacetyl chloride (0.12 mL, 1.6 mmol, 2.0 eq.) were added to this mixture. The mixture was stirred for 30 minutes, diluted with saturated sodium hydrogen carbonate solution and extracted twice with DCM. The combined extracts were dried over magnesium sulfate, filtered and concentrated to give 332 mg (100%) (8)-2-chloro-X-(3-cyano-1-phenylazetidin-3-yl)-X-(1-(4( trifluoromethyl)phenyl)ethyl)acetamide in the form of red oil. HPMS (ES) m/z 422 (M+H).

^! H NMR (400 MHz, methylene chloride-b ₂ ) δ 7.72-7.67 (m, 2H), 7.59-7.54 (m, 2H), 7.28-7.21 (m, 2H) , 6.896.84 (m, 1H), 6.45-6.41 (m, 2H), 5.19-5.11 (m, 1H), 4.49-4.45 (m, W), 4 .42-4.39 (m, 1H), 4.07-3.94 (m, ZN), 3.83-3.79 (m, 1H), 1.96 (d, >7.1 Hz, ZN).

5. Synthesis of intermediate 10-6

YU

To a solution of (S)-2-xnop-N-(3-cyano-1-phenylazetidine-3-mi)-N-(l -(4-(trifluoromethyl)phenyl)ethyl)acetamide (0.332 g, 0.787 mmol, 1 .0 eq.) in dry DCM (3 ml) was added isopropylamine (3.4 ml, 39 mmol, 50 eq.). The mixture was stirred for 3 days at room temperature, concentrated and purified by chromatography on silica gel (12 g, 60 µm, 0-10% methanol in dichloromethane, gradient over 22 min) to give 314 mg (90%) (8) -H-(3-cyano-1-phenylazetidin-3-yl)-2-(isopropylamino)-I-(1-(4(trifluoromethyl)phenyl)ethyl) acetamide in the form of a clear, slightly yellowish oil. HPMS (ES) m/z 445 (M+H).

^! H NMR (400 MHz, methylene chloride-ad δ 7.64-7.60 (m, 2H), 7.43-7.38 (m, 2H), 7.24-7.18 (m, 2H), 6.826 .77 (m, 1H), 6.43-6.39 (m, 2H), 5.90-5.80 (m, 1H), 4.60-4.46 (m, 1H), 4.41 -4.35 (m, 1H), 4.30-4.21 (m, 1H), 4.07-3.99 (m, 2H), 3.90-3.83 (m, 1H), 3 .79-3.73 (m, 1H), 1.87 (d, >7.2 Hz, ZN), 1.28-1.21 (m, 6H).

6. Synthesis of compound 328

+6 Connection 328

To a solution of (8)-M-(3-cyano-1-phenylazetidin-3-yl)-2-(isopropylamino)-I-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide (54 mg, 0. 12 mmol, 1.0 eq.) in dry toluene (0.5 ml) was heated to 150°C in a microwave reactor for 30 min. The mixture was concentrated and purified by reverse phase HPLC (Phenomenex, dimeric 5 µm C18 150x21.2 mm, gradient 10-100% acetonitrile in water with 0.1% formic acid over 25 min) to obtain 28 mg (52%) (8 )-9-imino-8-isopropyl-2-phenyl-5-(1-(4(trifluoromethyl)phenyl)ethyl)-2,5,8-triazaspiro[3.5]nonan-6-one as a clear, colorless oil. HPMS (ES) m/z 445 (M+H).

^! H NMR (400 MHz, methanol-a ₄ ) δ 8.38 (s, 1H), 7.69-7.63 (m, 2H), 7.56-7.50 (m, 2H), 7.25 -7.19 (m, 2H), 6.89-6.82 (m, 1H), 6.56-6.48 (m, 2H), 5.73-5.61 (m, 1H), 4 .54-4.45 (m, 2H), 4.32-4.14 (m, 5H), 1.86 (d, >7.1 Hz, ZN), 1.46-1.39 (m, 6H).

-256 045362

Example 11 Synthesis of compound 332.

1. Synthesis of intermediate 11-2

To a solution of racemic 3-amino-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (2.00 g, 8.69 mmol) in NaOH (1 M, 15 ml) was added di-tert-butyl dicarbonate (3.79 g, 17.37 mmol, 2.0 eq.) in 1,4-dioxane (15 ml). The resulting mixture was stirred at room. pace. over 18 hours, the pH was adjusted to 3 using 3 M aqueous HCl, and the resulting mixture was extracted twice with EA (total volume = 125 ml). The organic extracts were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 1-(tert-butoxycarbonyl)-3-((tert-butoxycarbonyl)amino)pyrrolidine-3-carboxylic acid (2.93 g, 7. 98 mmol, yield 92%) in the form of a sticky foam, which was used in the next step without further purification. HPMS (CIAD) m/z 329.1 (M-N).

^1H NMR (400 MHz, DMSO-bb) δ 12.68 (s, 1H), 7.54 (s, 1H), 3.74-3.66 (m, 1H), 3.51 (dd, J =20.3, 11.4 Hz, 1H), 3.34-3.26 (m, 2H), 2.21-2.04 (m, 2H), 1.39 (s, 18H).

2. Synthesis of intermediate 11-3

To a solution of 1-(tert-butoxycarbonyl)-3-((tert-butoxycarbonyl)amino)pyrrolidine-3-carboxylic acid (2.93 g, 7.98 mmol) in a mixture of DCM (40 ml) and MeOH (20 ml) (diazomethyl)trimethylsilane (11.97 mL of 2.0 M in hexanes, 23.95 mmol, 3.0 eq.) was added in portions. The resulting solution was stirred at room. pace. for 30 min, quenched with glacial acetic acid (1 ml) until gas evolution ceased, and concentrated under reduced pressure. The remaining residue was dissolved in DCM (100 ml) and washed with 2 M aqueous K ₂ CO ₃ solution (25 ml). The organic phase was dried over sodium sulfate, concentrated and purified with silica gel using 30% EA/Hex to give 2.12 g (77%) 1-(tert-butyl)-3-methyl-3-((tert-butoxycarbonyl)amino) pyrrolidine 1,3-dicarboxylate as a colorless sticky solid. HPMS (CIAD) m/z 245.2 (M+H) (loss of Boc).

1H NMR (400 MHz, methanol-04) δ 3.84-3.75 (m, 1H), 3.64 (s, 3H), 3.57-3.44 (m, 1H), 3.43- 3.30 (m, 2H), 2.24-2.13 (m, 1H), 2.12-2.02 (m, 1H), 1.41-1.32 (m, 18H).

3. Synthesis of intermediates 11-4A and 11-4B

V οΥ οΥ

About AC RuOj'HjO, EtOAc'у уАО у -yh- γ st Yy γ

J J lO

11-3 11-4Д1MB

This step corresponds to the method published in Chem. Pharm. Bull. 42(8) 1302-1306, 1995. To a mixture of ruthenium oxide hydrate (386 mg, 2.90 mmol, 0.5 eq.) and sodium periodate (6.21 g, 29.04 mmol, 5.0 eq.) in a round bottom flask (250 ml) add water (25 ml) and 1-(tert-butyl)-3-methyl-3-((tert-butoxycarbonyl)amino)pyrrolidine-1,3-dicarboxylate (2.00 g, 5.81 mmol, 1.0 eq.) in EA (25 ml). The resulting two-phase mixture was stirred vigorously for 3 hours, diluted with an additional portion of EA (50 ml) and filtered through celite. The layers were separated and the aqueous phase was extracted once with EA (50 ml). The organic phases were combined and diluted with MeOH (5 ml). The resulting black solution was stirred at room. pace. for 30 min and filtered again through celite. The solvent was evaporated in vacuo and the remaining solid was purified on silica gel using 30% EA/Hex to give 1.44 g (69%) 1-(tert-butyl)-3-methyl-3-((tert-butoxycarbonyl) amino)-5-oxopyrrolidine-1,3dicarboxylate (11-4A) and 437 mg (21%) 1-(tert-butyl)-3-methyl-3-((tert-butoxycarbonyl)amino)-2oxopyrrolidine-1,3 -dicarboxylate (11-4B), both visualized by TLC showing KMnO ₄ .

Characterization for intermediate 11-4A: HPMC (CIAD) m/z 203.1 (M+H) (loss of Boc and loss of tert-butyl).

1H NMR (400 MHz, methanol-04) δ 4.21 (d, J=11.5 Hz, 1H), 3.95 (d, J=11.5 Hz, 1H), 3.78 (s, 3H ), 3.13 (d, J=17.5 Hz, 1H), 2.80 (dd, J=17.5, 0.8 Hz, 1H), 1.55 (s, 9H), 1.46 (s, 9H).

Characterization for intermediate 11-4B: HPMS (CIAD) m/z 203.1 (M+H) (loss of Boc and loss of tert-butyl).

- 257 045362

1H NMR (400 MHz, methanol-a ₄ ) δ 3.94-3.74 (m, 5H), 2.63 (ddd, J=13.4, 7.9, 2.2 Hz, 1H), 2 .42 (dt, J=13.5, 9.2 Hz, 1H), 1.56 (s, 9H), 1.46 (s, 9H).

4. Synthesis of intermediate 11-5

To a solution of 1-(tert-butyl)-3-methyl-3-((tert-butoxycarbonyl)amino)-5-oxopyrrolidine-1,3dicarboxylate (916 mg, 2.56 mmol) in DCM (5 ml) was added TFA ( 5 ml). The resulting mixture was stirred at room. pace. within 30 min. Solvents were removed under reduced pressure and dried under high vacuum to obtain 692 mg (quantitative yield) of methyl 3-amino-5-oxopyrrolidine-3carboxylate as the TFA salt without further purification. HPMS (CIAD) m/z 159.1 (M+H).

5. Synthesis of intermediate 11-6

To a mixture of TFA salt methyl 3-amino-5-oxopyrrolidine-3-carboxylate (692 mg, 2.55 mmol) and pchlorobenzaldehyde (1.07 g, 7.63 mmol, 3.0 eq.) in a mixture of THF (30 ml) and dichloroethane (10 ml) were stirred for 15 min, NaBH(OAc) ₃ (2.69 g, 12.71 mmol, 5.0 eq.) was added. The resulting mixture was stirred at room. pace. for 1 hour, during which time a homogeneous solution was observed. The solvents were evaporated under reduced pressure and the remaining residue was partitioned between DCM (60 ml) and saturated aqueous NaHCO ₃ (60 ml). The aqueous phase was extracted with DCM (25 ml). The organic phases were combined, dried over sodium sulfate, filtered through celite and concentrated under reduced pressure. The remaining residue was purified on silica gel using a gradient of 0-100% EA/Hex as eluent to give 548 mg (76%) methyl 3-((4-chlorobenzyl)amino)-5-oxopyrrolidine-3carboxylate, HPMC (CIAD) m /z 159.1 (M+H).

6. Synthesis of intermediate 11-7

To a mixture of CuI (25 mg, 0.13 mmol, 0.5 eq.) and K ₂ CO ₃ (143 mg, 1.03 mmol, 4.0 eq.) methyl 3-((4-chlorobenzyl) amino)-5-oxopyrrolidine-3-carboxylate (73 mg, 0.26 mmol, 1.0 eq.) in anhydrous 1,4-dioxane (2 ml), 2-iodopyridine (41 μl, 0.39 mmol, 1 .5 eq.) and N,Ndimethylethylenediamine (13 μl, 0.13 mmol, 0.5 eq.). The resulting mixture was purged with nitrogen, sealed and heated at 115°C in an oil bath for 18 hours. The reaction mixture was filtered through a syringe filter, concentrated under reduced pressure and purified by reverse phase HPLC using 10-100% ACN/water (both with 0.1% formic acid; Phenomenex Gemini C18 5 micron column) to give 59 mg (62%) methyl-3-((4-chlorobenzyl)amino)-5-oxo-1-(pyridin-2yl)pyrrolidin-3- carboxylate. HPMS (CIAD) m/z 360.1 (M+H).

1H NMR (400 MHz, methanol-04) δ 8.40-8.23 (m, 2H), 7.79 (ddd, J=8.3, 7.3, 2.1 Hz, 1H), 7, 33 (d, 2H), 7.26 (d, 2H), 7.14 (ddd, J=7.3, 4.8, 1.1 Hz, 1H), 4.37 (d, J=11, 8 Hz, 1H), 4.19 (dd, J=11.7, 0.7 Hz, 1H), 3.81 (s, 3H), 3.73 (d, J=2.1 Hz, 2H) , 3.22 (d, J=17.1 Hz, 1H), 2.80 (dd, J=17.2, 0.7 Hz, 1H).

7. Synthesis of compound 332

- 258 045362

To a solution of methyl 3-((4-chlorobenzyl)amino)-5-oxo-1-(pyridin-2-yl)pyrrolidine-3-carboxylate (59 mg, 0.16 mmol) in DCM (3 mL) was added Et ₃ N (229 µl, 1.64 mmol, 10.0 eq.). To the resulting solution, cooled to 0°C in an ice bath, chloroacetyl chloride (131 μL, 1.64 mmol, 10.0 eq.) was added dropwise. The ice bath was removed and the resulting mixture was stirred at room. pace. for 30 min, diluted with DCM (20 ml), washed with saturated aq. NaHCO ₃ (15 ml), dried over sodium sulfate, and concentrated in vacuo. To the remaining residue, dissolved in ACN (3 ml), Et ₃ N (229 μl, 1.64 mmol, 10.0 eq.) and isopropylamine (140 μl, 1.64 mmol, 10.0 eq.) were added. The resulting solution was heated in a hermetically sealed vessel at 100°C in an oil bath for 45 minutes, cooled to room temperature. temp., concentrated under reduced pressure and purified by reverse phase HPLC using 10-100% ACN/water (both with 0.1% formic acid; Phenomenex Gemini C18 5 micron column) and silica gel using 50% EA/Hex as eluent, yielding 32 mg (46%) 6-(4chlorobenzyl)-9-isopropyl-2-(pyridin-2-yl)-2,6,9-triazaspiro[4.5]decane-3,7,10-trione in as a white solid. HPMS (CIAD) m/z 427.2 (M+H).

1H NMR (400 MHz, methanol^) δ 8.31-8.22 (m, 2H), 7.78 (ddd, J=8.5, 7.3, 2.0 Hz, 1H), 7.20 (s, 4H), 7.13 (ddd, J=7.3, 4.9, 1.0 Hz, 1H), 4.98-4.89 (m, 1H), 4.80-4.68 (m, 2H), 4.46 (d, J=12.4 Hz, 1H), 4.33-4.25 (m, 2H), 4.18 (d, J=17.8 Hz, 1H) , 3.40 (d, J=17.8 Hz, 1H), 3.11 (d, J=17.8 Hz, 1H), 1.30-1.22 (m, 6H).

Example 12. Synthesis of compound 331 (X ~ X l UC g D / ⁰

A method similar to Example 11 was used, except that iodobenzene was used in step 6 instead of 2-iodopyridine.

Example 13 Synthesis of compound 330.

1. Synthesis of intermediate 13-1

TFA ( 5 ml). The resulting mixture was stirred at room. pace. for 30 minutes, dried under reduced pressure and concentrated to obtain 330 mg (quantitative yield) of TFA salt of methyl 3-amino-2-oxopyrrolidine-3-carboxylate. HPMS (CIAD) m/z 159.1 (M+H).

2. Synthesis of intermediate 13-2

To a mixture of TFA salts of methyl 3-amino-2-oxopyrrolidine-3-carboxylate (330 mg, 1.22 mmol) and pchlorobenzaldehyde (513 mg, 3.65 mmol, 3.0 eq.) in a mixture of dichloroethane (5 ml) and MeOH (5 ml) were stirred at room. pace. NaBH ₃ CN (229 mg, 3.65 mmol, 3.0 eq.) was added over 15 min. The resulting mixture was stirred at room. pace. for 18 hours. An additional portion of p-chlorobenzaldehyde (513 mg, 3.65 mmol, 3.0 eq.) and NaBH ₃ CN (229 mg, 3.65 mmol, 3.0 eq.) was added to this mixture. The mixture was heated in an oil bath at 65°C for 2 hours, evaporated in vacuo and partitioned between EA (40 ml) and saturated aqueous NaHCO ₃ (40 ml). The layers were separated and the aqueous phase was extracted with an additional portion of EA (30 ml). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel chromatography using EA/Hex (0-100%) to give 258 mg (75%) methyl-3-((4-chlorobenzyl)amino) -2-oxopyrrolidine-3-carboxylate. HPMS (CIAD) m/z 283.1 (M+H).

1H NMR (400 MHz, methanolO δ 7.37-7.15 (m, 4H), 3.74 (d, J=12.4 Hz, 1H), 3.59 (d, J=12.4 Hz, 1H), 3.47-3.33 (m, 2H), 2.59 (ddd, J=13.4, 7.3, 3.6 Hz, 1H), 2.23 (ddd, J=13, 4, 8.7, 7.5 Hz, 1H).

- 259 045362

3. Synthesis of intermediate 13-3

13-2 T3-3

To a mixture of CuI (6 mg, 0.033 mmol, 0.2 eq.), 4-iodo-1-methyl-1H-pyrazole (41 mg, 0.195 mmol, 1.2 eq.) and K ₂ CO ₃ (90 mg, 0.651 mmol, 4.0 eq.) was added methyl 3-((4-chlorobenzyl)amino)-2-oxopyrrolidine-3carboxylate (46 mg, 0.163 mmol, 1.0 eq.) in anhydrous 1,4-dioxane (2 ml) and N,N-dimethylethylenediamine (4 µl, 0.033 mmol, 0.2 eq.). The resulting mixture was purged with nitrogen, sealed, heated in an oil bath at 115°C for 18 hours, cooled to room temperature, filtered through a syringe filter and purified by reverse phase HPLC using 10-100% ACN/water (both with 0. 1% formic acid; Phenomenex Gemini C18 5 micron column) to give 8 mg (14%) methyl-3-((4chlorobenzyl)amino)-1-(1-methyl-1H-pyrazol-4-yl)-2-oxopyrrolidine -3-carboxylate. HPMS (CIAD) m/z 363.2 (M+H).

4. Synthesis of compound 330

To a solution of methyl 3-((4-chlorobenzyl)amino)-1-(1-methyl-1H-pyrazol-4-yl)-2-oxopyrrolidine-3 carboxylate (8 mg, 0.022 mmol) in DCM (1 ml) Et ₃ N (31 μl, 0.22 mmol, 10.0 eq.) was added. To the resulting solution, cooled to 0°C in an ice bath, chloroacetyl chloride (18 μL, 0.22 mmol, 10.0 eq.) was added dropwise, and the ice bath was removed after addition was complete. The resulting mixture was stirred at room. pace. for 30 min, diluted with DCM (10 ml), washed once with saturated aq. NaHCO ₃ (10 ml), dried over sodium sulfate and concentrated in vacuo. The remaining residue was dissolved in ACN (1 ml). To this mixture were added sequentially Et ₃ N (62 μl, 0.44 mmol, 20.0 eq.) and isopropylamine (38 μl, 0.44 mmol, 20.0 eq.). The resulting solution was heated in a hermetically sealed vessel at 100°C in an oil bath for 45 minutes, cooled to room temperature. temp., evaporated under reduced pressure and purified by reverse phase HPLC using 10-100% ACN/water (both with 0.1% formic acid; Phenomenex Gemini C18 5 micron column) to give 5 mg (53%) 6-( 4-chlorobenzyl)-9-isopropyl-2-(1-methyl-1H-pyrazol-4-yl)-2,6,9-triazaspiro[4.5]decane-1,7,10trione. HPMS (CIAD) m/z 430.2 (M+H).

1H NMR (400 MHz, methanol- _d4 ) δ 7.91 (s, 1H), 7.64 (s, 1H), 7.34-7.23 (m, 4H), 4.84 (d, J =16.1 Hz, 1H), 4.68 (p, J=6.9 Hz, 1H), 4.55 (d, J=16.1 Hz, 1H), 4.27 (d, J=17 .7 Hz, 1H), 4.17 (d, J=17.7 Hz, 1H), 3.93-3.83 (m, 4H), 3.70 (td, J=9.4, 2, 6 Hz, 1H), 2.82 (dd, J=14.0, 8.4, 2.6 Hz, 1H), 2.57-2.45 (m, 1H), 1.23 (dd, J =10.0, 6.8 Hz, 6H).

Example 14 Synthesis of Compound 333

333

A method similar to Example 13 was used, except that 4-iodo-2-methylpyridine was used in step 4 instead of 4-iodo-1-methyl-1H-pyrazole.

- 260 045362

Example 15. Synthesis of compound 389.

1. Synthesis of intermediate 15-2 sg

To a solution of N)-1-(4-chlorophenyl)ethan-1-amine (2.4 ml, 16.7 mmol, 1.0 eq.) and tert-butyl-3oxopyrrolidine-1-carboxylate (3.1 g, 16.7 mmol, 1.0 eq.) in MeOH (16 ml) was added 2isocyanopropane (1.6 ml, 16.7 mmol, 1.0 eq.) and chloroacetic acid (1.6 g, 16.7 mmol, 1.0 eq.). The mixture was stirred for 30 minutes, concentrated and purified by silica gel chromatography to give 3.2 g (39%) tert-butyl-3-(2-chloro-^(^)-1-(4-chlorophenyl)ethyl)acetamido) -3(isopropylcarbamoyl)pyrrolidine-1-carboxylate as a mixture of diastereomers. HPMS (ES) m/z 486.2 (M+H).

2. Synthesis of intermediate 15-3

•S5-2 15-3

To a solution of tert-butyl-3-(2-chloro-X-((8)-1-(4-chlorophenyl)ethyl)acetamido)-3(isopropylcarbamoyl)pyrrolidine-1-carboxylate (3.2 g, 6.6 mmol, 1.0 eq.) Potassium carbonate (0.9 g, 6.6 mmol, 2.0 eq.) was added to ACN (20 mL). The mixture was heated to 80°C for 2 hours, filtered, concentrated and purified by silica gel chromatography (80 g, 0-100% EtOAc in hexanes) to give 1.0 g (34%) tert-butyl-6-(^) -1-(4-chlorophenyl)ethyl)-9-isopropyl-7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2carboxylate as a mixture of diastereomers. HPMS (ES) m/z 394.15 (M+H-tBu).

3. Synthesis of intermediate 15-4

To a solution of tert-butyl-6-((8)-1 -(4-chlorophenyl)ethyl)-9-isopropyl-7,10-dioxo-2,6,9triazaspiro[4.5]decane-2-carboxylate (1.0 g, 2.2 mmol, 1.0 eq.) in DCM (5.0 ml) was added TFA (5 ml). The mixture was stirred for 20 minutes, concentrated, diluted with saturated aqueous NaHCO ₃ (200 ml), and the layers were separated. The aqueous layer was extracted three times with DCM, the combined organic washes were dried over MgSO ₄ , filtered and concentrated and purified by silica gel chromatography (24 g column, 0-40% MeOH in DCM) to give 380 mg (49%) 6-((S)- 1-(4-chlorophenyl)ethyl)-9isopropyl-2,6,9-triazaspiro[4,5]decane-7,10-dione as a mixture of diastereomers. HPMS (ES) m/z 350.2 (M+H).

4. Synthesis of compound 389 (diastereomers 389A and 389B)

Compound 38S mixture of diastereomers 389Ам 38SS

To a mixture of 6-((S)-1-(4-chlorophenyl)ethyl)-9-isopropyl-2,6,9-triazaspiro[4.5]decane-7,10-dione (190 mg,

- 261 045362

0.54 mmol, 1.0 eq.) and 2-fluoropyridine (132 mg, 1.4 mmol, 2.5 eq.) IPA (3 ml) was added in a microwave vessel. The mixture was heated at 180°C in a microwave reactor for 75 min, concentrated, and purified by reverse phase HPLC (Phenomenex, dimeric, 5 µM C18 150x21.2 mm, gradient 10-100% acetonitrile in water with 0.1% formic acid for 40 min) to obtain 16 mg (14%) of the first eluting peak as diastereomer 389A and 15 mg of the second eluting peak as diastereomer 389B.

Characteristics of diastereomer 389A: HPMS (ES) m/z 427.1 (M+H).

1H NMR (methanol-d ₄ , 400 MHz, ppm) δ 8.01 (ddd, J=5.3, 1.9, 0.9 Hz, 1H), 7.59 (ddd, J=8 ,9, 7.1, 1.9 Hz, 1H), 7.29 (s, 4H), 6.69 (ddd, J=7.2, 5.2, 0.9 Hz, 1H), 6, 57 (dt, J=8.7, 0.9 Hz, 1H), 4.70 (p, J=6.9 Hz, 1H), 4.194.00 (m, 3H), 3.83 (d, J =11.9 Hz, 2H), 3.60 (k, J=8.5 Hz, 1H), 2.73-2.52 (m, 2H), 1.89 (d, J=6.9 Hz , 3H), 1.23 (dd, J=6.8, 2.1 Hz, 6H).

Characteristics of diastereomer 389B: HPMS (ES) m/z 427.1 (M+H).

1H NMR (methanol-d ₄ , 400 MHz, ppm) δ 8.06 (ddd, J=5.2, 1.9, 0.8 Hz, 1H), 7.63 (ddd, J=8 ,8, 7.1, 1.9 Hz, 1H), 7.37-7.27 (m, 4H), 6.73 (ddd, J=7.1, 5.3, 0.9 Hz, 1H ), 6.62 (d, J=8.6 Hz, 1H), 4.70 (p, J=6.9 Hz, 1H), 4.08 (d, J=2.6 Hz, 2H), 4.02 (d, J=11.3 Hz, 1H), 3.92 (d, J=11.8 Hz, 1H), 3.71 (td, J=9.2, 4.0 Hz, 1H ), 3.60 (t, J=8.5 Hz, 1H), 2.77 (ddd, J=13.8, 8.2, 3.9 Hz, 1H), 2.52 (dt, J= 13.8, 8.3 Hz, 1H), 1.87 (d, J=6.9 Hz, 3H), 1.23 (dd, J=6.8, 3.4 Hz, 6H).

The following compound was prepared using methods similar to the method described for compound 389:

Enantiomer No. H PMC (ES) m/z

504A

M+H=468.2

Example 16. Synthesis of compound 367.

1. Synthesis of intermediate 16-2

To a solution of 6-[(4-chlorophenyl)methyl]-9-(propan-2-yl)-2,6,9-triazaspiro[4.5]decane-7,10-dione (150 mg, 0.45 mmol, 1 .00 eq.) in DCM (5 ml) at room. pace. isocyanatotrimethylsilane (103 mg, 0.89 mmol, 2.00 eq) and TEA (90 mg, 0.89 mmol, 2.00 eq) were added. The mixture was stirred at room. pace. for 2 h, concentrated under reduced pressure and purified by reverse phase HPLC under the following conditions [(2#-Analyse HPLC-SHIMADZU): Column, XBridge Prep OBD C18 column, 5 µm, 30x150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (22.0% ACN to 35.0% for 8 min); detector, UV 220 nm] to obtain 105 mg (62%) 6-[(4-chlorophenyl)methyl]-7,10-dioxo-9-(propan-2-yl)-2,6,9triazaspiro[4.5]decane -2-carboxamide as a white solid. HPMS (ES) m/z 379 (M+H).

1H NMR (300 MHz, DMSO- _d6 ) δ 7.40-7.28 (m, 2H), 7.16-7.07 (m, 2H), 5.77 (s, 2H), 4.69 (d, J=16.8 Hz, 1H), 4.62-4.45 (m, 2H), 4.04 (d, J=2.8 Hz, 2H), 3.77 (d, J= 11.7 Hz, 1H), 3.34 (s, 1H), 3.27 (s, 2H), 2.20 (dt, J=8.8, 4.7 Hz, 2H), 1.09 ( d, J=6.8 Hz, 6H).

2. Branch of connection 367

Racemic compound 6-[(4-chlorophenyl)methyl]-7,10-dioxo-9-(propan-2-yl)-2,6,9triazaspiro[4.5]decane-2-carboxamide (80 mg, 0.21 mmol , 1.00 eq.) were separated by chiral HPLC under the following conditions (Column: CHIRALPAK IC, 2x25 cm, 5 µm; mobile phase A: Hex-HPLC, mobile phase B: EtOH-HPLC; flow rate: 16 ml/min; isocratic at 50% B for 28 min; 254/220 nm) to obtain 37.7 mg of the first eluting peak as enantiomer 367A and 33.2 mg of the second eluting peak as enantiomer 367B. Chiral analytical data (CHIRALPAK IC-3; 0.46 cm x 5 cm; 3 microns; Hex(0.1% DEA):EtOH=50:50 at 1 ml/min) illustrates that the first peak (RT: 3. 75 min) represents the enantiomer 367A, and the second peak (RT: 4.61 min) represents the enantiomer

- 262 045362

367V.

Enantiomer 367A: HPMC (ES) m/z 379 (M+H).

*H NMR (300 MHz, DMSO-b ₆ ) δ 7.40-7.30 (m, 2H), 7.16-7.07 (m, 2H), 5.77 (s, 2H), 4, 69 (d, >16.8 Hz, 1H), 4.62-4.45 (m, 2H), 4.04 (d, >2.8 Hz, 2H), 3.77 (d, >11, 7 Hz, 1H), 3.34 (s, 1H), 3.27 (s, 2H), 2.26-2.14 (m, 2H), 1.09 (d, >6.8 Hz, 6H ).

Enantiomer 367B: HPMC (ES) m/z 379 (M+H).

*H NMR (300 MHz, DMSO-a ₆ ) δ 7.40-7.30 (m, 2H), 7.17-7.07 (m, 2H), 5.77 (s, 2H), 4, 69 (d, >16.7 Hz, 1H), 4.62-4.45 (m, 2H), 4.04 (d, >2.8 Hz, 2H), 3.77 (d, >11, 7 Hz, 1H), 3.34 (s, 1H), 3.27 (s, 2H), 2.20 (dt, >8.9, 4.7 Hz, 2H), 1.09 (d, > 6.8 Hz, 6H).

Example 17 Synthesis of Compound 347

^7L Connection 3-47

To a solution of 6-(5-(4-chlorobenzyl)-8-isopropyl-6,9-dioxo-2,5,8-triazaspiro[3,5]nonan-2yl)nicotinonitrile (100 mg, 0.236 mmol, 1.0 eq.) in THF (4 ml) at -78°C, LHMDS (1 M in THF, 354 μl, 0.35 mmol, 1.5 eq.) and chloromethyl methyl ether (38 mg, 0.47 mmol, 2 ,0 eq.). The mixture was stirred for 5 minutes at -78°C, heated to room. pace, over a period of 1 h, quenched with MeOH (0.5 ml) and purified by reverse phase HPLC (Phenomenex, dimeric 5 μm C18 150x21.2 mm, gradient 20-100% acetonitrile in water with 0.1% formic acid in for 40 min) to obtain 7.2 mg (7%) 6-(5-(4-chlorobenzyl)-8-isopropyl-7-(methoxymethyl)-6,9-dioxo-2,5,8triazaspiro[3,5 ]nonan-2-yl)nicotinonitrile as a white solid. HPMS (ES) m/z 468.2 (M+H).

* H NMR (methanol-b ₄ , 400 MHz, ppm) δ 8.38 (dd, >2.2, 0.8 Hz, 1H), 7.77 (dd, >8.8, 2, 2 Hz, 1H), 7.357.30 (m, 2H), 7.25 (d, >8.6 Hz, 2H), 6.48 (dd, >8.8, 0.9 Hz, 1H), 5 .12 (d, >16.4 Hz, 1H), 4.75 (d, >10.0 Hz, 1H), 4.40-4.31 (m, 2H), 4.26 (d, >10 ,2 Hz, 1H), 4.18-4.04 (m, 2H), 3.81 (dd, >9.8, 1.7 Hz, 1H), 3.74 (dd, >9.8, 2.7 Hz, 1H), 3.40 (s, ZN), 1.40 (dd, >6.8, 5.1 Hz, 6H).

Example 18 Synthesis of compound 348.

1. Synthesis of intermediate 18-2

C.I.

18-2

To a solution of (4-chlorophenyl)methanamine (0.27 g, 1.9 mmol, 1.0 eq.) and tert-butyl-3-oxopyrrolidine-1-carboxylate (0.36 g, 1.9 mmol, 1.0 eq. .) 1-isocyano-4-nitrobenzene (0.30 g, 2.0 mmol, 1.05 equiv.) and chloroacetic acid (0.18 g, 1.9 mmol, 1.0 eq.) were added to MeOH (5 ml). eq.). The mixture was stirred for 15 hours at room temperature, concentrated and purified by silica gel chromatography (0-100% EtOAc in hexanes) to obtain 200 mg of tert-butyl-3-(2-chloro-X-(4-chlorobenzyl)acetamido )-3-((4nitrophenyl)carbamoyl)pyrrolidine-1-carboxylate. HPMS (ES) m/z 495.1 (M+H^Bu).

2. Synthesis of intermediate 18-3

1+2 1S-3

To a solution of tert-butyl-3-(2-chloro-X-(4-chlorobenzyl)acetamido)-3-((4-nitrophenyl)carbamoyl)pyrrolidine-1-carboxylate (200 mg, 0.36 mmol, 1.0 eq.) potassium carbonate (151 mg, 1.1 mmol, 3.0 eq.) was added to IPA (5 ml). The mixture was heated at 120°C for 30 min, cooled to room temperature, filtered, concentrated and purified by silica gel chromatography (0-100% EtOAc in hexanes) to give tert-butyl-6-(4-chlorobenzyl)-9 -(4-nitrophenyl)-7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2carboxylate. HPMS (ES) m/z 459.1 (M+H^Bu).

-263 045362

3. Synthesis of intermediate 18-4

18-3 18-4

To a solution of tert-butyl-6-(4-chlorobenzyl)-9-(4-nitrophenyl)-7,10-dioxo-2,6,9-triazaspiro[4.5]decane2-carboxylate (0.36 mmol, 1.0 eq., assuming a yield of 100%), TFA (2 ml) was added to DCM (2 ml). The mixture was stirred for 20 min, concentrated, diluted with saturated NaHCO ₃ (200 ml) and extracted three times with DCM. The combined organic washes were dried over MgSO ₄ , filtered and concentrated to give 6-(4-chlorobenzyl)-9-(4-nitrophenyl)-2,6,9-triazaspiro[4.5]decane-7,10dione. This material was divided into two equal parts and used in the subsequent reaction. HPMS (ES) m/z 415.1 (M+H).

4. Synthesis of compound 348

S-4 From CW

To a mixture of 6-(4-chlorobenzyl)-9-(4-nitrophenyl)-2,6,9-triazaspiro[4.5]decane-7,10-dione (0.18 mmol, 1.0 eq.), 5- Cyano-2-fluoropyridine (33 mg, 0.27 mmol, 1.5 eq.) and potassium carbonate (50 mg, 0.36 mmol, 2.0 eq.) were added to IPA (3 ml) in a microwave tube. The mixture was sealed and heated at 150°C in a microwave reactor for 20 min, concentrated and purified by reverse phase HPLC (Phenomenex, dimeric 5 μm C18 150x21.2 mm, gradient 20-100% acetonitrile in water with 0.1% formic acid for 40 min) to obtain 16 mg (17% in 3 stages) 6-(6-(4-chlorobenzip)-9-(4nitrophenyl)-7,10-dioxo-2,6,9-triazaspiro[4.5] decane-2-yl)nicotinonitrile as a white foamy solid. HPMS (ES) m/z 517.0 (M+H).

1H NMR (methanol-d4, 400 MHz, ppm) δ 8.41-8.27 (m, 3H), 7.81-7.68 (m, 3H), 7.35-7.29 ( m, 2H), 7.287.20 (m, 2H), 6.49 (d, J=8.9 Hz, 1H), 4.99 (d, J=16.6 Hz, 1H), 4.85- 4.69 (m, 3H), 4.23 (d, J=12.6 Hz, 1H), 3.99 (d, J=12.6 Hz, 1H), 3.79-3.58 (m , 2H), 2.79 (ddd, J=13.1, 8.2, 4.7 Hz, 1H), 2.68 (dt, J=13.6, 8.1 Hz, 1H).

Example 19 Synthesis of compound 349

Connection 349

To a solution of 6-(4-chlorobenzyl)-9-(4-nitrophenyl)-2,6,9-triazaspiro[4.5]decane-7,10-dione (0.18 mmol, 1.0 eq.) in DCM ( 4 ml) TEA (55 mg, 0.54 mmol, 3.0 eq.) and methyl isocyanate (31 mg, 0.54 mmol, 3.0 eq.) were added. The mixture was stirred for 30 min, concentrated and purified by reverse phase HPLC (Phenomenex, dimeric 5 µm C18 150x21.2 mm, gradient 20-100% acetonitrile in water with 0.1% formic acid over 40 min) to obtain 17 mg (20% in 3 steps) 6-(4-chlorobenzyl)-N-methyl-9-(4nitrophenyl)-7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2-carboxamide as a white foam solid matter. HPMS (ES) m/z 472.1 (M+H).

1H NMR (methanol- _d4 , 400 MHz, ppm) δ 8.37-8.30 (m, 2H), 7.77-7.69 (m, 2H), 7.40-7.34 (m, 2H), 7.327.28 (m, 2H), 4.92 (d, J=16.8 Hz, 1H), 4.81-4.63 (m, 3H), 4.09 (d, J=11.8 Hz, 1H), 3.72 (d, J=11.9 Hz, 1H), 3.47 (dd, J=8.1, 6.4 Hz, 2H), 2.70 ( s, 3H), 2.64-2.46 (m, 2H).

The following compounds were prepared by methods similar to those described for compound 349:

- 264 045362

Connection No. HPMS (ES) m/z 552 M+H= 500 559 M+H=506 560 M+H=494 561 M+H=508.1 562 M+H=550.1 563 M+H=480 564 M+HM81 565 Μ+Ή=499 567 M+H=481 568 M+H=451 569 M+H=530.9 570 M+H=499.1 571 M+H=543 592 M+H=514 615 M+H=515

Example 20 Synthesis of Compound 350

1. Synthesis of intermediate 20-2

To a mixture of ethyl 3-((4-(trifluoromethyl)benzyl)amino)azetidine-3-carboxylate (1.53 g, 5.1 mmol, 1.0 eq.) and 5-cyano-2-fluoropyridine (1. 86 g, 15.2 mmol, 3.0 eq.) to NMP (15 mL) was added diisopropylethylamine (4.4 mL, 25 mmol, 5.0 eq.). The mixture was heated at 130°C for 15 min, diluted with water and extracted three times with DCM. The combined extracts were dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (0-50% ethyl acetate in hexanes, 26 min gradient) to give 1.7 g (83%) ethyl-1-(5-cyanopyridine-2- yl)-3-((4(trifluoromethyl)benzyl)amino)azetidine-3-carboxylate as a clear yellow oil. HPMS (ES) m/z 405 (M+H).

1H NMR (400 MHz, methylene chloride-b ₂ ) δ 8.43-8.41 (m, 1H), 7.69-7.61 (m, 3H), 7.59-7.53 (m, 2H) , 6.356.31 (m, 1H), 4.44-4.40 (m, 2H), 4.30 (k, J=7.1 Hz, 2H), 4.13-4.07 (m, 2H ), 3.87 (s, 2H), 1.34 (t, J=7.1 Hz, 3H).

2. Synthesis of intermediate 20-3

To a solution of ethyl 1-(5-cyanopyridin-2-yl)-3-((4-(trifluoromethyl)benzyl)amino)azetidine-3carboxylate (1.7 g, 4.2 mmol, 1.0 eq.) in DCM (17 ml) was cooled to 0°C and TEA (3.6 ml, 25 mmol, 6.0 eq.) and chloroacetyl chloride (1.4 ml, 17 mmol, 4.0 eq.) were added dropwise. The mixture was stirred at 0°C for 30 min, diluted with saturated sodium hydrogen carbonate solution and extracted three times with DCM. The combined organic extracts were dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (0-40% ethyl acetate in hexanes, gradient over 25 min) to give 2.1 g (100%) ethyl-3-(2-chloro- N-(4-(trifluoromethyl)benzyl)acetamido)-1-(5cyanopyridin-2-yl)azetidin-3-carboxylate as a clear yellow oil. HPMS (ES) m/z 481 (M+H).

1H NMR (400 MHz, methylene chloride-b ₂ ) δ 8.38-8.35 (m, 1H), 7.70-7.66 (m, 3H), 7.53-7.48 (m, 2H) , 6.366.32 (m, 1H), 4.83-4.81 (m, 2H), 4.61-4.56 (m, 2H), 4.31 (k, J=7.2 Hz, 2H ), 4.27-4.21 (m, 2H), 4.01 (s, 2H), 1.31

- 265 045362 (t, J=7.1 Hz, 3H).

3. Synthesis of intermediate 20-4

To a solution of ethyl 3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-1-(5-cyanopyridin-2yl)azetidine-3-carboxylate (214 mg, 0.45 mmol, 1.0 eq.), a solution of ammonia (7N in MeOH, 1.3 ml, 8.9 mmol, 20 eq.) was added to a round-bottom flask. The mixture was hermetically sealed, heated at 80°C for 2 hours, cooled to room. temp., diluted with water and extracted three times with EA. The combined organic extracts were dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (0-10% MeOH/DCM, gradient over 11 min) to give 185 mg (quantitative) 6-(6,9-dioxo-5-( 4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-2-yl)nicotinonitrile in the form of a clear, colorless oil. HPMS (ES) m/z 416 (M+H).

1H NMR (400 MHz, methylene chloride-02) δ 8.43 (dd, J=2.2, 0.8 Hz, 1H), 7.69 (dd, J=8.7, 2.2 Hz, 1H) , 7.667.62 (m, 2H), 7.42-7.37 (m, 2H), 6.79 (s, 1H), 6.32 (dd, J=8.7, 0.9 Hz, 1H ), 5.09 (s, 2H), 4.69-4.63 (m, 2H), 4.284.23 (m, 2H), 4.22-4.18 (m, 2H).

4. Synthesis of compound 350

20-4 Connection 350

To a mixture of copper(1) iodide (10 mg, 0.06 mmol, 0.5 eq.) and potassium carbonate (61 mg, 0.44 mmol, 4.0 eq.) in a flask, which was evacuated and purged 3 times, added bromobenzene (0.017 ml, 0.16 mmol, 1.5 eq.), N,N'-dimethylethylenediamine (0.006 ml, 0.06 mmol, 0.5 eq.), 6-(6,9-dioxo-5 -(4(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3,5]nonan-2-yl)nicotinonitrile (46 mg, 0.11 mmol, 1.0 eq.) and dioxane (1 ml). The mixture was then heated to 115°C for 15 hours, cooled to room. pace. filtered and purified by reverse phase HPLC (Phenomenex, dimer 5 µm C18 150x21.2 mm, gradient 10-100% acetonitrile in water with 0.1% formic acid over 25 min) to obtain 12 mg (22%) 6-( 6,9dioxo-8-phenyl-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-2-yl)nicotinonitrile as a white solid. HPMS (ES) m/z 492 (M+H).

1H NMR (400 MHz, methanol-I4) δ 8.38 (dd, J=2.2, 0.7 Hz, 1H), 7.77 (dd, J=8.8, 2.2 Hz, 1H) , 7.69-7.64 (m, 2H), 7.61-7.56 (m, 2H), 7.53-7.44 (m, 4H), 7.42-7.37 (m, 1H), 6.49 (dd, J=8.8, 0.8 Hz, 1H), 5.19 (s, 2H), 4.714.66 (m, 2H), 4.58 (s, 2H), 4.44-4.38 (m, 2H).

The following compounds were prepared by methods similar to those described for compound 350:

Connection No. HPMS (ES) m/z 882 Μ+Η=482Ό 883 M+H=466.1 884 M+N-500 0 885 M+H=484.0 886 M+H=507.0 887 M+H=491 _; 0

- 266 045362

Example 21. Synthesis of compound 334.

1. Synthesis of intermediate 21-2

1.4-chlorobenzyl amine, MeOH

2.4-methoxybenzylisocyanide, chloroacetic acid

21-1

Cl

21-2

To a mixture of tert-butyl-3-oxopyrrolidine-1-carboxylate (1.26 g, 6.8 mmol, 1.0 eq.) and 4-chlorobenzylamine (0.96 g, 6.8 mmol, 1.0 eq.) in MeOH (15 ml) was added with 4-methoxybenzylisocyanide (1.0 g, 6.8 mmol, 1.0 eq) and chloroacetic acid (0.64 g, 6.8 mmol, 1.0 eq). The mixture was stirred for 2 hours at room temperature, diluted with EA, washed with saturated sodium hydrogen carbonate and saturated ammonium chloride, dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (0-30% ethyl acetate in hexanes, gradient in for 25 min) to obtain 1.2 g (32%) tert-butyl-3-(2-chloro-I-(4-chlorobenzyl)acetamido)-3-((4methoxybenzyl)carbamoyl)pyrrolidine-1-carboxylate as white foam. HPMS (ES) m/z 494 (M+Ntret-butyl).

Y NMR (400 MHz, methylene chloride-b ₂ ) δ 7.41-7.37 (m, 2H), 7.25-7.18 (m, 4H), 6.92-6.87 (m, 2H) , 4.824.64 (m, 2H), 4.55-4.47 (m, W), 4.41-4.36 (m, 2H), 4.08-4.02 (m, W), 4 .01-3.96 (m, W), 3.82 (s, ZN), 3.54-3.48 (m, 1H), 3.45-3.34 (m, 1H), 3.33 -3.24 (m, 1H), 2.69-2.52 (m, 1H), 2.19-2.08 (m, 1H), 1.44 (s, 9H).

2. Synthesis of intermediate 21-3

To a solution of tert-butyl-3-(2-chloro-K-(4-chlorobenzyl)acetamido)-3-((4methoxybenzyl)carbamoyl)pyrrolidine-1-carboxylate (1.6 g, 2.9 mmol, 1.0 eq.) in THF (16 ml), cooled to 0°C, LHMDS (1.0 M in THF, 9.0 ml, 8.6 mmol, 3.0 eq.) was added dropwise. The mixture was stirred at 0°C for 1 hour, quenched with MeOH, concentrated and purified by chromatography on silica gel (0-100% ethyl acetate in hexanes, gradient over 14 minutes) to obtain 54 mg (4%) tert-butyl 6-(4- chlorobenzyl)-9-(4-methoxybenzyl)-7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2-carboxylate as a clear, colorless oil.

'H NMR (400 MHz, methylene chloride-a ₂ ) δ 7.23-6.68 (m, 8H), 5.11-4.62 (m, 2H), 4.53-4.13 (m, ZN ), 3.913.79 (m, 1H), 3.69-3.57 (m, ZN), 3.51-3.22 (m, ZN), 2.43-1.95 (m, 2H), 1.39-1.20 (m, 9H).

3. Synthesis of intermediate 21-4

To a solution of tert-butyl-6-(4-chlorobenzyl)-9-(4-methoxybenzyl)-7,10-dioxo-2,6,9-triazaspiro[4,5]decane-2-carboxylate (0.055 g, 0 .11 mmol, 1.0 eq.) in DCM (1 ml) was added TFA (0.080 ml, 1.0 mmol, 10 eq.). The mixture was heated at 40°C for 1 hour, concentrated and vacuum dried for 2 hours to obtain 56 mg (quantitative) 6-(4-chlorobenzyl)-9-(4-methoxybenzyl)-2,6,9 triazaspiro [4 ,5]decane-7,10-dione as TFA salt. HPMS (ES) m/z 414 (M+H).

-267 045362

4. Synthesis of compound 334

To a solution of TFA salt 6-(4-chlorobenzyl)-9-(4-methoxybenzyl)-2,6,9-triazaspiro[4.5]decane-7,10-dione (56 mg, 0.11 mmol, 1.0 equiv .) in DCM (1 ml) cooled to 0°C, TEA (0.06 ml, 0.4 mmol, 4 eq.) and methyl isocyanate (9 mg, 0.2 mmol, 1.5 eq.) were added. The mixture was stirred at 0°C for 30 min, concentrated and purified by reverse phase HPLC (Phenomenex, dimeric 5 µm C18 150x21.2 mm, gradient 10-70% acetonitrile in water with 0.1% formic acid over 25 min) to obtain 46 mg (90%) 6(4-chlorobenzyl)-9-(4-methoxybenzyl)-N-methyl-7,10-dioxo-2,6,9-triazaspiro[4.5]decane-2-carboxamide as clear colorless oil. HPMS (ES) m/z 471 (M+H).

1H NMR (400 MHz, methanol- _d4 ) δ 7.36-7.31 (m, 2H), 7.29-7.23 (m, 2H), 7.20-7.14 (m, 2H) , 6.98-6.93 (m, 2H), 4.87-4.81 (m, 1H), 4.66-4.59 (m, 3H), 4.17-4.06 (m, 2H), 3.98-3.93 (m, 1H), 3.82 (s, 3H), 3.63-3.58 (m, 1H), 3.55-3.44 (m, 2H) , 2.71 (s, 3H), 2.47-2.39 (m, 2H).

Example 22 Synthesis of compound 202.

1. Synthesis of intermediate 22-2 d'e-/ _t

...... θ Ύη λ—S

Ρ million AXIS Γ(4 •gigs _Ζ Ν·'··' ⁵ &

4-(Trifluoromethyl)benzaldehyde ( 15.7 g, 90.2 mmol, 1.10 eq.) and AcOH (9.8 g, 163.2 mmol, 2.0 eq.) at room. pace. The mixture was stirred for 10 minutes. To this mixture was added STAB (26 g, 122.676 mmol, 1.50 eq.) in portions. The mixture was stirred for 4 hours, quenched with water (200 ml) and extracted twice with DCM (200 ml). The combined organic layers were washed with aqueous NaHCO ₃ (200 ml) and twice with brine (200 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 33 g of 1-tert-butyl-3-ethyl-3-([[ 4(trifluoromethyl)phenyl]methyl]amino)azetidine-1,3-dicarboxylate (crude) as a yellow oil. HPMS (ES) m/z 347 (M+H-56).

2. Synthesis of intermediate 22-3

To a mixture of 1-tert-butyl-3-ethyl-3-([[4-(trifluoromethyl)phenyl]methyl]amino)azetidine-1,3dicarboxylate (33 g, 82.005 mmol, 1 eq.) in DCM (300 ml) and K ₂ CO ₃ (17 g, 123.0 mmol, 1.50 eq., 0.5) in water (246 ml) was cooled to 0°C, 2-bromoacetyl bromide (19.8 g, 98.1 mmol, 1.2 eq.) dropwise over a period of 15 min. The mixture was stirred at room. pace. overnight and extracted twice with DCM (300 ml). The combined organic layers were washed twice with brine (300 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 42 g (95%) 1t-butyl-3-ethyl-3-(2-bromo-N-[ [4-(trifluoromethyl)phenyl]methyl]acetamido)azetidine-1,3-dicarboxylate as a yellow oil. HPMS (ES) m/z 467 (M+H-56).

- 268 045362

3. Synthesis of intermediate 22-4

22-4

To 1-tert-butyl-3-ethyl-3-(2-bromo-N-[[4-(trifluoromethyl)phenyl]methyl]acetamido)azetidine-1,3dicarboxylate (42 g, 80.3 mmol, 1 eq. ) NH ₃ in MeOH (7 M, 300 ml) was added to a round bottom flask. The mixture was stirred at room. pace, overnight, concentrated under reduced pressure and diluted with EtOAc (300 ml). The solid was collected and dried to yield 29 g (87%) tert-butyl 6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonane-2-carboxylate as a white solid. HPMS (ES) m/z 358 (M+H-56).

4. Synthesis of intermediate 22-5

22-5

To a solution of tert-butyl-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonane2-carboxylate (33 g, 79.8 mmol, 1 eq. .) in ACN (330 ml) at room. temp, 3,4difluorobenzonitrile (16.6 g, 119.3 mmol, 1.5 eq.) and CS2CO3 (52 g, 159.6 mmol, 2.0 eq.) were added. The mixture was stirred at 80°C for 2 days, cooled to room. temp, and filtered to remove solids. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography using EA/MeOH (7:3) as eluent and again by reverse phase chromatography using ACN/water (35-45% gradient over 20 min) to give 20 g (45%) tert-butyl-8(4-carbamoyl-2-fluorophenyl)-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5] nonane2-carboxylate as a white solid with a metallic tint. HPMS (ES) m/z 495 (M+H56).

5. Synthesis of intermediate 22-6

To a solution of tert-butyl-8-(4-carbamoyl-2-fluorophenyl)-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonan- 2-carboxylate (20 g, 36.3 mmol, 1 eq.) in DCM (200 ml) cooled at 0°C, TEA (11 g, 108.7 mmol, 3.0 eq.) and TFUA (15 g. 71.4 mmol, 2.0 eq.). The mixture was stirred at room. temp, overnight, quenched with water (200 ml) and extracted twice with DCM (200 ml). The combined organic layers were washed twice with brine (300 ml), dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, purified by silica gel chromatography using PE/EtOAc (1:2) as eluent to give 13 g (68% ) tert-butyl-8-(4-cyano-2fluorophenyl)-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonane-2-carboxylate in the form of a yellow oil. HPMS (ES) m/z 477 (M+H-56).

6. Synthesis of intermediate 22-7

-269045362

To a solution of tert-butyl-8-(4-cyano-2-fluorophenyl)-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]2,5,8-triazaspiro[3.5]nonane-2 -carboxylate (13 g, 24.4 mmol, 1 eq.) in DCM (120 ml) was added TFA (30 ml) at room. pace. The mixture was stirred at room. pace. for 4 h and concentrated under reduced pressure to obtain 10 g (98%) 4-(6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8triazaspiro[3.5]nonan- 8-yl)-3-fluorobenzonitrile in the form of TFA salt. HPMS (ES) m/z 433 (M+H).

7. Synthesis of compound 202

To a solution of 4-(6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3,5]nonan-8-yl)-3fluorobenzonitrile (10 g, 23 .1 mmol, 1 eq.) in DCM (100 ml) at room. pace. acetyl acetate (3.5 g, 34.3 mmol, 1.5 eq) and TEA (7 g, 69.2 mmol, 3.0 eq) were added. The mixture was stirred at room. pace. for 3 h, quenched with water (100 ml) and extracted twice with DCM (100 ml). The combined organic layers were washed twice with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and purified by reverse phase chromatography using ACN/water (10 M NH4HCO3, gradient from 35-45% over 20 min ) to obtain 7.8 g (70%) 4-(2-acetyl6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)- 3-fluorobenzonitrile in the form of a white solid with a metallic tint. HPMS (ES) m/z 475 (M+H).

1H NMR (400 MHz, methanol-d ₄ , ppm) δ 7.83-7.77 (m, 1H), 7.77-7.67 (m, 4H), 7.57 (d, J =8.1 Hz, 2H), 4.86 (s, 2H), 4.75-4.68 (m, 1H), 4.60-4.55 (m, 2H), 4.55-4, 47 (m, 2H), 4.25 (d, J=11.0 Hz, 1H), 1.87 (s, 3H).

Example 23. Synthesis of compound 169.

1. Synthesis of intermediate 23-2

23-1 23-2

To a solution of 1-(tert-butyl)-3-ethyl-3-aminoazetidine-1,3-dicarboxylate (6.0 g, 24.6 mmol, 1.0 eq.) in a mixture of THF (30 ml) and DCE ( 10 ml) 4-trifluoromethylbenzaldehyde (6.4 g, 36.8 mmol, 1.5 eq.) was added. The mixture was stirred for 15 minutes. STAB (26.0 g, 123 mmol, 5.0 eq.) and AcOH (5 ml) were added to this mixture. The mixture was stirred for 2 hours, evaporated under reduced pressure and partitioned between DCM (60 ml) and saturated aqueous sodium hydrogen carbonate (60 ml). The layers were separated and the aqueous phase was extracted with DCM (25 ml). The combined organic phases were dried over sodium sulfate, filtered through celite, concentrated under reduced pressure and purified by silica gel chromatography using EtOAc/hexanes (0-100% gradient) to give 9.4 g (95%) 1-(tert- butyl)-3ethyl-3-((4-(trifluoromethyl)benzyl)amino)azetidine-1,3-dicarboxylate. HPMS (ES) m/z 347.1 (M+H-tBu).

2. Synthesis of intermediate 23-3

23-2 33 3

To a solution of 1-(tert-butyl)-3-ethyl-3-((4-(trifluoromethyl)benzyl)amino)azetadine-1,3-dicarboxylate (5.0 g, 12.4 mmol, 1.0 eq. ) in DCM (50 ml) at 0°C were added TEA (8.7 ml, 62.1 mmol, 5.0 eq.) and chloroacetyl chloride (4.0 ml, 49.7 mmol, 4.0 eq.). The ice bath was removed and the mixture was stirred at room. pace. for 60 hours before pouring into saturated aqueous NH ₄ Cl (200 ml). The layers were separated and the aqueous layer was extracted with DCM three times. The combined organic layers were dried over MgSO ₄ and concentrated under reduced pressure to give 1-(tert-butyl)-3-ethyl-3-(2-chloro-N-(4(trifluoromethyl)benzyl)acetamido)azetidine-1,3- dicarboxylate. The product was used directly in the next reaction without further purification.

- 270 045362

3. Synthesis of intermediate 23-4

To a solution of 1-(tert-butyl)-3-ethyl-3-(2-chloro-^(4-(trifluoromethyl)benzyl)acetamido)azetidine-1,3dicarboxylate (5.75 g, 12.4 mmol) in the microwave 7 M NH ₃ in MeOH (7 N, 30 ml) was added to the vessel. The mixture was sealed, heated at 100°C in a microwave reactor for 1 hour, concentrated under reduced pressure and purified by silica gel chromatography using EtOAc/hexanes 9 gradient from 0-100%) and MeOH/DCM (isocratic at 20%) in as eluent to obtain 3.6 g (70% in 2 steps) tert-butyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2carboxylate in as a white solid. HPMS (ES) m/z 358.1 (M+H-tBu).

II NMR (methanol-d4, 400 MHz, ppm) δ 7.68 (d, J=7.7 Hz, 2H), 7.50 (d, J=7.9 Hz, 2H), 5, 06 (s, 2H), 4.41 (d, J=9.7 Hz, 2H), 4.19-3.93 (m, 4H), 1.44 (s, 9H). Intermediate 23-4 has a structure similar to intermediate 22-4. In some embodiments, intermediate 23-4 is prepared according to steps 1-3 in Example 22. In some embodiments, intermediate 22-4 is prepared according to steps 1-3 in Example 23.

4. Synthesis of intermediate 23-5

To a mixture of copper iodide (12 mg, 0.06 mmol, 0.5 eq.), potassium carbonate (67 mg, 0.48 mmol, 4 eq.), 4bromo-3-fluorobenzonitrile (36 mg, 0.18 mmol, 1.5 equiv.) and tert-butyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylate (50 mg, 0.12 mmol , 1.0 eq.) dioxane (1 ml) and N,N'-dimethylethylenediamine (7 μl, 0.06 mmol, 0.5 eq.) were added to the vessel (3.0 ml). The mixture was hermetically sealed in a vessel, heated at 100°C for 15 hours, cooled to room temperature. temp., filtered and concentrated under reduced pressure to give tert-butyl-8-(4-cyano-2-fluorophenyl)6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro [3.5]nonane-2-carboxylate, which was used in the next step without purification.

5. Synthesis of intermediate 23-6

To a solution of tert-butyl-8-(4-cyano-2-fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8triazaspiro[3.5]nonane-2-carboxylate (64 mg, 0.12 mmol) to DCM (2 ml) was added TFA (2 ml). The mixture was stirred at room. pace. for 45 min and then concentrated to give 4-(6,9-dioxo-5(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)-3-fluorobenzonitrile in as a glassy solid. The product was used in the next reaction without further purification.

6. Synthesis of compound 169

To a solution of 4-(6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)-3fluorobenzonitrile (52 mg, 0.12 mmol) in DXM (2 ml) was added successively with TEA (0.5 ml) and methyl

- 271 045362 lysocyanate (15 mg, 0.26 mmol, 2.2 eq.). The mixture was stirred for 15 min, concentrated under reduced pressure and purified by reverse phase HPLC (Phenomenex, dimeric 5 µm C18 150x21.2 mm, gradient 10-100% acetonitrile in water with 0.1% formic acid over 40 min) with obtaining 15.6 mg (yield 27% in 3 stages) 8-(4-cyano-2-fluorophenyl)-X-methyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)-2,5,8 -triazaspiro[3.5]nonane-2-carboxamide as a white foamy solid. HPMS (ES) m/z 490.2 (M+H).

Ή NMR (methanol-sc, 400 MHz, ppm) δ 7.82-7.77 (m, 1H), 7.75-7.67 (m, 4H), 7.57 (d, J= 8.6 Hz, 2H), 5.15 (s, 2H), 4.56 (s, 2H), 4.48 (d, J=9.5 Hz, 2H), 4.17 (d, J= 9.5 Hz, 2H), 2.68 (s, ZN).

The following compounds were prepared by methods similar to those described for compound 169:

Connection No. HPMS (ES) m/z 145 M+H=477.2 146 M+H=472.1 147 M+H=473.1 148 M+H=505.1 149 M+H=465.2 150 M+H=481.1 151 M+H=515.1 152 M+H=483.2 153 M+H=461.1 154 M+H=478.2 155 M+H=499.1 156 M+H=482.1 157 M+H=497.1 158 M+H=487.2 159 M+H=513.1 160 Ί6Ϊ Ϊ62 M+H-531.1 MYhAsz/ M+N=49OD............. 163 M+HM81.1 164 M+H=438.1 165 M+H=565.2 186 187 M+H=457.1 M+H=471.2 188 M+N-473.1 189 M+NA88.1 190 M+H=443.1 191 M+H=479.2 193 M+H=497.2 194 M-N=459.2 198 M+N=506D

-272 045362

196 No mass signal 197 M+H>75.1 Ϊ98 .......... 199 M+N-516.2 200 No mass product 201 M+N-504.2 1b................................... M+N=495D...... 167................................... ................ 168 Μ+Η=499 _η 1 Ϊ70 M+4=495.1 171 M+N-531.1 203 M+N-501.1 204 M+H=476.1 172 M+H=551.2 173 M+H=530.2 174 M+N^bOZD 175 M+H=441.1 176 M+H=425.1 177 M+H=515.1 178 M+H=529.2 179 M+H=461.1 180 M+H=515.1 181 M+H=555.1 182 M+H=451.1 566 M+H=487 593 M+H=521

Example 24 Synthesis of compound 335.

1. Synthesis of intermediate 24-1

22-4 or 23-4 24-1

To a mixture of tert-butyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2carboxylate (50 mg, 0.12 mmol, 1.0 eq. ) and 4-(trifluoromethyl)benzyl bromide (32 mg, 0.13 mmol, 1.1 eq.) in DMF (1 ml) was added NaH (60% in mineral oil, 5 mg, 0.13 mmol, 1.1 eq. .) at 0°C. The mixture was stirred at 0°C for 30 min, quenched with water and extracted three times with EA. The combined organic washes were dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (0-100% ethyl acetate in hexanes, gradient over 1 min) to give 33 mg (48%) tert-butyl-6,9-dioxo-5 ,8-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2carbokeylate as a clear, colorless oil. HPMS (ES) m/z 516 (M+H-tert-butyl).

2. Synthesis of intermediate 24-2

24-1 24-2

To a mixture of tert-butyl-6,9-dioxo-5,8-bis(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2carboxylate (33 mg, 0.058 mmol, 1.0 eq. .) in DCM (1 ml) was added TFA (0.10 ml, 1.3 mmol, 22 eq.)

-273 045362 at room. pace. The mixture was heated at 40°C for 2 hours, concentrated and vacuum dried to obtain 34 mg (100%) of 5,8-bis(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane -6,9-dione 2,2,2-trifluoroacetate as a clear yellow oil. HPMS (ES) m/z 472 (M+H).

3. Synthesis of compound 335

To a solution of 5,8-bis(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione 2,2,2trifluoroacetate (34 mg, 0.06 mmol, 1.0 eq.) in DCM (1 ml) was cooled to 0°C, TEA (32 μl, 0.23 mmol, 4.0 eq.) and methyl isocyanate (5 mg, 0.087 mmol, 1.5 eq.) were added. The mixture was stirred at 0°C for 30 min, concentrated and purified by reverse phase HPLC (Phenomenex, dimeric 5 µm C18 150x21.2 mm, gradient 10-100% acetonitrile in water with 0.1% formic acid over 25 min) to give 21 mg (69%) N-methyl-6,9-dioxo-5,8-bis(4-(trifluoromethyl)benzyl)-2,5,8triazaspiro[3.5]nonane-2-carboxamide as a white solid . HPMS (ES) m/z 529 (M+H).

1H NMR (400 MHz, methanol) δ 7.73-7.69 (m, 2H), 7.69-7.64 (m, 2H), 7.60-7.56 (m, 2H), 7. 52-7.47 (m, 2H), 5.08 (s, 2H), 4.79 (s, 2H), 4.48-4.43 (m, 2H), 4.14 (s, 2H) , 4.12-4.05 (m, 2H), 2.70 (s, 3H).

Example 25. Synthesis of compound 192.

1. Synthesis of intermediate 25-1

To a mixture of tert-butyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2carboxylate (0.871 g, 2.11 mmol, 1.0 eq. ), 4-bromobenzonitrile (0.575 g, 3.16 mmol, 1.5 eq.), copper(I) iodide (0.201 g, 1.05 mmol, 0.50 eq.) and potassium carbonate (0.873 g, 6. 32 mmol, 3.0 eq.) suspended in anhydrous 1,4-dioxane, N,N'-dimethylethylenediamine (0.11 ml, 1.0 mmol, 0.50 eq.) was added. The mixture was purged with nitrogen, hermetically sealed and heated at 100°C for 15 hours, cooled to room. temp., filtered through Celite, concentrated and purified by silica gel chromatography using EtOAc/hexanes (gradient 0-100%) to give 0.968 g (89%) tert-butyl-8-(4-cyanophenyl)6,9- dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylate as a white foam. HPMS (ES) m/z 459 (M+H-tert-butyl).

2. Synthesis of intermediate 25-2

To a solution of tert-butyl-8-(4-cyanophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8triazaspiro[3.5]nonane-2-carboxylate (0.968 g, 1. 88 mmol, 1.0 eq.) in DCM (14 ml) was added TFA (1.4 ml, 19 mmol, 10 eq.). The mixture was heated at 40°C for 3 hours, concentrated, diluted with saturated aqueous sodium hydrogen carbonate and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to give 0.751 g (96%) 4-(6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5 ]nonan-8yl)benzonitrile in the form of a white foam. HPMS (ES) m/z 415 (M+H).

1H NMR (400 MHz, methylene chloride-d ₂ ) δ 7.70-7.66 (m, 2H), 7.57-7.53 (m, 2H), 7.46-7.42 (m, 2H) , 7.387.34 (m, 2H), 5.19 (s, 2H), 4.34 (s, 2H), 4.31-4.24 (m, 2H), 3.74-3.66 (m , 2H).

- 274 045362

3. Synthesis of compound 192

2^2 Connection 192

To a mixture of 4-(6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)benzonitrile (67 mg, 0.16 mmol, 1, 0 eq.) and 5-cyano-2-fluoropyridine (0.024 g, 0.19 mmol, 1.2 eq.) in DMF (1 ml) was added DIEA (0.042 ml, 0.24 mmol, 1.5 eq.) . The mixture was heated at 100°C for 15 hours, cooled to room. pace. and purified by reverse phase HPLC (Phenomenex, dimer 5 µm C18 150x21.2 mm, gradient 10-100% acetonitrile in water with 0.1% formic acid over 25 min) to obtain 40 mg (48%) 6-(8 -(4-cyanophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-2yl)nicotinonitrile in the form of a clear, colorless oil. HPMS (ES) m/z 517 (M+H).

1H NMR (400 MHz, methanol-d ₄ ) δ 8.38 (dd, J=2.2, 0.8 Hz, 1H), 7.89-7.83 (m, 2H), 7.77 (dd , J=8.8, 2.2 Hz, 1H), 7.72-7.68 (m, 2H), 7.68-7.63 (m, 2H), 7.60-7.55 (m , 2H), 6.49 (dd, J=8.8, 0.8 Hz, 1H), 5.18 (s, 2H), 4.714.66 (m, 2H), 4.64 (s, 2H) , 4.43-4.38 (m, 2H).

Example 26. Synthesis of compound 336.

1. Synthesis of intermediate 26-1

To a mixture of tert-butyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2carboxylate (0.050 g, 0.12 mmol, 1.0 eq. ) and 4-(bromomethyl)benzonitrile (25 mg, 0.13 mmol, 1.1 eq.) in DMF (1 ml) at 0°C was added NaH (60% in mineral oil, 5 mg, 0.13 mmol, 1.1 eq) at 0°C, and then 60% sodium hydride in mineral oil (0.005 g, 0.13 mmol, 1.1 eq) was added. The mixture was stirred at 0°C for 30 min, quenched with water and extracted three times with EA. The combined organic washes were dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (0-100% ethyl acetate in hexanes, gradient over 11 min) to give 55 mg (87%) tert-butyl-8-(4-cyanobenzyl) -6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8triazaspiro[3.5]nonane-2-carboxylate as a clear, colorless oil. HPMS (ES) m/z 473 (M+H-tert-butyl).

2. Synthesis of intermediate 26-2

To a mixture of tert-butyl-8-(4-cyanobenzyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8triazaspiro[3.5]nonane-2-carboxylate (55 mg, 0. 10 mmol, 1.0 eq.) in DCM (1 ml) was added TFA (0.10 ml, 1.3 mmol, 12 eq.) at room. pace. The mixture was heated at 40°C for 2 hours, concentrated and vacuum dried to give 57 mg (100%) 4-((6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8 triazaspiro [3.5]nonan-8-yl)methyl)benzonitrile 2,2,2-trifluoroacetate as a clear yellow oil. HPMS (ES) m/z 429 (M+H).

- 275 045362

3. Synthesis of compound 336

4-((6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8 dissolved yl)methyl)benzonitrile 2,2,2-trifluoroacetate (57 mg, 0.10 mmol, 1.0 eq.) in DCM (1 ml) was cooled to 0°C, TEA (59 μl, 0.42 mmol, 4.0 eq.) and methyl isocyanate (9 mg, 0.087 mmol, 1.0 eq.) were added. 5 eq.). The mixture was stirred at 0°C for 30 min, concentrated and purified by reverse phase HPLC (Phenomenex, dimeric 5 µm C18 150x21.2 mm, 10-80% acetonitrile in water both with 0.1% formic acid for 25 min) to give 32 mg (62%) 8-(4-cyanobenzyl)-N-methyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2- carboxamide as a white solid. HPMS (ES) m/z 486 (M+H).

1H NMR (400 MHz, DMSO- _d6 ) δ 7.89-7.84 (m, 2H), 7.74-7.69 (m, 2H), 7.57-7.47 (m, 4H) , 6.43-6.38 (m, 1H), 4.94 (s, 2H), 4.69 (s, 2H), 4.28-4.20 (m, 2H), 4.08 (s , 2H), 3.91-3.83 (m, 2H), 2.54-2.47 (m, 3H).

Example 27. Synthesis of compound 338.

1. Synthesis of intermediate 27-1

To a solution of tert-butyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2carboxylate and 4-(1-bromoethyl)benzonitrile (50 mg, 0 .12 mmol, 1.0 eq.) NaH (5 mg of 60% dispersion in mineral oil, 0.13 mmol, 1.1 eq.) was added to DMF (1 ml) at 0°C. The resulting mixture was stirred at 0°C for 1 hour, quenched by adding water (1 ml) dropwise and extracted with EA three times. The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated under reduced pressure and purified on silica gel using a gradient of 0-100% EtOAc/hexanes to give 58 mg (88%) tert-butyl-8-(1-(4 -cyanophenyl)ethyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2-carboxylate in the form of a clear, colorless oil. HPMS (ES) m/z 487 (M+H-tert-butyl).

2. Synthesis of intermediate 27-2

To a solution of tert-butyl-8-(1-(4-cyanophenyl)ethyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8triazaspiro[3.5]nonane-2-carboxylate ( 58 mg, 0.11 mmol, 1.0 eq.) to DCM (1 mL) was added trifluoroacetic acid (0.082 mL, 1.1 mmol, 10 eq.). The mixture was heated at 40°C for 1 hour and then concentrated under reduced pressure to obtain 59 mg (100%) 4-(1-(6,9-dioxo-5-(4(trifluoromethyl)benzyl)-2,5 ,8-triazaspiro[3.5]nonan-8-yl)ethyl)benzonitrile 2,2,2-trifluoroacetate as a yellow oil. HPMS (ES) m/z 443 (M+H).

- 276 045362

3. Synthesis of compound 338

27-2 ns- ZZY

To a solution of 4-(1-(6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8yl)ethyl)benzonitrile 2,2,2-trifluoroacetate ( 59 mg, 0.11 mmol, 1.0 eq.) in dry DCM (1 ml) at 0°C added TEA (59 μl, 0.42 mmol, 4.0 eq.) and methyl isocyanate (9 mg, 0.0 eq.) 16 mmol, 1.5 eq.). The mixture was stirred at 0°C for 30 min, concentrated and purified by reverse phase HPLC (Phenomenex, dimeric 5 µm C18 150x21.2 mm, gradient 10-80% acetonitrile in water with 0.1% formic acid over 25 min) to give 34 mg (63%) 8-(1-(4-cyanophenyl)ethyl)-N-methyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5 ]nonane-2-carboxamide as a clear red oil. HPMS (ES) m/z 500 (M+H).

1H NMR (400 MHz, methanol^) δ 7.81-7.76 (m, 2H), 7.69-7.64 (m, 2H), 7.63-7.58 (m, 2H), 7 ,50-7.45 (m, 2H), 5.95 (k, J=7.1 Hz, 1H), 5.06 (s, 2H), 4.46-4.40 (m, 2H), 4.21-4.13 (m, 1H), 4.11-4.03 (m, 2H), 3.74-3.65 (m, 1H), 2.69 (s, 3H), 1. 67 (d, J=7.2 Hz, 3H).

Example 28 Synthesis of compound 216.

1. Synthesis of intermediate 28-2

O I) iks. MUN, hsxY&s. opinion 24 h * h * M' 2} M . H

Ύ I / Еы »2

This stage corresponds to the method published in Aust. J. Chem., 1993, 46, 73-93 and Org. Biomol. Chem., 2010, 8, 5120-5125. (S)-S-Methylcysteine (5.61 g, 41.5 mmol) was treated with a solution of NaOH (1.7 g, 41.5 mmol, 1 eq.) in water (25 ml) and after 5 min the resulting homogeneous solution was evaporated to dryness under reduced pressure to obtain a white solid. To this mixture was added a solution of pivaldehyde (5.35 g, 62.2 mmol, 1.5 eq.) in hexanes (75 ml). The resulting suspension was heated to boiling while stirring for 24 h with a Dean-Stark trap to remove water. Refluxing was interrupted periodically to scrape solid material from the sides of the flask to facilitate mixing. After refluxing for 24 hours, the reaction mixture was evaporated to dryness to obtain a white solid. Benzyl chloroformate (8.88 mL, 62.2 mmol, 1.5 eq.) was added to a white solid suspended in DCM (75 mL) cooled to 0°C in an ice bath. The resulting mixture was stirred at room. pace. for 36 hours, quenched with saturated aqueous NaHCO ₃ (50 ml), stirred for 3 hours, and the layers were separated. The aqueous phase was extracted with DCM (50 ml). The combined organic phases were dried over sodium sulfate, concentrated under reduced pressure and purified by chromatography on silica gel using EA/HE (1/9) as eluents to give 3.0 g (21%) benzyl-(2R,4S)-2 -(tert-butyl)-4((methylthio)methyl)-5-oxooxazolidine-3-carboxylate (visualized with iodine) as a viscous colorless oil, HPMC (CIAD) m/z 338.2 (M+H).

1H NMR (400 MHz, chloroform-d) δ 7.35-7.28 (m, 5H), 5.48 (s, 1H), 5.12 (d, J=1.7 Hz, 2H), 4 .43 (dd, J=7.9, 5.7 Hz, 1H), 2.93 (dd, J=14.0, 8.0 Hz, 1H), 2.79 (dd, J=14.0 , 5.7 Hz, 1H), 2.03 (s, 3H), 0.89 (s, 9H).

2. Synthesis of intermediate 28-3

To a solution of benzyl-(2R,4S)-2-(tert-butyl)-4-((methylthio)methyl)-5-oxooxazolidine-3-carboxylate (2.95 g, 8.7 mmol) in DCM (100 ml ) m-CPBA (3.77 g, 21.8 mmol, 2.5 eq.) was added. The resulting solution was stirred at room. pace. for 18 hours and quenched with saturated aqueous NaHCO ₃ (150 ml). The aqueous phase was extracted with DCM (50 ml). The combined organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure and purified by chromatography on silica gel using EA/Hex (1/3) as eluent to give 3.1 g (95%) benzyl-(2R,4S) -2-(tert-butyl)4-((methylsulfonyl)methyl)-5-oxooxazolidine-3-carboxylate. HPMS (CIAD) m/z 370.1 (M+H).

1H NMR (400 MHz, chloroform-d) δ 7.46-7.37 (m, 5H), 5.65 (s, 1H), 5.34-5.20 (m, 2H), 5.01 ( dd, J=8.0, 3.7 Hz, 1H), 3.60 (dd, J=15.1, 8.0 Hz, 1H), 3.49-3.36 (m, 1H), 3 .14 (s, 3H), 0.97 (s, 9H).

- 277 045362

3. Synthesis of intermediate 28-4

RVCDHM ^z Cbz

2SS _W

At this stage the method published in Org. Biomol. Chem., 2010, 8, 5120-5125. To a solution of benzyl-(2K.48)-2-(tert-butyl)-4-((methylsulfonyl)methyl)-5-oxooxazolidine-3-carboxylate (3.05 g, 8.3 mmol) in DCM (50 ml ) cooled to 0°C with an ice bath, DBU (1.36 mL, 9.1 mmol, 1.1 eq.) was added dropwise. The resulting solution was stirred at 0°C for 30 min, diluted with water (50 ml), and the layers were separated. The organic phase was washed twice with additional water (50 ml), dried over sodium sulfate, concentrated under reduced pressure and purified through a short plug of silica gel using EA/Hex (1/2) as eluents to give 2.3 g (94% ) benzyl (K)-2-(tert-butyl)-4-methylene-5-oxooxazolidine-3-carboxylate as a colorless oil. HPMS (CIAD) m/z 290.0 (M+H).

'n NMR (400 MHz, chloroform-d) δ 7.46-7.37 (m, 5H), 5.79-5.58 (m, ZH), 5.28 (d, J=1.5 Hz , 2H), 0.96 (s, 9H).

4. Synthesis of intermediate 28-5

28-4 ^{26 5}

At this stage the method published in Tetrahedron Letters, Vol. 33, No. 45, pp. 6755-6758, 1992 and Synthetic Communications, 25(9), 1295-1302 (1995). To a solution of benzyl-(K)-2-(tert-butyl)-4-methylene-5-oxooxazolidine-3-carboxylate (1.49 g, 5.1 mmol) in DCM (25 ml) was added N(methoxymethyl)-K- (trimethylsilylmethyl)benzylamine (3.95 ml, 15.4 mmol, 3 eq.). To the resulting solution, cooled to 0°C in an ice bath, TFA (0.079 ml, 0.2 eq.) was added dropwise. The mixture was stirred at 0°C for 5 minutes and the ice bath was removed. The mixture was stirred at room. pace, over 1 h, diluted with DCM (40 ml), washed with saturated aqueous XaHCO3 (50 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel chromatography using EA/HE (1/4) as eluents to give 2.2 g (96%) benzyl-(2K.58)-7-benzyl-2(tert-butyl)-4-oxo-3-oxa-1,7-diazaspiro[4.4]nonane-1- carboxylate (2.20 g, 4.9 mmol, 96% yield) as a colorless viscous oil. HPMS (CIAD) m/z 423.3 (M+H).

'n NMR (400 MHz, DMSO-ds) δ 7.45-7.32 (m, 5H), 7.28-7.17 (m, 5H), 5.58 (s, 1H), 5.16 (d, J=12.l Hz, 1H), 5.09 (d, J=12.2 Hz, 1H), 3.46 (s, 2H), 3.01-2.58 (m, 4H) , 2.22 (t, J=6.5 Hz, 2H), 0.83 (s, 9H).

5. Synthesis of intermediate 28-6

To a solution of benzyl-(2E.58)-7-benzyl-2-(tert-butyl)-4-oxo-3-oxa-1,7-diazaspiro[4,4]nonane-1carboxylate (2.18 g, 5 .2 mmol) in MeOH (30 ml), NaOMe (2.8 ml 25% in MeOH) was added dropwise at room. pace. The resulting mixture was stirred at room. temp for 30 min and diluted with EA Ac (200 ml), saturated NH ₄ C1 (100 ml) and water (100 ml). The layers were separated and the aqueous phase was extracted with EA Ac (100 ml). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel chromatography using EA/HE (1/1) as eluents to give 1.8 g (94%) methyl-(8) -1-benzyl-3(((benzyloxy)carbonyl)amino)pyrrolidine-3-carboxylate as a colorless sticky solid. HPMS (CIAD) m/z 369.2 (M+H).

Ή NMR (400 MHz, methanol-BD) δ 7.37-7.18 (m, JH), 5.04 (s, 2H), 3.73-3.43 (m, 5H), 3.12 ( d, >10.7 Hz, 1H), 2.89 (d, >10.7 Hz, 1H), 2.84-2.74 (m, 1H), 2.61 (dt, >9.3, 7.1 Hz, 1H), 2.40 (ddd, >13.2, 7.4, 5.6 Hz, 1H), 2.05 (dt, >13.6, 7.0 Hz, 1H).

6. Synthesis of intermediate 28-7

Concentrated HC1 (0.150 ml) and palladium (5% on carbon,

-278 045362

300 mg). The resulting mixture was purged with hydrogen for 30 minutes and then stirred at room temp under a hydrogen atmosphere (1 atm) for 18 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give 691 mg (61%) methyl -(8)-3aminopyrrolidine-3-carboxylate dihydrogen chloride in the form of a sticky salt. HPMS (CIAD) m/z 145.1 (M+H).

'n NMR (400 MHz, methanol-sc) δ 3.73 (s, ZH), 3.42-3.31 (m, 2H), 3.28-3.20 (m, 1H), 3.03 (d, J=11.9 Hz, 1H), 2.29 (dt, >13.3, 8.5 Hz, 1H), 1.92 (td, >8.0, 3.9 Hz, 1H) .

7. Synthesis of intermediate compound 28-8 wL G Voc/X Bod/

7

To a solution of methyl (8)-3-aminopyrrolidine-3-carboxylate dihydrogen chloride (631 mg, 2.9 mmol) in DCM (20 mL) was added TEA (3.1 mL, 22.0 mmol, 7.6 eq.) and (Boc) _2O (960 mg, 4.4 mmol, 1.5 eq.) in DCM (5 ml). The resulting solution was stirred at room. temp, for 15 min, quenched with diethylamine (0.453 ml, 4.4 mmol, 1.5 eq.), stirred at room. pace for 15 min, washed with saturated aqueous NaHCOa (25 ml), dried over sodium sulfate, concentrated and purified by silica gel chromatography using EA/HE (0-100% gradient) to give 656 mg (61%) 1- (tert-butyl)-3-methyl(S)-3-aminopyrrolidine-1,3-dicarboxylate. HPMS (CIAD) m/z 189.1 (M+H)-C ₄ H ₉ ).

'H NMR (400 MHz, methanol-sc) δ 3.77 (s, ZH), 3.72 (dd, >11.2, 4.4 Hz, 1H), 3.53 (dk, >8.4 ,4.6, 3.7 Hz, 2H), 3.32-3.31 (m, 1H), 2.33 (dk, >12.8, 8.2 Hz, 1H), 2.00-1 .88 (m, 1H), 1.48 (s, 9H).

8. Synthesis of intermediate 28-9

O 1_

VmN 1 ^MI · i. J fMWAch Β«Ν ί * .......

F ₃ C'V

AS2S-G

To a mixture of 1-(tert-butyl)-3-methyl (S)-3-aminopyrrolidine-1,3-dicarboxylate (1.20 g, 4.91 mmol) and p-trifluoromethylbenzaldehyde (1.71 g, 9.8 mmol, 2.0 eq.) in a mixture of THF (30 ml) and DCE (10 ml) was added HO Ac (1 ml). The resulting mixture was stirred at room. pace, STAB (5.21 g, 24.56 mmol, 5.0 eq.) was added over 5 min. The mixture continued to stir at room. pace, for 48 hours, evaporated under reduced pressure and partitioned between DCM (150 ml) and saturated NaHCO3 (60 ml). The aqueous phase was extracted with DCM (25 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure and purified by chromatography on silica gel using EA/Hex (1/4) as eluents to give 1.2 g (62%) 1-(tert-butyl)-3- methyl (8)-3-((4(trifluoromethyl)benzyl)amino)pyrrolidine-1,3-dicarboxylate. HPMS (CIAD) m/z 403.1 (M+H).

Ή NMR (400 MHz, methanol-b ₄ ) δ 7.61 (d, J=8.1 Hz, 2H), 7.55 (d, >8.1 Hz, 2H), 3.90-3.79 (m, 1H), 3.793.65 (m, 5H), 3.55 (cd, >8.3, 7.9, 4.2 Hz, 1H), 3.50-3.40 (m, 2H) , 2.37-2.26 (m, 1H), 2.09 (ddt, >12.0, 7.5, 3.7 Hz, 1H), 1.46 (d, >20.4 Hz, 9H ).

9. Synthesis of intermediate 28-10

28-9 28-10

To a mixture of 1 -(tert-butyl)-3-methyl-(8)-3-((4-(trifluoromethyl)benzyl)amino)pyrrolidine-1,3dicarboxylate (1.20 g, 2.98 mmol) and TEA ( 6.24 ml, 44.73 mmol, 15.0 eq.) in DCM (50 ml), cooled to 0°C, add chloroacetyl chloride (3.37 g, 29.82 mmol, 10.0 eq.) dropwise using a syringe. Once addition was complete, the ice bath was removed. The resulting brown suspension was stirred at room. temp, diluted with DCM (75 ml) over 1.5 h and washed with saturated aqueous NaHCO3 (75 ml). The organic phase was dried over sodium sulfate, concentrated and purified by chromatography on silica gel using EA/Hex (4/6) as eluents to give 0.92 g (64%) 1-(tert-butyl)-3-methyl (8) -3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)pyrrolidine-1,3-dicarboxylates. HPMS (CIAD) m/z 373.2 (M+H with loss of Boc).

Ή NMR (400 MHz, methanol-BD δ 7.75 (d, >8.1 Hz, 2H), 7.63 (d, >6.9 Hz, 2H), 5.02 (d, >19.3 Hz, 1H), 4.85 (d, 1H), 4.34-4.16 (m, ZN), 3.78 (s, ZN), 3.53-3.42 (m, 1H), 3 .40-3.33 (m, 2H), 2.46-2.21 (m, 2H), 1.46 (d, >4.3 Hz, 9H).

-279 045362

10. Synthesis of intermediate 28-11

28-11

K 1-(tert-butyl)-3-methyl-(8)-3-(2-chloro-M-(4-(trifluoromethyl)benzyl)acetamido)pyrrolidine-1,3dicarboxylate (0.90 g, 1.88 mmol) NH ₃ was added in MeOH (7 M, 25 ml). The mixture was sealed, heated at 80°C for 1.5 hours, cooled to room temperature, evaporated under reduced pressure and partitioned between DCM (100 ml) and water (50 ml). The aqueous phase was extracted with DCM (25 ml). The combined organic phases were dried over sodium sulfate, concentrated and purified by silica gel chromatography using EA/Hex (gradient from 0-100% and 100%) as eluents to give 0.72 g (89%) tert-butyl-(8 )-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-2carboxylate. HPMS (CIAD) m/z 372.1 (M+H) (-C ₄ H ₉ ).

Ή NMR (400 MHz, methanol-b ₄ ) δ 7.66 (d, >7.9 Hz, 2H), 7.43 (d, >8.0 Hz, 2H), 5.01 (dd, >33 .8, 17.0 Hz, 1H), 4.69 (dd, >37.6, 17.1 Hz, 1H), 4.18 (d, >4.5 Hz, 2H), 3.95-3 .84 (m, 1H), 3.61-3.46 (m, ZN), 2.49-2.33 (m, 2H), 1.42 (d, >24.0 Hz, 9H).

11. Synthesis of intermediate 28-12

28-11 28-12

To a mixture of tert-butyl-(8)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decane-2carboxylate (280 mg, 0.63 mmol), Cui (60 mg, 0.32 mmol, 0.5 eq.), K ₂ CO ₃ (349 mg, 2.53 mmol, 4.0 eq.) and aryl iodide (234 mg, 0.95 mmol, 1.5 eq.) in 1,4-dioxane (6 ml) was added N,N-dimethylethylenediamine (0.034 ml, 0.32 mmol, 0.5 eq.). The resulting mixture was heated at 115°C in an atmosphere of N ₂ for 18 hours in a hermetically sealed vessel, cooled to room temperature, filtered through celite, washed with an additional portion of dioxane (15 ml) and DCM (30 ml), concentrated under reduced pressure and purified by silica gel chromatography using EA/Hex (1/1) as eluents to give 187 mg (54%) tert-butyl-(8)-9-(4-cyano-2-fluorophenyl)-7.10 -dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9triazaspiro[4.5]decane-2-carboxylate. HPMS (CIAD) m/z 491.1 (M+H) (-C ₄ H ₉ ).

F NMR (400 MHz, methanol-a ₄ ) δ 7.82-7.64 (m, 5H), 7.50 (d, >8.0 Hz, 2H), 5.15-5.02 (m, 1H), 4.81-4.57 (m, ZN), 4.00 (d, >12.1 Hz, 1H), 3.66 (d, >12.3 Hz, 1H), 3.62- 3.47 (m, 2H), 2.59-2.48 (m, 2H), 1.43 (d, >15.3 Hz, 9H).

12. Synthesis of intermediate 28-13

26-12 28-13

To a solution of tert-butyl-(8)-9-(4-cyano-2-fluorophenyl)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9triazaspiro[4,5]decane -2-carboxylate (186 mg, 0.34 mmol) in DCM (3 ml) was added TFA (3 ml). The resulting mixture was stirred at room. pace for 30 min and concentrated under reduced pressure to give 189 mg (99%) (8)-4-(7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9triazaspiro [4.5 ]decane-9-yl)-3-fluorobenzonitrile in the form of TFA salt. HPMS (CIAD) m/z 447.1 (M+H).

13. Synthesis of compound 216

To a mixture of (8)-4-(7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9-triazaspiro[4.5]decan-9-yl)-3-280 045362 fluorobenzonitrile (30 mg TFA salt, 0.054 mmol) and DIEA (0.047 ml, 0.27 mmol, 5.0 eq.) to DCM (1.0 ml) was added methyl chloroformate (0.012 ml, 0.16 mmol, 3.0 eq.). The mixture was stirred at room. pace. for 5 min, evaporate under reduced pressure and purify by reverse phase HPLC using 10-100% ACN/water (both with 0.1% formic acid; Phenomenex Gemini C18 5 micron column) to give 21 mg (78%) methyl -(8)-9-(4-cyano-2-fluorophenyl)-7,10-dioxo-6-(4-(trifluoromethyl)benzyl)-2,6,9triazaspiro[4.5]decane-2-carboxylate (21 mg , 0.042 mmol, 78% yield, compound 216) as a white amorphous solid. HPMS (CIAD) m/z 505 (M+H).

1H NMR (400 MHz, methanol^) δ 7.84-7.65 (m, 5H), 7.49 (d, J=8.0 Hz, 2H), 5.05 (dt, J=9.5 , 5.2 Hz, 1H), 4.87-4.73 (m, 1H), 4.73-4.56 (m, 2H), 4.05 (d, J=12.2 Hz, 1H) , 3.76-3.48 (m, 6H), 2.64-2.45 (m, 2H).

The following compounds were prepared by methods similar to those described for compound 216:

Connection No. HPMS (ES) m/z 183 M+H=486.1 184 M+H=487.2 185 M+H=452.1 205 M+H=455.1 206 M+N-455.1 207 M+N-Vos=413.1 208 M+N-Vos-447.1 209 M+H=489.2 210 M+H=497.2 211 M+H=471.1 212 M+N-495.2 213 M+H=481.2 214 M+N-469.1 215 M+H=531.2 217 M+H=529.2 218 M+N-503.2 219 M+N-515.2 220 M+H=441.1 221 M+N-483.2 222 M+H=475.1 223 M+H=517.2 224 M+H=478.1 225 M+H=443.2

Example 29 Synthesis of compound 211

A method similar to Example 28 was used, except that p-chlorobenzaldehyde was used in step 8 instead of n-CF ₃ benzaldehyde.

Example 30 Synthesis of compound 320

1. Synthesis of intermediate 30-2

CR

ZOL 30-2

To a solution of 1-(tert-butyl)-3-ethyl-3-aminoazetidine-1,3-dicarboxylate (5.0 g, 20.5 mmol, 1.0 eq.) in

- 281 045362 4-trifluoromethylbenzaldehyde (5.3 g, 30.7 mmol, 1.5 eq.) was added to a mixture of THF (50 ml) and DCE (10 ml). To this mixture was stirred for 15 minutes and added STAB (13.0 g, 61.4 mmol, 3.0 eq.) and AcOH (5 ml). The mixture was stirred at room. pace. for 2 hours, evaporated under reduced pressure and partitioned between DCM (60 ml) and saturated aqueous sodium hydrogen carbonate (60 ml). The layers were separated and the aqueous phase was extracted with DCM (25 ml). The combined organic phases were dried over sodium sulfate, filtered through celite, concentrated under reduced pressure and purified by silica gel chromatography (0-100% EtOAc/hexanes gradient) to give 1-(tert-butyl)-3-ethyl-3-(( 4(trifluoromethyl)benzyl)amino)azetidine-1,3-dicarboxylate. HPMS (ES) m/z 347.15 (M+H-tBu).

2. Synthesis of intermediate 30-3

30-2 303

To a solution of 1-(tert-butyl)-3-ethyl-3-((4-(trifluoromethyl)benzyl)amino)azetidine-1,3-dicarboxylate (20.5 mmol, 1.0 eq.) in DCM (50 mL) at 0°C, TEA (14.3 mL, 102 mmol, 5.0 eq.) and chloroacetyl chloride (3.3 mL, 40.9 mmol, 2.0 eq.) were added. The ice bath was removed and the mixture was stirred at room. pace. for 2 hours before pouring into saturated aqueous NH ₄ Cl (200 ml). The layers were separated and the aqueous layer was extracted three times with DCM (100 ml). The combined organic layers were dried over MgSO ₄ , concentrated and purified by silica gel chromatography (0-100% EtOAc/hexanes gradient) to give 8.2 g (84% in 2 steps) 1-(tert-butyl)-3-ethyl- 3-(2-chloro-N-(4(trifluoromethyl)benzyl)acetamido)azetadine-1,3-dicarboxylate as a white solid with a metallic tint. HPMS (ES) m/z 479.15 (M+H).

3. Synthesis of intermediate 30-4

To a solution of 1-(tert-butyl)-3-ethyl-3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)azetidine-1,3dicarboxylate (0.20 g, 0.42 mmol, 1 .0 eq.) in ACN (2 ml) in a microwave vessel was added 3-aminobutanenitrile hydrochloride (76 mg, 0.63 mmol, 1.5 eq.) and TEA (175 μl, 1.3 mmol, 3.0 eq.). The mixture was heated at 110°C in a microwave reactor for 1 hour. A mixture containing tert-butyl-8-(1cyanopropan-2-yl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2, 5,8-triazaspiro[3.5]nonane-2-carboxylate was used directly in the next step. HPMS (ES) m/z 481.1 (M+H).

4. Synthesis of intermediate 30-5

30-4 30-5

To this mixture containing tert-butyl-8-(1-cyanopropan-2-yl)-6,9-dioxo-5-(4(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-2 -carboxylate (202 mg, 0.42 mmol) in DCM, TFA (2 ml) was added. The mixture was stirred at room. pace. for 20 min and concentrated to give 3-(6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)butanenitrile 2,2,2trifluoroacetate . HPMS (ES) m/z 381.1 (M+H).

- 282 045362

5. Synthesis of compound 320

dhm TEA. to t 20 m

ZO-δ Connection 32 O

To a solution of 3-(6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8yl)butanenitrile 2,2,2-trifluoroacetate (160 mg, 0. 42 mmol) in DCM (3 ml) was added TEA (0.5 ml) and methyl isocyanate (200 mg, 3.5 mmol, 8.3 eq.). The mixture was stirred at room. temp, for 20 min, evaporated under reduced pressure and purified by reverse phase HPLC (Phenomenex, dimeric 5 µm C18 150x21.2 mm, gradient 10-70% acetonitrile in water with 0.1% formic acid over 40 min) with obtaining 6.8 mg (4% in 3 stages) 8-(1-cyanopropan-2-yl)-X-methyl-6,9-dioxo-5-(4(trifluoromethyl)benzyl)-2,5,8- triazaspiro[3.5]nonane-2-carboxamide. HPMS (ES) m/z 438.1 (M+H).

Ή NMR (methanol-a ₄ , 400 MHz, ppm) δ 7.66 (d, 1=8.0 Hz, 2H), 7.50 (d, 1=8.6 Hz, 2H), 5 .22-5.01 (m, 2H), 4.87-4.75 (m, 1H), 4.44 (dd, J=17.3, 9.3 Hz, 2H), 4.18 (d , J=1.6 Hz, 2H), 4.07 (dd, J=9.3, 0.6 Hz, 2H), 2.98 (dd, J=17.1, 8.6 Hz, 1H) , 2.86 (dd, J=17.1, 6.1 Hz, 1H), 2.68 (s, ZN), 1.40 (d, J=6.9 Hz, ZN).

The following compounds were prepared by methods similar to those described for compound 320:

Connection No. HPMS (ES) m/z 518A M+H=464.2 516A M+H=452.2 323 M+H=466.2 324 M*H=488.2 520A M+H=463.2 326 M+H=452.2

Example 31. Synthesis of compound 429B.

1. Synthesis of intermediate 31-1

Intermediate 31-1

To a mixture of 4-trifluoromethylbenzylamine (1.8 g, 10.4 mmol, 1.0 eq.) and tert-butyl-3-oxocyclobutane-1-carboxylate (1.8 g, 10.4 mmol, 1.0 eq.) in MeOH (30 ml) was added (isocyanomethylene)dibenzene (2.1 g,

10.9 mmol, 1.05 eq.) and chloroacetic acid (1.0 g, 10.4 mmol, 1.05 eq.). The mixture was stirred at room. rate, over 15 hours, concentrated under reduced pressure and purified by chromatography on silica gel EA/HE (gradient from 0-100%) to obtain 4.5 g (70%) tert-butyl-3-(benzhydrylcarbamoyl)3 -(2 -χπορ-Ν-(4-(trifluoromethyl)benzyl)acetamido)cyclobutane-1-carboxylate (intermediate 1-1). HPMS (ES) m/z 615.2 (M+H).

2. Synthesis of diastereomer 31-2A and diastereomer 31-2B

6C 2h +

To a solution of tert-butyl-3-(benzhydrylcarbamoyl)-3-(2-chloro-H-(4-(trifluoromethyl)benzyl)acetamido)cyclobutane-1-carboxylate (intermediate 31-1) (4.5 g, 7 .3 mmol, 1.0 eq.) in THF (20 ml), cooled to 0°C in an ice bath, add LIHMDS (1 M in THF, 8.8 mmol, 1.2 eq.) dropwise over 10 min. The mixture was stirred at 0°C for 2 hours, quenched with MeOH (5 ml), concentrated on SiO ₂ (20 g) and purified by silica gel chromatography using EA/HE (0-100% gradient) to give the corresponding diastereomers. Diastereomer 31-2A (1.8 g, 42%), diastereomer 31-2B (1.8 g,

-283 045362

42%).

Characteristics of diastereomer 31-2A: HPMC (ES) m/z 579.2 (M+H).

^! H NMR (methanol-a ₄ , 400 MHz, ppm) δ 7.60-7.48 (m, 2H), 7.35-7.24 (m, 8H), 7.17-7.06 (m, 4H), 6.89 (s, 1H), 4.76 (s, 2H), 3.76 (s, 2H), 2.88-2.76 (m, 1H), 2.68- 2.46 (m, 4H), 1.29 (s, 9H).

Characteristics of diastereomer 31-2B: HPMS (ES) m/z 579.2 (M+H).

Ή NMR (methanol-a ₄ , 400 MHz, ppm) δ 7.49 (d, >7.9 Hz, 2H), 7.34-7.25 (m, 6H), 7.21 (d , >7.9 Hz, 2H), 7.13-7.07 (m, 4H), 6.88 (s, 1H), 4.86 (s, 2H), 3.68 (s, 2H), 3.01-2.79 (m, ZN), 2.59-2.40 (m, 2H), 1.32 (s, 9H).

Diastereomer 31-2B was used in subsequent examples. The final compounds obtained from diastereomer 31-2A were isolated using diastereomer 31-2A as starting material in a similar sequence.

3. Synthesis of intermediate 31-ZV

Diastereomer 31-2В 31-ЗВ

To a solution of diastereomer 31-2B (1.8 g, 3.1 mmol, 1.0 eq.) in EtOAc (20 ml) was added Pd(OH) ₂ (20% on carbon, 2 g). The mixture was purged with hydrogen for 10 minutes, heated at 60°C under a hydrogen atmosphere (initially at 700 psi) for 24 hours, cooled to room temperature, filtered through celite, concentrated under reduced pressure and purified by chromatography on silica gel using MeOH/DCM (0-20% gradient) to give 1.0 g (78%) of intermediate 31-ZV. HPMS (ES) m/z 357.1 (M+H^Bu).

^! H NMR (methanol-b ₄ , 400 MHz, ppm) δ 7.67 (d, >8.0 Hz, 2H), 7.44 (d, >7.9 Hz, 2H), 5.04 (s, 2H), 4.04 (s, 2H), 3.16-3.02 (m, 1H), 3.02-2.86 (m, 2H), 2.73-2.59 (m , 2H), 1.46 (s, 9H).

In this example, the dotted linkage indicates that the stereochemical configuration of the starting material is retained in the product compound.

4. Synthesis 429V

428V connection

To a mixture of copper iodide (109 mg, 0.57 mmol, 0.5 eq.), potassium carbonate (0.32 g, 2.3 mmol, 2.0 eq.), 4-bromo-3-fluorobenzonitrile (0.27 g , 1.4 mmol, 1.2 eq.) and intermediate 1-ZV (0.47 g, 1.1 mmol, 1.0 eq.) 1,4-dioxane (5 ml) and N, N'-dimethylethylenediamine (61 µl, 0.57 mmol, 0.5 eq.). The mixture was sealed and heated at 100°C for 4 hours, cooled to room temperature, filtered through celite and purified by silica gel chromatography using EA/HE (gradient from ΟΙ 00%), to give 0.40 g (66 %) connections 429V. HPMS (ES) m/z 476.1 (M+H^Bu).

'n NMR (methanol ₄ , 400 MHz, ppm) δ 7.80-7.74 (m, 1H), 7.71-7.66 (m, 4H), 7.53-7, 46 (m, 2H), 5.10 (s, 2H), 4.50 (s, 2H), 3.15-2.99 (m, ZN), 2.85-2.71 (m, 2H) , 1.42 (s, 9H).

Example 32. Synthesis of compound 486B.

1. Synthesis of intermediate 32-1B

Connection 429Q

TFA (5 mL) was added to the flask containing compound 429B (0.36 g, 0.68 mmol, 1.0 eq.). The mixture was stirred at room. temp. for 15 hours and concentrated to give intermediate 32-1B. HPMS (ES) m/z 474.1 (M-H). In this example, the dotted linkage indicates that the stereochemical configuration of the starting material is retained in the product compound.

-284045362

2. Synthesis of intermediate 32-2B

^-23

To intermediate 32-1B (0.32 g, 0.68 mmol, 1.0 eq.) dissolved in DCM (5 mL) was added oxalyl chloride (0.17 g, 1.36 mmol, 2.0 eq. ) and a drop of DMF (~50 mg). The mixture was stirred at room. pace. for 1 hour and concentrated to give intermediate 32-2B, which was used directly without characterization.

3. Synthesis of 486V compound

To intermediate 32-2B (50 mg, 0.10 mmol, 1.0 eq.) dissolved in DCM (3 mL) was added methylamine (2 M in THF, 2 mL). The mixture was stirred at room. pace. for 1 hour and concentrated. This material was dissolved in DMF (2.0 ml), filtered and purified by reverse phase HPLC (Phenomenex, dimer 5 µm C18 150x21.2 mm, gradient 20-100% acetonitrile in water with 0.1% formic acid over 25 min ) to obtain 31.4 mg (64%) of compound 486B. HPMS (ES) m/z 489.1 (M+H).

'H NMR (400 MHz, methanol^) δ 7.78-7.74 (m, 1H), 7.72-7.65 (m, 4H), 7.50-7.45 (m, 2H), 5.12 (s, 2H), 4.49 (s, 2H), 3.18-3.07 (m, 3H), 2.78-2.67 (m, 5H).

The following compounds were prepared by methods similar to those described for compound 486B:

- 285 045362

Diastereomer No. HPMS (ES) m/z Ή NMR 429V M+N-*Vi=476.1 (400 MHz, methanol-ph) δ 7.78 - 7.64 (m, 5H), 7.53 - 7.47 (m, 2H), 5.06 (s, 2H), 4.50 (s, 2H), 2.99 - 2.89 (m, 1H), 2.87 - 2.79 (m, 2H), 2.75 - 2.67 (m, 2H), 1.40 (s, 9H) 429A M+H=532.2 (400 MHz, methanol-ph) b 7.77 - 7.72 (m, 1H), 7.70 - 7.64 (m, 4H), 7.50 - 7.45 (m, 2H), 5, 09 (s, 2N), 4.48 (s, 2N), 3.12 - 3.01 (m, ZN), 2.81 -2.71 (m, 2N), 1.40 (s, 9N) 485A M+H=475.1 (400 MHz, methanol- _d4 ) b 7.81 - 7.76 (m, 1H), 7.75 - 7.69 (m, 2H), 7.68 - 7.63 (m, 2H), 7 .51 - 7.45 (m, 2H), 5.15 (s, 2H), 4.51 (s, 2H), 3.10-2.99 (m, 1H), 2.82 - 2.76 (m, 4H) 485V M+N-475D (400 MHz, methanol- _d4 ) δ 7.78 - 7.73 (m, 1H), 7.71 - 7.64 (m, 4H), 7.51 - 7.46 (m, 2H), 5 .12 (s, 2H), 4.49 (s, 2H), 3.22 - 3.08 (m, ZN), 2.79-2.68 (m, 2H) 486V M+H=489.1 (400 MHz, methanol- _d4 ) δ 7.78 - 7.74 (m, 1H), 7.72 - 7.65 (m, 4H), 7.50 - 7.45 (m, 2H), 5 .12 (s, 2N), 4.49 (s, 2N), 3.18 - 3.07 (m, ZN), 2.78-2.67 (m, 5N) 487A M+H=503.2 (400 MHz, methanol- _d4 ) b 7.80 - 7.76 (m, 1H), 7.76 - 7.69 (m, 2H), 7.68 - 7.63 (m, 2H), 7 .50 - 7.45 (m, 2H), 5.07 (s, 2H), 4.52 (s, 2H), 3.38 - 3.27 (m, 1H), 2.94 (s, ZN ), 2.92 (s, ZN), 2.88-2.76 (m, 4N) 486A M+H=489.2 (400 MHz, methanol- _d4 ) δ 7.80 - 7.75 (m, 1H), 7.74 - 7.68 (m, 2H), 7.68 - 7.64 (m, 2H), 7 .51 - 7.46 (m, 2H), 5.18 (s, 2H), 4.51 (s, 2H), 3.04 - 2.93 (m, 1H), 2.84 - 2.68 (m, 7N) 487V M+H=503.2 (400 MHz, methanol- _d4 ) δ 7.78 - 7.73 (m, 1H), 7.72 - 7.64 (m, 4H), 7.54 - 7.48 (m, 2N), 5.15 (s, 2N), 4.50 (s, 2N), 3.29 - 3.09 (m, ZN), 2.87 (s, ZN), 2.83 (s, ZN ), 2.78 - 2.69 (m, 2H) 877A M+H=485 (400 MHz, DMSO-ab) δ 8.52 (d, J = 2.1 Hz, 1H), 8.29 (dd, J = 9.5, 2.2 Hz, 1H), 7.72 (d , J = 8.1 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.38 (s, 1H), 6.89 (s, 1H), 5.04 (s , 2H), 4.57 (s, 2H), 2.95 - 2.82 (m, 1H), 2.67 - 2.56 (m, 4H).

Example 33. Synthesis of compound 444B.

1. Synthesis of intermediate 33-1

33-1

To a mixture of 4-trifluoromethylbenzylamine (3.2 g, 18.4 mmol, 1.0 eq.) and tert-butyl-3-oxocyclobutane-1-carboxylate (3.1 g, 18.4 mmol, 1.0 eq.) in MeOH (30 ml) (isocyanomethylene)dibenzene (3.7 g, 19.3 mmol, 1.05 eq) and chloroacetic acid (1.8 g, 19.3 mmol, 1.05 eq) were added. The mixture was stirred at room. rate, over 15 hours, concentrated under reduced pressure and purified by chromatography on silica gel EA/HE (gradient from 0-100%) to obtain 10.5 g (93%) tert-butyl-3-(benzhydrylcarbamoyl)3-(2 -chloro-K-(4-(trifluoromethyl)benzyl)acetamido)cyclobutane-1-carboxylate (intermediate

-286 045362 tion 33-1). HPMS (ES) m/z 615.25 (M+H).

2. Synthesis of diastereomer 33-2B

--------33 ;d + <Ъз< az ,& O S. A

Hch

To a solution of tert-butyl 3-(benzhydrylcarbamoyl)-3-(2-chloro-M-(4-(trifluoromethyl)benzyl)acetamido)cyclobutane-1-carboxylate (intermediate 33-1) (10.5 g, 17 .1 mmol, 1.0 eq.) in THF (200 ml), cooled to 0°C in an ice bath, LHMDS (1 M in THF, 20.5 mmol, 1.2 eq.) was added dropwise over 10 min. The mixture was stirred at 0°C for 2 hours and MeOH was added (5 ml), concentrated on SiO ₂ (20 g) and purified by chromatography on silica gel using EA/HE (gradient from 00%) to give the corresponding diastereomers. Diastereomer 33-2A ((discarded), diastereomer 33-2B (3.0 g, 30%).

Characteristics of diastereomer 33-2B: HPMS (ES) m/z 579.2 (M+H).

Y NMR (methanol-b ₄ , 400 MHz, ppm) δ 7.49 (d, J=7.9 Hz, 2H), 7.34-7.25 (m, 6H), 7.21 ( d, J=7.9 Hz, 2H), 7.13-7.07 (m, 4H), 6.88 (s, 1H), 4.86 (s, 2H), 3.68 (s, 2H ), 3.01-2.79 (m, ZN), 2.59-2.40 (m, 2H), 1.32 (s, ZN).

3. Synthesis of intermediate 33-ZV

Diastereomer 33-2V ZZ-ZV

To a solution of diastereomer 33-2B (3.0 g, 5.2 mmol, 1.0 eq.) in EtOAc (80 ml) was added Pd(OH) ₂ (20% on carbon, 6 g). The mixture was purged with hydrogen for 10 minutes, heated at 60°C under a hydrogen atmosphere (initially at 500 psi) for 24 hours, cooled to room temperature, filtered through celite, concentrated under reduced pressure and purified by chromatography on silica gel using MeOH/DCM (0-20% gradient) to give 1.75 g (82%) of the 33-33 intermediate. HPMS (ES) m/z 357.1 (M+H- ¹ Vi). ^-NMR: (methanol-(1 ₄ , 400 MHz, ppm) δ 7.67 (d, J=8.0 Hz, 2H), 7.44 (d, J=7.9 Hz, 2H ), 5.04 (s, 2H), 4.04 (s, 2H), 3.16-3.02 (m, 1H), 3.02-2.86 (m, 2H), 2.73- 2.59 (m, 2H), 1.46 (s, 9H) In this example, the dotted bond indicates that the stereochemical configuration of the starting material is retained in the product compound.

4. Synthesis of intermediate 33-4B

To a mixture of copper iodide (369 mg, 1.9 mmol, 0.5 eq.), potassium carbonate (1.6 g, 11.6 mmol, 3.0 eq.), 4-bromo-3-fluorobenzonitrile (1.4 g , 7.0 mmol, 1.8 eq.) and the intermediate 33-33 (1.6 g, 3.9 mmol, 1.0 eq.) 1,4-dioxane (16 ml) and N were added to the vessel. N'-dimethylethylenediamine (209 µl, 1.9 mmol, 0.5 eq.). The mixture was sealed and heated at 100°C for 15 hours, cooled to room temperature, filtered through celite and purified by silica gel chromatography using EA/HE (0-100% gradient) to give 1.7 g (84 %) intermediate connection 33-4V. HPMS (ES) m/z 476.1 (M+H*Wi).

Y NMR (CD ₂ C1 ₂ , 400 MHz, ppm) δ 7.70-7.65 (m, 2H), 7.63-7.60 (m, 1H), 7.60-7.56 (m, 1H), 7.56-7.51 (m, 1H), 7.44-7.39 (m, 2H), 5.02 (s, 2H), 4.40-4.38 (m , 2H), 3.19-3.11 (m, 2H), 3.03-2.94 (m, 1H), 2.70-2.62 (m, 2H), 1.42 (s, 9H ).

-287 045362

5. Synthesis of intermediate 33-5V

To a solution of intermediate 1-4B (1.7 g, 3.3 mmol, 1.0 eq) in DCM (18 ml) was added TFA (18 ml). The mixture was stirred at room. pace. For 1 hour and concentrated to give intermediate 33-5B. HPMS (ES) m/z 474.0 (M-N).

6. Synthesis of 444V compound

To a mixture of morpholine (9.0 mg, 0.10 mmol, 1.0 eq), PyBroP (49 mg, 0.10 mmol, 1.0 eq) and intermediate 33-5B (50 mg, 0.10 mmol, 1.0 eq.) in DCM (1 mL) cooled to 0°C in an ice bath, DIEA (0.073 mL, 0.42 mmol, 4.0 eq.) was added dropwise. The mixture was heated to room. temp., stirred for 30 min, concentrated under reduced pressure and purified by reverse phase HPLC (Phenomenex, dimeric 5 µm C18 150x21.2 mm, gradient 10-80% acetonitrile in water with 0.1% formic acid over 25 min ) to obtain a mixture, which was again purified by chromatography on silica gel using MeOH/DCM (1/9) to obtain 26.4 mg (46%) of compound 444B. HPMS (ES) m/z 545 (M+H).

'H NMR (400 MHz, methanol-ad δ 7.81-7.75 (m, 1H), 7.74-7.66 (m, 4H), 7.55-7.49 (m, 2H), 5.15 (s, 2H), 4.52 (s, 2H), 3.65-3.57 (m, 4H), 3.55-3.49 (m, 2H), 3.31-3, 14 (m, 5H), 2.81-2.72 (m, 2H).

The following compounds were prepared by methods similar to those described for compound 444B:

Diastereomer No. HPMS (ES) m/z ^1H NMR 446V M+H=515.2 (400 MHz, methanol- _d4 ) δ 7.80 - 7.76 (m, 1H), 7.73 - 7.66 (m, 4H), 7.56 - 7.50 (m, 2H), 5 .15 (s, 2H), 4.51 (s, 2H), 4.06 - 3.94 (m, 4H), 3.19-3.11 (m, 2H), 3.06-2.95 (m, 1H), 2.73 - 2.64 (m, 2H), 2.33 - 2.23 (m, 2H)

- 288 045362

448V M+H=529.2 (400 MHz, methanol- _d4 ) δ 7.80 - 7.76 (m, 1H), 7.75 - 7.67 (m, 4H), 7.60 - 7.49 (m, 2H), 5.20 - 5.13 (m, 2H), 4.54 - 4.50 (m, 2H), 3.52 - 3.41 (m, 1H), 3.29 - 3.20 (m, 2H ), 2.88 2.79 (m, ZN), 2.79 - 2.71 (m, 2H), 2.61 - 2.53 (m, 1H), 0.80 - 0.69 (m, 2H), 0.69 - 0.58 (m, 2H) 450V M+H=559.2 (400 MHz, methanol- _d4 ) δ 7.80 - 7.75 (m, 1H), 7.74 - 7.67 (m, 4H), 7.56 - 7.50 (m, 2H), 5.23 - 5.09 (m, 2H), 4.57 - 4.46 (m, 2H), 4.04 - 3.95 (m, 1H), 3.86 - 3.77 (m, 1H ), 3.51 3.42 (m, 1H), 3.30 - 3.01 (m, 5H), 2.81 - 2.71 (m, 2H), 1.85 - 1.77 (m, 2H), 1.45 - 1.34 (m, 2H) 452 V M+H=531.1 (400 MHz, methanol- _d4 ) δ 7.81 - 7.75 (m, 1H), 7.73 - 7.66 (m, 4H), 7.53 - 7.48 (m, 2H), 5.14 (s, 2H), 4.95 - 4.80 (m, ZN), 4.55 - 4.49 (m, 4H), 3.21 - 3.09 (m, ZN), 2, 84 - 2.72 (m, 2H) 458V M+H=515.10 (400 MHz, methanol- _d4 ) δ 7.80 - 7.75 (m, 1H), 7.73 - 7.66 (m, 4H), 7.51 - 7.45 (m, 2H), 5 .12 (s, 2H), 4.50 (s, 2H), 3.16 - 3.04 (m, ZN), 2.77 - 2.66 (m, 2H), 2.64 - 2.56 (m, 1H), 0.71 - 0.64 (m, 2H), 0.48 - 0.42 (m, 2H) 462 V M+H=545.1 (400 MHz, methanol- _d4 ) δ 7.80 - 7.75 (m, 1H), 7.74 - 7.66 (m, 4H), 7.52 - 7.46 (m, 2H), 5 .14 (s, 2H), 4.51 (s, 2H), 4.39 - 4.31 (m, 1H), 4.30 - 4.21 (m, 1H), 3.19-3.07 (m, ZN), 2.80 - 2.67 (m, 2N), 2.28 - 2.16 (m, 4N)

- 289 045362

469V M+H=519.2 (400 MHz, methanol- _d4 ) b 7.80 - 7.75 (m, 1H), 7.73 - 7.67 (m, 4H), 7.52 - 7.47 (m, 2H), 5 .14 (s, 2H), 4.51 (s, 2H), 3.57 (t, J = 5.8 Hz, 2H), 3.28 (t, J = 5.8 Hz, 2H), 3 .23 - 3.09 (m, ZN), 2.82-2.70 (m, 2N) 473V M+H=565.1 (400 MHz, methanol- _d4 ) b 7.80 - 7.75 (m, 1H), 7.73 - 7.67 (m, 4H), 7.52 - 7.47 (m, 2H), 5 .14 (s, 2H), 4.51 (s, 2H), 4.13 - 4.02 (m, 1H), 3.19 - 3.07 (m, ZN), 2.94 - 2.81 (m, 2H), 2.81 2.70 (m, 2H), 2.59 - 2.43 (m, 2H) 477V M+H=545.2 (400 MHz, methanol-U) δ 7.80 - 7.75 (m, 1H), 7.74 - 7.66 (m, 4H), 7.56 - 7.50 (m, 2H), 5, 24 - 4.67 (m, 7H), 4.54 - 4.49 (m, 2H), 3.36 - 2.91 (m, 6H), 2.84 - 2.73 (m, 2H) 462A M+H=545 (400 MHz, methanol-U) δ 7.81 - 7.75 (m, 1H), 7.73 - 7.66 (m, 4H), 7.52 - 7.46 (m, 2H), 5, 14 (s, 2H), 4.51 (s, 2H), 3.98 - 3.89 (m, 1H), 3.82 - 3.70 (m, 1H), 3.20 - 3.06 ( m, ZN), 2.78 - 2.67 (m, 2H), 2.67 - 2.58 (m, 2H), 1.84 -1.74 (m, 2H). 249V M+H=529 (400 MHz, methanol-U) δ 7.80 - 7.75 (m, 1H), 7.72 - 7.66 (m, 4H), 7.51 - 7.47 (m, 2H), 5, 14 (s, 2H), 4.50 (s, 2H), 4.30 - 4.19 (m, 1H), 3.20 - 3.06 (m, ZN), 2.77 - 2.65 ( m, 2H), 2.29-2.18 (m, 2H), 1.99-1.85 (m, 2H), 1.76 -1.61 (m, 2H). 878V M+H= 481.0 (400 MHz, methanol-s/ ₄ ) b 8.41 (s, 1H), 7.90 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.50 (d , J = 8.0 Hz, 2H), 5.18 (s, 2H), 4.65 (lat, 1H), 4.39 (lat, 1H), 3.08 (p, J = 8, 7 Hz, 1H), 2.82 (s, 4H), 2.30 (s, ZN). 879B M+H=467 (400 MHz, methanol-s/ ₄ ) δ 8.49 (d, J = 2.5 Hz, 1H), 8.11 (d, J = 8.9 Hz, 1H), 7.91 (dd, J = 8.9, 2.5 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 5.14 (s , 2H), 4.80 (s, 2H), 3.05 (p, J = 8.7 Hz, 1H), 2.80 (p, J = 11.4 Hz, 4H).

Example 34. Synthesis of compound 463B.

1. Synthesis of intermediate 34-1B

To a mixture of triethylamine (0.070 ml, 0.51 mmol, 1.2 eq.) and diphenylphosphoryl azide (0.10 ml, 0.46 mmol, 1.1 eq.) in t-butyl alcohol (1.3 ml) compound 33-5B (0.20 g, 0.42 mmol, 1.0 eq.). The mixture was heated to 83°C and stirred for 15 hours overnight. The reaction mixture was diluted with water and extracted with DCM three times. The DCM extracts were combined, dried over MgSO ₄ , filtered, evaporated and purified by silica gel chromatography using EA in hexanes (0-100% gradient) to give 94 mg (48%) of intermediate 34-1B.

1H NMR (400 MHz, methylene chloride-a ₂ ) δ 7.71-7.66 (m, 2H), 7.66-7.63 (m, 1H), 7.63-7.59 (m, 1H) , 7.577.50 (m, 1H), 7.46-7.39 (m, 2H), 4.99 (s, 2H), 4.49-4.37 (m, 3H), 3.05-2 .88 (m, 2H), 2.79-2.70 (m, 2H). In this

- 290 045362 example, a dotted bond indicates that the stereochemical configuration of the starting material is retained in the product compound.

2. Synthesis of 463B compound

To intermediate 34-1B (32 mg, 0.067, 1.0 eq) in dry dichloromethane (1 ml) was added diisopropylethylamine (0.035 ml, 0.20 mmol, 3.0 eq) followed by methylamine (2.0 M/THF, 0.10 ml, 0.20 mmol, 3.0 eq.). The mixture was stirred for 15 minutes at room. temp., evaporated and purified by reverse phase HPLC (Phenomenex, dimeric 5 µm C18 150x21.2 mm, 10-80% acetonitrile in water with 0.1% formic acid for 25 min) to obtain 15 mg (45%) of the compound 463B. HPMS (ES) m/z 504.1 (M+H).

'and NMR (400 MHz, methanol-a ₄ ) δ 7.81-7.77 (m, 1H), 7.74-7.66 (m, 4H), 7.52-7.46 (m, 2H ), 5.12 (s, 2H), 4.51 (s, 2H), 4.41-4.31 (m, 1H), 2.97-2.89 (m, 2H), 2.79- 2.71 (m, 2H), 2.66 (s, 3H).

The following compounds were prepared by methods similar to those described for compound 463B:

Diastereomer No. HPMS (ES) m/z Ή NMR 463V M+H=504.1 (400 MHz, methanol- _d4 ) δ 7.81 - 7.77 (m, 1H), 7.74 - 7.66 (m, 4H), 7.52 - 7.46 (m, 2H), 5.12 (s, 2H), 4.51 (s, 2H), 4.41 - 4.31 (M, 1H), 2.97 - 2.89 (m, 2H), 2.79 - 2, 71 (m, 2N), 2.66 (s, ZN) 465V M+H=530.1 (400 MHz, methanol- _d4 ) δ 7.82 - 7.77 (m, 1H), 7.75 - 7.66 (m, 4H), 7.53 - 7.47 (m, 2H), 5 .12 (C, 2H), 4.52 (s, 2H), 4.44 - 4.34 (m, 1H), 3.02 - 2.92 (m, 2H), 2.78 - 2.70 (m, 2H), 2.45 - 2.38 (m, 1H), 0.70 - 0.64 (m, 2H), 0.46-0.40 (m, 2H) 467V M+H=546.1 (400 MHz, methanol-d^b 7.82 - 7.77 (m, 1H), 7.75 - 7.66 (m, 4H), 7.52 - 7.46 (m, 2H), 5, 11 (s, 2H), 4.85 - 4.75 (m, ZN), 4.52 (s, 2H), 4.51 - 4.45 (m, 2H), 4.39 - 4.30 ( m, 1H), 2.99 - 2.89 (m, 2H), 2.78 - 2.70 (m, 2H)

Example 35 Synthesis of compound 454B.

1. Synthesis of intermediate 35-1B

TMSCHN2 (2 M in hexanes, 0.79 mL, 3.0 eq.). The mixture was stirred at room. pace. for 2 h and concentrated to give intermediate 35-1 B. HPMC (ES) m/z 490.1 (M+H). In this example, the dotted linkage indicates that the stereochemical configuration of the starting material is retained in the product compound.

- 291 045362

2. Synthesis of intermediate 35-2B

To a solution of intermediate 35-1B (259 mg, 0.53 mmol, 1.0 eq) in MeOH (5 mL) was added NH ₂ NH ₂ (35% in water, 1 mL). The mixture was heated at 70°C for 2 hours, cooled to room. temp., concentrated under reduced pressure and purified by silica gel chromatography using MeOH/DCM (1/4) to give 75 mg (29% in 2 steps) of intermediate 35-2B. HPMS (ES) m/z 490.2 (M+H).

'H NMR (methanol-d ₄ , 400 MHz, ppm) δ 7.76-7.71 (m, 1H), 7.67-7.61 (m, 4H), 7.44 (d, J=8.1 Hz, 2H), 5.09 (s, 2H), 4.46 (s, 2H), 3.17-3.02 (m, 3H), 2.78-2.62 (m , 2H), 1.87 (s, 2H).

3. Synthesis of 454B compound

To a solution of intermediate 35-2B (25 mg, 0.051 mmol, 1.0 eq.) in THF (1 mL) was added TEA (0.2 mL) and difluoroacetic anhydride (13 mg, 0.077 mmol, 1.5 eq.) . The resulting mixture was heated at 120°C in a microwave reactor for 20 min and purified by reverse phase HPLC (Phenomenex, dimeric 5 μm C18 150x21.2 mm, gradient 10-80% acetonitrile in water with 0.1% formic acid for 40 min) to obtain 10.2 mg (36%) of compound 454B. HPMS (ES) m/z 550.1 (M+H).

1H NMR (methanol-04, 400 MHz, ppm) δ 7.80-7.74 (m, 1H), 7.74-7.66 (m, 4H), 7.54 (d, J= 8.1 Hz, 2H), 7.09 (t, J=51.7 Hz, 1H), 5.20 (s, 2H), 4.55 (s, 2H), 3.92 (dk, J= 10.8, 6.0, 5.4 Hz, 1H), 3.39-3.28 (m, 2H), 3.16 (dd, J=14.1, 10.5 Hz, 2H).

The following compounds were prepared by methods similar to those described for compound 454B:

Diastereomer No. HPMS (ES) m/z ^1H NMR 430V M+H=500.1 (400 MHz, methanol-f) δ 8.82 (s, ΪΗ), 7.77 7.72 (m, 1H), 7.71 - 7.Θ6 (m, 4H), 7.54 - 7.49 (m, 2H), 5.19 (s, 2H), 4.52 (s, 2H), 3.92 - 3.81 (m, 1H), 3.38-3.26 (m, 2H), 3.15-3.06 (m, 2H) 440V M+H=514.2 (400 MHz, methanol- d ₄ } b 7.80 - 7.75 (m, 1H), 7.73 - 7.66 (m, 4H), 7.55 - 7.51 (m, 2H), 5 .20 (s, 2H), 4.54 (s, 2H), 3.86 - 3.75 (m, 1H), 3.31 3.25 (m, 2H), 3.13 - 3.04 ( m, 2N), 2.48 (s, ZN)

Example 36. Synthesis of compound 432B.

1. Synthesis of intermediate 36-1B

To a solution of intermediate 33-5B (100 mg, 0.21 mmol, 1.0 eq.) in DMF (2 mL) was added HATU (88 mg, 0.23 mmol, 1.1 eq.), acetamidine hydrochloride (30 mg, 0.32 mmol, 1.5 eq.) and TEA (106 mg, 1.1 mmol, 5.0 eq.). The mixture was stirred at room. pace. for 15 hours to obtain intermediate 36-1B, which was used directly in the next step, HPMC (ES) m/z 516.1 (M+H). In this example, the dotted bond --- indicates that the stereochemical confit

- 292 045362 guration of the starting material is preserved in the product compound.

2. Synthesis of 432V compound

^1st C &n 4 3 2B

Hydroxylamine hydrochloride (100 mg, 1.44 mmol, 6.9 eq.) and AcOH (2 ml) were added to a DMF solution containing 36-1B. The resulting mixture was heated at 80°C for 2 h, concentrated under reduced pressure and purified by reverse phase HPLC (Phenomenex, dimeric 5 μm C18 150x21.2 mm, gradient 20-100% acetonitrile in water with 0.1% formic acid in for 40 min) to obtain 15.3 mg (14% in 2 stages) of compound 432B. HPMS (ES) m/z 514.1 (M+H).

1H NMR (methanol-b ₄ , 400 MHz, ppm) δ 7.77-7.73 (m, 1H), 7.72-7.64 (m, 4H), 7.54-7.49 (m, 2H), 5.18 (s, 2H), 4.52 (s, 2H), 3.87-3.77 (m, 1H), 3.34-3.24 (m, 2H), 3.14-3.05 (m, 2H), 2.30 (s, 3H).

The following compounds were prepared by methods similar to those described for compound 432B:

Diastereomer No. HPMS (ES) m/z Ή NMR 432V M+H=514.1 (400 MHz, methanol- δ 7.77 - 7.73 (m, 1H), 7.72 - 7.64 (m, 4H), 7.54 - 7.49 (m, 2H), 5.18 ( s, 2H), 4.52 (s, 2H), 3.87 3.77 (m, 1H), 3.34 - 3.24 (m, 2H), 3.14 3.05 (m, 2H) , 2.30 (s, ZN) 434V M+H=544.1 (400 MHz, methanol-U) δ 7.79 - 7.74 (m, 1H), 7.74 - 7.66 (m, 4H), 7.56 - 7.51 (m, 2H), 5, 20 (s, 2H), 4.94 - 4.83 (m, 1H), 4.54 (C, 2H), 3.91 - 3.81 (m, 1H), 3.40 3.29 (m , 2H), 3.17 - 3.09 (m, 2H), 1.49 (d, J = 6.7 Hz, ZN) 438V M+H=540.10 (400 MHz, DMSO-d ₆ ) δ 8.06 - 8.00 (m, 1H), 7.86 - 7.82 (m, 1H), 7.79 - 7.72 (m, ZN), 7 .53 - 7.47 (m, 2H), 5.11 (s, 2H), 4.51 (s, 2H), 3.93 - 3.82 (m, 1H), 3.13 - 3.05 (m, 2H), 3.03 - 2.93 (m, 2H), 2.09 - 2.01 (m, 1H), 1.05 - 0.98 (m, 2H), 0.83 - 0 .78 (m, 2H) 456V M+H=550.1 (400 MHz, methanol-f) δ 7.78 - 7.74 (m, 1H) ₅ 7.73 - 7.65 (m, 4H), 7.57 - 7.51 (m, 2H), 6 .95 (t, J = 52.3 Hz, 1H), 5.20 (s, 2H), 4.54 (s, 2H), 3.99 - 3.89 (m, 1H), 3.39 - 3.30 (m, 2H), 3.23 - 3.14 (m, 2H) 880V M+H=482 (300 MHz, DMSO-de) δ 8.53 (d, J = 2.5 Hz, 1H), 8.06 - 7.90 (m, 2H), 7.32 (dd, J = 8.4, 5.6 Hz, 2H), 7.18 (t, J = 8.7 Hz, 2H), 4.96 (s, 2H), 4.71 (s, 2H), 3.65 (t, J = 7.9 Hz, 1H), 3.12 (dd, J = 13.4, 6.9 Hz, 2H), 2.92 (t, J = 11.7 Hz, 2H), 2.15 (tt, J = 8.5, 4.8 Hz, 1H), 1.12 - 1.01 (m, 2H), 0.97-0.88 (m, 2H)

- 293 045362

880A M*H=482 (300 MHz, flMCO-d6) b 8.56 (d, J = 2.4 Hz, 1H), 8.14-7.99 (m, 2H), 7.31 (dd, J = 8.5, 5.5 Hz, 2H), 7.16 (t, J = 8.8 Hz, 2H). 4.84 (s, 2H), 4.72 (s, 2H), 3.45 (k, J = 9.2 Hz, 1H), 3.03 (t, J = 10.7 Hz, 2H), 2.78 (t, J = 10.9 Hz, 2H), 2.15 (tt, J = 8.8, 4.9 Hz, 1H), 1.17-1.04 (m, 2H), 0 .98 -0.87 (m, 2H) 881B M+H=442 (300 MHz, DMSO-C16) δ 9.11 (s, 1H), 8.53 (d, J = 2.5 Hz, 1H), 8.05 - 7.89 (m, 2H), 7.39 - 7.28 (m, 2H), 7.18 (t, J = 8.8 Hz, 2H), 4.98 (s, 2H), 4.72 (s, 2H), 3.76 (t, J = 9.4 Hz, 1H), 3.15 (dd, J = 13.5, 6.8 Hz, 2H). 3.05-2.91 (m,2H). 881A M+H=442 (300 MHz, DMSO-ab) δ 9.12 (s, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.15 - 8.00 (m, 2H), 7.30 (dd, J = 8.6, 5.6 Hz, 2H), 7.15 (t, J = 8.7 Hz, 2H), 4.86 (s, 2H), 4.73 (s, 2H) , 3.65 - 3.48 (m, 1H), 3.07 (t, J = 10.5 Hz, 2H), 2.83 (t, J ~ 10.7 Hz, 2H).

Example 37. Synthesis of compound 442B.

1. Synthesis of intermediate 37-1B

To a solution of intermediate 33-5B (200 mg, 0.42 mmol, 1.0 eq) in DCM (2 mL) at 0°C was added HATU (192 mg, 0.51 mmol, 1.2 eq) 1,1-dimethoxypropan-2-amine (55 mg, 0.46 mmol, 1.1 eq.) and DIEA (106 mg, 1.1 mmol, 5.0 eq.). The mixture was stirred at 0°C for 30 min, concentrated under reduced pressure and purified by chromatography on silica gel (12 g, 60 μm, gradient 0-10% MeOH in DCM) to give intermediate 37-1B. HPMS (ES) m/z 577.2 (M+H).

2. Synthesis of intermediate 37-2B

To a solution of intermediate 37-1B in DCM (3 ml) was added TFA (0.3 ml). The mixture was stirred at room. pace. for 15 h, concentrated under reduced pressure and purified by silica gel chromatography (4 g, 60 μm, gradient 0-10% MeOH in DCM) to give intermediate 37-2B. HPMS (ES) m/z 531.2 (M+H). In this example, the dotted linkage indicates that the stereochemical configuration of the starting material is retained in the product compound.

3. Synthesis of 442V compound

- 294 045362

To a solution of intermediate 37-2B in DCE (2 ml) was added POCl ₃ (1 ml) and the mixture was stirred at 1000°C for 1 hour. The mixture was concentrated, diluted with DCM and poured into NaOH solution (1N). The aqueous layer was extracted with DCM (3X). The combined DCM layers were washed with saline, dried over MgSO ₄ , filtered, concentrated and purified by reverse phase HPLC (Phenomenex, dimer 5 µm C18 150x21.2 mm, gradient 10-100% acetonitrile in water with 0.1% formic acid over 40 min) to obtain 33.9 mg (33% in 3 steps) of compound 442B. HPMS (ES) m/z 513.1 (M+H).

1H NMR (methanol-I4, 400 MHz, ppm) δ 7.79-7.74 (m, 1H), 7.73-7.66 (m, 4H), 7.56-7.51 ( m, 2H), 7.49 (k, J=1.3 Hz, 1H), 5.20 (s, 2H), 4.53 (s, 2H), 3.75-3.65 (m, 1H ), 3.35-3.25 (m, 2H), 3.03-2.95 (m, 2H), 2.10 (d, J=1.3 Hz, 3H).

Example 38. Synthesis of compound 475B

To a mixture of intermediate 33-5B (50 mg, 0.10 mmol, 1.0 eq) in THF (5 mL) was added borane in THF (1.0 M, 0.21 mL, 0.21 mmol, 2. 0 eq.). The mixture was stirred at room. pace. for 3 h, quenched with MeOH, and concentrated under reduced pressure. This material was dissolved in 2 ml DMF and purified by reverse phase HPLC (Phenomenex, dimer 5 µm C18 150x21.2 mm, gradient 10-70% acetonitrile in water with 0.1% formic acid over 25 min) to obtain a mixture that purified again under the same conditions to obtain 4.3 mg (9%) of compound 475B. HPMS (ES) m/z 462.1 (M+H).

1H NMR (400 MHz, methanol-64) δ 7.79-7.74 (m, 1H), 7.72-7.65 (m, 4H), 7.52-7.47 (m, 2H), 5.12 (s, 2H), 4.48 (s, 2H), 3.57-3.54 (m, 2H), 2.72-2.63 (m, 2H), 2.63-2, 44 (m, 3H).

Example 39. Synthesis of compound 479B

1. Synthesis of intermediate 39-1

To a solution of ethyl 3-oxocyclobutanecarboxylate (5.0 g, 35 mmol, 1.0 eq.) in a mixture of dry dichloromethane (50 ml) and dry methanol (50 ml) was added successively trimethyl orthoformate (38 ml, 350 mmol, 10 eq. ) and p-toluenesulfonic acid monohydrate (0.67 g, 3.5 mmol, 0.10 eq.). The mixture was stirred overnight, concentrated, diluted with ethyl acetate, washed twice with saturated sodium bicarbonate brine, dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (80 g, gradient of 0-20% ethyl acetate in hexanes over 25 min) to give 4.6 g (70%) ethyl 3,3-dimethoxycyclobutane-1-carboxylate as a colorless oil (intermediate 39-1).

*H NMR (400 MHz, methylene chloride ₂ ) δ 4.26-4.11 (m, 2H), 3.17 (s, 3H), 3.15 (s, 3H), 2.91-2, 81 (m, 1H), 2.49-2.30 (m, 4H), 1.33-1.25 (m, 3H).

2. Synthesis of intermediate 39-2

Methyl magnesium bromide in diethyl ether (3 .0 M, 18 ml, 53 mmol, 10 eq.). The mixture was heated at 85°C for 2 hours, cooled to 0°C, and quenched with HCl (4 M). stirred for 1 hour and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography

- 295 045362 (12 g, gradient of 0-100% ethyl acetate in hexanes over 11 min) to give 0.78 g (quantitative) 3-(2-hydroxypropan-2-yl)cyclobutan-1-one (intermediate 39- 2) in the form of a transparent yellow oil.

1H NMR (400 MHz, methylene chloride-a ₂ ) δ 3.13-3.02 (m, 2H), 2.99-2.88 (m, 2H), 2.50-2.40 (m, 1H) , 1.28 (s, 6H).

3. Synthesis of intermediate 39-3

To a mixture of 3-(2-hydroxypropan-2-yl)cyclobutan-1-one (0.78 g, 6.0 mmol, 1.0 eq.) and 4(dimethylamino)pyridine (37 mg, 0.30 mmol, 0.05 eq.) in dry tetrahydrofuran (30 ml), cooled to 0°C, added triethylamine (1.6 ml, 12 mmol, 1.9 eq.) followed by dropwise addition of chlorotrimethylsilane (1.2 ml, 9 .1 mmol, 1.5 eq.). The mixture was warmed to room temperature, stirred for 3 days, diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (12 g, gradient 0-20% ethyl acetate in hexanes over 11 min) to give 1.1 g (92%) 3-( 2-((trimethylsilyl)oxy)propan-2-yl)cyclobutan-1-one (intermediate 39-3) as a colorless oil.

1H NMR (400 MHz, methylene chloride-b ₂ ) δ 3.07-2.98 (m, 2H), 2.86-2.76 (m, 2H), 2.32-2.23 (m, 1H) , 1.25 (s, 6H), 0.12 (s, 9H).

4. Synthesis of intermediate 39-4

M&ON 2 chyaor/xuenai pota

To a solution of 3-(2-((trimethylsilyl)oxy)propan-2-yl)cyclobutan-1-one (0.5 g, 2.5 mmol, 1.0 eq.) in dry methanol (7.5 ml) 4-(trifluoromethyl)benzylamine (0.36 g, 2.5 mmol, 1.0 eq) was added. The mixture was stirred for 5 minutes. Diphenylmethylisocyanide (0.48 g, 2.5 mmol, 1.0 eq) and chloroacetic acid (0.24 g, 2.5 mmol, 1.0 eq) were added to this mixture. The mixture was stirred for 1 hour, concentrated and purified by chromatography on silica gel (40 g, gradient of 0-20% ethyl acetate in hexanes over 14 minutes) to give 0.86 g (53%) N-benzhydryl-1-(2-chloro -N-(4(trifluoromethyl)benzyl)acetamido)-3-(2-((trimethylsilyl)oxy)propan-2-yl)cyclobutan-1-carboxamide (intermediate 39-4, mixture of stereoisomers) as a white solid . HPMS (ES) 573 (M+H-TMS).

1H NMR (400 MHz, methylene chloride-b ₂ ) δ 7.68-7.23 (m, 14H), 6.14-6.06 (m, 1H), 4.67-4.52 (m, 2H) , 3.943.80 (m, 2H), 2.69-2.59 (m, 2H), 2.26-2.16 (m, 2H), 1.94-1.82 (m, 1H), 1 .10-1.02 (m, 6H), 0.44- -0.00 (m, 9H).

5. Synthesis of diastereomer 39-5B

N-benzhydryl-1-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-3-(2 solution of ((trimethylsilyl)oxy)propan-2-yl)cyclobutan-1-carboxamide (0.86 g , 1.3 mmol, 1.0 eq.) in dry THF (9 ml) at 0°C, add LHMDS (1.0 M, 1.6 ml, 1.6 mmol, 1.2 eq.) dropwise to dry THF (9 ml). The mixture was stirred at 0°C for 2 hours, slowly quenched with MeOH, concentrated and purified by chromatography on silica gel (40 g, gradient of 0-20% ethyl acetate in hexanes over 28 minutes) to obtain

- 296 045362 diastereomer 39-5A, which was discarded, and 0.4 g (49%) of diastereomer 39-5B as a colorless oil. HPMS (ES) 537 (M+H-TMS).

1H NMR (400 MHz, methylene chloride-b ₂ ) δ 7.60-7.56 (m, 2H), 7.42-7.34 (m, 6H), 7.30-7.25 (m, 2H) , 7.217.17 (m, 4H), 6.99 (s, 1H), 4.97 (s, 2H), 3.71 (s, 2H), 2.98-2.88 (m, 2H), 2.17-2.04 (m, 3H), 1.06 (s, 6H), 0.12 (s, 9H).

6. Synthesis of intermediate 39-6B

39-5V 39-6V

To a solution of diastereomer 39-5B (0.40 g, 0.65 mmol, 1.0 eq.) in ethyl acetate (25 ml) was added 20% palladium hydroxide on carbon (1.5 g, 2.1 mmol, 3.3 eq.), and the resulting mixture was purged with hydrogen for 5 minutes, followed by stirring at 500 psi. inch in a Parr reactor at 50°C for 18 hours. The reaction mixture was then cooled, filtered through a pad of celite, concentrated and purified by chromatography (12 g, 60 μm, gradient of 0-10% methanol in dichloromethane over 22 minutes) to give 0 .13 g (57%) intermediate. 39-6B as a white solid. HPMS (ES) 371 (M+N).

1H NMR (400 MHz, methylene chloride-b ₂ ) δ 7.64-7.56 (m, 2H), 7.38-7.30 (m, 2H), 6.80-6.55 (m, 1H) , 5.014.93 (m, 2H), 4.05-4.02 (m, 2H), 2.98-2.85 (m, 2H), 2.48-2.24 (m, 3H), 1 .06-1.02 (m, 6H).

In this example, the dotted linkage indicates that the stereochemical configuration of the starting material is retained in the product compound.

7. Synthesis of 479B compound

Zromezhugomnoe connection ZMV Sovdakeniye 4798

4-Bromo-3-fluorobenzonitrile (65 mg, 0.33 mmol, 1.8 eq.), copper(1) iodide (17 mg, 0.090 mmol, 0.50 eq.) and potassium carbonate (75 mg, 0.5 eq. 54 mmol, 3.0 eq.) were combined in a flask, which was evacuated and filled with nitrogen 3 times. To this mixture was added N,N'-dimethylethylenediamine (0.010 ml, 0.090 mmol, 0.50 eq), intermediate 6-6B (67 mg, 0.18 mmol, 1.0 eq) and dry dioxane (1 ml ). The reaction vessel was then heated to 100°C with stirring overnight, cooled to room. temp., filtered and purified by reverse phase HPLC (Phenomenex, dimeric 5 µm C18 150x21.2 mm, 10-90% acetonitrile in water with 0.1% formic acid for 25 min. The combined fractions were again purified by chromatography on silica gel (4 g, 60 µm, gradient of 0-100% ethyl acetate in hexanes over 11 min) to obtain 34 mg (38%) of compound 479 B. HPMC (ES) 490 (M+H).

1H NMR (400 MHz, methanol-04) δ 7.78-7.73 (m, 1H), 7.70-7.63 (m, 4H), 7.49-7.44 (m, 2H), 5.14 (s, 2H), 4.48 (s, 2H), 3.00-2.87 (m, 2H), 2.47-2.32 (m, 3H), 1.05 (s, 6H).

The following compounds were prepared by methods similar to those described for compound 479B:

- 297 045362

Diastereomer No. HPMS (ES) m/z 'H NMR 479V M+H=490.2 (400 MHz, methanol-OE b 7.78 - 7.73 (m, 1H), 7.70 - 7.63 (m, 4H), 7.49 - 7.44 (m, 2H), 5.14 (s, 2H), 4.48 (s, 2H), 3.00 - 2.87 (m, 2H), 2.47-2.32 (m, ZN), 1.05 (s, 6H) 481V M+H=499.1 (400 MHz, methanol-s/ ₄ ) b 7.70 - 7.66 (m, 2H), 7.51 - 7.44 (m, ZN), 7.43 - 7.40 (m, 1H), 7.35 - 7.32 (m, 1H), 5.15 (s, 2H), 4.44 (s, 2H), 3.02 - 2.91 (m, 2H), 2.49 - 2, 33 (m, ZN), 1.07 (s, 6N)

Example 40. Synthesis of compound 436B.

1. Synthesis of intermediate 40-2

.O

40-1 "-2

To a solution of tert-butyl-3-oxocyclobutanecarboxylate (5.8 g, 34 mmol, 1.0 eq.) in dry methanol (75 ml) at 0°C was added 4-(trifluoromethyl)benzylamine (4.8 ml, 34 mmol , 1.0 eq.). The mixture was immediately warmed to room. temp., stirred for 5 minutes at room. pace. and cooled back to 0°C followed by the sequential addition of 4-methoxybenzylisocyanide (5.0 g, 34 mmol, 1.0 eq.) and chloroacetic acid (3.2 g, 34 mmol, 1.0 eq.), heated to room temp., stirred for 1 h, concentrated and purified by silica gel chromatography using EA/HE (gradient from 0-100% and 100%) and then MeOH/DCM (1/9) as eluents to give 11.4 g (79%) 3-(2-χλορ-Ν-(4(trifluoromethyl)benzyl)acetamido)-3-((4-methoxybenzyl)carbamoyl)cyclobutane-1-carboxylate as a mixture of isomers. HPMS (ES) m/z 569 (M+H).

1H NMR (400 MHz, methylene chloride-b2) δ 7.71-7.61 (m, 2H), 7.46-7.37 (m, 2H), 7.28-7.19 (m, 2H), 6.936.87 (m, 2H), 4.69-4.62 (m, 2H), 4.42-4.36 (m, 2H), 3.93-3.88 (m, 2H), 3. 84-3.81 (m, 3H), 3.03-2.75 (m, 3H), 2.73-2.61 (m, 1H), 2.55-2.45 (m, 1H), 1.43 (s, 9H).

2. Synthesis of intermediate 40-3B

40-2 40-M 4ft ZV

To a solution of 3-(2-chloro-N-(4-(trifluoromethyl)benzyl)acetamido)-3-((4-methoxybenzyl)carbamoyl)cyclobutane-1-carboxylate (11.4 g, 20 mmol, 1.0 eq. .) in THF (60 ml) was cooled to 0°C and sodium hydroxide (1N, 60.0 ml, 60.1 mmol, 3.0 eq.) in water was added dropwise. The mixture was left to warm to room. temp., stirred for 3 hours, partially concentrated and extracted three times with ethyl acetate. The combined organic washes were dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography using EA/HE (0-50% gradient, isocratic at 50%, 50-100% gradient) to give the first elutable diastereomer 40-3A, which was discarded, and 2.1 g (20%) of the second eluting diastereomer 40-3B. HPMS (ES) m/z 533 (M+H).

1H NMR (400 MHz, methylene chloride-02) δ 7.66-7.61 (m, 2H), 7.36-7.31 (m, 2H), 7.28-7.23 (m, 2H), 6.966.90 (m, 2H), 4.93 (s, 2H), 4.61 (s, 2H), 3.89 (s, 2H), 3.83 (s, 3H), 3.11-3 .04 (m, 2H), 3.02-2.93 (m, 1H), 2.582.51 (m, 2H), 1.48 (s, 9H).

In this example, the dotted linkage indicates that the stereochemical configuration of the starting material is retained in the product compound.

- 298 045362

3. Synthesis of intermediate 40-4B

4G-3B 40-48

To a solution of 40-3B (2.1 g, 3.9 mmol, 1.0 eq.) in acetonitrile (32 ml), cooled at 0°C, was added dropwise cerium ammonium nitrate (CA) (6.4 g , 11.7 mmol, 3.0 eq.) in water (16 ml). The mixture was treated with ultrasound for 10 minutes, stirred for 1 hour at room temperature. temp., concentrated and extracted three times with ethyl acetate. The combined organic washes were dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography using MeOH/DCM (0-10% gradient) as eluents. Fractions were collected and purified again by silica gel chromatography using EA/HE (0-100% gradient) as eluent to yield 0.44 g (28%) of 404B. HPMS (ES) m/z 357 (M+H-tert-butyl).

'H NMR (400 MHz, methylene chloride-er) δ 7.68-7.60 (m, 2H), 7.42-7.34 (m, 2H), 4.96 (s, 2H), 4.07 -4.04 (m, 2H), 3.09-2.92 (m, 3H), 2.62-2.54 (m, 2H), 1.46 (s, 9H).

4. Synthesis of intermediate compound 40-5V

To a mixture of 40-4B (0.37 g, 0.90 mmol, 1.0 eq.), 4-bromo-3-fluorobenzonitrile (0.33 g, 1.6 mmol, 1.8 eq.), copper iodide (1) (0.086 g, 0.45 mmol, 0.5 eq.) and potassium carbonate (0.38 g, 2.7 mmol, 3.0 eq.) in a flask evacuated and purged with nitrogen, N,N was added '-dimethylethylenediamine (0.049 ml, 0.45 mmol, 0.5 eq.) and dry dioxane (4 ml). The mixture was heated at 100°C for 15 hours, filtered through celite, concentrated and purified by chromatography on silica gel using EA/HE (gradient from 0-100%) as eluent to obtain 0.29 g (61%) 40-5B . HPMS (CIAD) m/z 476.1 (M+H-C4H9).

'H NMR (400 MHz, methylene chloride-b ₂ ) δ 7.70-7.66 (m, 2H), 7.63-7.60 (m, 1H), 7.60-7.56 (m, 1H ), 7.567.51 (m, 1H), 7.44-7.40 (m, 2H), 5.02 (s, 2H), 4.40-4.38 (m, 2H), 3.18- 3.11 (m, 2H), 3.03-2.94 (m, 1H), 2.70-2.62 (m, 2H), 1.42 (s, 9H).

5. Synthesis of intermediate compound 40-6B

40-5B (0.29 g, 0.55 mmol, 1.0 eq) and TFA (3.0 mL, 39 mmol, 71 eq) were combined, stirred for 30 min, concentrated and dried in vacuo to give 40-6B. HPMS (ES) m/z 476 (M+H).

- 299 045362

6. Synthesis of intermediate 40-7V

To a mixture of 1-aminopropan-2-one HCl (10 mg, 0.092 mmol, 0.92 eq.), RuVor (52 mg, 0.10 mmol, 1.0 eq.) and 40-6B (49 mg, 0.0 eq.) 10 mmol, 1.0 eq.) in dry DCM (1 ml) was added DIEA (0.073 ml, 0.42 mmol, 4.2 eq.). The mixture was stirred for 30 minutes at room. temp., concentrated and purified by silica gel chromatography using MeOH/DCM (0-10% gradient) to give 45 mg (92%) 40-7B. HPMS (ES) m/z 531 (M+H).

7. Synthesis of 436V compound

To a solution of 40-7B (45 mg, 0.085 mmol, 1.0 eq.) in DCE (1 mL) was added phosphorus(V) oxychloride (0.39 mL, 4.2 mmol, 50 eq.) dropwise. The mixture was heated at 100°C for 1 hour, cooled to 0°C, made alkaline to pH greater than 14 by dropwise addition of NaOH (1N), warmed to room. pace. and stirred overnight. The mixture was extracted with DCM three times. The combined organic layers were dried over magnesium sulfate, filtered, concentrated and purified by RP-HPLC (Phenomenex, dimeric 5 µm C18 150x21.2 mm, gradient 10-100% acetonitrile in water with 0.1% formic acid over 25 min) to obtain 14.9 mg (35%) compound 436B. HPMS (ES) m/z 513 (M+H).

1H NMR (400 MHz, methanol- _d4 ) δ 7.80-7.75 (m, 1H), 7.73-7.66 (m, 4H), 7.56-7.51 (m, 2H) , 6.66 (k, J=1.2 Hz, 1H), 5.20 (s, 2H), 4.54 (s, 2H), 3.74-3.63 (m, 1H), 3, 31-3.24 (m, 2H), 3.02-2.94 (m, 2H), 2.27 (d, J=1.2 Hz, 3H).

Example 41. Synthesis of compound 496.

1. Synthesis of intermediate 41-2

To a mixture of (4-(trifluoromethyl)phenyl)methanamine (143 mg, 0.82 mmol, 1.05 eq.) and 3-(5-methylthiazol-2yl)cyclobutan-1-one (130 mg, 0.78 mmol, 1.0 eq) to MeOH (10 ml) were added 2-isocyanopropane (56 mg, 0.82 mmol, 1.05 eq) and chloroacetic acid (77 mg, 0.82 mmol, 1.05 eq). The mixture was stirred at room. pace. for 1 h, concentrated under reduced pressure and purified by silica gel chromatography using EtOAc/hexanes (7/3) as eluents to give 380 mg of intermediate 41-2 as a mixture of isomers, which was used in the next step without further purification HPMS (ES) m/z 488.1 (M+H).

2. Synthesis of 496V compound

Oh oh

G?

'Vs

To a mixture of intermediate 41-2 (380 mg, 0.78 mmol, 1.0 eq.) in THF (5 ml), cooled

- 300 045362 to 0°C in an ice bath, LHMDS (1 M in THF, 0.78 ml, 0.78 mmol, 1.0 eq.) was added dropwise. The mixture was stirred at 0°C for 2 h, MeOH was added, concentrated under reduced pressure and purified by reverse phase HPLC (Phenomenex, dimeric 5 μm C18 150x21.2 mm, gradient 1080% acetonitrile in water with 0.1% formic acid in for 40 min) to obtain 3.6 mg (2% in 2 stages) of the first eluting peak of the eluent in the form of diastereomer 496B and 8.1 mg (5% in 2 stages) of the second eluting peak in the form of diastereomer 496A.

Characteristics of diastereomer 496B: HPMS (ES) m/z 452.1 (M+H).

1H NMR (methanol-I4, 400 MHz, ppm) δ 7.68 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 7, 31 (k, J=1.2 Hz, 1H), 5.14 (s, 2H), 4.70 (p, J=6.8 Hz, 1H), 4.06 (s, 2H), 3, 93-3.77 (m, 1H), 3.20-3.08 (m, 2H), 2.98-2.86 (m, 2H), 2.45 (d, J=1.2 Hz, 3H), 1.22 (d, J=6.8 Hz, 6H).

Characteristics of diastereomer 496A: HPMS (ES) m/z 452.1 (M+H).

1H NMR (400 MHz, methanol ₄ ) δ 7.65 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.36 (k, J=1.2 Hz, 1H), 5.07 (s, 2H), 4.86-4.74 (m, 1H), 4.08 (s, 2H), 3.69 (p, J=8 .9 Hz, 1H), 2.99 (ddd, J=10.0, 8.4, 2.7 Hz, 2H), 2.76 (td, J=9.5, 2.8 Hz, 2H) , 2.43 (d, J=1.2 Hz, 3H), 1.26 (d, J=6.8 Hz, 6H).

Example 42. Synthesis of compound 498B.

1. Synthesis of intermediate 42-1

To a mixture of (4-(trifluoromethyl)phenyl)methanamine (6.7 g, 38.0 mmol, 1.05 eq.) and tert-butyl-3 oxocyclobutane-1-carboxylate (6.2 g, 36.2 mmol, 1.0 eq.) in MeOH (100 ml) was added 2-isocyanopropane (3.0 g, 43.4 mmol, 1.2 eq.) and chloroacetic acid (3.6 mg, 38.0 mmol, 1.05 eq. ). The mixture was stirred at room. pace. for 1 h, concentrated under reduced pressure and purified by silica gel chromatography using EtOAc/hexanes (7/3) as eluents to give intermediate 42-1 as a mixture of diastereomers, which was used in the next step without further purification. HPMS (ES) m/z 491.2 (M+H).

2. Synthesis of diastereomer 42-2B

LHMDS (1 M in THF, 40.3 ml, 40.3 mmol, 1.2 eq.). The mixture was stirred at 0°C for 2 hours, MeOH was added, concentrated under reduced pressure and purified by chromatography on silica gel (220 g, gradient 0-50% EtOAc in hexanes) to give the crude product. This material was again purified by silica gel chromatography (120 g, gradient 0-50% EtOAc in hexanes) to give the first eluting diastereomer 42-2A, which was discarded, and 2.5 g (16%) of the second eluting diastereomer 42-2B.

Characteristics of diastereomer 42-2B: HPMS (ES) m/z 455.25 (M+H).

1H NMR (400 MHz, methanol-I4) δ 7.72-7.63 (m, 2H), 7.45-7.36 (m, 2H), 5.03 (s, 2H), 4.72 ( p, J=6.9 Hz, 1H), 4.02 (s, 2H), 3.11-2.89 (m, 3H), 2.71-2.56 (m, 2H), 1.46 (s, 9H), 1.23 (d, J=6.8 Hz, 6H).

3. Synthesis of intermediate 42-3B

To a solution of diastereomer 42-2B (2.5 g, 5.5 mmol, 1.0 eq) in DCM (10 ml) was added TFA (10 ml). The mixture was stirred at room. pace. for 1 hour and concentrated to give 2.2 g (99% yield) of intermediate 42-3B. HPMS (ES) m/z 399.2 (M+H).

- 301 045362

4. Synthesis of 498V compound

DCM, thionyl chloride, DMF

MeNH ₂ , THF, RT, 1 h

Compound 498B

To a solution of 42-ZV (0.20 g, 0.50 mmol, 1.0 eq.) in DCM (3 ml) was added thionyl chloride (0.2 ml, 2.7 mmol, 5.5 eq.) and a drop of DMF (-50 mg). The mixture was stirred at room. pace, for 1 min, followed by the addition of MeNH ₂ (2 M in THF, 6 ml, 12 mmol, 24 eq.), stirred at room. temp, for 1 hour, poured into water and extracted with DCM. The organic layer was concentrated and purified by reverse phase HPLC (Phenomenex, dimer 5 µm C18 150x21.2 mm, gradient 10-700% acetonitrile in water with 0.1% formic acid over 25 min) to give 8.6 mg (4% ) 498V connections. HPMS (ES) m/z 412.2 (M+H).

^Z H NMR (400 MHz, methanol-b ₄ ) δ 7.81-7.72 (m, 1H), 7.67-7.62 (m, 2H), 7.42-7.36 (m, 2H ), 5.04 (s, 2H), 4.70 (hept, J=6.8 Hz, W), 4.01 (s, 2H), 3.14-2.96 (m, ZN), 2 .74-2.69 (m, ZN), 2.66-2.56 (m, 2H), 1.20 (d, J=6.8 Hz, 6H).

Example 43. Synthesis of 500B compound.

1. Synthesis of intermediate 43-1B

NATC DtPEA, CHU _S

To a mixture of 3-aminobutan-2-one (68 mg, 0.55 mmol, 1.1 eq.), HATU (229 mg, 0.60 mmol, 1.2 eq.) and 42ZV (200 mg, 0.50 mmol, 1.0 eq.) in dry DCM (2 ml) was added DIEA (0.35 ml, 2.0 mmol, 4.0 eq.). The mixture was stirred for 1 hour at room temperature, concentrated and purified by silica gel chromatography using MeOH/DCM (0-10% gradient) to give 239 mg of 43-1B. HPMS (ES) m/z 468.2 (M+H). In this example, the dotted linkage indicates that the stereochemical configuration of the starting material is retained in the product compound.

2. Synthesis of 500V connection

To a solution of 43-1B (239 mg, 0.50 mmol, 1.0 eq.) in DCE (3 mL) was added phosphorus(U) oxychloride (2.4 mL, 25.5 mmol, 50 eq.) dropwise. The mixture was heated at 100°C for 1 hour, cooled to 0°C, made alkaline to pH greater than 14 by dropwise addition of NaOH (IN), warmed to room temp, and stirred overnight. The mixture was extracted with DCM three times. The combined organic layers were dried over magnesium sulfate, filtered, concentrated and purified by reverse phase HPLC (Phenomenex, dimeric 5 µm C18 150x21.2 mm, gradient 10-100% acetonitrile in water with 0.1% formic acid over 25 min) with obtaining 103 mg (45%) of compound 500B. HPMS (ES) m/z 450.2 (M+H).

^Z H NMR (400 MHz, methanol-b ₄ ) δ 7.70-7.65 (m, 2H), 7.47-7.42 (m, 2H), 5.11 (s, 2H), 4, 68 (hept, J=6.8 Hz, 1H), 4.05 (s, 2H), 3.63-3.51 (m, 1H), 3.21-3.13 (m, 2H), 2 .87-2.77 (m, 2H), 2.23-2.21 (m, ZN), 2.04-2.02 (m, ZN), 1.22 (d, J=6.8 Hz , 6H).

The following compounds were prepared using methods similar to those described for the 500B compound:

-302 045362

Diastereomer No. HPMS (ES) m/z ^1H NMR 500V M+H=450.2 (400 MHz, methanol-d ₄ ) δ 7.70 - 7.65 (m, 2H). 7.47 - 7.42 (m, 2H), 5.11 (s, 2H), 4.68 (hept, J = 6.8 Hz, 1H), 4.05 (s, 2H), 3.63 - 3.51 (m, 1H), 3.21 - 3.13 (m, 2H), 2.87 - 2.77 (m, 2H), 2.23 - 2.21 (m, ZN), 2 .04 - 2.02 (m, ZN), 1.22 (d, J = 6.8 Hz, 6H) 502 V M+H=436.2 (400 MHz, methanol- _d4 ) δ 7.70 - 7.65 (m, 2H), 7.51 (k, J = 1.3 Hz, 1H), 7.47 7.42 (m, 2H) , 5.12 (s, 2H), 4.67 (hept, J = 6.8 Hz, 1H), 4.05 (s, 2H), 3.68 - 3.58 (m, 1H), 3, 23-3.16 (m, 2H), 2.90-2.81 (m, 2H), 2.12 (d, J = 1.3 Hz, ZN), 1.22 (d, J = 6, 8 Hz, 6H)

Example 44. Synthesis of compounds 488B and 490B. 1. Synthesis of intermediate 44-2

44-2

To a mixture of 4-chlorobenzylamine (2.9 g, 20.2 mmol, 10 eq.) and tert-butyl-3-oxocyclobutane-1-carboxylate (3.4 g, 20.2 mmol, 1.0 eq.) in MeOH ( 30 ml) (isocyanomethylene)dibenzene (4.1 g, 21.2 mmol, 1.05 eq) and chloroacetic acid (2.0 g, 21.2 mmol, 1.05 eq) were added. The mixture was stirred at room. temp. over 15 h, concentrated under reduced pressure and purified by silica gel chromatography using EA/HE (0-100% gradient) to give 9.0 g (77%) tert-butyl-3(benzhydrylcarbamoyl)-3 -(2-chloro-X-(4-chlorobenzyl)acetamido)cyclobutane-1-carboxylate) as a mixture of diastereomers. HPMS (ES) m/z 581.2 (M+H).

2. Synthesis of diastereomer 44-2B

44-2

To a solution of tert-butyl 3-(benzhydrylcarbamoyl)-3-(2-chloro-X-4-(chlorobenzyl)acetamido)cyclobutane-1-carboxylate) (9.0 g, 15.5 mmol, 1.0 eq. ) in THF (200 mL) cooled to 0°C in an ice bath, LHMDS (1 M in THF, 18.6 mmol, 1.2 eq.) was added dropwise over 10 min. The mixture was stirred at 0°C for 2 hours, quenched with MeOH (5 ml), concentrated on S1O2 (20 g) and purified by silica gel chromatography using EA/HE (0-100% gradient) to give two separate diastereomers. The first eluting peak (diastereomer 44-2A) was discarded and the second eluting peak (diastereomer 44-2B) was collected (3.0 g, 36%). Characteristics of diastereomer 44-2B: HPMS (ES) m/z 545.3 (M+H).

^! H NMR (methanol-b ₄ , 400 MHz, ppm) δ 7.45-7.30 (m, 8H), 7.24-7.12 (m, 6H), 6.99 (s, 1H ), 4.88 (s, 2H), 3.77 (s, 2H), 3.08-2.86 (m, ZN), 2.69-2.51 (m, 2H), 1.44 ( s, 9H).

- 303 045362

3. Synthesis of intermediate 44-4B

2V 44-4V

Et ₃ SiH (20 ml) was added to a solution of diastereomer 44-2B (0.6 g, 1.1 mmol, 1.0 eq.) in TFA (20 ml). The mixture was stirred at 80°C for 60 hours, concentrated under reduced pressure and purified by silica gel chromatography using MeOH/DCM (0-30%) to give 0.3 g (84%) of intermediate 44-4B, HPMC (ES ) m/z 323.1 (M+H). In this example, the dotted linkage indicates that the stereochemical configuration of the starting material is retained in the product compound.

4. Synthesis of intermediate compound 44-5V ci CI

44-4V 44-5V

To a solution of intermediate 44-4B (354 mg, 1.1 mmol) in DCM (5 mL) and MeOH (5 mL) was added TMSCHN2 (2 M in hexanes, 2.8 mL, 5.1 eq). The mixture was stirred at room. temp. for 2 hours and concentrated under reduced pressure to give intermediate 445B. HPMS (ES) m/z 337.1 (M+H).

5. Synthesis of 488V compound

44.55

To a mixture of copper iodide (113 mg, 0.59 mmol, 0.5 eq.), potassium carbonate (492 mg, 3.6 mmol, 3.0 eq.), 4bromo-3-fluorobenzonitrile (428 mg, 2.1 mmol, 1.8 equiv.) and intermediate 44-5B (370 mg, 1.1 mmol, 1.0 equiv.), 1,4-dioxane (16 ml) and N,N'-dimethylethylenediamine (64 µl, 0.59 mmol, 0.5 eq.). The mixture was sealed and heated at 100°C for 15 hours, cooled to room temperature, filtered through celite and purified by silica gel chromatography using EA/HE (gradient from 0-100%) to give 100 mg (19% per 3 stages) connections 488V. HPMS (ES) m/z 456.1 (M+H).

*H NMR (400 MHz, methanol-a ₄ ) δ 7.78-7.73 (m, 1H), 7.71-7.63 (m, 2H), 7.40-7.35 (m, 2H ), 7.31-7.26 (m, 2H), 4.99 (s, 2H), 4.47 (s, 2H), 3.64 (s, ZN), 3.18-3.02 ( m, ZN), 2.87-2.78 (m, 2N).

6. Synthesis of 490V connection

Compound 488V Compound 490V

To a solution of compound 488B (70 mg, 0.15 mmol, 1.0 eq.) in MeOH (2 ml) was added NH ₄ OH (2 ml). The resulting mixture was stirred at room. temp, over 5 h, concentrated in vacuo and purified by reverse phase HPLC (Phenomenex, dimeric 5 µm C18 150x21.2 mm, gradient 10-100% acetonitrile in water with 0.1% formic acid over 40 min) to obtain 2.4 mg (4%) isomer B of compound 490 (490B). HPMS (ES) m/z 441.1 (M+H).

Ή NMR (methanol-b ₄ , 400 MHz, ppm) δ 7.80-7.75 (m, 1H), 7.73-7.65 (m, 2H), 7.43-7.36 (m, 2H), 7.347.28 (m, 2H), 5.04 (s, 2H), 4.49 (s, 2H), 3.21-3.06 (m, ZN), 2.84- 2.68 (m, 2H).

-304 045362

Example 45. Synthesis of compound 492B

1. Synthesis of intermediate 45-1B

SG CI

FMV 45-1V

To a mixture of piperidin-4-ol (263 mg, 2.7 mmol, 1.1 eq.), HATU (1.1 g, 2.9 mmol, 1.2 eq.) and 44-4B (0.78 g , 2.4 mmol, 1.0 eq.) in dry DCM (10 ml) was added TEA (1.0 ml, 7.3 mmol, 3.0 eq.). The mixture was stirred for 3 hours at room temperature, concentrated and purified by silica gel chromatography using MeOH/DCM (0-30% gradient) to give 150 mg (15%) of 45-1B. HPMS (ES) m/z 406.2 (M+H).

2. Synthesis of 492V compound

45LV U2B

To a mixture of copper iodide (12 mg, 0.062 mmol, 0.5 eq.), potassium carbonate (51 mg, 0.37 mmol, 3.0 eq.), 4bromo-3-fluorobenzonitrile (44 mg, 0.22 mmol, 1.8 equiv.) and intermediate 45-1B (50 mg, 0.12 mmol, 1.0 equiv.) 1,4-dioxane (3 ml) and N,N'-dimethylethylenediamine (7 µl, 0.062 mmol, 0.5 eq.). The mixture was sealed and heated at 100°C for 15 hours, cooled to room temperature, filtered through celite, and purified by reverse phase HPLC (Phenomenex, dimer 5 μm C18 150x21.2 mm, gradient 10-80% acetonitrile in water with 0.1% formic acid for 40 min) to obtain 13.1 mg (20%) of compound 492B. HPMS (ES) m/z 525.2 (M+H).

Ή NMR (400 MHz, methanol-a ₄ ) δ 7.79-7.75 (m, W), 7.72-7.66 (m, 2H), 7.43-7.39 (m, 2H) , 7.37-7.32 (m, 2H), 5.10-5.00 (m, 2H), 4.55-4.45 (m, 2H), 4.04-3.95 (m, 1H), 3.86-3.78 (m, 1H), 3.51-3.42 (m, 1H), 3.22-3.01 (m, 5H), 2.81-2.70 ( m, 2H), 1.87-1.77 (m, 2H), 1.45-1.34 (m, 2H).

The following compounds were prepared by methods similar to those described for compound 492B:

Connection No. HPMS (ES) m/z ^1H NMR 492V M+H=525.2 (400 MHz, methanol- _d4 ) δ 7.79 - 7.75 (m, 1H), 7.72 - 7.66 (m, 2H), 7.43 - 7.39 (m, 2H), 7 .37 - 7.32 (m, 2H), 5.10 - 5.00 (m, 2H), 4.55 - 4.45 (m, 2H), 4.04 - 3.95 (m, 1H) , 3.86 - 3.78 (m, 1H), 3.51 - 3.42 (m, 1H), 3.22 - 3.01 (m, 5H), 2.81 - 2.70 (m, 2H), 1.87 - 1.77 (m, 2H), 1.45 - 1.34 (m, 2H) 494V M+N-534.1 (400 MHz, methanol- _d4 ) δ 7.48 - 7.43 (m, 1H), 7.42 - 7.36 (m, ZN), 7.35 - 7.29 (m, ZN), 5 .09 - 4.98 (m, 2H), 4.47 - 4.37 (m, 2H), 4.02 - 3.93 (m, 1H), 3.84 - 3.76 (m, 1H) , 3.49 - 3.40 (m, 1H), 3.20 - 2.99 (m, 5H), 2.78 - 2.68 (m, 2H), 1.85 - 1.75 (m, 2H), 1.43-1.32 (m, 2H)

- 305 045362

Example 46. Synthesis of compound 483B.

1. Synthesis of diastereomers 46-1A and 46-1B

Diastereomer 46-1A

MeOH

TBDMSO

Diastereomer 46-1B

To a mixture of 3-((tert-butyldimethylsilyl)oxy)cyclobutan-1-one (1.0 g, 5.0 mmol) and (4(trifluoromethyl)phenyl)methanamine (874 mg, 5.0 mmol) in a round bottom flask was added MeOH (10 ml). The mixture was stirred at room. pace, for 5 min. To this mixture were added sequentially (isocyanomethylene)dibenzene (965 mg, 5.0 mmol) and 2-chloroacetic acid (472 mg, 5.0 mmol). The resulting mixture was stirred at room. pace, over 5 hours, diluted with EtOAc (150 ml), washed with saturated aqueous NaHCO ₃ (50 ml), saturated aqueous NH4CI (50 ml) and brine, dried over sodium sulfate, concentrated under reduced pressure and purified by chromatography on silica gel, using 20% EA/Hex to provide 1.2 g (1.8 mmol, 36% yield) of the first eluting diastereomer 46-1A and 698 mg (1.08 mmol, 21% yield) of the second eluting diastereomer 46-1B.

Characteristics of diastereomer 46-1 A: HPMC (CIAD) m/z 645.3 (M+H).

'll NMR (400 MHz, methanol^) δ 7.57 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.l Hz, 2H), 7.41-7.10 (m, JH), 6.13 (s, 1H), 4.82 (s, 2H), 4.24 (s, 2H), 4.18 (t, J=7.0 Hz, 1H), 3 .07 (ddd, J=9.8, 6.8, 3.0 Hz, 2H), 2.26 (t, J=9.9 Hz, 2H), 0.84 (s, 9H), 0, 00 (s, 6H).

Characteristics of diastereomer 46-1B: HPMS (CIAD) m/z 645.3 (M+H).

'll NMR (400 MHz, methanol^) δ 7.66 (d, J=8.l Hz, 2H), 7.51 (d, J=8.l Hz, 2H), 7.37-7.25 (m, JH), 6.18 (s, 1H), 4.75 (s, 2H), 4.28-4.22 (m, 1H), 4.18 (s, 2H), 2.85- 2.74 (m, 2H), 2.66-2.53 (m, 2H), 0.74 (s, 9H), -0.12 (s, 6H).

2. Synthesis of intermediate 46-2B

Diastereomer 46-1B

Intermediate 46-2V

To a solution of diastereomer 46-1B (698 mg, 1.08 mmol) in THF (5 ml), cooled to 0°C in an ice bath, was added LHMDS (1.3 ml, 1.3 mmol, 1.2 eq.) drop by drop for 5 minutes. The mixture was stirred at 0°C for 1 hour, quenched with saturated aqueous NH4Cl (30 ml) and diluted with EtOAc (75 ml). The organic phase was washed with brine, dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel chromatography using 10% EtOAc/Hex as eluent to give 600 mg (92%) of intermediate 46-2B. HPMS (CIAD) m/z 609.3 (M+H).

3. Synthesis of intermediate 46-ZV

46-2B

Pd(OH) ₂ , n ₂

EtOAc, MeOH, HOAC

46-ZV

Pd(OH) ₂ was added to a solution of intermediate 46-2B (600 mg, 0.99 mmol) in a mixture of MeOH (25 ml), EtOAc (25 ml) and acetic acid (0.5 ml). The mixture was purged with hydrogen for 5 minutes, stirred under a hydrogen pressure of 400 psi. inch for 20 hours, filtered through celite, concentrated in vacuo and dissolved in EtOAc (75 ml). The organic phase was washed with saturated aqueous

- 306 045362

NaHCO ₃ (50 ml) and brine, dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel chromatography using 50% EtOAc/Hex and 5% MeOH/DCM as eluent to give 256 mg (79%) of intermediate connections 46-ZV. HPMS (CIAD) m/z 329.1 (M+H).

*H NMR (400 MHz, methanol ₄ ) δ 7.72 (d, >8.1 Hz, 2H), 7.48 (d, >8.1 Hz, 2H), 5.03 (s, 2H ), 4.35 (p, >7.2 Hz, 1H), 4.10 (s, 2H), 2.79 (d, >7.2 Hz, 4H).

4. Synthesis of 483B compound

46-ZV Compound 483B

To a mixture of intermediate 46-ZV (100 mg, 0.31 mmol), K ₂ CO ₃ (126 mg, 0.91 mmol, 3.0 eq.), Cui (29 mg, 0.15 mmol, 0.5 eq.) and 1-bromo-4-chloro-2-fluorobenzene (57 μl, 0.46 mmol, 1.5 eq.), anhydrous 1,4-dioxane (3 ml) and N,N-dimethylethylene mamine (16 μl) were added , 0.15 mmol, 0.5 eq.). The resulting suspension was heated in a sealed vessel under nitrogen at 115 °C for 18 h, cooled to room temperature, filtered through celite, washed with additional 1,4-dioxane (20 ml), evaporated in vacuo and purified by reverse phase HPLC using 10-100% ACN/water (both with 0.1% formic acid; Phenomenex Gemini 5 micron C18 column) and silica gel chromatography using 75% EA/Hex as eluent to give 19 mg (14%) of compound 483B. HPMS (CIAD) m/z 457.1 (M+H).

*H NMR (400 MHz, methanol-iD δ 7.69-7.64 (m, 2H), 7.49-7.39 (m, 4H), 7.35-7.31 (m, 1H), 5.03 (s, 2H), 4.43 (s, 2H), 4.33-4.24 (m, 1H), 2.86-2.76 (m, 4H).

The following compounds were prepared by methods similar to those described for compound 483B:

The final compounds obtained from diastereomer 46-1A were isolated using diastereomer 46-1A as starting material in a similar sequence.

Connection No. HPMS (ES) m/z ^1H NMR 483V M+H=457.1 (400 MHz, methanol- _d4 ) δ 7.69 - 7.64 (m, 2H), 7.49 - 7.39 (m, 4H), 7.35 - 7.31 (m, 1H), 5 .03 (s, 2H), 4.43 (s, 2H), 4.33 - 4.24 (m, 1H), 2.86-2.76 (m, 4H) 484V M+H=448.1 (400 MHz, methanol- _d4 ) b 7.79 - 7.74 (m, 1H), 7.71 - 7.64 (m, 4H), 7.49 - 7.43 (m, 2H), 5 .03 (s, 2H), 4.49 (s, 2H), 4.33 - 4.23 (m, 1H), 2.88-2.76 (m, 4H) 483A M+H=457.1 (400 MHz, methanol- _d4 ) b 7.70 - 7.62 (m, 2H), 7.51 - 7.37 (m, 4H), 7.36 - 7.29 (m, 1H), 5 .07 (s, 2H), 4.44 (s, 2H), 4.21 - 4.11 (m, 1H), 3.00 - 2.89 (m, 2H), 2.47 - 2.36 (m, 2H) 484A M+H=448.1 (400 MHz, methanol- _d4 ) δ 7.78 - 7.73 (m, 1H), 7.72 - 7.64 (m, 4H), 7.49 - 7.43 (m, 2H), 5 .07 (s, 2H), 4.50 (s, 2H), 4.20 - 4.12 (m, 1H), 3.00 - 2.91 (m, 2H), 2.47 - 2.37 (m, 2H)

Example 47. Synthesis of compound 339.

1. Synthesis of intermediate 47-2

Ph

47^2

At this stage the method published in Synlett 2007, No. was followed. 2, pp. 0227-0230. Briefly to a solution of 1-benzhydrylazetidin-3-one (1.84 g, 7.76 mmol) and (8)-1-(4-(trifluoromethyl)phenyl)ethan-1-amine (1.47 g, 7.76 mmol, 1.0 eq.) in MeOH (10 ml) diphenylmethylisocyanide (1.50

- 307 045362 g, 7.76 mmol, 1.0 eq.) and 2-chloroacetic acid (733 mg, 7.76 mmol, 1.0 eq.). The resulting mixture was stirred at room. pace, over 5 hours, diluted with EA (150 ml), washed with saturated aqueous NaHCO3 (100 ml), saturated aqueous NH4CI (100 ml) and brine, dried over sodium sulfate, concentrated under reduced pressure and purified by chromatography on silica gel using EA/Hex (1/4) to give 2.0 g (36%) (8)-M,1-dibenzhydryl-3-(2-chloro-M-(1-(4(trifluoromethyl)phenyl)ethyl) acetamido)azetidine-3-carboxamide. HPMS (CIAD) m/z 696.3 (M+H).

2. Synthesis of intermediate 47-3

47-2 47-3

To a solution of (8)-K,1-dibenzhydryl-3-(2-chloro-K-(1-(4(trifluoromethyl)phenyl)ethyl)acwtamido)azetidine-3-carboxamide (1.97 g, 2.83 mmol ) in THF (25 mL) cooled to 0°C in an ice bath, LHMDS (3.39 mL of 1.0 M in THF, 3.39 mmol, 1.2 eq.) was added dropwise over 5 min. The resulting mixture was stirred at 0°C for 1 hour, quenched with saturated aqueous NH4CI (30 ml) and diluted with EA (75 ml). The organic phase was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel chromatography using EA/HE (15/85) to give 1.1 g (59%) of (8)-2,8-dibenzhydryl-5- (1-(4-(trifluoromethyl)phenyl)ethyl)-2,5,8triazaspiro[3.5]nonane-6,9-dione. HPMS (CIAD) m/z 660.4 (M+H).

'll NMR (400 MHz, methanol-a ₄ ) δ 7.61 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.2 Hz, 2H), 7.34-7 .03 (m, 20H), 6.85 (s, 1H), 5.84 (t, J=7.0 Hz, 1H), 4.12 (s, 1H), 3.76 (d, J= 8.9 Hz, 1H), 3.71-3.59 (m, 2H), 3.49 (d, J=8.8 Hz, 1H), 3.39 (t, J=9.l Hz, 2H), 1.79 (d, J=7.l Hz, ZN).

3. Synthesis of intermediate 47-4

T O Ph AcOH o

Ph

47-3 47-4

To a solution of (8)-2,8-dibenzhydryl-5-(G(4-(trifluoromethyl)phenyl)ethyl)-2,5,8-triazaspiro[3.5]nonane6,9-dione (1.10 g, 1. 66 mmol) in a mixture of MeOH (100 ml) and EA (100 ml), Pd(OH) ₂ (20% on carbon, 1.3 g) and acetic acid (0.5 ml) were added. The resulting mixture was purged with hydrogen for 5 minutes, heated at 50°C under hydrogen (initially at 500 psi) for 20 hours, filtered through celite and concentrated under reduced pressure to give 640 mg of (S)-5- (l-(4(trifluoromethyl)phenyl)ethyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione acetate. HPMS (CIAD) m/z 328.1 (M+H).

4. Synthesis of intermediate 47-5

47-4 47-5

To a mixture of (8)-5-(1-(4-(trifluoromethyl)phenyl)ethyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione acetate (320 mg, 0.83 mmol) in DCM (10 ml) was cooled to 0°C in an ice bath, TEA (346 µl, 3.0 eq.) and acetyl chloride (1.66 ml of a 1.0 M solution in DCM, 1.66 mmol, 2.0 eq.) were added successively. ). Once addition was complete, the ice bath was removed. The mixture was stirred at room. pace, for 30 min, diluted with DCM (20 ml) and washed with saturated aqueous Nai ICO; (15 ml). The aqueous phase was extracted with DCM (20 ml). The combined organic phases were dried over sodium sulfate and concentrated. The mixture was suspended in Et ₂ O (10 ml), sonicated, filtered and dried to give 188 mg (61%) (8)-2-acetyl-5-(1-(4-(trifluoromethyl)phenyl)ethyl)-2 ,5,8-triazaspiro[3.5]nonane-6,9-dione. HPMS (CIAD) m/z 370.1 (M+H).

¹ II NMR (400 MHz, DMSO-de) δ 8.52 (s, 1H), 7.67 (d, J=8.l Hz, 2H), 7.55 (d, J=8.l Hz, 2H), 5.1-5.30 (bs, 1H), 4.51 (dd, J=36,l, 9.5 Hz, 1H), 4.40-4.24 (m, 1H), 4 .18 (t, J=9.5 Hz, 1H), 4.06-3.82 (m, ZN), 1.87 (dd, J=6.9,

- 308 045362

3.5 Hz, ZN), 1.74 (d, J=23.2 Hz, ZN).

5. Synthesis of compound 339

To a mixture of (8)-2-acetyl-5-(1-(4-(trifluoromethyl)phenyl)ethyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione (102 mg, 0.28 mmol), Cui (26 mg, 0.14 mmol, 0.5 eq.), K ₂ CO ₃ (115 mg, 0.83 mmol, 3.0 eq.) and 3-fluoro-4iodobenzonitrile (136 mg, 0 .55 mmol, 2.0 eq.) 1,4-dioxane (1.5 ml) and N,Ndimethylethylenediamine (15 μl, 0.14 mmol, 0.5 eq.) were added to the test tube. The mixture was purged with _N2 , hermetically sealed, heated at 115°C for 18 hours, cooled to room. temp, and filtered through celite. The solid was washed with 1,4-dioxane (20 ml). The filtrate was evaporated in vacuo and purified by reverse phase HPLC using ACN/water (both with 0.1% formic acid gradient from 10 to 100%; Phenomenex Gemini 5 micron C18 column). The collected fractions gave a mixture which was again purified by silica gel chromatography using EA/Hex (3/7) and MeOH/DCM (1/9) as eluents to give 24 mg (18%) (S)-4-(2 -acetyl-6,9-dioxo-5-(1-(4-(trifluoromethyl)phenyl)ethyl)-2,5,8-triazaspiro[3.5]nonan8-yl)-3-fluorobenzonitrile. HPMS (CIAD) m/z 489.2 (M+H).

'H NMR (400 MHz, methanol-DO δ 7.83-7.61 (m, 7H), 5.4-5.6 (br, 1H), 4.82-4.43 (m, 5H) , 4.37 (d, J=11.0 Hz, 1H), 2.03 (t, J=6.8 Hz, ZN), 1.88 (d, J=23.l Hz, ZN).

Example 48 Synthesis of Compound 340

CF ₃

Compound 340

A method similar to Example 47 was used, except that 1-bromo-4-chloro-2fluorobenzene was used in step 5 instead of 3-fluoro-4-iodobenzonitrile.

Example 49. Synthesis of compound 341.

1. Synthesis of intermediate 49-2

To a mixture of 4-trifluoromethylbenzylamine (1.2 g, 7.0 mmol, 1.1 eq.) and 1-benzhydryl azetidin-3-one (1.5 g, 6.3 mmol, 1.0 eq.) in MeOH ( 30 ml) (isocyanomethylene)dibenzene (1.3 g, 7.0 mmol, 1.1 eq) and 2-chloropropionic acid (0.76 g, 7.0 mmol, 1.1 eq) were added. The resulting mixture was stirred at room temp for 15 hours, concentrated under reduced pressure and purified by chromatography on silica gel using EA/HE (1/3) as eluents to obtain 1.8 g (41%) of X,1- dibenzhydryl-3-(2-chloroX-(4-(trifluoromethyl)benzyl)propanamido)azetidine-3-carboxamide. HPMS (ES) m/z 696.3 (M+H).

2. Synthesis of intermediate 49-3

49-2 49-3

To a solution of X,1-dibenzhydryl-3-(2-chloro-X-(4-(trifluoromethyl)benzyl)propanamido)azetidine-3-309 045362 carboxamide (1.8 g, 2.6 mmol, 1.0 eq. ) in THF (200 mL) cooled to 0°C in an ice bath, LHMDS (1 M in THF, 3.1 mL, 3.1 mmol, 1.2 eq.) was added dropwise over 10 min. The resulting mixture was stirred at 0°C for 2 hours, quenched with MeOH (5 ml), and concentrated on SiO2 (20 g). The mixture was purified by silica gel chromatography using EA/HE (0-100% gradient) to give 1.2 g (70%) 2,8-dibenzhydryl-7-methyl-5-(4-(trifluoromethyl)benzyl)- 2,5,8-triazaspiro[3.5]nonane-6,9-dione. HPMS (ES) m/z 660.3 (M+H).

3. Synthesis of intermediate 49-4

Ph

49-3 49-4

To a solution of 2,8-dibenzhydryl-7-methyl-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9dione (1.2 g, 1.8 mmol, 1 .0 eq.) in EtOAc (100 ml) was added Pd(OH)2 (20% on carbon, 6 g). The resulting mixture was purged with hydrogen for 10 minutes, heated at 50°C under a hydrogen atmosphere (initially at 500 psi) for 60 hours, cooled to room temperature, filtered through celite and concentrated under reduced pressure to give 887 mg 8-benzhydryl-7-methyl-5-(4(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione as a mixture. HPMS (ES) m/z 494.2 (M+H).

4. Synthesis of intermediate 49-5

49-4 49-5

To a solution of 8-benzhydryl-7-methyl-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9dione (887 mg, 1.8 mmol, 1.0 eq. ) in DCM (20 ml), TEA (1 ml) and acetyl chloride (1 Μ in DCM, 5 ml, 5.0 mmol, 2.8 eq.) were added. The resulting mixture was stirred at room. temp., for 2 hours, concentrated under reduced pressure and purified by silica gel chromatography using EtOAc (100%) and MeOH/DCM (1/4) as eluents to obtain 963 mg of 2-acetyl-8-benzhydryl-7- methyl 5-(4(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione as a mixture. HPMS (ES) m/z 536.2 (M+H).

5. Synthesis of intermediate 49-6

49-5 ^{49 'S}

To a solution of 2-acetyl-8-benzhydryl-7-methyl-5-(4-(trifluoromethyl)benzyl)-2,5,8triazaspiro[3.5]nonane-6,9-dione (963 mg, 1.8 mmol, 1 .0 eq.) in EtOAc (100 ml) was added Pd(OH)2 (20% on carbon, 6 g). The resulting mixture was purged with hydrogen for 10 minutes, heated at 50°C under a hydrogen atmosphere (initially at 600 psi) for 15 hours, cooled to room temperature, filtered through celite, concentrated under reduced pressure and purified by chromatography on silica gel using EtOAc (100%) and MeOH/DCM (1/4) as eluents to give 200 mg of 2-acetyl-7methyl-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro [3.5]nonane-6,9-dione. HPMS (ES) m/z 370.2 (M+H).

6. Synthesis of compound 341

To a mixture of copper iodide (26 mg, 0.14 mmol, 0.5 eq.), potassium carbonate (112 mg, 0.81 mmol, 3.0 eq.), 1-310045362 bromo-4-chloro-2-fluorobenzene (102 mg, 0.49 mmol, 1.8 eq.) and 2-acetyl-7-methyl-5-(4(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9- dione (200 mg, 0.27 mmol, 1.0 eq.) 1,4-dioxane (3 ml) and N,N'-dimethylethylenediamine (15 μl, 0.14 mmol, 0.5 eq.) were added to the vessel. . The vessel was sealed and the mixture was heated at 100°C for 15 hours. The mixture was cooled to room temperature, filtered through celite, concentrated under reduced pressure and purified by reverse phase HPLC (Phenomenex, dimer 5 µm C18 150x21.2 mm, gradient of 10-70% acetonitrile in water with 0.1% formic acid over 40 min) to give 1.4 mg (1%) 2-acetyl-8-(4-chloro-2-fluorophenyl)-7-methyl- 5-(4(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione. HPMS (ES) m/z 498.1 (M+H).

Ή NMR (methanol-04, 400 MHz, ppm) δ 7.71 (d, J=8.1 Hz, 2H), 7.55 (dd, J=8.1, 4.8 Hz, ZN ), 7.50-7.44 (m, 1H), 7.40 (dt, J=8.5, 1.6 Hz, 1H), 5.22 (d, J=16.8 Hz, 1H) , 5.11-5.01 (m, 1H), 4.68-4.41 (m, 4H), 4.26 (t, J=11.5 Hz, 1H), 1.88 (d, J =6.l Hz, ZN), 1.45 (d, J=7.0 Hz, ZN).

Example 50. Synthesis of compound 278.

1. Synthesis of intermediate 50-2

50-2

4-Trifluoromethylbenzaldehyde (0.79 g, 4.5 mmol, 1.5 eq.). This mixture was stirred at room. pace, STAB (1.9 g, 9.1 mmol, 3.0 equiv.) and AcOH (5 ml) were added over 15 min. The mixture was stirred at room. temp, for 15 hours, evaporated under reduced pressure and partitioned between DCM (60 ml) and saturated aqueous sodium hydrogen carbonate (60 ml). The layers were separated and the aqueous phase was extracted with DCM (25 ml). The combined organic phases were dried over sodium sulfate, filtered through celite and concentrated under reduced pressure to give ethyl 1-((4-(trifluoromethyl)benzyl)amino)cyclopropane-1-carboxylate as a viscous oil.

2. Synthesis of intermediate 50-3

50-2 50-3

To a solution of ethyl 1-((4-(trifluoromethyl)benzyl)amino)cyclopropane-1-carboxylate (861 mg, 3.0 mmol, 1.0 eq.) in DCM (50 ml) was added TEA (1.5 g , 15.1 mmol, 5.0 eq.) and chloroacetyl chloride (0.68 g, 6.0 mmol, 2.0 eq.). The mixture was stirred at room. temp for 2 hours before pouring into water (50 ml). The organic phase was separated, dried over MgSO4 and concentrated under reduced pressure to give ethyl 1-(2-chloro-M-(4-(trifluoromethyl)benzyl)acetamido)cyclopropane-1-carboxylate.

3. Synthesis of intermediate 50-4

K-4

To a solution of ethyl 1-(2-chloro-M-(4-(trifluoromethyl)benzyl)acetamido) cyclopropane-1-carboxylate (1.1 g, 3.0 mmol) in MeOH (5 ml) was added NH ₃ in MeOH (7Ν, 5 ml). The resulting mixture was heated at 80°C in a sealed vessel for 15 hours, cooled to room temperature, concentrated under reduced pressure and purified by chromatography on silica gel using EA/HE (gradient from 0-100%) and MeOH/DCM ( 3/7) to obtain 4-(4-(trifluoromethyl)benzyl)-4,7-diazaspiro[2.5]octane-5,8-dione. HPMS (ES) m/z 299.1 (M+H).

-311 045362

4. Synthesis of compound 278

Compound 278

To a mixture of copper iodide (33 mg, 0.18 mmol, 0.5 eq.), potassium carbonate (146 mg, 1.1 mmol, 3.0 eq.), 4bromo-3-fluorobenzonitrile (126 mg, 0.63 mmol, 1.8 eq.) and 4-(4-(trifluoromethyl)benzyl)-4,7diazaspiro[2.5]octane-5,8-dione (200 mg, 0.35 mmol, 1.0 eq.) was added to the vessel ,4-dioxane (16 ml) and Ν,N'-dimethylethylenediamine (19 µl, 0.18 mmol, 0.5 equiv.). The vessel was sealed and the mixture was heated at 100°C for 15 hours. The mixture was cooled to room temperature, filtered through celite, concentrated under reduced pressure and purified by reverse phase HPLC (Phenomenex, dimer 5 µm C18 150x21.2 mm, gradient of 10-100% acetonitrile in water with 0.1% formic acid over 40 min) to give 40 mg (27%) 4-(5,8-dioxo-4-(4-(trifluoromethyl)benzyl)-4, 7-diazaspiro[2.5]octan-7-yl)-3fluorobenzonitrile. HPMS (ES) m/z 418.1 (M+H).

^! H NMR (methanol-sc 400 MHz, ppm) δ 7.76 (dd, >10.2, 1.6 Hz, 1H), 7.71-7.62 (m, 4H), 7.48 (d, >8.0 Hz, 2H), 4.74 (s, 2H), 4.66 (s, 2H), 1.55-1.30 (m, 4H).

The following compounds were prepared by methods similar to those described for compound 278:

Connection No. HPMS (ES) m/z 269 M+H=436.1 270 M+H=445.1 271 M+H=427.1 272 M+H=441.1 273 M+H=429.1 274 M+H=443.1 277 M+H=401.0 279 M+H=420.1 280 M+H=434.1 281 M+H=457.1 282 M+H=448.1 286 M+H=448.0

5. Separation of enantiomers.

The racemic compound was separated by chiral HPLC under the following conditions (Column: CHIRAL ART Cellulose-SB, 2x25 cm, 5 µm; mobile phase A: Hex-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 ml/min; gradient: from 300 to 300 mL/min; for 10 min; 220/254 nm) to obtain the first eluting peak and the second eluting peak.

The following compounds were separated using the method described above:

Connection No. HPMS (ES) m/z 275 M+H=415.1 276 M+H=415.1 283 M+H=434.0 285 M+H=478.1 287 M+H=422.1

Example 51 Synthesis of compound 284.

1. Synthesis of intermediate 51-2

51+ 51-2

To a solution of (8)-methyl-2-amino-cyclobutyl acetate HC1 (0.50 g, 2.8 mmol, 1.0 eq.) in dry MeOH (16 ml) was added 4-(trifluoromethyl)benzaldehyde (0.42 ml, 3 .1 mmol, 1.1 eq.) and acetic acid

-312045362 (0.32 ml, 5.6 mmol, 2.0 eq.). To this mixture was stirred for 1 hour and sodium cyanoborohydride (0.306 g, 4.87 mmol, 1.8 eq.) was added. The mixture was stirred overnight, diluted with water, and extracted with DCM three times. The combined organic layers were dried over magnesium sulfate, filtered, evaporated and purified by silica gel chromatography through silica gel using EA/HE (0-20% gradient) as eluents to give 138 mg (16%) methyl-(8)-2 -cyclobutyl-2-((4(trifluoromethyl)benzyl)amino)acetate in the form of a clear, colorless oil. HPMS (ES) m/z 302 (M+H).

2. Synthesis of intermediate 51-3

51-2 51-3

A solution of methyl (8)-2-cyclobutyl-2-((4-(trifluoromethyl)benzyl)amino)acetate (138 mg, 0.46 mmol, 1.0 eq.) in DCM (2 ml) was cooled to 0 °C TEA (0.38 ml, 2.8 mmol, 6.0 equiv.) and chloroacetyl chloride (0.15 ml, 1.8 mmol, 4.0 equiv.) were added dropwise. The mixture was stirred at 0°C for 1 hour, diluted with saturated sodium hydrogen carbonate solution, extracted twice with DCM, the combined organic layers were dried over magnesium sulfate, filtered, evaporated and purified by chromatography on silica gel through silica gel using EA/HE (gradient from 0-30 %) as eluents to obtain 0.162 g (93%) methyl (8)-2-(2-chloro-K-(4-(trifluoromethyl)benzyl)acetamido)-2-cyclobutyl acetate as a clear yellow oil. HPMS (ES) m/z 378 (M+H).

3. Synthesis of intermediate 51-4

51-3 51-4

To a solution of methyl (8)-2-(2-chloro-M-(4-(trifluoromethyl)benzyl)acetamido)-2-cyclobutyl acetate (162 mg, 0.43 mmol, 1.0 eq.) in dry methanol ( 1.2 ml) 7 Μ ammonia in methanol (1.2 ml, 8.6 mmol, 20 eq.) was added. The mixture was sealed, heated at 80°C overnight, diluted with water and extracted twice with EA. The combined organic layers were dried over magnesium sulfate, filtered, evaporated and purified by silica gel chromatography through silica gel using MeOH/DCM (0-10% gradient) as eluents to give 123 mg (88%) (8)-6-cyclobutyl -1-(4(trifluoromethyl)benzyl)piperazine-2,5-dione as a clear, colorless oil. HPMS (ES) m/z 327 (M+H).

'H NMR (400 MHz, methylene chloride-< ₁₂ ) 5 7.70-7.61 (m, 2H), 7.45-7.37 (m, 2H), 6.63-6.46 (m, 1H), 5.385.34 (m, 1H), 4.17-4.04 (m, 2H), 4.00-3.90 (m, 1H), 3.72-3.65 (m, 1H) , 2.85-2.71 (m, 1H), 2.12-1.66 (m, 6H).

4. Synthesis of compound 284

To a mixture of 4-bromo-3-fluorobenzonitrile (68 mg, 0.34 mmol, 1.8 eq.), copper(1) iodide (1.8 mg, 0.09 mmol, 0.50 eq.) and potassium carbonate (78 mg, 0.56 mmol, 3.0 eq.) N,N'-dimethylethylenediamine (0.010 ml, 0.094 mmol, 0.50 eq.) and (S)-6cyclobutyl were added to a vessel that was evacuated and filled with nitrogen. -1-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione (61 mg, 0.19 mmol, 1.0 eq.) in dry dioxane (1 ml). The vessel was sealed and the mixture was heated at 100°C overnight. The mixture was cooled to room temperature, filtered, and purified by reverse phase HPLC (Phenomenex, dimer 5 µm C18 150x21.2 mm, gradient 10-90% acetonitrile in water with 0.1% formic acid over 25 min) to obtain 39 mg (47%) (8)-4-(3-cyclobutyl-2,5-dioxo-4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)-3fluorobenzonitrile as a clear, colorless oil. HPMS (ES) m/z 446 (M+H).

'll NMR (400 MHz, methanol-0 ₄ ) δ 7.77-7.72 (m, 1H), 7.71-7.62 (m, 4H), 7.55-7.50 (m, 2H ), 5.26-5.18 (m,

-313 045362

1H), 4.83-4.76 (m, IH), 4.43-4.36 (m, 1H), 4.25-4.17 (m, 1H), 4.02-3.97 ( m, 1H), 3.04-2.91 (m, 1H), 2.16-1.75 (m, 6H).

Example 52 Synthesis of compound 528.

1. Synthesis of intermediate 52-1

22-4 or 23-4 52-1

To a solution of tert-butyl-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonane2-carboxylate (450 mg, 1.1 mmol, 1 eq. .) NaHMDS (0.82 mL, 1.6 mmol, 1.5 eq., 2 M in THF) was added dropwise to NMP (5 mL) at 0°C. After stirring at room. pace, 5-chloro-2,3-difluoropyridine (243 mg, 1.6 mmol, 1.5 eq.) was added to this mixture over 30 min. The resulting mixture was stirred at 80°C for 5 hours and cooled to 0°C. The reaction mixture was quenched with water (10 ml) at 0°C and extracted with EtOAc (20 ml). The organic layer was washed twice with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and purified by silica gel column chromatography using PE/EA (5/1) as eluent to obtain 350 mg of tert-butyl8- (5-chloro-3-fluoropyridin-2-yl)-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8triazaspiro[3.5]nonane-2-carboxylate (intermediate 52-1) in the form of a yellow oil. HPMS (ES) m/z 487 (M+H-56).

2. Synthesis of intermediate 52-2

To a solution of tert-butyl-8-(5-chloro-3-fluoropyridin-2-yl)-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[ 3.5]nonane-2-carboxylate (350 mg, 0.6 mmol, 1 eq.) in DCM (3 ml) was added 2,2,2-trifluoroacetic acid (1 ml). The resulting mixture was stirred at room. pace for 3 hours and concentrated under reduced pressure to obtain 300 mg of 8-(5-chloro-3-fluoropyridin-2-yl)-5-[[4(trifluoromethyl)phenyl]methyl]-2,5,8- triazaspiro[3.5]nonane-6,9-dione trifluoroacetate (intermediate 52-2) as a yellow oil. HPMS (ES) m/z 443 (M+H).

3. Synthesis of compound 528

52-2 Connection^

To a solution of 8-(5-chloro-3-fluoropyridin-2-yl)-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonane-6,9-dione trifluoroacetate (300 mg, 0.6 mmol, 1 eq.) in DCM (5 ml) was added acetyl acetate (85 mg, 0.8 mmol, 1.5 eq.) and TEA (168 mg, 1.67 mmol, 3.0 eq.). The resulting mixture was stirred at room. pace, for 2 hours, concentrated in vacuum and purified by preparative HPLC under the following conditions (SHIMADZU (HPLC-01)): Column, XBridge Prep OBD C18 column, 30x150 mm 5 µm; mobile phase, water (10 mM, NH ₄ HCO ₃ ) and ACN (31% gradient to 49% over 8 min); detector, UV 254 nm) to obtain 90 mg of 2-acetyl-8-(5-chloro-3-fluoropyridin-2-yl)-5-(4-(trifluoromethyl)benzyl)-2,5,8triazaspiro[3.5]nonane -6,9-dione (compound 528) as a white solid. HPMS (ES) m/z 485 (M+H).

*H NMR (400 MHz, methanol-a ₄ ) δ 8.43 (d, >1.9 Hz, 1H), 7.98 (dt, >9.3, 2.0 Hz, 1H), 7.77 -7.67 (m, 2H), 7.56 (d, >8.0 Hz, 2H), 5.13 (s, 2H), 4.71 (d, >10.1 Hz, ZN), 4 .50 (d, >10.2 Hz, 2H), 4.25 (d, >10.9 Hz, 1H), 1.87 (s, ZN).

-314045362

The following compounds were prepared by methods similar to those described for compound 528:

Connection No. HPMS (ES) m/z 529 M+H=472 530 M+H=476 556 M+H=465 619 M+H=479 620 M+H=485

Example 53. Synthesis of compound 531.

1. Synthesis of compound 531

To a solution of 4-(6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonan-8-yl)-3fluorobenzonitrile (35.0 mg, 0 .08 mmol, 1.0 eq.) in DMF (1.0 ml) added 2-(methylamino)benzoic acid (12.0 mg, 0.08 mmol, 1.0 eq.), HATU (37.0 mg , 0.1 mmol, 1.2 eq.) and DIEA (21.0 mg, 0.2 mmol, 2.0 eq.). The resulting mixture was stirred at room. pace, for 2 hours. The solution was purified by preparative HPLC under the following conditions (SHIMADZU (HPLC-01)): Column, XBridge Shield RP18 OBD column, 5 µm, 19x150 mm; mobile phase, water (10 mM, NH4HCO3) and ACN (30% gradient to 50% over 8 min); detector, UV 254/220 nm) to obtain 20 mg of 3-fluoro-4-(2-(2-(methylamino)benzoyl)-6,9-dioxo-5(4-(trifluoromethyl)benzyl)-2,5, 8-triazaspiro[3.5]nonan-8-yl)benzonitrile (compound 531) as a white solid. HPMS (ES) m/z 566 (M+H).

Y NMR (400 MHz, methanol-b ₄ ) δ 7.79 (d, J=9.8 Hz, 1H), 7.76-7.65 (m, 4H), 7.58 (d, J=8 ,l Hz, 2H), 7.31 (t, J=8.0 Hz, 1H), 7.15 (dd, J=7.7, 1.5 Hz, 1H), 6.72 (d, J =8.4 Hz, 1H), 6.57 (t, J=7.4 Hz, 1H), 5.17 (s, 2H), 4.68 (d, J=10.6 Hz, 2H), 4.57 (s, 2H), 4.46 (d, J=10.6 Hz, 2H), 2.83 (s, ZN).

Example 54. Synthesis of compound 536.

1. Synthesis of compound 536

To a solution of 4-(6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonan-8-yl)-3fluorobenzonitrile (100.0 mg, 0 .23 mmol, 1.0 eq.) in dioxane (2.0 ml), 3-bromo-N-methylaniline (50.0 mg, 0.27 mmol, 1.2 eq.), Pd ₂ (dba) ₃ was added (24.0 mg, 0.03 mmol, 0.11 eq.), X-phos (22.0 mg, 0.05 mmol, 0.2 eq.) and Cs ₂ CO ₃ (151.0 mg, 0 .5 mmol, 2.0 eq.). The resulting mixture was stirred at 80°C for 3 hours in a nitrogen atmosphere, cooled to room. temp, and purified by preparative TLC (PE/EtOAc 1/1) to obtain a mixture, which was purified by preparative HPLC under the following conditions (SHIMADZU (HPLC-01)): Column, Xselect CSH OBD 30x150 mm 5 µm column; mobile phase, water (10 mM, NH ₄ HCO ₃ ) and ACN (45% gradient to 80% over 9 min); detector, UV 254/220 nm) to obtain 43 mg of 3-fluoro-4-[2-[3(methylamino)phenyl]-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2 ,5,8-triazaspiro[3.5]nonan-8yl]benzonitrile (compound 536) as a white solid with a metallic tint. HPMS (ES) m/z 538 (M+H).

Y NMR (300 MHz, chloroform-d) δ 7.69-7.38 (m, 7H), 7.07 (t, J=7.9 Hz, 1H), 6.17 (d, J=8, 0 Hz, 1H), 5.87 (d, J=7.9 Hz, 1H), 5.70 (s, 1H), 5.28 (s, 2H), 4.53 (d, J=8, 3 Hz, 2H), 4.45 (s, 2H), 4.12 (d, J=8.3 Hz, 2H), 2.83 (s, ZN).

The following compounds were prepared by methods similar to those described for compound 536:

-315 045362

Connection No. HPMS (ES) m/z 535 M+H=538 538 M*H=538

Example 55. Synthesis of compound 539.

1. Synthesis of intermediate 55-1

To a solution of methyl 3-iodobenzoate (250.0 mg, 1.0 mmol, 1.0 eq.) in a mixture of EtOH (4.0 ml) and water (1.0 ml) was added NaOH (115 mg, 3.0 mmol, 3.0 eq.). The mixture was stirred at 60°C for 2 hours, cooled to room temperature, acidified to pH 3 and extracted with EA (20 ml). The organic layer was washed twice with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain 200 mg of 3-iodobenzoic acid (intermediate 55-1) as a white metallic solid. HPMS (ES) m/z 249 (M+H).

2. Synthesis of intermediate 55-2

55-1 55-2

To a solution of methyl 3-iodobenzoic acid (250.0 mg, 0.81 mmol, 1.0 eq.) in DMF (3.0 mL) was added methylamine (0.6 mL, 1.2 mmol, 1.5 eq. ., 2 M/THF), HATU (368 mg, 1.0 mmol, 1.2 eq.) and DIEA (208 mg, 1.6 mmol, 2.0 eq.). The mixture was stirred at room. pace, overnight, diluted with water and extracted with EA (20 ml). The organic layer was washed twice with brine, dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by silica gel column chromatography using PE/EA (4/1) as eluent to obtain 200 mg of 3-iodo-I-methylbenzamide ( intermediate 55-2) as a white solid with a metallic tint. HPMS (ES) m/z 262 (M+H).

3. Synthesis of compound 539

Λ

Ν 55-2 Compound 539

To a solution of 4-(6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonan-8-yl)-3fluorobenzonitrile (100.0 mg, 0 .23 mmol, 1.0 eq.) in dioxane (2.0 ml), 3-iodo-Nmethylbenzamide (90.0 mg, 0.35 mmol, 1.5 eq.), Pd ₂ (dba) ₃ (24 .0 mg, 0.03 mmol, 0.11 eq.), X-phos (22.0 mg, 0.05 mmol, 0.2 eq.) and Cs ₂ CO ₃ (151.0 mg, 0.5 mmol, 2.0 eq.). The resulting mixture was stirred at 90°C for 2 hours under a nitrogen atmosphere, cooled to room temperature, filtered and purified by preparative TLC (PE/EtOAc 1/8) to obtain a mixture that was further purified by preparative HPLC under the following conditions (SHIMADZU ( HPLC-01)): Column, Xselect CSHOBD 30x150 mm 5 µm column, mobile phase, water (10 mM, NH ₄ HCO ₃ ) and ACN (35% gradient to 58% over 10 min); detector, UV 254/220 nm) to obtain 45 mg of 3-(8-(4-cyano-2-fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8triazaspiro[ 3.5]nonan-2-yl)-M-methylbenzamide (compound 539) as a white solid. HPMS (ES) m/z 566 (M+H).

Ή NMR (400 MHz, methanol-b ₄ ) δ 7.82-7.75 (m, 1H), 7.78-7.68 (m, 2H), 7.68 (d, J=8.l Hz , 2H), 7.57 (d, J=8.l Hz, 2H). 7.30 (t, J=7.8 Hz, 1H), 7.21 (dt, J=7.8, 1.3 Hz, 1H). 6.92 (t, J=2.0 Hz, 1H), 6.68-6.61 (m, 1H), 5.29 (s, 2H), 4.60 (s, 2H), 4.48 (d, J=8.7 Hz, 2H), 4.27 (d, J=8.7 Hz, 2H), 2.90 (s, ZN).

The following compounds were prepared by methods similar to those described for compound 539:

-316045362

Connection No. HPMS (ES) m/z 532 M+H=567 533 M+H=567 534 M+H=567 537 M+H=5byo 540 M+H=566

Example 56. Synthesis of compound 541.

1. Synthesis of intermediate 56-1

Br (Voc) ₂ O

Br

/О -----------х° о _NH2 tea,dmap,dcm _о hn. _Boc

56-1

To a solution of methyl 2-amino-4-bromobenzoate (1.5 g, 6.5 mmol, 1.0 eq.) in DCM (15.0 ml) was added TEA (2.0 g, 19.8 mmol, 3. 0 eq.), DMAP (797 mg, 6.5 mmol, 1.0 eq.) and (Boc) _2O (1.7 g, 7.8 mmol, 1.2 eq.) at 0°C. The mixture was stirred at room. pace, overnight, diluted with DCM (50 ml), washed twice with brine (50 ml), dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by silica gel chromatography using PE/EA as eluent to give 1 ,1 g methyl 4-bromo-2-[[(tert-butoxy)carbonyl]amino]benzoate (intermediate 56-1) as a white solid. HPMS (ES) m/z 274 (M+H-56).

2. Synthesis of intermediate 56-2

To a solution of methyl 4-bromo-2-[[(tert-butoxy)carbonyl]amino]benzoate (1.1 g, 3.3 mmol, 1.0 eq.) in DMF (15.0 ml) was added NaH ( 60% in mineral oil, 160 mg, 4.0 mmol, 1.2 eq.) at 0°C. After stirring for 30 min at 0°C, sweep (521 mg, 3.7 mmol, 1.1 eq.) was added to this mixture. The mixture was then stirred at room. temp, overnight, quenched with water and extracted with EA (100 ml). The organic layer was washed once with saturated sodium hydrogen carbonate solution (20 ml) and twice with brine (20 ml), dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by chromatography on silica gel using PE/EA (50/1), in as eluent to give 800 mg of methyl 4-bromo-2-[[(tert-butoxy)carbonyl](methyl)amino]benzoate (intermediate 562) as a yellow oil. HPMS (ES) 288 m/z (M+H-56).

3. Synthesis of intermediate 56-3

Λ A ^D J . ,<kD4 ί ί : ί

Ο ο Υ

Si* i 58 J

TFA was added to a solution of methyl 4-bromo-2-[[(tert-butoxy)carbonyl](methyl)amino]benzoate (400 mg, 3.3 mmol, 1.0 eq.) in DCM (4.0 mL). (1.0 ml). The mixture was stirred at room. temp, over 2 hours, brought the pH to 9 sat. sodium bicarbonate solution and extracted with EA (20 ml). The organic layer was washed twice with brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give methyl 4-bromo-2-(methylamino)benzoate (intermediate 563) as a yellow oil. HPMS (ES) 244 m/z (M+H).

4. Synthesis of compound 541

To a solution of 4-(6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonan-8-yl)-3fluorobenzonitrile (100.0 mg, 0 .2 mmol, 1.0 eq.) in dioxane (2.0 ml) was added methyl 4-bromo-2(methylamino)benzoate (80.0 mg, 0.3 mmol, 1.4 eq.), Pd ₂ (dba) ₃ CHCl ₃ (24.0 mg, 0.023 mmol, 0.10 eq.), Xphos (22.0 mg, 0.05 mmol, 0.2 eq.) and Cs ₂ CO ₃ (151.0 mg , 0.5 mmol, 2.0 eq.). The resulting mixture was stirred at 80°C for 2 hours in a nitrogen atmosphere, cooled to room. temp, and purified by preparative TLC

-317045362 (PE/EtOAc 1:1) to obtain a mixture that was purified by preparative HPLC under the following conditions (SHIMADZU (HPLC-01)): Column, XBridge Prep OBD C18 column, 30x150 mm 5 µm; mobile phase, water (10 mM NH4HCO3) and ACN (50% gradient to 80% over 8 min); detector UV 254 nm) to obtain 80 mg of methyl 4-(8-(4-cyano-2-fluorophenyl)-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8 triazaspiro[3.5 ]nonan-2-yl)-2-(methylamino)benzoate (compound 541) as a white solid. HPMS (ES) m/z 596 (M+H).

Ή NMR (300 MHz, methanol-b ₄ ) δ 7.83-7.62 (m, 6H), 7.56 (d, >8.1 Hz, 2H), 5.73 (dd, >8.6 , 2.2 Hz, 1H), 5.54 (d, >2.2 Hz, 1H), 5.22 (s, 2H), 4.59 (s, 2H), 4.52 (d, >9 ,1 Hz, 2H), 4.27 (d, >9.0 Hz, 2H), 3.77 (s, ZN), 2.84 (s, ZN).

The following compounds were prepared by methods similar to those described for compound 541:

Connection No. HPMS (ES) m/z 542 M+H=595 543 M+H=596 544 M+H=596 545 M+H=595 546 M+H=596 547 M+H=595

Example 57 Synthesis of compound 550.

1. Synthesis of intermediate 57-1

57-1

To a stirred solution of ethyl 1-aminocyclopropane-1-carboxylate hydrochloride (1.14 g, 7 mmol, 1.2 eq.) and 4-(trifluoromethyl)benzaldehyde (1.0 g, 6 mmol, 1.0 eq.) acetic acid (0.69 g, 11 mmol, 2.0 eq.) was added to DCE (20 mL). After stirring at room. pace, over 5 min, STAB (1.83 g, 9 mmol, 1.5 eq.) was added to this mixture. The resulting mixture was stirred overnight at room temp, diluted with DCM (20 ml) and washed with brine (20 ml), dried over anhydrous Na2SO ₄ and concentrated under reduced pressure to give 1.48 g (73%) ethyl -1((4-(trifluoromethyl)benzyl)amino)cyclopropane-1-carboxylate (intermediate 57-1) as a yellow oil. HPMS (ES) m/z 274 (M+H).

2. Synthesis of intermediate 57-2

57-1 57-2

To a stirred solution of ethyl 1-((4-(trifluoromethyl)benzyl)amino)cyclopropane-1carboxylate (1.48 g, 5.4 mmol, 1.0 eq.) in DCM (90 ml) cooled to 0°C was added K ₂ CO ₃ (16.2 ml, 0.5 M in water, 1.5 eq.) and 2-bromoacetyl bromide (1.31 g, 6 mmol, 1.2 eq.) dropwise. The resulting mixture was stirred for an additional 3 hours at room temperature, washed with brine (80 ml), dried over anhydrous Na2SO ₄ , concentrated under reduced pressure to obtain 1.8 g (82%) ethyl 1-(2-bromo -M-(4-(trifluoromethyl)benzyl)acetamido)cyclopropane-1-carboxylate (intermediate 57-2) as a yellow oil. HPMS (ES) m/z 394 (M+H).

3. Synthesis of intermediate 57-3

To a stirred solution of ethyl 1-(2-bromo-X-(4-(trifluoromethyl)benzyl)acetamido)cyclopropane 1-carboxylate (1.79 g, 4.4 mmol, 1.0 eq.) in MeOH (5 ml) added ammonia solution (25.0 ml, 7 M in

-318045362

MeOH). The resulting mixture was stirred for an additional 1.5 hours at room temperature, concentrated under reduced pressure and triturated with EA (10 ml) to obtain 1.0 g (76%) 4-(4(trifluoromethyl)benzyl)-4,7- diazaspiro[2.5]octane-5,8-dione (intermediate 57-3) as a yellow solid. HPMS (ES) m/z 299 (M+H).

4. Synthesis of compound 550

To a stirred solution of 4-(4-(trifluoromethyl)benzyl)-4,7-diazaspiro[2,5]octane-5,8-dione (300.0 mg, 1.0 mmol, 1.0 eq.) in ACN (3 ml) Cs ₂ CO ₃ (651.0 mg, 2.0 mmol, 2.0 eq.) was added. After stirring for 5 minutes at room. temp, 5-chloro-2,3-difluoropyridine (179.3 mg, 1.2 mmol, 1.2 eq.) was added to this mixture. The resulting mixture was stirred for 2 days at 80°C, cooled to room. temp, filtered to remove Cs ₂ CO ₃ , concentrated under reduced pressure and purified by preparative HPLC under the following conditions: (SHIMADZU (HPLC-01)): Column, XBridge Shield RP18 OBD column, 5 µm, 19x150 mm; mobile phase, water (10 mM NH ₄ HCO ₃ +0.1% NH ₃ .H ₂ O) and ACN (41% gradient to 71% over 8 min); detector, UV 254 nm) to obtain 6.7 mg (2%) 7-(5-chloro-3fluoropyridin-2-yl)-4-(4-(trifluoromethyl)benzyl)-4,7-diazaspiro[2.5]octane -5,8-dione (compound 550) as a white solid. HPMS (ES) m/z 428 (M+H).

A NMR (300 MHz, DMSOch1 ₆ ) δ 8.48 (d, J=2.l Hz, 1H), 8.25 (dd, J=9.6, 2.1 Hz, 1H), 7.73 ( d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 4.67 (s, 4H), 1.34 (d, J=4.4 Hz, 4H).

The following compounds were prepared by methods similar to those described for compound 550:

Connection No. HPMS (ES) m/z 548 M+H=442 554 M+H=444 555 M+H=456 577 M+H=394 616 M+H=408 629 M+H=473 632 M+H=439 660 M+H=406

Example 58 Synthesis of compound 574.

1. Synthesis of intermediate 58-1

To a solution of 3-(benzyloxy)cyclobutan-1-one (1.80 g, 10.215 mmol, 1.07 eq.) in 2,2,2-trifluoroethanol (15 ml) was added 1-(4-trifluoromethyl)phenyl)methanamine (1.9 g, 10.8 g, 1.1 eq.). After stirring at room. temp., 5-chloro-3-fluoro-2isocyanopyridine (1.5 g, 9.6 mmol, 1.0 eq.) and chloroacetic acid (994.0 mg, 10.5 mmol) were added to this resulting mixture over 5 min. , 1.1 eq.). The resulting mixture was stirred at room. pace, overnight, concentrated under reduced pressure and purified with a C18 column, eluted with water (0.5% NH ₄ HCO ₃ )/ACN (1:1) to give 1.5 g of 3(benzyloxy)-M-(5- chloro-3-fluoropyridin-2-yl)-1-(2-chloro-C-(4(trifluoromethyl)benzyl)acetamido)cyclobutane-1-carboxamide (intermediate 58-1) as a yellow oil. HPMS (ES) m/z 584 (M+H).

-319045362

2. Synthesis of intermediate 58-2

To a solution of 3 -(benzyloxy)-N-(5-chloro-3-fluoropyridin-2-yl)-1 -(2-xnop-N-(4(trifluoromethyl)benzyl)acetamido)cyclobutane-1-carboxamide (1, 4 g, 2.4 mmol, 1.0 eq.) in DMF (15.0 ml) at room. temp, added K ₂ CO ₃ (994 mg, 7.1 mmol, 3.0 eq.). The mixture was stirred at 60°C for 30 minutes, cooled to room. temp, and diluted with water (30 ml). The precipitate was collected, washed with water and dried to obtain 1.2 g of 2-(benzyloxy)-8-(5-chloro-3-fluoropyridin-2-yl)-5-(4(trifluoromethyl)benzyl)-5,8-diazaspiro [3.5]nonane-6,9-dione (intermediate 58-2). HPMS (ES) m/z 548 (M+H).

3. Synthesis of intermediate 58-3

58-2 58-3

To a solution of 2-(benzyloxy)-8-(5-chloro-3-fluoropyridin-2-yl)-5-(4-(trifluoromethyl)benzyl)-5,8diazaspiro[3.5]nonane-6,9-dione (500 mg, 0.9 mmol, 1.0 eq.) in MeOH (5.0 ml) and THF (5.0 ml) was added Pd(OH) ₂ /C (20 wt.%, 250 mg). The mixture was stirred at room. temp, for 1 hour under a hydrogen atmosphere (1 atm, hydrogen from a cylinder), filtered through a plug of silica gel and concentrated under reduced pressure to obtain 400 mg of 8-(5-chloro-3-fluoropyridin-2-yl)-2-hydroxy -5-(4-(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane-6,9-dione (intermediate 58-3) as a yellow oil. HPMS (ES) 458 m/z (M+H).

4. Synthesis of compound 574

58-3 Compound 574

To a solution of 8-(5-chloro-3-fluoropyridin-2-yl)-2-hydroxy-5-(4-(trifluoromethyl)benzyl)-5,8diazaspiro[3.5]nonan-6,9-dione (200.0 mg, 0.4 mmol, 1.0 eq.) in DCM (3.0 mL) was added DAST (211 mg, 1.3 mmol, 3.0 eq.). The mixture was stirred at room. temp, for 1 h, concentrated under reduced pressure and purified by preparative HPLC under the following conditions (SHIMADZU (HPLC-01)): Column, Xselect CSH OBD Cl8 column, 30x150 mm 5 µm; mobile phase, water (0.1% FA) and ACN (10% gradient to 50% over 9 min); UV detector 254 nm) to obtain 70 mg of 8-(5-chloro-3-fluoropyridin-2yl)-2-fluoro-5-(4-(trifluoromethyl)benzyl)-5,8-diazaspiro[3.5]nonane-6, 9-Dione (compound 574) as a white solid. HPMS (ES) m/z 460 (M+H).

'H NMR (DMSO-de) δ 8.52 (d, J=2.l Hz, 1H), 8.29 (dd, J=9.5, 2.1 Hz, 1H), 7.75 (d , J=8.1 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 5.12-4.80 (m, ZN), 4.61 (s, 2H), 2 .99 (s, 2H), 2.71 (d, J=21.3 Hz, 2H).

Example 59. Synthesis of compound 575.

1. Synthesis of intermediate 59-1

59-1

To a solution of 1-(4-chlorophenyl)methanamine (497.0 mg, 3.5 mmol, 1.1 equiv.) in 2,2,2-trifluoroethanol (10.0

- 320 045362 ml) 3-oxetanone (254.0 mg, 3.5 mmol, 1.1 eq.) was added. After stirring at room. temp, 5-chloro-3-fluoro-2-isocyanopyridine (500.0 mg, 3.2 mmol, 1.0 eq.) and chloroacetic acid (331.0 mg, 3.5 eq.) were added to the resulting mixture over 10 min. mmol, 1.1 eq.). The resulting mixture was stirred at room. pace, overnight, concentrated under reduced pressure and purified with a C18 column, eluted with water (0.05% NH ₄ HCO ₃ )/ACN (1:1) to obtain 260 mg of X-(5-chloro-3-fluoropyridine-2 -yl)-3-[2chloro-X-[(4-chlorophenyl)methyl]acetamido]oxetane-3-carboxamide (intermediate 59-1) as a yellow solid. HPMS (ES) m/z 596 (M+H).

2. Synthesis of compound 575 ci CI

59-1 Compound 575

To a solution of N-(5-x lor-3-fluoropyridin-2-yl)-3-[2-chloro-X-[(4-chlorophenyl)methyl]acetamido]oxetane-3carboxamide (260.0 mg, 0.58 mmol, 1.0 eq.) Potassium carbonate (242.0 mg, 1.7 mmol, 3.0 eq.) was added to DMF (5.0 mL). The resulting mixture was stirred at 60°C for 30 min and diluted with water (5 ml). The precipitates were collected by filtration, washed twice with water (5 ml) and purified by preparative HPLC: Column: Xseiect CSH OBD Column 30x150 mm 5 µm; mobile phase A: water (10 mM, NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 35% to 65% over 9 minutes; UV 254 nm) to obtain 60 mg of 8-(5-chloro-3-fluoropyridin-2-yl)-5-(4-chlorobenzyl)-2-oxa-5,8diazaspiro[3.5]nonane-6,9-dione ( compound 575) as a white solid. HPMS (ES) m/z 410 (M+H).

^! H NMR (300 MHz, DMSO- _c16 ) δ 8.52 (d, >2.1 Hz, 1H), 8.29 (dd, >9.6, 2.2 Hz, 1H), 7.47- 7.32 (m, 4H), 5.08 (s, 2H), 4.93 (d, >7.4 Hz, 2H), 4.75 (d, >7.3 Hz, 2H), 4, 54 (s, 2H).

The following compounds were prepared by methods similar to those described for compound 575:

Connection No. HPMS (ES) m/z 549 M+H=430 551 M+H=444.0 553 M+H= 458 558 M-N=422 572 M+H=513.1 573 M+H=446 576 M+H=396 610 M+H=476 623 M+H=472.0 624 M+H=438 652 M+H=468 663 M+H=434 665 M+H= 418.0 687 M+H=502.0 688 M+H=486.0 689 M+H=534 756 M+H=494.0 757 M+H=390.0 768 M+H=428.0 799 M-N=391 813 M+H=484.0 814 M+H=466.0 815 M+H=434.1 816 M+H=430.1

-321 045362

Example 60. Synthesis of compound 857.

1. Synthesis of intermediate 60-1

60-1

To a stirred solution of methyl O-(tert-butyl)-E-serinate hydrochloride (1.0 g, 4.7 mmol, 1.0 eq., 1.0 eq.) and 4-(trifluoromethyl)benzaldehyde (818 mg , 4.7 mmol, 1.1 equiv.) in ALL (10.0 ml) at room temperature, AcOH (564 mg, 9.4 mmol, 2 equiv.) and STAB (1.50 g, 7, 3 mmol, 1.5 eq.). The resulting mixture was stirred at room temperature for 2 hours, neutralized to pH 7 with ammonium hydroxide and diluted with CH ₂ Cl ₂ (50 ml). The organic layer was washed twice with brine (50 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 1.2 g of methyl-O-(tert-butyl)-X-(4-(trifluoromethyl)benzyl)- E-serinate (intermediate 60-1) as a light yellow oil.

2. Synthesis of intermediate 60-2

To a stirred solution of methyl-O-(tert-butyl)-X-(4-(trifluoromethyl)benzyl)-E-serinate (1.2 g, 3.6 mmol, 1.0 eq.) and K ₂ CO ₃ ( 0.5 Μ, 11 ml, 5.4 mmol, 1.5 equiv.) Bromoacetyl bromide (869 mg, 4.3 mmol, 1.2 equiv.) was added dropwise to DCM (30 ml) at 0°C. The resulting mixture was stirred at room temperature overnight, diluted with CH ₂ C1 ₂ (50 ml). The organic layer was washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 1.3 g of methyl-X-(2-bromoacetyl)-O-(tert-butyl)-X-(4 -(trifluoromethyl)benzyl)-E-serinate (intermediate 60-2) as a light yellow oil.

3. Synthesis of intermediate 60-3

60-2 60-3

To a solution of ammonia (7N in MeOH, 15.0 ml) was added methyl X-(2-bromoacetyl)-O-(tert-butyl)-X(4-(trifluoromethyl)benzyl)-E-serinate (1.3 g , 2.9 mmol, 1.0 eq.). The mixture was stirred at room temperature for 5 hours, concentrated under reduced pressure and triturated with ethyl acetate (10 ml) to obtain 500 mg of (8)-6-(tert-butoxymethyl)-1-(4-(trifluoromethyl)benzyl)piperazine- 2,5-Dione (intermediate 60-3) as a white solid.

4. Synthesis of intermediate 60-4

60-3 60-4

To a stirred solution of (8)-6-(tert-butoxymethyl)-1-(4-(trifluoromethyl)benzyl)piperazine-2,5dione (500.0 mg, 1.4 mmol, 1.0 eq.) in NMP ( 6 ml) at 0°C, NaHMDS (2 ml, 1 M in THF, 1.5 eq.) was added dropwise. After stirring at room temperature for 15 minutes, 5chloro-2,3-difluoropyridine (314 mg, 2.1 mmol, 1.5 eq.) was added to this mixture. The mixture was stirred at room. temp. for 2 hours and purified by reverse phase flash chromatography under the following aqueous conditions (0.05% NH ₄ HCO ₃ ): ACN=1:1 to give 300 mg (44%) 3-(tert-butoxymethyl)- 1-(5-chloro-3-fluoropyridin-2-yl)-4-(4(trifluoromethyl)benzyl)piperazine-2,5-dione (intermediate 60-4).

-322 045362

5. Synthesis of compound 857

Compound 857

To a stirred solution of 3-(tert-butoxymethyl)-1-(5-chloro-3-fluoropyridin-2-yl)-4-(4(trifluoromethyl)benzyl)piperazine-2,5-dione (300.0 mg, 0 .6 mmol, 1.0 eq.) in DCM (24.0 ml) was added TFA (6.0 ml) at room temperature. The resulting mixture was stirred at 40°C for 2 hours, concentrated under reduced pressure and purified by preparative HPLC under the following conditions (SHIMADZU (HPLC-01)): Column, X Bridge Prep OBD C18 column, 30x150 mm 5 μm; mobile phase A: Water (10 mM NH ₄ HCO ₃ +0.l% NH ₃ .H ₂ O) and mobile phase B: ACN (30% gradient to 60% over 8 min); UV detector 254/220 nm to obtain 150 mg of 1-(5-chloro-3-fluoropyridin-2-yl)-3-(hydroxymethyl)-4(4-(trifluoromethyl)benzyl)piperazine-2,5-dione (compound 857).

6. Separation of enantiomers of compound 857.

Enantiomers 857A and 857B

CH

chiral-HPLC

Enantiomer 857A + Enantiomer 857B

Cl

Compound 857

The racemic mixture of 1 -(5-chloro-3-fluoropyridin-2-yl)-3 -(hydroxymethyl)-4-(4(trifluoromethyl)benzyl)piperazine-2,5-dione (320 mg) was separated by chiral HPLC under the following conditions : Column, CHIRALPAK IG, 2 cm x 25 cm L (5 µm); mobile phase A: Hex (8 mM NH ₃ .MeOH) and mobile phase B: EtOH; flow rate: 18 ml/min; (50% B/A for 18 min); detector, UV 254/220 nm to obtain 98 mg (first eluting peak) of enantiomer 857A and 91 mg (second eluting peak) of enantiomer 857B.

Enantiomer 857A: LC-MS (ESI), m/z 432 (M+H).

^! H NMR (300 MHz, DMSO-a ₆ ) δ 8.48 (t, >2.2 Hz, 1H), 8.24 (dt, >9.5, 2.3 Hz, 1H), 7.79- 7.70 (m, 2H), 7.58 (d, >7.8 Hz, 2H), 5.64-5.54 (m, 1H), 5.06 (d, >15.6 Hz, 1H ), 4.79 (dd, >16.1, 2.0 Hz, W), 4.44 (d, >15.6 Hz, 1H), 4.28-4.15 (m, 2H), 3 .88-3.80 (m, 2H).

Analytical chiral HPLC RT: 1.72 min (CHIRALPAK IG-3; 0.46 cm x 5 cm; 3 microns; Hex (0.1% DEA): EUN=50:50 at 1 ml/min).

Enantiomer 857B: LC-MS (ESI), m/z 432 (M+H).

^! H NMR (300 MHz, DMSO-a ₆ ) δ 8.48 (d, >2.1 Hz, 1H), 8.24 (dd, >9.5, 2.2 Hz, 1H), 7.75 ( d, >8.1 Hz, 2H), 7.58 (d, >8.0 Hz, 2H), 5.59 (t, >4.8 Hz, 1H), 5.06 (d, >15, 6 Hz, 1H), 479 (d, >16.2 Hz, 1H), 4.44 (d, >15.6 Hz, 1H), 4.27-4.15 (m, 2H), 3.83 (dd, >5.0, 2.4 Hz, 2H. Analytical chiral HPLC RT: 2.61 min (CHIRALPAK IG-3; 0.46 cm x 5 cm; 3 microns; Hex (0.1% DEA): EUN=50:50 at 1 ml/min).

The following compounds were prepared by methods similar to those described for enantiomers 857A and 857B:

Enantiomer No. HPMS (ES) m/z Retention time (min) HPLC separation conditions 862A M+H=398 1.34 CHIRALPAK ID-3; 0.46 cm x 5 cm; 3 microns; Hex(0.1% DEA):EtOH=50:50 at 1 ml/min 862V M+H=398 1.83

-323 045362

Example 61. Synthesis of compound 859.

1. Synthesis of intermediate 61-1

61-1

Ethyl 3-oxocyclobutane-1-carboxylate was added to a solution of (4-(trifluoromethyl)phenyl)methanamine (2.76 g, 15.73 mmol, 1.1 eq.) in 2,2,2-trifluoroethanol (10.0 mL). (2.03 g, 14.30 mmol, 1.0 eq.). After stirring at room. pace, over 10 minutes, 5chloro-3-fluoro-2-isocyanopyridine (2.53 g, 14.30 mmol, 1.0 eq.) and chloroacetic acid (1.49 g, 15.73 eq.) were added to this resulting mixture. mmol, 1.1 eq.). The resulting mixture was stirred at room. pace for 3 hours, concentrated under reduced pressure and purified by silica gel chromatography, eluting with EA/HE to give 1.6 g (20%) ethyl 3-((5-chloro-3-fluoropyridin-2-yl)carbamoyl )-3-(2-chloro-X-(4-(trifluoromethyl)benzyl)acetamido)cyclobutane-1-carboxylate (intermediate 61-1) as a foam. HPMS (ES) m/z 550 (M+H). ^! H NMR (400 MHz, methylene chloride-( ₁₂ ) δ 9.55 (s, OH), 9.36 (s, 1H), 8.15 (dd, >4.5, 2.1 Hz, 1H), 7.57 (dd, >17.6, 8.1 Hz, 2H), 7.46 (dd, >9.2, 2.1 Hz, 1H), 7.34 (t, J=6.6 Hz , 2H), 4.57 (s, 2H), 4.09-3.97 (m, 2H), 3.90 (d, >10.6 Hz, 2H), 3.07-2.97 (m , ZN), 2.83 (p, >8.9 Hz, 1H), 2.74-2.61 (m, 1H), 2.52 (dd, >12.3, 9.6 Hz, 1H) , 1.12 (k, >6.9 Hz, ZN).

2. Synthesis of compound 859 (a mixture of diastereoisomers 859A and 859B)

To a solution of ethyl 3-((5-chloro-3-fluoropyridin-2-yl)carbamoyl)-3-(2-χπορ-Ν-(4(trifluoromethyl)benzyl)acetamido)cyclobutan-1-carboxylate (1.5 g, 2.73 mmol, 1.0 eq.) in DMF (10.0 ml) at room. temp, added K ₂ CO ₃ (1.14 g, 8.18 mmol, 3.0 eq.). The mixture was stirred at 80°C for 1 hour, diluted with EA (20 ml), filtered and concentrated. The residue was purified on a silica gel column with EA/HE as eluent to give the corresponding diastereomers 859A (680 mg, 49%) and 859B (610 mg, 44%) ethyl-8-(5-chloro-3-fluoropyridin-2-yl )-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)5,8-diazaspiro[3.5]nonane-2-carboxylate (i.e. diastereomers (2g,4g) and (2s,4s)).

Characteristics of diastereomer 859A: HPMS (ES) m/z 514 (M+H).

'H NMR (400 MHz, methylene chloride-c1 ₂ ) δ 8.23 (d, >2.1 Hz, 1H), 7.58-7.50 (m, ZN), 7.30 (d, >8, 0 Hz, 2H), 4.95 (s, 2H), 4.43 (s, 2H), 4.01 (k, >7.1 Hz, 2H), 3.01 (i, >8.8 Hz , 1H), 2.83-2.72 (m, 2H), 2.63 (dd, >12.9, 9.4 Hz, 2H), 1.12 (t, >7.1 Hz, ZN) . Characteristics of diastereomer 859B: HPMC (ES) m/z 514 (M+H).

Ή NMR (400 MHz, methylene chloride-a ₂ ) δ 8.22 (s, 1H), 7.58-7.49 (m, 3H), 7.29 (d, >8.0 Hz, 2H), 4 .91 (s, 2H), 4.41 (s, 2H), 4.00 (k, >7.1 Hz, 2H), 3.11-3.01 (m, 2H), 3.01-2 .87 (m, 1H), 2.64-2.53 (m, 2H), 1.10 (t, >7.1 Hz, ZN).

The following compounds were prepared by methods similar to those described for compound 859:

-324045362

Connection No. HPMS (ES) m/z ^1H NMR 860A M+H=480 (400 MHz, methylene chloride-s/g) δ 8.23 (d, J = 2.1 Hz, 1H), 7.54 (dd, J = 8.9, 2.1 Hz, 1H), 7.28 - 7.18 (m, 2H), 7.12 (d, J = 8.3 Hz. 2H), 4.85 (s, 2H), 4.41 (s, 2H), 4.02 (k, J = 7.1 Hz, 2H), 3.07 - 2.93 (m, 1H), 2.81 - 2.71 (m, 2H), 2.69-2.59 (m, 2H), 1.13 (t, 4=7.1 Hz, ZN) 860V M+N-480 (400 MHz, methylene chloride-02) δ 8.34 (d, J = 2.1 Hz, 1H), 7.65 (dd, J = 8.9, 2.1 Hz, 1H), 7.38 (d , J - 8.2 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 4.94 (s, 2H), 4.52 (s, 2H), 4.13 (k , J = 7.1 Hz, 2H), 3.22 - 3.12 (m, 2H), 3.10 - 2.96 (m, 1H), 2.77-2.66 (m, 2H), 1.24 (t, J = 7.1 Hz, ZN)

Example 62. Synthesis of compound 861.

1. Synthesis of intermediate 62-1

62-1

Oxetane-3-carbaldehyde (7.5 g, 87.1 mmol, 1.1 eq.). After stirring at room. temp, 5-chloro-3-fluoro-2-isocyanopyridine (12.4 g, 79.2 mmol, 1.0 eq.) and chloroacetic acid (8.2 g, 87.1 eq.) were added to this mixture over 10 min. mmol, 1.1 eq.). The resulting mixture was stirred at room. pace, overnight, concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE/EtOAc (2/1) to give 33.5 g of 2-chloro-I-(2-((5chloro-3-fluoropyridine -2-yl)amino)-1-(oxetan-3-yl)-2-oxoethyl)-M-(4-(trifluoromethyl)benzyl)acetamide (intermediate 62-1) as a yellow oil. HPMS (ES) m/z 494 (M+H).

2. Synthesis of compound 861

-з CF ₃

N'T/ ⁰ ' F ^СОз^ _F

62-1 Compound 861

To a solution of 2-chloro-M-(2-((5-chloro-3-fluoropyridin-2-yl)amino)-1-(oxetan-3-yl)-2-oxoethyl)-X-(4(trifluoromethyl) benzyl)acetamide (33.5 g, 67.8 mmol, 1.0 eq.) in DMF (350.0 ml) was added potassium carbonate (18.9 g, 135.6 mmol, 2.0 eq.). The resulting mixture was stirred at room. temp, water (800 ml) was added over 30 minutes. The precipitates were collected by filtration, washed twice with water (400 ml) and dried under high vacuum to yield 26 g of 1-(5-chloro-3-fluoropyridin-2-yl)-3-(oxetan-3-yl)-4-(4 (trifluoromethyl)benzyl)piperazine-2,5-dione (compound 861) as a white solid with a metallic tint. HPMS (ES) m/z 458 (M+H).

The following compounds were prepared by methods similar to those described for compound 861:

-325 045362

Connection No. HPMS (ES) m/z 612 M+H=508 633 M+H=424 636 M+H=432 639 M+H=472 640 M+H=438 645 M+H=454.0 646 M+H=408 647 M+H=426 648 M+H=442 649 M+H=476 650 M+HM40 651 M+H=468 654 M+H=420 655 M*H=434 656 M+H=487 657 M+H=466 661 M+H=513 662 M+NA79 664 M+H= 422.0 666 M+H= 404.0 667 M+H=422.0 668 M+H=442.0 700 M+H=451 706 MtH=398.0 707 M+H=452.0 708 Μ+Η=468Ό 714 МъН=404 717 M+H=438 720 M+H=422 724 M+H=418 727 M+N-418 730 M+N-438 733 M+H=400 3. Separation of enantiomers Enantiomers 861A and 861B A + . Αΐ connections 861. Chiral separation iA ““ ‘ Enantiomer 861B

Compound 861

Racemic compound 1 -(5-chloro-3-fluoropyridin-2-yl)-3-(oxetan-3-yl)-4-(4(trifluoromethyl)benzyl)piperazine-2,5-dione (26 g, 57 mmol , 1.0 eq.) were separated by preparative SFC under the following conditions (preparative SFC80-1): Column, CHIRALPAK IC, 3x25 cm, 5 µm; mobile phase, CO ₂ (65%) and EtOH - (35%); detector, UV 254 nm) to obtain 11.4 g (first eluting peak) of enantiomer 861A and 11.2 g (second eluting peak) of enantiomers 861B as white solids.

Characterization of enantiomer 861 A, LC-MS (ESI), m/z 458 (M+H).

Ή NMR (300 MHz, DMSO-a ₆ ) δ 8.48 (d, J=2.l Hz, 1H), 8.24 (dd, J=9.5, 2.1 Hz, 1H), 7, 72 (d, J=8.l Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 4.84 (dd, J=16.4, 11.0 Hz, 2H), 4.71-4.51 (m, ZN), 4.54-4.38 (m, 2H), 4.37 (d, J=16.9 Hz, 1H), 4.25 (dd, J= 7.9, 6.0 Hz, 1H), 3.76 (g, J=7.7 Hz, 1H).

Analytical chiral HPLC RT: 0.51 min (CHIRALPAK IC-U; 0.3 cm x 5 cm; 1.6 micron; MtBE

-326 045362 (0.1% DEA): EtOH=60:40 at 0.7 ml/min).

Characterization of enantiomer 861B, LC-MS (ESI), m/z 458 (M+H).

1H NMR (300 MHz, DMSO-a ₆ ) δ 8.48 (d, J=2.1 Hz, 1H), 8.24 (dd, J=9.4, 2.2 Hz, 1H), 7, 72 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 4.84 (dd, J=16.4, 11.1 Hz, 2H), 4.71-4.51 (m, 3H), 4.54-4.38 (m, 2H), 4.38 (d, J=16.9 Hz, 1H), 4.25 (dd, J= 7.9, 6.0 Hz, 1H), 3.76 (g, J=7.8 Hz, 1H).

Analytical chiral HPLC RT: 0.64 min (CHIRALPAK IC-U; 0.3 cm x 5 cm; 1.6 micron; MtBE (0.1% DEA): EtOH=60:40 at 0.7 ml/min) .

The following compounds were prepared by methods similar to those described for enantiomers 861A and 861B:

HPLC separation conditions

Symbol HPLC CONDITIONS 1 CHIRALPAK IE-3; 0.46 cm x 5 cm; 3 microns; Hex(0.1% DEA):EtOH=50:50 at 1 ml/min J CHIRALPAK ID-3; 0.46 cm x 5 cm; 3 microns; Hex(0.1% DEA):EtOH=50:50 at 1 ml/min TO CHIRALPAK IA-U; 0.3 cm x 5 cm; 1.6 microns; MtBE(O.1% DEA):EtOH=50:50 at 0.7 ml/min L CHIRALPAK IE-3; 0.46 cm x 5 cm; 3 microns; MtBE(O.1% DEA):MeOH=50:50 at 1 ml/min M CHIRALPAK IG-3; 0.46 cm x 5 cm; 3 microns; MtBE(0.1%DEA):EtQH=50:50 at 1 ml/min N CHIRALPAK IC-3; 0.46 cm x 5 cm; 3 microns; (Hex:flXM=3:1)(0.1%DEA):EtOH=50:50 at 1 ml/min ABOUT CHIRALPAK IC-3; 0.46 cm x 5 cm; 3 microns; (Hex:DCM=3:1)(0.1% DEA):EtOH=50:50 at 2 ml/min R CHIRALPAK IC-3; 0.46 cm x 5 cm; 3 microns; (Hex:DXM=1:1)(0.1%OEA):EUN=50:50 at 1 ml/min Q CHIRALPAK IE-3; 0.46 cm x 5 cm; 3 microns; MtBE(0.1%DEA):EtQH=50:50 at 1 ml/min R CHIRALPAK ID-3; 0.46 cm x 5 cm; 3 microns; MtBE(O.1% DEA):MeOH=50:50 at 1 ml/min S CHIRAL Cellulose-SB; 0.46 cm x 10 cm; 3 microns; MtBE(O.1% DEA):EtOH=70:30 at 1 ml/min T CHIRALPAK IE-3; 0.46 cm x 5 cm; 3 microns; (Hex:flXM=3:1)(0.1%DEA):EtOH=50:50 at 1 ml/min X CHIRALPAK ID-3; 0.46 cm x 5 cm; 3 microns; MtBE (0.1% DEA):EtOH=50:50 at 1 ml/min

- 327 045362

Connection No. HPMS (ES) m/z Retention time (min) HPLC separation conditions 863A M+H=410 1,982 I 863B M+H=410 2.875 I 573A M+HM46 1,196 J 573B M+H=446 1,640 J 864A M+H=458 1.111 J 864B M+H=458 2,081 J 612A M+H=508 0.899 TO 612V M+H=508 1.179 To 633A M+H=424 1.038 L 633B M+H=424 1.94 L 636A M+N-432 0.97 M 636V M+H=432 1.33 m 657A M+H=466 1.29 I 657B M+H=466 2.30 \ 650A M+H=440 2.17 N 650V M+H=440 3.16 N 654A M+H=420 2.18 N 654B M+H=420 2.90 N 639A M+H=472 1.77 N 639V M+H=472 3.10 N 640A M+H=438 1.34 ABOUT 640V M+H=438 2.02 ABOUT 643A M+H=499 1.38 ABOUT 644A M+H=465 2.28 R 649A M+N-476 1.55 N 649V M+H=476 2.86 N 647A M+H=426 1.47 R 647V M+H=426 2.55 R 646A M+H=408 2.24 N 646V M+H=408 3.46 N 648A M+H=442 1.52 R 648V M+H=442 2.64 R 645A M+H=454 1.01 Q 664A M+H=422 2.61 N 664V M+H=422 3.91 N 667A M+H=422 2.21 N 667B M+H=422 2.93 N 668A M+H=442 2.07 N 668V M+H=442 3.30 N 714A M+H=404 1.10 R 714B M+H=404 3.07 R 717A M+H=438 2.87 S 717B M+H=438 3.27 S 720A M+H=422 1.02 R 720V M+H=422 2.76 R 724A M+H=418 1.46 X 724V M+H=418 3.89 X 727V M+H=418 1.78 T 727A M+H=418 2.58 T 730A M+H=438 1.14 Q 730V M+H=438 2.15 Q 730A M+H=400 1.31 Q 730V M+H=400 2.54 Q

- 328 045362

Connection No. HPMS (ES) m/z Retention time (min) Conditions of the agricultural sector 666A M+H=404 1.39 CHIRALPAK AS-3; 0.3 cm x 10 cm; 3 microns; gradient A: CO2; gradient (V%): MeOH (0.1% DEA); gradient (V%): from 5% to 20% for 2 minutes, hold for 1 minute at 20%; at 2 ml/min 666V M+H=404 1.83

Connection No. HPMS (ES) m/z NMR 865A M+H=446 (300 MHz, DMSO-ds) b 8.50 (d, J = 2.1 Hz 1H), 8.26 (dd, J = 9.0, 2.4 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 5.52 (t, J = 4.6, Hz, 1H), 5.04 (d, J = 15.6 Hz, 1H), 4.64 (k, J = 6.9 Hz, 1H), 4.41 (d, J = 15.9 Hz, 1H), 4.11 (s, 1H), 3.90-3.75 (m, 2 N), 1.53 (d, 4 =6.9 Hz, ZN) 888A M+H=446 (300 MHz, DMSO-£/ ₆ ) δ 8.52 (s, 1H), 8.50 (d, 4 = 2.1 Hz 1H), 8.25 (dd, J = 9.3, 2.1 Hz, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 5.52 (lat, 1H), 5.13 (d, J = 15.9 Hz, 1H), 4.85 (k, J = 7 Hz, 1H), 4.42 (d, J = 15.9 Hz, 1H), 4.21 (s, 1H ), 3.92-3.73 (m, 2 N), 1.18 (d, 7= 7 Hz, ZN)

The following compounds were prepared by methods similar to those described for enantiomers 861A and 861B, and using racemic 2-((tert-butyldimethylsilyl)oxy)propanal instead of oxetane-3-carbaldehyde:

Connection No. HPMS (ES) m/z Ή NMR 858A M+H=446 (400 MHz, methylene chloride-s/ ₂ ) b 8.21 (d, J- 2.1 Hz, 1H), 7.58 - 7.47 (m, ZH), 7.33 (d, J = 8, 0 Hz, 2H), 5.37 (d, J = 15.5 Hz, 1H), 4.72 (dd, J = 16.7, 4.1 Hz, 1H), 4.29 - 4.19 ( m, 2H), 4.16 (d, J = 15.5 Hz, 1H), 3.91 (d, J = 4.1 Hz, 1H), 2.57 (s, 1H), 1.27 ( dd, J = 6.5, 4.1 Hz, ZN) 858B M+H=446 (400 MHz, methylene chloride-su b 8.19 (d, J- 2.1 Hz, 1H), 7.57 - 7.46 (m, ZN), 7.35 (d, J = 8.0 Hz, 2H), 5.19 (s, 1H), 4.72 (d, J = 16.6 Hz, 1H), 4.28 - 4.13 (m, ZN), 3.79 (d, J = 2 .4 Hz, 1H), 3.00 (s, 1H), 1.24 (d, J=6.6 Hz, ZN)

The following compounds were prepared by methods similar to those described for enantiomers 861A and 861B, and using (8)-2-((tert-butyldimethylsilyl)oxy)propanal instead of oxetane-3-carbaldehyde:

Connection No. HPMS (ES) m/z ^Ί Η NMR 858С M+H=446 (400 MHz, methylene chloride-cy δ 8.21 (d, J- 2.1 Hz, 1H), 7.58 - 7.47 (m, ZH), 7.35 (dd, J = 13.0, 8 .0 Hz, 2H), 5.18 (d, J= 15.5 Hz, 1H), 4.72 (dd, J= 16.7, 3.2 Hz, 1H), 4.24 (dd, J = 16.0, 6.2 Hz, 2H), 4.22 - 4.12 (m, 1H), 3.81 (d, J = 2.4 Hz, 1H), 2.28 (s, 1H) , 1.27 (d, J= 6.5 Hz, ZN). 858D M+H=446 (400 MHz, methylene chloride-cy δ 8.21 (d, J = 2.0 Hz, 1H), 7.58 - 7.48 (m, ZN), 7.33 (d, J = 8.0 Hz, 2H), 5.37 (d, J = 15.5 Hz, 1H), 4.71 (d, J = 16.8 Hz, 1H), 4.28 - 4.16 (m, 2H), 4, 15 (d, J = 15.5 Hz, 1H), 3.90 (d, J = 4.1 Hz, 1H), 2.76 (s, 1H), 1.27 (d, J = 6.5 Hz, ZN).

Example 63. Synthesis of tert-butyl-3-((5-chloro-3-fluoropyridin-2-yl)carbamoyl)-3-(2-chloro-X-(4-329 045362 (difluoromethyl)benzyl)acetamido)cyclobutane- 1-carboxylate (mixture of diastereomers of intermediates 71-1A and 71-1B)

He

2,2,2-Trifluoroethanol, rt, 3h

Diastereomer 71-1A (less polar)

Diastereomer 71-1B (more polar)

To a solution of (4-(difluoromethyl)phenyl)methanamine (1.0 g, 6.3 mmol, 1.0 eq.) in 2,2,2-trifluoroethanol (5.0 ml) was added tert-butyl-3-oxocyclobutane -1-carboxylate (1.1 g, 6.3 mmol, 1.0 eq.). After stirring at room. pace, over 10 min, 5-chloro-3-fluoro-2-isocyanopyridine (1.0 g, 6.3 mmol, 1.0 eq.) and chloroacetic acid (0.66 g, 7.0 eq.) were added to this resulting mixture. mmol, 1.1 eq.). The resulting mixture was stirred at room. pace, overnight, concentrated under reduced pressure and purified by silica gel chromatography, eluting with EA/HE to give 800 mg (22%) of the diastereomer of intermediate 71-1A (first peak, less polar) and 1.0 g (28%) diastereomer of intermediate 71-1B (second peak, more polar). HPMS (ES) m/z 560 (M+H) for both isomers.

Example 64 Synthesis of compound 630.

1. Synthesis of intermediate 64-1

ACN, 80 C

Potassium 1,3dioxoisoindolin-2-ide (7.5 g, 40.5 mmol, 1.11 eq.). The mixture was stirred at 80°C for 2 hours, cooled to room. temp, and quenched with water (50 ml) and extracted twice with DCM (50 ml). The combined organic layer was washed with brine (100 ml), dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by silica gel column chromatography using PE/EA (1/2) as eluent to obtain 6.6 g 2 -(2-oxopropyl)isoindoline-1,3-dione (intermediate 64-1) as a yellow solid. HPMS (ES) m/z 204 (M+H).

2. Synthesis of intermediate 64-2

To a solution of 1-[4-(trifluoromethyl)phenyl]methanamine (1.7 g, 9.7 mmol, 1.5 eq.) in trifluoroethanol (10.0 ml) was added 2-(2-oxopropyl)isoindoline-1, 3-dione (2.0 g, 9.6 mmol, 1.5 eq.). After stirring at room. pace, over 10 minutes, 5-chloro-3-fluoro-2-isocyanopyridine (1.0 g, 6.4 mmol, 1.0 eq.) and chloroacetic acid (899.4 mg, 9.0 eq.) were added to this mixture. 5 mmol, 1.5 eq.). The resulting mixture was stirred at 60°C overnight, concentrated in vacuo and purified with a C18 column, eluting with water (0.5% NH ₄ HCO ₃ )/ACN (1/5), to obtain 750 mg of X-(5-chloro- 3-fluoropyridin-2-yl)-2-(2-chloro-X-[[4(trifluoromethyl)phenyl]methyl]acetamido)-3-(1,3-dioxoisoindol-2-yl)-2-methylpropanamide (intermediate compound 64-2) as a yellow oil. HPMS (ES) m/z 611 (M+H).

3. Synthesis of intermediate 64-3

64-2 64-3

To a solution of M-(5-chloro-3-fluoropyridin-2-yl)-2-(2-chloro-M-[[4-(trifluoromethyl)phenyl]methyl]acetamido)-3-(1,3-dioxoisoindol- 2-yl)-2-methylpropanamide (700.0 mg, 1.1 mmol, 1.0 eq.) in dimethylformamide (7.0 ml) was added potassium carbonate (317.0 mg, 2.3 mmol, 2.0 eq.). The resulting mixture was stirred at 60°C for 30 minutes, cooled to room. temp, and diluted with water (15 ml). Precipitation from

-330 045362 was collected by filtration, washed twice with water (10 ml), dried and purified by silica gel column chromatography, eluted with PE/EtOAc (4:8) to obtain 400 mg of 2-((4-(5-chloro-3-fluoropyridine- 2-yl)-2methyl-3,6-dioxo-1-(4-(trifluoromethyl)benzyl)piperazin-2-yl)methyl)isoindoline-1,3-dione (intermediate 64-3) as a white solid with a metallic tint. HPMS (ES) m/z 575 (M+H).

4. Synthesis of intermediate 64-4

64-3 64-4

To a solution of 2-((4-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-3,6-dioxo-1 -(4-(trifluoromethyl)benzyl)piperazin-2-yl)methyl) NH ₂ NH ₂ .H ₂ O (83.0 mg, 1.7 mmol, 3.0 eq.). The resulting mixture was stirred at 80°C for 2 hours, cooled to room. temp, filtered to remove solids, and concentrated under reduced pressure to obtain 200 mg of 3-(aminomethyl)-1-(5-chloro-3-fluoropyridin-2-yl)-3-methyl-4-(4(trifluoromethyl) benzyl)piperazine-2,5-dione (intermediate 64-4) as a yellow oil. HPMS (ES) m/z 445 (M+H).

5. Synthesis of compound 630

64-4 Compound 630

To a solution of 3-(aminomethyl)-1-(5-chloro-3-fluoropyridin-2-yl)-3-methyl-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione (200 mg, 0 .45 mmol, 1.0 eq.) in DCM (2 ml) were added acetic anhydride (55 mg, 0.54 mmol, 1.2 eq.) and TEA (91 mg, 0.9 mmol, 2.0 eq. ). The mixture was stirred at room. pace, for 2 hours, concentrated under reduced pressure and purified by preparative HPLC under the following conditions: (SHIMADZU (HPLC-01)): Column, XBridge Prep OBD Cl8 column, 30x150 mm 5 µm; mobile phase, water (10 mM NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O) and ACN (38% gradient to 60% over 9 min); detector UV 254 nm) to obtain 140 mg of X-((4-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-3,6-dioxo-1-(4(trifluoromethyl)benzyl)piperazin- 2-yl)methyl)acetamide (compound 630) as a white solid. LC-MS (ESI), m/z 487 (M+H).

'H NMR (300 MHz, methanol-b ₄ ) δ 8.42 (d, J=1.9 Hz, 1H), 7.94 (d, J=9.1 Hz, 1H), 7.66 (d , J=8.l Hz, 2H), 7.53 (d, J=8.l Hz, 2H), 5.29 (d, J=16.7 Hz, 1H), 4.83-4.75 (m, 1H), 4.58-4.44 (m, 2H), 3.96 (d, J=14.0 Hz, 1H), 3.53 (d, J=14.4 Hz, 1H) , 1.96 (d, J=1.5 Hz, ZN), 1.58-1.51 (m, ZN).

The following compound was prepared using methods similar to the method described for compound 861:

6. Separation of enantiomers of compound 630. Enantiomers 630A and 630B

Racemic compound of N-((4-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-3,6-dioxo-1 -(4(trifluoromethyl)benzyl)piperazin-2-yl)methyl)acetamide (90 mg, 0.19 mmol, 1.0 eq.) was purified by chiral preparative HPLC under the following conditions ((preparative HPLC-009): Column, CHIRALPAK IE,

-331 045362

2x25 cm, 5 µm; mobile phase, 30% EtOH in Hex (8 mM _NH3.MeOH ) for 15 min; detector, UV 254 nm) to obtain 37 mg (first eluting peak) of enantiomer 630A and 39 mg (second eluting peak) of enantiomer 630B as a white solid.

Characteristics of enantiomer 630A. LC-MS (ESI), m/z 487 (M+H).

Y NMR (300 MHz, DMSO-b ₆ ) δ 8.51 (d, J=2.l Hz, 1H), 8.29-8.20 (m, 2H), 7.70 (d, J=8 ,l Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 5.07 (d, J=16.9 Hz, 1H), 4.64 (d, J=17.0 Hz, 1H), 4.46 (t, J=17.5 Hz, 2H), 3.81 (dd, J=14,l, 7.1 Hz, 1H), 3.37 (dd, J=14 ,l, 5.4 Hz, 1H), 1.82 (s, ZN), 1.43 (s, ZN).

Analytical chiral HPLC RT: 2.33 min (CHIRALPAK IE-3; 0.46 cm x 5 cm; 3 microns; Hex (0.1% DEA): EUN=70:30 at 1 ml/min).

Characteristics of enantiomer 630B. LC-MS (ESI), m/z 487 (M+H).

A NMR (300 MHz, DMSO-b ₆ ) δ 8.51 (d, J=2.l Hz, 1H), 8.30-8.20 (m, 2H), 7.70 (d, J=8 ,l Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 5.07 (d, J=16.9 Hz, 1H), 4.64 (d, J=17.0 Hz, 1H), 4.46 (t, J=17.5 Hz, 2H), 3.81 (dd, J=14,l, 7.1 Hz, 1H), 3.44-3.33 (m , 1H), 1.82 (s, ZN), 1.43 (s, ZN).

Analytical chiral HPLC RT: 2.71 min (CHIRALPAK IE-3; 0.46 cm x 5 cm; 3 microns; Hex (0.1% DEA): EUN=70:30 at 1 ml/min).

Example 65. Synthesis of compound 691.

1. Synthesis of intermediate 65-1

To a solution of methyl 2-amino-2-(oxetan-3-yl)acetate (3.0 g, 20.7 mmol, 1.0 eq.) in DCE (60.0 ml) was added 4-(trifluoromethyl)benzaldehyde (3.6 g, 21 mmol, 1.0 eq.). After stirring at room. temp., AcOH (2.50 g, 41.631 mmol, 2.01 eq.) and STAB (8.80 g, 41.521 mmol, 2.01 eq.) were added to this mixture over 30 min at room temperature. The resulting mixture was stirred at room. pace, overnight, adjusted pH to 8 with ammonium hydroxide (200 ml) and extracted twice with DCM (300 ml). The combined organic layers were washed twice with brine (200 ml), dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and purified on a C18 column eluting with water (0.5% NH ₄ HCO ₃ )/ACN (L1) to give 5 .2 g methyl 2-(oxetan-3-yl)-2-((4(trifluoromethyl)benzyl)amino)acetate (intermediate 65-1) as a yellow solid. HPMS (ES) m/z 304 (M+H).

2. Synthesis of intermediate 65-2

To a solution of methyl 2-(oxetan-3-yl)-2-((4-(trifluoromethyl)benzyl)amino)acetate (5.0 g, 16.5 mmol, 1.0 eq.) in DCM (100 ml ) at 0°C, K ₂ CO ₃ (0.5 M, 49 ml, 24.6 mmol, 1.5 eq.) and bromoacetyl bromide (4.0 g, 19.8 mmol, 1.2 eq.) were added. The resulting mixture was stirred at room. temp. for 2 h and extracted twice with DCM (50 ml). The combined organic layers were washed twice with brine (100 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 7.1 g of methyl 2-(2-bromo-X-[[4-(trifluoromethyl)phenyl] methyl]acetamido)-2-(oxetan-3-yl)acetate (intermediate 65-2) as a yellow oil. HPMS (ES) m/z 424 (M+H).

3. Synthesis of intermediate 65-3

65-2 65-3

To methyl 2-(2-bromo-M-[[4-(trifluoromethyl)phenyl]methyl]acetamido)-2-(oxetan-3-yl)acetate (7.0 g, 16.5 mmol, 1.0 eq.) in a round bottom flask was added NH ₃ in MeOH (70.0 ml, 7 M). The mixture was stirred at room. pace, overnight, concentrated in vacuo and triturated with ethyl acetate (100 ml) from the floor

- 332 045362 with 5.7 g of 6-(oxetan-3-yl)-1-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione (intermediate 65-3) as a white metallic solid . HPMS (ES) m/z 329 (M+H).

4. Synthesis of compound 691

65-3 Compound 691

To a solution of 6-(oxetan-3-yl)-1-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione (120.0 mg, 0.37 mmol, 1.0 eq.) in dioxane (4 ml) at room. temp, added (2-aminoethyl)dimethylamine (18.0 mg, 0.21 mmol, 0.56 eq.), 2-bromo-3-fluoro-5-methylpyridine (102.1 mg, 0.54 mmol, 1 .5 eq.), Cui (36.2 mg, 0.19 mmol, 0.5 eq.) and K ₂ CO ₃ (150.0 mg, 1.1 mmol, 3.0 eq.). The resulting mixture was stirred at 115°C for 2 hours under a nitrogen atmosphere, cooled to room temperature, diluted with water (10 ml) and extracted twice with ESO Ac (10 ml). The combined organic layers were washed twice with brine (10 ml), dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and purified by preparative HPLC under the following conditions (SHIMADZU (HPLC-01)): Column, XBridge Shield RP18 OBD column, 5 μm , 19x150 mm; mobile phase, water (0.05% TFA) and ACN (43% gradient 45% over 9 min); detector, UV 254 nm) to obtain 100 mg of 1-(3-fluoro-5-methylpyridin-2-yl)-3-(oxetan-3-yl)-4-(4(trifluoromethyl)benzyl)piperazine-2,5 -dione (compound 691) as a yellow oil. HPMS (ES) m/z 438 (M+H).

'H NMR (300 MHz, methanol-0 ₄ ) δ 8.21 (s, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.60 (d, J=10.5 Hz , 1H), 7.52 (d, J=8.l Hz, 2H), 5.00 (d, J=16.l Hz, 1H), 4.842-4.897 (m, 1H), 4.76 (d , J=17.4 Hz, 1H), 4.68-4.55 (m, ZN), 4.554.39 (m, ZN), 3.78 (dt, J=17.4, 8.4 Hz, 1H), 2.42 (d, J=0.8 Hz, ZN).

5. Separation of enantiomers of compound 691.

Enantiomers 691A and 691B

Racemic compound 1-(3-fluoro-5-methylpyridin-2-yl)-3-(oxetan-3-yl)-4-(4(trifluoromethyl)benzyl)piperazine-2,5-dione (80 mg, 0. 18 mmol, 1.0 eq.) was purified by chiral preparative HPLC under the following conditions ((Preparative HPLC-009): Column, CHIRALPAK IE, 2x25 cm, 5 µm; mobile phase, 40% EUN in MTBE (8 mM NH ₃ .MeOH ) for 19 min; detector, UV 254 nm) to obtain 25 mg (first eluting peak) of enantiomer 691A and 17 mg (second eluting peak) of enantiomer 691B as white solids.

Characterization of enantiomer 691 A. LC-MS (PER), m/z 438 (M+H).

'H NMR (300 MHz, methanol-0 ₄ ) δ 8.21 (s, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.60 (d, J=10.4 Hz , 1H), 7.52 (d, J=8.l Hz, 2H), 5.00 (d, J=15.9 Hz, 1H), 4.84-4.89 (m, 1H), 4 .76 (d, J=17.4 Hz, 1H), 4.68-4.56 (m, ZN), 4.56-4.40 (m, ZN), 3.86-3.72 (m , 1H), 2.42 (s, ZN).

Analytical chiral HPLC RT: 1.16 min (CHIRALPAK IE-3; 0.46 cm x 5 cm; 3 microns; MtBE (0.1% DEA): EUN=50:50 at 1 ml/min).

Characteristics of enantiomer 691B. LC-MS (ESI), m/z 438 (M+H).

'H NMR (300 MHz, methanol-0 ₄ ) δ 8.21 (s, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.60 (d, J=10.4 Hz , 1H), 7.52 (d, J=8.0 Hz, 2H), 5.00 (d, J=15.9 Hz, 1H), 4.84-4.89 (m, 1H), 4 .76 (d, J=17.4 Hz, 1H), 4.68-4.55 (m, ZN), 4.55-4.40 (m, ZN), 3.86-3.72 (m , 1H), 2.42 (s, ZN).

Analytical chiral HPLC RT: 2.76 min (CHIRALPAK IE-3; 0.46 cm x 5 cm; 3 microns; MtBE (0.1% DEA): EUN=50:50 at 1 ml/min).

- 333 045362

Example 66 Synthesis of compound 701.

1. Synthesis of intermediate 66-1

Compound 202 66-1

Hydroxylamine (2.0 mL, 50 wt% in water) was added to a suspension of compound 202 (3.0 g, 6.3 mmol, 1.0 eq.) in ethanol (20.0 mL). After stirring at room. pace, overnight, the precipitate was collected by filtration, washed with additional water and dried to obtain 1.6 g (50%) 4-(2acetyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2, 5,8-Triazaspiro[3.5]nonan-8-yl)-3-fluoro-Ihydroxybenzimidamide (intermediate 66-1) as a white solid. HPMS (ES) m/z 508 (M+H).

*H NMR (400 MHz, DMSO- _c16 ) δ 9.87 (d, >1.6 Hz, 1H), 7.78-7.71 (m, 2H), 7.60 (dt, >19, 1, 8.2 Hz, 5H), 5.97 (s, 2H), 5.03 (s, 2H), 4.56 (d, J=9.9 Hz, 1H), 4.49 (s, 2H), 4.38 (d, >9.7 Hz, 1H), 4.28 (d, >10.5 Hz, 1H), 4.04 (d, >10.5 Hz, 1H), 1, 75 (s, ZN).

2. Synthesis of compound 701

To a solution of 4-(2-acetyl-6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5]nonan-8-yl)3-fluoro-N-hydroxybenzimidamide ( 100 mg, 0.2 mmol, 1.0 eq.) in trimethoxymethane (1.0 ml) at room temperature, PTSA (3.39 mg, 0.02 mmol, 0.1 eq.) was added. The mixture was stirred at reflux overnight, cooled to room temp, concentrated to dryness and triturated with ACN (5.0 ml). The solid was collected and dried to give 81 mg (79%) 2-acetyl-8-(2-fluoro-4-(1,2,4oxadiazol-3-yl)phenyl)-5-(4-(trifluoromethyl)benzyl) -2,5,8-triazaspiro[3.5]nonane-6,9-dione (compound 701). HPMS (ES) m/z 518.1 (M+H).

*H NMR (400 MHz, methylene chloride-(1 ₂ ) δ 8.90 (d, >1.7 Hz, 1H), 8.07 (dd, >16.1, 9.6 Hz, 2H), 7, 71 (d, >7.9 Hz, 2H), 7.60-7.51 (m, 1H), 7.47 (d, >8.0 Hz, 2H), 5.21 (d, >16, 5 Hz, 1H), 5.00 (d, >16.4 Hz, 1H), 4.77 (d, >9.3 Hz, 1H), 4.61 (d, >10.6 Hz, 1H) , 4.51 (s, 2H), 4.27 (dd, >20.0, 9.9 Hz, 2H), 1.86 (d, >1.7 Hz, ZN).

The following compound was prepared using methods similar to the method described for compound 701:

Compound No. HPMS (ES) m/z

702 M+H=532.0

Example 67. Synthesis of compound 703.

1. Synthesis of intermediate 67-1

67-1

K ₂ CO3 (697, 9 mg, 5.1 mmol, 1.5 eq.) and sweep (524.4 mg, 3.7 mmol, 1.1 eq.). The resulting mixture was stirred at 60°C for 2 hours, cooled to room temperature, diluted with water (20 ml) and extracted twice with EtOAc (30 ml). The combined organic layers were washed twice with brine (30 ml), dried over anhydrous Na ₂ SO4, and concentrated under reduced pressure to obtain 500 mg of 2-chloro-3-fluoro-5-methoxypyridine (intermediate 67-1) as a yellow oil . HPMS (ES) m/z 162 (M+H).

- 334 045362

2. Synthesis of compound 703

Compound 703

To a solution of 6-(oxetan-3-yl)-1-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione (150.0 mg, 0.46 mmol, 1.0 eq.) in dioxane (1 .0 ml) at room. temp, added copper(1) iodide (45.3 mg, 0.24 mmol, 0.5 eq.), 2chloro-3-fluoro-5-methoxypyridine (112.2 mg, 0.7 mmol, 1.5 eq. .), (2-aminoethyl)dimethylamine (22.6 mg, 0.26 mmol, 0.56 eq.) and K ₂ CO ₃ (187.6 mg, 1.36 mmol, 3.0 eq.). The resulting mixture was stirred at 110°C for 2 hours, cooled to room temperature, filtered with solids, diluted with water (10 ml) and extracted twice with EA (10 ml).

The combined organic layers were washed twice with brine (10 ml), dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and purified by preparative HPLC under the following conditions ((SHIMADZU (HPLC-01)): Column, XBridge Prep OBD C18 column, 30x150 mm 5 µm; mobile phase, water (0.05% TFA) and ACN (40% gradient to 48% over 9 min); detector, UV 254 nm) to obtain 100 mg 1-(3-fluoro-5-methoxypyridine -2-yl)-3-(oxetan-3-yl)-4-(4(trifluoromethyl)benzyl)piperazine-2,5-dione (compound 703) as a white solid. HPMS (ES) m/z 454 (M+H).

Ή NMR (300 MHz, methanol-sC) δ 8.08 (d, J=2.6 Hz, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.52 (d, J =8.1 Hz, 2H), 7.42 (dd, J=10.9, 2.6 Hz, 1H), 5.00 (d, J=15.8 Hz, 1H), 4.83-4 .69 (m, 2H), 4.69-4.35 (m, 6H), 3.93 (s, ZN), 3.863.69 (m, 1H).

The following compounds were prepared by methods similar to those described for compound 703:

Connection No. HPMS (ES) m/z 691 M+HM38 711 M+H=490 723 M+H=416.1 736 M+H=449 747 M"457 758 M+H=400 761 M+N-418 769 M+N-420 772 M+N-438 775 M+H=438

5. Separation of enantiomers of compound 703. Enantiomers 703A and 703B

Racemic compound 1 -(3-fluoro-5-methoxypyridin-2-yl)-3 -(oxetan-3-yl)-4-(4(trifluoromethyl)benzyl)piperazine-2,5-dione (80 mg, 0 .18 mmol, 1.0 eq.) was purified by chiral preparative HPLC under the following conditions (Ageia high pressure flash chromatography): Column, CHIRALPAK IC, 2x25 cm, 5 µm; mobile phase, Hex:DCM=3:1 and EtOH (1/1 for 19 min); detector, UV 254 nm) to obtain 28 mg (first eluting peak) of enantiomer 703A and 28 mg (second eluting peak) of enantiomer 703B as white solids.

Characteristics of enantiomer 703A. LC-MS (ESI), m/z 454 (M+H).

Ή NMR (300 MHz, methanol-b ₄ ) δ 8.08 (d, J=2.5 Hz, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 7.42 (dd, J=11.0, 2.6 Hz, 1H), 5.00 (d, J=15.9 Hz, 1H), 4.82 ( t, J=7.0 Hz, 1H), 4.75 (d, J=17.3 Hz, 1H), 4.684.55 (m, ZN), 4.49 (dd, J=12.6, 8 ,6 Hz, 2H), 4.47-4.36 (m, 1H), 3.93 (s, ZN), 3.79 (dk, J=16.2, 7.8 Hz, 1H).

Analytical chiral HPLC RT: 1.99 min (CHIRALPAK IC-3; 0.46 cm x 5 cm; 3 microns;

- 335 045362 (Hex:DCM=3:1)(0.1% DEA):EtOH=50:50 at 1 ml/min).

Characteristics of enantiomer 703B. LC-MS (ESI), m/z 454 (M+H).

1H NMR (300 MHz, methanol-64) δ 8.08 (d, J=2.5 Hz, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.52 (d, J =8.0 Hz, 2H), 7.42 (dd, J=11.0, 2.6 Hz, 1H), 5.00 (d, J=15.9 Hz, 1H), 4.85-4 .68 (m, 2H), 4.68-4.55 (m, 3H), 4.54-4.32 (m, 3H), 3.93 (s, 3H), 3.79 (dk, J =16.2, 7.8 Hz, 1H).

Analytical chiral HPLC RT: 2.63 min (CHIRALPAK IC-3; 0.46 cm x 5 cm; 3 microns; (Hex:DCM=3:1)(0.1% DEA):EtOH=50:50 at 1 ml/min).

The following compounds were prepared by methods similar to those described for enantiomers 703A and 703B:

HPLC separation conditions

Symbol HPLC CONDITIONS Q CHIRALPAK IE-3; 0.46 cm x 5 cm; 3 microns; MtBE(0.1%DEA):EtOH=50:50 at 1 ml/min And CHIRALPAK IE-3; 0.46 cm x 5 cm; 3 microns; MtBE(0.1%DEA):EtOH=65:35 at 1 ml/min

Enantiomer No. HPMS (ES) m/z Retention time (min) HPLC 691A M+H=438 1.16 Q 691B Μ+ΗΛ33 2.76 Q 71ΪΑ M+H=490 2.30 S 711B M+H=490 2.92 S 281A M+H=457 1.20 T 281V M+H=457 1.63 T 747A M+H=457 0.79 And 747B M*H=457 1.66 And 758A M+H=400 2.43 T 758B M+H=400 4.44 T 761A M+H=418 1.41 And 761B M+H=418 3.37 And 769A M+H=420 1.56 Q 769B M+H=420 4.19 Q 772A M+H=438 1.23 L 772 V M+H=438 3.21 L 775A M+H=438 1.32 Q 775V M+H=438 3.32 Q

Example 68. Synthesis of compound 739.

1. Synthesis of intermediate 68-1

Mixture of (7s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutane-1-(680 mg, 3.17 mmol, 1.0 eq.) and (4(trifluoromethyl)phenyl)methanamine (556 mg, 3 .17 mmol, 1.0 eq.) in 2,2,2-trifluoroethanol (8.0 ml) was stirred at room. pace. within 10 min. To this mixture were added 5-chloro-3-fluoro-2isocyanopyridine (500 mg, 3.17 mmol, 1.0 eq.) and 2-chloroacetic acid (300 mg, 3.17 mmol, 1.0 eq.). The mixture was stirred at room. pace. for 3 h, evaporate, purify with 20% EA/Hex to obtain 933 mg (47%) 2-((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-N-(5-chloro- 3-fluoropyridin-2-yl)-2-(2chloro-N-(4-(trifluoromethyl)benzyl)acetamido)acetamide (intermediate 68-1). HPMS (CIAD) m/z 623.1 (M+H).

- 336 045362

2. Synthesis of intermediate 68-2

To a solution of 2-((1 s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-X-(5-chloro-3-fluoropyridin-2ip)-2-(2-chloro-H-(4 -(trifluoromethyl)benzyl)acetamido)acetamide (933 mg, 1.5 mmol, 1.0 eq.) in DMF (10 ml) was added to ₂ CO ₃ (626 mg, 4.5 mmol, 3.0 eq.) . The resulting mixture was stirred at 80°C for 15 min, cooled to room temperature, diluted with EA (100 ml), washed three times with water (50 ml) and once with saline (50 ml), dried over sodium sulfate and concentrated at under reduced pressure to give 760 mg (87%) 3-((18.38)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-1-(5-chloro-3fluoropyridin-2-yl)-4-(4 -(trifluoromethyl)benzyl)piperazine-2,5-dione (intermediate 68-2) as a white foam. HPMS (CIAD) m/z 586.1 (M+H).

3. Synthesis of compound 739

Compound 739

To a solution of 3 -((1 s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-1 -(5-chloro-3-fluoropyridin-2yl)-4-(4-(trifluoromethyl)benzyl)piperazine -2,5-dione (760 mg, 1.30 mmol, 1.0 eq.) in THF (10 ml) was added TBAF (2.59 ml 1.0 M in THF, 2.59 mmol, 2.0 eq. .). The resulting mixture was stirred at room temperature for 30 min, quenched with saturated aqueous sodium hydrogen carbonate (30 ml) and diluted with DCM (125 ml). The organic phase was washed with brine (75 ml), dried over sodium sulfate, concentrated in vacuo and purified on silica gel using a gradient of 0-100% EA/Hex to give 420 mg (69%) 1-(5-chloro-3-fluoropyridine -2-yl)-3-((18,38)-3-hydroxycyclobutyl)-4-(4(trifluoromethyl)benzyl)piperazine-2,5-dione (compound 739) as a white foam. (NRMS (CIAD) m/z 472.0 (M+H).

^! H NMR (400 MHz, DMSO-b ₆ ) δ 8.49 (d, >2.1 Hz, 1H), 8.26 (dd, >9.4, 2.1 Hz, 1H), 7.75 ( d, >8.1 Hz, 2H), 7.52 (d, >8.1 Hz, 2H), 5.10-5.01 (m, 2H), 4.75 (d, >17.0 Hz , 1H), 4.37 (dd, >17.0, 13.5 Hz, 2H), 4.05 (d, >8.0 Hz, 1H), 3.92-3.81 (m, 1H) , 2.35-2.14 (m, ZN), 1.76 (m, 2H).

Example 69. Synthesis of compound 740.

1. Synthesis of intermediate 69-1

Mixture of (1g,3g)-3-((tert-butyldimethylsilyl)oxy)cyclobutane-1-carbaldehyde (680 mg, 3.17 mmol, 1.0 eq.) and (4-(trifluoromethyl)phenyl)methanamine (556 mg , 3.17 mmol, 1.0 eq.) in 2,2,2-trifluoroethanol (8.0 ml) was stirred at room. pace, for 10 min. To this mixture were added 5-chloro-3-fluoro-2 isocyanopyridine (500 mg, 3.17 mmol, 1.0 eq.) and 2-chloroacetic acid (300 mg, 3.17 mmol, 1.0 eq.). The mixture was stirred at room. pace, for 3 hours, evaporated, purified with 20% EA/Hex to obtain 1.2 g (59%) 2-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-X-(5-chloro-3- fluoropyridin-2-yl)-2-(2-chloro-X(4-(trifluoromethyl)benzyl)acetamido)acetamide (intermediate 69-1; racemic mixture of cis and trans isomer) as a white foam. HPMS (CIAD) m/z 623.1 (M+H).

2. Synthesis of intermediate 69-2

- 337 045362

To a solution of 2-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-X-(5-chloro-3-fluoropyridin-2-yl)-2-(2chloro-X-(4-(trifluoromethyl)benzyl)acetamido )acetamide (1.2 g, 2.0 mmol, 1.0 eq.) in DMF (10 ml) was added to ₃ CO ₃ (781 mg, 5.6 mmol, 3.0 eq.). The resulting mixture was stirred at 80°C for 15 min, cooled to room temperature, diluted with EA (100 ml), washed three times with water (50 ml) and once with saline (50 ml), dried over sodium sulfate and concentrated at under reduced pressure to obtain 988 mg (90%) 3-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-1-(5-chloro-3fluoropyridin-2-yl)-4-(4-(trifluoromethyl)benzyl) piperazine-2,5-dione (intermediate 69-2; racemic mixture of cis and trans isomers) as a white foam. HPMS (CIAD) m/z 586.1 (M+H).

3. Synthesis of compound 740

69-2 Compound 740

To a solution of 3-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-1-(5-chloro-3-fluoropyridin-2-yl)-4-(4(trifluoromethyl)benzyl)piperazine-2,5-dione (988 mg, 1.69 mmol, 1.0 eq.) in THF (10 ml) was added TBAF (3.37 ml 1.0 M in THF, 3.37 mmol, 2.0 eq.). The resulting mixture was stirred at room. temp, for 30 min, quenched with saturated aqueous sodium bicarbonate (30 ml) and diluted with DCM (125 ml). The organic phase was washed with brine (75 ml), dried over sodium sulfate, concentrated in vacuo and purified on silica gel using a gradient from 0% EA/Hex to 100% EA/Hex to give 530 mg (66%) 1-(5-chloro -3-fluoropyridin-2-yl)-3-(3-hydroxycyclobutyl)-4-(4(trifluoromethyl)benzyl)piperazine-2,5-dione (compound 740; 1:1 mixture of cis and trans isomers) in in the form of white foam. HPMS (CIAD) m/z 472.0 (M+H).

4. Separation of stereoisomers of compound 740.

Stereoisomers 740A, 740B, 740C and 740D

Stereoisomers of 1-(4-chloro-2-fluorophenyl)-3-(3-hydroxycyclobutyl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5-dione (796 mg) were purified by chiral preparative HPLC under the following conditions: Column, CHIRALPAK IG, 2x25 cm, 5 µm; mobile phase, hexane (8 mM NH ₃ /MeOH) and EtOH (hold 35% EtOH for 18 min); detector, UV 254 nm/220 nm) to obtain 150 mg of stereoisomer 740C, 96 mg of stereoisomer 740D and 250 mg of a mixture of stereoisomer 740A and stereoisomer 740B, which was further purified by chiral HPLC under the following conditions; column CHIRALPAK IG 20x25 cm, 5 µm; mobile phase, hexane (8 mM NH ₃ /MeOH) and EtOH (hold 35% EtOH for 18 min); detector, UV 254 nm/220 nm)) to obtain 63 mg of stereoisomer 740B and 118 mg of stereoisomer 740A as white solids.

Characteristics of stereoisomer 740A. LC-MS (ESI), m/z 472 (M+H).

'H NMR (300 MHz, DMSO-ph) δ 8.47 (d, J=2.l Hz, 1H), 8.24 (dd, J=9.4, 2.2 Hz, 1H), 7, 73 (d, J=8.0 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 5.12-5.00 (m, 2H), 4.74 (d, J =17.0 Hz, 1H), 4.36 (dd, J=16.3, 9.8 Hz, 2H), 4.04 (d, J=7.7 Hz, 1H), 3.86 (k , J=6.6 Hz, 1H), 2.22 (di, J=17.1, 6.6 Hz, ZN), 1.73 (k, J=9.4 Hz, 2H).

Analytical chiral HPLC RT: 0.85 min (CHIRALPAK IG-3; 0.46 cm x 5 cm; 3 microns; MtBE (0.1% DEA):EtOH=60:40 at 1 ml/min).

Characteristics of the 740B stereoisomer. LC-MS (ESI), m/z 472 (M+H).

'H NMR (300 MHz, DMSO-ph) δ 8.47 (d, J=2.l Hz, 1H), 8.25 (dd, J=9.4, 2.2 Hz, 1H), 7, 72 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 5.09-4.97 (m, 2H), 4.78 (d, J =17.1 Hz, 1H), 4.49 (d, J=15.7 Hz, 1H), 4.35 (d, J=17.l Hz, 1H), 4.18 (t, J=8 .7 Hz, 2H), 2.95 (s, 1H), 2.23 (s, 2H), 1.87 (td, 1=8.8, 4.4 Hz, 2).

Analytical chiral HPLC RT: 0.82 min (CHIRALPAK IG-3; 0.46 cm x 5 cm; 3 microns; MtBE (0.1% DEA):EtOH=60:40 at 1 ml/min).

- 338 045362

Characteristics of stereoisomer 740C. LC-MS (ESI), m/z 472 (M+H).

'll NMR (300 MHz, DMSO-ph) δ 8.47 (d, J=2.l Hz, 1H), 8.24 (dd, J=9.4, 2.1 Hz, 1H), 7, 73 (d, J=8.l Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 5.11-5.00 (m, 2H), 4.74 (d, J =16.9 Hz, 1H), 4.36 (dd, J=16.3, 10.0 Hz, 2H), 4.04 (d, J=7.7 Hz, 1H), 3.87 (and , J=7.l Hz, 1H), 2.35-2.12 (m, 2H), 2.20 (s, 1H), 1.73 (k, J=9.4 Hz, 2H).

Analytical chiral HPLC RT: 1.56 min (CHIRALPAK IG-3; 0.46 cm x 5 cm; 3 microns; MtBE (0.1% DEA):EtOH=60:40 at 1 ml/min).

Characteristics of stereoisomer 740D. LC-MS (ESI), m/z 472 (M+H), 'll NMR (300 MHz, DMSO-de) δ 8.47 (t, J=l.9 Hz, 1H), 8.25 (dt , J=9.4, 1.8 Hz, 1H), 7.72 (d, J=7.9 Hz, 2H), 7.49 (d, J=7.9 Hz, 2H), 5.09 -4.97 (m, 2H), 4.78 (d, J=17.l Hz, 1H), 4.49 (d, J=15.7 Hz, 1H), 4.35 (d, J= 17.l Hz, 1H), 4.24-4.12 (m, 2H), 2.95 (d, J=9.3 Hz, 1H), 2.28-2.17 (m, 2H), 1.94-1.80 (m, 2H).

Analytical chiral HPLC RT: 2.98 min (CHIRALPAK IG-3; 0.46 cm x 5 cm; 3 microns; MtBE (0.1% DEA):EtOH=60:40 at 1 ml/min).

Example 70 Synthesis of compound 750

1. Synthesis of intermediate 70-1

CI 70-1

EDCI (1 .8 g, 9.3 mmol, 2.0 eq.), HOBt (0.63 g, 4.6 mmol, 1.0 eq.) and TEA (1.3 ml, 9.3 mmol, 2.0 eq.). After stirring at room. pace, 5-chloro-3-fluoropyridin-2-amine (0.8 g, 5.6 mmol, 1.2 eq.) was added to this mixture over 5 min. The mixture was continued to stir overnight, concentrated to dryness, diluted with EA, washed with water and brine, dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified on silica gel using EA/HE as eluent to give 730 mg (46 %) tert-butyl-(8)-(2-((5-chloro-3-fluoropyridin-2yl)amino)-1-cyclopropyl-2-oxoethyl)carbamate (intermediate 70-1) as a white solid. HPMS (ES) m/z 344.1 (M+H).

2. Synthesis of intermediate 70-2

To a solution of tert-butyl-(8)-2-((5-chloro-3-fluoropyridin-2-yl)amino)-1-cyclopropyl-2oxoethyl)carbamate (560 mg, 1.6 mmol, 1.0 eq. .) in DCM (10.0 ml) at room. temp, TFA (2.0 ml) was added. The mixture was stirred at room. pace for 1 hour and concentrated to dryness to obtain 550 mg (98%) (8)-2-amino-K-(5-chloro-3-fluoropyridin-2-yl)-2-cyclopropylacetamide 2,2,2- trifluoroacetate (intermediate 70-2). HPMS (ES) m/z 244.0 (M+H).

3. Synthesis of intermediate 70-3

To a solution of (8)-2-amino-K-(5-chloro-3-fluoropyridin-2-yl)-2-cyclopropylacetamide 2,2,2trifluoroacetate (280 mg, 0.8 mmol, 1.0 eq.) in DXM (5.0 ml) at room. temp, 4(trifluoromethyl)benzaldehyde (177 mg, 1.0 mmol, 1.3 eq.) was added. After stirring at room. pace, STAB (497 mg, 2.3 mmol, 3.0 eq.) was added to this mixture over 5 min. The mixture was kept for 4 hours at room temperature, quenched by adding HC1 (1N) until Ph reached 1-2, stirred for 10 minutes, alkalinized pH 9-10 sat. sodium bicarbonate solution and extracted five times with DCM. The combined organic extracts were dried over MgSO ₄ , concentrated and purified on silica gel using a 20-100% EA/HE gradient as eluent to give 300 mg (95%) (S)-N-(5chloro-3-fluoropyridin-2-yl )-2-cyclopropyl-2-((4-(trifluoromethyl)benzyl)amino)acetamide (intermediate 70-3). HPMS (ES) m/z 402 (M+H).

- 339 045362

4. Synthesis of intermediate 70-4

70-3 70-4

To a solution of (8)-M-(5-chloro-3-fluoropyridin-2-yl)-2-cyclopropyl-2-((4-(trifluoromethyl)benzyl)amino)acetamide (300 mg, 0.7 mmol, 1 ,0 eq.) in DCM (10.0 ml), cooled to 0°C, added 2chloroacetyl chloride (PO mg, 1.0 mmol, 1.3 eq.) and TEA (0.2 ml, 1.5 mmol, 2.0 eq.). The mixture was stirred at 0°C for 30 minutes, quenched with sat. NH ₄ C1 solution and extracted twice with DCM. The combined organic extracts were dried over MgSO ₄ and concentrated to give 350 mg of (8)-2-chloro1M-(2-((5-chloro-3-fluoropyridin-2-yl)amino)-1-cyclopropyl-2-oxoethyl)- M-(4-(trifluoromethyl)benzyl)acetamide (intermediate 70-4). HPMS (ES) m/z 478 (M+H).

5. Synthesis of compound 750

Compound 750

To a solution of (8)-2-chloro-X-(2-((5-chloro-3-fluoropyridin-2-yl)amino)-1-cyclopropyl-2-oxoethyl)-M-(4(trifluoromethyl)benzyl) acetamide (350 mg, 0.7 mmol, 1.0 eq.) in DMF (5.0 ml) at room. temp, added K ₂ CO ₃ (204 mg, 1.5 mmol, 2.0 eq.). The mixture was stirred at 80°C for 1 hour, cooled, diluted with EA, filtered through celite, concentrated and purified by reverse phase HPLC (Phenomex, dimeric 5 μm C18 150x21.2 mm, gradient 10-100% acetonitrile in water, both with 0 .1% formic acid for 30 min) to give 34 mg (10% in two steps) (8)-1-(5-chloro-3-fluoropyridin-2-yl)3-cyclopropyl-4-(4-( trifluoromethyl)benzyl)piperazine-2,5-dione (compound 750). HPMS (ES) m/z 442 (M+H).

Y NMR (400 MHz, methylene chloride ₂ ) δ 8.22 (d, J=2.l Hz, 1H), 7.58-7.47 (m, ZH), 7.34 (d, J=8 .0 Hz, 2H), 5.18 (d, J=15.6 Hz, 1H), 4.59 (d, J=17.0 Hz, 1H), 4.45-4.29 (m, 2H ), 3.25 (d, J=8.7 Hz, 1H), 1.15-1.02 (m, 1H), 0.67-0.45 (m, ZN), 0.38-0, 27 (m, 1H).

The following compound was prepared using methods similar to the method described for compound 750:

Connection No. HPMS (ES) m/z ”75Ϊ Μ+Η=392.0

Example 71. Synthesis of diastereomer 875A.

1. Synthesis of the diastereomer of intermediate 71 -2A

To a solution of the diastereomer of intermediate 71-1A (800 mg, 1.4 mmol, 1.0 eq.) in DMF (3.0 ml) at room. temp, added K ₂ CO3 (397 mg, 2.9 mmol, 2.0 eq.). The mixture was stirred at 80°C for 30 min, cooled to room temperature, filtered and purified by reverse phase HPLC (Phenomepex, dimeric 5 μm C18 150x21.2 mm, gradient 40-100% acetonitrile in water with 0.1% formic acid for 25 min) to obtain 510 mg, 68% diastereomer tert-butyl-8-(5-chloro-3-fluoropyridin2-yl)-5-(4-(difluoromethyl)benzyl)-6,9-dioxo- 5,8-diazaspiro[3.5]nonane-2-carboxylate (diastereomer of intermediate 71-2A). HPMS (ES) m/z 468 (M+H-tBu). In this example, the dotted linkage indicates that the stereochemical configuration of the starting material is retained in the product compound.

-340045362

2. Synthesis of the diastereomer of intermediate 71-ZA

To a solution of the diastereomer of intermediate 71-2A (510 mg, 1.0 mmol, 1.0 eq.) in DCM (5.0 ml) at room. temp, TFA (1.0 ml) was added. The mixture was stirred at room. pace for 30 min and concentrated to give the corresponding acid as the diastereomer 8-(5-chloro-3fluoropyridin-2-yl)-5-(4-(difluoromethyl)benzyl)-6,9-dioxo-5,8- diazaspiro[3.5]nonane-2-carboxylic acid (a diastereomer of intermediate 71-3A), which was used in the next step without further purification.

3. Synthesis of the diastereomer of intermediate 71-4A

71-FOR

71-4A

To a solution of the diastereomer of intermediate 71-ZA (455 mg, 1.0 mmol, 1.0 eq.) in DCM (5.0 ml) at room. temp, oxalyl chloride (1.0 ml) and one drop of DMF were added. The mixture was stirred at room. pace for 30 min and concentrated to give the diastereomer 8-(5-chloro-3fluoropyridin-2-yl)-5-(4-(difluoromethyl)benzyl)-6,9-dioxo-5,8-diazaspiro[3.5] nonane-2-carbonyl chloride (a diastereomer of intermediate 71-4A), which was used in the next step without further purification.

4. Synthesis of diastereomer 875A

To a solution of the diastereomer of intermediate 71-4A (472 mg, 1.0 mmol, 1.0 eq.) in DCM (10.0 ml) at room. temp, ammonium hydroxide (1.0 ml, 30 wt.%) was added. The mixture was stirred at room. rate, over 30 min, concentrated and purified by reverse phase HPLC (Phenomenex, dimeric 5 µm C18 150x21.2 mm, gradient 10-100% acetonitrile in water with 0.1% formic acid over 25 min) to obtain 121 mg (27% in three steps) of the diastereomer 8-(5-chloro-3-fluoropyridin-2-yl)5-(4-(difluoromethyl)benzyl)-6,9-dioxo-5,8-diazaspiro[3.5]nonan- 2-carboxamide (diastereomer 875A). HPMS (ES) m/z 467 (M+H).

'H NMR (400 MHz, methylene chloride-ph) δ 8.36 (s, 1H), 7.71-7.63 (d, J=8.0 Hz, 1H), 7.53 (d, J=7 ,9 Hz, 2H), 7.39 (d, J=7.9 Hz, 2H), 6.70 (t, J=56.4 Hz, 1H), 5.58 (s, 1H), 5, 51 (s, 1H), 5.13 (s, 2H), 4.55 (s, 2H), 3.04 (u, J=8.5 Hz, 1H), 2.90-2.76 (m , 4H), 2.01 (s, ZN).

The following compounds were prepared by methods similar to those described for diastereomer 875A:

-341 045362

Diastereome r No. HPMS (ES) m/z H NMR 870A M+H=499 (400 MHz, methylene chloride-02) δ 8.36 (d, J = 2.0 Hz, 1H), 7.71 - 7.59 (m, ZH), 7.45 (d, J = 8.0 Hz , 2H), 5.47 (br, 1H), 5.20 (s, 2H), 4.55 (s, 2H), 3.05 - 2.69 (m, 8H). 871A M+N-513 (400 MHz, methylene chloride-s/2) b 8.37 (d, J = 2.0 Hz, 1H), 7.71 - 7.61 (m, ZN), 7.43 (d, J = 8, 0 Hz, 2H), 5.10 (s, 2H), 4.56 (s, 2H), 3.41 - 3.27 (m, 1H), 2.92 (d, J = 5.6 Hz, 6H), 2.84 (d, J - 8.9 Hz, 4H). 872A M+H=451 (400 MHz, methylene chloride-02) δ 8.36 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 9.0, 2.0 Hz, 1H), 7.36 (d , J = 8.3 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 5.43 (s, 1H), 5.32 (s, 1H), 5.05 (s , 2H), 4.54 (s, 2H), 3.03 (p, J = 8.5 Hz, 1H), 2.83 (t, J = 7.3 Hz, 4H). 873A M+H=465 (400 MHz, methylene chloride-s/ ₂ ) δ 8.23 (s, 1H), 7.57 7.50 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.2 Hz, 2H), 5.43 (s, 1H), 4.96 (s, 2H), 4.40 (s, 2H), 2, 84 - 2.68 (m, ZN), 2.71 - 2.59 (m, 5N). 874A M+H=479 (400 MHz, methylene chloride-cy δ 8.23 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.9, 2.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 4.86 (s, 2H), 4.40 (s, 2H), 3.19 (p, 8.7 Hz, 1H), 2.81 (s, ZN), 2.78 (d, J= 0.9 Hz, ZN), 2.70 (d, J = 8.8 Hz, 4H). 876A M+H=435.0 (400 MHz, methylene chloride-cfe) δ 8.23 (s, 1H), 7.53 (d, J = 8.9 Hz, 1H), 7.21 - 7.13 (m, 2H), 6.94 (t, J = 8.5 Hz, 2H), 5.30 (s, 1H), 5.19 (s, 1H), 4.91 (s, 2H), 4.40 (s, 2H), 2 .97 - 2.84 (m, 1H), 2.79 - 2.63 (m, 4H).

Example 72. Synthesis of diastereomer 875B.

1. Synthesis of the diastereomer of intermediate 71-2B

To a solution of diastereomer 71-2B intermediate (1000 mg, 1.8 mmol, 1.0 eq.) in DMF (3.0 ml) at room. temp, added K ₂ CO3 (497 mg, 3.6 mmol, 2.0 eq.). The mixture was stirred at 80°C for 30 min, cooled to room temperature, filtered and purified by reverse phase HPLC (Phenomenex, dimer 5 µm C18 150x21.2 mm, gradient 40-100% acetonitrile in water with 0.1% formic acid for 25 min) to obtain 680 mg, 72% diastereomer tert-butyl-8-(5-chloro3-fluoropyridin-2-yl)-5-(4-(difluoromethyl)benzyl)-6,9-dioxo- 5,8-diazaspiro[3.5]nonane-2-carboxylate (diastereomer of intermediate 71-2B). HPMS (ES) m/z 524 (M+H). In this example, the dotted linkage indicates that the stereochemical configuration of the starting material is retained in the product compound.

2. Synthesis of the diastereomer of intermediate 71-ZV

To a solution of the diastereomer of intermediate 71-2B (680 mg, 1.3 mmol, 1.0 eq.) in DCM

-342045362 (5.0 ml) at room. temp, TFA (1.0 ml) was added. The mixture was stirred at room. pace for 30 min and concentrated to give the corresponding acid as the diastereomer 8-(5-chloro-3fluoropyridin-2-yl)-5-(4-(difluoromethyl)benzyl)-6,9-dioxo-5,8- diazaspiro[3.5]nonane-2-carboxylic acid (a diastereomer of intermediate 71-ZV), which was used in the next step without further purification.

3. Synthesis of the diastereomer of intermediate 71-4B

To a solution of the diastereomer of intermediate 71-ZV (606 mg, 1.0 mmol, 1.0 eq.) in DCM (5.0 ml) at room. temp, oxalyl chloride (1.0 ml) and one drop of DMF were added. The mixture was stirred at room. temp., for 30 min and concentrated to give the corresponding acid chloride as the diastereomer 8-(5-chloro-3-fluoropyridin-2-yl)-5-(4-(difluoromethyl)benzyl)-6,9-dioxo5,8 -diazaspiro[3.5]nonane-2-carbonyl chloride (diastereomer of intermediate 71-4B), which was used in the next step without further purification.

4. Synthesis of diastereomer 875B

Diastereomer 875B

To a solution of the diastereomer of intermediate 71-4B (626 mg, 1.0 mmol, 1.0 eq.) in DCM (10.0 ml) at room. temp, ammonium hydroxide (1.5 ml, 30 wt.%) was added. The mixture was stirred at room. pace, over 30 min, concentrated and purified by reverse phase HPLC (Phenomenex, dimeric 5 µm C18 150x21.2 mm, gradient 10-100% acetonitrile in water with 0.1% formic acid over 25 min) to obtain 340 mg (57% in three steps) of the diastereomer 8-(5-chloro-3-fluoropyridin-2-yl)5-(4-(difluoromethyl)benzyl)-6,9-dioxo-5,8-diazaspiro[3.5]nonan- 2-carboxamide (diastereomer 875B). HPMS (ES) m/z 467 (M+H).

'll NMR (400 MHz, methylene chloride-c^) δ 8.36 (d, J=l.8 Hz, 1H), 7.67 (dd, J=9.0, 2.1 Hz, 1H), 7 .56 (d, J=7.9 Hz, 2H), 7.41 (d, J=7.9 Hz, 2H), 6.71 (t, J=56.4 Hz, 1H), 6.32 (s, 1H), 5.52 (s, 1H), 5.03 (s, 2H), 4.56 (s, 2H), 3.22-3.11 (m, 2H), 3.10- 2.96 (m, 1H), 2.82-2.71 (m, 2H).

The following compounds were prepared by methods similar to those described for diastereomer 875B:

- 343 045362

Diastereomer No. HPMS (ES) m/z Ή NMR 870V M+H=499 (400 MHz, methylene chloride-cy δ 8.36 (d, J = 2.0 Hz, 1H), 7.71 - 7.63 (m, ZN), 7.43 (d, J = 8.0 Hz, 2H), 6.25 (s, 1H), 5.04 (s, 2H), 4.55 (s, 2H), 3.21 - 3.11 (m, 2H), 3.09-2.96 (m, 1H), 2.79-2.65 (m, 5H). 871B M+H=513 (400 MHz, methylene chloride-s/ ₂ ) b 8.34 (d, J = 2.0 Hz, 1H), 7.72-7.61 (m, ZH), 7.46 (d, >8.0 Hz, 2H), 5.08 (s, 2H), 4.55 (s, 2H), 3.28 (dd, J = 13.8, 8.0 Hz, 2H), 3.00 (p, J = 8.9 Hz, 1H), 2.83 (lat, 6H), 2.65 - 2.54 (m, 2H). 872 V M+H=451 (400 MHz, methylene chloride-L) b 8.23 (d, J = 2.0 Hz, 1H), 7.54 (dt, J = 9.0, 1.6 Hz, 1H), 7.26 (d , J = 8.1 Hz, 2H), 7.14 (d, J = 8.2 Hz, 2H), 6.17 (s, 1H), 5.23 (s, 1H), 4.82 (s , 2H), 4.41 (d, > 1.1 Hz, 2H), 3.08 - 2.98 (m, 2H), 2.95-2.82 (m, 1H), 2.70-2 .59 (m, 2H). 873B M+H=465 (400 MHz, methylene chloride-C ₂ ) δ 8.35 (d, J = 1.9 Hz, 1H), 7.67 (dd, J = 9.0, 2.0 Hz, 1H), 7.38 ( d, J= 8.1 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 6.20 (s, 1H), 4.95 (s, 2H), 4.53 ( s, 2H), 3.18 - 3.08 (m, 2H), 3.04 - 2.90 (m, 1H), 2.79-2.66 (m, 5H). 874B M+HM79 (400 MHz, methylene chloride-c/ ₂ ) δ 8.20 (d, J = 2.0 Hz, 1H), 7.51 (dd, J~ 8.9, 2.1 Hz, 1H), 7.26 (d, J~ 8.4 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H), 4.85 (s, 2H), 4.40 (s, 2H), 3.18 - 3.07 (m, 2H), 2.90 - 2.76 (m, 1H), 2.76 (s, ZN), 2.64 (s, ZN), 2.53-2.42 (m , 2H). 876B M+H=435.0 (400 MHz, methylene chloride-U) δ 8.35 (d, J = 1.8 Hz, 1H), 7.66 (dd, J = 8.8, 2.2 Hz, 1H), 7.31 (dd , J = 8.2, 5.3 Hz, 2H), 7.10 (t, J = 8.5 Hz, 2H), 6.33 (s, 1H), 5.56 (s, 1H), 5 .36 (s, OH), 4.95 (s, 2H), 4.54 (s, 2H), 3.20 - 3.10 (m, 2H), 3.07 - 2.93 (m, 1H ), 2.83 - 2.72 (m, 2H). 877B M+H=485 (400 MHz, methylene chloride-02) δ 8.36 (d, J = 2.0 Hz, 1H), 7.71 - 7.63 (m, ZH), 7.44 (d, J = 8.0 Hz , 2H), 6.30 (s, 1H). 5.44 (s, 1H), 5.04 (s, 2H), 4.56 (s, 2H), 3.23 3.13 (m, 2H), 3.05 (cd, J = 10.3 , 6.8 Hz, 1H), 2.81 - 2.70 (m, 2H).

Example 73. Synthesis of compound 784.

1. Synthesis of intermediate 73-1

C.I.

73-1

Methyl-3-formylbicyclo[1.1.1]pentane was added to a solution of (4-(trifluoromethyl)phenyl)methanamine (568 mg, 3.2 mmol, 1.0 eq.) in 2,2,2trifluoroethanol (5.0 mL). -1-carboxylate (500 mg, 3.2 mmol, 1.0 eq.). After stirring at room. pace, over 10 min, 5-chloro-3-fluoro-2-isocyanopyridine (511 mg, 3.2 mmol, 1.0 eq.) and chloroacetic acid (337 mg, 3.6 mmol, 1.1 eq.). The resulting mixture was stirred at room. temp., overnight, concentrated under reduced pressure and purified by silica gel chromatography, eluting with EA/HE to give 1.8 g (99%) methyl-3-(2-((5-chloro-3-fluoropyridin-2-yl )amino)-1-(2-chloro-H-(4(trifluoromethyl)benzyl)acetamido)-2-oxoethyl)bicyclo[1,1,1]pentane-1-carboxylate (intermediate 73-1) as foam . HPMS (ES) m/z 562 (M+H).

-344 045362

2. Synthesis of intermediate 73-2

73-1 73-2

To a solution of methyl-3 -(2-((5-chloro-3-fluoropyridin-2-yl)amino)-1 -(2-xnop-N-(4(trifluoromethyl)benzyl)acetamido)-2-oxoethyl)bicyclo [1.1.1]pentane-1-carboxylate (1.8 g, 3.2 mmol, 1.0 eq.) in DMF (5.0 ml) at room. temp, added K ₂ CO ₃ (0.9 g, 6.4 mmol, 2.0 eq.). The mixture was stirred at 80°C for 30 min, diluted with EA (20 ml), filtered and concentrated. The residue was triturated with ACN to obtain 1.2 g (71%) methyl 3-(4-(5-chloro-3-fluoropyridin-2-yl)-3,6-dioxo-1-(4(trifluoromethyl)benzyl) piperazin-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (intermediate 73-2). HPMS (ES) m/z 526.1 (M+H).

'H NMR (400 MHz, methylene chloride-<1 ₂ ) δ 8.31 (d, J=2.0 Hz, 1H), 7.68-7.57 (m, ZH), 7.43 (d, J =8.0 Hz, 2H), 5.45 (d, J=15.3 Hz, 1H), 4.50 (s, 2H), 4.04 (s, 1H), 4.01 (d, J =15.3 Hz, 1H), 3.66 (s, ZN), 2.16 (s, 6H).

3. Synthesis of intermediate 73-3

To a solution of methyl 3-(4-(5-chloro-3-fluoropyridin-2-yl)-3,6-dioxo-1-(4(trifluoromethyl)benzyl)piperazin-2-yl)bicyclo[1.1.1] pentane-1-carboxylate (1.2 g, 2.3 mmol, 1.0 eq.) in dioxane (2.0 ml) at room. temp, LiOH (2.3 mL, 2N, 4.6 mmol, 2.0 eq.) was added. The mixture was stirred at room. pace, for 30 minutes, acidified to pH 1-3 and extracted three times with EA. The combined extracts were washed with brine, dried over MgSO ₄ and concentrated to give 1.16 g (99%) 3-(4-(5-chloro-3-fluoropyridin-2-yl)-3,6-dioxo-1-( 4-(trifluoromethyl)benzyl)piperazin-2yl)bicyclo[1.1.1]pentane-1-carboxylic acid (intermediate 73-3). HPMS (ES) m/z 512 (M+H).

'H NMR (400 MHz, chloroform-d) δ 8.23 (d, J=2.l Hz, 1H), 7.59-7.48 (m, ZH), 7.31 (d, J=8 .0 Hz, 2H), 5.43 (d, J=15.2 Hz, 1H), 4.44 (s, 2H), 3.97 (s, 1H), 3.89 (d, J=15 .2 Hz, 1H), 2.14 (s, 6H).

4. Synthesis of intermediate 73-4

To a solution of 3-(4-(5-chloro-3-fluoropyridin-2-yl)-3,6-dioxo-1-(4-(trifluoromethyl)benzyl)piperazin-2yl)bicyclo[1.1,1]pentane-1 -carboxylic acid (80 mg, 0.16 mmol, 1.0 eq.) in DCM (6.0 ml) at room temperature, oxalyl chloride (0.5 ml) and one drop of DMF were added. The mixture was stirred at room. pace for 30 min and concentrated to give 3-(4-(5-chloro-3-fluoropyridin-2-yl)-3,6-dioxo-1-(4(trifluoromethyl)benzyl)piperazin-2-yl) bicyclo[1.1.1]pentane-1-carbonyl chloride (intermediate 73-4), which was used in the next step without further purification.

- 345 045362

5. Synthesis of compound 784

73-4 Compound 784

To a solution of 3-(4-(5-chloro-3-fluoropyridin-2-yl)-3,6-dioxo-1-(4-(trifluoromethyl)benzyl)piperazin-2yl)bicyclo[1.1,1]pentane-1 -carbonyl chloride (0.16 mmol, 1.0 eq.) in THF (6.0 ml) was cooled to 0°C and sodium borohydride (12 mg, 0.31 mmol, 2.0 eq.) was added. The mixture was stirred at 0°C for 30 min, acidified to pH 1-3 with HCl (1N) and extracted three times with EA. The combined extracts were washed with saline, dried over MgSO ₄ , concentrated and purified by reverse phase HPLC (Phenomenex, dimeric 5 µm C18 150x21.2 mm, gradient 10-100% acetonitrile in water both with 0.1% formic acid for 25 min ) to give 14 mg (18% in two steps) 1-(5-chloro-3-fluoropyridin-2yl)-3-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-4-( 4-(trifluoromethyl)benzyl)piperazine-2,5-dione (compound 784). HPMS (ES) m/z 498.1 (M+H).

'H NMR (400 MHz, chloroform-d) δ 8.22 (d, J=2.l Hz, 1H), 7.58-7.46 (m, ZH), 7.31 (d, J=8 ,0 Hz, 2H), 5.45 (d, J=15.2 Hz, 1H), 4.42 (k, J=15.l Hz, 2H), 3.95 (s, 1H), 3, 89 (d, J=15.l Hz, 1H), 3.57 (d, J=4.l Hz, 2H), 1.78 (s, 6H).

Example 74. Synthesis of compound 866.

1. Synthesis of intermediate 74-1

74-1

A mixture of Ac ₂ O (14 g, 137 mmol, 4.0 eq.) and formic acid (154 g, 154 mmol, 4.5 eq.) was stirred at 55 ° C for 2 hours. To this mixture, cooled to 0 °C, 4-chloro-2fluoroaniline (5 g, 34.4 mmol, 1.0 eq.) was added dropwise. The mixture was stirred at room. pace, for 2 hours, concentrated under reduced pressure and triturated with Et ₂ O to obtain 5.3 g (84%) N-(4-χπορ-2fluorophenyl)formamide (intermediate 74-1) as a white solid. HPMS (ES) m/z 174 (M+H).

'll NMR (NMR (300 MHz, DMSOM ₆ ) δ 10.23 (s, 1H), 8.31 (s, 1H), 8.13 (t, J=8.7 Hz, 1H), 7.56 -7.36 (m, 1H), 7.25 (ddd, J=8.8, 2.4,1.3 Hz, 1H).

2. Synthesis of intermediate 74-2

N F ₊ I >| Triphosgene T \>- _C l TEA, DCM, 0 °C

74-1 74-2

To a stirred solution of M-(4-chloro-2-fluorophenyl)formamide (5.1 g, 29.4 mmol, 1.0 eq.) and TEA (9.0 g, 87.9 mmol, 6 eq.) in With DCM (100 mL) cooled to 0°C, triphosgene (3.8 g, 12.6 mmol, 0.43 eq.) in DCM (20 mL) was added dropwise over a period of 10 min. The mixture was stirred at room temp overnight, cooled to 0°C, quenched with MeOH, concentrated under reduced pressure and purified on silica gel using PE/EA (10/1) as eluent to give 13 g (27% purity) 4chloro-2-fluoro-Hisocyanobenzene (intermediate 74-2) as a yellow solid. HPMS (ES) m/z 156 (M+H).

3. Synthesis of intermediate 74-3

ABOUT

74-3

BH ₃ -THF ( 1 M in THF, 157.6 ml, 157.6 mmol, 5.0 eq.) dropwise over a period of 1 hour. The mixture was stirred at room temperature. temp, overnight, cooled to 0°C, quenched with MeOH and concentrated under reduced pressure to give 6.9 g (3

- 346 045362 (benzyloxy)cyclobutyl)methanol (intermediate 74-3) as a yellow solid.

HPMS (ES) m/z 193 (M+H).

4. Synthesis of intermediate 74-4

74-3 74-4

To a solution of PCC (11.4 g, 53.1 mmol, 1.5 eq) in DCM (70 mL) was added celite (13 g, 216.3 mmol, 6.1 eq). After stirring at room. temp., (3(benzyloxy)cyclobutyl)methanol (6.8 g, 35.3 mmol, 1.0 eq.) was added to this mixture over 30 min. The mixture was stirred at room. pace, over 2 hours, diluted with Et ₂ O (140 ml), filtered the solid and concentrated under reduced pressure to obtain 6 g of 3-(benzyloxy)cyclobutane-1-carbaldehyde (intermediate 74-4) as a yellow solid . HPMS (ES) m/z 191 (M+H).

5. Synthesis of intermediate 74-5

74-5

3-(Benzyloxy)cyclobutane-1-carbaldehyde (673 mg, 3 .5 mmol, 1.0 eq.) After stirring at room. pace, 4-chloro-2-fluoro-1isocyanobenzene (1.85 g, 27% pure, 3.2 mmol, 1.0 eq.) and chloroacetic acid (331 mg, 3.0 eq.) were added to this resulting mixture over 10 min. 5 mmol, 1.0 eq.). The resulting mixture was stirred at room. pace, overnight, concentrated under reduced pressure and purified by silica gel chromatography, eluting with EA/PE (1/6) to give 1.1 g of 2(3-(benzyloxy)cyclobutyl)-X-(4-chloro-2- fluorophenyl)-2-(2-chloro-X-(4-fluorobenzyl)acetamido)acetamide (intermediate 74-5) as a yellow oil. HPMS (ES) m/z 562 (M+H).

6. Synthesis of intermediate 74-6

74-5 74-6

To a solution of 2-(3-(benzyloxy)cyclobutyl)-X-(4-chloro-2-fluorophenyl)-2-(2-chloro-X-(4fluorobenzyl)acetamido)acetamide (1.1 g, 2.0 mmol , 1.0 eq.) in DMF (15.0 ml) at room. temp, added K ₂ CO ₃ (555 mg, 4.0 mmol, 2.0 eq.). The mixture was stirred at room. pace, within 30 min, was diluted with water (30 ml) and extracted twice with EA (30 ml). The combined organic layers were washed twice with brine (30 ml), dried over Na ₂ SO4 and concentrated under reduced pressure to give 1 g of 3-(3-(benzyloxy)cyclobutyl)-1-(4-chloro-2-fluorophenyl)-4 -(4-fluorobenzyl)piperazine-2,5dione (intermediate 74-6). HPMS (ES) m/z 511 (M+H).

7. Synthesis of compound 866

Solution of 3-(3-(benzyloxy)cyclobutyl)-1-(4-chloro-2-fluorophenyl)-4-(4-fluorobenzyl)piperazine-2,5dione (700 mg, 1.4 mmol, 1.0 eq. ) in HC1 (6N, 15 ml) was stirred at 100°C overnight, cooled

- 347 045362 to room temperature, concentrated under reduced pressure, diluted with water, adjusted pH to 9 with sodium bicarbonate and extracted twice with EA (20 ml). The combined organic layer was washed with brine (20 ml), dried over Na ₂ SO _4; concentrated under reduced pressure and purified by preparative HPLC under the following conditions: (SHIMADZU (HPLC-01)): Column, XBridge Prep C18 OBD column, 5 µm, 19x150 mm; mobile phase, water (10 mM NH ₄ HCO ₃ ) and ACN (25% gradient to 50% over 8 min); detector UV 254 nm) to obtain 230 mg of 1-(4-chloro-2-fluorophenyl)-4-(4-fluorobenzyl)-3(3-hydroxycyclobutyl)piperazine-2,5-dione (compound 866). HPMS (ES) m/z 421 (M+H).

8. Separation of stereoisomers of compound 866.

Stereoisomers 866A, 866B, 866C and 866D

Stereoisomers of 1-(4-chloro-2-fluorophenyl)-4-(4-fluorobenzyl)-3-(3-hydroxycyclobutyl)piperazine-2,5dione (230 mg, 0.55 mmol, 1.0 eq.) were purified by chiral preparative HPLC under the following conditions: Column, CHIRALPAK IF, 2 x 25 cm, 5 µm; mobile phase, MTBE (10 mM NH ₃ /MeOH) and EtOH (hold 5% EtOH for 13 min); detector, UV 254 nm/220 nm) to obtain 86 mg of stereoisomer 866A, 23 mg of stereoisomer 866D and 100 mg of a mixture of stereoisomer 866B and stereoisomer 866C, which was further purified by chiral HPLC under the following conditions; column CHIRALPAK IG 20x25 cm, 5 µm; mobile phase, MTBE (10 mM NH ₃ /MeOH) and EtOH (holding 30% EtOH for 10 min); detector, UV 254 nm/220 nm) to obtain 68 mg of stereoisomer 866B and 18 mg of stereoisomer 866C as white solids.

Characteristics of stereoisomer 866A. LC-MS (ESI), m/z 421 (M+H).

'H NMR (300 MHz, DMSO-de) δ 7.65-7.50 (m, 2H), 7.44-7.32 (m, ZN), 7.22 (t, J=8.8 Hz , 2H), 5.13-4.98 (m, 2H), 4.72 (d, J=17.0 Hz, 1H), 4.21 (d, J=15.2 Hz, 1H), 4 .09 (d, J=17.0 Hz, 1H), 3.89 (d, J=7.l Hz, 2H), 2.23 (s, ZN), 1.75 (s, 2H).

Analytical chiral HPLC RT: 0.90 min (CHIRALPAK IG-3; 0.46 cm x 5 cm; 3 micron; MtBE(0.l% DEA):EtOH=70:30 at 1 ml/min).

Characterization of stereoisomer 866B, LC-MS (ESI), m/z 421 (M+H).

'H NMR (300 MHz, DMSO-de) δ 7.66-7.50 (m, 2H), 7.44-7.32 (m, ZN), 7.22 (t, J=8.8 Hz , 2H), 5.09 (d, J=6.5 Hz, 1H), 5.03 (d, J=15.2 Hz, 1H), 4.73 (d, J=17.l Hz, 1H ), 4.21 (d, J=15.l Hz, 1H), 4.09 (d, J=17.l Hz, 1H), 3.89 (d, J=7.0 Hz, 2H), 2.27-2.17 (m, ZN), 1.74 (s, 2H).

Analytical chiral HPLC RT: 1.5 min (CHIRALPAK IG-3; 0.46 cm x 5 cm; 3 micron; MtBE(0.l% DEA):EtOH=70:30 at 1 ml/min).

Characteristics of stereoisomer 866C. LC-MS (ESI), m/z 421 (M+H).

'H NMR (300 MHz, DMSO-de) δ 7.65-7.49 (m, 2H), 7.44-7.29 (m, ZN), 7.27-7.13 (m, 2H) , 5.06-4.94 (m, 2H), 4.77 (d, J=17.l Hz, 1H), 4.32 (d, J=15.2 Hz, 1H), 4.19 ( s, 1H), 4.08 (d, J=17.l Hz, 1H), 4.00 (d, J=8.9 Hz, 1H), 2.94 (dk, J=9.2.4 ,7, 2.8 Hz, 1H), 2.23 (cd, J=8.0, 6.6, 4.7 Hz, 2H), 1.88 (td, J=8.8, 4.5 Hz, 2H).

Analytical chiral HPLC RT: 0.89 min (CHIRALPAK IG-3; 0.46 cm x 5 cm; 3 micron; MtBE(0.l% DEA):EtOH=70:30 at 1 ml/min).

Characteristics of stereoisomer 866D. LC-MS (ESI), m/z 421 (M+H).

'H NMR (300 MHz, DMSO-de) δ 7.65-7.50 (m, 2H), 7.44-7.29 (m, ZN), 7.27-7.14 (m, 2H) , 5.07-4.94 (m, 2H), 4.77 (d, J=17.l Hz, 1H), 4.32 (d, J=15.2 Hz, 1H), 4.18 ( d, J=4.8 Hz, 1H), 4.08 (d, J=17.l Hz, 1H), 4.00 (d, J=8.9 Hz, 1H), 2.95 (k, J=7.2 Hz, 1H), 2.23 (cd, J=8.2, 6.6, 4.5 Hz, 2H), 1.87 (ddd, J=13.0, 8.9, 4.2 Hz, 2H).

Analytical chiral HPLC RT: 1.86 min (CHIRALPAK IG-3; 0.46 cm x 5 cm; 3 micron; MtBE(0.l% DEA):EtOH=70:30 at 1 ml/min).

The following compounds were prepared by methods similar to those described for stereoisomers 866A, 866B, 866C and 866D:

- 348 045362

Number HPLC CONDITIONS Q CHIRALPAK IE-3; 0.46 cm x 5 cm; 3 microns; MtBE(0.1%DEA):EtOH=50:50 at 1 ml/min V CHIRALPAK IG-3; 0.46 cm x 5 cm; 3 microns; MtBE(0.1%DEA):EtOH=70:30 at 1 ml/min W CHIRALPAK Yu-3; 0.46 cm x 5 cm; 3 microns; M1BE (0.1% CEA): EYNA0:40 at 1 ml/min Connection No. HPMS (ES) m/z ^1H NMR 889A M+H=530.0 (400 MHz, methylene chloride-s/ ₂ ) δ 8.44 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 7.6 Hz, 2H ), 7.46 (d, J = 7.9 Hz, 2H), 5.37 (d, J = 15.5 Hz, 1H), 4.74 - 4.39 (m, 2H), 4.21 (d, J = 15.5 Hz, 1H), 3.94 (dd, J = 7.7, 1.6 Hz, 1H), 3.74 (p, J = 7.2 Hz, 1H), 3 .24 - 3.19 (m, ZN), 2.56-2.23 (m, ZN), 1.91 (k, 7 = 10.2 Hz, 2H). 889B M+H=530.0 (400 MHz, methylene chloride-c/ ₂ ) δ 8.44 (d, J - 2.0 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.45 (d, J= 7.9 Hz, 2H), 5.36 (d, J= 15.6 Hz, 1H), 4.694.45 (m, 2H), 4.25 (d, J = 15.7 Hz, 1H), 3.99 - 3.89 (m, 2H), 3.23 (s, ZN), 3.05 (g, J = 8.4 Hz , 1H), 2.38 - 2.09 (m, 4H). 890A M+H=436.1 (400 MHz, methylene chloride-c/ ₂ ) δ 8.34 (d, J = 2.1 Hz, 1H), 7.63 (dd, J = 8.9, 2.1 Hz, 1H), 7.36 -7.25 (m, 2H), 7.16 - 7.05 (m, 2H), 5.28 (d, J = 15.2 Hz, 1H), 4.69 4.42 (m, 2H) , 4.13 (d, J = 15.2 Hz, 1H), 3.97 - 3.84 (m, 2H), 3.23 (s, ZN), 3.11 - 2.95 (m, 1H ), 2.36 - 2.23 (m, 2H), 2.23-2.07 (m, 2H). 890V M+H=436.0 (400 MHz, methylene chloride-s/ ₂ ) δ 8.33 (d, J = 2.1 Hz, 1H), 7.63 (dd, J = 8.9, 2.1 Hz, 1H), 7.36 -7.27 (m, 2H), 7.10 (t, J = 8.7 Hz, 2H), 5.28 (d, J = 15.1 Hz, 1H), 4.65 4.43 (m , 2H), 4.12 (d, J = 15.1 Hz, 1H), 3.93 (d, J = 7.7 Hz, 1H), 3.73 (tt, A 7.9, 6.4 Hz, 1H), 3.21 (s, ZN), 2.51 -2.33 (m, 2H), 2.36-2.23 (m, 1H), 1.96-1.82 (m, 2H). 891A M+H=468.1 (400 MHz, methylene chloride-c/ ₂ ) δ 8.34 (d, J = 2.1 Hz, 1H), 7.64 (dd, J = 8.9, 2.1 Hz, 1H), 7.56 (d, J = 7.9 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 6.71 (t, J = 56.4 Hz, 1H), 5.36 (d , J = 15.5 Hz, 1H), 4.66-4.46 (m, 2H), 4.22 (d, J = 15.4 Hz, 1H), 3.98 - 3.85 (m, 2H), 3.23 (s, ZN), 3.12 2.92 (m, 1H), 2.54-2.07 (m, 4H), 891B M+N-468.1 (400 MHz, methylene chloride-c/ ₂ ) δ 8.34 (d, J = 2.1 Hz, 1H), 7.64 (dd, J = 8.9, 2.1 Hz, 1H), 7.56 (d, J = 7.9 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 6.71 (t, J = 56.4 Hz, 1H),

- 349 045362

5.36 (d, J = 15.5 Hz, 1H), 4.66-4.46 (m, 2H), 4.22 (d, J = 15.4 Hz, 1H), 3.98 - 3 .85 (m, 2H), 3.23 (s, ZN), 3.12 2.92 (m, 1H), 2.54-2.07 (m, 4H). 740A M+N-472 (300 MHz, DMSO-s/ ₆ ) δ 8.47 (d, J = 2.1 Hz, 1H), 8.24 (dd, J = 9.4, 2.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 5.12-5.00 (m, 2H), 4.74 (d, 17, 0 Hz, 1H), 4.36 (dd, J = 16.3, 9.8 Hz, 2H), 4.04 (d, J = 7.7 Hz, 1H), 3.86 (k, J = 6.6 Hz, 1H), 2.43 - 2.12 (m, ZN), 1.73 (k, J = 9.4 Hz, 2H). 740V M+H=472 (300 MHz, DMSO-06) b 8.47 (d, J = 2.1 Hz, 1H), 8.25 (dd, J = 9.4, 2.2 Hz, 1H), 7.72 (d , J = 8.0 Hz, 2H), 7.49 (d, J - 8.0 Hz, 2H), 5.09-4.97 (m, 2H), 4.78 (d, J = 17, 1 Hz, 1H), 4.49 (d, J - 15.7 Hz, 1H), 4.35 (d, J - 17.1 Hz, 1H), 4.18 (t, J = 8.7 Hz , 2H), 2.97-2.94 (t 1H), 2.262.28 (m, 2H), 1.87 (td, J = 8.8, 4.4 Hz, 2H). 740C M+H=472 (300 MHz, DMSSMz) δ 8.47 (d, J = 2.1 Hz, 1H), 8.24 (dd, J = 9.4, 2.1 Hz, 1H), 7.73 (d, 7 = 8.1 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 5.11 -5.00 (m, 2H), 4.74 (d, J = 16.9 Hz , 1H), 4.36 (dd, J = 16.3, 10.0 Hz, 2H), 4.04 (d, Ϋ 7.7 Hz, 1H), 3.87 (p, J = 7.1 Hz, 1H), 2.37 - 2.04 (m, ZN), 1.73 (k, Y 9.4 Hz, 2H). 740D M+H=472 (300 MHz, DMSO-cfc) δ 8.47 (t, J = 1.9 Hz, 1H), 8.25 (dt, J = 9.4, 1.8 Hz, 1H), 7.72 (d , J = 7.9 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H), 5.09-4.97 (m, 2H), 4.78 (d, J = 17, 1 Hz, 1H), 4.49 (d, J = 15.7 Hz, 1H), 4.35 (d, J = 17.1 Hz, 1H), 4.24-4.12 (m, 2H) , 2.95 (d, J= 9.3 Hz, 1H), 2.282.17 (m, 2H), 1.94-1.80 (m, 2H). 892A M+N-422 (300 MHz, methanol-ph) δ 8.39 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 9.1, 2.2 Hz, 1H), 7.42 - 7 .30 (m, 2H), 7.17 7.04 (m, 2H), 5.20 (d, J = 15.2 Hz, 1H). 4.73 (d, J = 17.2 Hz, 1H), 4.46 (d, J = 17.2 Hz, 1H), 4.25 (d, J = 15.1 Hz, 1H), 4, 01 (dd, J = 26.0, 6.9 Hz, 2H), 2.50 - 2.26 (m, J = 6.5 Hz, ZN), 1.87 (t, J = 7.2 Hz , 2H).

- 350 045362

892 V M+H=422 (300 MHz, methanol-^) δ 8.40 (d, J = 2.1 Hz, 1H), 7.94 (dd, J = 9.2, 2.1 Hz, 1H), 7.42 - 7 .31 (m, 2H), 7.18 7.04 (m, 2H), 5.16 (d, 4 = 15.3 Hz, 1H), 4.73 (d, J = 17.3 Hz, 1H ), 4.49 (d, J = 17.3 Hz, 1H), 4.39 - 4.24 (m, 2H), 4.03 (d, 4 = 8.7 Hz, 1H), 3.19 -3.00 (m, 1H), 2.38 (dtt, 4 = 13.3, 6.6, 3.1 Hz, 2H), 2.15-1.96 (m, 2H). 892С M+H=422 (300 MHz, methanol-^) b 8.39 (d, 4= 2.1 Hz, 1H), 7.94 (dd, 4= 9.1, 2.1 Hz, 1H), 7.37 (dd , 4 = 8.7, 5.3 Hz, 2H), 7.12 (t. 4 = 8.8 Hz, 1H), 5.20 (d, J = 15.2 Hz, 1H), 4.74 (d, J = 17.2 Hz, 1H), 4.47 (d, 4 = 17.2 Hz, 1H), 4.25 (d, 4 = 15.1 Hz, 1H), 4.09 - 3 .92 (m, 2H), 2.39 (dh, 4 - 14.1, 7.4, 6.9 Hz, ZN), 1.94 - 1.80 (m, 2H). 892 D M+H=422 (300 MHz, methanol-s/ ₄ ) δ 8.40 (d, 4 = 2.1 Hz, 1H), 7.94 (dd, 4 = 9.2, 2.1 Hz, 1H), 7.42 - 7.31 (m, 2H), 7.18 7.05 (m, 2H), 5.16 (d, 4 = 15.2 Hz, 1H), 4.73 (d, 4 = 17.3 Hz , 1H), 4.49 (d, 4 = 17.3 Hz, 1H), 4.39 - 4.24 (m, 2H), 4.03 (d, 4 = 8.7 Hz, 1H), 3 .08 (dk, 4= 15.5, 8.3, 7.7 Hz, 1H), 2.39 (dtt, J~ 12.3, 6.0, 3.3 Hz, 2H), 2.05 (dtt, J = 13.1, 8.9, 4.1 Hz, 2H). 893A M+H=438 (300 MHz, DMSO-E ₆ ) b 8.48 (d, 4 = 2.1 Hz, 1H), 8.26 (dd, 4 = 9.4, 2.1 Hz, 1H), 7.44 ( d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 5.09 (d, 4 = 6.4 Hz, 1H), 4.99 (d, 4 = 15.2 Hz, 1H), 4.73 (d, 4 = 17.0 Hz, 1H), 4.29 (dd, 4 = 23.0, 16.1 Hz, 2H), 3.98 ( d, 4 = 7.6 Hz, 1H), 3.86 (d, 4 = 6.7 Hz, 1H), 2.21 (dd, 4 = 15.7, 9.6 Hz, ZN), 1, 79-1.67 (m, 2H). 893B M+HM38 (300 MHz, DMSO-s? ₆ ) b 8.48 (d, 4 = 2.1 Hz, 1H), 8.26 (dd, 4 = 9.4, 2.1 Hz, 1H), 7.48 - 7.38 (m, 2H), 7.36 7.27 (m, 2H), 5.07 - 4.90 (m, 2H), 4.77 (d, 4 = 17.1 Hz, 1H) , 4.35 (dd, 4 = 16.3, 8.1 Hz, 2H), 4.19 (k, 4 = 5.9 Hz, 1H), 4.10 (d, 4 = 9.3 Hz, 1H), 3.06 - 2.81 (m, 1H), 2.22 (dt, 4 = 12.3, 6.6 Hz, 2H), 1.94-1.77 (m, 2H). 893С M+H=438 (300 MHz, DMSO-s/ ₆ ) δ 8.48 (d, 4 = 2.1 Hz, 1H), 8.25

- 351 045362

(dd, J = 9.4, 2.2 Hz, 1H), 7.49 - 7.39 (m, 2H), 7.33 (d, J = 8.4 Hz, 2H), 5.09 ( d, J = 6.4 Hz, 1H), 4.99 (d, J = 15.3 Hz, 1H), 4.73 (d, J = 17.0 Hz, 1H), 4.33 (d, J = 17.0 Hz, 1H), 4.26 (d, J = 15.3 Hz, 1H), 3.98 (d, J = 7.6 Hz, 1H), 3.86 (k, J= 7.0 Hz, 1H), 2.32-2.12 (m, ZN), 1.72 (k, J = 9.0 Hz, 2H). 893D M+H=438 (300 MHz, DMSO-ύ) 5 8.48 (d, J = 2.1 Hz, 1H), 8.26 (dd, J = 9.4, 2.2 Hz, 1H), 7.47 - 7 .38 (m, 2H), 7.36 7.27 (m, 2H), 5.03 (d, J = 5.1 Hz, 1H), 4.96 (d, J = 15.4 Hz, 1H ), 4.77 (d, U = 17.0 Hz, 1H), 4.35 (dd, 7 = 16.3, 8.1 Hz, 2H), 4.23 - 4.15 (m, 1H) , 4.10 (d, J = 9.3 Hz, 1H), 2.96 (d, J = 22.1 Hz, 1H), 2.22 (dt, 12.3, 6.5 Hz, 2H) , 1.86 (td, J = 11.9, 11.2, 4.2 Hz, 2H). 894A M+H=418 (300 MHz, methanol-sad δ 8.39 (d, J= 2.1 Hz, 1H), 7.92 (dd, J = 9.1, 2.1 Hz, 1H), 7.20 (s, 4H), 5.25 (d, J = 15.1 Hz, 1H), 4.73 (d, 7 = 17.2 Hz, 1H), 4.46 (d, 7 = 17.2 Hz, 1H) , 4.16 (d, J = 15.0 Hz, 1H), 4.10-3.95 (m, 1H), 3.91 (d, J = 7.3 Hz, 1H), 2.50 - 2.35 (m, ZN), 2.34 (s, ZN), 1.88 (t, 8.7 Hz, 2H). 894B M+H=418 (300 MHz, methanol-^) δ 8.39 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 9.2, 2.1 Hz, 1H), 7.20 (s , 4H), 5.22 (d, J = 15.1 Hz, 1H), 4.72 (d, J = 17.3 Hz, 1H), 4.49 (d, J = 17.3 Hz, 1H ), 4.36-4.18 (m, 2H), 3.97 (d, J = 8.8 Hz, 1H), 3.09 (k, J = 7.9 Hz, 1H), 2.43 -2.35 (m, 2H), 2.34 (s, ZN), 2.16 -1.95 (m, 2H). 894C M+N-418 (300 MHz, methanol-^) δ 8.39 (d, J = 2.1 Hz, 1H), 7.92 (dd, 7 = 9.1, 2.1 Hz, 1H), 7.20 (s , 4H), 5.25 (d, J= 15.0 Hz, 1H), 4.73 (d, J = 17.2 Hz, 1H), 4.46 (d, J= 17.2 Hz, 1H ), 4.16 (d, 7= 15.0 Hz, 1H), 4.03 (t, 7= 7.3 Hz, 1H), 3.91 (d, 7= 7.3 Hz, 1H), 2.49-2.29 (m, 6H), 1.86 (d, 7 = 8.6 Hz, 2H). 894D M+H=418 (300 MHz, methanol-^) δ 8.39 (d, 7 = 2.1 Hz, 1H), 7.93 (dd, 7 = 9.1, 2.1 Hz, 1H), 7.20 (s , 4H), 5.22 (d, 7 = 15.1 Hz, 1H), 4.72 (d, 7= 17.2 Hz, 1H), 4.48 (d, 7= 17.3 Hz, 1H), 4.36-4.18 (m, 2H), 3.97 (d, 7 = 8.7 Hz, 1H), 3.09 (d, 7 = 8.3 Hz, 1H), 2.37 (dt, 7 = 13.5, 6.8 Hz, 5H ), 2.161.93 (m, 2H).

CONNECTION NO. TIME HPLC CONDITIONS 740A 0.85 W 740V 0.82 W 740C 1.56 W 740D 2.98 W 892A 0.95 Q 892V 0.98 Q 892C 1.49 Q 892D 1.88 Q 893A 1.37 T 893B 1.40 T 893С 2.00 T 893D 2.80 T 894A 2.73 V 894B 3.86 V 894C 1.16 V 894D 1.17 V

- 352 045362

Example 75. Synthesis of compound 867.

1. Synthesis of intermediate 75-1

3-(Benzyloxy)cyclobutan-1-one (500 mg, 2 .8 mmol, 1.0 eq.). After stirring at room. temp., 4-chloro-2-fluoro-1-isocyanobenzene (1.5 g, crude mixture) and chloroacetic acid (266 mg, 2.8 mmol, 1.0 eq.) were added to this resulting mixture over 10 min. The resulting mixture was stirred at room. pace, overnight, concentrated under reduced pressure and purified by silica gel chromatography, eluting with EA/PE (1/5) to give 1.1 g (21%) 3-(benzyloxy)-C-(4chloro-2-fluorophenyl) -1-(2-chloro-M-(4-fluorobenzyl)acetamido)cyclobutane-1-carboxamide (intermediate 75-1) as a yellow oil. HPMS (ES) m/z 533 (M+H).

2. Synthesis of intermediate 75-2

To a solution of 3-(benzyloxy)-M-(4-chloro-2-fluorophenyl)-1-(2-chloro-M-(4fluorobenzyl)acetamido)cyclobutane-1-carboxamide (546 mg, 1.0 mmol, 1, 0 eq.) in DMF (8.0 ml) was added K ₂ CO ₃ (285 mg, 2.0 mmol, 2.0 eq.). The mixture was stirred at room. pace, within 1 hour, was diluted with water (20 ml) and extracted three times with EA (60 ml). The combined organic layers were washed twice with brine (30 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain 550 mg of 2-(benzyloxy)-8-(4-chloro-2-fluorophenyl)-5-(4- fluorobenzyl)-5,8-diazaspiro[3.5]nonane6,9-dione (intermediate 75-2). HPMS (ES) m/z 497 (M+H).

3. Synthesis of compound 867

To a stirred solution of 2-(benzyloxy)-8-(4-chloro-2-fluorophenyl)-5-(4-fluorobenzyl)-5,8diazaspiro[3.5]nonane-6,9-dione (660 mg, 1.3 mmol , 1.0 eq.) in MeOH (7 ml) and THF (7 ml) was added Pd(OH) ₂ /C (132 mg) in portions. The mixture was stirred at room. temp, for 3 hours hydrogen atmosphere (balloon), filtered the solid, concentrated and purified by preparative HPLC under the following conditions: (SHIMADZU) Column, XBridge Prep Cl8 OBD column, 5 µm, 30x150 mm; mobile phase, water (10 mM NH ₄ HCO ₃ ) and ACN (25% gradient to 50% over 8 min); detector UV 254 nm) to obtain 150 mg (27%) 8-(4-chloro-2-fluorophenyl)-5-(4-fluorobenzyl)-2-hydroxy-5,8diazaspiro[3.5]nonane-6,9-dione (connection 867). HPMS (ES) m/z 407 (M+H).

4. Separation of diastereomers of compound 867: Diastereomers 867A and 867B

Racemic compound 8-(4-chloro-2-fluorovinyl)-5-(4-fluorobenzyl)-2-hydroxy-5,8- 353 045362 diazaspiro[3.5]nonane-6,9-dione (150 mg, 0.37 mmol, 1.0 eq.) was purified by chiral preparative HPLC under the following conditions: Column, CHIRALPAK IF-3, 2x25 mm, 5 µm; mobile phase, Hex (8 mM, NH ₃ in MeOH) and EtOH (60/40); detector, UV 254 nm) to obtain 89 mg of the first eluting peak (diastereomer 867A) and 31 mg of the second eluting peak (diastereomer 867B) as white solids.

Characteristics of diastereomer 867A. LC-MS (ESI), m/z 407 (M+H).

1H NMR (NMR (300 MHz, DMSO-d6) δ 7.67-7.50 (m, 2H), 7.40 (ddd, J=8.6, 2.3, 1.0 Hz, 1H), 7.29 (dd, J=8.6, 5.5 Hz, 2H), 7.19 (t, J=8.9 Hz, 2H), 5.30 (d, J=6.2 Hz, 1H ), 4.83 (s, 2H), 4.38 (s, 2H), 4.09 (k, J=7.3 Hz, 1H), 2.65 (s, 3H), 2.75-2 .55 (m, 1H).

Analytical chiral HPLC RT: 1.79 min (CHIRALPAK IF-3; 0.46 cm x 5 cm; 3 microns; HEX (0.1% DEA):EtOH=60:40 at 1 ml/min).

Characteristics of diastereomer 867B. LC-MS (ESI), m/z 407 (M+H).

1H NMR (300 MHz, DMSO- _d6 ) δ 7.66-7.54 (m, 2H), 7.46-7.37 (m, 1H), 7.31-7.13 (m, 4H) , 5.32 (d, J=7.0 Hz, 1H), 4.89 (s, 2H), 4.40 (s, 2H), 3.93 (k, J=6.8 Hz, 1H) , 2.79 (s, 2H), 2.31 (d, J=9.7 Hz, 2H).

Analytical chiral HPLC RT: 2.66 min (CHIRALPAK IF-3; 0.46 cm x 5 cm; 3 microns; HEX (0.1% DEA):EtOH=60:40 at 1 ml/min).

The following compounds were prepared by methods similar to those described for diastereomers 867A and 867B:

Connection No. HPMS (ES) m/Z ^1H NMR 764 M+N-408.0 ^1H NMR (400 MHz, methylene chloride- ₇₂ ) δ 8.28 - 8.20 (m, 1H), 7.60 - 7.50 (m, 1H), 7.20 - 7.11 (m, 2H ), 7.03 6.93 (m, 2H), 4.83 (s, 1H), 4.75 (s, 1H), 4.42 (d, 7= 9.1 Hz, 2H), 4, 29-4.04 (m, 1.5Н), 3.22 (s, 0,ЗН), 2.91 (ddd, J = 10.1, 7.0, 3.0 Hz, 1Н), 2, 86 - 2.72 (m, 1H), 2.60 (dd, J = 14.9, 3.8 Hz, 1H), 2.31 (dd, J = 10.0, 6.8, 3.0 Hz, 1H), 0.83 (s, OH). 764A M+H=408.0 Ή NMR (400 MHz, DMSO-7 ₆ ) δ 8.53 (d, 7 = 2.1 Hz, 1H), 8.30 (dd, J = 9.5, 2.1 Hz, 1H), 7, 33 - 7.24 (m, 2H), 7.22 (t, J = 8.8 Hz, 2H), 5.38 (d, J = 6.9 Hz, 1H), 4.93 (s, 2H ), 4.56 (s, 2H), 4.04 - 3.91 (m, 1H), 2.88 - 2.78 (m, 2H), 2.40-2.31 (m, 2H). 764B M*H=408.0 ^Ί Η NMR (400 MHz, DMSO-7 ₆ ) δ 8.53 (d, 7 = 2.1 Hz, 1H), 8.30 (dd, 7 = 9.4, 2.1 Hz, 1H), 7 .31 (dd, 7 = 8.5, 5.5 Hz, 2H), 7.22 (t, 7 = 8.8 Hz, 2H), 4.87 (s, 2H), 4.54 (s, 2H), 4.18 - 4.06 (m, 1H), 3.61 (s, 1H), 2.81 - 2.70 (m, 2H), 2.69-2.58 (m, 2H) .

- 354 045362

868A M+H=404.0 Ή NMR (400 MHz, methylene chloride-c? ₂ ) δ 8.21 (d, J 2.1 Hz, 1H), 7.52 (dd, J = 9.0, 2.1 Hz, 1H), 7, 05 (k, J = 8.1 Hz, 4H), 4.79 (s, 2H), 4.38 (s, 2H), 4.23 - 4.11 (m, 1H), 2.92 - 2 .82 (m, 2H), 2.36 - 2.25 (m, 2H), 2.24 (s, ZN), 1.91 (s, 1H). 868V M+H=404.0 ^1H NMR (400 MHz, methylene chloride-^ ₂ ) δ 8.23 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.9, 2.1 Hz, 1H), 7 .11 - 6.98 (m, 4H), 4.72 (s, 2H), 4.40 (s, 2H), 4.10 (s, 1H), 3.21 (d, J = 9.7 Hz, 1H), 2.84 - 2.73 (m, 2H), 2.56 (dd, J = 14.8, 3.8 Hz, 2H), 2.24 (s, ZN). 869A M-N=422 ^Ί Η NMR (300 MHz, DMSO-de) δ 8.49 (d, J= 2.1 Hz, 1H), 8.27 (dd, 4=9.5, 2.1 Hz, 1H), 7, 47 - 7.37 (m, 2H), 7.327.22 (m, 2H), 5.35 (d, J = 6.2 Hz, 1H), 4.85 (s, 2H), 4.52 (s , 2H), 4.08 (p, J = 7.4 Hz, 1H), 2.78 - 2.65 (m, 2H), 2.65-2.53 (m, 2H). 869B M+H=424 ^1H NMR (300 MHz, DMSO-cfe) δ 8.50 (d, J= 2.1 Hz, 1H), 8.27 (dd, J = 9.5, 2.2 Hz, 1H), 7, 47 - 7.38 (m, 2H), 7.24 (d, J= 8.4 Hz, 2H), 5.36 (d, 4= 7.1 Hz, 1H), 4.90 (s, 2H ), 4.53 (s, 2H), 3.94 (k, 4 = 6.9 Hz, 1H), 2.79 (t, 4 = 9.7 Hz, 2H), 2.31 (dd, 4 = 11.3, 8.1 Hz, 2H).

Example 76. Synthesis of compound 838.

1. Synthesis of intermediate 76-1

76-1

To a solution of methyl 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (23.0 g, 135.2 mmol, 1.0 eq.) in THF (400.0 ml) at 0°C BH ₃ -THF (1 M/THF, 162 ml, 162 mmol, 1.2 eq.) was added dropwise over a period of 1 hour. The mixture was stirred at room temperature. temp, overnight, cooled to 0°C, quenched with MeOH and concentrated under reduced pressure to give 21 g (99%) methyl 3(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (intermediate 76-1 ) as a yellow oil. HPMS (ES) m/z 157 (M+H).

2. Synthesis of intermediate 76-2

To a stirred solution of methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (15.0 g, 96.0 mmol, 1.0 eq.) and imidazole (18.0 g, 264.4 mmol , 2.75 eq.) in DCM (300.0 mL) cooled to 0°C, TBSC1 (19.0 g, 126.1 mmol, 1.3 eq.) was added. The mixture was stirred at room. temp. for 1 hour and filtered through a celite plug. The filtrate was concentrated under reduced pressure, redissolved in EA (300 ml) and water (300 ml) was added to the mixture. The aqueous layer was extracted with EA (300 ml). The combined organic layers were washed twice with brine (300 ml), dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by silica gel column chromatography using PE/EA (20/1) as eluent to give 28 g (86% ) methyl 3-(((tertbutyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylate (intermediate 76-2) as a yellow oil. HPMS (ES) m/z 271 (M+H).

3. Synthesis of intermediate 76-3

76-2

76-3

To a solution of methyl 3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylate

- 355 045362 (28.0 g, 103.5 mmol, 1.0 eq.) NaOH (4.6 g, 115.0 mmol, 1.1 eq.) was added to MeOH (250.0 ml). The mixture was stirred at 60°C for 1 hour, cooled to room temperature, acidified to pH 4 with HCl (4M/water), concentrated under reduced pressure, water (300 ml) was added to this mixture and extracted twice with EA ( 300 ml). The combined organic layer was washed twice with brine (300 ml), dried over Na ₂ SO4 and concentrated under reduced pressure to give 24 g (90%) 3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentane -1-carboxylic acid (intermediate 76-3) as a yellow oil. HPMS (ES) m/z 257 (M+H).

4. Synthesis of intermediate 76-4

76-3 76-4

To a solution of 3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (24.0 g, 93.6 mmol, 1.0 eq.) in DCM (400.0 ml) EDCI (23.3 g, 121.7 mmol, 1.3 eq.). After stirring at room. temp, HOBt (2.4 g, 17.8 mmol, 0.19 eq.), DIEA (38.7 g, 299.5 mmol, 3.2 eq.) and N were added to this mixture over 10 min. Ο-Dimethylhydroxylamine hydrochloride (18.0 g, 184.4 mmol, 2.0 eq.). The mixture was stirred at room. pace for 2 hours, washed once with saturated sodium carbonate solution (300 ml) and twice with brine (300 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain 28 g (90% purity) 3-( ((tert-butyldimethylsilyl)oxy)methyl)-Kmethoxy-K-methylbicyclo[1.1.1]pentane-1-carboxamide (intermediate 76-4) as a yellow oil. HPMS (ES) m/z 300 (M+H).

5. Synthesis of intermediate 76-5

To a solution of 3-(((tert-butyldimethylsilyl)oxy)methyl)-C-methoxy-C-methylbicyclo[1.1.1]pentane-1 carboxamide (28.0 g, 93.5 mmol, 1.0 eq.) in With THF (280.0 mL) cooled to 0° C., phenylmagnesium bromide (3 M, 38 mL, 114 mmol, 1.22 eq.) was added dropwise over a period of 30 min under nitrogen. The mixture was stirred at room. temp, for 2 hours, cooled to 0°C, quenched with a saturated solution of NH ₄ C1 (300 ml), and extracted twice with EA (400 ml). The combined organic layers were washed twice with brine (400 ml), dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE/EA (10/1) to give 17 g (57%) (3 -(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)(phenyl)methanone (intermediate 76-5) as a yellow oil. HPMS (ES) m/z 317 (M+H).

6. Synthesis of intermediate 76-6

O.T.B.S.

76-5 76-6

To a solution of (3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)(phenyl)methanone (17.0 g, 53.7 mmol, 1.0 eq.) in DCM (340.0 mL) was added with m-CPBA (24.0 g, 118.2 mmol, 2.2 eq., 85% purity). The mixture was stirred at 50°C for 2 days, cooled to 0°C, quenched with saturated NaHSO ₃ solution (200 ml) and extracted twice with EA (200 ml). The combined organic layers were washed once with saturated sodium carbonate solution (200 ml) and twice with brine (200 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 18 g (90% purity, 90%) 3-(( (tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-ylbenzoate (intermediate 76-6) as a yellow oil. HPMS (ES) m/z 333 (M+H).

7. Synthesis of intermediate 76-7

To a solution of 3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-ylbenzoate (18.0 g, 54.1 mmol, 1.0 eq.) in DCM (180.0 ml ) HC1 (4K/dioxane, 45 ml, 180 mmol) was added. Mixture varies

- 356 045362 sewed at room. pace, for 2 hours, concentrated under reduced pressure, diluted with water (200 ml) and extracted twice with EA (200 ml). The combined organic layers were washed twice with brine (200 ml), dried over Na ₂ SO4, concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE/EA (3/1) to give 6.2 g (52%) 3 (hydroxymethyl)bicyclo[1.1.1]pentan-1-ylbenzoate (intermediate 76-7) as a yellow oil. HPMS (ES) m/z 219 (M+H).

8. Synthesis of intermediate 76-8

76-7 76-8

To a solution of 3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-ylbenzoate (6.2 g, 28.4 mmol, 1.0 eq.) in DCM (60.0 ml) at room. pace, PCC (7.35 g, 34.1 mmol, 1.2 eq.) was added in portions. The mixture was stirred at room. pace, over 2 hours, diluted with ether (120 ml), stirred for 20 minutes, filtered off the solid, concentrated under reduced pressure and purified by column chromatography on silica gel, eluting with PE/EA (10/1) to give 2.7 g (65% purity) 3formylbicyclo[1,1.1]pentan-1-ylbenzoate (intermediate 76-8) as a yellow solid. HPMS (ES) m/z 217 (M+H).

9. Synthesis of intermediate 76-9

To a solution of (4-(trifluoromethyl)phenyl)methanamine (221.5 mg, 1.3 mmol, 1.1 eq.) in trifluoroethanol (5.0 ml) was added 3-formylbicyclo[1.1,1]pentan-1-ylbenzoate (420 mg, 1.3 mmol, 1.1 eq., ~65% purity). After stirring at room. pace, 5-chloro-3-fluoro2-isocyanopyridine (180 mg, 1.15 mmol, 1.0 eq.) and chloroacetic acid (119.5 mg, 1.3 mmol, 1.0 eq.) were added to this mixture over 10 min. 1 eq.). The resulting mixture was stirred at room. temp, overnight, concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE/EtOAc (5:1) to give 640 mg (89%) 3-(2-((5-chloro-3-fluoropyridine-2 -yl)amino)-1-(2-chloro-X-(4(trifluoromethyl)benzyl)acetamido)-2-oxoethyl)bicyclo[1.1.1]pentan-1-ylbenzoate (intermediate 76-9) as yellow oils HPMS (ES) m/z 624 (M+H).

10. Synthesis of intermediate 76-10

To a solution of 3 -(2-((5-chloro-3-fluoropyridin-2-yl)amino)-1 -(2-xnop-N-(4(trifluoromethyl)benzyl)acetamido)-2-oxoethyl)bicyclo[1.1 .1]pentan-1-ylbenzoate (640 mg, 1.0 mmol, 1.0 eq.) in DMF (10.0 ml) was added potassium carbonate (283 mg, 2.0 mmol, 2.0 eq.). The resulting mixture was stirred at room. pace, for 30 min, was diluted with water (20 ml) and extracted twice with EA (20 ml). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 600 mg (99%) 3-(4-(5-chloro-3-fluoropyridin-2yl)-3,6 -dioxo-1-(4-(trifluoromethyl)benzyl)piperazin-2-yl)bicyclo[1.1.1]pentan-1-ylbenzoate (intermediate 76-10) as a brown oil. HPMS (ES) m/z 588 (M+H).

- 357 045362

I. Synthesis of compound 838

76-10 Compound 838

To a solution of 3-(4-(5-chloro-3-fluoropyridin-2-yl)-3,6-dioxo-1 -(4-(trifluoromethyl)benzyl)piperazin-2yl)bicyclo[1.1.1]pentane-1 -yl benzoate (450 mg, 0.77 mmol, 1.0 eq.) in a mixture of MeOH and water (5/1, 12 ml) was added potassium carbonate (105.8 mg, 0.77 mmol, 1.0 eq.) . The mixture was stirred at room. temp, for 1 h, concentrated under reduced pressure and purified by RP-HPLC using the following conditions: XBridge Prep OBD Cl8 Column 3x15 cm, 5 µm; mobile phase acetonitrile in water (10 mM NH4HCO3) gradient from 45 to 75% over 8 min; detector, UV 254 nm to obtain 190 mg 1-(5-chloro3-fluoropyridin-2-yl)-3-(3-hydroxybicyclo[ 1.1.1 ]pentan-1 -yl)-4-(4-(trifluoromethyl)benzyl )piperazine 2,5-dione (compound 838) as a white oil. HPMS (ES) m/z 484 (M+H).

Y NMR (300 MHz, DMSO-th ₆ ) δ 8.49 (d, >2.1 Hz, 1H), 8.27 (dd, >9.5, 2.1 Hz, 1H), 7.74 ( d, >8.1 Hz, 2H), 7.52 (d, >8.0 Hz, 2H), 5.12 (d, >15.9 Hz, 1H), 4.73 (d, >17, 5 Hz, 1H), 4.67 (s, 1H), 4.50 (dd, >16.8, 8.9 Hz, 2H), 3.58 (d, >16.6 Hz, 1H), 3 .43 (s, 1H), 2.51 (s, 1H), 2.48 (s, 1H), 1.36 (s, ZN),

12. Separation of enantiomers of compound 838.

Enantiomers 83 8A and 838B

Racemic compound 1-(5-chloro-3-fluoropyridin-2-yl)-3-(3-hydroxybicyclo[1.1.1]pentan-1yl)-4-(4-(trifluoromethyl)benzyl)piperazine-2,5- dione (140 mg) was separated by chiral HPLC under the following conditions (Column, CHIRALPAK ID-2, 2x25 cm, 5 μm; mobile phase, 50% MTBE (10 mM NH ₃ in MeOH) in EtOH; flow rate: 13 ml/min; detector, UV 220/254 nm) to obtain 60 mg (first eluting peak) of enantiomer 838A and 60 mg (second eluting peak) of enantiomer 838B as white solids.

Characteristics of enantiomer 838A. LC-MS (ESI), m/z 484 (M+H).

Y NMR (300 MHz, DMSO-th ₆ ) δ 8.49 (d, >2.1 Hz, 1H), 8.27 (dd, >9.4, 2.2 Hz, 1H), 7.74 ( d, >8.1 Hz, 2H), 7.52 (d, >8.0 Hz, 2H), 5.12 (d, >16.0 Hz, 1H), 4.73 (d, >17, 6 Hz, 1H), 4.67 (s, 1H), 4.50 (dd, >16.8, 9.0 Hz, 2H), 3.58 (d, >16.8 Hz, 1H), 3 .41 (d, >16.2 Hz, 1H), 2.63-2.54 (m, 1H), 2.45 (d, >7.7 Hz, 1H), 1.36 (s, ZN) .

Analytical chiral HPLC RT: 0.89 min (CHIRALPAK ID-3; 0.46 cm x 5 cm; 3 microns; MtBE (0.1% DEA): EUN=50:50 at 1 ml/min).

Characteristics of enantiomer 838B. LC-MS (ESI), m/z 484 (M+H).

Y NMR (300 MHz, DMSO-th ₆ ) δ 8.49 (d, >2.1 Hz, 1H), 8.27 (dd, >9.4, 2.2 Hz, 1H), 7.74 ( d, >8.1 Hz, 2H), 7.52 (d, >8.0 Hz, 2H), 5.12 (d, >16.0 Hz, 1H), 4.73 (d, >17, 6 Hz, 1H), 4.67 (s, 1H), 4.50 (dd, >16.8, 9.0 Hz, 2H), 3.58 (d, >16.8 Hz, 1H), 3 .41 (d, >16.2 Hz, 1H), 2.63-2.54 (m, 1H), 2.45 (d, >7.7 Hz, 1H), 1.36 (s, ZN) .

Analytical chiral HPLC RT: 1.75 min (CHIRALPAK ID-3; 0.46 cm x 5 cm; 3 micron; MtBE (0.1% DEA):EtOH=50:50 at 1 ml/min).

The following compounds were prepared by methods similar to those described for compound 838:

Connection No. HPMS (ES) m/z 841 M+H=450 844 M+H=434 849 M+H=466 852 M+H=430

The following compounds were prepared by methods similar to those described for enantiomers 83 8A and 838B:

- 358 045362

HPLC separation conditions

Number HPLC CONDITIONS X CHIRALPAK ID-3; 0.46 cm x 5 cm: 3 microns; MtBE (0.1% DEA):EtOH=50:50 at 1 ml/min Y CHIRALPAK IA-3; 0.46 cm x 5 cm; 3 microns; MtBE (0.1%DEA):EtOH = 50:50 at 1 Z CHIRALPAK IE-3; 0.46 cm x 5 cm; 3 microns; (Hex:DCM = 3:1)(0.1% DEA):EtOH = 50:50 at 1 ml/min

Enantiomer No. HPMS (ES) m/z Retention time (min) HPLC separation conditions 841A M+H=450 1.06 X 841B M+H=450 2.38 X 844A M+H=434 1.46 Y 844B M+H=434 2.27 Y 849A M+H=466 1.60 Z 849B M+H=466 2.32 Z 852A M+H=430 1.58 Y 852B M+H=430 2.11 Y

Example 77 Synthesis of intermediate 77-2 (5-chloro-3-fluoro-2-isocyanopyridine). 1. Synthesis of intermediate 77-1

77-1

A mixture of Ac ₂ O (280 g, 2.74 mol, 4.0 eq.) and formic acid (140 g, 3.43 mol, 4.5 eq.) was stirred at 55°C for 2 hours. To this mixture cooled to 0°C, 5-chloro-3-fluoropyridine-2amine (100 g, 682 mmol, 1.0 eq.) was added dropwise. The mixture was stirred for 2 hours at room temperature, concentrated under reduced pressure and triturated with Et ₂ O to obtain 100 g (84%) M-(5-chloro-3fluoropyridin-2-yl)formamide (intermediate 77-1 ) as a white solid. HPMS (ES) m/z 175 (M+H).

Y NMR (400 MHz, DMSO-a ₆ ) δ 10.90 (s, 1H), 9.16 (s, 1H), 8.24 (s, 1H), 8.11 (dd, J=10.1 , 2.1 Hz, 1H).

2. Synthesis of intermediate 77-2

77-1 77-2

To a stirred solution of X-(5-chloro-3-fluoropyridin-2-yl)formamide (40 g) and TEA (140.1 g, 1.38 mol, 6 eq.) in DCM (400 ml), cooled to - 78°C, POC1 ₃ (40.4 g, 263.5 mmol, 1.15 eq.) in DCM (100 ml) was added dropwise. The mixture was stirred at room. temp, overnight, cooled to 0°C, quenched with MeOH (32 ml), concentrated under reduced pressure and purified on silica gel using PE/EA (10/1) as eluent to give Ig (31%) 5-chloro -3-fluoro-2-isocyanopyridine (intermediate 77-2) as a yellow solid. HPMS (ES) m/z 156 (M+H).

Example 78 Synthesis of compound 202

1. Synthesis of intermediate compound 78-1%! Yfp AC2O

M-NH* ⁰⁰⁰ ”YA)

H

78-1

A mixture of Ac ₂ O (500 ml) and FA (200 ml) was stirred at 60°C for 2 hours and cooled to room temp. To this mixture was added 4-amino-3-fluorobenzonitrile (120.0 g, 0.88 mol, 1.0 eq.). The mixture was stirred for 2 hours at room temperature and concentrated under reduced pressure. The solid was triturated with Et ₂ O (2 L) to obtain 124 g of X-(4-cyano-2-fluorophenyl)formamide (intermediate 78-1) as a white solid.

- 359 045362

2. Synthesis of intermediate 78-2

78-1

78-2

TEA (135 g, 1334.8 mmol, 3.1 eq.) and a solution of triphosgene (54.4 g, 183.4 mmol, 0.43 eq.) in DCM (300 ml) dropwise over a period of 30 min. The mixture was stirred at room temperature overnight, cooled to 0°C, quenched with MeOH (200 ml), concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PE/DCM (5/1) to give 54 g (87%) 3-fluoro-4-isocyanobenzonitrile (intermediate 78-2) as a yellow solid.

3. Synthesis of intermediate 78-3

Tert-butyl-3-oxoazetidine-1-carboxylate (69, 6 g, 406.5 mmol, 1.1 eq.)). After stirring at room. temp, 3-fluoro-4-isocyanobenzonitrile (54 g, 369.5 mmol, 1.0 eq.) and chloroacetic acid (38.4 g, 406.5 mmol, 1.1 eq.) were added to this mixture over 10 min. .). The resulting mixture was stirred at room. pace, overnight, concentrated under reduced pressure and triturated with MeOH (500 ml) to obtain 113 g (54%) tert-butyl-3-(2-chloro-K-(4(trifluoromethyl)benzyl)acetamido)-3 -((4-cyano-2-fluorophenyl)carbamoyl)azetidine-1-carboxylate intermediate 78-3) as a yellow solid.

(pro-

4. Synthesis of intermediate 78-4

To a solution of tert-butyl-3-(2-chloro-I-(4-(trifluoromethyl)benzyl)acetamido)-3-((4-cyano-2fluorophenyl)carbamoyl)azetidine-1-carboxylate (113 g, 210 mmol, 1.0 eq.) in DMF (550 ml) was added K ₂ CO ₃ (88 g, 630 mmol, 3.0 eq.). The resulting mixture was stirred for 30 min at 60°C in an argon atmosphere, cooled to room temperature and diluted with water (1000 ml). The precipitates were collected by filtration and dried in an oven at below 45°C to obtain 106 g (95%) tert-butyl-8-(4-cyano-2fluorophenyl)-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl ]methyl]-2,5,8-triazaspiro[3.5]nonane-2-carboxylate (intermediate 78-4) as a white solid.

5. Synthesis of intermediate 78-5

78-4 78-5

To a solution of tert-butyl-8-(4-cyano-2-fluorophenyl)-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]2,5,8-triazaspiro[3.5]nonane-2 -carboxylate (106 g, 200 mmol, 1.0 eq.) in DCM (1000 ml) was added 2,2,2-trifluoroacetic acid (200 ml) at room temperature. The mixture was stirred for 2 hours at room temperature and concentrated under reduced pressure to obtain 106 g (95%) of 4(6,9-dioxo-5-(4-(trifluoromethyl)benzyl)-2,5,8-triazaspiro[3.5 ]nonan-8-yl)-3-fluorobenzonitrile 2,2,2trifluoroacetate (intermediate 78-5) as a brown oil.

-360045362

5. Synthesis of compound 202

78-5 Compound 202

To a solution of 4-(6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5]nonan-8-yl)-3fluorobenzonitrile (150 g of the product described above ) in DCM (1000 ml) was added TEA (7 g, 69.2 mmol, 3.0 eq.) and acetyl acetate (3.5 g, 34.3 mmol, 1.5 eq.) at 0°C. The mixture was stirred for 4 hours at room temperature, washed with brine (200 ml), dried over anhydrous Na ₃ SO ₄ , concentrated under reduced pressure and purified by reverse phase flash chromatography under the following conditions: column, silica gel C18; mobile phase, A:water (10 mM NH ₄ HCO ₃ ), B:ACN gradient from 35% to 45% (B/A) over 20 min; detector, UV 210/254 nm to obtain 75 g (71%) 4-(2acetyl-6,9-dioxo-5-[[4-(trifluoromethyl)phenyl]methyl]-2,5,8-triazaspiro[3.5] nonan-8-yl)-3fluorobenzonitrile (compound 202) as a white solid. HPMS (ES) m/z 475 (M+H).

^! H NMR (400 MHz, methanol- ₄ , ppm) δ 7.83-7.77 (m, 1H), 7.77-7.67 (m, 4H), 7.57 (d, J =8.1 Hz, 2H), 4.86 (s, 2H), 4.75-4.68 (m, 1H), 4.60-4.55 (m, 2H), 4.55-4, 47 (m, 2H), 4.25 (d, J=11.0 Hz, 1H), 1.87 (s, ZH).

The following compounds were prepared by methods similar to that described for compound 202, as described in Example 78:

Connection No. HPMS (ES) m/z 641 M+H=514.1 642 M+H=480 643 M+H=499 644 M+H=465 653 Μ+Η-495Ί 785 M+N-434 825 M+HU25 0 826 M+H=507.1 827 M+H=475.1 828 M+H=461.0 829 M+H=371.1 830 M+H=457.1 831 M+H=493.0 832 M+H=379.0

Example 79. Synthesis of compound 835.

1. Synthesis of intermediate 79-1

79-1

To a solution of methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (2.0 g, 12.81 mmol, 1.0 eq.) in DCM (68.0 ml) at room. pace, PCC (4.1 g, 19.21 mmol, 1.5 eq.) was added in portions. The mixture was stirred at room. pace, over 2 hours, diluted with ether (180 ml), stirred for 20 minutes, filtered the solid, concentrated under reduced pressure to give 1.9 g (96%) methyl-3-formylbicyclo[1.1.1]pentane- 1-carboxylate (intermediate 79-1) as a brown solid.

-361 045362

2. Synthesis of intermediate 79-2

To a solution of (4-chlorophenyl)methanamine (498 mg, 3.5 mmol, 1.1 eq.) in trifluoroethanol (5.0 ml) was added methyl 3-formylbicyclo[1.1,1]pentane-1-carboxylate (541 mg , 3.5 mmol, 1.1 equiv.). After stirring at room. temp., 5-chloro-3-fluoro-2isocyanopyridine (500 mg, 1.0 eq.) and chloroacetic acid (332 mg, 3.5 mmol, 1.1 eq.) were added to this mixture over 10 min. The resulting mixture was stirred at room. temp., overnight, concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE/EtOAc (3:1) to give 600 mg (36%) methyl-3-(2-((5-chloro-3-fluoropyridine -2-yl)amino)-1-(2-chloro-K-(4-chlorobenzyl)acetamido)-2oxoethyl)bicyclo[1.1.1]pentane-1-carboxylate (intermediate 79-2) as a yellow oil. HPMS (ES) m/z 528 (M+H).

3. Synthesis of intermediate 79-3

To a solution of methyl 3-(2-((5-chloro-3-fluoropyridin-2-yl)amino)-1-(2-chloro-K-(4-chlorobenzyl)acetamido)2-oxoethyl)bicyclo[1.1. 1]pentane-1-carboxylate (580 mg, 1.1 mmol, 1.0 eq.) in DMF (6.0 ml) was added potassium carbonate (305 mg, 2.2 mmol, 2.0 eq.). The resulting mixture was stirred at room. temp for 1 hour and filtered. The filtrate was concentrated under reduced pressure, redissolved in EA (20 ml), washed twice with brine (10 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 500 mg (93%) methyl-3-(4- (5-chloro-3-fluoropyridin-2-yl)-1-(4chlorobenzyl)-3,6-dioxopiperazin-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (intermediate 79-3) as brown butter. HPMS (ES) m/z 492 (M+H).

4. Synthesis of compound 835 ci CI

79-3 Compound 835

A solution of methyl 3-(4-(5-chloro-3-fluoropyridin-2-yl)-1-(4-chlorobenzyl)-3,6-dioxopiperazin-2yl)bicyclo[1.1.1]pentane-1-carboxylate ( 490 mg, 1.0 mmol, 1.0 eq.) in a solution of NH ₃ (7N in MeOH) was stirred at room. temp, for 3, concentrated under reduced pressure and purified by HPLC using the following conditions: Silica gel C18; mobile phase acetonitrile in water (both with 0.5% NH4HCO3) gradient from 40 to 50% over 10 min; detector, UV 254 nm to obtain 350 mg (74%) 3(4-(5-chloro-3-fluoropyridin-2-yl)-1 -(4-chlorobenzyl)-3,6-dioxopiperazin-2-yl)bicyclo [1.1.1]pentane-1 carboxamide (compound 835) as a brown oil. HPMS (ES) m/z 477 (M+H).

'll NMR (400 MHz, DMSO-ph) δ 8.50 (d, J=2.l Hz, 1H), 8.29 (dd, J=9.4, 2.1 Hz, 1H), 7, 49-7.41 (m, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.31 (s, 1H), 7.00 (s, 1H), 5.05 (d , J=15.l Hz, 1H), 4.58 (d, J=17.3 Hz, 1H), 4.39 (d, J=17.3 Hz, 1H), 4.26 (s, 1H ), 4.12 (d, J=15.0 Hz, 1H), 1.94 (cd, J=9.5, 1.6 Hz, 6H).

The following compounds were prepared by methods similar to those described for compound 835:

- 362 045362

Connection No. HPMS (ES) m/z 778 M+H=528.1 779 M+H=508.0 780 M+H=476.0 781 M+H=472.1 782 M+H=540.0 "783 M+H=511.0 790 M+H~493.0 791 M+H=461.1 792 M+H=457.0

5. Separation of enantiomers of compound 835. Enantiomers 835A and 835B

Racemic compound 3-(4-(5-chloro-3-fluoropyridin-2-yl)-1-(4-chlorobenzyl)-3,6dioxopiperazin-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (270 mg) were separated by chiral HPLC under the following conditions (Column, CHIRALPAK IF, 2x 25 cm, 5 µm; mobile phase, 50% MTBE (10 mM NH ₃ in MeOH) in EtOH; flow rate: 13 ml/min; detector, UV 220 /254 nm) to obtain 123 mg (first eluted peak) of enantiomer 835A and 123 mg (second eluted peak) of enantiomer 835B as white solids.

Characteristics of enantiomer 835A. LC-MS (ESI), m/z 477 (M+H).

Y NMR (300 MHz, DMSO-a ₆ ) δ 8.48 (d, J=2.l Hz, 1H), 8.27 (dd, J=9.4, 2.2 Hz, 1H), 7, 44 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.28 (s, 1H), 6.97 (s, 1H), 5, 04 (d, J=15.1 Hz, 1H), 4.56 (d, J=17.3 Hz, 1H), 4.37 (d, J= 17.4 Hz, 1H), 4.25 ( s, 1H), 4.11 (d, J=15.0 Hz, 1H), 1.99-1.85 (m, 6H).

Analytical chiral HPLC RT: 1.09 min (CHIRALPAK IF-3; 0.46 cm x 5 cm; 3 microns; MtBE (0.1% DEA):EtOH=50:50 at 1 ml/min).

Characteristics of enantiomer 835B. LC-MS (ESI), m/z 477 (M+H).

Y NMR (300 MHz, DMSO-a ₆ ) δ 8.48 (d, J=2.l Hz, 1H), 8.27 (dd, J=9.4, 2.1 Hz, 1H), 7, 43 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.28 (s, 1H), 6.97 (s, 1H), 5, 04 (d, J=15.1 Hz, 1H), 4.56 (d, J=17.2 Hz, 1H), 4.37 (d, J=17.3 Hz, 1H), 4.24 ( s, 1H), 4.10 (d, J=15.1 Hz, 1H), 1.99-1.85 (m, 6H).

Analytical chiral HPLC RT: 1.82 min (CHIRALPAK IF-3; 0.46 cm x 5 cm; 3 microns; MtBE (0.1% DEA):EtOH=50:50 at 1 ml/min).

The following compounds were prepared by methods similar to those described for enantiomers 835A and 835B:

- 363 045362

Number HPLC conditions J CHIRALPAK ID-3; 0.46 cm x 5 cm; 3 microns; Hex(0.1% DEA):EtOH=50:50 at 1 ml/min AA CHIRALPAK IE-3; 0.46 cm x 5 cm; 3 microns; MtBE(0.1%DEA):EtOH=60:40 at 1 ml/min bb CHIRALPAK IE-3; 0.46 cm x 5 cm; 3 microns; (Hex:DXM=3:1)(0.1%OEA):EUN=70:30 at 1 ml/min

Enantiomer No. HPMS (ES) m/z Retention time (min) HPLC separation conditions 783A M+H=511 1.01 AA 783B M+H=511 1.37 AA 791A M+N-461 2.15 J 791B M+H=461 3.13 J 790A M+H=493 2.03 BB 790V M+H=493 2.53 BB 792A M+H=457 1.19 AA 792V M+H=457 1.64 AA

Biological example B-1. Myofibril analysis.

To evaluate the effect of the compounds on the ATPase activity of full-length cardiac myosin in the context of the native sarcomere, myofiber skin assays were performed. Bovine cardiac myofibrils were prepared by homogenizing left ventricular tissue from bovine hearts in the presence of a detergent such as Triton X-100. This treatment removes membranes and most soluble cytoplasmic proteins, but leaves the cardiac sarcomeric actomyosin apparatus intact. Myofibril preparations retain the ability to hydrolyze ATP in a Ca ²⁺ regulated manner. The ATPase activities of such myofibril preparations in the presence and absence of compounds were analyzed at concentrations of Ca ²⁺ activating up to a certain fraction of the maximum rate (i.e., 25%, 75%). Small molecule agents were evaluated for their ability to inhibit the steady-state ATPase activity of bovine cardiac myofibers using the pyruvate kinase-lactate dehydrogenase (PK/LDH) enzyme system. This assay reduces ADP produced by myosin to ATP by oxidizing NADH, causing a change in absorbance at 340 nm. Before testing small molecule agents, cardiac myofibers were assessed for their calcium sensitivity and a calcium concentration that achieved either 50% (pCa ₅₀ ) or 75% (pCa ₇₅ ) of activation of the myofibril system was chosen as the endpoint for assessing the inhibitory activity of small molecule agents . All enzymatic activities were measured in a buffered solution containing 12 mM PIPES (piperazine-N,N'-bis(2ethanesulfonic acid), 2 mM magnesium chloride at pH 6.8 (PM 12 buffer). Final assay conditions: 1 mg/ml cardiac myofibrils bovine, 4 U/ml pyruvate kinase, 6 U/ml lactate dehydrogenase, 50 µM ATP, 0.1 mg/ml BSA (bovine serum albumin), 10 ppm antifoam, 1 mM DTT, 0.5 mM NADH , 1.5 mM PEP, 0.6 mM EGTA and sufficient CaCl ₂ to achieve both 50% and 75% myofibril ATPase activity. The results for the test compounds are shown in Table A. The test compounds were prepared in accordance with the procedures synthesis described in this document.

Table A

Conn. Ns CDMF75 1C ₁₅ (µM) Conn. No. CDMF75 1C ₁₅ (µM) Conn. No. CDMF75 1C ₁₅ (µM) Conn. Na CDMF75 1С ₁ 5 (µM) 1 9.5 199 2.3 475V 0.6 717A 4.0 2 1.8 200 0.9 477V 0.4 717B 33.2 3 1.7 201 5.1 479V 2.8 720 9.2 4 2.5 202 0.8 481V 3.7 720A 5.4 5 1.9 203 0.6 483A 0.4 720V >39 6 0.9 204 0.2 483V 0.7 723 7.1 7 1.9 205 0.7 484A 0.5 724 13.8 8 3.3 206 0.5 484V 0.6 724A 8.7 9 2.4 207 4.8 485A 2.1 724V >39 10 5.2 208 3.6 485V 0.7 727 3.2

- 364 045362

eleven 17.4 209 0.5 486A 12.7 727A 1.5 12 6.6 210 1.7 486V 0.7 727V 24.3 13 7.1 211 0.4 487A 3.2 730 3.4 14 6.0 212 0.9 487V 0.61 730A 1.6 15 2.7 213 0.4 488V 0.2 730V 19.1 16 2.7 214 0.5 492V 0.4 733 11.8 17 1.7 215 1.3 494V 0.4 733A 7.2 18 3.1 216 0.3 496A >39 733B >39 19 5.7 217 0.9 496V 17.7 736 2.0 20 7.5 218 0.4 498V 29.8 739 2.2 21 2.6 219 0.4 500V 35.5 740 2.3 22 4.1 220 0.8 502V 15.2 740A 1.1 23 2.2 221 4.1 504A 21.9 740V 0.97 24 5.7 222 0.7 528 2.9 740C >39 25 8.8 223 2.3 529 5.5 740D >39 26 3.0 224 12.1 530 4.7 747 3.7 27 8.6 225 29.6 531 5.0 747A 1.6 28 3.1 249V 0.2 532 0.2 747B 10.8 29 5.6 266 0.7 533 0.3 750 1.0 thirty 21.1 269 1.2 534 0.2 751 1.3 31 2.7 270 1.9 535 0.3 756 5.0 32 9.6 271 0.6 536 0.2 757 7.2 33 5.4 272 0.5 537 0.3 758 19.4 34 10.4 273 1.8 538 0.2 758A 8.3 35 14.6 274 1.0 539 0.2 758B >39 36 24.5 275 6.0 540 0.2 761 16.3 37 6.0 276 3.0 541 0.2 761A 8.4 38 12.4 277 32.7 542 0.2 761B >39 39 3.9 278 0.5 543 0.3 764 1.6 40 7.2 279 1.2 544 0.3 764A 1.4 41 7.0 280 0.9 545 0.2 764B 2.5 42 5.4 281 4.3 546 1.0 768 4.3

- 365 045362

43 3.3 281A 1.7 547 0.4 769 7.9 44 2.4 281V 11.8 550 0.8 769A 4.1 45 12.8 282 3.8 551 2.48 769B >39 46 0.9 283 0.6 552 0.5 772 7.7 47 3.7 284 0.5 553 1.4 772A 4.2 48 1.6 285 8.3 554 0.4 772V >39 49 9.3 286 0.7 555 0.9 775 8.0 50 5.8 287 3.2 556 2.7 775A 3.7 51 5.7 288 1.8 558 7.04 775V >39 52 17.8 288A 0.8 559 25.1 778 2.4 53 14.7 288V >39 560 8.6 779 2.9 54 7.8 293 36.0 561 19.8 780 3.6 55 6.7 293A >39 562 29.0 781 4.0 56 18.3 293V 15.4 563 2.2 782 3.6 57 33.3 294 33.3 564 13.0 783 3.08 58 4.1 297 11.6 565 17.8 783A 2.35 59 23.4 297A 6.5 566 4.0 783B >39 60 14.3 297V >39 567 1.2 784 6.8 61 22.9 298 5.4 568 1.2 785 5.0 62 1.8 299 7.0 569 2.6 790 4.9 63 5.1 300 28.3 570 2.2 791 2.7 64 23.6 301 18.6 571 2.0 791A 1.8 65 9.8 302 15.2 572 7.4 791B >39 66 17.6 303 3.7 573 6.5 792 3.8 67 6.0 304 16.4 573A 2.5 799 3.9 68 9.2 305 6.0 573B >39 813 0.4 69 15.4 306 27.0 574 0.3 814 0.8 70 9.5 307 36.7 575 1.5 815 0.7 71 4.8 308 22.7 576 2.2 816 0.9 72 9.0 309 2.8 577 0.9 821 2.1 73 5.7 310 13.1 592 1.3 822 >39 74 4.2 311 5.9 593 2.3 823 2.3

- 366 045362

75 1.1 312 4.9 610 1.7 824 >39 76 2.2 313 3.9 612 13.6 825 0.7 77 13.0 314 8.4 612A 6.27 826 1.26 78 4.1 315 28.9 612V >39 827 2.68 79 3.8 316 14.3 615 1.3 828 1.37 80 1.7 317 2.3 616 11.85 829 2.19 81 1.4 318 7.3 619 14.7 830 1.75 82 8.1 319 24.0 620 1.8 831 0.53 83 1.3 320 17.8 623 3.0 832 0.48 84 4.0 321 22.1 624 2.0 835 1.64 85 14.3 322 10.8 625 14.5 836 1.42 86 8.6 323 6.4 626 >39 837 >39 87 1.9 324 11.5 629 32.4 838 3.8 88 4.0 325 22.8 630 18.7 838A 2.3 89 3.3 326 23.7 630A 9.7 838V >39 90 1.7 327 9.8 630V >39 841 2.7 91 1.1 328 19.3 631 17.3 841A 1.5 92 1.0 329 9.3 632 31.7 842V >39 93 19.7 330 10.7 633 1.3 844 8.6 94 36.1 331 30.9 633A 0.7 844A 4.3 95 5.0 332 16.6 633B 5.0 844B >39 96 4.5 333 16.6 636 1.3 849 5.7 97 3.1 334 8.0 636A 0.6 849B 1.8 98 2.4 335 12.2 636V >39 849A >39 107 12.7 336 1.1 639 1.4 852 6.5 108 9.4 337 1.63 639A 1.0 852A 3.1 109 8.3 338 1.51 639V >39 852B >39 110 34.4 339 0.5 640 1.6 857A 5.3 111 19.8 340 0.7 640A 0.9 857B >39 112 33.0 341 5.4 640V >39 858A 7.79 113 18.5 347 26.4 641 12.2 858B 3.7 114 7.9 348 0.7 642 10.9 858С 2.9

- 367 045362

115 10.2 349 0.9 643 5.8 858D 5.2 116 7.2 350 5.5 643A 3.2 859A 0.6 117 16.6 351A >39 644 6.8 859B 0.3 118 14.0 351B 2.3 644A 3.2 860A 0.7 119 10.8 353A >39 645 5.8 860V 0.2 120 18.3 353B 2.0 645A 3.3 861A 1.0 121 9.9 355A 0.5 646 3.3 861B 5.8 122 20.5 355V >39 646A 1.4 862A 3.2 123 11.2 357A 0.6 646V >39 862V >39 127 0.8 357V >39 647 2.1 863A 0.3 128 0.8 359A >39 647A 1.2 863B >39 129 4.6 359V 1.7 647B 28.0 864A 6.2 138 7.0 361A >39 648 2.0 864B >39 139 14.8 361B 2.1 648A 0.8 865A 10.2 140 4.4 363A >39 648V 8.1 866A 4.4 141 10.7 363V 0.8 649 2.9 866B >39 142 0.8 365A >39 649A 1.5 866С 2.3 145 3.8 365V 2.1 649V 7.3 866D >39 146 1.2 367A 8.8 650 2.5 867A 2.1 147 8.1 367V >39 650A 1.7 867B 1.7 148 2.3 369A 8.5 650V 10.1 868A 1.6 149 8.9 369V >39 651 7.3 868V 3.8 150 1.1 371A 8.2 652 9.0 869A 1.04 151 12.2 371B >39 653 19.9 869B 0.59 152 2.8 373A 0.4 654 5.3 870A 12.7 153 6.4 373V >39 654A 2.9 870V 0.6 154 19.8 375A >39 654B 38.8 871A 4.2 155 0.6 375V 0.4 655 7.0 871B 1.4 156 7.1 377A >39 656 9.9 872A 0.99 157 5.5 377V 2.8 657 1.4 872V 1.3 158 9.7 379A 4.8 657A 0.7 873A 15.3 159 3.2 379V >39 657B >39 873B 0.7

- 368 045362

160 7.1 381A 6.7 660 0.84 874A 4.0 161 4.7 381B >39 661 17.0 874B 1.1 162 0.4 383 >39 662 16.4 875A 2.2 163 7.3 383A 18.0 663 7.3 875V 3.2 164 1.6 383V >39 664 2.9 876A 2.7 165 1.4 385 >39 664A 1.7 876B 2.7 166 2.4 385A 20.1 664V 23.7 877A 1.1 167 1.3 385V >39 665 7.3 877B 1.1 168 0.3 387 >39 666 2.3 878V 3.4 169 0.2 387A 24.2 666A 26.9 879B 9.3 170 2.9 387V >39 666V 1.3 880A >39 171 2.0 389A 3.1 667 1.1 880V 1.9 172 18.5 389V 22.3 667A 0.9 881B 9.3 173 0.6 429A 33.1 667B 8.7 881A >39 174 8.0 429V 0.2 668 1.4 882 0.3 175 1.2 430V 0.4 668A 0.7 883 0.4 176 8.5 432 V 0.5 668V 8.4 884 0.5 177 1.8 434V 0.4 687 6.2 885 0.5 178 0.8 436V 0.3 688 3.7 886 0.7 179 0.3 438V 0.4 689 27.9 887 0.9 180 1.6 440V 0.2 691 27.6 888A >39 181 6.2 442 V 0.4 691A 12.06 889A 5.9 182 2.9 444V 0.2 691B >39 889B 1.9 183 4.6 446V 0.9 700 3.4 890A 18.7 184 25.5 448V 0.8 701 3.9 890V 5.4 185 3.2 450V 0.3 702 25.5 891A 14.6 186 15.8 452 V 0.3 703 10.1 891B 5.7 187 15.9 454V 0.1 703A 4.0 892A 3.6 188 2.6 456V 0.3 703B 37.2 892B 2.9 189 1.4 548 0.6 706 4.5 892C >39 190 4.0 458V 0.4 707 2.9 892D >39 191 14.3 459 4.5 708 1.4 893A 1.2 192 0.6 462A 0.2 711 24.6 893B 1.0 193 1.7 462 V 0.4 711A 10.1 893С >39 194 0.4 463V 0.4 711B >39 893D >39 195 0.4 465V 0.3 714 12.4 894A >39 196 0.4 467V 0.8 714A 6.8 894B >39 197 2.7 469V 0.6 714B >39 894С 3.3 198 0.5 473B 0.2 717 7.3 894D 3.0

Biological example B-2. Myocyte tests.

(i) Preparation of adult rat ventricular myocytes.

Adult male Sprague-Dawley rats were anesthetized, hearts were quickly excised, washed, and the ascending aorta was cannulated. The hearts were started on continuous retrograde perfusion at a perfusion pressure of 60 cm H ₂ O. The hearts were first perfused with a nominal modified Krebs solution without Ca ²⁺ of the following composition: 113 mM NaCl, 4.7 mM KCl, 0.6 mM KH ₂ PO ₄ , 0.6 mM Na ₂ HPO ₄ , 1.2 mM MgSO ₄ , 12 mM NaHCO ₃ , 10 mM KHCO ₃ , 30 mM taurine, 5.5 mM glucose, and 10 mM Hepes (all from Sigma). This medium was not recirculated and was a mixture of 95% O ₂ /5% CO ₂ . After approximately 3 min, the heart was perfused with modified Krebs buffer supplemented with collagenase (Worthington) and 12.5 μM final calcium concentration. The heart was removed from the cannulas after it became pale and soft. The atria and vessels were removed, and the ventricles were carefully dissected into smaller pieces using forceps. The tissue was homogenized by repeated pipetting and the collagenase reaction was stopped with 10% bovine calf serum (BCS), sedimentation and resuspension in perfusion buffer containing 5% BCS and 12.5 μM CaCl ₂ . Myocytes were made calcium tolerant by stepwise addition of CaCl ₂ solution to a final concentration of 1.2 mM. Cells were then washed and resuspended in Tyrode's buffer (137 mM NaCl, 3.7 mM KCl, 0.5 mM MgCl, 11 mM glucose, 4 mM Hepes and 1.2 mM CaCl ₂ , pH 7.4). Cells were stored for

- 369 045362 min at 37°C before experiments and used within 5 h after isolation. Cell preparations were used only if cells first met QC criteria by demonstrating a contractile response to standard (>150% basal) and isoproterenol (ISO; >250% basal) treatments. Additionally, in subsequent compound experiments, only cells with basal contractility between 3 and 8% were used.

(ii) Experiments related to the compressibility of gastric myocytes.

Aliquots of myocytes in Tyrode buffer were placed in perfusion chambers (Series 20 RC-27NE; Warner Instruments) complete with heating platforms. Myocytes were allowed to attach, chambers were heated to 37°C, and cells were perfused at 37°C with Tyrode buffer. Myocytes were stimulated with a field at 1 Hz using platinum electrodes (20% above threshold). Only cells that had clear striations and were inactive before stimulation were used for contraction experiments. To determine basal contractility, myocytes were imaged through a 40x objective. Using a charge-coupled device camera with a variable frame rate (60–240 Hz), images were digitized and displayed on a computer screen at a sampling rate of 240 Hz (IonOptix Milton, MA). Once cell contraction became stable over time, test compounds (0.01-15 μM) were perfused into the chambers on the myocytes for 5 min. Myocyte contractility and contraction and relaxation rates were then recorded using edge detection.

(iii) Contractility analysis.

Five or more individual myocytes were tested against a compound of two or more different myocyte preparations. For each cell, twenty or more short-term contractions were averaged and compared at basal (defined as 1 min before compound infusion) and after compound addition (defined 5 min after the start of compound perfusion). These midtones were analyzed using IonWizard software (IonOptix) to determine changes in diastolic length and fractional shortening. Contraction fraction was calculated as: ((resting length - length at peak contraction) divided by resting length). The percentage change in fractional shortening from baseline was calculated as: ((post-dose fractional shortening / basal fractional shortening) x 100). The percentage reduction in contraction fraction relative to the baseline was calculated as: (100% change in contraction fraction relative to the baseline). The maximum contraction and relaxation rates (µm/s) were also determined. Results from individual cells were averaged and SEM was calculated.

The effect of compounds on fractional shortening (FS) of myocytes is demonstrated in Table. IN.

Table B

Connection No. Concentration (µM) %FS (% REDUCTION RELATIVELY ISOLINES) ± SEM Ns TEST SUBJECTS CELLS 206 10 95.1±1.6 6 202 5 68.4±9.5 7 373A 10 76.6±8.8 5 288A 5 64.4 ±9.7 6 861A 5 88.0 ±3.31 5 633A 1 77.5 ±5.26 6

% reduction in FS = 100 - (average for each cell (FS after injection / before FS injection) x 100).

Biological example B-3. Echocardiographic assessment of the acute pharmacodynamic effect of cardiac contraction in rats.

In vivo assessment of cardiac function by echocardiography was performed in male SpregDawley rats under isoflurane (1-3%) anesthesia. 2-D M-mode images of the left ventricle were obtained in a parasternal long-axis view before, during, and after administration of compounds by continuous intravenous infusion or oral gavage. In vivo contraction fraction was determined by M-mode image analysis with the following calculation: ((End-diastolic diameter - end-systolic diameter) / End-diastolic diameter x 100). For continuous infusion experiments, three initial predose M-mode contour images were taken at 1-min intervals prior to compound infusion. Compounds were formulated in 50% propylene glycol (PEG): 16% captisol: 10% dimethylacetamide (DMA) and delivered through a jugular venous catheter at a rate of 1 ml/kg/hour. During infusion, M-mode images were taken at 5-minute intervals. The infusion was stopped when the contraction fraction reached 60% reduction relative to the baseline. Blood samples were collected to determine plasma concentrations of compounds. Data were presented as an estimated IC50 value, which is the concentration at which the contractile fraction is 50% of the predose contractile isoline. The results of IC ₅₀ 370 045362 are summarized in Table. WITH.

Table C

Connection No. !C50 (Mean ± SD, µM) 150 5.44 ±0.12 202 3.24 ± 0.07

For oral administration studies, three predose M-mode baseline images were taken at 1-min intervals prior to compound administration. Compounds were formulated in a 0.5% hydroxypropyl methylcellulose 2910 (HPMC 2910): 0.1% Tween 80 suspension and delivered as a single dose (5 mL/kg) via gavage. One and four hours after dosing, rats were lightly anesthetized for M-mode echocardiography measurements. The effect of the compound on cardiac shortening fractions is presented as a percentage reduction in the initial shortening fractions (=100%) in Table. D.

Table D

Connection No. Dose (mg/kg) FS (% reduction from baseline) at 1 h (Mean ± SEM) FS (% reduction from baseline) at 4 h (Mean ± SEM) 202 3 21.88 ±2.66 11.25 ±5.54 15 51.08 ± 1.93 20.18 ±3.59 278 3.0 15.8 + 2.0 10.6 ±5.6 6.0 34.4 ± 3.3 12.2 ±4.2 484A 2.5 21.4 ±2.4 6.1 ±3.0 5.0 49.7 ±3.7 14.3 ±5.3 339 2.5 21.8 ± 2.8 5.8 ±4.4 5.0 66.2 ±2.9 19.9 ±2.0 179 3.0 33.8 ±2.6 4.5 ±4.2 6.0 51.9 ±4.0 15.0 ±5.4 877A 9.0 12.0 ± 1.9 7.5 ± 1.5 30.0 49.6 + 4.6 43.3 ±5.5 861A 10 13.4 ± 1.6 2.0 ±3.1 100 50.0 ±4.0 48.8 ±5.0 650A 10.0 7.0 ±2.1 -3.2 ± 1.1 70.0 59.7 ±3.8 51.8 ±2.3 633A 20.0 25.2 ±2.1 1.1 ±3.5 50.0 54.8 + 1.8 33.0 ±3.0 646A 37.5 28.4 ±4.2 6.9 ±6.0 100 57.5 ±2.0 35.4 ± 6.4 666V 25 10.4 ± 1.3 0.6 ±3.1 100 53.2 ± 1.1 29.8 ±3.7

Simultaneously with the echocardiographic measurements, blood samples are collected to determine the corresponding plasma concentration of the compound, which can be expressed as IC ₅₀ and IC ₁₀ values, which represent the concentration at which the fractional shortening is 50% and 10% of the predose contractility isoline. respectively.

Biological example B-4. Longitudinal echocardiographic evaluation of a mouse model of NSM.

In vivo assessment of cardiac function by echocardiography is performed using a previously described mouse model of familial hypertrophic cardiomyopathy, which is derived from an arginine and glutamine mutation at residue 403 (R403Q) of the cardiac alpha-myosin heavy chain (MHC) gene (Geisterfer-Lowrance et al. , Science. 1996 May 3;272(5262):731-4). Cardiac dysfunction, fibrosis, and measures of cardiac hypertrophy (including ventricular wall thickness) increase with age in this mouse model (Geisterfer-Lowrance, supra; Jiang et al., Science. 2013, 342(6154):111-4).

R403Q mice receive vehicle or test compound formulated with food for 24 weeks. Longitudinal echocardiography measurements are performed every 4 weeks. Echocardiography measurements are performed in mice under isoflurane (1-3%) anesthesia. 2-D M-mode images of the left ventricle are obtained as a short-axis view. In vivo, the contraction fraction is determined by M-mode image analysis with the following calculation: ((End diastolic diameter - ko

- 371 045362 end systolic diameter) / end diastolic diameter x 100).

Biological example B-5. Reduction of fibrosis in a rat model of cardiac hypertrophy.

Fibrosis reduction was assessed using Dahl salt-sensitive (DSS) rats, a previously reported rat model of hypertension-induced heart failure with preserved ejection fraction (Fillmore et al., Mol Med. 2018, 24(1):3; Dahl et al., J Exp Med. 1962, 115:117390). DSS rats fed a high-salt diet exhibit progressive cardiovascular dysfunction, including increased systolic blood pressure, diastolic dysfunction, cardiac hypertrophy, and cardiac fibrosis (Fillmore, supra; Dahl, supra; Sakata et al., J Am Coll Cardiol. 2001 Jan;37(1):293-9; Kim-Mitsuyama et al., Hypertens Res. 2004 Oct;27(10):771-9). DSS rats are administered vehicle or test compound formulated with a low- or high-salt diet for 8 weeks. Perivascular and interstitial cardiac tissue samples are imaged and analyzed for % cardiac fibrosis.

While the foregoing written description of the compounds, uses, and methods described herein will enable one skilled in the art to make and use the compounds, uses, and methods described herein, those skilled in the art will understand and appreciate that variations, combinations, and equivalents of a particular embodiment, method and examples herein. The compounds, uses and methods proposed herein are therefore not intended to be limited to the embodiments, methods or examples described above, but rather cover all embodiments and methods within the scope and spirit of the compounds, uses and methods proposed herein.

All references disclosed herein are incorporated by reference in their entirety.

Claims (32)

1. Compound of formula (I): O R ⁵ O (O or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of phenyl and pyridyl, each of which is unsubstituted or substituted with 1-4 substituents selected from the group consisting of cyano, halogen, unsubstituted C1-C6 alkoxy, C ₁ -C ₆ -alkyl, which is unsubstituted or substituted with 1-3 fluorine, and diazirinyl, which is unsubstituted or substituted with one trifluoromethyl; r ^2a , r ^2b , r ³ and R ⁴ are defined by any of (i)-(iii): (i) R ^2a represents H or unsubstituted C ₁ -C ₆ -alkyl; R ^2B is selected from the group consisting of H; C3-C7-cycloalkyl, which is unsubstituted or substituted with 1-5 hydroxyl, unsubstituted _C1 - _C6 -alkyl, unsubstituted _C1 - _C6- aminoacyl, unsubstituted C1-C6alkoxy, unsubstituted _C1 - _C6- alkoxycarbonyl or hydroxymethyl; -CH ₂ N(H)C(O)CH ₃ ; -CH2CH2SCH3; -CH2CH2S(O)2CH3; -CH2CH2CONH2; 4-7 membered heterocyclyl which contains 1-4 N, O or S atoms and which is unsubstituted or substituted with 1-5 unsubstituted C ₁ -C ₆ alkyl, unsubstituted C ₁ -C ₆ acyl or unsubstituted C ₁ -C ₆ -aminoacyl; unsubstituted C ₆ -C ₁₀ -aryl; unsubstituted 5-12 membered heteroaryl, which contains 1-4 N, O or S atoms; and C ₁ -C ₆ -alkyl, which is unsubstituted or substituted with 1-3 halogen, hydroxyl, C ₁ -C ₆ -alkoxy, which is unsubstituted or substituted with 1-3 halogen or 4-7-membered heterocyclyl, which contains 1-4 atoms N, O or S and which is unsubstituted or substituted with 1-5 unsubstituted C ₁ -C ₆ -alkyl; R ³ represents phenyl or pyridyl, wherein said phenyl is substituted with 2-5 substituents selected from the group consisting of cyano and halogen, and wherein said pyridyl is unsubstituted or substituted with 1-4 substituents selected from the group consisting of halogen, cyano, unsubstituted C ₁ -C ₆ -alkyl, unsubstituted C ₂ -C ₆ -alkenyl and C ₁ -C ₆ -alkoxy, which is unsubstituted or substituted with 1-3 halogen; And R ⁴ represents H, unsubstituted C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkyl substituted with 1-3 unsubstituted C ₁ -C ₆ -alkoxy; or (ii) R ^2a represents H or unsubstituted C ₁ -C ₆ -alkyl; R ^2B represents phenyl or pyridyl, each of which is unsubstituted or substituted with 1-4 substituents selected from the group consisting of halogen, unsubstituted C1-C6 alkoxy and C ₁ -C ₆ alkyl, which is unsubstituted or substituted with 1-3 halogen; And R ³ represents unsubstituted C ₂ -C ₄ -alkyl; And R ⁴ represents H, unsubstituted C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkyl substituted with 1-3 unsubstituted C ₁ -C ₆ -alkoxy; or - 372 045362 (iii) R ^2a and R ^2b are taken together with the carbon atom to which they are attached to form G ¹ , where G ¹ represents a C ₃ -C ₇ cycloalkyl or a 4-7 membered heterocyclyl which contains 1 -4 N, O or S atoms, wherein each G ¹ is optionally fused to a phenol ring, wherein when G ¹ is C ₃ -C ₇ -cycloalkyl, it is unsubstituted or substituted with 1-5 substituents selected from the group consisting of from: halogen; hydroxyl; C ₆ -C ₁₀ -aryl, which is unsubstituted or substituted with 1-5 halogen, cyano, hydroxyl, unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted C1-C ₆ -alkoxycarbonyl, unsubstituted carboxyl, unsubstituted With ₆ -C ₁₀ -aryl, unsubstituted amino, amino, substituted 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C1-C ₆ -aminoacyl or C1-C ₆ -aminoacyl, substituted 1-2 unsubstituted C1-C ₆ - alkyl; 5-12 membered heteroaryl which contains 1-4 N, O or S atoms and which is unsubstituted or substituted with 1-4 halogen, cyano, unsubstituted C1- _C6 alkyl or unsubstituted _C3 - _C7 cycloalkyl; unsubstituted C1-C ₆ -alkoxycarbonyl; C1- _C6- aminoacyl, which is unsubstituted or substituted with 1-2 unsubstituted C1- _C6 -alkyl, unsubstituted _C3 - _C7- cycloalkyl or unsubstituted 4-7-membered heterocyclyl, which contains 1-4 N, O or S atoms ; C1-C ₆ -acyl, which is unsubstituted or substituted with 1-3 unsubstituted 4-7-membered heterocyclyl, which contains 1-4 N, O or S atoms, unsubstituted C ₆ -C ₁₀ -aryl or C ₆ -C ₁₀ -aryl , substituted with 1-5 unsubstituted amino; unsubstituted aminothionyl; unsubstituted aminosulfonyl; aminocarbonylamino, which is unsubstituted or substituted with 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl or unsubstituted 4-7-membered heterocyclyl, which contains 1-4 N, O or S atoms; And C1- _C6 alkyl, which is unsubstituted or substituted with 1-3 halogen or hydroxyl; and wherein G ¹ is a 4-7 membered heterocyclyl which contains 1-4 N, O or S atoms, it is unsubstituted or substituted with 1-5 substituents selected from the group consisting of: halogen; hydroxyl; oxo; C ₆ -C ₁₀ -aryl, which is unsubstituted or substituted with 1-5 halogen, cyano, hydroxyl, unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted C1-C ₆ -alkoxycarbonyl, unsubstituted carboxyl, unsubstituted With ₆ -C ₁₀ -aryl, unsubstituted amino, amino, substituted 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C1-C ₆ -aminoacyl or C1-C ₆ -aminoacyl, substituted 1-2 unsubstituted C1-C ₆ - alkyl; 5-12 membered heteroaryl, which contains 1-4 N, O or S atoms and which is unsubstituted or substituted with 1-4 halogen, hydroxyl, cyano, unsubstituted C1-C ₆ -alkyl, unsubstituted C ₆ -C ₁₀ -aryl, unsubstituted With ₃ -C ₇ -cycloalkyl, unsubstituted C1-C ₆ -alkoxycarbonyl, unsubstituted carboxyl, unsubstituted C1-C ₆ -alkoxy or unsubstituted C1-C ₆ -aminoacyl; unsubstituted C1-C ₆ -alkoxycarbonyl; C1-C ₆ -aminoacyl, which is unsubstituted or substituted with 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted C ₆ -C ₁₀ -aryl, unsubstituted C1-C ₆ -alkoxyalkyl, unsubstituted 4 -7-membered heterocyclyl, which contains 1-4 N, O or S atoms, or unsubstituted 5-12-membered heteroaryl, which contains 1-4 N, O or S atoms; C1-C ₆ -acyl, which is unsubstituted or substituted with 1-3 unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted 4-7-membered heterocyclyl, which contains 1-4 atoms N, O or S, unsubstituted C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ -aryl substituted with 1-5 unsubstituted amino; pyridin-on-yl, which is unsubstituted or substituted with 1-4 unsubstituted C1-C ₆ -alkyl; aminothionyl, which is unsubstituted or substituted with 1-2 unsubstituted C1-C ₆ -alkyl; aminosulfonyl, which is unsubstituted or substituted with 1-2 unsubstituted C1- _C6 alkyl; aminocarbonylamino which is unsubstituted or substituted with 1-2 unsubstituted C1- _C6 alkyl, unsubstituted C3-C7 cycloalkyl or unsubstituted 4-7 membered heterocyclyl which contains 1-4 N, O or S atoms; unsubstituted 9-membered bicyclic heterocyclyl, which contains 1-4 N, O or S atoms, and C1- _C6 alkyl, which is unsubstituted or substituted with 1-3 halogen or hydroxyl; R ³ is selected from the group consisting of unsubstituted C ₂ -C ₆ -alkyl; C1- _C6 alkyl substituted with 1-3 unsubstituted C1- _C6 alkoxy, cyano or halogen; C ₃ -C ₇ -cycloalkyl, which is unsubstituted or substituted with 1-5 unsubstituted C1-C ₆ -alkyl, cyano or halogen; unsubstituted 4-7-membered heterocycle - 373 045362 la, which contains 1-4 atoms of N, O or S; C ₆ -C ₁₀ -aryl, which is unsubstituted or substituted with 1-5 nitro, unsubstituted C1-C ₆ -alkoxy, C1-C ₆ -alkoxy, substituted with 1-3 halogen, halogen, unsubstituted C ₃ C ₇ -cycloalkyl, cyano, unsubstituted C ₂ -C ₆ -alkenyl, unsubstituted C1-C ₆ -alkoxycarbonyl, unsubstituted phenylcarbonyl or unsubstituted C1-C ₆ -alkyl; and 5-12 membered heteroaryl which contains 1-4 N, O or S atoms and which is unsubstituted or substituted with 1-4 halogen, cyano or unsubstituted C1- _C6 alkyl; And R ⁴ represents H or unsubstituted C1-C ₆ -alkyl; And R ⁵ represents H, unsubstituted C1-C ₆ -alkyl or C1-C ₆ -alkyl substituted with 1-3 hydroxyl; wherein, when one of provisions (a)-(b) is used, then R ¹ represents unsubstituted pyridyl, or pyridyl or phenyl substituted with 1-4 substituents selected from the group consisting of cyano, halogen, unsubstituted C1- _C6 -alkoxy, unsubstituted C1-C ₆ -alkyl, C1-C ₆ -alkyl substituted with 1-3 fluorine, unsubstituted diazirinyl and diazirinyl substituted with one trifluoromethyl, where the phenyl is substituted with 1-4 substituents other than methyl or methoxy: (a) R ^2a and R ^2b are as defined in (i), and R ³ is phenyl substituted with 2 to 5 substituents selected from the group consisting of cyano and halogen; (b) R2 ^a and R ³ are as defined in (ii), and R ^2B is 4-methoxyphenyl. 2. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ^2a represents H or unsubstituted C1- _C6 alkyl; R ^2B is selected from the group consisting of H; C ₃ -C ₇ -cycloalkyl, which is unsubstituted or substituted with 1-5 hydroxyl, unsubstituted C1-C ₆ -alkyl, unsubstituted C1-C ₆ -aminoacyl, unsubstituted C1-C6 alkoxy, unsubstituted C1-C ₆ -alkoxycarbonyl or hydroxymethyl; -CH ₂ N(H)C(O)CH ₃ ; -CH ₂ CH ₂ SCH ₃ ; -CH ₂ CH ₂ S(O) ₂ CH ₃ ; -CH ₂ CH ₂ CONH ₂ ; a 4-7 membered heterocyclyl which contains 1-4 N, O or S atoms and which is unsubstituted or substituted with 1-5 unsubstituted C1-C ₆ -alkyl, unsubstituted C1-C ₆ -acyl or unsubstituted C1-C ₆ -aminoacyl; unsubstituted C ₆ -C ₁₀ -aryl; unsubstituted 5-12 membered heteroaryl, which contains 1-4 N, O or S atoms; and C1-C ₆ -alkyl, which is unsubstituted or substituted with 1-3 halogen, hydroxyl, C1-C ₆ -alkoxy, which is unsubstituted or substituted with 1-3 halogen or 4-7-membered heterocyclyl, which contains 1-4 N atoms, O or S and which is unsubstituted or substituted with 1-5 unsubstituted C1-C ₆ -alkyl; And R ³ represents phenyl or pyridyl, wherein said phenyl is substituted with 2-5 substituents selected from the group consisting of cyano and halogen, and wherein said pyridyl is unsubstituted or substituted with 1-4 substituents selected from the group consisting of halogen, cyano, unsubstituted C1-C ₆ -alkyl, unsubstituted C ₂ -C ₆ -alkenyl and C1-C ₆ -alkoxy, which is unsubstituted or substituted with 1-3 halogen. 3. A compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein R ³ is phenyl substituted with 2-5 substituents selected from the group consisting of cyano and halogen, or pyridyl which is unsubstituted or substituted with 1-4 substituents selected from the group consisting of halogen, cyano, unsubstituted C1- _C6 alkyl, unsubstituted _C2 - _C6 alkenyl and C1- _C6 alkoxy which is unsubstituted or substituted with 1-3 halogen; for example, where R ³ represents phenyl substituted with 2-5 halogen substituents selected from the group consisting of F and Cl; in particular, where R ³ is further substituted with one, two or three -CN substituents. 4. A compound or a pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein R ^2A represents a substituted C1-C ₆ alkyl. 5. A compound or a pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein R ^2A represents H. 6. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 5, wherein R ^2B represents a C1-C6 alkyl which is unsubstituted or substituted with 1-3 halogen, hydroxyl, C1-C6 alkoxy which is unsubstituted or substituted with 1 -3 halogen, or 4-7 membered heterocyclyl, which contains 1-4 N, O or S atoms and which is unsubstituted or substituted with 1-4 unsubstituted C1-C6 alkyl; (i) for example, wherein R ^2B is selected from the group consisting of methyl, hydroxymethyl and isopropyl; or (ii) for example, where R ^2B represents a C1-C6 alkyl substituted by a) 1-3 C1- _C6 alkoxy, which is unsubstituted or substituted with 1-3 halogen, or b) 1-3 oxetanyl, which is unsubstituted or substituted with 1-5 unsubstituted C1-C ₆ -alkyl; in particular, where R ^2B represents methyl substituted with 1-3 unsubstituted 3-oxetanyl; or (iii), for example, where R ^2B represents a C3-C7 cycloalkyl which is unsubstituted or substituted with 1-5 hydroxyl, unsubstituted C1-C6 alkyl, unsubstituted C1-C6 aminoacyl, unsubstituted C1-C6 alkoxy, unsubstituted C1 -C6-alkoxycarbonyl or hydroxymethyl; in particular, wherein R ^2B is cyclobutanyl which is unsubstituted or substituted with 1-5 hydroxyl, unsubstituted C1-C6 alkyl, unsubstituted C1- _C6 aminoacyl, unsubstituted C1- _C6 alkoxy, unsubstituted C1- _C6 alkoxycarbonyl, or hydroxymethyl; or (iv) for example, where R ^2B represents a 4-7 membered heterocyclyl which contains 1-4 N, O or S atoms and which is unsubstituted or substituted with 1-5 unsubstituted C1-C6 alkyl, unsubstituted C1-C6 acyl or unsubstituted C1-C6-aminoacyl; in particular, where R ^2B represents oxetanyl, which is unsubstituted or substituted with 1-5 unsubstituted C1-C6 alkyl, - 374 045362 unsubstituted C1-C ₆ -acyl or unsubstituted C1-C ₆ -aminoacyl; in particular, where R ^2B represents 3-oxetanyl, which is unsubstituted or substituted with 1-5 unsubstituted C1- _C6 alkyl, unsubstituted C1- _C6 acyl or unsubstituted C1- _C6 aminoacyl. 7. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ^2a represents H or unsubstituted C1- _C6 alkyl; R ^2b is phenyl or pyridyl, each of which is unsubstituted or substituted with 1-4 substituents selected from the group consisting of halogen, unsubstituted C1-C ₆ alkoxy and C ₁ -C ₆ alkyl, which is unsubstituted or substituted with 1-3 halogen; And R ³ represents unsubstituted C ₂ -C ₄ -alkyl. 8. A compound or a pharmaceutically acceptable salt thereof according to claim 7, wherein R ^2A represents H. 9. A compound or a pharmaceutically acceptable salt thereof according to claim 7 or 8, wherein R ^2B represents phenyl or pyridyl, each of which is substituted with 1-4 substituents selected from the group consisting of halogen, unsubstituted C1-C6 alkoxy and C1 -C6-alkyl, which is unsubstituted or substituted with 1-3 halogen; for example, where R ^2B represents phenyl or pyridyl, each of which is substituted with 1-4 substituents independently selected from the group consisting of halogen, unsubstituted C1C6 alkoxy and C1- _C6 alkyl substituted with 1-3 halogen; in particular, where R ^2B represents phenyl or pyridyl, each of which is substituted with 1-4 -SB ₃ or methoxy. 10. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 7 to 9, wherein R ³ is isopropyl. 11. A compound or a pharmaceutically acceptable salt thereof according to claim 1, where R ^2a and R ^2b are taken together with the carbon atom to which they are attached to form G ¹ , where G ¹ represents a C ₃ -C ₇ cycloalkyl or a 4-7 membered heterocyclyl, which contains 1-4 N, O atoms or S, wherein each G ¹ is optionally fused to a phenol ring, wherein when G ¹ is C ₃ -C ₇ -cycloalkyl, it is unsubstituted or substituted with 1-5 substituents selected from the group consisting of: halogen; hydroxyl; C ₆ -C ₁₀ -aryl, which is unsubstituted or substituted with 1-5 halogen, cyano, hydroxyl, unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted C1-C ₆ -alkoxycarbonyl, unsubstituted carboxyl, unsubstituted With ₆ -C ₁₀ -aryl, unsubstituted amino, amino, substituted 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C1-C ₆ -aminoacyl or C1-C ₆ -aminoacyl, substituted 1-2 unsubstituted C1-C ₆ - alkyl; 5-12 membered heteroaryl which contains 1-4 N, O or S atoms and which is unsubstituted or substituted with 1-4 halogen, cyano, unsubstituted C1- _C6 alkyl or unsubstituted _C3 - _C7 cycloalkyl; unsubstituted C1-C ₆ -alkoxycarbonyl; C1- _C6- aminoacyl, which is unsubstituted or substituted with 1-2 unsubstituted C1- _C6 -alkyl, unsubstituted _C3 - _C7- cycloalkyl or unsubstituted 4-7-membered heterocyclyl, which contains 1-4 N, O or S atoms ; C1-C ₆ -acyl, which is unsubstituted or substituted with 1-3 unsubstituted 4-7-membered heterocyclyl, which contains 1-4 N, O or S atoms, unsubstituted C ₆ -C ₁₀ -aryl or C ₆ -C ₁₀ -aryl , substituted with 1-5 unsubstituted amino; unsubstituted aminothionyl; unsubstituted aminosulfonyl; aminocarbonylamino, which is unsubstituted or substituted with 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl or unsubstituted 4-7-membered heterocyclyl, which contains 1-4 N, O or S atoms; And C1- _C6 alkyl, which is unsubstituted or substituted with 1-3 halogen or hydroxyl; and wherein G ¹ is a 4-7 membered heterocyclyl which contains 1-4 N, O or S atoms, it is unsubstituted or substituted with 1-5 substituents selected from the group consisting of: halogen; hydroxyl; oxo; C ₆ -C ₁₀ -aryl, which is unsubstituted or substituted with 1-5 halogen, cyano, hydroxyl, unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted C1-C ₆ -alkoxycarbonyl, unsubstituted carboxyl, unsubstituted C6-C10-aryl, unsubstituted amino, amino substituted with 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C1-C ₆ -aminoacyl or C1-C ₆ -aminoacyl substituted with 1-2 unsubstituted C1-C ₆ -alkyl; 5-12 membered heteroaryl, which contains 1-4 N, O or S atoms and which is unsubstituted or substituted with 1-4 halogen, hydroxyl, cyano, unsubstituted C1-C ₆ -alkyl, unsubstituted C ₆ -C ₁₀ -aryl, unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted C1-C ₆ -alkoxycarbonyl, unsubstituted carboxyl, unsubstituted C ₁ -C ₆ -alkoxy or unsubstituted C ₁ -C ₆ -aminoacyl; - 375 045362 unsubstituted C1-C ₆ -alkoxycarbonyl; C1-C ₆ -aminoacyl, which is unsubstituted or substituted with 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted C ₆ -Ciu-aryl, unsubstituted C1-C ₆ -alkoxyalkyl, unsubstituted 4- 7-membered heterocyclyl, which contains 1-4 N, O or S atoms, or unsubstituted 5-12-membered heteroaryl, which contains 1-4 N, O or S atoms; C1-C ₆ -acyl, which is unsubstituted or substituted with 1-3 unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted 4-7-membered heterocyclyl, which contains 1-4 atoms N, O or S, unsubstituted C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ -aryl substituted with 1-5 unsubstituted amino; pyridin-on-yl, which is unsubstituted or substituted with 1-4 unsubstituted C1-C ₆ -alkyl; aminothionyl, which is unsubstituted or substituted with 1-2 unsubstituted C1-C ₆ -alkyl; aminosulfonyl, which is unsubstituted or substituted with 1-2 unsubstituted C1- _C6 alkyl; aminocarbonylamino, which is unsubstituted or substituted with 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl or unsubstituted 4-7-membered heterocyclyl, which contains 1-4 N, O or S atoms; unsubstituted 9-membered bicyclic heterocyclyl, which contains 1-4 N, O or S atoms, and C1- _C6 alkyl, which is unsubstituted or substituted with 1-3 halogen or hydroxyl; And R ³ is selected from the group consisting of unsubstituted C ₂ -C ₆ -alkyl; C1- _C6 alkyl substituted with 1-3 unsubstituted C1- _C6 alkoxy, cyano or halogen; C ₃ -C ₇ -cycloalkyl, which is unsubstituted or substituted with 1-5 unsubstituted C1-C ₆ -alkyl, cyano or halogen; unsubstituted 4-7-membered heterocyclyl, which contains 1-4 N, O or S atoms; C ₆ -C ₁₀ -aryl, which is unsubstituted or substituted with 1-5 nitro, unsubstituted C1-C ₆ -alkoxy, C1-C ₆ -alkoxy, substituted with 1-3 halogen, halogen, unsubstituted C ₃ C ₇ -cycloalkyl, cyano, unsubstituted C ₂ -C ₆ -alkenyl, unsubstituted C1-C ₆ -alkoxycarbonyl, unsubstituted phenylcarbonyl or unsubstituted C1-C ₆ -alkyl; and a 5-12 membered heteroaryl which contains 1-4 N, O or S atoms and which is unsubstituted or substituted with 1-4 halogen, cyano or unsubstituted C1- _C6 alkyl. 12. The compound or its pharmaceutically acceptable salt according to claim 11, where G ¹ is selected from the group consisting of unsubstituted 2,3-dihydro-1H-indene, C ₃ -C ₇ -cycloalkyl and 4-7-membered heterocyclyl, which contains 1-4 atoms N, O or S, wherein when G ¹ represents C ₃ -C ₇ -cycloalkyl, it is unsubstituted or substituted with 1-5 substituents selected from the group consisting of: halogen; hydroxyl; C ₆ -C ₁₀ -aryl, which is unsubstituted or substituted with 1-5 halogen, cyano, hydroxyl, unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted C1-C ₆ -alkoxycarbonyl, unsubstituted carboxyl, unsubstituted With ₆ -C ₁₀ -aryl, unsubstituted amino, amino, substituted 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C1-C ₆ -aminoacyl or C1-C ₆ -aminoacyl, substituted 1-2 unsubstituted C1-C ₆ - alkyl; 5-12 membered heteroaryl which contains 1-4 N, O or S atoms and which is unsubstituted or substituted with 1-4 halogen, cyano, unsubstituted C1- _C6 alkyl or unsubstituted _C3 - _C7 cycloalkyl; unsubstituted C1-C ₆ -alkoxycarbonyl; C1- _C6- aminoacyl, which is unsubstituted or substituted with 1-2 unsubstituted C1- _C6 -alkyl, unsubstituted C3-C7-cycloalkyl or unsubstituted 4-7-membered heterocyclyl, which contains 1-4 N, O or S atoms; C1-C ₆ -acyl, which is unsubstituted or substituted with 1-3 unsubstituted 4-7-membered heterocyclyl, which contains 1-4 N, O or S atoms, unsubstituted C ₆ -C ₁₀ -aryl or C ₆ -C ₁₀ -aryl , substituted with 1-5 unsubstituted amino; unsubstituted aminothionyl; unsubstituted aminosulfonyl; aminocarbonylamino, which is unsubstituted or substituted with 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl or unsubstituted 4-7-membered heterocyclyl, which contains 1-4 N, O or S atoms; And C1- _C6 alkyl, which is unsubstituted or substituted with 1-3 halogen or hydroxyl; and wherein G ¹ is a 4-7 membered heterocyclyl which contains 1-4 N, O or S atoms, it is unsubstituted or substituted with 1-5 substituents selected from the group consisting of: halogen; hydroxyl; oxo; C ₆ -C ₁₀ -aryl, which is unsubstituted or substituted with 1-5 halogen, cyano, hydroxyl, unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted C1-C ₆ -alkoxycarbonyl, unsubstituted carboxyl, unsubstituted With ₆ -C ₁₀ -aryl, unsubstituted amino, amino, substituted 1-2 - 376 045362 unsubstituted C1-C ₆ -alkyl, unsubstituted C1-C ₆ -aminoacyl or C1-C ₆ -aminoacyl substituted with 1-2 unsubstituted C1-C6-alkyl; 5-12 membered heteroaryl, which contains 1-4 N, O or S atoms and which is unsubstituted or substituted with 1-4 halogen, hydroxyl, cyano, unsubstituted C1-C ₆ -alkyl, unsubstituted C ₆ -C ₁₀ -aryl, unsubstituted With ₃ -C ₇ -cycloalkyl, unsubstituted C1-C ₆ -alkoxycarbonyl, unsubstituted carboxyl, unsubstituted C1-C ₆ -alkoxy or unsubstituted C1-C ₆ -aminoacyl; unsubstituted C1-C ₆ -alkoxycarbonyl; C1-C ₆ -aminoacyl, which is unsubstituted or substituted with 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted C ₆ -C ₁₀ -aryl, unsubstituted C1-C ₆ -alkoxyalkyl, unsubstituted 4 -7-membered heterocyclyl, which contains 1-4 N, O or S atoms, or unsubstituted 5-12-membered heteroaryl, which contains 1-4 N, O or S atoms; C1-C ₆ -acyl, which is unsubstituted or substituted with 1-3 unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted 4-7-membered heterocyclyl, which contains 1-4 atoms N, O or S, unsubstituted C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ -aryl substituted with 1-5 unsubstituted amino; pyridin-on-yl, which is unsubstituted or substituted with 1-4 unsubstituted C1-C ₆ -alkyl; aminothionyl, which is unsubstituted or substituted with 1-2 unsubstituted C ₁ -C ₆ -alkyl; aminosulfonyl, which is unsubstituted or substituted with 1-2 unsubstituted C ₁ -C ₆ -alkyl; aminocarbonylamino, which is unsubstituted or substituted with 1-2 unsubstituted C ₁ -C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl or unsubstituted 4-7-membered heterocyclyl, which contains 1-4 N, O or S atoms; unsubstituted 9-membered bicyclic heterocyclyl, which contains 1-4 N, O or S atoms, and C1- _C6 alkyl, which is unsubstituted or substituted with 1-3 halogen or hydroxyl; (i) for example, where G ¹ is selected from the group consisting of: where * indicates the point of attachment to the original structure; where when G ¹ is or it is unsubstituted or substituted with 1-5 substituents selected from the group consisting of: halogen; hydroxyl; C ₆ -C ₁₀ -aryl, which is unsubstituted or substituted with 1-5 halogen, cyano, hydroxyl, unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted C1-C ₆ -alkoxycarbonyl, unsubstituted carboxyl, unsubstituted With ₆ -C ₁₀ -aryl, unsubstituted amino, amino, substituted 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C1-C ₆ -aminoacyl or C1-C ₆ -aminoacyl, substituted 1-2 unsubstituted C1-C ₆ - alkyl; 5-12 membered heteroaryl which contains 1-4 N, O or S atoms and which is unsubstituted or substituted with 1-4 halogen, cyano, unsubstituted C1- _C6 alkyl or unsubstituted _C3 - _C7 cycloalkyl; unsubstituted C1-C ₆ -alkoxycarbonyl; C1- _C6- aminoacyl, which is unsubstituted or substituted with 1-2 unsubstituted C1- _C6 -alkyl, unsubstituted _C3 - _C7- cycloalkyl or unsubstituted 4-7-membered heterocyclyl, which contains 1-4 N, O or S atoms ; C1-C ₆ -acyl, which is unsubstituted or substituted with 1-3 unsubstituted 4-7-membered heterocyclyl, which contains 1-4 N, O or S atoms, unsubstituted C ₆ -C ₁₀ -aryl or C ₆ -C ₁₀ -aryl , substituted with 1-5 unsubstituted amino; unsubstituted aminothionyl; unsubstituted aminosulfonyl; aminocarbonylamino, which is unsubstituted or substituted with 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl or unsubstituted 4-7-membered heterocyclyl, which contains 1-4 N, O or S atoms; And C1- _C6 alkyl, which is unsubstituted or substituted with 1-3 halogen or hydroxyl; and where, when G ¹ represents - 377 045362 it is unsubstituted or substituted with 1-5 substituents selected from the group consisting of: halogen; hydroxyl; oxo; C ₆ -C ₁₀ -aryl, which is unsubstituted or substituted with 1-5 halogen, cyano, hydroxyl, unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted C1-C ₆ -alkoxycarbonyl, unsubstituted carboxyl, unsubstituted With ₆ -C ₁₀ -aryl, unsubstituted amino, amino, substituted 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C1-C ₆ -aminoacyl or C1-C ₆ -aminoacyl, substituted 1-2 unsubstituted C1-C ₆ - alkyl; 5-12 membered heteroaryl, which contains 1-4 N, O or S atoms and which is unsubstituted or substituted with 1-4 halogen, hydroxyl, cyano, unsubstituted C1-C ₆ -alkyl, unsubstituted C ₆ -C ₁₀ -aryl, unsubstituted With ₃ -C ₇ -cycloalkyl, unsubstituted C1-C ₆ -alkoxycarbonyl, unsubstituted carboxyl, unsubstituted C1-C ₆ -alkoxy or unsubstituted C1-C ₆ -aminoacyl; unsubstituted C1-C ₆ -alkoxycarbonyl; C1-C ₆ -aminoacyl, which is unsubstituted or substituted with 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted C ₆ -C ₁₀ -aryl, unsubstituted C1-C ₆ -alkoxyalkyl, unsubstituted 4 -7-membered heterocyclyl, which contains 1-4 N, O or S atoms, or unsubstituted 5-12-membered heteroaryl, which contains 1-4 N, O or S atoms; C1-C ₆ -acyl, which is unsubstituted or substituted with 1-3 unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted 4-7-membered heterocyclyl, which contains 1-4 atoms N, O or S, unsubstituted C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ -aryl substituted with 1-5 unsubstituted amino; pyridin-on-yl, which is unsubstituted or substituted with 1-4 unsubstituted C1-C ₆ -alkyl; aminothionyl, which is unsubstituted or substituted with 1-2 unsubstituted C1-C ₆ -alkyl; aminosulfonyl, which is unsubstituted or substituted with 1-2 unsubstituted C1- _C6 alkyl; aminocarbonylamino, which is unsubstituted or substituted with 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl or unsubstituted 4-7-membered heterocyclyl, which contains 1-4 N, O or S atoms; unsubstituted 9-membered bicyclic heterocyclyl, which contains 1-4 N, O or S atoms, and C1- _C6 alkyl, which is unsubstituted or substituted with 1-3 halogen or hydroxyl; in particular, where G ¹ represents which is unsubstituted or substituted with 1-5 substituents selected from the group consisting of: halogen; hydroxyl; oxo; C ₆ -C ₁₀ -aryl, which is unsubstituted or substituted with 1-5 halogen, cyano, hydroxyl, unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted C1-C ₆ -alkoxycarbonyl, unsubstituted carboxyl, unsubstituted With ₆ -C ₁₀ -aryl, unsubstituted amino, amino, substituted 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C1-C ₆ -aminoacyl or C1-C ₆ -aminoacyl, substituted 1-2 unsubstituted C1-C ₆ - alkyl; 5-12 membered heteroaryl, which contains 1-4 N, O or S atoms and which is unsubstituted or substituted with 1-4 halogen, hydroxyl, cyano, unsubstituted C1-C ₆ -alkyl, unsubstituted C ₆ -C ₁₀ -aryl, unsubstituted With ₃ -C ₇ -cycloalkyl, unsubstituted C1-C ₆ -alkoxycarbonyl, unsubstituted carboxyl, unsubstituted C1-C ₆ -alkoxy or unsubstituted C1-C ₆ -aminoacyl; unsubstituted C1-C ₆ -alkoxycarbonyl; C1-C ₆ -aminoacyl, which is unsubstituted or substituted with 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted C ₆ -C ₁₀ -aryl, unsubstituted C1-C ₆ -alkoxyalkyl, unsubstituted 4 -7-membered heterocyclyl, which contains 1-4 N, O or S atoms, or unsubstituted 5-12-membered heteroaryl, which contains 1-4 N, O or S atoms; C1-C ₆ -acyl, which is unsubstituted or substituted with 1-3 unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted 4-7-membered heterocyclyl, which contains 1-4 atoms N, O or S, unsubstituted C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ -aryl substituted with 1-5 unsubstituted amino; pyridin-on-yl, which is unsubstituted or substituted with 1-4 unsubstituted C1-C ₆ -alkyl; aminothionyl, which is unsubstituted or substituted with 1-2 unsubstituted C1-C ₆ -alkyl; aminosulfonyl, which is unsubstituted or substituted with 1-2 unsubstituted C1- _C6 alkyl; aminocarbonylamino, which is unsubstituted or substituted with 1-2 unsubstituted C1-C ₆ -alkyl, irreplaceable - 378 045362 substituted C ₃ -C ₇ -cycloalkyl or unsubstituted 4-7-membered heterocyclyl, which contains 1-4 N, O or S atoms; unsubstituted 9-membered bicyclic heterocyclyl, which contains 1-4 N, O or S atoms, and C1- _C6 alkyl, which is unsubstituted or substituted with 1-3 halogen or hydroxyl; or (ii) for example, where G ¹ is substituted with one, two or three substituents selected from the group consisting of: halogen; hydroxyl; oxo; C ₆ -C ₁₀ -aryl, which is unsubstituted or substituted with 1-5 halogen, cyano, hydroxyl, unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted C1-C ₆ -alkoxycarbonyl, unsubstituted carboxyl, unsubstituted With ₆ -C ₁₀ -aryl, unsubstituted amino, amino, substituted 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C1-C ₆ -aminoacyl or C1-C ₆ -aminoacyl, substituted 1-2 unsubstituted C1-C ₆ - alkyl; 5-12 membered heteroaryl, which contains 1-4 N, O or S atoms and which is unsubstituted or substituted with 1-4 halogen, hydroxyl, cyano, unsubstituted C1-C ₆ -alkyl, unsubstituted C ₆ -C ₁₀ -aryl, unsubstituted With ₃ -C ₇ -cycloalkyl, unsubstituted C1-C ₆ -alkoxycarbonyl, unsubstituted carboxyl, unsubstituted C1-C ₆ -alkoxy or unsubstituted C1-C ₆ -aminoacyl; unsubstituted C1-C ₆ -alkoxycarbonyl; C1-C ₆ -aminoacyl, which is unsubstituted or substituted with 1-2 unsubstituted C1-C ₆ -alkyl, unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted C ₆ -C ₁₀ -aryl, unsubstituted C1-C ₆ -alkoxyalkyl, unsubstituted 4 -7-membered heterocyclyl, which contains 1-4 N, O or S atoms, or unsubstituted 5-12-membered heteroaryl, which contains 1-4 N, O or S atoms; C1-C ₆ -acyl, which is unsubstituted or substituted with 1-3 unsubstituted C ₃ -C ₇ -cycloalkyl, unsubstituted 4-7-membered heterocyclyl, which contains 1-4 atoms N, O or S, unsubstituted C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ -aryl substituted with 1-5 unsubstituted amino; pyridin-on-yl, which is unsubstituted or substituted with 1-4 unsubstituted C1-C ₆ -alkyl; aminothionyl, which is unsubstituted or substituted with 1-2 unsubstituted C1-C ₆ -alkyl; aminosulfonyl, which is unsubstituted or substituted with 1-2 unsubstituted C1- _C6 alkyl; aminocarbonylamino which is unsubstituted or substituted with 1-2 unsubstituted C1- _C6 alkyl, unsubstituted C3-C7 cycloalkyl or unsubstituted 4-7 membered heterocyclyl which contains 1-4 N, O or S atoms; And C1- _C6 alkyl, which is unsubstituted or substituted with 1-3 halogen or hydroxyl; o /k in particular, where G ¹ represents /. 13. The compound or its pharmaceutically acceptable salt according to claim 11 or 12, where R ³ is selected from the group consisting of unsubstituted C2-C6 alkyl, C1-C6 alkyl substituted with 1-3 unsubstituted C1-C6 alkoxy, cyano or halogen; C3-C7 cycloalkyl which is unsubstituted or substituted with 1-5 unsubstituted C1-C6 alkyl, cyano or halogen; unsubstituted 4-7-membered heterocyclyl, which contains 1-4 N, O or S atoms; and C6-C10-aryl, which is unsubstituted or substituted with 1-5 nitro, unsubstituted C1-C6 alkoxy, C1-C6 alkoxy, substituted 1-3 halogen, halogen, unsubstituted C3-C7 cycloalkyl, cyano, unsubstituted C2-C6 alkenyl , unsubstituted C1-C6 alkoxycarbonyl, unsubstituted phenylcarbonyl or unsubstituted C1-C6 alkyl; (i) for example, where R ³ is phenyl substituted with 1-5 substituents selected from the group consisting of nitro, unsubstituted C1-C6 alkoxy, C1-C ₆ alkoxy substituted with 1-3 halogen, halogen, unsubstituted C ₃ -C ₇ -cycloalkyl, cyano, unsubstituted C ₂ -C ₆ -alkenyl, unsubstituted C1 -C ₆ -alkoxycarbonyl, unsubstituted phenylcarbonyl and unsubstituted C1 -C ₆ -alkyl; in particular, where R ³ represents phenyl substituted with 1-5 F and CN; or (ii) for example, where R ³ represents C3-C7 cycloalkyl substituted with 1-5 substituents selected from the group consisting of unsubstituted C1-C6 alkyl, cyano and halogen; or (iii) for example, where R ³ represents C1-C6 alkyl substituted with 1-3 substituents selected from the group consisting of unsubstituted C1- _C6 alkoxy, cyano and halogen. 14. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R ⁴ represents H or C1- _C6 alkyl substituted with 1-3 unsubstituted C1- _C6 alkoxy. 15. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R ⁵ represents H. 16. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-15, where R ¹ represents phenyl or pyridyl, each of which is substituted with 1-4 substituents independently selected from the group consisting of cyano, halogen, unsubstituted C1-C ₆ -alkoxy, C1-C ₆ -alkyl, which is unsubstituted or substituted with 1-3 fluorine, and diazirinyl, which is unsubstituted or substituted with one trifluoromethyl; for example, where R ¹ represents phenyl substituted with 1-5 trifluoromethyl. 17. A connection selected from the group consisting of: - 379 045362 - 380 045362 - 381 045362 - 382 045362 - 383 045362 - 384 045362 - 385 045362 - 386 045362 - 387 045362 52 Cl I HN-N * N—\ ⁰ /— 53 Cl І F. NN . N—7 ⁰ /— 54 0 — H ₂ N NN z\Y ^N oM=T ^N Q Cl , 55 A )— Х^оЪ N-N N—К I Cl, 56 0 — N=\ . FN n nF ^Cl , 57 O /— F F - 388 045362 - 389 045362 - 390 045362 - 391 045362 76 ъ О X 77 VyYS ύ l i 78 ° /х Μ \Αν ^/ ^' - S CI, 79 fy-oY' - Cl, 80 X η -------' / ⁴ ο 4 81 + : + Υ - 392 045362 - 393 045362 - 394 045362 94 Cl+ Λ o 1 > 0, 95 O+lA / Yj a Λ 97 Jp 98 '+Λ A. 99 Cl - 395 045362 100 Cl, 101 ^xr °f Ci, 102 XY^ Cl 103 CT c° Cl 104 fc ^N 'Z ° \__ s O Cl 105 Cl - 396 045362 106 J ( ⁰ b Cl 107 4. 108 ° )=o IZ \ 109 O \ _ h /—\ U A °A . 110 %' w 111 Q. F Y - 397 045362 112 Η ΓΛ/Υ υ ^ν _υ ^ν Ύ> ¹ 0 0 \— 113 U. οΑ ΖΙ <5 114 „=, °» Χ.Λ ν η '—' F ⁰ ' , 115 ό Αν ο / 116 117 ⁿ πΥ Υυ ^ν Υ< ¹ 0 ο \— - 398 045362 - 399 045362 - 400 045362 130 V ⁷ ^ σ°8 o ci, 131 A'J Cl, 132 Cl, 133 134 I F ^NH 135 dw Yy. ^/ ^NH / - 401 045362 - 402 045362 - 403 045362 - 404 045362 - 405 045362 - 406 045362 - 407 045362 - 408 045362 - 409 045362 - 410 045362 - 411 045362 - 412 045362 - 413 045362 - 414 045362 - 415 045362 - 416 045362 - 417 045362 - 418 045362 - 419 045362 - 420 045362 - 421 045362 - 422 045362 - 423 045362 - 424 045362 - 425 045362 280 +-N N-Z y—=N 281 x /V. J I I 282 o X..+ Ϊ ,+ΟΟ 283 Λ J ί Ϊ χη 284 .,0¾ 285 '—N N—ά y =N 0^^ , - 426 045362 286 Υ. Υ к с Ху w _F 287 //4/¾ 288 T T XX, 289 290 291 - 427 045362 - 428 045362 - 429 045362 - 430 045362 - 431 045362 - 432 045362 - 433 045362 - 434 045362 - 435 045362 345 346 γΎ ^N ^ ^H0 b Cl , 348 Cl o. and II 349 \ NH 0=( N—\ A. AA ρ o '—^ci o. AV 'N ⁺ ^^ 0- 350 f η> ^Ν Ό 351 O--F Cl - 436 045362 - 437 045362 - 438 045362 - 439 045362 - 440 045362 - 441 045362 - 442 045362 - 443 045362 394 z ¥ 395 N N—C p—ΞΝ -Ύ, 396 F. F Ak \ / \ / \ ^N \/ ^N /^ ^N П ^f n° , 397 To N—/ 4—=N / > 0 F N Г~1° o-J, 398 τ + o 399 ъ N 7—=N С 2 0 F N о ^Л о 1, - 444 045362 400 \ °=<° Cl, 401 K N—V ')—=N 0 ⁴ x° , 402 0 + cr 403 N—C Υ^ΞΝ O ⁴ - 404 About ° Gl, 405 bk^_ N—/E—=N A, - 445 045362 - 446 045362 - 447 045362 - 448 045362 - 449 045362 430 ___Ν. U----Ν ΛΑΟ Yal, 431 ggL Λξ V N 432 433 Mx 434 To 435 Λ EY Π' ⁰ , - 450 045362 - 451 045362 - 452 045362 448 V A P ΤΊ “Π 449 fAf O Y An a ^{n F} ^ ^N , 450 Υγ <: 0=( )=0 at N, 451 /—\ 0 but—( n+ _ _F oC )=o N , 452 HN—\ P /7 /— 2y-NF ¥ ^N , 453 O—i O. _Z AJA OTs )=o -n Z—' P - 453 045362 454 ό 455 γΫγ 456 Ύ Μ -Ρ “Π -Π 457 F 458 V y “Π “Π 459 νΥ ^{ζ χ} )—=Ν ^ΝΗ <ί . - 454 045362 460 OH f HN^O J 461 Y-o N—£ HN-K >OH b U F F 462 N To A F F 463 F.F N-? E—=N >NH —NH , 464 J Ή °k Y° Λ 465 ^F\^F A_n n—-ΞΝ ₀ ρΛ F %NH Onh, - 455 045362 - 456 045362 - 457 045362 478 Ν N—\ ^X )—=N A N— . 479 F.F N A\—=N on , 480 T" Uto. 481 F. F N4 ^{Z x} >—Cl yA HO ⁴ , 482 0 A , A 483/ ^CL J - 458 045362 - 459 045362 490 h ₂ n Cl, 491 ъ oK nh ₂ 492 ъ 493 Q he 494 F 495 V°YA, Q OH - 460 045362 496 497 /— mA >N Υ, 498 LL A °bb y z 499 LL LL —z >-z ¹ ° / 500 A 501 ° Lk O LL - 461 045362 - 462 045362 - 463 045362 - 464 045362 - 465 045362 - 466 045362 532 N—C ')--ΞΝ /=/o- 533 st Y° ^f 534 ^%ul NN—\ ^X )—ΞΝ 535 N—V \—ΞΝ _Y=^ <Y^ ^n/ h 536 Yo rY ^{υ H} 0 Г , 537 •A / ^NH / ^N ₄ XiCOb Xr Λ - 467 045362 - 468 045362 544 1 /° / ^N XiCOb ^N , 545 H + ϊσ 4 Ν , 546 Χι Ν 5 547 ⁰ > ^Ν , 548 +^0% 549 Ϋ" 0 , - 469 045362 - 470 045362 - 471 045362 - 472 045362 - 473 045362 - 474 045362 - 475 045362 - 476 045362 - 477 045362 - 478 045362 - 479 045362 - 480 045362 - 481 045362 - 482 045362 628 R F / And N—ζ Y-Cl 629 F F / fA A QiK N—ζ Cl 630 ^F \ ^F /+h,. o ^z , 631 Cl oU o ^z , 632 C! oU O , 633 - 483 045362 - 484 045362 - 485 045362 - 486 045362 - 487 045362 - 488 045362 - 489 045362 - 490 045362 676 ^f -0° 677 l/ ci—d Yn Y F Ό / G 678 N ' У Γ ^Ν Υ ^Ν γΑ , 0 , 679 A f ° ^Z / 7, 680 ZrX' ~ ^F °^b ^<0 , 681 F Z^N Cl—/YN N—-' Y% ° , - 491 045362 - 492 045362 688 GgS 689 Cl—(( y—Ν N—' 690 ⁰ 691 '% ⁰ , ^692F ° ^z /+, 693 "To/ —(/ y—Ν N—' , - 493 045362 - 494 045362 - 495 045362 - 496 045362 712 ^F V ^{F F} Ό , 713 eV -0' Y “Π 714 715 ό A 716 ό ύ ^γ Ά. 717 γ Υ JQC^ - 497 045362 - 498 045362 - 499 045362 - 500 045362 - 501 045362 - 502 045362 - 503 045362 - 504 045362 - 505 045362 - 506 045362 - 507 045362 - 508 045362 - 509 045362 - 510 045362 - 511 045362 - 512 045362 - 513 045362 814 A Α ^Ν α γΛ ci—/ An A 815 F O C7 816 p <c5 #-N gL ci—(/ y—N A Αγ 817 > _F γ/ΥΥς nh ₂ 818 0 V ^nh ₂ Am FF , 819 Aft nh ₂ , - 514 045362 - 515 045362 - 516 045362 - 517 045362 - 518 045362 - 519 045362 - 520 045362 856 F h α". _857nXlL > 858 ALf ό l/ 859 F ABOUT H - 860 b 861 fAf Lxc> - 521 045362 - 522 045362 - 523 045362 873 A POISON 874 Cl O YES 0 Yes 875 J/AAA 876 D 877 F FU/ A •m 878 F In AJ - 524 045362 - 525 045362 - 526 045362 or a pharmaceutically acceptable salt thereof. 18. A pharmaceutical composition containing a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 and a pharmaceutically acceptable excipient. 19. A method of treating heart disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 or a pharmaceutical composition according to claim 18. 20. The method of claim 19, wherein the heart disease is hypertrophic cardiomyopathy. 21. The method according to claim 20, where the hypertrophic cardiomyopathy is obstructive or non-obstructive or caused by sarcomeric and/or non-sarcomeric mutations. 22. The method of claim 19, wherein the heart disease is heart failure with preserved ejection fraction. 23. The method according to claim 19, where the heart disease is selected from the group consisting of diastolic dysfunction, primary or secondary restrictive cardiomyopathy, myocardial infarction and angina, left ventricular outflow tract obstruction, hypertensive heart disease, congenital heart defects, cardiac ischemia, coronary artery disease heart disease, diabetic heart disease, congestive heart failure, right-sided heart failure, cardiorenal syndrome and infiltrative cardiomyopathy. 24. The method of claim 19, wherein the heart disease is or is associated with a condition selected from the group consisting of physiological cardiac aging, diastolic dysfunction due to aging, left ventricular hypertrophy, and left ventricular concentric remodeling. 25. A method of treating a heart disease or condition associated with hypertrophic cardiomyopathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, or a pharmaceutical composition according to claim 18 . 26. The method of claim 25, wherein the disease or condition is selected from the group consisting of Fabry disease, Danon disease, mitochondrial cardiomyopathy and Noonan syndrome. 27. A method of treating a heart disease or condition that is associated with secondary thickening of the left ventricular wall in a subject in need thereof, comprising administering to the subject a therapeutically effective amount or a pharmaceutically acceptable salt thereof of a compound of any one of claims 1 to 17, or a pharmaceutical composition according to paragraph 18. 28. The method according to claim 27, where the disease or pathological condition is selected from the group consisting of hypertension, heart valve disease, aortic stenosis, mitral valve regurgitation, metabolic syndromes, diabetes, obesity, end-stage renal failure, scleroderma- - 527 045362 miia, sleep apnea, amyloidosis, Fabry disease, Friedreich disease, Friedreich ataxia, Danon disease, Noonan syndrome and Pompe disease. 29. A method of treating a heart disease or condition associated with left ventricular small cavity and cavity obliteration, left ventricular hyperdynamic contraction, myocardial ischemia, or cardiac fibrosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-17, or a pharmaceutical composition according to claim 18. 30. A method of treating a heart disease or condition selected from muscular dystrophies and glycogen storage diseases in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, or a pharmaceutical composition according to paragraph 18. 31. A method of inhibiting a cardiac sarcomere, comprising contacting the cardiac sarcomere with a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, or a pharmaceutical composition according to claim 18. 32. An in vitro method of inhibiting a cardiac sarcomere, comprising contacting the cardiac sarcomere with a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, or a pharmaceutical composition according to claim 18.