Certain amino-pyrimidines, compositions thereof, and methods for their use.

(54) Title: CERTAIN AMINO-PIRIMIDINES, COMPOSITIONS OF THE SAME AND METHODS FOR THE USE OF THEM.

(54) Title: CERTAIN AMINO-PYRIMIDINES, COMPOSITIONS THEREOF, AND METHODS FOR THEIR USE.

(57) Summary

Compounds of Formula (I) are provided: (see formula) a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, X and m are as defined in present memory. Also provided is a pharmaceutically acceptable composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof. Methods of using a compound of Formula I, or a pharmaceutically acceptable salt thereof, are also provided.

(57) Abstract

Provided are compounds of Formula (I) or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, R6, R7, R8, R9, X and m are as defined herein. Also provided is a pharmaceutically acceptable composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof. Also provided are methods of using a compound of Formula I, or a pharmaceutically acceptable salt thereof.

- 1 CERTAIN AMINO-PIRIMIDINE, COMPOSITIONS OF THE SAME AND

METHODS FOR THE USE OF THE SAME

This application claims priority benefit from United States Provisional Applications No. 61 / 327,597, filed on April 23, 2010 and 61 / 412,299 filed on November 10, 2010, each of which is incorporated by reference in its totality for all purposes.

The cytoskeleton of skeletal and cardiac muscle cells is unique compared to that of all other cells. It consists of an almost crystalline series of tightly compacted cytoskeletal proteins called a sarcomere. The sarcomere is elegantly arranged as an interspersed series of fine and thick filaments. The thick filaments are made up of myosin, the motor protein responsible for transducing the chemical energy of ATP hydrolysis into force and directed motion. The fine filaments are made up of actin monomers arranged in a helical series. There are four regulatory proteins bound to actin elements, which allow contraction to be modulated by calcium ions. An inflow of intracellular calcium initiates muscle contraction; coarse and fine filaments glide across one another driven by repeated interactions of the myosin motor domains

-2with fine actin filaments.

Of the thirteen different classes of myosin in human cells, the myosin II class is responsible for the contraction of skeletal, cardiac, and smooth muscle. This class of myosin is significantly different in amino acid composition and overall myosin structure in the twelve other distinct classes. Myosin II forms homodimers resulting in two globular head domains linked together by a long helical alpha supercoiling tail to form the core of the sarcomere thick filament. Globular heads have a catalytic domain in which the binding functions of actin and myosin ATPase take place. Once bound to an actin filament, the release of phosphate (confer ADP-Pi to ADP) signals a change in the structural makeup of the catalytic domain which in turn alters the orientation of the light chain binding lever arm domain that it extends from the globular head; This movement is called an energy discharge. This change in the orientation of the myosin head relative to actin causes the thick filament of which it is part to move relative to the fine actin filament to which it is attached. Disunity of the globular head of the actin filament (regulated by Ca²⁺) coupled with the return of the domain

-3catalytic and the light chain to its conformation / starting orientation completes the catalytic cycle, responsible for intracellular movement and muscle contraction.

Tropomyosin and troponin mediate the effect of calcium on the interaction of actin and myosin. The troponin complex is comprised of three polypeptide chains: troponin C, which binds calcium ions; troponin I that binds to actin; and troponin T, which binds tropomyosin. The skeletal troponin-tropomyosin complex regulates myosin binding sites by spreading over several actin units at once.

Troponin, a complex of the three polypeptides described above, is an accessory protein that is closely related to actin filaments in vertebrate muscle. The troponin complex works together with the muscular form of tropomyosin to mediate Ca dependence.²⁺ of ATPase myosin activity and thereby regulate muscle contraction. Troponin T, I, and C polypeptides are named for their tropomyosin-binding, inhibitory, and calcium-binding activities, respectively. Troponin T binds to tropomyosin and is believed to be responsible for the positioning of the troponin complex in the fine muscle filament. Troponin I binds to actin and the complex formed by troponins I and T and tropomyosin inhibits

-4the interaction of actin and myosin. Skeletal troponin C is capable of binding up to four calcium molecules. Studies suggest that when the muscle calcium level rises, troponin C exposes a binding site for troponin I, separating it from actin. This causes the tropomyosin molecule to change its position as well, thereby exposing the myosin binding sites in actin and stimulating myosin activity.

ATPase.

Human skeletal muscle is made up of different types of contractile fibers, classified by their myosin type and called slow or fast fibers. Table 1 summarizes the different proteins that make up these types of muscle.

Table 1

<td rowspan="2"></td><td colspan="2">Muscle Fiber Type</td>

<td>Skeletal Fast</td><td>Skeletal Slow</td>

<td>Heavy Chain Myosin</td><td>Ha, (Ilb *), Ilx / d</td><td>β Cardiac</td>

<td>Troponin I (Tnl)</td><td>SK Quick Tnl</td><td>SK slow Tnl</td>

<td>Troponin T (TnT)</td><td>SK fast TnT</td><td>SK slow TnT</td>

<td>Troponin C (TnC)</td><td>SK fast TnC</td><td>slow / cardiac TnC</td>

<td>Tropomyosin</td><td>ΤΜ-β / TM- a / TPM 3</td><td>ΤΜ-β / TM-as</td>

* MHC Ilb is not expressed in human muscle but is present in rodents and other mammals.

In healthy humans, most skeletal muscles are made of both fast and slow fibers, although the proportions of each vary according to the type of muscle. Slow skeletal fibers, often called type I fibers, have more structural similarities to cardiac muscle and tend to be used more for fine and postural control. They usually have a higher oxidative capacity and are more resistant to fatigue with continued use. Rapid skeletal muscle fibers, often referred to as type II fibers, are classified into fast oxidative (lia) and fast glycolytic (Ilx / d type) fibers. Although these muscle fibers have different types of myosin, they share many components including the troponin and tropomyosin regulatory proteins. Rapid skeletal muscle fibers tend to exert greater force but fatigue faster than slow skeletal muscle fibers and are functionally useful for sharp, large-scale movements such as rising from a chair or correcting falls.

-6Muscle contraction and force generation are controlled through nerve stimulation by innervation of motor neurons. Each motor neuron can innervate many (approximately 100-380) muscle fibers as a contractile whole, called the motor unit. When a muscle is required to contract, motor neurons send stimuli such as nerve impulses (action potentials) from the brain stem or spinal cord to each fiber within the motor unit. The region of contact between muscle fibers and nerves is a specialized synapse called the neuromuscular junction (NMJ). Here, the membrane depolarizing action potentials in the nerve are translated into a boost in the muscle fiber through the release of the neurotransmitter acetylcholine (ACh). ACh triggers a second action potential in muscle that spreads rapidly along the fiber and invaginations in the membrane, called T tubules. T tubules are physically connected to Ca2 + stores within the muscle sarcoplasmic reticulum (SR) via the dihydropyridine receptor (DHPR). DHPR stimulation activates a second Ca2 + channel in the SR, the ryanodine receptor to trigger the release of Ca2 + from reserves in the SR into the muscle cytoplasm where it can interact with the troponin complex to initiate

-7 muscle contraction. If muscle stimulation stops, calcium is rapidly re-taken up in the SR via the ATP-dependent Ca2 + pump, SERCA.

Muscle function can be compromised in diseases by many mechanisms. Examples include frailty associated with old age (called sarcopenia) and cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), and chronic kidney disease / dialysis. Severe muscle dysfunction can arise from neuromuscular diseases (such as Amyotrophic Lateral Sclerosis (ALS), spinal muscular atrophy (SMA), and myasthenia gravis), or muscle myopathies (such as muscular dystrophies). Additionally, muscle function may be compromised due to rehabilitation-related deficits, such as those associated with recovery from surgery (eg, post-surgical muscle weakness), prolonged bed rest, or stroke rehabilitation. Additional examples of diseases or conditions in which muscle function is compromised include peripheral vascular disease (eg, claudication), chronic fatigue syndrome, metabolic syndrome, and obesity.

Consequently, there is a need for the development of new compounds that modulate muscle contractility.

-8 skeleton. There remains a need for agents to exploit the new mechanisms of action and to have better outcomes in terms of symptom relief, patient safety and mortality, both long-term and short-term, and an improved therapeutic index.

A compound of Formula I is provided:

R¹

<img file="MX2012012189A_D0001.tif" />

Formula I or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, X and m are as defined herein.

Also provided is a pharmaceutically acceptable composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof.

Methods are also provided to treat a disease or condition sensitive to modulation of skeletal sarcomere contractility, for example, modulation of the troponin complex of the fast skeletal muscle sarcomere through one or more of myosin, actin, tropomyosin, troponin C, troponin I and troponin

-9T rapid skeletons, and fragments and isomers thereof.

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

Throughout this application, unless the context indicates otherwise, references to a compound of Formula I include all subgroups of Formula I defined herein, including all substructures, sub-genres, preferences, embodiments, examples and Particular compounds defined and / or described herein.

References to a compound of Formula I and to subgroups thereof include ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, isomers, tautomers, oxides (eg, Oxides, S-oxides), esters, prodrugs. , isotopes and / or protected forms thereof. Crystalline, polymorphic and novel forms can be used interchangeably herein, and are intended to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), co-crystals, unsolvated polymorphs

-10 (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless reference is made to a particular crystalline or amorphous form. In some embodiments, references to a compound of Formula I and to subgroups thereof include polymorphs, solvates, co-crystals, isomers, tautomers and / or oxides thereof. In some embodiments, references to a compound of Formula I and to subgroups thereof include polymorphs, solvates, and / or co-crystals thereof. In some embodiments, references to a compound of Formula I and to subgroups thereof include isomers, tautomers and / or oxides thereof. In some embodiments, references to a compound of Formula I and to subgroups thereof include solvates thereof. Similarly, the term salts includes computer salt solvates .

By optional or optionally it is understood that the event or circumstance described below may or may not happen, and that the description includes cases in which the event or circumstance occurs and cases in which it does not. For example, optionally substituted alkyl includes both alkyl and substituted alkyl as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that said groups are not intended

-11 introduce any substitution or substitution patterns that are sterically impractical, synthetically infeasible and / or intrinsically unstable.

When a range of values ​​is given (eg, Ci-β-alkyl), each value is included within the range, as well as the intermediate ranges. For example, Ci-6 alkyl includes Ci, C alkyl₂, C3, C₄, C₅, Ce, C1-6, C₂-6, C3-6,

C4-6, C5-6, C1-5,

C₂-5, C3-5, C4-5, C1-4, C₂-4, C3-₄, C1-3, C2-3 and C1-2.

When a residue is defined as optionally substituted, it may be substituted by itself or as part of another residue. For example, if R^x is defined as alkyl Ci_₆ or Oalquilo Ci_₆, where the C1-6 alkyl is optionally substituted with halogen, then both the Ci- alkyl group₆ just like the alkyl Ci_₆ which is part of the Oalquilo Ci_ group₆ they can be substituted with halogen.

Alkyl includes straight and branched carbon chains having the indicated 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, C1-6alkyl includes straight or branched chain alkyl of 1 to 6 carbon atoms. When an alkyl moiety having a specified number of carbons is named, all chain versions are intended to be included

- 12branched and linear that have that number of carbons; therefore, 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, tere-butyl, pentyl, 2pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2hexyl, 3-hexyl and 3-methylpentyl. Lower alkyl refers to alkyl groups having 1 to 6 carbons.

Haloalkyl includes linear carbon chains and

<td>branched they have</td><td>the</td><td>indicated number</td><td>of</td><td>atoms of</td>

<td>carbon (for example</td><td>of</td><td>1 to 6 atoms</td><td>of</td><td>carbon)</td>

<td>replaced with at least</td><td>a</td><td>halogen atom</td><td>. In</td><td>the cases</td>

Where the haloalkyl group contains more than one halogen atom, the halogens can be the same (eg, dichloromethyl) or different (eg, chlorofluoromethyl). Examples of haloalkyl groups include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 2-fluoroethyl, 2,2difluoroethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2chloroethyl, 2 , 2-dichloroethyl, 2,2,2-trichlorethyl, 1,2-dichloroethyl, pentachloroethyl and pentafluoroethyl.

Alkenyl refers to an unsaturated, straight or branched chain alkyl group having the number

- 13indicated carbon atoms (eg 2 to 8, or 2 to 6 carbon atoms) and at least one carbon-carbon double bond obtained from the removal of a hydrogen molecule from adjacent carbon atoms of the corresponding alkyl. The group may be in the cis or trans configuration (Z or E configuration) around the double bond (s). Alkenyl groups include, but are not limited to, ethenyl, propenyl (eg, prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop -2-en-2-yl) and butenyl (for example, but-1en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2en -l-yl, but-2-en-l-yl, but-2-en-2-yl, buta-1,3-dien-lilo, buta-1,3-dien-2-yl). Lower alkenyl refers to alkenyl groups having 2 to 6 carbons.

Alkynyl refers to an unsaturated straight or branched chain alkyl group having the indicated number of carbon atoms (for example, 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond obtained at from the removal of two hydrogen molecules from adjacent carbon atoms of the corresponding alkyl. Alkynyl groups include, but are not limited to, ethynyl, propynyl (eg, prop-l-in-1-yl, prop-2-in-l-yl), and butynyl (eg, but-l-in-1-yl, but- l-in-3-yl, but-3-in-l-yl). Lower alkynyl refers to alkynyl groups having 2 to 6 carbons.

- 14Cycloalkyl indicates a fully saturated, non-aromatic, carbocyclic ring having the indicated number of carbon atoms, for example, 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms. Cycloalkyl groups can be monocyclic or polycyclic (eg, bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl, as well as closed and bridged ring groups (eg, norborne, bicyclo [2.2.2] octane). Furthermore, a ring of a polycyclic cycloalkyl group may be aromatic, provided that the polycyclic cycloalkyl group is attached to the parent structure through a non-aromatic carbon. For example, a 1,2,3,4-tetrahydronaphthalen-l-yl group (in which the moiety is attached to the parent structure through a non-aromatic carbon atom) is a cycloalkyl group, while 1,2,3 4tetrahydronaphthalen-5-yl (where the moiety is attached to the parent structure through 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 indicates a non-aromatic carbocyclic ring containing the indicated number of atoms of

-15bicyclics, carbon (eg, 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms) and at least one carbon-carbon double bond obtained from the removal of a molecule of Hydrogen from adjacent carbon atoms of the corresponding cycloalkyl can be monocyclic or tricyclic).

Polycyclic cycloalkenyl groups (for example, from groups

Examples cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl, as well as closed and bridged ring groups (eg, bicyclo [2.2.2] octene). Furthermore, a ring of a polycyclic cycloalkenyl group may be aromatic, provided that the polycyclic alkenyl group is attached to the parent structure through a non-aromatic carbon atom. For example, inden-l-yl (where the moiety is attached to the parent structure through a non-aromatic carbon atom) is considered a cycloalkenyl group, while inden-4-yl (where the moiety is attached to the parent structure through a 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.

Aryl indicates an aromatic carbon ring having the indicated number of carbon atoms, for example,

- 16 from 6 to 12 or from 6 to 10 carbon atoms. Aryl groups can be monocyclic or polycyclic (eg bicyclic, tricyclic). In some cases, the two rings of a polycyclic aryl group are aromatic (eg, naphthyl). In other cases, the polycyclic aryl groups may include a non-aromatic ring (eg, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused with an aromatic ring, provided that the polycyclic aryl group is attached to the parent structure via an atom of the aromatic ring. Therefore, a 1,2,3,4-tetrahydronaphthalen-5-yl group (in which the moiety is attached to the parent structure through an aromatic carbon atom) is considered an aryl group, while

1,2,3,4-tetrahydronaphthalen-l-yl (where the moiety is attached to the parent structure through a non-aromatic carbon atom) is not considered an aryl group. Similarly, a 1,2,3,4-tetrahydroquinolin-8-yl group (in which the moiety is attached to the parent structure through an aromatic carbon atom) is considered an aryl group, while the group 1,2,3,4-Tetrahydroquinolin-l-yl (where the moiety is attached to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term aryl does not include or overlap with heteroaryl,

As defined herein, regardless of the point of attachment (for example, quinolin-5-yl and quinolin2-yl are heteroaryl groups). In some cases, aryl is phenyl or naphthyl. In certain cases, aryl is phenyl. Other examples of aryl groups comprising an aromatic carbon ring fused with a non-aromatic ring are described below.

Aralkyl refers to a moiety having the indicated number of carbon atoms (for example, 7 to 12 or 7 to 10 carbon atoms) in which an aryl moiety is attached to the parent structure through an alkyl moiety . The alkyl moiety can be straight chain or branched. Examples include benzyl, phenethyl, and 1phenylethyl.

Heteroaryl denotes an aromatic ring containing the indicated number of atoms (eg, 5 to 12 or 5 to 10 membered heteroaryl) consisting of one or more heteroatoms (eg, 1, 2, 3, or 4 heteroatoms) selected from N , O and S and in which the remaining atoms of the ring are carbon. Heteroaryl groups do not

<td>contain atoms</td><td>from S</td><td colspan="3">and 0 adjacent.</td><td>In</td><td>some</td>

<td>accomplishments the</td><td>number</td><td>total of</td><td>atoms</td><td>of</td><td>S and</td><td>0 in the</td>

<td>heteroaryl group</td><td>not</td><td>is older</td><td>than</td><td> 2.</td><td>In</td><td>some</td>

<td>accomplishments the</td><td>number</td><td>total of</td><td>atoms</td><td>of</td><td>S and</td><td>0 in the</td>

aromatic heteroaryl group is not greater than 1. Unless

-18 otherwise stated, heteroaryl groups may be attached to the parent structure through a carbon or nitrogen atom, as allowed by valence. For example, pyridyl includes 2-pyridyl, 3-pyridyl, and 4-pyridyl groups, and pyrrolyl includes 1-pyrrolyl, 2pyrrolyl, and 3-pyrrolyl groups. When nitrogen is present in a heteroaryl ring, it can exist, when the nature of adjacent atoms and groups allows, in an oxidized state (i.e., N⁺-0 ”). Furthermore, when sulfur is present in a heteroaryl ring, it can exist, when the nature of adjacent atoms and groups permits, in an oxidized state (i.e., S⁺-O ”or SO₂). Heteroaryl groups can be monocyclic or polycyclic (eg bicyclic, tricyclic).

In some cases, a heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (eg 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (for example,

1.2.3- oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (for example, 1,2,3thiadiazole, 1,2,4-thiadiazole, 1, 3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (for example,

1.2.4- triazine, 1,3,5-triazine) and tetrazine.

In some cases, the two rings in a group

-19 Examples Benzoimidazole, Benzoisoxazole, Polycyclic heteroaryl are aromatic include indole, isoindole, indazole, benzotriazole, benzofuran, benzoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole, lH-pyridol [2,3-b] pyridine 3,4b] pyridine, 3H-imidazo [4,5-b] pyridine, 3H [1,2,3] triazolo [4,5-b] pyridine, lH-pyrrolo [3,2-b] pyridine, lH- pyrazolo [4,3-b] pyridine, ΙΗ-imidazo [4,5-b] pyridine, 1H [1.2.3] triazolo [4,5-b] pyridine, lH-pyrrolo [2,3-c] pyridine, lH-pyrazolo [3,4-c] pyridine, 3H-imidazo [4,5-c] pyridine, 3H [1.2.3] triazolo [4,5-c] pyridine, lH-pyrrolo [3,2-c] pyridine, lH-pyrazolo [4,3-c] pyridine, ΙΗ-imidazo [4,5-c] pyridine, 1H [1.2.3] triazolo [4,5-c] pyridine, furo [2,3-b] pyridine, oxazolo [5,4-b] pyridine, isoxazolo [5,4-b] pyridine, [1.2.3] oxadiazolo [5,4-b] pyridine, oxazolo [4,5-b] pyridine, [1.2. 3] oxadiazolo [4,5-b] pyridine, oxazolo [5,4-c] pyridine, [1.2.3] oxadiazolo [5,4-c] pyridine, oxazolo [4,5-c] pyridine, [1.2. 3] oxadiazolo [4,5-c] pyridine, thiazolo [5,4 —b] pyridine, furo [3,2-b] pyridine, isoxazolo [4,5-b] pyridine, furo [2,3-c] pyridine, isoxazolo [5,4-c] pyridine, furo [3,2-c] pyridine, isoxazolo [4,5-c] pyridine, thieno [2,3-b] pyridine, isothiazolo [5.4-b] 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,

-20isothiazolo [5,4-c] pyridine, thieno [3,2-c] pyridine, isothiazolo [4,5-c] pyridine, quinoline, isoquinoline, thiazolo [5,4-c] pyridine, [1.2.3] thiadiazolo [5,4-c] pyridine, thiazolo [4,5-c] pyridine, [1.2.3] thiadiazolo [4,5-c] pyridine, cinnoline, quinazoline, quinoxaline, phthalazine, naphthiridine (eg 1, 8-naphthyridine, 1,7-naphthyridine, 1,6naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6naphthyridine), imidazo [1,2-a] pyridine, lH-pyrazolo [3,4djtiazol, lH -pirazolo [4,3-d] thiazole and imidazo [2,1-b] thiazole.

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

-21 Heterocycloalkyl denotes a fully saturated, non-aromatic ring having the indicated number of atoms (eg, 3-10 membered or 3-7 membered heterocycloalkyl) composed of one or more heteroatoms (eg, 1, 2, 3 or 4 heteroatoms) selected from N, O and S and in which the remaining ring atoms are heterocycloalkyl groups may be or polycyclic (eg bicyclic, Examples of heterocycloalkyl oxiranyl, aziridinyl, azetidinyl, imidazolidinyl, pyrazolidinyl, carbon. Tricyclic monocyclics).

They include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

of

When nitrogen is present in a heterocycloalkyl ring, it can exist, when the nature of adjacent atoms and groups permits, in an oxidized state (i.e., N⁺-0 '). Examples include piperidinyl oxide morpholinyl N-oxide. Furthermore, when sulfur is present in a heterocycloalkyl ring, it can exist, when the nature of adjacent atoms and groups permits, in an oxidized state (i.e., S⁺-0 or -SO2-). Examples include thiomorpholine S-oxide and S, thiomorpholine S-dioxide. In addition, a ring of a polycyclic heterocycloalkyl group may be aromatic (eg, aryl or heteroaryl), provided that the

-22 polycyclic heterocycloalkyl group is attached to the parent structure through a non-aromatic carbon atom or a nitrogen atom. For example, a group

1,2,3,4-Tetrahydroquinolin-l-yl (in which the moiety is attached to the parent structure through a non-aromatic nitrogen atom) is considered a heterocycloalkyl group, while the 1,2,3 group , 4-tetrahydroquinolin-8-yl (where the moiety is attached to the parent structure through an aromatic carbon atom) is not considered a heterocycloalkyl group. Examples of polycyclic heterocycloalkyl groups consisting of an aromatic ring fused heterocycloalkyl group are described below.

Heterocycloalkenyl denotes a non-aromatic ring having the indicated number of atoms (eg, 3-10 or 3-7 membered heterocycloalkyl) composed of one or more heteroatoms (eg, 1, 2, 3, or 4 heteroatoms) selected from N, 0 and S and where the remaining atoms in the ring are carbon, and at least one double bond obtained through the removal of a hydrogen molecule from adjacent carbon atoms, adjacent nitrogen atoms or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl. Heterocycloalkenyl groups can be monocyclic or polycyclic (eg bicyclic,

-23tricyclic). When nitrogen is present in a heterocycloalkenyl ring, it can exist, when the nature of adjacent atoms and groups allows, in an oxidized state (i.e., N⁺-0 '). Furthermore, when sulfur is present in a heterocycloalkenyl ring, it can exist, when the nature of adjacent atoms and groups allows, in an oxidized state (i.e., S⁺-0^_ or -SO2-) · Examples of heterocycloalkenyl groups include dihydrofuranyl (eg 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (eg 2,3-dihydrothiophenyl, 2,5 dihydrothiophenyl), dihydropyrrolyl (eg , 2,3-dihydro-lH-pyrrolyl, 2,5-dihydro-lH-pyrrolyl), dihydroimidazolyl (for example, 2,3-dihydro-lHimidazolyl, 4,5-dihydro-lH-imidazolyl), pyranyl, dihydropyranyl (for example , 3,4-dihydro-2H-pyranyl, 3,6dihydro-2H-pyranyl), tetrahydropyridinyl (for example,

1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl) and dihydropyridine (eg 1,2-dihydropyridine, 1,4dihydropyridine). In addition, a ring of a polycyclic heterocycloalkenyl group may be aromatic (eg, aryl or heteroaryl), provided that the polycyclic heterocycloalkenyl group is attached to the parent structure through a non-aromatic carbon atom or a nitrogen atom . For example, a group

-241.2- dihydroquinolin-l-yl (where the moiety is attached to the parent structure through a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, while the 1,2-dihydroquinolin-8-yl group ( where the moiety is attached to the parent structure through an aromatic carbon atom) is not considered a heterocycloalkenyl group. Examples of polycyclic heterocycloalkenyl groups consisting of an aromatic ring fused heterocycloalkenyl group are described below.

Examples of polycyclic rings consisting of an aromatic ring (eg, aryl or heteroaryl) fused with a non-aromatic ring (eg, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl, 2,3-dihydro-lHindenyl, 1, 2,3,4-tetrahydronaphthalenyl, benzo [1,3] dioxolyl, tetrahydroquinolinyl, 2,3dihydrobenzo [1,4] dioxinyl, indolinyl, isoindolinyl, 2,3dihydro-lH-indazolyl, 2,3-dihydro-lH-benzo [ d] imidazolyl,

2.3- dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 1,3dihydrobenzo [c] isoxazolyl, 2,3-dihydrobenzo [d] isoxazolyl,

2.3- dihydrobenzo [d] oxazolyl, 2,3-dihydrobenzo [b] thiophenyl,

1.3- dihydrobenzo [c] thiophenyl, 1,3dihydrobenzo [c] isothiazolyl, 2,3dihydrobenzo [d] isothiazolyl, 2,3-dihydrobenzo [d] thiazolyl,

-255,6-dihydro-4H-cyclopenta [d] thiazolyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, 5,6-dihydro-4H-pyrrolo [3,4d] thiazolyl, 4,5,6,7 -tetrahydrothiazolo [5,4-c] pyridinyl, indolin-2-one, indolin-3-one, isoindolin-l-one, 1,2-dihydroindazol-3-one, ΙΗ-benzo [d] imidazol-2 (3H) - ona, benzofuran-2 (3H) -one, benzofuran-3 (2H) -one, isobenzofuranl (3H) -one, benzo [c] isoxazol-3 (1H) -one, benzo [d] isoxazol3 (2H) -one , benzo [d] oxazol-2 (3H) -one, benzo [b] thiophene-2 ​​(3H) one, benzo [b] thiophene-3 (2H) -one, benzo [c] thiophene-1 (3H) - ona, benzo [c] isothiazol-3 (1H) -one, benzo [d] isothiazol-3 (2H) -one, benzo [d] thiazol-2 (3H) -one, 4,5-dihydropyrrolo [3,4-d ] thiazol6-one, 1,2-dihydropyrazolo [3,4-d] thiazol-3-one, quinolin4 (3H) -one, quinazolin-4 (3H) -one, quinazoline-2,4 (1H, 3H) dione , quinoxalin-2 (1H) -one, quinoxaline-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, lH-pyrrolo [3,2b] pyridin-2 (3H) -one, lH-pyrrolo [3,2-c] pyridin-2 (3H ) -one, lH-pyrrolo [2,3-c] pyridin-2 (3H) -one, lH-pyrrolo [2,3-b] pyridin-2 (3H) -one, 1,2-dihydropyrazolo [3,4-d] thiazol-3-one and 4,5-dihydropyrrolo [3,4-d] thiazole -6-one. As discussed herein, whether each indyl is considered an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group is determined by the atom through which the remainder is attached to the parent structure.

-26 Halogen or halo refers to fluorine, chlorine, bromine or iodine.

Isomers are different compounds that have the same molecular formula. Stereoisomers are isomers that differ only in the way the atoms are arranged in space. Enantiomers are stereoisomers that are mirror images that can overlap each other. A 1: 1 mixture of a pair of enantiomers is a racemic mixture. The symbol (±) can be used to designate a racemic mixture when appropriate. Diaestereoisomers are stereoisomers that have at least two asymmetric atoms, but are not mirror images of each other. A mesocomposite or mesoisomer is a non-optically active member of a set of stereoisomers. Mesoisomers contain two or more stereocenters but are not chiral (that is, there is a plane of symmetry within the molecule). Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. The resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in the that rotate the plane polarized to the wavelength of the sodium D line. Some of the

-27 compounds disclosed and / or described herein contain one or more asymmetric centers and, therefore, may give rise to enantiomers, diastereomers, mesoisomers and after stereoisomeric forms. 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. Enantiomers, diastereomers, mesoisomers, and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Unless otherwise specified, when the compounds disclosed and / or described herein contain olefinic double bonds or other centers of geometric asymmetry, the compounds are understood to include both E and Z isomers.

The stereochemistry represented in the cyclic mesocomposite structures is not absolute; rather, stereochemistry is intended to indicate the position of the substituents on each other, for example, cis or trans. For example,

-28F

<img file="MX2012012189A_D0002.tif" />

/ ~ Ν Γ $ Ύ ~ ΝΗ \ = Μ

<img file="MX2012012189A_D0003.tif" />

· = Ν is intended to designate a compound in which the fluorine and pyridyl substituents on the cyclobutyl ring are in cis configuration with each other, while

F

<img file="MX2012012189A_D0004.tif" />

N is intended to designate a compound in which the fluorine and pyridyl substituents on the cyclobutyl ring are in a trans configuration with each other.

When a compound can exist in the form of one or more mesoisomers, all possible mesoisomers are intended to be included. For example, the compound {[3— fluoro-l- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} pyrimidin-2-amine is intended to include both cis and trans mesoisomers:

N r NH

V

-29 and mixtures thereof. Unless otherwise indicated, the compounds disclosed and / or described herein include all possible mesoisomers and mixtures thereof.

Tautomers are structurally different isomers that are interconverted by tautomerization. Tautomerization is a form of isomerization and includes prototropic and proton displacement tautomerization, which is considered a subset of acid-base chemistry. Prototropic tautomerization or proton displacement tautomerization involves migration of a proton accompanied by changes in the binding order, usually the exchange of a single bond for an adjacent double bond. When tautomerization is possible (eg, in solution), a chemical balance of tautomers can be achieved. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxy-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. When the compounds described herein contain residues that can undergo tautomerization, and unless

-30- As otherwise specified, the compounds are understood to include all possible tautomers.

Protective group has the meaning usually associated with it in organic synthesis, that is, a group that selectively blocks one or more reactive sites in a multifunctional compound in such a way that a chemical reaction can be carried out selectively on another unprotected reactive site, and such that the group can be easily removed after the selective reaction is complete. A variety of protecting groups are described, for example, in TH Greene and PG M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley &amp; Sons, New York (1999). For example, a protected form of hydroxy contains at least one hydroxy group protected with a hydroxy protecting group. Similarly, amines and other reactive groups can be similarly protected.

The term "pharmaceutically acceptable salt" refers to salts that maintain biological efficacy and

<td>properties</td><td>of the</td><td>compounds described in</td><td>the</td><td>Present</td>

<td>memory and</td><td>are not</td><td>biologically, or</td><td>other</td><td>shape,</td>

<td>undesirable.</td><td colspan="2">Examples can be found</td><td>of</td><td>you go out</td>

<td colspan="2">pharmaceutically</td><td>acceptable in Berge</td><td>et</td><td>to the.,</td>

Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66 (1), 1-19. In many cases, compounds

-31 described herein can form acid and / or base addition salts due to the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be obtained include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be obtained 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, acid tartaric, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, ptoluenesulfonic acid, stearic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Organic bases from which salts can be obtained include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be obtained include, for example, primary, secondary, and tertiary amines; substituted amines, including

-32 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 chosen from ammonium, potassium, sodium, calcium and magnesium salts.

If the compound described herein is obtained in the form of an acid addition salt, the free base can be obtained by basification of a solution of the acid salt. Conversely, if the compound is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent, and by treating the solution with an acid, according to conventional procedures for preparing acid addition salts from basic compounds (see, eg, Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66 (1), 1-19). Those of skill in the art will recognize various synthetic methodologies that can be used to prepare pharmaceutically acceptable addition salts.

A solvate is formed by the interaction of a solvent and a compound. Suitable solvents include, for example, water and alcohols (for example,

-33ethanol). Solvates include hydrates that have any ratio of compound to water, such as monohydrates, dihydrates, and hemi-hydrates.

A chelate is formed by the coordination of a compound with a metal ion at two (or more) points. The term compound is intended to include chelates of compounds. Similarly, salts includes chelates of salts and solvates includes chelates of solvates.

A non-covalent complex is formed by the interaction of a compound and another molecule in which a covalent bond between the compound and the molecule does not form. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding). Such non-covalent complexes are included in the term compound.

The term "prodrug" refers to a substance administered in an inactive or less active form that is then transformed (eg, by metabolic processing of the prodrug in the body) into an active compound. The rationale behind administering a prodrug is to optimize drug absorption, distribution, metabolism, and / or excretion. Prodrugs may be obtained by preparing a derivative of an active compound (eg, a compound of Formula I or another disclosed compound and / or

-34 described herein) which will undergo transformation under the conditions of use (eg, within the body) to form the active compound. The transformation of the prodrug to the active compound can happen spontaneously (for example, through a hydrolysis reaction) or it can be catalyzed or induced by another agent (for example, an enzyme, light, acid or base and / or

<td colspan="2">temperature).</td><td>The</td><td colspan="2">agent can</td><td>to be</td><td>endogenous</td><td>at</td>

<td>terms</td><td>of</td><td>use</td><td>(by</td><td>example one</td><td colspan="2">enzyme present</td><td>in the</td>

<td>cells to</td><td>the</td><td>than</td><td>I know</td><td>administers</td><td>the</td><td>prodrug</td><td>waves</td>

<td>terms</td><td colspan="2">acidic</td><td>of the</td><td>stomach)</td><td>or</td><td>the agent</td><td>can</td>

<td colspan="2">provide</td><td>of :</td><td>shape</td><td>exogenous.</td><td>The</td><td>prodrugs</td><td>they can</td>

Obtained by converting one or more functional groups in the active compound to another functional group, which is then converted back to the original functional group when administered to the body. For example, a hydroxyl functional group can be converted to a sulfonate, phosphate, ester, or carbonate group, which in turn can be hydrolyzed back to the hydroxyl group in vivo. Similarly an amino functional group can be converted, for example, into an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenyl functional group, which can be hydrolyzed in vivo back to the amino group. A carboxyl functional group can be converted, for example, into an ester functional group (including thioesters and silyl esters), amide or

-35hydrazide, which can hydrolyze in vivo back to the carboxyl group. Examples of prodrugs include, but are not limited to, phosphate, acetate, formate and benzoate derivatives of functional groups (such as alcohol or amine groups) present in the compounds of Formula I and other compounds disclosed and / or described herein.

The compounds disclosed and / or described herein may be enriched isotopic forms, eg, enriched for ²H ³H ^{1: L}C, ¹³C and / or ¹⁴C. In one embodiment, the compound contains at least one deuterium atom. Such deuterium forms can be prepared, for example, by the procedure described in US Patent Nos. 5,846,514 and 6,334,997. Such deuterium compounds can improve the efficacy and increase the duration of action of compounds disclosed and / or described herein. Deuterium-substituted compounds can be synthesized using various 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 carrier" includes each and every solvent, dispersion medium, coating, antibacterial and antifungal agent, isotonic and absorption retardant agent, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art.

Except insofar as any conventional medium or agent is incompatible with the active ingredient, its use in pharmaceutical compositions is contemplated. Complementary active ingredients can also be incorporated into pharmaceutical compositions.

The term "active agent" is used to indicate a compound that has biological activity. In some embodiments, an active agent is a compound that has therapeutic utility. In some embodiments, the compound enhances at least one aspect of skeletal muscle function or activity, such as power output, skeletal muscle strength, skeletal muscle endurance, oxygen consumption, efficacy, and / or sensitivity to calcium. In some embodiments, an active agent is a compound of Formula I, or its acceptable pharmaceutical sai

The terms patient and subject refer to an animal, such as a mammal, bird, or fish. In some

-37 embodiments, 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, for example a human who has been or will be the object of treatment, observation, or experimentation. The compounds, compositions, and methods described herein can be useful in both human and veterinary therapy applications.

As used herein, skeletal muscle includes skeletal muscle tissue as well as components thereof, such as skeletal muscle fibers, myofibrils comprising skeletal muscle fibers, skeletal sarcoma comprising myofibrils, and the various components of the described skeletal sarcomere. herein, including myosin, actin, tropomyosin, troponin C, troponin I, skeletal troponin T and fragments and isoforms thereof. In some embodiments, skeletal muscle includes rapid skeletal muscle tissue as well as components thereof, such as rapid skeletal muscle fibers, myofibrils comprising rapid skeletal muscle fibers, rapid skeletal sarcomere comprising myofibrils, and various components of rapid skeletal sarcomere.

-38 (and modulated terms, described herein, including skeletal myosin, actin, tropomyosin, troponin C, troponin I and troponin T and fragments and isoforms thereof. Skeletal muscle does not include cardiac muscle or a combination of sarcomeric components appearing in said combination in its entirety in cardiac muscle.

As used herein, the term "therapeutic" refers to the ability to modulate skeletal muscle contractility rapidly. As used herein, related modulation, such as modulating, modulating) refers to a change in the function or efficacy of one or more components of rapid skeletal muscle sarcoma, including myosin, actin, tropomyosin, troponin C, troponin I and rapid skeletal muscle troponin T, including fragments and isoforms thereof, as a direct or indirect response to the presence of a compound described herein, in relation to the activity of the fast skeletal sarcomere in the absence of the compound. The change may be an increase in activity (potentiation) or a decrease in activity (inhibition) and may be due to the direct interaction of the compound with the sarcomere or due to the interaction of the compound with one or more other factors which in turn affect the sarcomere or one

-39o more of its components. In some embodiments, modulation is an enhancement of the function or efficacy of one or more components of the rapid skeletal muscle sarcomere, including myosin, actin, tropomyosin, troponin C, troponin I, and rapid skeletal muscle troponin T, including fragments and isoforms. from the same. Modulation can be mediated by any mechanism and at any physiological level, for example, through sensitization of rapid skeletal sarcomere to contraction at lower concentrations of Ca²⁺. As used herein, muscle efficacy or efficacy means the ratio of mechanical work performance to total metabolic cost.

The term "therapeutically effective amount" or "effective amount" refers to the amount of a compound disclosed and / or described herein that is sufficient to affect treatment, as defined herein, when administered to a patient in need of said treatment. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease sensitive to rapid skeletal muscle modulation. The therapeutically effective amount will vary depending on, for example, the subject and the disease to be treated, the weight and age of the subject, the severity of the disease, the particular compound, the

-40 dosage regimen to be followed, timing of administration, form of administration, all of which can be readily determined by a person skilled in the art. The therapeutically effective amount can be determined experimentally, for example by testing the blood concentration of the chemical entity or theoretically, calculating bioavailability.

Treatment (and related terms, such as treating, treating, treating) includes one or more of: preventing a disease or disorder (ie, causing the clinical symptoms of the disease or disorder to not develop); inhibit a disease or disorder;

slow down or stop the development of clinical symptoms of a disease or disorder; and / or alleviate a disease or disorder (ie, cause relief or regression of clinical symptoms). The term encompasses situations in which the disease or disorder is already being experienced by a patient, as well as situations in which the disease or disorder is not currently being experienced but is expected to arise. The term encompasses both complete and partial reduction or prevention of the condition or disorder and complete or partial reduction of clinical symptoms of a disease or disorder. Therefore, the compounds described and / or disclosed herein can prevent an existing disease or disorder from worsening,

-41 aiding the treatment of disease or disorder or reducing or eliminating the disease or disorder. When used prophylactically, the compounds disclosed and / or described herein can prevent a disease or disorder from developing or reduce the scope of a disease or disorder that may develop.

As used herein a muscle's power output means work / cycle time and its PoLo / cycle time units scale can be increased based on the properties of the muscle. The output power can be modulated, changing, for example, the activation parameters during cyclical length changes, including activation moments (activation phase) and the activation period (utilization coefficient).

ATPase refers to an enzyme that hydrolyzes ATP. ATPases include proteins that comprise molecular motors such as myosins.

As used herein, "selective binding or selective 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 rapid skeletal troponin C if the compound preferentially binds troponin C in the troponin complex of a sarcomere or muscle fiber.

-42 Rapid skeletal compared to troponin C in the troponin complex of a sarcomere or slow muscle fiber or to troponin C in the troponin complex of a cardiac sarcomere.

A compound of Formula I is provided:

R¹

<img file="MX2012012189A_D0005.tif" />

Formula I or a pharmaceutically acceptable salt thereof, in which:

R¹ is selected from hydrogen, halogen, CN, Ci-6 alkyl, Ci_6 haloalkyl, C (O) OR^to, C (O) NR^bR °, OR^to, NR^bR^c, C6-io aryl and 5-10 membered heteroaryl;

R² is selected from C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, CS-io aryl, 5-10 membered heteroaryl and NR^bR^c, where each of the C3-8 cycloalkyl groups, C3_cycloalkenyl₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆-i₀ and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5

-43 substituents selected from halogen, CN, oxo, (CH₂)_nOR^to, (CH2) nOC (O) R^to, (CH2) _nOC (O) OR^to, (CH₂) _nOC (O) NR^bR^c, (CH₂)_nNR^bR^c, (CH₂) _nNR ° C (O) R^to, (CH₂) _nNR^dC (O) OR^to, (CH₂) nNR^dC (0) NR^bR^c, (CH2) nNR^dC (O) C (O) NR^bR^c, (CH2) _nNR^dC (S) R^to, (CH₂) _nNR^dC (S) OR^to, (CH₂) _nNR^dC (S) NR^bR^c, (CH₂) _nNR^dC (NR^and) NR^bR^c, (CH₂) _nNR^QS (O) R^to, (CH2) nNR^toSO2R^to, (CH2) nNR^toSO2NR^bR^c, (CH₂) _nC (O) R^to, (CH₂) _nC (O) OR^to, (CH2) nC (O) NR^bR^c, (CH2) _nC (S) R^to, (CH₂) _nC (S) OR^to, (CH₂) _nC (S) NR^bR^c,

CH₂)_nC (NR^and) NR^bR^c, (CH₂)_nMR^to, CH₂)_nS (O) R^to, (CH₂)_nSW₂R, (CH₂) _nSW₂NR R, alkyl Ci-₆, haloalkyl Ci_₆, alkenyl C₂-6, alkynyl C₂-6, (CH₂) C3-8 cycloalkyl, (CH₂) 3-8 membered heterocycloalkyl, (CH₂)_nC6-10 aryl and (CH₂) 5-10 membered heteroaryl, where each of the Ci_ alkyl groups₆, alkenyl C₂-₆, alkynyl C₂.₆, (CH₂) cycloalkyl C₃_₈, (CH₂) 3-8 membered heterocycloalkyl, (CH₂)_naryl C₆-io and (CH₂) 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 R substituents^F;

R³ is selected from hydrogen, halogen, CN, Ci-6 alkyl, Ci_5 haloalkyl, C (O) OR^to, C (O) NR^bR^c, OR^to, NR^bR^c, C6_io aryl and 5-10 membered heteroaryl;

R⁴ is selected from hydrogen, Ci-6 alkyl, Ci-e haloalkyl, C (O) R^to, C (O) OR^to, C (O) NR^bR^c and SO2R^to;

each of R⁵ and R⁶ is independently selected from hydrogen, halogen, Ci- alkyl₆ and haloalkyl Ci-₆;

or alternatively R⁵ and R⁶ along with the atom of

-44carbon to which they are attached form cycloalkyl C₃_8, cycloalkenyl C₃-₈, 3-8 membered heterocycloalkyl or 3-8 membered heterocycloalkenyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, 0R^to, OC (O) R^to, OC (O) OR^to, NR^bR^c, C (O) R^to, C (O) OR^to, C (O) NR^bR^c, S (O) R^toSO2R^toSO2NR^bR^c, alkyl Ci-₆ and haloalkyl Ci-₆;

R⁷ is selected from C3-8 cycloalkyl, C cycloalkenyl₃-₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-10 aryl and 5-10 membered heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR^to, OC (O) R^to, OC (O) OR^to, OC (O) NR^bR^c, NR^bR^c, NR^dC (O) R^to, NR^dC (O) OR^to, NR^dC (0) NR^bR^c, NR^dC (O) C (O) NR^bR^c, NR^dC (S) R^to, NR^dC (S) OR^to, NR^dC (S) NR^bR^c, NR^dC (NR^and) NR^bR^c, NR^dS (O) R^to, NR^dSO2R^to, NR^dSO2NR^bR^c, C (O) R^to, C (O) OR^to, C (O) NR^bR^c, C (S) R^to, C (S) OR^to, C (S) NR^bR^c, C (NR^and) NR^bR^c, MR^to, S (O) R^toSO2R^toSO2NR^bR^c, C1-6 alkyl, Ci- haloalkyl₆, alkenyl C₂-6, alkynyl C₂_6, cycloalkyl C₃-₈, cycloalkenyl C₃-₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆-io, C7-11 aralkyl and 5-10 membered heteroaryl, where each of the C1-6 alkyl, C-alkenyl groups₂-6, alkynyl C₂_₆, cycloalkyl C₃_₈, cycloalkenyl C₃_₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-10 aryl, C aralkyl₇-n and 5-4510 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 R substituents^F;

each of R⁸ and R⁹, in each case, is independently selected from hydrogen, halogen, and Ci-6 alkyl;

X is selected from a bond, - (CH₂)_p-, (CH₂)_PC (O) (CH₂)_what-, - (CH₂) _p0 (CH₂) _what-, - (CH₂) _PS (CH₂) _what-, (CH₂) _pNR^d (CH2) q—, - (CH2) PC (O) O (CH2) q-, (CH2) POC (O) (CH2) q-, (CH2) pNR^dC (O) (CH2) _what-, - (CH₂) _PC (O) NR^d (CH₂) _what-, (CH₂) _pNR^dC (O) NR^d (CH2) q-, - (CH2) pNR^dSO2 (CH₂) _what- and (CH₂) _pSW₂NR^d (CH₂) q-;

or, alternatively, X, R² and R³, together with the carbon atoms to which they are attached, form a 5-6 membered ring optionally containing one or more heteroatoms selected from oxygen, nitrogen and sulfur, and optionally containing one or more double bonds, and optionally substituted with 1, 2, 3, 4 or 5 substituents

R^F;

R^to, in each case, is independently selected from hydrogen, Ci-6 alkyl, haloCi_alkyl₈, alkenyl C₂_ 6, alkynyl C₂_₆, cycloalkyl C₃_₈, cycloalkenyl C₃_₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, iloβ-ιο aryl, aralkyl C₇-and 510-membered heteroaryl, where each of the Ci_ alkyl groups₆, alkenyl C₂_₆, alkynyl C₂-₆, cycloalkyl C₃-₈, cycloalkenyl C₃_₈, 3-8 membered heterocycloalkyl,

-46 3-8 membered heterocycloalkenyl, C6-io aryl, C7-11 aralkyl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 R substituents^F;

each of R^b and R^c, in each case, is independently selected from hydrogen, C1-6 alkyl, Ci_6 haloalkyl, C2_6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkenyl, 3-8 membered heterocycloalkenyl , iloβ-ιο aryl, C7_n aralkyl, 5-10 membered heteroaryl, C (O) R^g, C (0) 0R⁹, C (O) NR¹R^j and SO2R^g, where each of the C1-6 alkyl, C-alkenyl groups₂-6, alkynyl C₂-6, C3s cycloalkyl, C cycloalkenyl₃-e, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C7-11 aralkyl, and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 R substituents^F;

R^d, in each case, is independently selected from hydrogen and Ci-ε alkyl;

R^and, in each case, is independently selected from hydrogen, CN, OH, Ci_alkoxy₆, alkyl Ci-₆ and haloalkyl Ci_₆;

R^F, in each case, is independently selected from halogen, CN, OR^h, OC (O) R^h, OC (O) OR^h, OCÍOJNR ^, NRⁱR^{; i}, NR^dC (O) R^h, NR^dC (O) OR^h, NR^dC (0) NRⁱR^j, NR^dC (O) C (0) NR^dR^j, NR^dC (S) R^h, NR^dC (S) OR^h, NR^dC (S) NRⁱR^j, NR^dC (NR^and) NRⁱR^j, NR^dS (0) R^h, NR^dSO2R^h, NR^dSO2NRⁱR^j, C (O) R^h, C (O) OR \ C (O) NRⁱR^j, C (S) R^h,

-47C (S) OR^h, CÍSJNR ^³, C (NR^and) NRⁱR^j, MR^h, S (O) R^hSO2R^hSO2NRⁱR^j, Ci-6 alkyl, Ci_ haloalkyl₆, alkenyl C₂-6, alkynyl C₂-6z cycloalkyl C₃.₈, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, 7β-ιοζ aralkyl C7-11, and 5-10 membered heteroaryl, where each of the C1-6 alkyl, C alkenyl groups₂-6z alkynyl C₂_₆, cycloalkyl C₃_₈, cycloalkenyl C₃.₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C7-11 aryl Οβ-ιοζ aralkyl and 510 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 R substituents^k;

or two R substituents^F attached to a single carbon atom, together with the carbon atom to which they are attached, form a group selected from carbonyl, cycloalkyl C₃-s and 3-8 membered heterocycloalkyl;

R⁹, in each case, is independently selected from Ci_alkyl₆, haloalkyl Ci_₆, phenyl, naphthyl, and C7-11 aralkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halogen, CN,

OH, C1-6 alkoxy, Ci- alkyl₆ and haloalkyl Ci_₆;

R^h, in each case, is independently selected from hydrogen, Ci_alkyl₆, C1-6 haloalkyl, C alkenyl₂₆, alkynyl C₂_₆, cycloalkyl C₃_₈, cycloalkenyl C₃_₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl Οβ-ιοζ aralkyl C₇-n and 5-4810 membered heteroaryl, where each of the Ci_ alkyl groups₆, alkenyl C₂_₆, alkynyl C₂-₆, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-10 aryl, C7-11 aralkyl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 , 4 or 5 substituents R^k;

each of R¹ and R^], in each case, is independently selected from hydrogen, C3-6 alkyl, Cx-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3-8 membered heterocycloalkyl, heterocycloalkenyl 3-8 membered, C6-10 aryl, C7-11 aralkyl, 5-10 membered heteroaryl, C (0) R⁹ and C (O) OR^g, where each of the groups C1-6alkyl, haloC1-6alkyl, C2_6alkenyl, C-alkynyl₂_6, C3-8 cycloalkyl, C cycloalkenyl₃-₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C7-11 aryl ilo-ηη aralkyl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, OH, alkoxy Ci-₆, C1-6 alkyl and C1-6 haloalkyl;

R^k, in each case, is independently selected from halogen, CN, OH, C-alkoxy₅, NH₂, NH (Ci_alkyl₆), N (Ci-6 alkyl)₂, NHC (0) alkyl Ci_₆, NHC (O) aralkyl C₇_n, NHC (0) Oalkyl Ci-₆, NHC (0) Oaralkyl C₇-u, 0C (0) Ci6 alkyl, OC (0) C aralkyl₇-u, OC (O) Oalkyl Ci-₆, OC (0) Oaralkyl

-49C₇-n, C (O) Ci-6 alkyl, C (O) C7-11 aralkyl, C (O) O C1-6 alkyl, C (O) C7-11 alkyl, C1-6 alkyl, Cx-6 haloalkyl, alkenyl C2-6 and C-alkynyl₂-6z where each Ci_ alkyl substituent₆, alkenyl C₂-6, alkynyl C₂-6 and C7-11 aralkyl is optionally substituted with 1, 2 or 3 substituents selected from OH, C1-6 alkoxy, NH₂, NH (Ci_6-alkyl), N (Cx-alkyl₆)₂, NHC (O) alkyl Ci-₆, NHC (O) aralkyl C₇-n, NHC (O) Oal-Οχalkyl and NHC (O) Oaralkyl C7-11;

or two R substituents^k attached to a single carbon atom, together with the carbon atom to which they are attached, form a carbonyl group;

month 0, 1 or 2;

n, in each case, is independently 0, 1 or 2;

weight, 162; and q is 0, 1 or 2.

In some embodiments of compounds of Formula I, m is 0, i.e., a compound of Formula II, or a pharmaceutically acceptable salt thereof:

R¹

<img file="MX2012012189A_D0006.tif" />

R⁴

Formula ii

-50 where R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and X are as defined herein.

In some embodiments of compounds of Formula I, m is 1, i.e., a compound of Formula III, or a pharmaceutically acceptable salt thereof:

R¹

<img file="MX2012012189A_D0007.tif" />

Formula III in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and X are as defined herein.

In some embodiments of compounds of Formula I, II or III, one of R⁵ and R⁶ it is hydrogen and the other is Ci-6 alkyl.

In some embodiments of compounds of Formula I, II or III, each of R⁵ and R⁶ is independently Ci-6 alkyl

In some embodiments of compounds of Formula I, II or III, each of R⁵ and R⁶ it is methyl.

In some embodiments, the compounds are of Formula IV (a) or IV (b), or a pharmaceutically salt

-51 acceptable thereof:

R¹

<img file="MX2012012189A_D0008.tif" />

R⁷

R⁴

Formula IV (a)

R¹

<img file="MX2012012189A_D0009.tif" />

Formula IV (b) in which R¹, R², R³, R⁴, R⁷, R⁸, R⁹ and X are as defined herein .

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶ together with the carbon atom to which they are attached they form C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl or 3-8 membered heterocycloalkenyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, 0R^to, OC (O) R^to, OC (O) OR^to, NR^bR^c, C (O) R^to, C (O) OR^to, C (O) NR^bR^c, S (O) R^toSO2R^toSO2NR^bR^c, alkyl Ci-₆ and haloalkyl

-52Cl-6

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶, together with the carbon to which they are attached, form cycloalkyl C₃-₆ optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, 0R^to, OC (O) R^to, OC (O) OR^to, NR^bR^c, C (O) R^to, C (O) OR^to, C (O) NR^bR^c, S (0) R^toSO2R^toSO2NR^bR^c, Cx-alkyl₆ and Ci-6 haloalkyl.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶, together with the carbon to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, 0R^to, OC (O) R^to, OC (O) OR^to, NR^bR^c, C (0) R^to, C (O) OR^to, C (O) NR^bR^c, S (O) R^toSO2R^toSO2NR^bR^c, alkyl Ci-₆ and haloalkyl Ci-₆.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶, together with the carbon to which they are attached, form cyclobutyl optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, 0R^to, OC (O) R^to, OC (O) OR^to, NR^bR^c, C (O) R^to, C (O) OR^to, C (O) NR^bR^c, S (O) R^toSO2R^toSO2NR^bR^c, alkyl Ci_₆ and haloalkyl Ci_₆.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶, together with the carbon to which they are attached, form cyclobutyl substituted with a substituent selected from halogen, CN, oxo, 0R^to, OC (O) R^to,

-53OC (O) OR^to, NR^bR^c, C (O) R^to, C (O) OR^to, C (O) NR^bR^c, S (O) R^toSO2R^toSO2NR^bR^c, Ci-6 alkyl and Ci-6 haloalkyl, where the substituent and R⁷ they are in trans configuration relative to each other in the cyclobutyl ring.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶, together with the carbon to which they are attached, form cyclobutyl substituted with a substituent selected from halogen, CN, oxo, OR^to, OC (O) R^to, OC (O) OR^to, NR^bR^c, C (O) R^to, C (O) OR^to, C (O) NR^bR^c, S (0) R^toSO2R^toSO2NR^bR^c, Ci-g alkyl and Ci-6 haloalkyl, where the substituent and R⁷ they are in cys configuration with respect to each other in the cyclobutyl ring.

In some embodiments, the compounds are of Formula V (a) or V (b), or a pharmaceutically acceptable salt thereof:

<img file="MX2012012189A_D0010.tif" />

<img file="MX2012012189A_D0011.tif" />

R⁴

Formula V (a)

<img file="MX2012012189A_D0012.tif" />

Formula V (b) in which each of R^m and Rⁿ is independently selected from hydrogen, halogen, and Ci-6 alkyl, and R¹, R², R³, R⁴, R⁷, R⁸, R⁹ and X are as defined herein.

In some embodiments of compounds of Formula V (a)

<td>OV (b), In</td><td>each some</td><td>from R^m and Rⁿ is achievements</td><td>hydrogen. compounds</td><td>of</td><td>Formula</td><td>Goes)</td><td>or</td>

<td colspan="4">V (b), each of R^m and Rⁿ it is halogen.</td><td></td><td></td><td></td><td></td>

<td>In</td><td>some</td><td>achievements</td><td>compounds</td><td>of</td><td>Formula</td><td>Goes)</td><td>or</td>

<td colspan="4">V (b), each of R^m and Rⁿ it's fluorine.</td><td></td><td></td><td></td><td></td>

<td>In</td><td>some</td><td>achievements</td><td>compounds</td><td>of</td><td>Formula</td><td>Goes)</td><td>or</td>

V (b), one of R^m and Rⁿ it is hydrogen and the other is halogen. In some embodiments of said compounds, the halogen and R⁷ they are in trans configuration relative to each other in the cyclobutyl ring. In some embodiments of said compounds, the halogen and R⁷ they are in cis configuration with respect to each other in the cyclobutyl ring.

-55 In some embodiments compounds of Formula V (a) or V (b), one of R^m and Rⁿ it is hydrogen and the other is fluorine. In some embodiments of said compounds, fluorine and R⁷they are in trans configuration relative to each other in the cyclobutyl ring. In some embodiments of said compounds, fluorine and R⁷ they are in cis configuration with respect to each other in the cyclobutyl ring.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶, together with the carbon atom to which they are attached, form 3-6 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, 0R^to, OC (O) R^to, 0C (0) 0R^to, NR^bR^c, C (O) R^to, C (O) OR^to, C (O) NR^bR^c, S (0) R^toSO2R^toSO2NR^bR^c, alkyl Ci_₆ and Ci-6 haloalkyl.

In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶, together with the carbon atom to which they are attached, form aziridine, azetidine, pyrrolidine, oxirane, oxetane or tetrahydrofuran, each of which is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, 0R^to, OC (O) R^to, OC (O) OR^to, NR^bR^c, C (O) R^to, C (O) OR^to, C (O) NR^bR^c, S (O) R^toSO2R^to, S02NR^bR^c, alkyl Ci-₆ and haloalkyl Ci_₆.

In some embodiments of compounds of Formula I, II or III, each of R⁵ and R⁶ is independently alkyl

-56Ci_6, or R⁵ and R⁶ together with the carbon atom to which they are attached they form C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl or 3-8 membered heterocycloalkenyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, 0R^to, OC (O) R^to, OC (O) OR^to, NR^bR^c, C (O) R^to, C (O) OR^to, C (O) NR^bR^c, S (O) R^toSO2R^toSO2NR^bR^c, alkyl Ci-₆ and C1-6 haloalkyl

In some embodiments of compounds of Formula I, II or III, each of R⁵ and R⁶ is methyl, or R⁵ and R⁶ together with the carbon atom to which they are attached they form C3-8 cycloalkyl, cycloalkenyl C₃-₈, 3-8 membered heterocycloalkyl or 3-8 membered heterocycloalkenyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR^to, OC (O) R^to, OC (O) OR^to, NR^bR^c, C (O) R^to, C (O) OR^to, C (O) NR^bR^c, S (O) R^toSO2R^toSO2NR^bR^c, alkyl Ci-₆ and haloalkyl Ci_₆.

In some embodiments of compounds of Formula I, II or III, each of R⁵ and R⁶ is independently C1-6alkyl, or R⁵ and R⁶, together with the carbon to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, 0R^to, OC (O) R^to, OC (O) OR^to, NR^bR^c, C (O) R^to, C (O) OR^to, C (O) NR^bR^c, S (O) R^toSO2R^toSO2NR^bR^c, alkyl Ci-₆ and C1-6 haloalkyl.

-57 In some embodiments of compounds of Formula I, II or III, each of R⁵ and R⁶ is methyl, or R⁵ and R⁶, together with the carbon to which they are attached, form cyclobutyl optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR^to, OC (O) R^to, br&gt; C

OC (O) OR^to, NR^bR^c, C (O) R^to, C (O) OR^to, C (O) NR ° R^c, S (O) R^toSO2R^toSO2NR^bR^c, alkyl Ci-₆ and haloalkyl Ci-₆.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a) or V (b), R⁷ is selected from C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆-io and 5-10 membered heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR^to, OC (O) R^to, OC (0) OR^to, OC (O) NR^bR^c, NR^bR^c, NR^dC (O) R^to, NR^dC (O) OR^to, NR^dC (0) NR^bR^c, NR^dC (O) C (O) NR^bR^c, NR^dC (S) R^to, NR^dC (S) OR^to, NR^dC (S) NR^bR^c, NR^dC (NR^and) NR^bR^c, NR^dS (O) R^to, NR^dSO2R^to, NR^dSO2NR^bR^c, C (O) R^to, C (O) OR^to, C (O) NR^bR^c, C (S) R^to, C (S) OR^to, C (S) NR^bR^c, C (NR^and) NR^bR^c, MR^to, S (O) R^toSO2R^toSO2NR^bR^c, C1-6 alkyl, Ci- haloalkyl_6/ alkenyl C₂-6, alkynyl C₂.₆, cycloalkyl C₃.₈, cycloalkenyl C₃.₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆-io, C7-11 aralkyl and 5-10 membered heteroaryl, where each of the Ci_alkyl groups₆, alkenyl C₂-6, alkynyl C₂-6, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, heterocycloalkenyl of

-583-8 members, aril C₆-io, aralkyl C₇-n and 510-membered heteroaryl is optionally substituted with 1, 2, 3, 4 or R substituents^F.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a) or V (b), R⁷ it is phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR^to, OC (O) R^to, OC (O) OR^to,

OC (O) NR^bR^c,

NR^bR^c,

NR C (O) R, NR^dC (S) R^to,

NR C (O) OR, NR^dC (S) OR^to,

NR^dC (0) NR^bR^c,

NR^dC (O) C (0) NR^bR^c, ibnC

NR^ORC (S) NR^bR^c, NR^dC (NR^and) NR^bR^c, NR^dS (O) R^to, NR^dSO2R^to, NR^dSO2NR^DR^c, C (O) R^to, C (O) OR^to, C (O) NR^bR^c, C (S) R^to, C (S) OR^to, C (S) NR^bR^c, C (NR^and) NR^bR^c, MR^to, S (O) R^toSO2R^toSO2NR^bR^c, alkyl Ci-₆, haloalkyl Ci_6, alkenyl C₂_6, alkynyl C₂-6, C3-B cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl Οβ-ιο, aralkyl C₇-_n and 5-10 membered heteroaryl, where each of the Ci- alkyl groups₆, alkenyl C₂_₅, alkynyl C₂6, cycloalkyl C₃_₈, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, Οδ-ίο aryl, C aralkyl₇-n and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 R substituents^F.

In some embodiments, the compounds are of Formula VI, or a pharmaceutically acceptable salt thereof:

<img file="MX2012012189A_D0013.tif" />

Formula VI in which r is 0, 1, 2, 3 or 4, and R¹, R², R³, R⁴, R⁵, R⁶, R⁸,

R⁹, R^F, X and m are as defined herein.

In some embodiments, the compounds are of Formula VII (a) or VII (b), or a pharmaceutically acceptable salt thereof:

R¹

<img file="MX2012012189A_D0014.tif" />

Formula VII (a)

<img file="MX2012012189A_D0015.tif" />

Formula VII (b) where r is 0, 1, 2, 3 or 4, and R¹, R², R³, R⁴, R⁸, R⁹, R^F10 and X are as defined herein.

In some embodiments, the compounds are of Formula VIII (a) or VIII (b), or a pharmaceutically acceptable salt thereof:

<img file="MX2012012189A_D0016.tif" />

Formula VIII (a)

<img file="MX2012012189A_D0017.tif" />

<img file="MX2012012189A_D0018.tif" />

(R^F) r

Formula VIII (b) in which each of R^m and Rⁿ is independently selected from hydrogen, halogen, and Ci-6 alkyl; r is 0, 1, 2, 3 or 4; and R¹, R², R³, R⁴, R⁸, R⁹, R^F and X are as defined herein.

In some embodiments of compounds of Formula VIII (a) or VIII (b), each of R^m and Rⁿ it is hydrogen.

In some embodiments, compounds of Formula VIII (a) or VIII (b), each of R^m and Rⁿ it is halogen.

In some embodiments, compounds of Formula VIII (a) or VIII (b), each of R^m and Rⁿ it's fluorine.

In some embodiments compounds of Formula VIII (a) or VIII (b), one of R^m and Rⁿ it is hydrogen and the other is halogen. In some embodiments of such compounds, the halogen and the phenyl ring are in trans configuration relative to each other in the cyclobutyl ring. In

-62 Some embodiments of said compounds, the halogen and the phenyl ring are in cis configuration with respect to each other in the cyclobutyl ring.

In some embodiments compounds of Formula VIII (a) or VIII (b), one of R^ra and Rⁿ it is hydrogen and the other is fluorine. In some embodiments of such compounds, the fluorine and the phenyl ring are in trans configuration relative to each other in the cyclobutyl ring. In some embodiments of said compounds, the fluorine and the phenyl ring are in cis configuration with respect to each other in the cyclobutyl ring.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a) or V (b), R⁷ is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3 , 4-dichlorophenyl, 3,5-dichlorophenyl, 2-methylphenyl, 3-methylphenyl, 2,4-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2- (hydroxymethyl) phenyl, 3- (hydroxymethyl) phenyl, 4- ( hydroxymethyl) phenyl, 2 (aminomethyl) phenyl, 3- (aminomethyl) phenyl, 4 (aminomethyl) phenyl, 2-phenol, 3-phenol, 4-phenol, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 4difluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 3-63trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-cyanophenyl-2-cyanophenyl methyl-2-benzamine, N-methyl-3benzamide, N-methyl-4-benzamide, N, N-dimethyl-2-benzamine, N, N-dimethyl-3-benzamide and N, N-dimethyl-4-benzamide.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a) or V (b), R⁷ it is 510-membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR^to, br&gt; c

OC (O) R^to, OC (O) OR^to, OC (O) NR^bR^c, NR ° R^C, NR^toC (O) R^to, NR^QC (O) OR^to,

NR ° C (O) NR^bR^c,

NR^dC (O) C (O) NR^bR^c,

NR^dC (S) R^to,

NR^dC (S) OR^to,&gt; brjC b_nc

NR^toC (S) NR^bR^c, NR^toC (NR^and) NR^DR^C, NR ° S (O) R^to, NR SO2R^to, NR SO2NR^DR^C,

C (S) NR^bR^c,

C (O) R^to, C (O) OR^to, C (O) NR^bR^c, C (S) R^to, C (S) OR^to,

C (NR^and) NR^bR^c, MR^to, S (O) R^toSO2R^toSO2NR^bR^c, alkyl Ci_₆, haloalkyl Ci_6, alkenyl C₂-6, alkynyl C₂-6, C3-8 cycloalkyl, C cycloalkenyl₃-₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-10 aryl, C7-11 aralkyl and 5-10 membered heteroaryl, where each of the C1-6 alkyl, C alkenyl groups₂-6, alkynyl C₂6, cycloalkyl C₃_g, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-10 aryl, C aralkyl₇-n and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 R substituents^F.

In some embodiments of compounds of Formula I,

-64II, III, IV (a), IV (b), V (a) or V (b), R⁷ is pyridyl optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, 0R^to, OC (O) R^to, OC (O) OR^to,

OC (O) NR^bR^c,

NR^bR^c,

NR^dC (0) NR^bR^c,

NR^dC (0) C (0) NR^bR^c,

NRC (0) R,

NR^dC (S) R^to,

NR C (O) OR,

NR^dC (S) OR^to,

-.bnC b_Dc

NR ° C (S) NR^bR^c, NR^toC (NR^and) NR^DR^C, NR ° S (O) R^to, NR SO2R^to, NR SO2NR^DR^C,

C (O) R^to, C (O) OR^to, C (O) NR^bR^c, C (S) R^to, C (S) OR^to, C (S) NR^bR^c, C (NR^and) NR^bR^c, MR^to, S (O) R^toSO2R^toSO2NR^bR^c, alkyl Ci-₆, Ci-6 haloalkyl, C alkenyl₂-6, alkynyl C₂_6, cycloalkyl C₃-₈, cycloalkenyl C₃_₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, iloβ-ιο aryl, aralkyl C₇-n and 5-10 membered heteroaryl, where each of the Ci-6-alkyl, C-alkenyl groups₂_6, alkynyl C₂_ 6, cycloalkyl C₃-s, cycloalkenyl C₃-s, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, Cg-io aryl, C7-11 aralkyl, and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 R substituents^F.

In some embodiments of compounds of Formula I,

II, III, IV (a), IV (b), V (a) or V (b), R 'is selected from

2-pyridyl, 3-pyridiium and 4-pyridiium, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, 0R^to, OC (O) R^to, OC (0) OR^to, OC (O) NR^bR^c, NR^bR^c, NR^dC (O) R^to, NR^dC (O) OR^to, NR^dC (O) NR^bR^c, NR^dC (O) C (0) NR^bR^c, NR^dC (S) R^to, NR^dC (S) OR^to, NR^dC (S) NR^bR^c, NR^dC (NR^and) NR^bR^c, NR^dS (O) R^to,

-65NR^dSO2R^to, NR^dSO2NR^bR^c, C (O) R^to, C (O) OR^to, C (O) NR^bR^c, C (S) R^to, C (S) OR^to, C (S) NR^bR^c, C (NR^and) NR^bR^c, MR^to, S (O) R^toSO2R^toSO2NR^bR^c, alkyl Ci_₆, haloalkyl Ci_₆, alkenyl C₂-₆, alkynyl C₂-6, C3-6 cycloalkyl, C3-6 cycloalkenyl, heterocycloalkyl of

3-6 members, 3-6 members heterocycloalkenyl, phenyl, naphthyl, aralkyl C₇-very 5-10 membered heteroaryl, where each of the C- alkyl groups₆, alkenyl C₂_6, alkynyl C₂-6, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, heterocycloalkenyl of

3-8 members, aryl Οβ-ιο, aralkyl C₇-n and 510-membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 R substituents^F.

In some embodiments, the compounds are of Formula IX, or a pharmaceutically acceptable salt thereof:

<img file="MX2012012189A_D0019.tif" />

Formula IX in which r is 0, 1, 2, 3 or 4, and R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R^F, X and m are as defined herein.

In some embodiments, the compounds are of

-66 Formula X (a) or X (b), or a pharmaceutically acceptable salt thereof:

R¹

<img file="MX2012012189A_D0020.tif" />

Formula X (a)

R¹

<img file="MX2012012189A_D0021.tif" />

Formula X (b) in which r is 0, 1, 2, 3 or 4, and R¹, R², R³, R⁴, R⁸, R⁹, R^F and 20X are as defined herein.

In some embodiments, the compounds are of

Formula XI (a) or XI (b), acceptable thereof:

or a pharmaceutically salt

<img file="MX2012012189A_D0022.tif" />

(R^F) r

Formula XI (b) in which each of R^m and Rⁿ is independently selected from hydrogen, halogen, and C1-5 alkyl; r is 0, 1, 2, 3 or 4; and R¹, R², R³, R⁴, R⁸, R⁹, R^F and X are as defined herein.

In some embodiments of compounds of Formula XI (a) or XI (b), each of R^m and Rⁿ it is hydrogen.

In some embodiments compounds of Formula XI (a) or

-68XI (b), each of R^m and Rⁿ it is halogen.

In some composite embodiments of Formula XI (a) or XI (b), each of R^m and Rⁿ it's fluorine.

In some embodiments, compounds of Formula XI (a) or XI (b), one of R^m and Rⁿ it is hydrogen and the other is halogen. In some embodiments of such compounds, the halogen and the pyridyl ring are in trans configuration with respect to each other in the cyclobutyl ring. In some embodiments of such compounds, the halogen and the pyridyl ring are in cyc configuration with respect to each other in the cyclobutyl ring.

In some embodiments, compounds of Formula XI (a) or XI (b), one of R^m and Rⁿ it is hydrogen and the other is fluorine. In some embodiments of such compounds, the fluorine and the pyridyl ring are in trans configuration with respect to each other in the cyclobutyl ring. In some embodiments of such compounds, the fluorine and the pyridyl ring are in cis configuration with respect to each other in the cyclobutyl ring.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a) or V (b), R⁷ is selected from pyrid-2-yl, 3-fluoro-pyrid-2-yl, 4-fluoro-pyrid-2-yl, 5-fluoro-pyrid-2-yl, 6-fluoro-pyrid-2-yl, 3-chloro -pyrid-2yl, 4-chloro-pyrid-2-yl, 5-chloro-pyrid-2-yl, 6-chloropyrid-2-yl, 3-cyano-pyrid-2-yl, 4-cyano-pyrid-2 -yl, 5-69hydroxymethyl-pyrid-2-yl, aminomethyl-pyrid-2-yl, cyano-pyrid-2-yl, 6-cyano-pyrid-2-yl, 3-methyl-pyrid-2-yl, 4-methyl -pyrid-2-yl, 5-methyl-pyrid-2-yl, 6-methylpyrid-2-yl, 3-difluoromethyl-pyrid-2-yl, 4-difluoromethylpyrid-2-yl, 5-difluoromethyl-pyrid-2-yl, 6-difluoromethylpyrid-2-yl, 3-trifluoromethyl-pyrid-2-yl, 4trifluoromethyl-pyrid-2-yl, 5-trifluoromethyl-pyrid-2-yl, 6-trifluoromethyl- pyrid-2-yl, 3-hydroxymethyl-pyrid-2-yl,

4-hydroxymethyl-pyrid-2-yl, 5-hydroxymethyl-pyrid-2-yl, 63-aminomethyl-pyrid-2-yl, 45-aminomethyl-pyrid-2-yl, 6-aminomethyl-pyrid-2-yl, 3- hydroxy-pyrid-2-yl, 4-hydroxypyrid-2-yl, 5-hydroxy-pyrid-2-yio, 6-hydroxy-pyrid-2-yl,

3- methoxy-pyrid-2-yl, 4-methoxy-pyrid-2-yl, 5-methoxy-pyrid2-yl, 6-methoxy-pyrid-2-yl, 3-difluoromethoxy-pyrid-2-yl,

4- difluoromethoxy-pyrid-2-yl, 5-difiuoromethoxy-pyrid-2-yl,

6-difluoromethoxy-pyrid-2-yl,

3-trifluoromethoxy-pyrid-2-yl, 4-trifluoromethoxy-pyrid-2-yl, 5-trifluoromethoxypyrid-2-yl, 6-trifluoromethoxy-pyrid-2-yl, 3-methylthiopyrid-2-yl, 4-methylthio-pyrid- 2-yl, 5-methylthio-pyrid-2-yl, 6-methylthio-pyrid-2-yl, 3-carboxamide-pyrid-2-yl, 4-carboxamide-pyrid-2-yl, 5-carboxamide-pyrid-2-yl, 6carboxamide-pyrid-2-yl and 3-fluoro-6-methyl-pyrid-2-yl.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a) or V (b), R⁷ is selected from pyrid-3-yl, 2-fluoro-pyrid-3-yl, 4-fluoro-pyrid-3-yl, 5-70fluoro-pyrid-3-yl, 6-fluoro-pyrid-3-yl, 2 -chloro-pyrid-3-yl, 4-chloro-pyrid-3-yl, 5-chloro-pyrid-3-yl, 6-chloropyrid-3-yl, 2-cyano-pyrid-3-yl, 4-cyano-pyrid -3-yl, 5-cyano-pyrid-3-yl, 6-cyano-pyrid-3-yl, 2-methyl-pyrid-3-yl, 4-methyl-pyrid-3-yl, 5-methyl-pyrid-3-yl , 6-methylpyrid-3-yl, 2-difluoromethyl-pyrid-3-yl, 4-difluoromethylpyrid-3-yl, 5-difluoromethyl-pyrid-3-yl, 6-difluoromethylpyrid-3-yl, 2-trifluoromethyl-pyrid-3-yl, 4trifluoromethyl-pyrid-3-yl, 5-trifluoromethyl-pyrid-3-yl,

6-trifluoromethyl-pyrid-3-yl, 2-hydroxymethyl-pyrid-3-yl, 4-hydroxymethyl-pyrid-3-yl, 5-hydroxymethyl-pyrid-3-yl, 62-aminomethyl-pyrid-3-yl, 45-aminomethyl-pyrid-3-yl, 6-aminomethyl- pyrid-3-yl, 2-hydroxy-pyrid-3-yl, 4-hydroxypyrid-3-yl, 5-hydroxy-pyrid-3-yl, 6-hydroxy- pyrid-3-yl,

2- methoxy-pyrid-3-yl, 4-methoxy-pyrid-3-yl, 5-methoxy-pyrid3-yl, 6-methoxy-pyrid-3-yl, 2-difluoromethoxy-pyrid-3-yl,

4- difluoromethoxy-pyrid-3-yl, 5-difluoromethoxy-pyrid-3-yl, hydroxymethyl-pyrid-3-yl, aminomethyl-pyrid-3-yl,

6-difluoromethoxy-pyrid-3-yl,

2-trifluoromethoxy-pyrid-3-yl, 4-trifluoromethoxy-pyrid-3-yl, 5-trifluoromethoxypyrid-3-yl, 6-trifluoromethoxy-pyrid-3-yl, 2-methylthiopyrid-3-yl, 4-methylthio-pyrid- 3-yl, 5-methylthio-pyrid-3-yl, 6-methylthio-pyrid-3-yl, 2-carboxamide-pyrid-3-yl, 4-carboxamide-pyrid-3-yl, 5-carboxamide-pyrid-3-yl and 6carboxamide-pyrid-3-yl.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIIII (a), VIII (b), IX, X (a), X (b), XI (a) or XI (b), X is selected from one bond, - (CH₂)_P-, - (CH₂) _p0 (CH₂) _what-, (CH₂)_PC (O) (CH₂)_what-, - (CH₂) _pS (CH₂) q-, - (CH₂)_pNR^d(CH₂) q-, (CH₂) pC (O) O (CH₂) q—, (CH₂)_pOC (O) (CH₂) _what-,

- (CH₂) _pNR^dC (O) (CH2) g-, - (CH2) PC (O) NR^d (CH2) _what-, (CH₂) _pNR^dC (O) NR^d (CH2) q-, - (CH2) pNR^dSO2 (CH₂) _what- and (CH₂) _pSW₂NR^d (CH₂ ) q—.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), vni (a), vni (b), IX, X (a), X (b), xi (a) or XI (b), X is a bond.

In some embodiments, the compound .is of Formula XII (a), XII (b), XII (c), XII (d), XII (e), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (n), or XII (o), or a pharmaceutically acceptable salt thereof:

R¹

<img file="MX2012012189A_D0023.tif" />

Formula XII (a)

<img file="MX2012012189A_D0024.tif" />

R⁷

Formula XII (b)

R¹

<img file="MX2012012189A_D0025.tif" />

Formula XII (c)

<img file="MX2012012189A_D0026.tif" />

Formula XII (d)

<img file="MX2012012189A_D0027.tif" />

Formula XII (f)

R¹

<img file="MX2012012189A_D0028.tif" />

Formula XII (g)

-74 Formula

Formula

R¹

<img file="MX2012012189A_D0029.tif" />

XII (i)

<img file="MX2012012189A_D0030.tif" />

Formula XII (j)

<img file="MX2012012189A_D0031.tif" />

Formula XII (k)

<img file="MX2012012189A_D0032.tif" />

Formula XII (m)

<img file="MX2012012189A_D0033.tif" />

Formula XII (η)

<img file="MX2012012189A_D0034.tif" />

Formula XII (o) in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^F, R^m, Rⁿ, m and r are as defined herein.

In some embodiments of compounds of Formula I,

II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b),

Vlll (a), VIII (b), IX, X (a), X (b), XI (a) or XI (b), X is -O-.

In some embodiments of compounds of Formula I,

-77II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b),

VIII (a), VIII (b), IX, X (a), X (b), XI (a) or XI (b), X is selected from -CH₂O- and -OCH₂-.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIII (a), VIII (b), IX, X (a), X (b), XI (a) or XI (b), X is -NR^dIn some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIII (a), VIII (b), IX, X (a), X (b), XI (a) or XI (b), X is selected from -CH2NR^d- and -NR^dCH2-.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b),

VlII (a), VIII (b), IX, X (a), X (b), XI (a) or XI (b), X is selected from -NR^dC (O) - and -C (O) NR^d-,

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIII (a), VIII (b), IX, X (a), X (b), XI (a) or XI (b), X is selected from -CH₂NR^dC (O) - and -C (O) NR^dCH₂-.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d), XII (e ), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (n) or XII (or ), R²is selected from cycloalkyl C₃-₈, cycloalkenyl C₃-₈,

-78 (CH₂)_nNR^bR^c, (CH₂) _nNR^dC (0) NR^bR^c, (CH₂) _nNR C (S) OR, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, Cg-io aryl and 5-10 membered heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, (CH₂)_nOR^to, (CH2) n0C (0) R^to, (CH2) _n0C (O) 0R^to, (CH₂) _nOC (0) NR^bR^c, (CH₂) _nNR^dC (0) R^to, (CH₂) _nNR^dC (O) OR^to, (CH₂) _nNR^dC (O) C (0) NR^bR^c, (CH₂) _nNR^dC (S) R^to, (CH₂) _nNR^dC (S) NR^bR^c, (CH₂) _nNR^dC (NR^and) NR^bR^c, (CH₂) _nNR^toS (0) R '*, (CH2) nNR^QSO2R^to, (CH2) nNR^orS02NR^bR^c, (CH₂)_nC (O) R \ (CH₂) _nC (0) 0R^to, (CH2) nC (0) NR^bR^c, (CH2) _nC (S) R^to, (CH₂) _nC (S) OR^to, (CH₂) _nC (S) NR^bR^c, (CH₂) _nC (NR^and) NR^bR^c, (CH2) nSR^to, (CH2) _nS (0) R^to, (CH₂)_nS0₂R^to, (CH2) nS02NR R^c, Ci-6 alkyl, Ci_6 haloalkyl, C alkenyl₂-6, alkynyl C₂-₆, (CH₂) _ncycloalkyl C₃-8, (CH₂) 3-8 membered nh'eterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) _n5-10 membered heteroaryl, where each of the C1-6 alkyl, C-alkenyl groups₂-6, C2-6 alkynyl, (CH₂) _ncycloalkyl C₃.₈, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) _n5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b),

Vlll (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a),

XII (b), XII (c), XII (d), XII (e), XII (f), XII (g), XII (h),

-79XII (i), XII (j), XII (k), XII (l), XII (m), XII (n) or XII (o), R² is phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, (CH₂)_nOR^to, (CH2) n0C (0) R^to, (CH2) _n0C (0) 0R^to, (CH2) n0C (0) NR^bR^c, (CH2)_nNR^bR^c, (CH2) nNR^dC (0) R^to, (CH2) _nNR^dC (0) 0R^to, (CH₂) _nNR^dC (0) NR^bR^c, (CH₂) _nNR^dC (0) C (O) NR^bR^c, (CH2) nNR^dC (S) R^to, (CH2) _nNR^dC (S) 0R^to, (CH2) nNR^dC (S) NR^bR^c, (CH2) _nNR^dC (NR^and) NR^bR^c, (CH₂) _nNR^dS (0) R^to, (CH₂)_nNR^dSO2R^to, (CH2) _nNR^dSO2NR^bR^c, (CH2) _nC (0) R^to, (CH₂) _nC (O) OR^to, (CH2) nC (0) NR^bR^c, (CH2) _nC (S) R^to, (CH₂) _nC (S) OR^to, (CH2) nC (S) NR^bR^c, (CH2) _nC (NR^and) NR^bR^c, (CH2) nSR^to, (CH2) _nS (0) R^to, (CH2) nSO2R^to, (CH2) _nSW₂NR^bR^c, alkyl Ci-₅, Ci-6 haloalkyl, C alkenyl₂.g, alkynyl C₂-6, (CH₂) _nC3-8 cycloalkyl, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) _n5-10 membered heteroaryl, where each of the C1-6 alkyl, C-alkenyl groups₂-6, alkynyl C₂-e, (CH₂) _ncycloalkyl C₃.₈, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaf linden and (CH₂) _n5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents

R^F.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d), XII (e ), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (η) or XII (or ), R²

-80 is phenyl substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, (CH₂)_nOR^to, (CH2) nOC (O) R^to, (CH2) _nOC (O) OR^to, (CH2) nOC (O) NR^bR^c, (CH2)_nNR^bR^c, (CH2) nNR^dC (0) R^to, (CH2) _nNR^dC (O) 0R^to, (CH2) nNR^dC (0) NR^bR^c, (CH2) _nNR^dC (O) C (0) NR^bR^c, (CH₂) _nNR^dC (S) R^to, (CH2) nNR^dC (S) 0R^to, (CH2) _nNR^dC (S) NR^bR^c, (CH₂) _nNR^dC (NR^and) NR^bR^c, (CH2) nNR^dS (0) R^to, (CH2) _nNR^dSW₂R^to, (CH₂) _nNR^dSO2NR^bR^c, (CH2) _nC (O) R^to, (CH₂) _nC (O) 0R^to, (CH2) nC (O) NR^bR^c, (CH2) _nC (S) R^to, (CH₂) _nC (S) OR^to, (CH2) nC (S) NR^bR^c, (CH2) _nC (NR^and) NR^bR^c, (CH2) nSR^to, (CH2)_nS (O) R^to, (CH2) nSO2R^to, (CH2) _nSW₂NR^bR^c, Ci6-alkyl, Ci-6-haloalkyl, C-alkenyl₂_6, alkynyl C₂_6, (CH₂) C3-8 cycloalkyl, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) _n5-10 membered heteroaryl, where each of the C1-6 alkyl, C-alkenyl groups₂_₆, alkynyl C₂-6, (CH₂) _nC3-8 cycloalkyl, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) _n5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents

R^F; where at least one substituent is attached at the meta position.

In some embodiments of compounds of Formula I,

<td>II, III, IV (a),</td><td>IV (b), V (a),</td><td>V (b),</td><td>SAW,</td><td>VII (a)</td><td>, VII (b),</td>

<td>VIII (a), VIII (b)</td><td colspan="3">, IX, X (a), X (b), XI (a),</td><td>XI (b)</td><td>, XII (a),</td>

<td>XII (b), XII (c),</td><td>XII (d), XII (e)</td><td>, XII</td><td>(F),</td><td>XII (g)</td><td>, XII (h),</td>

<td>Xll (i), XII (j),</td><td>XII (k), XII (l),</td><td>XII (m)</td><td colspan="2">, XII (n) 0</td><td>XII (0), R²</td>

is phenyl substituted with a substituent selected from

-81 (CH₂) nOC (O) NR^bR^c, (CH₂) _nNR^dC (O) OR^to, (CH₂) _nNR^dC (S) R^to, (CH₂) _nC (0) OR^to and (CH2) nC (O) NR^bR^c; and optionally substituted with 1, 2 or 3 additional substituents selected from halogen, CN, (CH2)_nOR^to, (CH2) n0C (O) R^to, (CH2) _nOC (O) OR^to, (CH₂)_nNR^bR^c, (CH₂) _nNR^dC (0) R^to, (CH₂) _nNR^dC (0) NR^bR^c, (CH₂) _nNR^dC (0) C (0) NR^bR^c, (CH₂) _nNR^dC (S) 0R^to, (CH₂) _nNR^dC (S) NR^bR^c, (CH₂)_nNR^toC (NR^and) NR^DR^c, (CH2) nNR^dS (0) R^to, (CH2) _nNR^dSW₂R^to, (CH₂) _nNR^dSO2NR^bR^c, (CH2) _nC (0) R^to, (CH₂) _nC (0) 0R^to, (CH2) nC (O) NR^bR^c, (CH2) _nC (S) R^to, (CH₂) _nC (S) 0R^to, (CH2) nC (S) NR^bR^c, (CH2) _nC (NR^and) NR^bR^c, (CH2) nSR^to, (CH2)_nS (0) R^to, (CH2) nSO2R^to, (CH2) _nSW₂NR^bR^c, Ci_6-alkyl, Ci-6-haloalkyl, C-alkenyl₂-6, alkynyl C₂-g, (CH₂) C3-8 cycloalkyl, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) 5-10 membered heteroaryl, where each of the Ci_6-alkyl, C-alkenyl groups₂-6, alkynyl C₂-₆, (CH₂) _nC3-8 cycloalkyl, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) _n5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents

R^F.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a),

XII (b), XII (c), XII (d), XII (e), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (n) or XII (o), R²is phenyl substituted with a substituent selected from

-82C (O) OH, C (O) NH₂, C (0) 0 alkyl Cx-g, C (O) NHalkyl Cx_₆ and C (O) N (Cx-6 alkyl) 2; and optionally substituted with 1, 2 or additional substituents selected from halogen, Cx_alkyl₆ and Cx-6 haloalkyl.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d), XII (e ), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (η) or XII (or ), R²is phenyl substituted at the meta position with a substituent selected from (CH₂) _nC (O) OR^to and (CH₂) _nC (O) NR^bR^c; and optionally substituted with 1, 2, or 3 additional substituents selected from halogen, CN, (CH₂)_nOR^to, (CH2) nOC (O) R^to, (CH2) _nOC (O) OR^to, (CH2) nOC (0) NR^bR^c, (CH2) _nNR^dC (0) R^to, (CH₂)_nNR^bR^c, (CH₂) _nNR^dC (O) NR^bR^c, (CH₂)_nNR^dC (O) C (O) NR^bR^c, (CH₂) _nNR C (O) OR, (CH₂)_nNR^dC (S) R^to, (CH₂) _nNR^dC (S) 0R^to, (CH2) nNR^dC (S) NR^bR^c, (CH2) _nNR^dC (NR^and) NR^bR^c, (CH₂) _nNR “S (0) R^to, (CH2) nNR^toSO2R^to, (CH2) nNR^toSO2NR^bR^c, (CH₂) _nC (0) R^to, (CH₂) _nC (0) 0R^to, (CH₂) _nC (S) NR^bR^c, (CH₂) _nC (0) NR^bR^c, (CH2) nC (S) R^to, (CH2) _nC (S) OR^to, (CH₂) _nC (NR^and) NR^bR^c, (CH2) nSR^to, (CH2) _nS (0) R^to, (CH₂)_nSW₂R^to, (CH2) nSO2NR^bR^c, Cx-6 alkyl, C haloalkyl

1-6, alkenyl C₂-6, alkynyl C₂-₆, (CH₂)_ncycloalkyl C₃-g, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) _n5-10 membered heteroaryl, where each of the Cx-6 alkyl, C alkenyl groups₂-6,

-83alkynyl C₂-g, (CH₂) _ncycloalkyl C₃_₈, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) _n5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents

R^F.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b),

VIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d ), XII (e), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (η ) or XII (o), R²is phenyl substituted at the meta position with a substituent selected from (CH₂) _nC (O) OR^to and (CH₂) _nC (O) NR^bR^c, and optionally substituted with 1, 2 or 3 additional substituents selected from halogen, hydroxyl, Cx-alkoxy₆, CN, alkyl Ci-₆ and Ci-g haloalkyl.

In some embodiments of compounds of Formula I,

II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIII (a), VIII (b), IX, X ( a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d), XII (e), XII (f), XII ( g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (n) or XII (o), R²is phenyl substituted at the meta position with a substituent selected from C (O) OH, C (O) NH₂, C (0) Oalkyl Ci_₆, C (O) NHalkyl Ci_₆ and C (O) N (alkyl Ci_₆)₂; and optionally substituted with 1, 2 or 3 additional substituents selected from halogen, hydroxyl, alkoxy

-84Ci_6, CN, Ci-6 alkyl and Ci-6 haloalkyl.

In some embodiments of compounds of Formula I,

II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b),

VIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a),

XII (b), XII (c), XII (d), XII (e), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (n) or XII (o), R²is phenyl substituted with (CH₂) _nNR^dC (O) R^to, where R^to is Ci-6 alkyl or 3-8 membered heterocycloalkyl, each optionally substituted with 1, 2 or 3 additional substituents selected from halogen, CN, oxo, (CH₂)_nOR^to, (CH2) nOC (O) R^to, (CH2) _nOC (O) OR^to, (CH2) nOC (O) NR^bR^c, (CH2)_nNR^bR^c, (CH2) nNR^dC (O) R^to, (CH2) _nNR^dC (O) OR^to, (CH₂) _nNR^dC (O) NR^bR^c, (CH2) nNR^dC (O) C (O) NR^bR^c, (CH2) _nNR^dC (S) R^to,; CH₂) nNR^dC (S) OR^to, (CH₂) nNR^dC (S) NR^bR^c, (CH₂) _nNR^toC (NR^and) NR^dR^c, (CH₂) _nNR^toS (O) R^d, (CH₂) _nNR ° SO₂R^to, (CH2) nNR^toSO2NR^bR^c, (CH₂) _nC (O) R^to, (CH₂) _nC (O) OR^to, (CH2) nC (O) NR^bR^c, (CH2) _nC (S) R^to, (CH₂) _nC (S) OR^to, (CH₂) _nC (S) NR^bR^c, (CH₂) _nC (NR^and) NR^bR^c, (CH2) nSR^to, (CH2) _nS (0) R^to, (CH2) nSO2R^to, (CH2) _nSW₂NR^bR^c, C] -6alkyl, C1-5 haloalkyl, C-alkenyl₂_6, alkynyl C₂_₆, (CH₂) _nC3-8 cycloalkyl, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) _n5-10 membered heteroaryl; and optionally substituted with 1, 2 or 3 additional substituents selected from halogen, CN, (CH₂)_nOR^to, (CH2) nOC (O) R^to, (CH2) _nOC (O) OR^to, (CH2) nOC (O) NR^bR^c, (CH2)_nNR^bR^c, (CH₂) _nNR^dC (O) R^to, (CH₂) _nNR^dC (O) OR^to, (CH₂) _nNR^dC (O ) NR^bR^c,

-85 (CH₂) _nNR^dC (O) C (O) NR^bR^c, (CH2) nNR^dC (S) R^to, (CH2) _nNR^dC (S) OR^to, (CH₂) _nNR^dC (S) NR^bR^c, (CH2) nNR^dC (NR^and) NR^bR^c, (CH2) _nNR^dS (O) R^to, (CH₂)_nNR^dSW₂R \ (CH₂)_nNR^dSO2NR^bR^c, (CH2) _nC (O) R^to, (CH₂) _nC (O) OR^to, (CH2) nC (O) NR^bR^c, (CH2) _nC (S) R \ (CH₂) _nC (S) OR \ (CH₂) _nC (S) NR^bR^c, (CH₂) _nC (NR^and) NR^bR^c, (CH2) nSR^to, (CH2) _nS (O) R^to, (CH2) nSO2R^to, (CH2) _nSW₂NR^bR^c, Ci-g alkyl, Ci_6 haloalkyl, C alkenyl₂-g, alkynyl C₂-₆, (CH₂) _nC3-8 cycloalkyl, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) _n5-10 membered heteroaryl, where each of the Ci- alkyl groups₆, alkenyl C₂-6, alkynyl C₂_₆, (CH₂) _nC3-8 cycloalkyl, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents

R^F.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d), XII (e ), XII (f), xil (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (η) or XII (or ), R²is phenyl substituted with (CH2) nNR^dC (O) R^to, where R^to is selected from Ci-6 alkyl, Ci-g-OH alkyl and Ci_gNH alkyl₂, each optionally substituted with 1, 2 or 3 additional substituents selected from halogen, CN, oxo, (CH₂)_nOR^to, (CH₂) _nOC (O) R^to, (CH₂) _nOC (O) OR^to,

-86 (CH₂) _nOC (O) NR^bR^c, (CH₂) _nNR^dC (O) OR^to, (CH₂)_nNR^bR^c, (CH₂) _nNR^dC (O) NR^bR^c, (CH₂)_nNR^dC (O) R \ (CH₂)_nNR^dSW₂R^to, b_Dc (CH₂)_nNR^QSO2NR^bR^c, (CH2) _nC (O) R^to, (CH2) nC (O) OR^to, (CH2) _nC (O) NR ° R^C, (CH₂)_nMR^to, (CH2) nS (O) R \ (CH2) nSO2R^to, (CH2) _nSW₂NR^bR^c, Ci6z-halo Ci-6-alkyl, C-alkenyl₂-6z alkynyl C₂_6, (CH₂) cycloalkyl C₃-g, members, (CH₂)_nphenyl, (CH₂) 3-8 heterocycloalkyl and (CH₂) 5-10 membered heteroaryl; and optionally substituted with 1, 2 or 3 additional substituents selected from halogen, CN, (CH₂)_nOR^to, (CH2) n0C (0) R^to, (CH2) _n0C (0) 0R^to, (CH2) n0C (0) NR^bR^c, (CH2) _nNR^dC (0) R^to, (CH₂) _nNR^dC (O) C (O) NR^bR^c, (CH₂)_nNR^bR^c, (CH₂) _nNR^dC (O) NR^bR^c, (CH₂) _nNR^dC (O) OR^to, (CH₂) _nNR^dC (S) R^to, (CH₂) _nNR^dC (S) 0R^to, (CH₂) _nNR^dC (S) NR^bR^c, (CH₂) _nNR^dC (NR^and) NR^bR^c, (CH₂) _nNR^toS (O) R^to, (CH2) nNR^toSÓ2R^to, (CH2) nNR^toSO2NR^bR^c, (CH₂) _nC (O) R^to, (CH₂) _nC (0) 0R^to, (CH2) nC (0) NR^bR^c, (CH2) _nC (S) R^to, (CH₂) _nC (S) 0R^to, (CH₂) _nC (S) NR^bR^c, (CH₂) _nC (NR^and) NR^bR^c, (CH₂)_nMR^to, CH₂)_nS (0) R^to, (CH₂)_nSW₂R^to, (CH2) nSO2NR^bR^c, Ci-6 alkyl, Ci_ haloalkyl₆, alkenyl C₂-₆, alkynyl C₂.₆, (CH₂) _ncycloalkyl C₃.₈, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) _n5-10 membered heteroaryl, where each of the Ci_ alkyl groups₆, alkenyl C₂-6z alkynyl C₂_₆, (CH₂) _ncycloalkyl C₃.₈, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) _n5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents

-87R^F.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d), XII (e ), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (n) or XII (or ), R²is 3-benzamide, N-methyl-3-benzamide, N, N-dimethyl-3benzamide, 4-fluoro-3-benzamide, N-methyl-4-fluoro-3benzamide, N, N-dimethyl-4-fluoro-3 -benzamide, 3-benzoic acid, methyl 3-benzoate, 4-fluoro-3-benzoic acid and methyl 4-fluoro-3-benzoate.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d), XII (e ), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (n) or XII (or ), R²it is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, (CH₂)_nOR^to, (CH2) nOC (O) R^to, (CH2) _nOC (O) OR^to, (CH₂) _nOC (O) NR^bR^c, (CH₂)_nNR^bR^c, (CH₂)_nNR^toC (O) R^to, (CH₂) _nNR^toC (O) 0R^to, (CH2) nNR^toC (O) NR^bR^c, (CH2) _nNR^toC (O) C (0) NR^BR^C, (CH₂) _nNR^dC (S) R^to,

ICH₂) _nNR^dC (S) OR^to, (CH₂) _nNR ° C (S) NR^bR^c, (CH₂) _nNR^dC (NR^and) NR^bR^c, (CH2) nNR^dS (O) R^to, (CH2) _nNR^dSW₂R^to, (CH₂)_nNR^dSO2NR^bR^c, (CH2) _nC (O) R^to, (CH₂) _nC (O) OR^to, (CH2) nC (O) NR^bR^c, (CH2) _nC (S) R^to, (CH₂) _nC (S) 0R^to, (CH2) nC (S) NR^bR^c, (CH2) _nC (NR^and) NR^bR^c,

-88 (CH₂) nSR \ (CH₂) _ns (O) R^d, (CH2) nSO2R^to, (CH2) _nSW₂NR^bR^c, C-alkyl pyridazyl, thiazolyl, isoxazolyl,

6, Ci-6 haloalkyl, C alkenyl₂_6, alkynyl C₂-6, (CH₂) cycloalkyl C₃-₈, (CH₂) _n3-8 membered heterocycloalkyl, (CH₂) _nfcnilo, (CH₂) _nnaphthyl and (CH₂) _n5-10 membered heteroaryl, where each of the Ci_6-alkyl, C-alkenyl groups₂-6, alkynyl C₂-6z (CH₂) C3-8 cycloalkyl, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents

R^F.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d), XII (e ), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (η) or XII (or ), R²is selected from pyridyl, pyrimidyl, pyrazyl, triazyl, furanyl, pyrrolyl, thiophenyl, isothiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, and tetrazolyl, each optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, CN, oxo, (CH₂)_nOR^to, (CH2) nOC (O) R^to, (CH2) _nOC (O) OR^to, (CH₂) _nNR^bR^c, (CH₂) _nNR^dC (0) R^to, (CH₂) _nOC (O) NR^bR^c, (CH₂) _nNR^dC (O) OR^to, (CH₂)_nNR^dC (O) NR^bR^c, (CH₂) _nNR ° C (O) C (O) NR^bR^c, (CH₂) _nNR^dC (S) R^to, (CH₂) _nNR^dC (S) OR^to, (CH₂)_nNR^QC (S) NR^bR^c, (CH₂)_nNR^dC (NR^and) NR^bR^c,

-89 (CH₂)_nNR^dS (0) R^to, (CH₂)_nNR^dSO2R^to, (CH2) _nNR^dSO2NR^bR^c, (CH2) _nC (O) R^to, (CH₂) _nC (O) OR^to, (CH2) nC (0) NR^bR^c, (CH2) _nC (S) R^to, (CH₂) _nC (S) OR^to, (CH₂) _nC (S) NR^bR^c, (CH₂) _nC (NR^and) NR^bR^c, (CH2) nSR^to, (CH2) _nS (O) R^to, (CH2) nSO2R^to, (CH2) _nSW₂NR^bR^c, alkyl Ci-₆, haloalkyl Ci-₆, alkenyl C₂-6, alkynyl C₂-6z (CH₂) _ncycloalkyl C₃-g, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) _n5-10 membered heteroaryl, where each of the C1-6 alkyl, C-alkenyl groups₂_6, alkynyl C₂-6, (CH₂) cycloalkyl C₃.₈, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) _n5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents

R^F.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a),

XII (b), XII (c), XII (d), XII (e), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (n) or XII (o), R²is selected from pyridyl, pyrimidyl, pyrazyl, triazyl, furanyl, pyrrolyl, thiophenyl, isothiazolyl, thiadiazolyl, pyridazyl, thiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl tetrazolyl, each optionally substituted with one substituent selected from (₂) _nC (O) OR^to (CH₂) _nC (0) NR^bR^c; and optionally substituted with 1, 2 or 3

-90 additional substituents selected from halogen, CN, oxo, (CH₂)_nOR^to, (CH2) n0C (0) R^to, (CH2) _n0C (O) OR^to, (CH₂) _n0C (0) NR^bR^c, (CH2) nNR^bR^c, (CH2) _nNR^dC (0) R^to, (CH₂) _nNR^dC (0) 0R^to, (CH2) nNR^dC (0) NR^bR^c, (CH2) _nNR^dC (0) C (0) NR^bR^c, (CH₂) _nNR^dC (S) R^to, (CH2) nNR^dC (S) 0R^to, (CH2) _nNR^dC (S) NR^bR^c, (CH₂) _nNR^dC (NR^and) NR^bR^c, (CH2) nNR^dS (0) R^to, (CH2) _nNR^dSW₂R^to, (CH₂)_nNR^dSO2NR^bR^c, (CH2) _nC (0) R^to, (CH₂) _nC (0) 0R^to, (CH2) nC (O) NR^bR^c, (CH2) _nC (S) R^to, (CH₂) _nC (S) 0R^to, (CH2) nC (S) NR^bR^c, (CH2) _nC (NR^and) NR^bR^c, (CH2) nSR^to, (CH2) _nS (0) R^to, (CH2) nSO2R^to, (CH2) _nSW₂NR^bR^c, alkyl C_X6, haloalkyl Ci-₆, alkenyl C₂-6, alkynyl C₂_6, (CH₂) C3-8 cycloalkyl, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) _n5-10 membered heteroaryl, where each of the C1-6 alkyl, C-alkenyl groups₂-6 &lt;alkynyl C₂-₆, (CH₂)_ncycloalkyl C₃-₈, (CH₂) _n3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) _n5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents

R^F.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d), XII (e ), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), ΧΙΙ (η) or XII (or ), R²is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl, and triazyl, each optionally substituted

-91 with (CH₂) _nC (0) NR^bR^c.

In some embodiments of compounds of Formula I,

II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b),

VlII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d ), XII (e), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (n ) or XII (o), R²is selected from furanyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, imidazolyl, triazolyl and each optionally substituted with thiophenyl, oxazolyl, isoxazolyl, tetrazolyl, (CH₂) _nC (0) NR^bR^c .

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d), XII (e ), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (η) or XII (or ), R²is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl, and triazyl, each optionally substituted with (CH₂) _nC (0) NH₂ .

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d), XII (e ), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (n) or XII (or ), R²is selected from furanyl, pyrrolyl, thiophenyl,

-92thiazolyl, isoxazolyl, tetrazolyl, (CH₂) nC (0) nh₂ .

isothiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl and each optionally substituted with

In some embodiments of compounds of Formula I,

II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VlII (a), VIII (b), IX, X ( a), X (b), XI (a), XI (b), XII (a),

XII (b), XII (c), XII (d), XII (e), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (n) or XII (o), R²is selected from pyridyl, pyrimidyl, pyrazyl, triazyl, furanyl, pyrrolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, imidazolyl, triazolyl and each optionally substituted with (CH₂) _nNR^dC (0) R^to, where R^to is alkyl Ci-₆ or 3-8 membered heterocycloalkyl, each optionally substituted with 1,2-pyridazyl, thiazolyl, isoxazolyl, tetrazolyl, thiophenyl, oxazolyl, or 3 additional substituents selected from halogen, CN, oxo, (CH₂)_nOR^to, (CH2) nOC (0) R^to, (CH2) _n0C (0) 0R^to, (CH2) n0C (0) NR^bR^c, (CH2)_nNR^bR^c, (CH₂) _nNR^dC (0) R^to, (CH₂)_nNR^dC (O) OR \ (CH2) nNR^dC (0) NR^bR^c, (CH2) _nNR^dC (O) C (0) NR^bR^c, (CH₂) _nNR^dC (S) R^to, (CH2) nNR^dC (S) 0R^to, (CH2) _nNR^dC (S) NR^bR^c, (CH₂) _nNR^dC (NR^and) NR^bR^c, (CH2) nNR^dS (0) R^to, (CH2) _nNR^dSW₂R^to, (CH₂)_nNR^dSO2NR^bR^c, (CH2) _nC (0) R^to, (CH2) nC (0) 0R^to, (CHZ) „C (0) NR^bR^c, (CH2) nC (S) R^to, (CH2) _nC (S) 0R^to, (CH2) nC (S) NR^bR^c, (CH2) _nC (NR^and) NR^bR^c, (CH2) nSR^to, (CH2) _nS (0) R^to, (CH2) nSO2R^to, (CH2) _nSW₂NR^bR^c, alkyl Ci_

-936, haloalkyl Ci-₆, alkenyl C₂_₆, alkynyl C₂-6, (CH₂) C3-8 cycloalkyl, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) _n5-10 membered heteroaryl, where each of the C1-6 alkyl, C-alkenyl groups₂_6, alkynyl C₂-6, (CH₂) C3-8 cycloalkyl, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents

R^F.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a),

XII (b), XII (c), XII (d), XII (e), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (n) or XII (o), R²is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl, and triazyl, each optionally substituted with (CH2) nNR^dC (O) R^to, where R^to is selected from Ci6 alkyl, C1-6 alkyl, and Ci-6-NH2 alkyl, each optionally substituted with 1, 2, or 3 additional substituents selected from halogen, CN, (CH₂)_nOR^to, (CH₂) _nOC (O) R^to, br&gt; c (CH₂) _nOC (O) OR^to, (CH2) n0C (O) NR^bR^c, (CH2)_nNR^DR^c, (CH₂) _nNR^toC (0) R^to, (CH₂) _nNR^dC (O) 0R^to, (CH₂) _nNR^dC (0) NR^bR^c, (CH₂) nNR^dSW₂R^to, bnC (CH₂)_nNR^orSO2NR^bR^c, (CH2) _nC (O) R^to, (CH2) nC (O) 0R^to, (CH2) _nC (0) NR ° R^C, (CH2) nSR^to, (CH2) _nS (0) R^to, (CH2) nSO2R^to, (CH2) _nSW₂NR^bR^c, Cj alkyl₆, C1-6 haloalkyl, C alkenyl₂_₆, alkynyl C₂_₅,

-94 (CH₂) nCycloalkyl C₃-₈, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) heteroaryl of

5-10 members.

In some embodiments of compounds of Formula I, thiophenyl, oxazolyl,

II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIII (a), VIII (b), IX, X ( a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d), XII (e), XII (f), XII ( g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (η) or XII (o), R²is selected from furanyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl, and tetrazolyl, each optionally substituted with (CH₂) _nNR^dC (O) R^to, where R^to is selected from Ci-6 alkyl, Ci-6-alqu alkyl and Ci- alkyl₆-NH₂, each optionally substituted with 1, 2 or 3 additional substituents selected from halogen, CN, (CH₂)_nOR^to, (CH₂) _nOC (O) R^to, (CH₂) _nOC (O) OR^to, (CH2) nOC (O) NR^bR^c, (CH2)_nNR^DR^c, (CH2) nNR^toC (O) R^to, (CH2) _nNR^dC (O) OR^to, (CH2) nNR^dC (0) NR^bR^c, (CH2) _nNR^dSW₂R^to, (CH₂)_nNR^dSO2NR^bR^c, (CH2) _nC (0) R^to, (CH₂) _nC (O) OR^to, (CH2) nC (0) NR^bR^c, (CH2)_nMR^to, (CH₂) _nS (0) R^to, (CH2) nSO2R^to, (CH2) _nSW₂NR^bR^c, alkyl C_x_ 6, haloalkyl Ci-₆, alkenyl C₂-6, alkynyl C₂-e, (CH₂) _ncycloalkyl C₃-s, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) heteroaryl of

5-10 members.

In some embodiments of compounds of Formula I,

-95II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VlII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d), XII (e), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (n) or XII (o), R²is selected from indolyl, indazolyl, benzoimidazolyl, benzoxazolyl, and benzoisoxazolyl, each optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, CN, oxo, (CH2) nOR^to, (CH2) _nOC (O) R^to, (CH₂) _nOC (O) OR^to, (CH2) nOC (O) NR^bR^c, (CH2)_nNR^bR^c, (CH2) nNR^dC (0) R^to, (CH2) _nNR^dC (0) 0R^to, (CH2) nNR^dC (0) NR^bR^c, (CH2) _nNR^dC (0) C (0) NR^bR^c, (CH₂) _nNR^dC (S) R^to, (CH2) nNR^dC (S) 0R^to, (CH2) _nNR^dC (S) NR^bR^c, (CH₂) _nNR^dC (NR^and) NR^bR^c, (CH2) nNR^dS (O) R^to, (CH2) _nNR^dS0₂R^to, (CH₂) _nNR^dSO2NR^bR^c, (CH2) _nC (0) R^to, (CH₂) _nC (0) 0R^to, (CH2) nC (0) NR^bR^c, (CH2) _nC (S) R^to, (CH₂) _nC (S) OR^to, (CH2) nC (S) NR^bR^c, (CH2) _nC (NR^and) NR^bR^c, (CH2) nSR^to, (CH2) _nS (0) R^to, (CH2) nSO2R^to, (CH2) _nSW₂NR^bR^c, Ci alkyl₆, haloalkyl Ci-₆, alkenyl C₂.₆, alkynyl C₂-6, (CH₂) cycloalkyl C₃_₈, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) 5-10 membered heteroaryl, where each of the Ci-6 alkyl, C-alkenyl groups₂_₆, alkynyl C₂_₆, (CH₂) _ncycloalkyl C₃-g, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents

R^F.

In some embodiments of compounds of Formula I

-96II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d), XII (e), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (n) or XII (o), R²is selected from lH-indazol-6-yl, lH-indazol-5-yl, 1Hindazol-4-yl, 3-amino (lH-indazol-5-yl), 3-amino (lHindazol-6-yl), 3 -amino (lH-indazol-7-yl), l-methyl (lHindazol-6-yl), 3-methyl (lH-indazol-6-yl), 3-amino-lmethyl (lH-indazol-5-yl) , 3-cyano (lH-indazol-5-yl), 3-carboxamide (lH-indazol-5-yl), 3-carboxamidine (lH-indazol5-yl), 3-vinyl (lH-indazol-5-yl), 3 -ethyl (lH-indazol-5yl), 3-acetamide (lH-indazol-5-yl), 3-methylsulfonylamine (lH-indazol-5-yl), 3methoxycarboxamide (lH-indazol-5-yl), 3-methylamino (1Hindazol-5-yl), 3-dimethylamino (lH-indazol-5-yl), 3-ethylamino (ΙΗ-indazol-5-yl), 3- (2-aminoethyl) amino (1 zol-5- armor i lo), 3- (2-hydroxyethyl) amino (ΙΗ-indazol-5-yl), 3 - [(methylethyl) amino] (lH-indazol-5-yl), 6-benzoimidazol-5yl, 6- (2 -methylbenzoimidazol-5-yl), 2-aminobenzoimidazol5-yl, 2-hydroxybenzoimidazol-5-yl, 2acetamidabenzoimidazol-5-yl, 3-aminobenzo [3,4-d] isoxazol5-yl, 3-aminobenzo [d] isoxazole- 6-yl, 3-aminobenzo [d] isoxazol-7-yl, 2-methylbenzoxazol-5-yl and 2-methylbenzoxazol-6-yl.

In some embodiments of compounds of Formula I

-97II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b),

VIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d ), XII (e), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (n ) or XII (o), R²is selected from 3-6 heterocycloalkyl members and 3-6 heterocycloalkenyl members, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, (CH2) nOR^to, (CH2) _nOC (O) R^to, (CH₂) nOC (O) OR^to, (CH2) nOC (O) NR^bR^c, (CH2)_nNR^bR^c, (CH2) nNR^dC (O) R^to, (CH2) _nNR^dC (O) OR^to, (CH₂) _nNR^dC (O) NR^bR^c, (CH2) nNR^dC (O) C (O) NR^bR^c, (CH2) _nNR^dC (S) R^to, (CH₂) _nNR^dC (S) OR^to, (CH₂) _nNR^dC (S) NR^bR^c, (CH₂) _nNR^dC (NR^and) NR^bR^c, (CH2) nNR^dS (O) R^to, (CH2) _nNR^dSW₂R^to, (CH₂)_nNR^dSO2NR^bR^c, (CH2) _nC (O) R^to, (CH₂) _nC (O) OR^to, (CH2) nC (O) NR^bR^c, (CH2)_nC (S) R^to, (CH₂) _nC (S) OR^to, (CH2) nC (S) NR^bR^c, (CH2) _nC (NR^and) NR^bR^c, (CH2) nSR^to, (CH2) _nS (O) R^to, (CH2) nSO2R^to, (CH2) _nSW₂NR^bR^c, alkyl C_X6, haloalkyl Ci_₆, alkenyl C₂_₆, alkynyl C₂-6, (CH₂) nCycloalkyl C₃__s, (CH₂) _n3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) _n5-10 membered heteroaryl, where each of the C-alkyl groups_x-6, alkenyl C₂_₆, alkynyl C₂_₆, (CH₂) _ncycloalkyl C₃-₈, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents

R^F,

In some embodiments of compounds of Formula I,

-98II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d), XII (e), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (n) or XII (o), R²is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halogen, CN, oxo, (CH₂)_nOR^to, (CH2) nOC (0) R^to, (CH2) _n0C (0) 0R^to, (CH₂) _n0C (0) NR^bR^c, (CH₂)_nNR^bR^c, (CH₂) _nNR^dC (O) NR^bR^c, (CH₂) _nNR^dC (0) R^to, (CH₂) _nNR^dC (S) OR^to, (CH₂) _nNR^toC (S) NR^bR^c, (CH₂) _nNR^toC (0) C (0) NR^bR^c, (CH₂) _nNR^dC (0) 0R^to, (CH2) nNR^dC (S) R^to, (CH2)_nNR^dC (NR^and) NR^bR^c, (CH₂) _nNR^dS (0) R^to, (CH₂) _nNR^dSO2R^to, (CH2) _nNR^dSO2NR^bR^c, (CH2) _nC (0) R^to, (CH₂) _nC (S) NR^bR^c, (CH₂) _nC (0) 0R^to, (CH₂) nC (O) NR^bR^c, (CH2) nC (S) R^to, (CH2) _nC (S) OR^to, (CH₂) „C (NR^and) NR^bR^c, (CH2) nSR^to, (CH2) _nS (0) R^to, (CH₂)_nSW₂R^to, (CH2) nSO2NR^bR^c, Ci_6 alkyl, Cx-s haloalkyl, C alkenyl₂-₆, alkynyl C₂-₆, (CH₂) _ncycloalkyl C₃-₈, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenyl, (CH₂) _nnaphthyl and (CH₂) 5-10 membered heteroaryl, where each of the Ci-6 alkyl, C-alkenyl groups₂-e, alkynyl C₂-6, (CH₂) _ncycloalkyl C₃-g, (CH₂) 3-8 membered heterocycloalkyl, (CH₂) _nphenium, (CH₂) _nnaphthyl and (CH₂) 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents

-99 In some embodiments of compounds of Formula I,

<td>II, III, IV (a),</td><td>iv (b), V (a), V (b), VI,</td><td>VII (a),</td><td>VII (b),</td>

<td>VIII (a), VIII (b),</td><td>IX, X (a), X (b), XI (a)</td><td>or XI (b)</td><td>, R² is</td>

<td>NR^bR^c, where R^b and</td><td>R^c are as defined</td><td>in the</td><td>Present</td>

memory.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b),

VlII (a), VIII (b), IX, X (a), X (b), XI (a) or XI (b), R² is

NR^bR^cwhere one of R^b and R^c is hydrogen and the other is Ci-6 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents R^F.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b),

VHI (a), VIII (b), IX, X (a), X (b), XI (a) or XI (b), X is C (0) - and R² is NR^bR^c, where R^b and R^c they are as defined herein.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b),

VIII (a), VIII (b), IX, X (a), X (b), XI (a) or XI (b), X is C (O) - and R² is NR^bR^cwhere one of R^b and R^c is hydrogen and the other is Ci- alkyl₆ optionally substituted with 1, 2, 3, 4 or 5 R substituents^F.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b),

VlII (a), VIII (b), IX, X (a), X (b), XI (a) or XI (b), X is - 100 (CH₂)_P- and R² is NR^bR^c, where R^b and R^c they are as defined herein.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b),

VlII (a), VIII (b), IX, X (a), X (b), XI (a) or XI (b), X is (CH₂)_P- and R² is NR^bR^cwhere one of R^b and R^c is hydrogen and the other is Ci_6 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents R^F.

In some embodiments, X, R² and R³, together with the carbon atoms to which they are attached, form a 5-6-membered ring optionally containing one or more heteroatoms selected from oxygen, nitrogen and

<td>sulfur,</td><td>and that optionally contains one</td><td>or</td><td>plus</td><td>double</td>

<td>links,</td><td>and optionally substituted with 1,</td><td> 2,</td><td> 3,</td><td>4 or 5</td>

<td colspan="2">substituents R^F.</td><td></td><td></td><td></td>

<td>In</td><td>some embodiments, the compound</td><td>is</td><td>of</td><td>Formula</td>

XIII, or a pharmaceutically acceptable salt thereof:

<img file="MX2012012189A_D0035.tif" />

Formula XIII

- 101 wherein A is a 5- or 6-membered ring optionally containing one or more heteroatoms selected from oxygen, nitrogen and sulfur, and optionally containing one or more double bonds; t is 0, 1, 2, 3, or 4; and R¹, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^F and m are as defined herein.

In some embodiments of compounds of Formula XIII, ring A together with the · pyrimidine ring to which it is attached forms a group selected from quinazoline, pyrido [2,3-d] pyrimidine, pyrido [3,4-d] pyrimidine, pyrido [4,3-d] pyrimidine, pyrido [3,2-d] pyrimidine, 5,6,7,8tetrahydroquinazoline, 5,6,7,8-tetrahydropyrido [2,3- d] pyrimidine, 5,6, 7,8-tetrahydropyrido [3,4-d] pyrimidine, 5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine, 5,6,7,8tetrahydropyrido [3,2-d] pyrimidine, thieno [ 3,2-d] pyrimidine, thiazolo [4,5-d] pyrimidine, 5H-pyrrolo [3,2-d] pyrimidine, 7Hpurine, thieno [2,3-d] pyrimidine, thiazolo [5,4-d] pyrimidine, 7H-pyrrolo [2, 3-d] pyrimidine, 9H-purine, lH-pyrazolo [4,3d] pyrimidine, lH-pyrazolo [3,4-d] pyrimidine, 1H [1,2,3] triazolo [4,5-d] pyrimidine, 3H- [1,2,3] triazolo [4,5d] pyrimidine, 6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine, 6,7dihydro-5H-pyrrolo [3,4-d] pyrimidine , 6,7-dihydro-5Hpyrrolo [3,2-d] pyrimidine and 6,7-dihydro-5H-cyclopenta [d] pyrimidine, each optionally substituted

- 102 with 1, 2, 3, 4 or 5 R substituents^F.

In some embodiments of compounds of Formula XIII, Ring A together with the pyrimidine ring to which it is attached forms a group selected from quinazoline, 5,6,7,8-tetrahydropyrido [4, 3-d] pyrimidine, 5,6 , 7,8tetrahydropyrido [3,4-d] pyrimidine, lH-pyrazolo [3,4d] pyrimidine, thieno [2,3-d] pyrimidine and thiazolo [5.4d] pyrimidine, each optionally substituted with 1, 2,

3, 4 or 5 substituents R^F.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), Vlll (a), vni (b), IX, X (a), X (b), XI (a), XI (b), XII (a),

XII (b), XII (c), XII (d), XII (e), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (η), XII (o) or XIII, R¹ is selected from hydrogen, halogen, CN, alkyl Ci-₆, haloalkyl Ci-₅, C (O) OR^to, C (O) NR^bR^c, OR^to, NR^bR^c, Cg-io aryl and 5-10 membered heteroaryl.

In some embodiments of compounds of Formula I,

<td>II, III, IV (a),</td><td>IV (b),</td><td>Goes) ,</td><td>V (b), VI,</td><td>VII (a)</td><td>, VII (b),</td>

<td>VIII (a), VIII (b)</td><td colspan="3">, IX, X (a), X (b), XI (a)</td><td>, XI (b)</td><td>, XII (a),</td>

<td>XII (b), XII (c),</td><td>XII (d),</td><td>XII (e</td><td>), XII (f),</td><td>XII (g)</td><td>, XH (h),</td>

<td>Xll (i), XII (j),</td><td>XII (k),</td><td>XII (1)</td><td>, XII (m),</td><td>XII (n),</td><td>XII (o) or</td>

<td colspan="2">XIII, R¹ is selected</td><td>between</td><td colspan="3">hydrogen, halogen, CN,</td>

<td colspan="2">Ci_6 alkyl, haloalkyl</td><td>Ci-6,</td><td>hydroxyl,</td><td>alkoxy</td><td>Ci-6, NH₂,</td>

<td colspan="2">NHalkyl Ci-6 and N (alkyl</td><td>Cl-s) 2 /</td><td></td><td></td><td></td>

- 103 In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b),

VIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a),

XII (b), XII (c), XII (d), XII (e), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (η), XII (o) or XIII, R¹ it is selected from hydrogen, halogen, CN, CF3 and methyl.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d), XII (e ), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (n), XII (or ) O XIII, R¹ it is hydrogen.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d), XII (e ), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (η) or XII (or ), R³is selected from hydrogen, halogen, CN, C1-5 alkyl, haloalkyl-₆, C (O) OR^to, C (O) NR^bR^c, OR^to, NR^bR^c, Cg-io aryl and 5-10 membered heteroaryl.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d), XII (e ), XII (f), XII (g), XII (h),

- 104 XII (i), XII (j), XII (k), XII (l), XII (m), XII (n) or XII (o), R³is selected from hydrogen, halogen, CN, Ci_6-alkyl, Ci_6-haloalkyl, hydroxyl, Ci-6-alkoxy, NH₂, NHalquilo Ci_₆, and N (alkyl Ci_₆)₂,

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b),

VIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a),

XII (b), XII (c), XII (d), XII (e), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (η) or XII (o), R³it is selected from hydrogen, halogen, CN, CF3 and methyl.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b), VIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d), XII (e ), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (n) or XII (or ), R³it is hydrogen.

In some embodiments of compounds of Formula I,

<td>II, III,</td><td>IV (a),</td><td>IV (b), V (a), V (b), VI,</td><td>VII (a),</td><td>vile (b),</td>

<td>VIII (a),</td><td>VIII (b)</td><td>, IX, X (a), X (b), XI (a)</td><td>, XI (b),</td><td>XII (a),</td>

<td>XII (b),</td><td>XII (c),</td><td>XII (d), XII (e), XII (f),</td><td>XII (g),</td><td>XII (h),</td>

<td>Xll (i),</td><td>XII (j),</td><td>XII (k), XII (l), XII (m),</td><td>XII (n) 0</td><td>XII (0),</td>

<td>each</td><td>from R¹ and</td><td>R³ it is hydrogen.</td><td></td><td></td>

<td>In</td><td>some</td><td colspan="3">embodiments of compounds of Formula I,</td>

<td>II, III,</td><td>IV (a),</td><td>IV (b), V (a), V (b), VI,</td><td>VII (a),</td><td>VII (b),</td>

<td>VIII (a),</td><td>VIII (b)</td><td>, IX, X (a), X (b), XI (a)</td><td>, XI (b),</td><td>XII (a),</td>

- 105XII (b), XII (c), XII (d), XII (e), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k) , XII (l), XII (m), XII (η), XII (o), or XII, R⁴ is selected from hydrogen, Ci_6 alkyl, Ci_6 haloalkyl, C (O) R^to, C (O) OR^to, C (O) NR^bR^c and SO2R^to.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, VII (a), VII (b),

VIII (a), VIII (b), IX, X (a), X (b), XI (a), XI (b), XII (a), XII (b), XII (c), XII (d ), XII (e), XII (f), XII (g), XII (h), XII (i), XII (j), XII (k), XII (l), XII (m), XII (η ), XII (o), or XII, R⁴ it is hydrogen.

In some embodiments of compounds of Formula I,

<td>II, III, IV (a),</td><td>iv (b),</td><td>V (a), V (b), VI,</td><td>vile,</td><td>vile (b),</td>

<td>VIIIII (a), VIII (b)</td><td>, IX,</td><td>X (a), X (b), XI (a)</td><td>, XI (b),</td><td>XII (a),</td>

<td>XII (b), XII. (C),</td><td>XII (d)</td><td>, XII (e), XII (f),</td><td>XII (g),</td><td>XII (h),</td>

<td>XII (i), XII (j),</td><td>XII (k),</td><td>XII (l), XII (m),</td><td>XII (n) or</td><td>XII (o),</td>

R¹, each of R³ and R⁴ it is hydrogen.

In some embodiments of compounds of Formula I, III, IV (b), V (b), VI, VII (b), VIII (b), IX, X (b), XI (b), XII (a), XII (c), XII (e), XII (f), XII (h), XII (j), XII (k), XII (m), XII (o) or XIII, each of R⁸ and R⁹, in each case, is independently selected from hydrogen, halogen and Ci- alkyl₆.

In some embodiments of compounds of Formula I, III, IV (b), V (b), VI, VII (b), VIII (b), IX, X (b), XI (b), XII (a), XII (c), XII (e), XII (f), XII (h), XII (j), XII (k),

- 106 XII (m), XII (o) or XIII, R⁸ and R⁹, in each case, each of is hydrogen.

In some embodiments, the compound is selected from the compounds in Table 2, or a pharmaceutically acceptable salt thereof.

The compounds and compositions described and / or disclosed herein modulate the contractility of skeletal sarcomere. Specifically, the compounds modulate the rapid skeletal muscle sarcomere troponin complex through one or more myosin, actin, tropomyosin, troponin C, troponin I and rapid skeletal troponin T and fragments and isoforms thereof. As used in this context, modulating means increasing or decreasing activity. In some cases, the compounds described and / or disclosed herein potentiate (i.e., increase activity) of one or more myosin, actin, tropomyosin, troponin C, troponin I, and rapid skeletal troponin T and fragments and isoforms of the same. In other cases, the compounds described and / or disclosed herein inhibit (i.e., reduce activity) of one or more myosin, actin, tropomyosin, troponin C, troponin I, and rapid skeletal troponin T and fragments and isoforms of the same.

In both preclinical and clinical situations,

-107 shown that activators of the rapid skeletal troponin complex amplify the response of the rapid skeletal muscle to nerve stimulation, resulting in increased development of muscle strength to submaximal muscle activation (see, eg, Russell et al., The Fast Skeletal Troponin Activator, CK-2017357, Increases Skeletal Muscle Forcé in vitro and in situ, 2009 Experimental Biology Conference, New Orleans, LA, April 2009). Rapid skeletal troponin complex activators have been shown to increase the sensitivity of skin-skeletal muscle fibers to calcium and in live muscle at the rate of stimulation, each of which results in increased development of muscle strength to sub-maximal muscle activation. Such activators have been shown to also reduce muscle fatigue and / or increase the total time to fatigue under normal and low oxygenation conditions (see, for example, Russell et al., The Fast Skeletal Troponin Activator, CK-2017357, Increases Skeletal Muscle Forcé and Reduces Muscle Fatigue in vitro and in situ, 5th Cachexia Conference, Barcelona, ​​Spain, December 2009; Hinken et al., The Fast Skeletal Troponin Activator, CK-2017357, Reduces Muscle Fatigue in an in situ Model of Vascular Insufficiency, Society for Vascular Medicine's 2010 Annual Meeting: 21st Annual Scientific Sessions, Cleveland, OH,

- April 108, 2010). Increased muscle strength in response to nerve impulse has also been demonstrated in healthy human volunteers (see, for example, Hansen et al., CK-2017357, a Novel Activator of Fast Skeletal Muscle, Increases Isometric Forcé Evoked by Electrical Stimulation of the Anterior Tibialis Muscle in Healthy Male Subjects, Society for Neuroscience 40th Annual Meeting: Neuroscience 2010, November 2010). Work on additional preclinical models of muscle function suggests that activators of the rapid skeletal troponin complex also cause an increase in muscle power and / or endurance. These pharmacological properties suggest that this mechanism of action could have application in conditions, for example, in which neuromuscular function is altered.

Methods are provided for enhancing the effectiveness of rapid skeletal muscle in a patient in need, comprising administering to said patient an effective amount of a compound or composition described and / or disclosed herein that selectively binds to the troponin complex of sarcomere or fast skeletal muscle fiber. In some embodiments, the compound described and / or disclosed herein activates sarcomeres or rapid skeletal muscle fibers. In some embodiments, the administration of a compound

- 109 disclosed and / or described herein results in an increase in the output power of the fast skeletal muscle. In some embodiments, administration of a disclosed and / or disclosed compound results in increased sensitivity of calcium ion sarcomeres or fast skeletal muscle fibers, compared to untreated sarcomeres or rapid skeletal muscle fibers with the compound. In some embodiments, administration of a disclosed and / or disclosed compound results in a lower concentration of calcium ions causing rapid skeletal muscle myosin to bind to actin. In some embodiments, the administration of a disclosed and / or disclosed compound results in rapid skeletal muscle fiber generating increased strength at submaximal levels of muscle activation.

Also provided is a method of sensitizing a fast skeletal muscle fiber to produce force in response to a lower concentration of calcium ion, which comprises contacting the fast skeletal muscle fiber with a compound or composition described and / or disclosed herein that selectively binds to troponin complexes in the fast skeletal muscle sarcomere. In some embodiments, putting

-110 contacting fast skeletal muscle fiber with the compound results in activation of fast skeletal muscle fiber at a lower calcium ion concentration than in untreated fast skeletal muscle fiber. In some embodiments, contacting the fast skeletal muscle fiber with the compound results in increased force production at a lower calcium ion concentration compared to an untreated fast skeletal muscle fiber.

A method of increasing the time to rapid skeletal muscle fatigue in a patient in need is also provided, comprising contacting the rapid skeletal muscle fibers with a compound or composition disclosed and / or disclosed herein that binds selectively to the troponin complexes of the fast skeletal muscle fibers. In some embodiments, the compound binds to form ligand-troponin-calcium ion complexes that activate rapid skeletal muscle fibers. In some embodiments, complex formation and / or activation of fast skeletal muscle fibers results in increased strength and / or increased time to fatigue compared to untreated fast skeletal muscle fibers contacted with a similar calcium ion concentration.

-111 The compounds and pharmaceutical compositions described and / or disclosed herein are capable of modulating the contractility of rapid skeletal sarcomere in vivo and may have application in both human and animal disease. Modulation would be desirable in various conditions or diseases, including, but not limited to, 1) neuromuscular disorders, such as Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), peripheral neuropathies, and myasthenia gravis; 2) voluntary muscle disorders, including muscular dystrophies, myopathies, and muscle wasting conditions such as sarcopenia and cachexia syndromes (eg, cachexia syndromes caused by diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD) ) and chronic kidney disease / dialysis) and rehabilitation-related deficits, such as those associated with recovery from surgery (eg, post-surgical muscle weakness), prolonged bed rest, or stroke rehabilitation; 3) disorders of the central nervous system (CNS) in which muscle weakness, atrophy and fatigue are prominent symptoms, such as multiple sclerosis, Parkinson's disease, stroke and spinal cord injury; and 4) muscle symptoms derived from systemic disorders, including disease

-112 peripheral vascular disease (PVD) or peripheral arterial disease (PAD) (for example, claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and frailty due to aging.

The compounds and compositions described and / or disclosed herein can be used to treat neuromuscular diseases, that is, diseases that affect any part of the nerve-muscle unit. Neuromuscular diseases include, for example: 1) motor unit diseases, including but not limited to amyotrophic lateral sclerosis (ALS) including variants of bulbar and primary lateral sclerosis (PLS); spinal muscular atrophy types 1-4; Kennedy syndrome; post-polio syndrome; Motor neuropathies including, for example, critically ill polyneuropathy; multifocal motor neuropathy with conduction block; Charcot-Marie-Tooth disease and other inherited sensory and motor neuropathies; and Guillain-Barre syndrome, 2) neuromuscular junction disorders, including myasthenia gravis, LambertEaton myasthenic syndrome, and prolonged neuromuscular blockade due to drugs or toxins; and 3) peripheral neuropathies, such as acute inflammatory demyelinating polyradiculoneuropathy, diabetic neuropathy, chronic inflammatory demyelinating polyradiculoneuropathy, nerve damage

- 113 traumatic peripherals, leprosy neuropathy, vasculitic neuropathy, dermatomyositis / polymyositis, and neuropathy of

Friedreich's ataxia.

The compounds and compositions described and / or disclosed herein can be used to treat voluntary muscle disorders. Voluntary muscle disorders include 1) muscular dystrophies (including, for example, Duchenne, Becker, limb-girdle, facioscapulohumeral, girdle, Emery-Dreyfus, oculopharyngeal, and congenital); and 2) myopathies, such as nemaline myopathy, central body disease, congenital myopathies, mitochondrial myopathies, acute myopathy, inflammatory myopathies (such as dermatomyositis / polymyositis, and inclusion body myositis), endocrine myopathies (such as those associated with hyper or hypothyroidism), Cushing's or Addison's syndrome or disease and disorders of the pituitary gland, metabolic myopathies (such as glycogen storage diseases, for example, McArdle's disease, Pompe's disease, etc.), drug-induced myopathy (spheroid myopathy, antiretroviral drugs, statins), restrictive lung disease, sarcoidosis, Schwartz-Jampel syndrome, focal muscle atrophies and distant myopathies.

The described compounds and compositions and / or

-114 disclosed herein can be used to treat amyotrophic lateral sclerosis (ALS). ALS is a disease that generally arises at a late age (age over 50) and has a rapid progression from initial limb weakness to paralysis and death. The usual life expectancy after diagnosis is 3-5 years. The cause of the disease for most ALS patients is unknown (called the spontaneous form), while a small proportion of patients have an inherited (familial) form of the disease. The condition causes progressive death of motor neurons through causes that are unclear. The surviving motor units attempt to compensate for the dying ones by innervating more fibers (called germination), but this can only partially correct muscle function, since the muscles are subsequently more prone to coordination problems and fatigue. Over time, the surviving motor neurons die, resulting in complete paralysis of the affected muscle. The disease is usually fatal through the final loss of innervation to the diaphragm, resulting in respiratory failure. The current treatment options for ALS are limited.

The compounds and compositions described and / or disclosed herein can be used to treat

-115 spinal muscular atrophy (SMA). SMA is a genetic disorder that arises through the mutation of a protein, SMN1, that appears to be required for the survival and health of motor neurons. The disease is more common in children since most patients only survive until 11-12 years of age. There is currently no treatment available for SMA.

The compounds and compositions described and / or disclosed herein can be used to treat myasthenia gravis. Myasthenia gravis is a chronic autoimmune neuromuscular disease in which the body produces antibodies that block, alter, or destroy proteins involved in signaling at the neuromuscular junction, thereby preventing muscle contraction from occurring. These proteins include nicotinic acetylcholine receptor (AChR) or, less frequently, a muscle-specific tyrosine kinase (MuSK) involved in AChR clustering (see, eg, Drachman, N. Eng. J. of Med., 330 : 1797-1810, 1994). The disease is characterized by varying degrees of weakness of the skeletal (voluntary) muscles of the body. The hallmark of myasthenia gravis is muscle weakness that increases during periods of activity and improves after periods of rest. Although myasthenia gravis can affect any muscle

-116voluntary, certain muscles, such as those that control the movement of the eyes and eyelids, facial expression, chewing, speaking and swallowing are frequently, but not always, involved in the disorder. The muscles that control breathing and neck and limb movements can also be affected. In most cases, the first noticeable symptom is weakness of the eye muscles. In others, difficulty swallowing and poorly articulated speech may be the first signs. The degree of muscle weakness involved in myasthenia gravis varies greatly between patients, ranging from a localized form, limited to the eye muscles (myasthenia ocularis), to a severe or generalized form in which many muscles, sometimes including those that they control breathing, they are affected. Symptoms, which can vary in type and severity, may include dropping of one or both eyelids (ptosis), blurred or double vision (diplopia), due to weak muscles that control eye movements, unsteady gait, or anserine , weakness in the arms, hands, fingers, legs and neck, a change in facial expression, difficulty swallowing and dyspnea, and difficulty speaking (dysarthria). Generalized weakness develops in approximately 85% of patients.

The described compounds and compositions and / or

-117 disclosed herein can be used to treat sarcopenia, eg, sarcopenia associated with aging or disease (eg, HIV infection). Sarcopenia is characterized by a loss of mass, quality, and strength of skeletal muscle. Clinically, a decrease in skeletal muscle tissue mass (muscle atrophy) contributes to frailty in older individuals. In human men, muscle mass decreases by a third between the ages of 50 and 80. In older adults, prolonged hospitalization can result in further disuse atrophy leading to a potential loss of the ability to live independently and a cascade of physical decline. Furthermore, the physical aging process profoundly affects body composition, including significant reductions in lean body mass and increases in central adiposity. Changes in global adiposity and fat distribution appear to be important factors in many common age-related diseases, such as hypertension, glucose intolerance and diabetes, dyslipidemia, and atherosclerotic cardiovascular disease. Furthermore, it is possible that the decrease associated with age in muscle mass and later in strength and endurance, may be a critical determinant for loss of function, dependency and disability. Muscle weakness too

-118 is a major factor predisposing the elderly to falls and the resulting morbidity and mortality.

The compounds and composition described and / or disclosed herein can be used to treat cachexia. Cachexia is a condition frequently associated with cancer or other serious diseases or conditions, (eg, chronic obstructive pulmonary disease, heart failure, chronic kidney disease, kidney dialysis), characterized by progressive weight loss, muscle atrophy, and fatigue, due to the suppression of adipose tissue and skeletal muscle.

The compounds and compositions described and / or disclosed herein can be used to treat muscular dystrophies. Muscular dystrophy can be characterized by progressive muscle weakness, destruction and regeneration of muscle fibers, and final replacement of muscle fibers by fatty and fibrous connective tissue.

The compounds and compositions described and / or disclosed herein can be used to treat post-surgical muscle weakness, which is a reduction in the strength of one or more muscles after a surgical procedure. Weakness can be generalized (i.e., total body weakness) or localized to a specific, lateral area of ​​the body, limb, or muscle.

-119The compounds and compositions described and / or disclosed herein can be used to treat post-traumatic muscle weakness, which is a reduction in the strength of one or more muscles after a traumatic episode (eg, bodily injury). Weakness can be generalized (i.e., total body weakness) or localized to a specific area, side of the body, limb, or muscle.

The compounds and compositions described and / or disclosed herein can be used to treat muscle weakness and fatigue caused by peripheral vascular disease (PVD) or peripheral arterial disease (PAD). Peripheral vascular disease is a disease or disorder of the circulatory system outside the brain and heart. Peripheral arterial disease (PAD), also known as peripheral arterial occlusive disease (PAOD), is a form of PVD in which there is partial or total blockage of an artery, usually one that leads to an arm or leg. PVD and / or PAD can result from, for example, atherosclerosis, inflammatory processes leading to stenosis, embolus / thrombus formation, or damage to blood vessels due to disease (eg, diabetes), infection, or injury. PVD and / or PAD can cause acute or chronic ischemia, typically of the legs. Symptoms of PVD and / or PAD include pain, weakness,

- 120 numbness or muscle cramps due to reduced blood flow (claudication), muscle pain, pain, cramps, numbness or fatigue that occurs during exercise and is relieved by a short period of rest (intermittent claudication), pain during rest (pain at rest) and loss of biological tissue (gangrene). Symptoms of PVD and / or PAD frequently occur in calf muscles, but symptoms may also be seen in other muscles, such as the thigh or hip. Risk factors for PVD and / or PAD include age, obesity, sedentary lifestyle, smoking, diabetes, high blood pressure, and high cholesterol (i.e., high LDL and / or high triglycerides and / or low HDL). People who have coronary heart disease or a history of heart attacks or strokes generally also have an increased frequency of occurrence of PVD and / or PAD. Rapid skeletal troponin complex activators have been shown to reduce muscle fatigue and / or increase the overall time to fatigue in in vitro and in situ models of vascular insufficiency (see, eg, Russell et al., The Fast Skeletal Troponin Activator , CK-2017357, Increases Skeletal Muscle Forcé and Reduces Muscle Fatigue in vitro and in situ, 5th Cachexia Conference, Barcelona, ​​Spain, December 2009; Hinken et al., The East

- 121 Skeletal Troponin Activator, CK-2017357, Reduces Muscle Fatigue in an in situ Model of Vascular Insufficiency, Society for Vascular Medicine's 2010 Annual Meeting: 21st Annual Scientific Sessions, Cleveland, OH, April 2010).

The compounds and compositions described and / or disclosed herein can be used to treat symptoms of frailty, eg, frailty associated with aging. Frailty is characterized by one or more of involuntary weight loss, muscle weakness, slow walking speed, exhaustion, and low physical activity.

The compounds and compositions described and / or disclosed herein can be used to treat muscle weakness and / or fatigue due to wasting syndrome, which is a condition characterized by involuntary weight loss associated with chronic fever and diarrhea. In some cases, patients with weakening syndrome lose 10% of their initial body weight within a period of one month.

The compounds and compositions described and / or disclosed herein can be used to treat muscle diseases and conditions caused by structural and / or functional abnormalities of skeletal muscle tissue, including muscular dystrophies, congenital muscular dystrophies, congenital myopathies, myopathies

- 122 distal, other myopathies (for example, myofibrillar, inclusion bodies), myotonic syndromes, ion channel muscle diseases, malignant hyperthermias, metabolic myopathies, congenital myasthetic syndromes, sarcopenia, muscular atrophy and cachexia.

The compounds and compositions described and / or disclosed herein can also be used to treat diseases and conditions caused by muscle dysfunction originating from neuronal dysfunction or transmission, including amyotrophic lateral sclerosis, spinal muscle atrophies, inherited ataxias, sensory and motor neuropathies hereditary, hereditary paraplegia, stroke, multiple sclerosis, brain injury with motor deficits, spinal cord injury, Alzheimer's disease, Parkinson's disease with motor deficits, myasthenia gravis, and Lambert-Eaton syndrome.

The compounds and compositions described and / or disclosed herein can also be used to treat diseases and conditions caused by dysfunction of the CNS, spinal cord, or muscle that results from endocrine and / or metabolic dysregulation, including claudication secondary to peripheral arterial disease, hypothyroidism, hyper or hypo parathyroidism, diabetes, adrenal dysfunction, pituitary dysfunction, and

- 123 acid / base imbalances.

The compounds and compositions described and / or disclosed herein can be administered alone or in combination with other therapies and / or therapeutic agents useful in the treatment of the aforementioned disorders.

The compounds and compositions described and / or disclosed herein can be combined with one or more therapies to treat ALS. Examples of suitable therapies include riluzole, baclofen, diazepam, trihexyphenidyl, and amitriptyline. In some embodiments, the compounds and compositions described and / or disclosed herein are combined with riluzole to treat a subject suffering from ALS.

The compounds and compositions described and / or disclosed herein can be combined with one or more additional therapies to treat myasthenia gravis. Examples of suitable therapies include administration of anticholinesterase agents (eg, neostigmine, pyridostigmine), which help improve neuromuscular transmission and increase muscle strength, administration of immunosuppressive drugs (eg, prednisone, cyclosporine, azathioprine, mycophenolate mofetil) that improve muscle strength by suppressing the production of abnormal antibodies; thymectomy (i.e., removal

- 124 surgical of the thymus gland, which is frequently abnormal in patients with myasthenia gravis); plasmapheresis; and intravenous immunoglobulin.

The compounds and compositions described and / or disclosed herein can be combined with one or more additional therapies to treat PVD or PAD (eg, claudication). Treatment of PVD and PAD is generally directed at increasing arterial blood flow, such as quitting smoking, controlling blood pressure, controlling diabetes, and exercising. Treatment may also include medication, such as medications to help improve walking distance (eg, cilostazol, pentoxifylline), antiplatelet agents (eg, aspirin, ticlopidine, clopidogrel), anticoagulants (eg, heparin, low heparin). molecular weight, warfarin, enoxaparin) thrombolytics, antihypertensive agents (eg diuretics, ACE inhibitors, calcium channel blockers, beta blockers, angiotensin II receptor antagonists) and cholesterol lowering agents (eg statins). In some patients, angioplasty, stent implantation, or surgery (for example, surgical revascularization or surgery to remove an atherosclerotic plaque) may be necessary.

- 125 Suitable therapeutic agents include, for example, anti-obesity agents, anti-sarcopenia agents, anti-weakening syndrome agents, antifragility agents, anti-cachexia agents, anti muscle spasm agents, agents against post-surgical and post-muscle weakness. traumatic and anti neuromuscular disease agents.

Suitable additional therapeutic agents include, for example, orlistat, sibramine, diethylpropion, phentermine, benzafetamine, phendimetrazine, estrogens, estradiol, levonorgestrel, norethindrone acetate, estradiol valerate, ethinyl estradiol, norgestimate, conjugated estrogens, estrogens medroxyprogesterone, testosterone, insulin-derived growth factor, human growth hormone, riluzole, cannabidiol, prednisone, albuterol, non-steroidal anti-inflammatory drugs and botulinum toxin.

Other suitable therapeutic agents include TRH, diethylstilbestrol, theophylline, enkephalins, E-series prostaglandins, compounds disclosed in U.S. Patent No. 3,239,345 (eg, zeranol), compounds disclosed in U.S. Patent No. 4,036. 979 (eg, sulbenox), peptides disclosed in US Patent No. 4,411,890, growth hormone secretagogues such as GHRP-6, GHRP-1 (disclosed in

- 126 US Patent No. 4,411,890 and Publications WO 89/07110 and WO 89/07111), GHRP-2 (disclosed in WO 93/04081), NN703 (Novo Nordisk), LY444711 (Lilly), MK-677 (Merck), CP424391 (Pfizer), and B-HT920, growth hormone-releasing factor and its analogues, growth hormone and its analogues, and somatomedins including IGF-1 and IGF-2, alpha-adrenergic agonists, such as agonists of clonidine or serotonin 5-HT_D, such as sumatriptan, agents that inhibit somatostatin or its release, such as physostigmine, pyridostigmine, parathyroid hormone, PTH (134), and bisphosphonates, such as MK-217 (alendronate).

Still other suitable therapeutic agents include estrogen, testosterone, selective estrogen receptor modulators, such as tamoxifen or raloxifene, other androgen receptor modulators, such as those disclosed in Edwards, JP et al., Bio. Med. Chem. Let., 9, 1003-1008 (1999) and Hamann, LG et al., J. Med. Chem., 42, 210-212 (1999) and progesterone receptor agonists (PRA), such as levonorgestrel, medroxyprogesterone acetate (MPA).

Other suitable therapeutic agents include anabolic agents, such as selective androgen receptor modulators (MRSA); antagonists of the activin receptor pathway, such as soluble anti-127 myostatin antibodies or activin receptor decoys, including ACE-031 (Acceleron Pharmaceuticals, a type IIB soluble activin receptor antagonist), MYO-027 / PFE- 3446879 (Wyeth / Pfizer, a myostatin inhibitory antibody), AMG-745 (Amgen, a myostatin inhibitory peptibody), and a decoy receptor for ActRIIB (see Zhou et al., Cell, 142, 531-543, 20 of August 2010); and anabolic steroids.

Other additional suitable therapeutic agents include aP2 inhibitors such as those disclosed in US Patent No. 6,548,529, PPAR gamma antagonists, PPAR delta agonists, beta 3 adrenergic agonists, such as AJ9677 (Takeda / Dainippon), L750355 (Merck ), or CP331648 (Pfizer), -other beta 3 agonists as disclosed in US Patent Nos.

5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064, a lipase inhibitor, such as orlistat or ATL-962 (Alizyme), a serotonin (and dopamine) reuptake inhibitor, such as sibutramine , topiramate (Johnson &amp; Johnson) or axokina (Regeneron), a beta thyroid receptor drug, such as a thyroid receptor ligand as disclosed in WO 97/21993, WO 99/00353 and GB98 / 284425 and anorectic agents, such as dexamphetamine, phentermine, phenylpropanolamine, or mazindol.

Other suitable additional therapeutic agents

- 128 include HIV and AIDS therapies such as indinavir sulfate, saquinavir, saquinavir mesylate, ritonavir, lamivudine, zidovudine, lamivudine / zidovudine combinations, zalcitabine, didanosine, stavudine, and megestrol acetate.

Other additional suitable therapeutic agents include antiresorptive agents, hormone replacement therapies, vitamin D analogues, calcium and elemental calcium supplements, cathepsin K inhibitors, MMP inhibitors, vitronectin receptor antagonists, Src SH.sub.2 antagonists, H inhibitors⁺Vacuolar ATPase, ipriflavone, fluoride, Tibolone, pro-stanoids, 17-beta hydroxysteroid dehydrogenase inhibitors and Src kinase inhibitors.

The above therapeutic agents, when used in combination with the compounds and compositions described herein, may be used, for example, in the amounts indicated in the Physicians Desk Reference (PDR) or as otherwise determined by one skilled in the art. matter.

The compounds and compositions disclosed and / or described herein are administered at a therapeutically effective dosage, eg, a dosage sufficient to provide treatment for pathology. Although human dosage levels

- 129 have yet to be optimized for the chemical entities described herein, generally, a daily dose ranges from about 0.05 to 100 mg / kg of body weight, in some embodiments, from about 0.10 to 10.0 mg / kg of body weight and in some embodiments, from about 0.15 to 1.0 mg / kg of body weight. Therefore, for administration to a 70 kg person, in some embodiments, the dosage range would be about 3.5 to 7,000 mg per day, in some embodiments, about 7.0 to 700.0 mg per day. and in some embodiments, from about 10.0 to 100.0 mg per day. The amount of the chemical entity administered will depend, for example, on the subject and the pathology to be treated, the severity of the condition, the manner and schedule of administration, and the opinion of the prescribing physician. For example, an exemplary dosage range for oral administration is from about 70 mg to about 700 mg per day and an exemplary intravenous administration dosage is from about 70 mg to about 700 mg per day, each depending on the pharmacokinetics of the compound.

Administration of the compounds and compositions disclosed and / or described herein may be by any accepted mode of administration for therapeutic agents including, but not limited to,

- 130 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, the 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 tablet, capsule, powder, liquid, suspension, suppository, and aerosol forms. The compounds disclosed and / or described herein can also be administered in prolonged or controlled release dosage forms (eg, controlled / extended release pill, prolonged release injection, osmotic pump, or transdermal patch forms (including electrotransport) ) for a long time and / or pulse delivery at a predetermined rate. In some embodiments, the compositions are provided in unit dosage forms suitable for easy administration of a precise dose.

The compounds disclosed and / or described herein can be administered alone or in combination with one

- 131 or more conventional pharmaceutical vehicles or excipients (for example, mannitol, lactose, starch, magnesium stearate, saccharin sodium, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition may also contain minor amounts of non-toxic adjuvant substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, and the like (eg, sodium acetate, sodium citrate, cyclodextrin derivatives, monolaureate sorbitan, triethanolamine acetate, triethanolamine oleate). Generally, depending on the intended mode of administration, the pharmaceutical composition will contain from about 0.005% to 95% or from about 0.5% to 50% by weight of a disclosed and / or disclosed compound herein. The methods of preparing such dosage forms themselves are known or will be apparent to those skilled in the art, for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

In some embodiments, the compositions will take the form of a pill or tablet and therefore the composition may contain, along with a disclosed and / or disclosed compound herein, one or more of a diluent (eg, lactose, sucrose phosphate

132 dicalcium), a lubricant (for example, magnesium stearate) and / or a binder (for example, starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives). Other solid dosage forms include a powder, marume, solution, or suspension (eg, in propiiene carbonate, vegetable oils, or triglycerides) encapsulated in a gelatin capsule.

Liquid pharmaceutically administrable compositions may, for example, be prepared by dissolution, dispersion, or suspension etc. of a compound disclosed and / or described herein and optional pharmaceutical additives in a vehicle (eg, water, saline, aqueous dextrose, glycerol, glycols, ethanol, or the like) to form a solution or suspension. Injectables can be prepared in conventional forms, as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of the 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, percentages of the active ingredient of 0.01% to 10% in solution can be used and may be higher if the composition is a solid that will be subsequently diluted to another concentration. In some embodiments, the

- 133 composition will comprise from about 0.2 to 2% of a compound disclosed and / or described herein in solution.

The pharmaceutical compositions of the compounds disclosed and / or described herein can also be administered to the respiratory tract as an aerosol or solution for a nebulizer or as a microfine powder for insufflation, alone or in combination with an inert vehicle such as lactose. In such a case, the particles of the pharmaceutical composition may have diameters of less than 50 microns or, in some embodiments, less than 10 microns.

Furthermore, the pharmaceutical compositions may include a compound disclosed and / or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, and the like.

suitable pharmaceutical and medicinal drugs described herein.

The following examples serve to more fully describe the invention described herein. It should be understood that these examples do not serve in any way to limit the true scope of the present invention, but are presented for purposes of illustration. Example 1: Preparation of (S) -2- (4-Fluorophenyl) propan-1 Agents include amines

- 134Cl

Ο

<img file="MX2012012189A_D0036.tif" />

OO

Λ

ON

Bn

<img file="MX2012012189A_D0037.tif" />

(S) -4-Benzyl-3- (2- (4-fluorophenyl) acetyl) oxazolidin-2one. To a cooled (-78 ° C) solution of (S) -4-benzyloxazolidin-2-one (10 g, 58 mmol, 1.0 equiv.) In 100 ml of THF, n-BuLi ( 40 ml, 1.6 M in hexanes, 64 mmol, 1.1 equiv.). After stirring for 30 minutes, 4-fluoro-phenylacetyl chloride (10 g, 58 mmol, 1.0 equiv.) Was added dropwise. After stirring for an additional 30 minutes, the reaction mixture was allowed to warm to room temperature. The reaction was stopped with NH₄C1 ac. saturated, extracted with dichloromethane and washed with brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification with silica gel (10-20% EtOAc / hexanes) provided the title compound as a thick oil (14.7g, 81%).

OO &lt;Λ

<img file="MX2012012189A_D0038.tif" />

Λ ° &lt;DN

I

Bn

<img file="MX2012012189A_D0039.tif" />

(S) -4-Benzyl-3 - ((S) -2- (4fluorophenyl) propanoyl) oxazolidin-2-one. To a solution to

-13510 room temperature of (S) -4-benzyl-3- (2- (4-fluorophenyl) acetyl) oxazolidin-2-one (5.1 g, 16.3 mmol, 1.0 equiv.) In dry THF (100 ml) iodomethane (1.0 ml, 16.2 mmol, 1.0 equiv.) was added via syringe. The resulting mixture was cooled to -78 ° C and NaHMDS (8.15 ml, 2M in THF, 16.3 mmol, 1.0 equiv.) Was added dropwise via syringe. After stirring for 15 minutes at -78 ° C and the reaction mixture was allowed to warm to room temperature. The reaction was stopped with NH₄C1 ac. saturated and diluted with EtOAc. The organic layer was washed with brine, dried over Na₂SW₄, filtered and concentrated in vacuo. Purification by chromatography on silica gel (7-20% EtOAc / hexanes) provided the title compound (2.6 g, 49%).

-F

<img file="MX2012012189A_D0040.tif" />

OO

I

Bn

HO

<img file="MX2012012189A_D0041.tif" />

Me (S) -2- (4-Fluorophenyl) propan-l-ol. To a room temperature solution of (S) -4-benzyl-3 - ((S) -2- (4fluorophenyl) propanoyl) oxazolidin-2-one (1.8 g, 5.5 mmol, 1.0 equiv .) in THF (18 ml) a NaBH solution was added₄ (1.0 g, 26.4 mmol, 4.8 equiv.) In water (6.0 ml). The reaction mixture was stirred for 3 h at room temperature and then quenched by adding

- 136 careful ac. 1M HCl. The reaction mixture was diluted with water and ethyl acetate. The layers were separated and the organic layer was subsequently washed with brine, dried over Na2SO₄, filtered and concentrated in vacuo. Purification by chromatography on silica gel (10-75% EtOAc / Hexanes) provided the title compound (0.824 g, 97%).

<img file="MX2012012189A_D0042.tif" />

(S) -2- (2- (4-Fluorophenyl) propyl) isoindolin-l, 3-dione. To a solution of (S) -2- (4-fluorophenyl) propan-l-ol (0.82 g, 5.35 mmol, 1.0 equiv.), Phthalimide (0.82 g, 5.6 mmol, 1.05 equiv.) And triphenylphosphine (2.1g, 8.03mmol, 1.5 equiv.) In dry THF (18ml) diethyl azodicarboxylate (3.6ml, 15%) was added dropwise in toluene, 8.0 mmol, 1.5 equiv.). The reaction mixture was stirred for 72 h and then concentrated in vacuo. Purification by chromatography on silica gel (15-25% EtOAc / hexanes) provided the title compound (0.9g, 59%).

<img file="MX2012012189A_D0043.tif" />

OR

- 137 (S) -2- (4-Fluorophenyl) propan-l-amine. To a room temperature solution of (S) —2— (2— (4— fluorophenyl) propyl) isoindolin-1,3-dione (900 mg, 3.2 mmol, 1.0 equiv.) In toluene (14 ml ) hydrazine hydrate (1.4 ml, 45 mmol, 14 equiv.) was added via syringe.

The resulting mixture was heated at 80 ° C for 30 minutes and then cooled to room temperature. The resulting solution was decanted from the solid in the reaction mixture, and the solid was washed with more toluene. The combined organic layers were combined and concentrated in vacuo to provide the title compound (491 mg, 99%), which was used without further purification.

Example 2: Preparation of 2- (4-Fluorophenyl) -2-methylpropan1-amine

<img file="MX2012012189A_D0044.tif" />

Me me

To a solution of 4-fluorophenylacetonitrile (50 g, 370 mmol, 1.0 equiv.) And iodomethane (70 ml, 1.1 mol, 3 equiv.) In THF (370 ml) was added potassium t-butoxide (124 g, 1.1 mol, 3 equiv.) as a solid in portions such that the reaction mixture did not exceed 50 ° C. The reaction mixture was stirred overnight and was then quenched by adding brine. The mixture is

- 138 diluted with EtOAc and washed twice with brine. The organic layer was dried over Na2SO₄, filtered and concentrated in vacuo to provide 2- (4-fluorophenyl) -2-methylpropanonitrile as a yellow oil (57g, 94%), which was used without further purification in the next step. To a solution of the nitrile in dry THF (800 ml) was added a solution of lithium aluminum hydride (210 ml, 2 M in ether, 420 mmol, 1.2 equiv.). After the mixture was refluxed overnight, the reaction was allowed to cool to room temperature and a Fieser and Fieser treatment (300 µ 300 of water / mmol, 1.0 ml of 3N / mmol NaOH, 300 µΐ was performed. of water / mmol). Filtration of the resulting solids provided the title compound as an orange oil (57g, 92%).

Example 3: Preparation of (1- (4Fluorophenyl) cyclobutyl) methanamine

<img file="MX2012012189A_D0045.tif" />

A solution of 4-fluorophenylacetonitrile (6.7 g, 75 mmol, 1.5 equiv.), 1,3-dibromopropane (10 mL, 50 mmol, 1 equiv.), KOH (10.2 g, 150 mmol, 3 (0 equiv.)) And tetrabutylammonium bromide (100 mg) in toluene (135 ml) was heated to

-139-100 ° C for 3 hours. The organic layer was separated and concentrated to dryness. Chromatography on silica gel using a gradient of 0-30% EtOAc / hexanes resulted in the partially purified product which was further purified by Kugelrohr distillation at 200 ° C to provide 3.76 g (22 mmol) of the product of intermediate nitrile in the form of an oil. The residue was dissolved in dry THF (22 ml) and treated with a solution of lithium aluminum hydride (27 ml, 2M in ether, 55 mmol, 2.5 equiv.). The mixture was stirred at 0 ° C for 2 hours followed by a Fieser and Eieser treatment (38 µΐ of water / mmol, 118 µΐ of 3N NaOH / mmol, 38 µΐ of water / mmol). The organic layer was concentrated to dryness to provide the desired product (3.6g, 40% overall) as a yellow oil.

Example 4: Preparation of (1- (6-Methoxypyridin-2yl) cyclobutyl) methanamine

Cl

F

2- (3-Fluoropyridin-2-yl) acetonitrile. To a 0 ° C solution of 2-chloro-3-f luoropyridine (3.0 g, 23 mmol, 1.0 equiv.) And acetonitrile (1.3 ml, 25 mmol, 1.1 equiv.) In toluene (50 ml) sodium hexamethyldisilazide was added

- 140 (NaHMDS) (2.0 M in THF, 13 ml, 25 mmol, 1.1 equiv.). The resulting mixture was stirred for 2 hours at ° C and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic phases were washed with saturated NaCl, dried over Na₂SW₄ and concentrated in vacuo to provide the desired crude product as an oil which was used without further purification.

Example 5: Preparation of (1- (6-Methoxypyridin-2yl) cyclobutyl) methanamine

<img file="MX2012012189A_D0046.tif" />

1- (6-Fluoropyridin-2-yl) cyclobutanecarbonitrile.

Following the same procedure as before for 2— (3— fluoropyridin-2-yl) acetonitrile with 2,6-difluoropyridine (5.0 g, 43 mmol, 1.0 equiv.), Cyclobutylcarbonitrile (3.5 g, 43 mmol , 1.0 equiv.) And NaHMDS (2.0 M in THF, 24 mL, 47 mmol, 1.1 equiv.) In toluene (100 mL) gave the desired product (4.9 g, 64%) as of a colorless oil after purification on silica gel using 25% EtOAc / hexanes as the eluent.

- 141 Ν

<img file="MX2012012189A_D0047.tif" />

F

<img file="MX2012012189A_D0048.tif" />

OMe

1- (6-Methoxypyridin-2-yl) cyclobutanecarbonitrile. Sodium metal (~ 1 g) was added to anhydrous methanol (6.0 ml) at 0 ° C under a nitrogen atmosphere and the mixture was stirred for 30 minutes. 1- (6-Fluoropyridin-2-yl) cyclobutanecarbonitrile (1.6 g, 9.1 mmol) was added to the reaction mixture followed by heating to 75 ° C and stirring for 45 minutes. The solution was cooled to room temperature and partitioned between water and EtOAc. The layers were separated, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with saturated NaCl, dried over Na₂SO4 and concentrated in vacuo to give the desired product (1.7g, 97%) as a colorless oil.

<img file="MX2012012189A_D0049.tif" />

(1- (6-Methoxypyridin-2-yl) cyclobutyl) methanamine. To a stirred solution of 1- (6-methoxypyridin-2yl) cyclobutanecarbonitrile (1.7 g, 8.8 mmol, 1.0 equiv.) In THF (20 ml) was added a solution of lithium aluminum hydride ( 1.0 M in THF, 11 mL, 11 mmol, 1.1 equiv.). The

- 142 mixture was heated under reflux for 1.5 hours and allowed to cool to room temperature. Water (0.43 ml) was added slowly followed by 0.43 ml of 3M NaOH and then three additions of 0.43 ml of water (Fieser and Fieser treatment). The resulting mixture was filtered through diatomaceous earth and rinsed with THF. The combined organic extracts were dried over Na₂SÜ4 and concentrated to dryness to give the desired product (1.6 g, 97%) as a viscous oil.

Example 6: Preparation of 1- (3-Fluoropyridin-2yl) cyclobutanamine

<img file="MX2012012189A_D0050.tif" />

1- (3-Fluoropyridin-2-yl) cyclobutanecarboxamide. To a 250 ml round bottom flask containing DMSO (60 ml) was added 1- (3-fluoropyridin-2yl) cyclobutanecarbonitrile (2.96 g, 16.8 mmol, 1.0 equiv.) And the mixture was added. stirred until homogeneous. Then, potassium carbonate (7.0 g, 50.4 mmol, 3.0 equiv.) Was added.

<td colspan="2">and the mix</td><td rowspan="2">reaction peroxide</td><td rowspan="2">He cooled hydrogen</td><td rowspan="2">to 0 to the</td><td rowspan="2">° C, 35%</td><td colspan="2">followed by the</td>

<td>addition</td><td>of</td><td>(6.5 mi).</td><td>The</td>

<td>reaction</td><td>I know</td><td>waved to 0</td><td>° C during</td><td> 30</td><td>min</td><td>and then</td><td>I know</td>

<td>heated</td><td>to</td><td>temperature</td><td>environment.</td><td>In</td><td>this</td><td>moment,</td><td>the</td>

-143 reaction was diluted with water (50 ml) and ethyl acetate (100 ml). After transferring to a settling funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (3 x 50 ml). Then the organic layer was dried over Na₂SO4 was filtered and concentrated to give a crude solid which was purified by chromatography on silica gel (10% EtOAc / hexanes) to provide 1.92 g (59%) of 1- (3-fluoropyridin-2yl) cyclobutanecarboxamide in the form of a white solid.

Methyl 1- (3-Fluoropyridin-2-yl) cyclobutylcarbamate.

1- (3-Fluoropyridin-2-yl) cyclobutanecarboxamide (1.92 g, 9.88 mmol, 1.0 equiv.) Was dissolved in methanol (20 mL) and potassium hydroxide (1.11 g, 19, 8 mmol, 2.0 equiv.). The reaction was sonicated until homogeneous, followed by the addition of iodobenzene diacetate (4.77 g, 14.8 mmol, 1.5 equiv.). The reaction was stirred for 20 min and then diluted with water (100 ml) and ethyl acetate (125 ml). After transferring to a settling funnel and shaking, the organic layer was separated from the aqueous layer and the aqueous layer was extracted with EtOAc (50 ml). Then the

- 144 combined organic layers dried over Na₂SO4, filtered and concentrated to give a crude oil which was purified by chromatography on silica gel (40% EtOAc / hexanes) to provide 1.47 g (67%) of l- (3-fluoropyridin-2- il) methyl cyclobutylcarbamate as a white solid.

<img file="MX2012012189A_D0051.tif" />

1- (3-Fluoropyridin-2-yl) cyclobutanamine. Methyl l- (3-fluoropyridin-2-yl) cyclobutylcarbamate (1.47 g, 6.56 mmol, 1.0 equiv.), Ethanol (12 mL) were added to a 20 ml microwave reaction vial. and 3N aqueous sodium hydroxide (7 ml). The reaction mixture was heated in the microwave reactor at 150 ° C for 30 min. Ethanol is

<td>evaporated</td><td>reduced pressure and</td><td>mix</td><td>I know</td><td>extracted</td><td>with</td>

<td>acetate</td><td colspan="2">ethyl (30 ml). Then the</td><td>cap</td><td>watery</td><td>I know</td>

<td colspan="2">extracted with ethyl acetate</td><td>(2 x 30</td><td>me) .</td><td colspan="2">The layers</td>

<td>organic</td><td>they were combined</td><td colspan="2">dried over</td><td>N32SO4 f</td><td>I know</td>

Filtered and concentrated to give 1- (3-fluoropyridin-2yl) cyclobutanamine (1.01g, 93%) as a crude yellow oil that was used in the next reaction step without further purification.

Example 6:

5- (2- (2- (4-Fluorophenyl) -2- 145methylpropylamino) pyrimidin-5-yl) -lH-indazol-3-amine

Br

<img file="MX2012012189A_D0052.tif" />

Br

<img file="MX2012012189A_D0053.tif" />

—N

5-Bromo-N- (2- (4-fluorophenyl) -2-methylpropyl) pyrimidin2-amine. 2-chloro-5bromopyridine (440 mg, 2.3 mmol, 1.1 equiv.), 2— (4— fluorophenyl) -2-methylpropan-l-amine (350 mg, 2) was added to a 20 drachm vial. 0.1 mmol, 1.0 equiv.), DIPEA (1.0 ml, 5.7 mmol, 2.7 equiv.) And toluene (5 ml). The vial was heated in an oil bath at 80 ° C, shaken for 12 h, concentrated and purified by column chromatography on silica gel (030% EtOAc / hexanes) to give 270 mg (40%) of 5-bromo-N- (2- (4fluorophenyl) -2-methylpropyl) pyrimidin-2-amine as a white solid.

Br

N

<img file="MX2012012189A_D0054.tif" />

<img file="MX2012012189A_D0055.tif" />

<img file="MX2012012189A_D0056.tif" />

"N

2-Fluoro-5- (2- (2- (4-fluorophenyl) -2- 146methylpropylamino) pyrimidin-5-yl) benzonitrile. 5-Bromo-N (2- (4-fluorophenyl) -2-methylpropyl) pyrimidin-2-amine (267 mg, 0.8 mmol, 1.0 equiv.) Was added to a 5 ml microwave reaction vial. ), 3-cyano-4-fluorophenylboronic acid (203 mg, 1.2 mmol, 1.5 equiv.), Cl2Pd (dppf) (60 mg, 82 pmol, 0.1 equiv.), potassium carbonate (1.2 ml of a 2N aqueous solution, 2.4 mmol, 3.0 equiv.) and dioxane (4 ml). The reaction was heated in a microwave reactor at 120 ° C for 20 min. The aqueous layer was removed from the reaction and the organic layer was directly purified by reverse phase column chromatography to give 220 mg (73%) of 2-fluoro-5- (2- (2- (4-fluorophenyl) -2-methylpropylamino) pyrimidin-5-yl) benzonitrile as a white solid.

<img file="MX2012012189A_D0057.tif" />

5- (2- (2- (4-Fluorophenyl) -2-methylpropylamino) pyrimidin5-yl) -lH-indazol-3-amine. 2-Fluoro-5- (2- (2- (4 (Fluorophenyl) -2-methylpropylamino) pyrimidin-5-yl) benzonitrile (220 mg, 0.6 mmol) was added to a 5 ml microwave reaction vial, hydrazine (500 μΐ) and propanol (5 ml). The reaction was heated to 120 ° C and stirred for 3h. The

- 147 reaction was concentrated and purified by reverse phase column chromatography to give 95 mg (42%) of 5- (2- (2- (4fluorophenyl) -2-methylpropylamino) pyrimidin-5-yl) -lH-indazol3 -amine as a white solid (m / z [M + H] = 377.1).

Example 7: Preparation of methyl 2- (2- (4-fluorophenyl) -2methylpropylamino) pyrimidin-5-carboxylate

<img file="MX2012012189A_D0058.tif" />

<img file="MX2012012189A_D0059.tif" />

Methyl 2-chloropyrimidin-5-carboxylate (250 mg, 1.4 mmol, 1.0 equiv.), 2- (4-fluorophenyl) -2-methylpropan-l-amine (468 mg) was added to a 20-drachm vial. , 2.8 mmol, 2.0 equiv.), DIPEA (1.0 ml, 5.6 mmol, 4.0 equiv.) And toluene (5 ml). The vial was heated in an oil bath at 60 ° C and stirred for 20 min, concentrated and purified by column chromatography on silica gel (0-50% EtOAc / hexanes) to give 325 mg (77% ) methyl 2- (2- (4-fluoro-phenyl) -2-methylpropylamino) pyrimidin-5-carboxylate as a white solid (m / z [M + H] = 304.1).

Example 8: Preparation of 3- (2- (2- (4-Fluorophenyl) -2methylpropylamino) pyrimidin-5-yl) benzamide.

- 148 Br

<img file="MX2012012189A_D0060.tif" />

NFH₂N

<img file="MX2012012189A_D0061.tif" />

Br

<img file="MX2012012189A_D0062.tif" />

5-Bromo-N- (2- (4-fluorophenyl) -2-methylpropyl) pyrimidin2-amine. To a solution of 5-bromo-2-fluoropyrimidine (1.0 g, 5.6 mmol, 1.0 equiv.) And 2- (4-fluorophenyl) -2-methylpropan1-amine (1.05 g, 6, Potassium carbonate (3.68 g, 11.2 mmol, 2.0 equiv.) Was added to 3 mmol. 1.1 equiv.) In isopropanol (12 ml) in a microwave vial equipped with a stir bar. The vial was equipped with a microwave vial cap and heated at 120 ° C for 45 min. The reaction mixture was filtered to remove the solid potassium carbonate and concentrated in vacuo. After dissolving the residue again in EtOAc and water, the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by chromatography on silica gel (3% -5% MeOH / DCM) provided the title compound as a yellow solid (1.15 g, 65%), (m / z [M + H ] = 324.2).

F

3- (2- (2- (4-Fluorophenyl) -2-methylpropylamino) pyrimidin-149 5-yl) benzamide. 5-Bromo-N- (2- (4-Fluorophenyl) -2-methylpropyl) pyrimidin-2-amine (75 mg, 0.23 mmol, 1.0 equiv) was added to a microwave vial equipped with a stir bar. ), 3- (carboxyamino) phenylboronic acid (25 mg, 0.35 mmol, 1.5 equiv.) and (dppf) PdCl2 (18 mg, 0.23 mmol, 1.0 equiv.) as solids. The vial was equipped with a rubber septum and purged with a stream of nitrogen for 5 min. Nitrogen sprayed dioxane (1 ml) and K2CO3 aq were added. 2 N (0.5 ml) via syringe and the rubber septum was quickly replaced by a microwave vial cap. After the reaction was heated in a microwave reactor for 30 min at 125 ° C, LCMS analysis indicated consumption of the bromide in v. The reaction mixture was diluted with EtOAc. The organic layer was washed once with NaHCO₃ ac. sat. and once with brine. The combined aqueous layers were washed once with EtOAc and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (3% -10% MeOH / DCM) provided the title compound as a light yellow solid (44 mg, 52%), (m / z [M + H] = 365.3).

Example 9: Preparation of (1- (3-Fluoropyridin-2yl) cyclobutyl) methanamine

- 150 CU

OR^cn

-►

NaHMDS

<img file="MX2012012189A_D0063.tif" />

1- (3-Fluoropyridin-2-yl) cyclobutanecarbonitrile. To a 0 ° C solution of 2-chloro-3-fluoropyridine (80.0 g, 611 mmol, 1.0 equiv.) And cyclobutane carbonitrile (49.5 g, 611 mmol, 1.0 equiv.) In toluene (500 ml) sodium hexamethyldisilazide (2.0 M in THF, 306 ml, 612 mmol, 1.0 equiv.) Was added dropwise. The resulting mixture was allowed to slowly warm to room temperature and was stirred overnight. Then, the reaction was quenched with water (500 ml) and the organic layer was separated from the aqueous layer. The aqueous layer was extracted with EtOAc (2 x 300 ml) and the combined organic phases were washed with a saturated brine solution (2 x 400 ml), dried over Na₂SW₄, concentrated to give a crude yellow oil, and chromatographed on silica gel (210% EtOAc / hex) to give 1- (3-fluoropyridin-2yl) cyclobutanecarbonitrile (88 g, 83%) as a pale yellow oil.

<img file="MX2012012189A_D0064.tif" />

(1- (3-Fluoropyridin-2-yl) cyclobutyl) methanamine. To one

-151 solution

0 ° C from

1- (3-fluoropyridin-2yl) cyclobutanecarbonitrile (88 g, 500 mmol, 1.0 equiv.) In THF (400 ml) LAH (2 M in THF, 575 ml, 1.15 mol) was added dropwise for an hour. The reaction was then warmed to room temperature and stirred for 15 min. After the reaction was complete, it was cooled back to 0 ° C and slowly quenched with water (43 ml), 3N NaOH (43 ml) and water (125 ml). The quenched reaction was stirred for 30 min and then filtered through Celite. The filtrate was concentrated and dried in vacuo to give (1- (3-fluoropyridin-2-yl) cyclobutyl) methanamine (80g, 88%) as a yellow crude oil which was used without purification.

Example 10: Preparation of 2- (6- (Difluoromethoxy) pyridin-2yl) propan-2-amine

<img file="MX2012012189A_D0065.tif" />

CN

NC

NaHMDS

2- (6-Fluoropyridin-2-yl) -2-methylpropanonitrile. To a 0 ° C solution of 2,6-difluoropyridine (69.6 g, 605 mmol, 1.0 equiv.) And isobutyronitrile (41.7 g, 610 mmol, 1.0 equiv.) In toluene (500 ml ) sodium hexamethyldisilazide (2.0 M in THF, 302 ml, 605 mmol, 1.0 equiv.) was added dropwise. The resulting mixture was allowed to warm

- Slowly at room temperature and stirred overnight. Then, the reaction was quenched with water (500 ml) and the organic layer was separated from the aqueous layer. The aqueous layer was extracted with EtOAc (2 x 300 ml) and the combined organic phases were washed with a saturated brine solution (2 x 400 ml), dried over Na₂SW₄, concentrated to give a crude yellow oil, and chromatographed on silica gel (210% EtOAc / hex) to give 2- (6-fluoropyridin-2-yl) -2methylpropanonitrile (55.7g, 56% ) in the form of a clear oil.

Ν (Τγ^Νγ^Ρ NaOMe Ν0Τγ^Νγ^Ο\

Ιί J MeOH II J

2- (6-Methoxypyridin-2-yl) -2-methylpropanonitrile. To a solution of 2- (6-fluoropyridin-2-yl) -2-methylpropanonitrile (10 g) in methanol (30 ml) was added sodium methoxide (50 ml of a 30% solution in methanol). The reaction was then heated at reflux for 1 h, cooled to rt, poured into ethyl acetate (400 ml) and washed with brine (3 x 200 ml). The organic layer was dried over Na₂SW₄ and concentrated to give

2- (6-methoxypyridin-2-yl) -2methylpropanonitrile (9.8 g, 92%) as a pale yellow oil.

- 153 NC '

Ν ^ Ο_χ 4N HCl / Dioxane

NC .O

2-Methyl-2- (6-oxo-l, 6-dihydropyridin-2yl) propaneitrile. 2- (6-Methoxypyridin-2-yl) -2-methylpropanonitrile (7g, 40mmol) and 4N HCl in dioxane (15ml) were added to a 20 drachm microwave vial. Then, the reaction was sealed and heated in a microwave reactor at 190 ° C for 30 min. This reaction was repeated six times using the above procedure. These reactions were combined and filtered. The resulting white solid was washed with 20% EtOAc / hexanes and then dried in vacuo to provide 2-methyl-2- (6-oxo-l, 6-dihydropyridin-2-yl) propaneitrile (24.7g, 77 %) in the form of a white solid.

<img file="MX2012012189A_D0066.tif" />

CIF₂BCC₂I CsCO₃, DMF ^NcX ^^Nand^0CF2^H

2- (6- (Difluoromethoxy) pyridin-2-yl) -2methylpropanonitrile. 2-Methyl-2- (6-oxo-l, 6-dihydropyridin-2yl) propanonitrile (8.2 g, 51 mmol, 1.0 equiv.) Was added to a 100 ml round bottom flask,

- 154 methyl chlorodifluoroacetate (14.9 g, 103 mmol, 2.0 equiv.), Cesium carbonate (23.3 g, 71 mmol, 1.4 equiv.) And DMF (100 ml). The reaction was heated to 95 ° C and stirred for 3 hours. The reaction was then quenched with water (100 mL) and diluted with EtOAc (500 mL). The organic layer was separated from the aqueous layer. The aqueous layer was extracted with EtOAc (100 ml) and the combined organic phases were washed with a saturated brine solution (3 x 200 ml), dried over Na₂SW₄, concentrated, and chromatographed on silica gel (2-5% EtOAc / hex) to give 2 - (6- (difluoromethoxy) pyridin-2-yl) -2methylpropanonitrile (6.2g, 57%) as a transparent oil.

<img file="MX2012012189A_D0067.tif" />

2- (6- (Difluoromethoxy) pyridin-2-yl) -2-methylpropanamide.

2— (6— (Difluoromethoxy) pyridin-2-yl) -2-methylpropanonitrile (19.2 g, 91 mmol, 1 equiv.), Potassium carbonate (37.0) was added to a 1 1 round-bottomed flask. g, 270 mmol, 3 equiv.) and DMSO (150 ml). The reaction was cooled to 0 ° C and 30% hydrogen peroxide (25 ml) was added slowly in 2 ml portions over ten minutes. The reaction was then warmed to room temperature and stirred

- 155 -

<td>during</td><td>1 hour.</td><td>Then</td><td>of</td><td>That</td><td>consume the</td><td>material of</td>

<td>departure,</td><td>the</td><td>reaction</td><td>I know</td><td>poured</td><td>in acetate</td><td>ethyl (600</td>

<td>me), I know</td><td>Washed</td><td colspan="2">with brine</td><td colspan="2">(3 x 300 mi), dried</td><td>about Na₂SW₄</td>

and concentrated to give 2- (6- (difluoromethoxy) pyridin-2-yl) 2-methylpropanamide (20g, 97%) as a clear oil.

<img file="MX2012012189A_D0068.tif" />

2- (6- (Difluoromethoxy) pyridin-2-yl) methyl propane-2-ylcarbamate. 2 - (6- (Difluoromethoxy) pyridin-2-i1) -2-methylpropanamide (20.0 g, 91 mmol, 1 equiv.) And methanol (150 ml) were added to a 500 ml round bottom flask. The mixture was cooled to 0 ° C and a sodium hydroxide solution (7.3 g dissolved in 150 ml of methanol, 182 mmol, 2.0 equiv.) Was added. The reaction was stirred for 2 minutes and iodobenzene diacetate (40.8 g, 127 mmol, 1.4 equiv.) Was added. The reaction was stirred for 2 hours while slowly warming to rt. Then the reaction was poured into ethyl acetate (700 ml), washed with a saturated brine solution (2 x 400 ml), dried over Na₂SW₄, concentrated and chromatographed on silica gel (10-20% EtOAc / hex) to provide methyl 2- (6- (difluoromethoxy) pyridin2-yl) propan-2-ylcarbamate (12.4 g, 55%) fit

- 156of a white solid.

<img file="MX2012012189A_D0069.tif" />

2- (6- (Difluoromethoxy) pyridin-2-yl) propan-2-amine. To a solution of 2- (6- (difluoromethoxy) pyridin-2-yl) propan-2ylcarbamate (12.4 g, 48 mmol) in acetonitrile (50 ml) was added TMSI (10 ml). The reaction was stirred 30 min and then poured into methanol (100 ml) and water (5 ml). The mixture was concentrated, dissolved in ethyl acetate (200 ml) and then washed with 1N NaOH (2 x 30 ml). The organic layer was separated, dried over Na2SO₄, concentrated and chromatographed on silica gel (50% EtOAc / hex and then 5-20% MeOH / ΟΗ₂Ο1₂) to provide 2- (6 (difluoromethoxy) pyridin-2-yl) propan-2-amine (8.8 g, 92%) as a yellow oil.

Example 11: Preparation of fcrans-3-Fluoro-1- (3fluoropyridin-2-yl) cyclobutyl) methanamine

<img file="MX2012012189A_D0070.tif" />

1- (3-Fluoropyridin-2-yl) -3- 157 methylenecyclobutanecarbonitrile. To a solution of 3-methylenecyclobutanecarbonitrile (150 g, 1.61 mol, 1 equiv.) And 2-chloro-3-fluoropyridine (212 g, 1.61 mmol, 1 equiv.) In toluene (1 1) was added dropwise to drop NaHMDS (2M in THF, 885 ml, 1.1 equiv.) at 0-10 ° C. After the addition was complete, the reaction mixture was warmed to rt, stirred overnight, and quenched with NH solution₄Cl (_Sat.). The organic layer was washed with water (2 x 500 ml) and brine (500 ml), dried over Na₂SW₄, filtered and concentrated to give the crude title compound (272g, 90%) which was used in the next step without further purification. LRMS (M + H⁺) m / z 189.1.

<img file="MX2012012189A_D0071.tif" />

1- (3-Fluoropyridin-2-yl) -3-oxocyclobutanecarbonitrile.

To a mixture of 1- (3-fluoropyridin-2-yl) -3methylenecyclobutanecarbonitrile (272 g, 1.45 mol) and RuC1₃-H₂Or (9.0 g, 0.044 mol) in a mixture of DCM (1 1), acetonitrile (1 1) and water (1.5 1) NaIO was added portionwise₄ solid (1235 g, 5.8 mol) at 10-30 ° C. After the addition was complete, the reaction was stirred 1h at 15 ° C and overnight at rt. The solid precipitate was removed

-158 by filtration and washed with DCM (2 x 1000 ml). The organic layer was washed with water (2 x 500 ml) and brine (500 ml), dried over Na2SO₄ and concentrated to provide the crude title compound as a dark solid (238g, 86.3%). LRMS (M + H⁺) m / z 191.1.

<img file="MX2012012189A_D0072.tif" />

1- (3-Fluoropyridin-2-yl) -3hydroxycyclobutanecarbonitrile. To a solution of 1— (3fluoropyridin-2-yl) -3-oxocyclobutanecarbonitrile (231 g, 1.22 mol) in a mixture of DCM (2 1) and MeOH (200 ml) was added portionwise NaBH₄ at -78 ° C. The reaction mixture was stirred at -78 ° C for 1 hr and quenched with a mixture of methanol and water (1/1). The organic layer was washed with water (500 ml x 3), dried over Na2SO₄ and concentrated. The residue was purified on silica gel (50% EtOAc / hexanes) to provide the title compound as an amber oil (185.8 g, 77.5%). LRMS (M + H⁺) m / z 193.2.

<img file="MX2012012189A_D0073.tif" />

-159 trans-3-Fluoro-l- (3-fluoropyridin-2yl) cyclobutanecarbonitrile To a solution of l— (3-fluoropyridin-2-yl) -3-hydroxycyclobutanecarbonitrile (185 g, 0.96 mol) in DCM (1 1) DAST was added portionwise at 0-10 ° C. After the addition was complete, the reaction was heated under reflux for 6 h. The reaction was cooled to rt and poured into a sat. by NaHCO₃. The mixture was separated and the organic layer was washed with water, dried over Na2SC&gt; 4, and concentrated. The residue was purified on silica gel (100% DCM) to provide the title compound as a brown oil (116g, 62%) in an 8: 1 trans: cis mixture. The above brownish oil (107 g) was dissolved in toluene (110 ml) and hexanes (330 ml) at 70 ° C. The solution was cooled to 0 ° C and stirred at 0 ° C overnight. The precipitate was filtered and washed with hexanes to provide the trans isomer as a white solid (87.3 g, 81.6%). LRMS (M + H⁺) m / z 195.1.

<img file="MX2012012189A_D0074.tif" />

<img file="MX2012012189A_D0075.tif" />

trans-3-Fluoro-1- (3-fluoropyridin-2yl) cyclobutyl) methanamine. A mixture of trans-3-fluoro-1 (3-fluoropyridin-2-yl) cyclobutanecarbonitrile (71 g, 0.37

-160 mol) and Raney nickel (~ 7 g) in 7N ammonia in methanol (700 ml) was charged with hydrogen (413,685 kPa (60 psi)) for 2 days. The reaction was filtered through a pad of celite and washed with methanol. The filtrate was concentrated under high vacuum to provide the title compound as a light green oil (70g, 97.6%). LRMS (M + H⁺) m / z 199.2.

Example 12: Preparation of t-butyl 5-bromopyrimidin-2-yl ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate

<img file="MX2012012189A_D0076.tif" />

one. DIPEA, NMP

2. Boc₂O, DMAP, THF

<img file="MX2012012189A_D0077.tif" />

A mixture of trans-3-fluoro-1- (3-fluoropyridin-2yl) cyclobutyl) methanamine (37.6g, 190mmol), 5-bromo-2fluoropyrimidine (32.0g, 181mmol), DIPEA (71ml 407 mmol) and NMP (200 ml) were stirred at rt overnight. Then, the reaction mixture was diluted with EtOAc (1500 ml) and washed with saturated sodium bicarbonate (500 ml). The organic layer was separated, dried over Na₂SW₄ and concentrated. The resulting solid was dissolved in THF (600 ml), followed by the slow addition of DMAP (14 g, 90 mmol) and Boc₂0 (117.3 g, 542 mmol). The reaction was heated to 60 ° C and stirred for 3h. Then, the reaction mixture was

161 was concentrated and purified by chromatography on silica gel (EtOAc / hex) to give 59.7 g of 5-bromopyrimidin-2yl ((trans-3-ίluoro-1- (3-fluoropyridin-2yl) cyclobutyl) methyl) t-butyl carbamate as a white solid.

Example 13: Preparation of 1- (2 - (((trans) -3-fluoro-1- (3fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) lH-pyrrole-3-carboxamide

<img file="MX2012012189A_D0078.tif" />

T-Butyl 5- (3-cyano-lH-pyrrole-l-yl) pyrimidin-2-yl (((trans) -3fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate. To a solution of t-butyl 5-bromopyrimidin-2yl ((3-fluoro-l- (3-fluoropyridin-2-yl) cyclobutyl) methyl) (1.0 g, 2.8 mmol) in 15 ml of toluene ( degassed with nitrogen) copper iodide (100 mg, 0.6 mmol), potassium phosphate (1.31 g, 6.2 mmol), trans-Ν, Ν'dimethylcyclohexane-1,2-diamine (320 mg) were added , 2.2 mmol) and 3-cyanopyrrole (310 mg, 3.6 mmol). The reaction was heated to 100 ° C and stirred for 2h. The reaction was then concentrated and purified by chromatography on silica gel (EtOAc / hexanes) to provide 1.1 g of 5- (3-cyano-lH-pyrrole-l-yl) pyrimidin-2-yl (((trans) T-butyl 3-fluoro-l- (3-162 fluoropyridin-2-yl) cyclobutyl) methyl) carbamate in the form of a clear oil.

<img file="MX2012012189A_D0079.tif" />

<img file="MX2012012189A_D0080.tif" />

1- (2 - (((trans) -3-fluoro-l- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyrimidin-5-yl) -lH-pyrrole-3carboxamide. To a solution of t-butyl 5- (3-cyano-lH-pyrrol-lyl) pyrimidin-2-yl (((trans) -3-fluoro-l- (3-fluoropyridin-2yl) cyclobutyl) methyl) carbamate (1.1 g, 3.1 mmol) in DMSO (10 ml) was added potassium carbonate (1.3 g, 9.3 mmol). The mixture was cooled to 0 ° C and hydrogen peroxide (3 ml) was added slowly. The reaction was warmed to rt and stirred for 90 min. The reaction was diluted with EtOAc (75 ml) and washed three times with brine (50 ml). Then the organic layer was dried over Na₂SO4, filtered, and concentrated to give a crude solid which was purified by chromatography on silica gel (10% MeOH / ΟΗ₂Ο1₂) to provide 1.07 g of 1- (2 - (((trans) -3-fluoro-1- (3fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-i1) lH-pyrrole-3-carboxamide in form of a white solid. This compound was dissolved in 25% TFA / CH₂Cl₂ and stirred for 1 hr. Then, the reaction was concentrated, dissolved in ethyl acetate (75 ml) and washed three times

-163 with potassium carbonate. Then the organic layer was dried over Na₂SW₄, filtered and concentrated to give a crude solid which was triturated with 75% ethyl acetate / hexanes. The resulting suspension was sonicated and filtered to give 500 mg of 1- (2- (((fcrans) -3-fluoro-l- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyrimidin-5-yl) -lH- pyrrole-3carboxamide as a white solid (M + H =

385) .

Example 14: Preparation of 2- (2 - ((trans-3-Fluoro-l- (3fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5yl) thiazol-5-carboxamide

<img file="MX2012012189A_D0081.tif" />

2. NH₄Oh

3. TFA, CH₂CI₂

one. CI₂Pd (PPh₃)₂JohnPhos

<img file="MX2012012189A_D0082.tif" />

T-Butyl 5-bromopyrimidin-2-yl ((trans-3-fluoro-1- (3-fluoropyridin-2yl) cyclobutyl) methyl) t-butyl carbamate (850 mg, 1.95 mmol) was added to a 20 ml microwave vial ), ethyl thiazol-5-carboxylate (459 mg, 2.92 mmol), Cl₂Pd (PPh₃)₂ (205mg, 0.29mmol), Johnphos (213mg, 0.58mmol), CS2CO3 (1.9g, 5.85mmol) and toluene (8ml). The reaction was stirred and heated at 140 ° C for 30 min in

- 164a microwave reactor. Then, the reaction mixture was poured into ethyl acetate (100 ml), washed with NaHCO₃ (50 ml), washed with brine (50 ml) and then dried over Na₂SC&gt; 4, filtered, concentrated, and purified by chromatography on silica gel (EtOAc / hexanes) to provide 191 mg of 2- (2- (t-butoxycarbonyl ((trans-3fluoro-1- (3-fluoropyridin- Methyl 2-cyclobutyl) methyl) amino) pyrimidin-5-yl) thiazol-5-carboxylate. This compound was subsequently dissolved in ethanol (4 ml) and ammonium hydroxide (2 ml) was added. The reaction was heated to 60 ° C and stirred for 30 min. Then, the reaction was concentrated, dissolved in CH₂C1₂ (30 mi), washed with NaHCO₃ (10 ml), washed with brine (10 ml) and then dried over MgSCú, filtered and concentrated. The crude solid was dissolved again in CH₂C1₂ (5 ml) and TEA (2 ml) was added. The reaction was stirred at rt for 30 min, concentrated, and then purified by reverse phase chromatography to yield 51 mg of 2- (2 - ((trans-3-fluoro-1- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyrimidin-5-yl) thiazol-5carboxamide as a white solid (M + H = 385.1).

Example 15: Preparation of 4-Fluoro-3- (2 - ((fcrans-3-fluoro1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5yl) -2-hydroxybenzamide

- 165 -

<img file="MX2012012189A_D0083.tif" />

<img file="MX2012012189A_D0084.tif" />

4-Fluoro-3- (2 - ((trans-3-fluoro-l- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyrimidin-5-yl) -2methoxybenzonitrile. T-butyl 5-bromopyrimidin-2-yl ((trans-3-fluoro-l- (3-fluoro-pyridin-2-yl) cyclobutyl) methyl) carbamate (5.0 g) was added to a 250 ml round bottom flask. , 11.0 mmol), 3-bromo-6-fluoro-2methoxyphenylboronic acid (2.7 g, 11.0 mmol), (dppf) PdCl₂ (0.80 g, 1.1 mmol), dioxane (25 ml degassed for 10 min with nitrogen), K₂CO₃ (3.0g, 22mmol) and water (4ml). The mixture was heated to 95 ° C and stirred overnight.

Then, the reaction mixture was poured into ethyl acetate (200 ml), washed sequentially with NaHCO₃ (50 ml) and brine (50 ml) and then dried over Na₂SW₄, filtered, concentrated, and purified by chromatography on silica gel to provide 2.4 g (4.1 mmol) of 5- (3bromo-6-fluoro-2-methoxyphenyl) -N - ((fcrans-3- fluoro-1- (3fluoropyridin-2-yl) cyclobutyl) methyl) pyrimidin-2-amine as a pale yellow solid. Zinc cyanide (0.76 g, 6.5 mmol), Pd (PPh) were added to this solid₃)₄ (2.9g, 2.5mmol) and DMF (25ml). The mixture was heated at 100 ° C for 2 h and then diluted with EtOAc

- 166 and washed with NaHCO₃ ac. sat. and brine. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified using reverse phase chromatography to provide 1.1 grams of 4-fluoro-3- (2 - ((trans-3-fluoro1- (3-fluoropyridin -2-yl) cyclobutyl) methylamino) pyrimidin-5yl) -2-methoxybenzonitrile.

<img file="MX2012012189A_D0085.tif" />

4-Fluoro-3- (2 - ((trans-3-fluoro-l- (3-fluoropyridin-2xl) cyclobutyl) methylamino) pyrimidin-5-yl) -2hydroxybenzamide. A mixture of 4-fluoro-3- (2 - ((trans-3fluoro-1- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyrimidin-5-yl) -2methoxybenzonitrile (1.0g, 1.9mmol) , K2CO3 (0.8g, 5.7mmol) and DMSO (5ml) were combined in a round bottom flask and cooled to 0 ° C. H2O2 (8.0 ml of a 35% solution) was added dropwise. The reaction was warmed to rt and stirred for 1 h. The reaction mixture was diluted with EtOAc and washed with NaHCÜ3 aq. sat. and brine (three times). The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by reverse phase chromatography to provide 0.55 g (1 mmol) of 4-fluoro3- (2 - ((trans-3-fluoro-1- (3-fluoropyridin-2- 167 yl) cyclobutyl) methylamino) pyrimidin-5-yl) -2-methoxybenzamide a white solid. This compound was mixed with pyridine (6 ml) and Lil (1.22 g, 9 mmol) and heated in a microwave reactor at 125 ° C for 15 min. The reaction mixture was diluted with EtOAc and washed with aq NaHCO3. sat. and brine. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by reverse phase chromatography to provide 163 mg of 4-fluoro-3- (2 ((trans-3-fluoro-1- (3-fluoropyridin- 2yl) cyclobutyl) methylamino) pyrimidin-5-yl) -2-hydroxybenzamide as a white solid (M + H + 430.1).

Example 16: Preparation of 2- (2- (2 - ((1- (3-Chloropyridin-2yl) cyclobutyl) methylamino) pyrimidin-5-yl) thiazol-5yl) acetamide

<img file="MX2012012189A_D0086.tif" />

To a 50 ml round bottom flask were added

T-Butyl 5-bromopyrimidin-2-yl ((1- (3-chloropyridin-2yl) cyclobutyl) methyl) carbamate (1.0g, 2.2mmol), Pd (PPh₃)₄ (0.25g, 0.22mmol), hexamethyldin (0.92ml, 2.2mmol), LiCl (0.25g, 5.9mmol) and dioxane (10ml). The mixture was heated at 90 ° C for 1 hr. To the resulting dark brown solution were added

-168 2- (2-Bromothiazol-5-yl) acetonitrile (0.89 g, 4.4 mmol), Pd (PPh₃)₄ (0.076g, 0.066mmol) and Cul (4.2g, 22.2mmol). The reaction mixture was stirred at 90 ° C for 1 hr. The reaction was then cooled to rt, diluted with ethyl acetate (50 ml) and filtered through Celite. The filtrate was washed with water (30 ml) and brine (30 ml). The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by chromatography on silica gel (EtOAc / hex) to provide 222 mg of (1- (3-chloropyridin-2yl) cyclobutyl) methyl (5- ( 5- (cyanomethyl) thiazol-2-yl) pyrimidin2-yl) carbamate in the form of a brown viscous oil. Potassium carbonate (185 mg, 1.3 mmol) and DMSO (3 ml) were added to this compound. The mixture was cooled to 0 ° C and hydrogen peroxide (0.5 ml) was added slowly. The reaction was warmed to rt and stirred for 1 h. The reaction was diluted with EtOAc (75 ml) and washed three times with brine (50 ml). Then the organic layer was dried over Na₂SW₄, filtered, and concentrated to give a crude solid which was purified by reverse phase chromatography to provide 48 mg of 5- (5- (2-amino-2oxoethyl) thiazol-2-yl) pyrimidin-2-yl (( 1- (3-Chloropyridin-2yl) cyclobutyl) methyl) carbamate in the form of a white solid. This compound was dissolved in 25% TFA / CH2Cl₂ and stirred for 10 min. After the reaction was concentrated, it was dissolved in ethyl acetate (75

- 169 ml) and washed three times with a saturated sodium bicarbonate solution. The organic layer was dried over Na2SO₄, filtered, and concentrated to give 39 mg of 2— (2— (2 - ((l— (3— chloropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5yl) thiazol-5-yl) acetamide as a white solid (M + H = 415.1).

Example 17: Preparation of 3- (2 - ((trans-3-Fluoro-1- (3fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -4hydroxy-N-methylbenzamide

<img file="MX2012012189A_D0087.tif" />

3- (2 - ((((trans) -3-fluoro-l- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyrimidin-5-yl) -4-hydroxybenzoic acid.

5-bromoN - ((((trans) -3-fluoro-l- (3-fluoropyridin-2yl) cyclobutyl) methyl) pyrimidin-2-amine (1.2 g, 3) was added to a 20 ml microwave tube , 8 mmol), 4-hydroxy-3- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2yl) benzoate (1.1 g, 4.0 mmol), (dppf) PdCl2 ( 0.25g, 0.38mmol), dioxane (15ml), K2CO3 (1.4g, 10.1mmol) and water (3ml). The mixture was heated to 135 ° C and stirred for 15 min. Then, the reaction mixture was poured into ethyl acetate (200 ml), washed with brine (50 ml) and

- 170 dried over Na2SO₄, filtered, concentrated, and purified by chromatography on silica gel (EtOAc / hex) to provide 0.65 g of 3- (2 - (((trans) -3-fluoro-1- (3fluoropyridin-2-yl ) Methyl cyclobutyl) methylamino) pyrimidin-5-yl) -4-hydroxybenzoate as a brown solid. This compound was dissolved in methanol (7 ml) and KOH (2 ml of a 3N aqueous solution) was added. The reaction was stirred at 80 ° C for 1 hr and then concentrated. The crude residue was purified by reverse phase chromatography to provide 0.24 g of 3- (2 - (((trans) -3fluoro-1- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyrimidin-5-yl acid. ) -4-hydroxybenzoic in the form of a white solid.

<img file="MX2012012189A_D0088.tif" />

3- (2 - ((trans-3-Fluoro-l- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyrimidin-5-yl) -4-hydroxy-N-methylbenzamide. 3- (2 - (((trans) -3-fluoro-1- (3-fluoropyridin2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -4hydroxybenzoic acid was added to a 50 ml round-bottom flask ( 147 mg, 0.36 mmol), HATU (204 mg, 0.54 mmol), HOBT (72 mg, 0.54 mmol), methylamine hydrochloride (239 mg, 3.6 mmol), DI PEA (187 μEA , 1.1 mmol) and DMF (1.5

- 171 mi). The reaction mixture was stirred at rt overnight. The reaction mixture was concentrated and purified by reverse phase chromatography to provide 93 mg of 3 (2 - ((trans-3-fluoro-1- (3 — fluoropyridin-2yl) cyclobutyl) methylamino) pyrimidin-5-yl) -4-hydroxy-Nmethylbenzamide as a white solid (M + H =

412,1) .

Example 18: Preparation of 6- (2- (2- (3-Chloropyridin-2yl) propan-2-ylamino) pyrimidin-5-yl) imidazo [2,1-b] thiazol-3carboxamide

<img file="MX2012012189A_D0089.tif" />

2-Bromo-1- (2- (2- (3-chloropyridin-2-yl) propan-2-amino-pyrimidin-5-yl) ethanone. To a stirred dioxane solution (50 ml, degassed) was added 5-bromoN- (2- (3-chloropyridin-2-yl) propan-2-yl) pyrimidin-2-amine (3.0 g, 12 mmol), Cl2Pd (PPh3) 2 (0.65 g, 1.2 mmol) and tributyl (lethoxyvinyl) tin (2.66 ml, 13.8 mmol). The reaction was heated to 90 ° C and stirred for 2h. The reaction was then concentrated, followed by the addition of EtOAc (100 ml) and potassium fluoride (50 ml of a saturated aqueous solution). The mixture was stirred for 10 min and then filtered through a pad of celite. The filtrate was concentrated and then dissolved in THF (20 ml)

- 172 and water (20 ml). Then, NBS (4.9 g, 27.6 mmol) was added and the reaction was stirred for 20 min at rt. The reaction mixture was poured into ethyl acetate (200 ml), washed with saturated aqueous sodium bicarbonate (50 ml), dried over Na₂SO4, filtered, concentrated, and purified by chromatography on silica gel to provide 1.5 g of 2-bromo-l- (2- (2- (3-chloropyridin-2-yl) propan-2-amino-pyrimidin- 5-yl) ethanone in the form of a white powder.

<img file="MX2012012189A_D0090.tif" />

<img file="MX2012012189A_D0091.tif" />

6- (2- (2- (3-Chloropyridin-2-yl) propan-2-ylamino) pyrimidin-5-yl) imidazo [2,1-b] thiazol-3-carboxamide.

2-bromo-l- (2- (2- (3 (chloropyridin-2-yl) propan-2-ylamino) pyrimidin-5-yl) ethanone (103 mg, 0.28 mmol) was added to a vial of 20 drachmas. , Ethyl 2-aminothiazol-4-carboxylate (48mg, 0.28mmol) and methyl ethyl ketone (2ml). The mixture was heated to 90 ° C in a sealed tube and stirred overnight. The reaction was then concentrated and purified by chromatography on silica gel (EtOAc / hex) to provide 33 mg of 6- (2- (2- (3 (chloropyridin-2-yl) propan-2-ylamino) pyrimidin-5yl) ethyl imidazo [2,1-b] thiazol-3-carboxylate in the form of

- 173 a solid of chestnut color. This compound was dissolved in methanol (1 ml) and ammonium hydroxide (3 ml) was added. The resulting mixture was heated in a microwave reactor to

135 ° C and stirred for 15 min. The reaction was concentrated, followed by the addition of HBTU (68 mg, 179 pmol), HOBt (24 mg, 179 pinol), NH₄C1 (48 mg, 1.1 mmol), DIPEA (78 pl, 441 pmol) and NMP (2 ml). The reaction was stirred for 2 h and then directly purified by reverse phase chromatography to provide 18 mg of 6- (2- (2- (3-chloropyridin2-yl) propan-2-ylamino) pyrimidin-5-yl) imidazo [ 2,1-b] thiazol3-carboxamide as an off-white solid (M + H = 414.1).

Example 19: Preparation of 4- (2 - (((cis) -3-fluoro-l- (3fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5yl) picolinamide

NC ^NC\ / = N

4- (2-chloropyrimidin-5-yl) picolinonitrile. 4-Bromoopicolinonitrile (11.8g, 74.5mmol), 2-chloropyrimidin-5-ylboronic acid (15.0g, 82.0mmol), (dppf) PdCl were combined₂ (5.5 g, 7.45 mmol), dioxane (150 ml, degassed with nitrogen) and K₂CC&gt; 3 ac. 2 N (33 ml) and heated in a round bottom flask at 100 ° C for one

- 174 night. The hot mixture was filtered through a pad of Celite, diluted with EtOAc, washed with water, concentrated, and purified using chromatography on silica gel to provide 4- (2-chloropyrimidin-5-yl) picolinonitrile as of a brown solid (2.1 g, 13%).

<img file="MX2012012189A_D0092.tif" />

4- (2 - (((cis) -3-fluoro-l- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyrimidin-5-yl) picolinamide. 4- (2-Chloropyrimidin-5-yl) picolinonitrile (0.9g, 4.2mmol), (3-fluoro-1- (3-fluoropyridin-2yl) cyclobutyl) methanamine (1.0g, 5) were mixed , 0 mmol), DIPEA (1 ml) and ACN (20 ml) and heated at 90 ° C for 4 h. The reaction mixture was concentrated, diluted with EtOAc, and washed with NaHCO₃ ac. sat. and brine. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified using reverse phase chromatography to provide 4 (2 - (((cis) -3-fluoro-l- (3-fluoropyridin-2yl) cyclobutyl) methylamino ) pyrimidin-5-yl) picolinonitrile as a clear oil (the cis isomer elutes first). This compound was then treated with DMSO (3 ml), K₂CO₃ (200 mg) and H₂OR₂ (2 ml). The reaction mixture was stirred for 4 h and then diluted with EtOAc and washed with

- 175 brine. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified using reverse phase chromatography to provide 93 mg of 4- (2 - (((cis) -3fluoro-1- (3-fluoropyridin-2yl) cyclobutyl ) methylamino) pyrimidin-5-yl) picolinamide as an off-white solid (m / z [M + H] = 397.2).

Example 20: Preparation and testing of fast skeletal myofibrils

Preparation of skeletal myofibrils. Rabbit skeletal myofibrils were prepared based on the method of Herrmann et al. (Biochem. 32 (28): 7255-7263 (1993). Rabbit psoas myofibrils obtained from Pel-Freez Biologicals (Arkansas) were prepared within 2 days after ordering, stored on ice. The minced muscle was homogenized in 10 volumes of standard frozen buffer (50 mM Tris, pH 7.4, 0.1 M potassium acetate, 5 mM KC1, 2 mM DTT, 0.2 mM PMSF, 10 μΜ leupeptin, 5 μΜ pepstatin and 0.5 mM sodium azide) containing 5 mM EDTA and 0.5% Triton X-100 using an Omni-Macro homogenizer. The myofibrils were recovered by low speed centrifugation (3,000 rpm for 10 minutes) and washed 2 times in the buffer containing Triton X-100 to ensure removal of the cell membrane. After Triton washes, myofibrils were washed 3 times in buffer

- 176 conventional containing 2 mM magnesium acetate. A final wash was performed in assay buffer (12mM PIPES, pH 6.8, 60mM KC1, 1mM DTT) and brought to 10% sucrose for ultra-quick freezing in liquid nitrogen and storage at -80 ° C.

Activation of rapid skeletal myofibrils. Rapid fiber activators were identified by measuring the enzyme activity of muscle myofibril preparations using the PUMA Assay System^T™ patented (see, for example, US Patent Nos. 6,410,254, 6,743,599, 7,202,051, and 7,378,254). The myofibril preparations consisted of rabbit skeletal muscle (approximately 90% fast fibrils) that had been mechanically homogenized and washed with a detergent (Triton X-100) to remove cell membranes. This preparation preserved all the sarcomeric components in a native conformation and the enzymatic activity was still regulated by calcium. The compounds were tested using a suspension of myofibrils and a level of calcium sufficient to increase the enzyme activity of the myofibrils to 25% of their maximum rate (called pCa25). Enzyme activity was tracked using an enzyme system coupled to lactate dehydrogenase and pyruvate kinase. This assay regenerates myosin-produced ADP to ATP by oxidizing NADH,

- 177 producing a change in absorbance at 340 nm. The buffering system was 12 mM Pipes, MgCl₂ 2mM, 1mM DTT at pH 6.8 (PM12 buffer). Data was reported as AC1,4, which is the concentration at which the compound increased enzyme activity by 40%. The results are summarized in Table 2 below.

Example 21: Preparation and Assay of Sarcomeric Skeletal Muscle Proteins

Powder Preparation

one. Volumes are provided by approximately 1000g of minced muscle.

<td>2. Pre-cut and boil cheesecloth</td><td>during</td><td> 10</td><td>minutes in</td>

<td>Water. Drain and pat dry.</td><td></td><td></td><td></td>

<td>3. Chop chicken breast into a</td><td>mincer</td><td>of</td><td>meat pre</td>

<td>cooled.</td><td></td><td></td><td></td>

<td>4. Extract with stirring in 2 1</td><td>from KC1</td><td> 0,1</td><td>M, phosphate</td>

0.15 M potassium, pH 6.5 for 10 minutes at 4 ° C. Centrifuge at 5000 rpm, 10 min, 4 ° C in JLA. Collect the sediment.

5. Extract the pellets with stirring with 2 1 of 0.05 M NaHCCb for 5 minutes. Centrifuge at 5000 rpm, 10 min, 4 ° C in JLA. Collect the sediment. Repeat the extraction once more.

6. Extract the filtered residue with 2 1 of 1mM EDTA, pH 7.0 for 10 minutes with stirring.

- 1787. Extract with 2 1 of H₂Or for 5 minutes with stirring. Centrifuge at 10,000 rpm, 15 min, 4 ° C in JLA. Carefully collect the sediment, part of which will be loose and gelatinous.

8. Extract 5 times with acetone (2 1 of acetone for 10 minutes each with stirring). Squeeze through the cheesecloth gently. All acetone extractions are performed at room temperature. Acetone should be precooled to 4 ° C.

9. Drying: place the filtered rest spread on cheesecloth in a large glass tray and leave in a hood overnight. When the rest is dry, place in a wide-mouth plastic bottle and store at 20 ° C.

Alternative Powder Preparation (See Zot &amp; Potter (1981) Prep. Biochem. 11 (4) p. 381395)

one. Dissect the left ventricles of the · heart muscle. Remove both pericardial tissue and fat

<td>whatever</td><td>possible.</td><td>Grind</td>

<td>cooled.</td><td>To weigh.</td><td></td>

2. Prepare 5 volumes of later). Homogenize times for 15 seconds in a meat grinder extraction buffer (see meat in a mixer, 4 mix with 15 seconds between them. Do this with one volume (weight / volume) of buffer

-179 taken from the 5 volumes already prepared. Add the homogenate back to the extraction buffer and shake until well mixed (5 minutes).

3. Filter through a layer of cheesecloth on a large polypropylene screen. Resuspend again in 5 volumes of extraction buffer as above.

Four. Repeat Stage 3 four more times. In the end, do not resuspend in extraction buffer but move to Stage

5. Sediments should be yellowish white.

5. Resuspend in 3 volumes (according to their original weight) of cold 95% ethanol. Shake for 5 minutes and squeeze through the cheesecloth as above, repeat twice more.

6. Weigh the squeezed residue and then resuspend in 3 volumes (new weight / volume) of cold diethyl ether.

7. Repeat Stage 6 a total of three times.

8. Leave overnight in a single layer in cheesecloth on a glass tray.

9. When dry, collect powder, weigh, and store in a wide-mouth jar at 4 ° C.

EXTRACTION BUFFER: KC1 50 mM, Tris 5 mM pH 8.0. Prepare as concentrate 50 times. For 2 1: 250 mM Tris pH 8.0. Tris base (121.14 g / mol, 60.6 g), pH 8.0 with concentrated HC1, then add 2.5M KC1 (74.55 g / mol, 372 g).

Achina Preparation

- 1801. Extract the powder (as described above) with 20 ml of buffer A (see below, add BME and ATP just before use in each of the following steps) per gram of powder (200 ml per 10 g) . Use a large 4 1 beaker for 150 g of powder. Mix vigorously until the powder dissolves. Shake at 4 ° C for 30 minutes.

2. Separate the extract from the hydrated powder by squeezing through several layers of cheesecloth. Cheesecloth can be pre-sterilized by microwaving it in moisture for 1-2 minutes.

3. Re-extract the rest with the same volume of buffer A and combine the extracts.

Four. Centrifuge in JLA10 rotor or rotors for 1 hour at 10,000 rpm (4 ° C). Collect the supernatant through 2 layers of cheesecloth.

5. Add 0.2 mM ATP and 50 mM MgCl2. Shake on a stir plate at 4 ° C for 60 minutes to allow the actin to polymerize / form para-crystals.

6. Slowly add solid 0.6 M KC1 (45 g / 1). Shake at 4 ° C for 30 minutes.

7. Centrifuge in JLA10 rotor or rotors at 10,000 rpm for 1 hour.

8. Depolymerization: Quickly rinse the surface of the sediments with buffer A and remove the wash.

- 181 Soften the pellets by pre-incubating on ice with a small amount of Buffer A in each tube (use less than half the volume of total final resuspension in all tubes). Resuspend by hand first with a cell scraper and combine the sediments. Wash the tubes with extra buffer using a 25 ml pipette and mechanical pipettor, forcefully removing the actin from the sides of the tubes.

Homogenize in large dounce homogenizer in cold buffer A on ice. Use 3 ml per gram of the powder originally extracted.

9. Dialyze against Buffer A with 4 changes over a 48 hour period.

10. Collect the dialyzed actin and centrifuge in the 45Ti rotor at 40,000 rpm for 1.5 hours (4 ° C).

eleven. Collect the supernatant (G-Actin). Keep a sample for gel analysis and determination of protein concentration.

12. To polymerize G-actin for storage, add 50 mM KC1 (3 de reserve), MgCl₂ at 1 mM and NaN₃ to 0.02% (10% reserve). Store at 4 ° C. Do not freeze.

Buffer A: 2 mM Tris / HCl, CaCl₂ 0.2 mM, 2-mercaptoethanol 0.5 mM (36 μΐ / ΐ), Na₂ 0.2 mM ATP (fresh addition) and 0.005% Na azide; pH 8.0.

Purification of Myosin from Skeletal Muscle.

(See Margossian, SS and Lowey, S. (1982) Methods Enzymol.

- 18285, 55-123; and Goldmann, WH and Geeves, MA (1991) Anal.

Biochem. 192, 55-58)

Solution A: KC1 0.3 M, potassium phosphate 0.15 M, EDTA 0.02 M, MgCl₂ 0.005 M, ATP 0.001 M, pH 6.5.

Solution B: 1M KC1, 0.025M EDTA, 0.06M potassium phosphate, pH 6.5.

Solution C: KC1 0.6 M, potassium phosphate 0.025 M, pH 6.5. Solution D: KC1 0.6M, potassium phosphate 0.05M, pH 6.5. Solution E: 0.15M potassium phosphate, 0.01M EDTA, pH 7.5. Solution F: KC1 0.04 M, potassium phosphate 0.01 M, DTT 0.001 M, pH 6.5.

Solution G: 3M KC1, 0.01M potassium phosphate, pH 6.5.

All procedures are carried out at 4 ° C.

one. Obtain approximately 1000 g of skeletal muscle, such as rabbit skeletal muscle.

2. Grind twice; extract with 2 1 of solution A for 15 minutes with stirring; add 4 i of H₂Or cold, filter through sieve; dilute with H₂Or cold at ionic strength of 0.04, (approximately 10 times); let stand for 3 hours; collect the precipitate at 7,000 rpm in GSA rotor for 15 minutes.

3. Disperse the sediment in 220 ml of solution B; dialyze overnight against 6 1 of solution C; slowly add ~ 400 ml of volume equal to H₂Or cold distilled; shake for 30 minutes; centrifuge at 10,000 rpm

- 183 for 10 minutes in GSA rotor.

Four. Centrifuge the supernatant at 19,000 rpm for 1 hour.

5. Dilute the supernatant to ionic strength of 0.04 (~ 8 times); let myosin sit overnight; Collect approximately 5-6 1 of fluffy myosin precipitate by centrifugation at 10,000 rpm for 10 minutes in GSA rotor.

6. Resuspend the pellet in minimal volume of solution G; dialyze overnight against 2 1 of solution D; centrifuge at 19,000 rpm for 2 hours, in cellulose nitrate tubes; perforate the tubes and separate myosin from fat and insoluble sediment.

7. Dilute the supernatant to 5-10 mg / ml and dialyze against solution E thoroughly, load on DEAEsephadex column.

8. Pre-balance with solution E; apply 500-600 g of myosin at 30 ml / h; wash with 350 ml of solution E; elute with linear gradient of KC1 0-0.5 M in solution E (2 x 1 liter); collect 10 ml fractions; pool myosin fractions (KC1&gt; 0.1M); concentrate by dialysis overnight against solution F; centrifuge at 25,000 rpm for 30 minutes; store as above.

9. The myosin is then cut with chymotrypsin or papain in the presence of EDTA to generate the SI fragment.

- 184 which is soluble under optimal low salinity conditions for ATPase activity (Margossian, mentioned above).

Preparation and Testing

Myosin is prepared by precipitation of saline extracts from rabbit psoas muscle and a soluble SI fraction is prepared by digestion with chymotrypsin (Margossian and Lowey, 1982).

Actin is purified by first preparing a heart muscle ether powder (Zot HG and Potter J D. (1981) Preparative Biochemistry 11: 381-395) as described above. Subsequently, actin alternates between the filamentous and soluble state through cycles of centrifugation and dialysis (Spudich JA and Watt S. (1971) J. Biol. Chem. 246: 4866-4871).

Tropomyosin is extracted from the ether powder and separated from the other proteins based on pH dependent precipitation followed by successive 53% and 65% ammonium sulfate cuts (Smillie LB. (1981) Methods Enzymol 85 Pt B: 234-41 ). Troponins are isolated as an intact complex of TnC, TnT, and Tnl. Ether powder is removed in a high saline buffer. Successive ammonium sulfate cuts of 30% and 45% are made; the precipitate is solubilized by dialysis in a low salinity buffer and then further purified on a DEAE Toyopearl column

- 185 with a KC1 gradient of 25-350 mM. There is no measurable ATPase in any of the components except for myosin which naturally has a very low baseline ATPase in the absence of actin.

Before scanning, actin, tropomyosin, and troponin complex are mixed together at the desired ratio (eg, 7: 1: 1) to achieve maximum calcium regulation in the actin filament. The scan is performed at a concentration that provides

25% activation. This calcium concentration is in the physiological range during muscle contraction.

To measure ADP generation during the reaction, an enzyme system coupled to NADH / lactate dehydrogenase / pyruvate kinase (PK / LDH) is added to actin. Myosin is kept separately and added to the regulated fine filaments to initiate the reaction. NADH oxidation is monitored in real time so that kinetic curves are obtained. Compounds are dissolved in DMSO and spotted on 384-well plate bottoms at final concentration of 10 to 40 pg / ml.

Using procedures similar to those described herein, using commercially available reagents and intermediates (eg, Sigma-Aldrich) or readily synthesized by one skilled in the art, the compounds in Table 2 were synthesized, characterized and

-186 10 rehearsed. AC1.4 values ​​were determined according to the procedure described in Example 20 and the indicated median of AC1.4 values ​​are as follows: A = &lt;1 µΜ; B = 1-10 μΜ; C = 10-20 μΜ; D =&gt; 20 μΜ. Table 2

Compound

- (2 - {[2- (4-fluorophenyl) 2-methylpropyl] amino} pyrimid in-5-yl) benzamide

3- (2 - {[2- (4-fluorophenyl) 2-methylpropyl] aminojpyrimid in-5-yl) benzamide

5- (2- {[2- (4-fluorophenyl) 2-methylpropyl] amino} pyrimid in-5-yl) pyridin-3carbonitrile

5- (2- ([2- (4-fluorophenyl) 2-methylpropyl] amino} pyrimid in-5-yl) pyridin-3carboxamide

<img file="MX2012012189A_D0093.tif" />

<img file="MX2012012189A_D0094.tif" />

<img file="MX2012012189A_D0095.tif" />

<img file="MX2012012189A_D0096.tif" />

- 18710

<td>3- (2-aminopyrimidin-5- il) benzamide</td><td>0 h₂n- '\ = N</td>

<td>[2- (4-fluorophenyl) -2- methylpropyl] -5,6,7,8- tetrahydropyridine [4.3— d] pyrimidin-2-ylamine</td><td></td>

<td>2 - {[2- (4-fluorophenyl) -2- methylpropyl] amino} pyrimid in-5-carboxylate methyl</td><td>or \ F</td>

<td>N- [2- (4-fluorophenyl) -2- methylpropyl] (2 - {[2— (4— fluorophenyl) -2- methylpropyl] aminojpirimid in-5-yl) carboxamide</td><td>'' NH! —N / ¹ xXx 0 '-N</td>

- 188-

<td>1- [(2- {[2- (4- fluorophenyl) -2- methylpropyl] aminojpirimid in-5- il) carbonylamino] cyclopro ethyl panocarboxylate</td><td colspan="2">r w</td><td></td>

<td>acid 2- {[2- (4- fluorophenyl) -2- methylpropyl] amino} pyrimid in-5-carboxylic</td><td>Kk c</td><td colspan="2">F</td>

<td>(5-bromopyrimidin-2- il) [2- (4-fluorophenyl) -2- methylpropyl] amine</td><td>F \ -_N</td><td colspan="2"></td>

<td>acid 1 - [(2 - {[2- (4- fluorophenyl) -2- methylpropyl] amino} pyrimid in-5- il) carbonylamino] cyclopro panocarboxylic</td><td colspan="2">HN Λ-N Xbq</td><td> 5</td>

-18910

1- [(2- {[2- (4fluorophenyl) -2methylpropyl] amino} pyrimid in-5yl) carbonylamino] cyclopro panocarboxamide

5- (2 - ([2- (4-fluorophenyl) 2-methylpropyl] amino [pyrimid in-5-yl) -3hydrobenzoimidazol-2-one

6- acetyl-2- {[2— (4-fluorophenyl) -2methylpropyl] amino} 5, 6,7,8tetrahydropyridino [4,3- d] pyrimidine

2 - {[2- (4-fluorophenyl) -2methylpropyl] amino} -6 (methylsulfonyl) -5,6,7,8tetrahydropyridino [4,3- d] pyrimidine

<img file="MX2012012189A_D0097.tif" />

F

<img file="MX2012012189A_D0098.tif" />

<img file="MX2012012189A_D0099.tif" />

-190 10

<td>[2- (4-fluorophenyl) -2- methylpropyl] (6- methyl (5,6,7,8- tetrahydropyridine [4.3— d] pyrimidin-2-yl)) amine</td><td>-Chy, X</td><td></td>

<td>2- {[2- (4-fluorophenyl) -2- methylpropyl] amino} - 5,6,7,8- tetrahydropyridine [4,3- d] pyrimidin-6-carboxamide</td><td>H₂N '--NH ^</td><td></td>

<td>2- (2 - ([2- (4-fluorophenyl) - 2- methylpropyl] amino} (5,6,7, 8-tetrahydropyridine [4,3— d] pyrimidin-6-yl)) - 2- oxoacetamide</td><td colspan="2"> 0 ^X= N \ -</td>

<td>2 - {[2- (4-fluorophenyl) -2- methylpropyl] amino} - 5, 6,7,8- tetrahydropyridine [3,4- d] pyrimidin-7-carboxamide</td><td>Q;&gt; - ^</td><td></td>

-191 10

<td>2- (2 - ([2- (4-fluorophenyl) - 2- methylpropyl] amino} (5,6,7, 8-tetrahydropyridine [3,4- d] pyrimidin-7-yl)) - 2- oxoacetamide</td><td>HjN 0 λ / i 0 N- &lt;/</td><td></td>

<td>2 - {[2- (4-fluorophenyl) -2- methylpropyl] amino} -7- (methylsulfonyl) -5, 6,7,8- tetrahydropyridine [3,4- d] pyrimidine</td><td colspan="2">V^or i &lt;^ \ A</td>

<td>[5- (3-amino (lH-indazol-5- il)) pyrimidin-2-yl] [2- (4- fluorophenyl) -2- methylpropyl] amine</td><td>NH₂-NH '</td><td>F</td>

<td>4-fluoro-3- (2 - {[(3— fluoro (2- pyridyl)) cyclobutyl] amino ) pyrimidin-5-yl) benzamide</td><td colspan="2">OR H₂Neither</td>

- 192-

<td> 4- (2-{[(4-</td><td>γ</td><td></td><td></td><td></td>

<td>fluorophenyl) cyclobutyl] am</td><td></td><td></td><td>ov</td><td>σ</td>

<td>ino} pyrimidin-5-</td><td></td><td></td><td>or</td><td></td>

<td>il) pyridin-2-carbonitrile</td><td></td><td></td><td></td><td></td>

<td>4-fluoro-3- (2 - {[(4-</td><td>0 H₂NV</td><td></td><td></td><td></td>

<td>fluorophenyl) cyclobutyl] am</td><td>z</td><td>TO</td><td></td><td>to</td>

<td>ino} pyrimidin-5-</td><td></td><td>F</td><td>or</td><td></td>

<td>il) benzamide</td><td></td><td></td><td></td><td></td>

<td>4- (2— {[(3-fluoro-2-</td><td>γ</td><td></td><td></td><td></td>

<td>pyridyl) cyclobutyl] amino}</td><td>and</td><td>and</td><td></td><td>''and</td>

<td>pyrimidin-5-i1) pyridin-2-</td><td></td><td></td><td></td><td>* F</td>

<td>carbonitrile</td><td></td><td></td><td></td><td></td>

<td>4 - (2 - {[(3-fluoro-2-</td><td colspan="2">NH₂ 0=^</td><td></td><td></td>

<td>pyridyl) cyclobutyl] amino}</td><td> /</td><td></td><td>r.-N ___</td><td>Ju</td>

<td>pyrimidin-5-yl) pyridin-2-</td><td></td><td></td><td></td><td>SF</td>

<td>carboxamide</td><td></td><td></td><td></td><td></td>

<td> 4-(2-( [ (4-</td><td>NH,</td><td></td><td></td><td></td>

<td>fluorophenyl) cyclobutyl] am</td><td></td><td>Λ</td><td></td><td>to</td>

<td>ino} pyrimidin-5-</td><td></td><td></td><td>or</td><td></td>

<td>il) pyridin-2-carboxamide</td><td></td><td></td><td></td><td></td>

<td>(5- (lH-indazol-5-</td><td>N ^ \ '/</td><td></td><td>-and ~ and_NM</td><td></td>

<td>il) pyrimidin-2-yl) [(3-</td><td></td><td></td><td>\ == N</td><td></td>

<td>fluoro (2-</td><td></td><td></td><td></td><td>'F</td>

<td>pyridyl)) cyclobutyl] amine</td><td></td><td></td><td></td><td></td>

- 193 10

<td>5- (2 - ([(3-fluoro-2- pyridyl) cyclobutyl] amino} pyrimidin-5-yl) -1H- indazol-3-carbonitrile</td><td>N ^ \ HN—</td><td>N F Λ</td><td>~ y</td><td>z</td><td>—N V », = N \</td><td>SF</td>

<td>5- (2 - {[(3-fluoro-2-</td><td></td><td></td><td>ΝΗ₂</td><td></td><td></td><td></td>

<td>pyridyl) cyclobutyl] amino} pyrimidin-5-yl) -1H- indazol-3-carboxamide</td><td>\ HN-</td><td>Λ</td><td>and.</td><td>z</td><td>-N ) ___⁼⁼⁼ny</td><td>and / F</td>

<td>[5 - (6-fluoro (lH-indazole- 5-yl)) pyrimidin-2-yl] [(3-</td><td>\ HN-</td><td>Λ</td><td>-and</td><td>z</td><td>—N NH —N \</td><td></td>

<td>fluoro (2-</td><td></td><td></td><td>F</td><td></td><td></td><td>F</td>

<td>pyridyl)) cyclobutyl] amine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>6-fluoro-5- (2 - {[(3-</td><td></td><td>Ν //</td><td></td><td></td><td></td><td></td>

<td>fluoro (2- pyridyl)) cyclobutyl] amino</td><td colspan="2">\ / HN --- //</td><td>and.</td><td>z</td><td>-N ) ___ ——Ν</td><td></td>

<td>} pyrimidin-5-yl) -1H-</td><td></td><td></td><td>F</td><td></td><td></td><td>F</td>

<td>indazol-3-carbonitrile</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>6-fluoro-5- (2 - {[(3-</td><td>HjN</td><td>you see*⁰</td><td></td><td></td><td></td><td></td>

<td>fluoro (2- pyridyl)) cyclobutyl] amino</td><td>HN · -</td><td>Ζ</td><td>and_</td><td>Γ</td><td>• N - = n yy</td><td>jü</td>

<td>} pyrimidin-5-yl) -1H-</td><td></td><td></td><td>F</td><td></td><td></td><td>F</td>

<td>indazol-3-carboxamide</td><td></td><td></td><td></td><td></td><td></td><td></td>

- 19410

<td>(5-bromopyrimidin-2- il) [(4- fluorophenyl) cyclobutyl] am ina</td><td></td>

<td>(5-bromopyrimidin-2- il) [(3-fluoro (2- pyridyl)) cyclobutyl] amine</td><td>Br- ('NH \ = /</td>

<td>(6-bromoquinazolin-2- il) [(3-fluoro (2- pyridyl)) cyclobutyl] amine</td><td></td>

<td>2 - {[(3-fluoro-2- pyridyl) cyclobutyl] amino} quinazoline-6- carbonitrile</td><td></td>

<td>[(3-fluoro (2- pyridyl)) cyclobutyl] quinine zolin-2-ylamine</td><td></td>

<td>2 - {[(3-fluoro-2- pyridyl) cyclobutyl] amino} quinazoline-6-carboxamide</td><td></td>

-195 10

<td>2 - {[(3-fluoro-2- pyridyl) cyclobutyl] amino} pyrimidin-5-carbonitrile</td><td>\ = N</td><td>SF</td>

<td>2 - {[(4- fluorophenyl) cyclobutyl] am ino} pyrimidin-5- carbonitrile</td><td> —</td><td>σ '</td>

<td>(5-bromopyrimidin-2- il) [1- (4-fluorophenyl) - isopropyl] amine</td><td></td><td>σ</td>

<td>2 - {[(4- fluorophenyl) cyclobutyl] am</td><td>-Λ¹</td><td>and</td>

<td>ino} pyrimidin-4-</td><td> 0</td><td></td>

<td>carboxamide</td><td></td><td></td>

<td> 2-{[(4-</td><td>V</td><td></td>

<td>fluorophenyl) cyclobutyl] am</td><td></td><td>and</td>

<td>ino} pyrimidin-4-</td><td>OR</td><td></td>

<td>carbonitrile</td><td></td><td></td>

<td> [ (4-</td><td>y., j</td><td>Ύ</td>

<td>fluorophenyl) cyclobutyl] pi</td><td></td><td></td>

<td>razolo [5,4-d] pyrimidin-6-</td><td>you</td><td></td>

<td>ylamine</td><td></td><td></td>

-196 -

<td>2 - ([(4- fluorophenyl) cyclobutyl] am ino} pyrimidin-5- carboxamide</td><td></td><td>σ '</td>

<td>2 - {[(3-fluoro-2-</td><td></td><td>ÁJ</td>

<td>pyridyl) cyclobutyl] amino}</td><td></td><td>'F</td>

<td>pyrimidin-5-carboxamide</td><td></td><td></td>

<td> 2-{[(4-</td><td></td><td></td>

<td>fluorophenyl) cyclobutyl] am</td><td></td><td>σ '</td>

<td>ino} -4-</td><td>χ o</td><td></td>

<td>(trifluoromethi1) pyrimidin</td><td></td><td></td>

<td>-5-carboxamide</td><td></td><td></td>

<td>acid 2 - {[(4-</td><td></td><td></td>

<td>fluorophenyl) cyclobutyl] am</td><td></td><td>σ</td>

<td>ino} -4-</td><td>'tC o</td><td></td>

<td>(trifluoromethyl) pyrimidin</td><td></td><td></td>

<td>-5-carboxylic</td><td></td><td></td>

<td>[ (4- fluorophenyl) cyclobutyl] [4 (trifluoromethyl) pyrimidin -2-yl] amine</td><td>- - F</td><td>σ '</td>

-197 10

<td>Ν— [(4 - fluorophenyl) cyclobutyl] (2 -{ [ (4-</td><td></td><td></td><td>and</td>

<td>fluorophenyl) cyclobutyl] am</td><td>ζ</td><td></td><td></td>

<td>ino} -4-</td><td>one F</td><td> 1</td><td></td>

<td>(trifluoromethyl) pyrimidin</td><td></td><td></td><td></td>

<td>-5-yl) carboxamide</td><td></td><td></td><td></td>

<td>2 - {[(3-fluoro (2- pyridyl)) cyclobutyl] amino</td><td></td><td>H₂N zN</td><td>V</td>

<td> }-4-</td><td></td><td>yr o F</td><td>F</td>

<td>(trifluoromethyl) pyrimidin</td><td></td><td></td><td></td>

<td>-5-carboxamide</td><td></td><td></td><td></td>

<td>2 - ([(3-fluoro (2- pyridyl)) cyclobutyl] amino</td><td></td><td>HO /. N my</td><td></td>

<td> }-4-</td><td></td><td>X or F</td><td>F</td>

<td>(trifluoromethyl) pyrimidin</td><td></td><td></td><td></td>

<td>-5-carboxylic</td><td></td><td></td><td></td>

<td>[(3-fluoro (2-</td><td></td><td></td><td></td>

<td>pyridyl)) cyclobutyl] [4-</td><td></td><td>and? or</td><td>F</td>

<td>(trifluoromethyl) pyrimidin</td><td></td><td>F</td><td></td>

<td>-2-yl] amine</td><td></td><td></td><td></td>

- 1981- ethyl [2- ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyrimidin-5yl] pyrazol-4-carboxylate

1- [2- ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyrimidin-5yl] pyrazol-4-carboxamide acid 1— [2 - ({[(3 — fluoro—

2pyridyl) cyclobutyl] methyl} amino) pyrimidin-5yl] pyrazol-4-carboxylic

2- [2 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] 1.3-thiazol-4-carboxamide

2- [2- ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] 1.3-thiazol-5-carboxamide

<img file="MX2012012189A_D0100.tif" />

<img file="MX2012012189A_D0101.tif" />

<img file="MX2012012189A_D0102.tif" />

<img file="MX2012012189A_D0103.tif" />

<img file="MX2012012189A_D0104.tif" />

-19910

2- [2- ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] 1.3-ethyl thiazol-4-carboxylate 2- [2 - ({[(3-fluoro2pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] 1.3-thiazol-4-carboxylic

2— [2 - {{1— [6— (difluoromethoxy) (2pyridyl)] isopropyl} amino) pyrimidine

-5-yl] -1,3-thiazol-5carboxamide

2- (2- {[(2pyridylcyclobutyl) methyl] a mino} pyrimidin-5-yl) -1,3 thiazol-5-carboxamide

2— (2— {[(2pyridylcyclobutyl) methyl] a mino} pyrimidin-5-yl) -1,3thiazol-5-carbonitrile

<img file="MX2012012189A_D0105.tif" />

<img file="MX2012012189A_D0106.tif" />

<img file="MX2012012189A_D0107.tif" />

<img file="MX2012012189A_D0108.tif" />

<img file="MX2012012189A_D0109.tif" />

-20010

2- [2— ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] 1,3-thiazol-5-carbonitrile

2- (2 - {[l- (4methoxypyrimidin-2-yl) isopropyl] amino [pyrimidin -5-yl) -1,3-thiazol-5carboxamide {4- [6 - {{[(3-fluoro (2pyridyl) ) cyclobutyl] methyl} amino) pyridazin-3yl] pyrimidin-2yl} (methylsulfonyl) amine

Ethyl ethyl 2 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) thiophene [2,3d] pyrimidin-6-carboxylate

2 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) thiophene [2,3d] pyrimidin-6-carboxamide

<img file="MX2012012189A_D0110.tif" />

<img file="MX2012012189A_D0111.tif" />

<img file="MX2012012189A_D0112.tif" />

<img file="MX2012012189A_D0113.tif" />

<img file="MX2012012189A_D0114.tif" />

-201 10 2 - ({[(3-Fluoro-2-pyridyl) cyclobutyl] methyl} amino) thiophene [2,3d] pyrimidin-6-carboxylic acid

4-fluoro-3- (2- {[2— (3-fluoro (2-pyridyl)) - 2-methylpropyl] amino} pyrimid in-5-yl) benzamide

4-fluoro-3- [2 - ({[(3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] benzamide

3- (2- ([2- (3-fluoro (2pyridyl)) - 2methylpropyl] aminojpirimid in-5-yl) benzamide

3- [2 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyrimidin-5yl] benzamide

<img file="MX2012012189A_D0115.tif" />

<img file="MX2012012189A_D0116.tif" />

<img file="MX2012012189A_D0117.tif" />

<img file="MX2012012189A_D0118.tif" />

<img file="MX2012012189A_D0119.tif" />

-202-

<img file="MX2012012189A_D0120.tif" />

-203 5 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) -1,3-thiazolo [5.4d] pyrimidin-2-carboxylic acid

4-fluoro-3- (2 - {[1— (3— fluoro (2-pyridyl)) isopropyl] aminoJpirimidin -5-yl) benzamide

N - {[4- (2 - {[1- (3-fluoro (2pyridyl)) isopropyl] amino} pyrimidine

-5yl) phenyl] methyl} acetamide [5- (2-aminopyrimidin-5yl) pyrimidin-2-yl] [l- (3fluoro (2-pyridyl)) isopropyl] amine

2- (2 - {[1- (3-fluoro (2pyridyl)) isopropyl] amino} pyrimidine

-5-yl) -l, 3-thiazol-5carboxamide

<img file="MX2012012189A_D0121.tif" />

<img file="MX2012012189A_D0122.tif" />

<img file="MX2012012189A_D0123.tif" />

<img file="MX2012012189A_D0124.tif" />

<img file="MX2012012189A_D0125.tif" />

-204-

<td rowspan="2">2- (2 - ([2- (3-fluoro (2-</td><td></td><td></td><td></td><td></td><td>r</td><td></td><td></td>

<td></td><td></td><td></td><td>P ^</td><td>and</td><td></td><td>N</td>

<td>pyridyl)) - 2-</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>methylpropyl] amino [pyrimid</td><td></td><td colspan="3">2-N \ = N</td><td></td><td></td><td></td>

<td>in-5-yl) pyrimidin-4-</td><td>H, N-</td><td></td><td>Ό</td><td></td><td></td><td></td><td></td>

<td>carboxamide</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>2- [4-fluoro-3- (2 - {[1- (3-</td><td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td rowspan="2">fluoro (2-pyridyl)) -</td><td>or;</td><td rowspan="2"> /</td><td></td><td>r.-N -</td><td>N</td><td></td><td></td>

<td> \</td><td colspan="2">V- / w</td><td>Λ</td><td></td><td></td>

<td>isopropyl] amino [pyrimidin</td><td></td><td></td><td></td><td> '^C= N</td><td>F</td><td></td><td></td>

<td>-5-yl) phenyl] acetate</td><td></td><td></td><td>F</td><td></td><td></td><td></td><td></td>

<td>methyl</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>N- {[3- (2- ([1- (3-fluoro (2-</td><td colspan="2">HN-</td><td></td><td></td><td></td><td>Ί =</td><td></td>

<td>pyridyl)) - isopropyl</td><td> 0=/</td><td></td><td></td><td>Λ- \ ^ 7 ~</td><td colspan="2">Λ</td><td> )</td>

<td>] amino [pyrimidin-5-</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>yl) phenyl] methyl} acetamide</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>3- (2- ([1- (3-chlorine (2-</td><td></td><td>n</td><td></td><td></td><td></td><td></td><td></td>

<td>pyridyl)) -</td><td>h₂n-</td><td></td><td></td><td></td><td>N</td><td> =</td><td></td>

<td>isopropyl] amino [pyrimidin</td><td></td><td>and</td><td colspan="2"></td><td></td><td></td><td> )</td>

<td>-5-yl) benzamide</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>3- (2 - {[1- (3-chloro (2-</td><td>h₂n-</td><td> 0</td><td></td><td></td><td>N</td><td> =</td><td></td>

<td>pyridyl)) -</td><td></td><td> /</td><td colspan="2">-λ Γ, -N ** 7-</td><td colspan="2">Λ</td><td> )</td>

<td>isopropyl] amino [pyrimidin</td><td></td><td></td><td>F</td><td></td><td></td><td></td><td></td>

<td>-5-yl) -4-fluorobenzamide</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

-205-

<td rowspan="2">1- (2 - ([1- (3-chlorine (2- pyridyl)) - isopropyl] amino¡pirimidin -5-yl) pyrazole-4- carbonitrile</td><td rowspan="2"></td><td rowspan="2">f, -N 4— \ ^ = N</td><td colspan="2">N = \</td>

<td>and Cl</td><td>J</td>

<td>1- (2 - ([1- (3-chlorine (2-</td><td></td><td></td><td>N =</td><td></td>

<td>pyridyl)) - isopropyl] amino¡pirimidin</td><td colspan="2"></td><td>Λ Cl</td><td>J</td>

<td>-5-yl) pyrazole-4-</td><td colspan="2"></td><td></td><td></td>

<td>carboxamide</td><td></td><td></td><td></td><td></td>

<td>2- [4-fluoro-3- (2 - {[1- (3-</td><td> 0</td><td></td><td>N =</td><td></td>

<td>fluoro (2-pyridyl)) -</td><td>HjN</td><td>&gt; .- Λ Λ-^Nand</td><td>TO.</td><td>J</td>

<td>isopropyl] amino¡pirimidin</td><td></td><td>'-—— S' -N F</td><td>F</td><td></td>

<td>-5-yl) phenyl] acetamide</td><td></td><td></td><td></td><td></td>

<td>2- (2— {[1- (3-fluoro (2-</td><td></td><td>and</td><td></td><td></td>

<td>pyridyl)) - isopropyl] amino¡pirimidin -5-yl) pyrimidin-4- carboxamide</td><td>h₂n-</td><td>\ ^ = s_N \==:_N</td><td>N = TO F</td><td>J</td>

<td>{5- [5- (aminomethyl) (1,3-</td><td></td><td></td><td>N =</td><td></td>

<td>thiazol-2-yl)] pyrimidin-2-</td><td>h₂n * ^</td><td>\ Λ-N 4- Ύ / -Υ Y-</td><td>TO</td><td>J</td>

<td>il} [1- (3-fluoro (2-</td><td></td><td>N \ = N</td><td>F</td><td></td>

<td>pyridyl)) - isopropyl] amine</td><td></td><td></td><td></td><td></td>

-206-

<td>Ν - {[2 - (2 - {[1- (3-fluoro (2- pyridyl)) - isopropyl] amino Jpirimidin -5-yl) -1,3-thiazol-5- il] methyl} acetamide</td><td></td>

<td>2-amino-N - {[2- (2 - ([1- (3- fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin -5-yl) (1,3-thiazol-5- il)] methyl} acetamide</td><td>ro &lt;: 'ρΦ CT η NF NHj</td>

<td>N - {[2- (2 - {[1- (3-fluoro (2- pyridyl)) - isopropyl] aminoJpirimidin -5-yl) (1,3-thiazol-5- il)] methyl} imidazol-5- ilcarboxamide</td><td>r</td>

<td>N - {[2- (2- ([1- (3-fluoro (2- pyridyl)) - isopropyl] aminoIpirimidin -5-yl) (1,3-thiazol-5- il)] methyl} (2- hydroxyimidazole-5- il) carboxamide</td><td>r</td>

-207-

<td>(aminocyclopropyl) -Ν - {[2- (2 - ([1- (3-fluoro (2- pyridyl)) - isopropyl] aminoJpirimidin -5-yl) (1,3-thiazol-5- il)] methyl} carboxamide</td><td></td>

<td>((2R) pyrrolidin-2-yl) -N- {[2- (2 - {[1- (3-fluoro (2- pyridyl)) - isopropyl] amino [pyrimidin -5-yl) (1,3-thiazol-5- il)] methyl} carboxamide</td><td></td>

<td>((2S) pyrrolidin-2-yl) -N- {[2- (2 - ([1- (3-fluoro (2- pyridyl)) - isopropyl] amino [pyrimidin -5-yl) (1,3-thiazol-5- il)] methyl} carboxamide</td><td></td>

<td>N - {[2- (2 - {[1- (3-fluoro (2- pyridyl)) - isopropyl] amino [pyrimidin -5-yl) -1,3-thiazol-4- il] methyl} acetamide</td><td>xoAP '^ 0 N \ = M p</td>

-20810

<td>2- [2- (2 - {[1- (3-fluoro (2- pyridyl)) - isopropyl] aminoJpirimidin -5-yl) -1,3-thiazol-4- il] acetamide</td><td></td>

<td>1- (2 - {[1- (3-chloro (2- pyridyl)) - isopropyl] amino [pyrimidin -5-yl) pirro1-3- carboxamide</td><td>OR \ ==_NC|</td>

<td>1- (2— {[1- (3-fluoro (2- pyridyl)) - isopropyl] aminoJpirimidin -5-yl) pyrazole-4- carboxamide</td><td>0 \ = n τ</td>

<td>(5- [4- (aminomethyl) (1,3— thiazol-2-yl)] pyrimidin-2- 11} [1- (3-fluoro (2- pyridyl)) - isopropyl] amine</td><td>frCrX nh₂</td>

<td>2- (2 - {[1- (3-fluoro (2- pyridyl)) - isopropyl] aminoJpirimidin -5-yl) -1,3-thiazol-4- carbonitrile</td><td>./ N \ = NF</td>

-209-

<td>2- (2- ([1- (3-fluoro (2-</td><td></td><td>N = \</td>

<td>pyridyl)) - isopropyl] amino (pyrimidin</td><td></td><td>F</td>

<td>-5-yl) -1,3-thiazol-4- carboxamide</td><td></td><td></td>

<td>2-amino-N - {[2- (2 - {[1- (3-</td><td></td><td>N-1</td>

<td>fluoro (2-pyridyl)) -</td><td>w</td><td>r</td>

<td>isopropyl] amino (pyrimidin</td><td></td><td></td>

<td>-5-yl) (1,3-thiazol-4- il)] methyl} acetamide</td><td>OR</td><td></td>

<td>((2S) pyrrolidin-2-yl) -N-</td><td>_N -4-</td><td></td>

<td>{[2- (2 - ([1- (3-fluoro (2-</td><td>MP^-</td><td>P F</td>

<td>pyridyl)) -</td><td>f xs</td><td></td>

<td>isopropyl] amino (pyrimidin -5-yl) (1,3-thiazol-4- il)] methyl} carboxamide</td><td>b</td><td></td>

<td>((2R) pyrrolidin-2-yl) -N-</td><td></td><td>N-&gt;</td>

<td>([2- (2- ([1- (3-fluoro (2-</td><td></td><td>F</td>

<td>pyridyl)) -</td><td> \</td><td></td>

<td>isopropyl] amino (pyrimidin -5-yl) (1,3-thiazol-4- il)] methyl} carboxamide</td><td></td><td></td>

-210-

<td>2- (2 - ([1- (3-fluoro (2- pyridyl)) - isopropyl] aminoJpirimidin -5-yl) -1,3-thiazol-5- carbonitrile</td><td></td>

<td>2— (2 - {[1- (3-chloro (2- pyridyl)) - isopropyl] aminoJpirimidin -5-yl) -l, 3-thiazol-5- carboxamide</td><td>0 ΛχρΚ? \ = N Cl</td>

<td>acid 1- (2 - ([1- (3- chlorine (2-pyridyl)) - isopropyl] aminoJpirimidin -5-yl) pyrazole-4- carboxylic</td><td>0 \ = N Cl</td>

<td>N- (2-carbamoylethyl) [1— (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] aminoJpirimidin -5-yl) pyrazole-4- il] carboxamide</td><td>0 η m \ =_{N c}, ' o ^ nh₂</td>

<td>[1- (2- {[1- (3-chloro (2- pyridyl)) - isopropyl] amino (pyrimidin -5-yl) pyrazol-4-yl] -N- (2- hydroxyethyl) carboxamide</td><td>0 &gt; N \ =_NCl Oh</td>

-211 -

<td>2- [1- (2- {[1- (3-chlorine (2- pyridyl)) - isopropyl] amino Jpirimidin -5-yl) pyrazole-4- il] propan-2-ol</td><td>Oh N</td><td>\ = N</td><td>N = "TO Cl ·</td><td> /</td>

<td>5- (2 - {[1- (3-chloro (2-</td><td></td><td></td><td>N =</td><td></td>

<td>pyridyl)) -</td><td>__0 N \_ORJU</td><td></td><td>and.</td><td> )</td>

<td>isopropyl] amino} pyrimidin</td><td></td><td></td><td></td><td></td>

<td>-5-yl) isoxazol-3-</td><td></td><td></td><td></td><td></td>

<td>carboxamide</td><td></td><td></td><td></td><td></td>

<td>[1- (3-chloro (2-pyridyl)) -</td><td>ι V-</td><td>ZN -</td><td>^N= \ yy</td><td></td>

<td>isopropyl] (5-pyrazole-4-</td><td></td><td>\ = N</td><td>Cl</td><td></td>

<td>ilpyrimidin-2-yl) amine</td><td></td><td></td><td></td><td></td>

<td>5- (2- ([1- (3-chlorine (2-</td><td> 0</td><td></td><td></td><td></td>

<td>pyridyl)) -</td><td>h₂n-</td><td></td><td>N =</td><td></td>

<td>isopropyl] amino} pyrimidin</td><td>or</td><td> \=_N</td><td>and_ Cl ·</td><td> )</td>

<td>-5-yl) pyridin-3-</td><td></td><td></td><td></td><td></td>

<td>carboxamide</td><td></td><td></td><td></td><td></td>

<td>5- (2- ([1— (3 -</td><td></td><td></td><td></td><td></td>

<td>chlorine (2-pyridyl)) - isopropyl] aminoJpirimidin -5-yl) thiophene-2- carboxylic</td><td>X)</td><td>n — n * 5 \ ==_N</td><td>N = and_ Cl</td><td> )</td>

-21210

<td>5- (2 - {[1- (3-chloro (2- pyridyl)) - isopropyl] amino} pyrimidin -5-yl) thiophene-2- carboxamide</td><td>0 \ = N Cl</td>

<td>(5-bromopyrimidin-2- il) [1- (3-fluoro (2- pyridyl)) - isopropyl] amine</td><td>F</td>

<td>2 - {[1- (3-chloro (2- pyridyl)) - isopropyl ·] aminojpirimidin -5-carbonitrile</td><td>x = N Cl</td>

<td>(5-bromopyrimidin-2- il) [1- (3-chloro (2- pyridyl)) - isopropyl] amine</td><td>Cl</td>

<td>2- (2- ([1- (3-chlorine (2- pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,3-oxazol-4-carboxamide</td><td>NHj</td>

<td>acid 2— (2— {[1— &lt;3 - chlorine (2-pyridyl)) - isopropyl] amino (pyrimidin -5-yl) -1,3-oxazol-4- carboxylic</td><td>Oh</td>

-21310

<td>4- [2 - ({[3-fluoro-l- (3- fluoro (2- pyridyl)) cyclobutyl] methyl lamino) pyrimidin-5- il] pyridin-2-carboxamide</td><td colspan="2"> /^NH¡</td>

<td rowspan="2">4- [2 - ({[3-fluoro-l- (3- fluoro (2- pyridyl)) cyclobutyl] methyl lamino) pyrimidin-5- il] pyridin-2-carboxamide</td><td colspan="2">l ^ l</td>

<td>/ and/ \ = / \ = N</td><td></td>

<td rowspan="2">4- [2- ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) pyrimidin-5- il] pyridin-2-carboxamide</td><td>and</td><td></td>

<td></td><td></td>

<td>[1- (3-chloro (2-pyridyl)) - isopropyl] (5-pyrrolo [3,2- b] pyridin-6-ylpyrimidin- 2-yl) amine</td><td colspan="2">\ / —V —C l¡ \ * \ = N Cl H</td>

<td>2- (2— {[1- (3-chlorine (2- pyridyl)) - isopropyl] amino} pyrimidin -5-yl) -1,3-oxazol-5- carboxamide</td><td colspan="2">i „I / = \ Cl</td>

-21410

<td>4- (2— {[1- (3-chlorine (2- pyridyl)) - isopropyl] amino [pyrimidin -5-yl) pyridin-2- carboxamide</td><td>H₂N-</td><td> 0 /</td><td></td><td>IN = to-^N 7 (\ .Γ And ¿\ - n cr</td><td> )</td>

<td>4- (2 - {[1- (3-chloro (2-</td><td></td><td></td><td></td><td>IN =</td><td></td>

<td>pyridyl)) -</td><td></td><td>s I</td><td>TO</td><td></td><td> )</td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td>isopropyl] amino [pyrimidin</td><td></td><td>F</td><td></td><td></td><td></td>

<td>-5-yl) -1,3-thiazol-2-</td><td></td><td></td><td></td><td></td><td></td>

<td>carboxamide</td><td></td><td></td><td></td><td></td><td></td>

<td>2 - {[1- (3-chloro (2-</td><td></td><td></td><td></td><td> 1 ^N=^=\</td><td></td>

<td>pyridyl)) -</td><td></td><td>&gt; H₂N</td><td colspan="2">\ = N Cl</td><td></td>

<td>isopropyl] amino [pyrimidin</td><td></td><td></td><td></td><td></td><td></td>

<td>-5-carboxamide</td><td></td><td></td><td></td><td></td><td></td>

<td>[5- (3-amino (lH-indazol-5-</td><td></td><td>N—</td><td></td><td> 1 ^{N =}r, —Ί / 4</td><td></td>

<td></td><td>HN-</td><td> /</td><td>TO</td><td>γ \ -í \ -</td><td>J</td>

<td>il)) pyrimidin-2-yl] [1— (3—</td><td> 1</td><td></td><td></td><td>\ / / '-N Cl</td><td></td>

<td>chlorine (2-pyridyl)) -</td><td></td><td>nh₂</td><td></td><td></td><td></td>

<td>isopropyl] amine</td><td></td><td></td><td></td><td></td><td></td>

<td>3- (2 - {[1-methyl-l- (4-</td><td></td><td></td><td></td><td></td><td></td>

<td>methylthiophenyl) ethyl] amino}</td><td> /</td><td>"Λ</td><td>i</td><td>yA-0-</td><td> -\</td>

<td>pyrimidin-5-</td><td></td><td></td><td></td><td>/ —N</td><td></td>

<td>il) benzenecarbonitrile</td><td></td><td></td><td></td><td></td><td></td>

-215-

<td>3- (2 - {[1-methyl-l- (2-</td><td>V</td><td></td><td></td><td>1 p = \</td>

<td>methylthiophenyl) ethyl] amino}</td><td></td><td>Λ</td><td>pp</td><td></td>

<td>pyrimidin-5-</td><td></td><td></td><td></td><td> \</td>

<td>il) benzenecarbonitrile</td><td></td><td></td><td></td><td></td>

<td>5- (2 - {[1- (3-chloro (2- pyridyl)) - isopropyl]</td><td>N I</td><td>H and-</td><td>pp \ = N</td><td>me Cl</td>

<td>amino} pyrimidin-5-</td><td>NHj</td><td></td><td></td><td></td>

<td>il) pyrazole-3-carboxamide</td><td></td><td></td><td></td><td></td>

<td> 3-(2-(2-(4-</td><td> 0</td><td></td><td></td><td></td>

<td>(methylsulfinyl) phenyl) prop</td><td>HjN- / Γ</td><td>and_</td><td colspan="2"></td>

<td>an-2-ylamino) pyrimidin-5-</td><td></td><td></td><td> \-_N</td><td></td>

<td>il) benzamide</td><td></td><td></td><td></td><td></td>

<td>3- [2 - ({1-methyl-l- [4-</td><td> 0</td><td></td><td></td><td></td>

<td>(methylsulfonyl) phenyl] ethyl</td><td>HjN- \</td><td></td><td colspan="2">pPCH-</td>

<td>} amino) pyrimidin-5-</td><td></td><td></td><td>'^ = N</td><td></td>

<td>il] benzamide</td><td></td><td></td><td></td><td></td>

<td>3- [2 - ({1-methyl-l- [2-</td><td>0 H; N 7 /</td><td></td><td></td><td> 1</td>

<td>(methylsulfonyl) phenyl] ethyl</td><td> /</td><td></td><td>ñ-^N ' pp</td><td>r \ J ° ^ ¿</td>

<td>} amino) pyrimidin-5-</td><td></td><td></td><td></td><td> /^°</td>

<td>il] benzamide</td><td></td><td></td><td></td><td></td>

<td>3- [2 - ({1-methyl-l- [3-</td><td>0 H₂NY</td><td></td><td></td><td>1 N = \</td>

<td>(methylsulfonyl) (2-</td><td></td><td>Λ</td><td>n — n &lt;p</td><td></td>

<td>pyridyl)] ethyl} amino) pyrim</td><td></td><td></td><td></td><td> /*°</td>

<td>idin-5-yl] benzamide</td><td></td><td></td><td></td><td></td>

-21610

<td>2- (2 - {[1- (3-chloro (2- pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,3-thiazol-4-carboxamide</td><td>NHj</td>

<td>acid 2— (2 - {[1— (3— chlorine (2-pyridyl)) - isopropyl] amino¡pirimidin -5-yl) -1,3-thiazol-4- carboxylic</td><td>Oh</td>

<td>acid 2— (2 - {[1— (3— chlorine (2-pyridyl)) - isopropyl] amino¡pirimidin -5-yl) -1,3-oxazol-5- carboxylic</td><td>0 N Cl</td>

<td>3- (2— {[1-methyl-l- (3- methylthio (2- pyridyl)) ethyl] aminojpirim idin-5- il) benzenecarbonitrile</td><td>N. (νγ-γίΖΟ</td>

<td>3- (2 - {[1-methyl-l- (2- methylthiophenyl) ethyl] amino} pyrimidin-5-yl) benzamide</td><td>Zxvop</td>

-217-

<td>3- (2- (2- (2- (methylsulfinyl) phenyl) prop an-2-ylamino) pyrimidin-5- il) benzamide</td><td> — —_N _₈ς 0</td>

<td>[1- (3-chloro (2-pyridyl)) - isopropyl] pyrimidin-2- ylamine</td><td>ryZHD \ == n cr</td>

<td>3- (2 - ([1-methyl-l- (3- methylthio (2- pyridyl)) ethyl] aminojpirim idin-5-yl) benzamide</td><td>0 H_SN-ΰ I KI-- Xy-yyr-O \ = / \ =. _x</td>

<td>3- (2- (2- (3- (methylsulfinyl) pyridin-2- il) propane-2- ylamino) pyrimidin-5- il) benzamide</td><td>0 H₂N- / IN = \ (ΧίΦ \ -f λ-n -s *</td>

<td>3- [2 - ({1-methyl-l- [3- (methylsulfonyl) (2- pyridyl)] ethyl] (hydroxyami no)) pyrimidin-5- il] benzamide</td><td> 0 ^— ~^N °^H</td>

-21810

<td>3- [2 - ({1- [3- (difluoromethyl) (2- pyridyl)] - isopropyl}</td><td>^N% 1</td><td>ν- TO</td><td> )</td>

<td>amino) pyrimidin-5-yl] -4-</td><td>F</td><td>F</td><td></td>

<td>fluorobenzenecarbonitrile</td><td></td><td></td><td></td>

<td> 3- [2-&lt;{1-[3-</td><td> 0</td><td></td><td></td>

<td>(difluoromethyl) (2- pyridyl)] -</td><td>HjN ¹ I \ -Λ zN 4-</td><td></td><td> )</td>

<td>isopropyl} amino) pyrimidin</td><td>F</td><td>F</td><td></td>

<td>-5-yl] -4-fluorobenzamide</td><td></td><td></td><td></td>

<td>(5- (5H-1,2,3,4-tetraazole- 5-yl) pyrimidin-2-yl) [1- (3-chloro (2-pyridyl)) - isopropyl] amine</td><td>N '= NC</td><td>NV OR</td><td></td>

<td>5- (2 - {[1- (3-chloro (2- pyridyl)) - isopropyl] aminoJpirimidin -5-yl) -1,3,4-oxadiazol-2- ethyl carboxylate</td><td>pX./</td><td>N = Cl</td><td> )</td>

<td>5- (2 - {[1- (3-chloro (2-</td><td></td><td>N =</td><td></td>

<td>pyridyl)) - isopropyl] amino} pyrimidin -5-yl) -1,3,4-oxadiazol-2- carboxamide</td><td>μκ / nh₂</td><td>and Cl</td><td> )</td>

-219-

<td>4- (2 - {[1- (3-chloro (2- pyridyl)) - isopropyl] amino} pyrimidin-5- il) thiophene-2-carboxylate methyl</td><td></td>

<td>5- (2 - {[1- (3-chloro (2- pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,3-thiazol-2-carboxamide</td><td>nh₂</td>

<td>5- (2- ([1- (3-chlorine (2- pyridyl)) - isopropyl] aminoJpirimidin -5-yl) -1,3,4-thiadiazol-2- carboxamide</td><td>../ΧΐΦ nh₂</td>

<td>4- (2 - {[1- (3-chloro (2- pyridyl)) - isopropyl] aminoJpirimidin -5-yl) -l-methylimidazol-2- methyl carboxylate</td><td>ψχρφ</td>

<td>6- (2— {[1- (3-chlorine (2- pyridyl)) - isopropyl] amino Jpirimidin -5-yl) pyridin-2- carboxamide</td><td>or H₂NV I N-, \ N z N ¿/) Γ y-Γ yJiyJ &gt; '\ = n cr</td>

-22010

<td rowspan="2">3- (2 - ([1- (3-chlorine (2- pyridyl)) - isopropyl] aminoJpirimidin -5-yl) -l, 2,4-oxadiazol-5- carboxamide</td><td rowspan="2">Η, Ν '' '</td><td rowspan="2">0 ίχρ \ = N</td><td colspan="2">N ^ = \</td>

<td>Cl</td><td></td>

<td>5- (2 - ([1- (3-chlorine (2-</td><td></td><td> 0</td><td></td><td></td>

<td>pyridyl)) -</td><td></td><td></td><td>N =</td><td></td>

<td>isopropyl] amino Jpirimidin</td><td></td><td>^ 0 ν N</td><td>Cl</td><td> )</td>

<td>-5-yl) -1,2,4-oxadiazol-3-</td><td></td><td></td><td></td><td></td>

<td>ethyl carboxylate</td><td></td><td></td><td></td><td></td>

<td>[5- (3-amino (lH-indazol-5-</td><td>HN-</td><td></td><td></td><td>and</td>

<td>il)) pyrimidin-2-yl] [1- (3-</td><td> /</td><td> \ / \ / )-' ^{X =}N</td><td>F</td><td></td>

<td>fluoro (2-pyridyl)) -</td><td></td><td>nh₂</td><td></td><td></td>

<td>isopropyl] amine</td><td></td><td></td><td></td><td></td>

<td>4- (2 - {[1- (3-chloro (2-</td><td></td><td></td><td>N =</td><td></td>

<td>pyridyl)) -</td><td> 0^.</td><td></td><td></td><td> )</td>

<td>isopropyl] aminoJpirimidin</td><td></td><td></td><td></td><td></td>

<td>-5-yl) thiophene-2-</td><td></td><td></td><td></td><td></td>

<td>carboxamide</td><td></td><td></td><td></td><td></td>

<td>[1- (3-chloro (2-pyridyl)) -</td><td></td><td></td><td></td><td></td>

<td>isopropyl] (5- (1,2,4-</td><td></td><td>CXk ^</td><td>Á_J</td><td></td>

<td>oxadiazol-5-yl) pyrimidine-</td><td></td><td></td><td></td><td></td>

<td>2-yl) amine</td><td></td><td></td><td></td><td></td>

-221 10

<td rowspan="2">4-fluoro-3- (2 - ([1- (3- methoxy (2-pyridyl)) - isopropyl] amino} pyrimidin -5-yl) benzenecarbonitrile</td><td colspan="2"> \ 1</td><td rowspan="2">N = "I 0 \</td><td rowspan="2"> )</td>

<td>Za F</td><td>zx \ =_N</td>

<td>4-fluoro-3- (2 - {[1-methyl-</td><td>0 H, N- &lt;1</td><td>I</td><td>N =</td><td> =\</td>

<td>1- (3-methyl (2-</td><td></td><td></td><td> 5</td><td>J</td>

<td>pyridyl)) ethyl] aminojpirim</td><td>F</td><td></td><td></td><td></td>

<td>idin-5-yl) benzamide</td><td></td><td></td><td></td><td></td>

<td>4-fluoro-3- (2- {[1— (3 -</td><td>0 H, N- /</td><td></td><td>N =</td><td></td>

<td>methoxy (2-pyridyl)) -</td><td></td><td></td><td>"Λ</td><td> _)</td>

<td>isopropyl] amino} pyrimidin</td><td>F</td><td></td><td> \</td><td></td>

<td>-5-yl) benzamide</td><td></td><td></td><td></td><td></td>

<td>{5- [5- (aminomethyl) (1,3— thiazol-2-yl)] pyrimidin-2-</td><td colspan="2">NH, ^ N \ =_N</td><td>N = Cl</td><td> )</td>

<td>il} [1- (3-chloro (2-</td><td></td><td></td><td></td><td></td>

<td>pyridyl)) - isopropyl] amine</td><td></td><td></td><td></td><td></td>

<td>N - {[2- (2— {[1- (3-chloro (2- pyridyl)) -</td><td> /</td><td></td><td>N =</td><td></td>

<td>isopropyl] aminoJpirimidin -5-yl) -l, 3-thiazol-5-</td><td colspan="2">W</td><td>Λ Cl</td><td> )</td>

<td>il] methyl} acetamide</td><td></td><td></td><td></td><td></td>

-222Ν - {[2- (2- ([1- (3-chloro (2pyridyl)) isopropyl] amino [pyrimidin -5-yl) (1,3-thiazol-5yl)] methyl} -2-hydroxy-2methylpropanamide N - {[2- (2 - ([1- (3-chloro (2pyridyl)) isopropyl] amino [pyrimidin -5-yl) (1,3-thiazol-5yl)] methyl} (2hydroxyimidazol-4yl) carboxamide

3- (2 - ([1- (3-chloro-6-hydroxy (2-pyridyl)) isopropyl] amino [pyrimidin -5-yl) benzamide

3- (2— {[1- (3-chloro-6methoxy (2-pyridyl)) isopropyl] amino} pyrimidine

-5-yl) benzamide [1- (3-chloro (2-pyridyl)) isopropyl] (5- (1,3-thiazol2-yl) pyrimidin-2-yl) amine

<img file="MX2012012189A_D0126.tif" />

<img file="MX2012012189A_D0127.tif" />

<img file="MX2012012189A_D0128.tif" />

<img file="MX2012012189A_D0129.tif" />

-22310

<td>2- [4- (2 - {[1- (3-chloro (2- pyridyl)) -</td><td></td><td>Γ</td><td>-N 4— 2-NH = N</td><td>N = b Cl</td><td> )</td>

<td>isopropyl] aminoipyrimidin</td><td>'"' '' OH</td><td></td><td></td><td></td><td></td>

<td>-5-yl) pyrazolyl] ethan-l-ol</td><td></td><td></td><td></td><td></td><td></td>

<td>acid 2- [4- (2- {[1- (3-</td><td>i</td><td>F</td><td>—N two-^NH</td><td>N = "B</td><td>J</td>

<td>chlorine (2-pyridyl)) -</td><td></td><td></td><td>= N</td><td>Cl</td><td></td>

<td>isopropyl] aminoIpirimidin</td><td>V</td><td></td><td></td><td></td><td></td>

<td>-5-yl) pyrazolyl] acetic</td><td></td><td></td><td></td><td></td><td></td>

<td>2- [4- (2 - {[1- (3-chloro (2-</td><td>i X-</td><td>Γ</td><td>N / - -NH</td><td>N = Λ</td><td> )</td>

<td>pyridyl)) -</td><td>c</td><td></td><td>N</td><td>Cl</td><td></td>

<td>isopropyl] aminoIpirimidin</td><td>or^z</td><td></td><td></td><td></td><td></td>

<td>-5-yl) pyrazolyl] acetamide</td><td></td><td></td><td></td><td></td><td></td>

<td>2- (2 - {[1- (3-chloro (2-</td><td></td><td></td><td></td><td>N =</td><td></td>

<td>pyridyl)) -</td><td></td><td>r</td><td>- N 7- 7-NH</td><td>b</td><td>J</td>

<td>isopropyl] aminoIpirimidin</td><td>\ = N</td><td></td><td>/ —N</td><td>Cl</td><td></td>

<td>-5-yl) pyridin-4-</td><td></td><td></td><td></td><td></td><td></td>

<td>carbonitrile</td><td></td><td></td><td></td><td></td><td></td>

<td>2- (2- {[1- (3-chlorine (2-</td><td></td><td></td><td></td><td></td><td></td>

<td>pyridyl)) - isopropyl] aminoIpirimidin -5-yl) pyridin-4- carboxamide</td><td>b</td><td> -&lt;</td><td>- * N</td><td>N &gt; Cl</td><td>_J</td>

-224Ν - {[1- (2 - {[1- (3-chloro (2pyridyl)) isopropyl] amino [pyrimidin -5-yl) pyrazol-4yl] methyl} acetamide

4-fluoro-3- [2 - ({[3fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] benzamide

3- [2 - ({[3-fluoro-1- (3fluoro (2-pyridyl)) cyclobutyl] methyl} amino) p irimidin-5-yl] benzamide

6- (2- ([1- (3-chloro (2pyridyl)) isopropyl] amino [pyrimidin -5-yl) -2-pyrrolino [3,2b] pyridin-2-one

6- (2- ([1- (3-chloro (2pyridyl)) isopropyl] amino} pyrimidin -5-yl) imidazo [2, lb] l, 3thiazolin-2-carboxamide

<img file="MX2012012189A_D0130.tif" />

Η₂Ν-V

TO

<img file="MX2012012189A_D0131.tif" />

<img file="MX2012012189A_D0132.tif" />

<img file="MX2012012189A_D0133.tif" />

<img file="MX2012012189A_D0134.tif" />

-225-

<td>β- (2 - ((1- (3-chloro (2- pyridyl)) - isopropyl] amino} pyrimidin-5- il) imidazo [2,1-b] 1, 3- thiazolin-3-carboxamide</td><td>ςοο-'Φ or</td>

<td>5- (2- ([1- (3-chlorine (2- pyridyl)) - isopropyl] amino¡pirimidin -5-yl) -2-methoxypyridin-3- carbonitrile</td><td>N. y '= n &amp;</td>

<td>5- (2- ([1- (3-chlorine (2- pyridyl)) - isopropyl] amino¡pirimidin -5-yl) -2-methoxypyridin-3- carboxamide</td><td> 0 / _N= / Cl</td>

<td>5- (2 - ([1- (3-chlorine (2- pyridyl)) - isopropyl] amino¡pirimidin -5-yl) -2-oxohydropyridin- 3-carboxamide</td><td>0 H_toN — 4 I HN- '' ^ = N Cl</td>

-226 2 - [(tert-butoxy) carbonylamino] -N {[1- (2 - {[1- (3-chloro (2pyridyl)) isopropyl] amino} pyrimidin -5-yl) pyrazol-4yl] methyl} acetamide

2- amino-N - {[1— (2 - {[1— (3— chloro (2-pyridyl)) isopropyl] aminoJpirimidin -5-yl) pyrazol-4yl] methyl} acetamide

3- [(tert-butoxy) carbonylamino] -N {[1- (2- {[1- (3-chloro (2pyridyl)) isopropyl] amino} pyrimidin -5-yl) pyrazol-4i1] methyl} propanamide

3-amino-N - {[1— (2 - {[1— (3— chloro (2-pyridyl)) isopropyl] aminoJpirimidin -5-yl) pyrazol-4yl] methyl} propanamide

<img file="MX2012012189A_D0135.tif" />

<img file="MX2012012189A_D0136.tif" />

<img file="MX2012012189A_D0137.tif" />

<img file="MX2012012189A_D0138.tif" />

-22710

1- [2- ({[3-fluoro-1- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] pyrazol-4-carbonitrile {[3-fluoro-l- (3-fluoro (2piridil) ) cyclobutyl] methyl} pyrimidin-2-ylamine

1- [2- ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] pyrazol-4-carboxamide

3- (2— {[2- (3-chloro (2pyridyl)) - 2methylpropyl] amino} pyrimid in-5-yl) benzamide

3- (2- {[2- (3-chloro (2pyridyl)) - 2methylpropyl] amino} pyrimid in-5-yl) -4fluorobenzamide

<img file="MX2012012189A_D0139.tif" />

<img file="MX2012012189A_D0140.tif" />

<img file="MX2012012189A_D0141.tif" />

<img file="MX2012012189A_D0142.tif" />

<img file="MX2012012189A_D0143.tif" />

-228-

<td>2- (2 - {[(IR) -1- (3-chlorine (2- pyridyl)) - 2- methylpropyl] amino} pyrimid in-5-yl) -1,3-thiazol-5- carbonitrile</td><td></td><td></td><td>N— Cl</td><td>λ</td>

<td>2- (2 - {[(IS) -1- (3-chlorine (2- pyridyl)) - 2- methylpropyl] amino} pyrimid in-5-yl) -1, 3-thiazol-5- carbonitrile</td><td>P</td><td>xp</td><td>N— _ / cr</td><td>Λ</td>

<td>2- (2 - {[(IR) -1- (3-chlorine (2-</td><td></td><td></td><td></td><td></td>

<td>pyridyl)) - 2-</td><td>rf</td><td rowspan="2">/ = N</td><td></td><td>Λ</td>

<td></td><td>or JL</td><td></td><td></td>

<td>methylpropyl] amino} pyrimid</td><td></td><td>S v-_N'</td><td>cr</td><td></td>

<td>in-5-yl) -1,3-thiazol-5-</td><td>nh₂</td><td></td><td></td><td></td>

<td>carboxamide</td><td></td><td></td><td></td><td></td>

<td>2- (2— {[(IS) -1- (3-chlorine (2-</td><td></td><td></td><td></td><td></td>

<td>pyridyl)) - 2- methylpropyl] aminojpirimid</td><td>P</td><td>kP</td><td>P cr</td><td>Λ</td>

<td>in-5-yl) -1,3-thiazol-5-</td><td>NH;</td><td></td><td></td><td></td>

<td>carboxamide</td><td></td><td></td><td></td><td></td>

<td>3- (2 - ([1- (3-chlorine (2-</td><td></td><td>I</td><td>N =</td><td> =\</td>

<td>pyridyl)) -</td><td>θ '*</td><td></td><td> 1</td><td> )</td>

<td>isopropyl] amino (pyrimidin</td><td></td><td></td><td></td><td></td>

<td>-5-yl) isoxazol-5-</td><td></td><td></td><td></td><td></td>

<td>ethyl carboxylate</td><td></td><td></td><td></td><td></td>

-229-

<img file="MX2012012189A_D0144.tif" />

-230-

<td>4-fluoro-3- (2 - {[(3- fluoro-1- (2- pyridyl) cyclobutyl) methyl] amino (pyrimidin-5- il) benzamide</td><td>nh₂</td>

<td>4-fluoro-3- (2 - {[(3- fluoro-1- (2- pyridyl) cyclobutyl) methyl] amino} pyrimidin-5- il) benzamide</td><td>nh₂</td>

<td>6— (2 - {[1- (3-chloro (2- pyridyl)) - isopropyl] amino (pyrimidin -5-yl) pyrimidin-4- carboxamide</td><td>0 H₂NI N-- \ = N \ =_NC|</td>

<td>6- (2- ([1- (3-chlorine (2- pyridyl)) - isopropyl] aminoJpirimidin -5-yl) pyrimidin-4- methyl carboxylate</td><td> 0 ^/ ryPyY) \ = N \ =_N ci</td>

<td>3- {2 - [(tert- butyl) amino] pyrimidin-5- ilbenzamide</td><td>0 HjN-V I</td>

-231 10 [5- (3-amino (lH-indazol-5yl)) pyrimidin-2-yl] (tert-butyl) amine

3- (2- ([1- (3-chloro (2pyridyl)) - 3fluorocyclobutyl] amino} pi rimidin-5-yl) -4fluorobenzamide

3- [2- ({[(3-chloro (2pyridyl)) cyclobutyl] methyl lamino) pyrimidin-5-yl] -4fluorobenzamide ·

3- [2- ({[(3-chloro-2pyridyl) cyclobutyl] methyl} amino) pyrimidin-5yl] benzamide

3- (2- ([(2pyridylcyclobutyl) methyl] a mino} pyrimidin-5yl) benzamide

<img file="MX2012012189A_D0145.tif" />

<img file="MX2012012189A_D0146.tif" />

<img file="MX2012012189A_D0147.tif" />

<img file="MX2012012189A_D0148.tif" />

<img file="MX2012012189A_D0149.tif" />

-232-

<td>4-fluoro-3- (2 - ([(2-</td><td>0 h₂n</td><td></td>

<td>pyridylcyclobutyl) methyl] a</td><td colspan="2"></td>

<td>mino [pyrimidin-5-</td><td>F</td><td></td>

<td>il) benzamide</td><td></td><td></td>

<td></td><td></td><td></td>

<td>3- [2— ({[(3-chlorine (2-</td><td colspan="2">\ c,&gt; V^N</td>

<td>pyridyl)) cyclobutyl] methyl</td><td></td><td>/ -NH</td>

<td>[amino) pyrimidin-5-yl] -4-</td><td>\ = ζ V = N</td><td></td>

<td>fluorobenzenecarbonitriium</td><td></td><td></td>

<td></td><td></td><td></td>

<td>3- [2 - ({[(3-chloro-2-</td><td colspan="2"></td>

<td>pyridyl) cyclobutyl] methyl}</td><td></td><td>/ -NH</td>

<td>amino) pyrimidin-5-</td><td></td><td></td>

<td>il] benzenecarbonitrile</td><td></td><td></td>

<td></td><td>c</td><td></td>

<td></td><td></td><td></td>

<td>{[(3-chlorine (2-</td><td>ryr</td><td></td>

<td>pyridyl)) cyclobutyl] methyl</td><td>'-N</td><td></td>

<td>} pyrimidin-2-ylamine</td><td></td><td></td>

<td>3- (2 - {[1- (2-chloro (3-</td><td>0 H₂N-</td><td>TO</td>

<td>pyridyl)) -</td><td>yyyyí</td><td>r \)</td>

<td>isopropyl] aminoJpirimidin</td><td>F</td><td></td>

<td>-5-yl) -4-fluorobenzamide</td><td></td><td></td>

-233-

<td>6- (2 - {[1- (3- chlorine (2-pyridyl)) - isopropyl] amino Jpirimidin -5-yl) imidazo [2,1-b] 1,3- thiazolin-3-carboxylic</td><td>CCXtip^η° Ά. 0</td>

<td>2- (2- {[1- (3- chlorine (2-pyridyl)) - isopropyl] aminoJpirimidin -5-il) -4- hydroimidazo [1,2- a] pyridin-6-carboxylic</td><td>yCCMIhxP Oh</td>

<td>2- (2 - {[1- (3-chloro (2- pyridyl)) - isopropyl] aminoJpirimidin -5-il) -4- hydroimidazo [1,2— a] pyridin-6-carboxamide</td><td>NHj</td>

<td>1- [2 - ({[3-fluoro-l- (3- fluoro (2- pyridyl)) cyclobutyl] methyl } amino) pyrimidin-5- yl] pyrrole-3-carboxylate methyl</td><td>yy</td>

-23410 1- [2 - ({[3-fluoro-l (3-fluoro (2pyridyl)) cyclobutyl] methyl lamino) pyrimidin-5yl] pyrrole-3-carboxylic acid

1- [2- ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] pyrrole-3-carboxamide

2— (2 - {[1- (3-chloro (2pyridyl)) isopropyl] amino} pyrimidin -5-yl) -4hydroimidazo [1,2a] pyridin-8-carboxamide 2- (2 - {[1- (3 -chlor (2pyridyl)) isopropyl] aminopyrimidin —5-yl) —4— hydroimidazo [1,2a] pyridin-7-carboxamide

<img file="MX2012012189A_D0150.tif" />

<img file="MX2012012189A_D0151.tif" />

<img file="MX2012012189A_D0152.tif" />

<img file="MX2012012189A_D0153.tif" />

-23510

<td>5— (2 - {[1- (3-chloro (2- pyridyl)) - isopropyl] aminoJpirimidin -5-yl) pyridazine-3- carboxamide</td><td colspan="2">p H¡N-íf I N-&gt; \ ^ = N Cl ·</td>

<td>N- (tert-butyl) [5— (2 - {[ΙΟ -chlor (2-pyridyl)) - isopropyl] aminoJpirimidin -5-yl) pyridazin-3- il] carboxamide</td><td colspan="2">0 HN-I N-1 T \ N- '\ = N Cl</td>

<td>{3— [2 - ({[3-fluoro-1- (3- fluoro (2- pyridyl)) cyclobutyl] methyl } amino) pyrimidin-5- yl] phenyl} -N- (methylsulfonyl) carboxamide</td><td>/ X HN-V ^h\ == Z \ = N</td><td></td>

<td rowspan="2">2- {2- [2 - ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] - 1,3-thiazol-5- ilJetanonitrile</td><td>.X</td><td> 5</td>

<td></td><td></td>

-236-

<img file="MX2012012189A_D0154.tif" />

-23710

<td>(tert-butoxy) -N - ({2- [2-</td><td></td><td></td><td></td><td></td><td> (</td><td></td>

<td>({[(3-fluoro (2-</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>pyridyl)) cyclobutyl] methyl</td><td></td><td>HN ^</td><td></td><td>/"and</td><td>/ - NH</td><td></td>

<td>} amino) pyrimidin-5- il] (1,3-thiazol-5- il)} methyl) carboxamide</td><td>OR?</td><td>^ 0 TO</td><td>'N</td><td></td><td></td><td></td>

<td>{5- [5- (aminomethyl) (1,3-</td><td></td><td></td><td></td><td></td><td>F</td><td></td>

<td>thiazol-2-yl)] pyrimidin-2-</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>il} {[(3-fluoro (2-</td><td colspan="2">H₂N X -'- ' X</td><td></td><td>/and</td><td></td><td></td>

<td>pyridyl)) cyclobutyl] methyl</td><td></td><td></td><td></td><td>'-N</td><td></td><td></td>

<td>}amine</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>N - ({2- [2 - ({[(3-fluoro-2-</td><td></td><td></td><td></td><td></td><td colspan="2">iT ^ j</td>

<td>pyridyl) cyclobutyl] methyl}</td><td colspan="2"> 0</td><td></td><td></td><td></td><td></td>

<td>amino) pyrimidin-5-yl] - 1,3-thiazol-5-</td><td></td><td colspan="3"></td><td> -</td><td></td>

<td>il} methyl) acetamide</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>(tert-butoxy) -N - ({2- [2-</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>({[(3-chlorine (2-</td><td></td><td rowspan="2">x = ° xz</td><td></td><td></td><td>X</td><td></td>

<td>pyridyl)) cyclobutyl] methyl } amino) pyrimidin-5-</td><td></td><td colspan="2"></td><td> -/</td><td>F Π</td>

<td>il] (1,3-thiazol-5-</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>il)} methyl) carboxamide</td><td></td><td></td><td></td><td></td><td></td><td></td>

-23810 {5- [5- (aminomethyl) (1,3thiazol-2-yl)] pyrimidin-2yl} {[(3-chloro (2pyridyl)) cyclobutyl] methyl} amine

N- ({2- [2 - ({[(3-chloro-2pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] 1,3-thiazol-5yl} methyl) acetamide ({2- [2- ( {[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] (1,3-thiazol-5yl) Jmethyl) (methylsulfonyl) amine

2- {2- [2 - ({[1- (3-chloro (2pyridyl)) - 3fluorocyclobutyl] methyl} am ino) pyrimidin-5-yl] -1,3-thiazol-5-yl} acetamide

<img file="MX2012012189A_D0155.tif" />

<img file="MX2012012189A_D0156.tif" />

<img file="MX2012012189A_D0157.tif" />

<img file="MX2012012189A_D0158.tif" />

-23910 (tert-butoxy) -N - {[2- (2 {[(2-pyridylcyclobutyl) methyl] amino} pyrimidin-5yl) (1,3-thiazol-5yl)] methyl} carboxamide [2 - ({[ (3-fluoro (2pyridyl)) cyclobutyl] methyl lamino) pyrimidin-5-yl] -Nisoxazol-3-ylcarboxamide [2- ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl ] -N (1,3-thiazol-2yl) carboxamide

2- ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyrimidin-5carboxamide (2- ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl lamino) pyrimidin-5-yl] -Nmethylcarboxamide

<img file="MX2012012189A_D0159.tif" />

<img file="MX2012012189A_D0160.tif" />

<img file="MX2012012189A_D0161.tif" />

N

<img file="MX2012012189A_D0162.tif" />

<img file="MX2012012189A_D0163.tif" />

<img file="MX2012012189A_D0164.tif" />

-24010

N-ethyl [2 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] carboxamide [2 - (([(3-fluoro (2-pyridyl)) cyclobutyl] methyl} ami no ) pyrimidin-5-yl] -N- (2hydroxyethyl) carboxamide

N— {2 - [(tert-butoxy) carbonylamino] ethyl} [2 ({[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pi rimidin-5-yl] carboxamide

N- (2 - {[2 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyrimidin-5yl] carbonylamino} ethyl) ace tamida

2 - {[2 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyrimidin-5yl] carbonylamino} methyl acetate

<img file="MX2012012189A_D0165.tif" />

<img file="MX2012012189A_D0166.tif" />

Oh

<img file="MX2012012189A_D0167.tif" />

<img file="MX2012012189A_D0168.tif" />

<img file="MX2012012189A_D0169.tif" />

-241 10 {3- [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] phenyl} -Nmethylcarboxamide {4-fluoro-3- [2 - ({ [3fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] phenyl} -Nmethylcarboxamide [2 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5 -il] -Npirazoi-5-ylcarboxamide

5-aminopyrazolyl-2 - ({[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) p irimidin-5-yl ketone

<img file="MX2012012189A_D0170.tif" />

<img file="MX2012012189A_D0171.tif" />

<img file="MX2012012189A_D0172.tif" />

r \ Y

<img file="MX2012012189A_D0173.tif" />

HN \ =_N

-NH / \

<img file="MX2012012189A_D0174.tif" />

r \ r

<img file="MX2012012189A_D0175.tif" />

,25

-242 10 [2 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N (3-methylpyrazol-5yl) carboxamide

N- (2-aminoethyl) [2 - ({[(3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] carboxamide [2 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N (2 [(methylsulfonyl) amino] eti

1} carboxamide 2- {[2 - ({[(3-fluoro2-pyridyl) cyclobutyl] methyl} amino) pyrimidin-5yl] carbonylamino} acetic acid

<img file="MX2012012189A_D0176.tif" />

<img file="MX2012012189A_D0177.tif" />

<img file="MX2012012189A_D0178.tif" />

<img file="MX2012012189A_D0179.tif" />

-24310 {3- [2 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] phenyl) -Nmethylcarboxamide {4-fluoro-3- [2 - ({[(3fluoro (2pyridyl) )) cyclobutyl] methyl} amino) pyrimidin-5yl] phenyl} -Nmethylcarboxamide [2 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl lamino) pyrimidin-5-yl] -Nbenzamide [2 - ({[( 3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N (3-pyridyl) carboxamide {3- [2 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -4-hydroxyphenyl} -Nmethylcarboxamide

<img file="MX2012012189A_D0180.tif" />

<img file="MX2012012189A_D0181.tif" />

<img file="MX2012012189A_D0182.tif" />

<img file="MX2012012189A_D0183.tif" />

<img file="MX2012012189A_D0184.tif" />

-244-

<img file="MX2012012189A_D0185.tif" />

3- [2- ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl lamino) pyrimidin-5-yl] -4hydroxybenzamide {3- [2 - ({[3-fluoro-l- (3fluoro (2pyridyl))) cyclobutyl] methyl} amino) pyrimidin-5-yl] -4hydroxyphenyl} -Nmethylcarboxamide

3- [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -4hydroxybenzamide {1- [2 - ({[3-fluoro-l- ( 3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] pyrrol-3-yl} -Nmethylcarboxamide nh₂ &lt;r \

Oh

<img file="MX2012012189A_D0186.tif" />

<img file="MX2012012189A_D0187.tif" />

<img file="MX2012012189A_D0188.tif" />

-245-

<img file="MX2012012189A_D0189.tif" />

[2 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N (l-methylpyrazol-5O,

HN r \

<img file="MX2012012189A_D0190.tif" />

yl) carboxamide [2 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N (4-pyridyl) carboxamide

2- ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl pyrazolyl ketone

<img file="MX2012012189A_D0191.tif" />

<img file="MX2012012189A_D0192.tif" />

\

<img file="MX2012012189A_D0193.tif" />

Γ \

<img file="MX2012012189A_D0194.tif" />

<img file="MX2012012189A_D0195.tif" />

NH

<img file="MX2012012189A_D0196.tif" />

[2 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N (1,3,4-thiadiazol-2yl) carboxamide [2- ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl lamino) pyrimidin-5-yl] -N (2fluorophenyl) carboxamide

<img file="MX2012012189A_D0197.tif" />

//

<img file="MX2012012189A_D0198.tif" />

-24610 [2 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N (3fluorophenyl) carboxamide [2- ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N (4fluorophenyl) carboxamide [2- ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N (6-methoxy (3pyridyl) )) carboxamide {2- [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl lamino) pyrimidin-5-yl] (4pyridyl)} - Nmethylcarboxamide

<img file="MX2012012189A_D0199.tif" />

<img file="MX2012012189A_D0200.tif" />

<img file="MX2012012189A_D0201.tif" />

F

<img file="MX2012012189A_D0202.tif" />

<img file="MX2012012189A_D0203.tif" />

F

<img file="MX2012012189A_D0204.tif" />

-247 {[2 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] amino} -N- (1,3-thiazol2-yl) carboxamide

<img file="MX2012012189A_D0205.tif" />

[2 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -Nmethyl-N- (1,3-thiazol-2yl) carboxamide

<img file="MX2012012189A_D0206.tif" />

([(3-fluoro (2pyridyl)) cyclobutyl] methyl} (5-imidazol-2ylpyrimidin-2-yl) amine

<img file="MX2012012189A_D0207.tif" />

N- [2 - ((((3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] 1,3-thiazol-2ylcarboxamide

<img file="MX2012012189A_D0208.tif" />

<img file="MX2012012189A_D0209.tif" />

ru

<img file="MX2012012189A_D0210.tif" />

-248-

<img file="MX2012012189A_D0211.tif" />

7- [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] indolin-2-one acid 3- [2 - ({[3 — fluoro-1 ( 3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -4hydroxybenzoic

3- [2 - ({[3-Fluoro-l- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -4-methyl hydroxybenzoate acid 1- [2 - ({[3-fluoro-l (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -6oxohydropyridin-3carboxylic

F

<img file="MX2012012189A_D0212.tif" />

<img file="MX2012012189A_D0213.tif" />

<img file="MX2012012189A_D0214.tif" />

<img file="MX2012012189A_D0215.tif" />

<img file="MX2012012189A_D0216.tif" />

-24910

1- [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -6oxohydropyridin-3carboxamide

2- [2- ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] pyrimidin-4carbonitrile {2— [2 - ({[3-fluoro-1- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] pyrimidin-4-yl} -Nmethylcarboxamide

2- [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] pyrimidin-4carboxamide

<img file="MX2012012189A_D0217.tif" />

<img file="MX2012012189A_D0218.tif" />

F

<img file="MX2012012189A_D0219.tif" />

<img file="MX2012012189A_D0220.tif" />

F

<img file="MX2012012189A_D0221.tif" />

<img file="MX2012012189A_D0222.tif" />

F

<img file="MX2012012189A_D0223.tif" />

-2507- [2 - ({[3-fluoro-l- (3fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pi rimidin-5-yl] isoindolin1-one {[3-fluoro-l- (3- fluoro (2pyridyl)) cyclobutyl] methyl} [5- (2-fluorophenyl) pyrimidin-2-yl] amine

2- [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] benzamide

2- {2- [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] phenyl} acetamide

N— [2— [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] phenyl} acetamide

<img file="MX2012012189A_D0224.tif" />

<img file="MX2012012189A_D0225.tif" />

<img file="MX2012012189A_D0226.tif" />

<img file="MX2012012189A_D0227.tif" />

<img file="MX2012012189A_D0228.tif" />

-251 10

2- [2- ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] benzene-1,4dicarboxamide

4-fluoro-2- [2 - ({[3fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] benzamide

- [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] pyridin-4-carbonitrile

2- [2- ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] pyridin-4-carboxamide

<img file="MX2012012189A_D0229.tif" />

OR

<img file="MX2012012189A_D0230.tif" />

<img file="MX2012012189A_D0231.tif" />

<img file="MX2012012189A_D0232.tif" />

-25210

2- {3- [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl (amino) -4-methylpyrimidin5-yl] phenyl (acetamide

4- [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl (amino) -4-methylpyrimidin5-yl] benzenecarbonitrile - [2 - ({[3-fluoro-l- (3fluoro ( 2pyridyl)) cyclobutyl] methyl lamino) -4-methylpyrimidin5-yl] benzamide

6- [2 - ({[3-fluoro-l- (3fluoro (2-pyridyl)) cyclo butyl] methyl} amino) pyrimid in-5-yl] pyridin-3-ol [5- (5-aminopyrazin-2yl ) pi rimidin-2-yl] {[3fluoro-l- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amine

<img file="MX2012012189A_D0233.tif" />

<img file="MX2012012189A_D0234.tif" />

<img file="MX2012012189A_D0235.tif" />

<img file="MX2012012189A_D0236.tif" />

-253-

<td>5- [2 - ({[3-fluoro-l- (3- fluoro (2- pyridyl)) cyclobutyl] methyl lamino) pyrimidin-5-yl] -2- hydroxybenzamide</td><td>X h₂n- / or</td><td></td><td></td>

<td>2- {4- [2 - ({[3-fluoro-l- (3- fluoro (2- pyridyl)) cyclobutyl] methyl lamino) -4-methylpyrimidin- 5-yl] phenylJacetamide</td><td>..X \ jH,</td><td></td><td></td>

<td>acid 2- {4- [2 - ({[3- fluoro-1- (3-fluoro (2- pyridyl)) cyclobutyl] methyl lamino) -4-methylpyrimidin- 5-yl] phenyl} acetic</td><td>_Λχ \ dh</td><td></td><td></td>

<td>[5- (2-amino-5- methylpyrimidin-4- il) pyrimidin-2-yl] {[3- fluoro-1- (3-fluoro (2- pyridyl)) cyclobutyl] methyl )amine</td><td>......... X to ¥ I</td><td colspan="2"> 1</td>

-25410 [5- (2-amino-4-methylpyrimidin-5yl) pyrimidin-2-yl] {[3fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amine

3- [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] pyridin-2-ol [5- (6-aminopyridazin-3yl) pyrimidin-2-yl ] {[3fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amine [5- (2-aminopyrimidin-5yl) pyrimidin-2-yl] {[3fluoro-1- (3-fluoro (2pyridyl))) cyclobutyl] methyl} amine

<img file="MX2012012189A_D0237.tif" />

<img file="MX2012012189A_D0238.tif" />

<img file="MX2012012189A_D0239.tif" />

<img file="MX2012012189A_D0240.tif" />

-25510

5- [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] pyridin-2-ol {[3-fluoro-1- (3-fluoro (2piridil) ) cyclobutyl] methyl} [5- (6-methoxy (3pyridyl)) pyrimidin-2yl] amine [5- (6-aminopyrazin-2yl) pyrimidin-2-yl] ([3fluoro-1- (3-fluoro (2pyridyl) ) cyclobutyl] methyl] amine [5- (2-aminopyrimidin-4yl) pyrimidin-2-yl] {[3fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amine

<img file="MX2012012189A_D0241.tif" />

<img file="MX2012012189A_D0242.tif" />

<img file="MX2012012189A_D0243.tif" />

<img file="MX2012012189A_D0244.tif" />

-25610 [5- (2-amino-5fluoropyrimidin-4yl) pyrimidin-2-yl] {[3fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amine

5- (2- [4- (3-fluoro-2pyridyl) -2azabicyclo [2.1.1] hex-2yl] pyrimidin-5yl} pyrimidin-2-ol (5-bromo-4methoxypyrimidin-2-yl) {[3fluoro- 1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amine (5-bromo-4methoxypyrimidin-2-yl) {[3fluoro-l- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amine

<img file="MX2012012189A_D0245.tif" />

<img file="MX2012012189A_D0246.tif" />

<img file="MX2012012189A_D0247.tif" />

-or

<img file="MX2012012189A_D0248.tif" />

-25710

3- [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) -4me toxipyrimidin-5yl] benzamide acid 3- [2 - ({[3-fluoro-l (3- fluoro (2pyridyl)) cyclobutyl] methyl} amino) -4hydroxypyrimidin-5yl] benzoic

3- [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) -4hydroxypyrimidin-5yl] benzamide

5— [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] pyrimidin-2-ol

<img file="MX2012012189A_D0249.tif" />

-or

<img file="MX2012012189A_D0250.tif" />

<img file="MX2012012189A_D0251.tif" />

HO

<img file="MX2012012189A_D0252.tif" />

-25810 {[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} [5- (2-methoxypyrimidin-5yl) pyrimidin-2-yl] amine

6- [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] pyridazin-3-ol {[3-fluoro-1- (3-fluoro (2piridil) ) cyclobutyl] methyl} [5- (6-methoxypyridazin-3yl) pyrimidin-2-yl] amine

1- [2- ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -4hydroxyhydropyridin-2-one

5-fluoro-6- [2 - ({[3fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] pyridin-3-ol

<img file="MX2012012189A_D0253.tif" />

<img file="MX2012012189A_D0254.tif" />

<img file="MX2012012189A_D0255.tif" />

<img file="MX2012012189A_D0256.tif" />

<img file="MX2012012189A_D0257.tif" />

-259 {3- [2 - ({[3-fluoro-l- (3fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimid in-5-yl] phenyl} -N- (1methylazetidin-3yl) carboxamide { 4-fluoro-3- [2 - ({[3fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] phenyl} -N- (1methylazetidin-3yl) carboxamide

N- (1-acetylazetidin-3yl) {3- [2 - ({[3-fluoro-l (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] phenyl} carboxamide

N- (l-acetylazetidin-3yl) {4-fluoro-3- [2 - ({[3fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] phenyl} carboxamide

<img file="MX2012012189A_D0258.tif" />

<img file="MX2012012189A_D0259.tif" />

<img file="MX2012012189A_D0260.tif" />

<img file="MX2012012189A_D0261.tif" />

-26010

<td>(4-fluoro-3- [2 - ({[3- fluoro-1- (3-fluoro (2- pyridyl)) cyclobutyl] methyl } amino) pyrimidin-5- yl] phenyl) -N- [1- (methylsulfonyl) azetidin- 3-yl] carboxamide</td><td>and Ό- HN Y ^F = /%, \</td>

<td>{3- [2 - ({[3-fluoro-l- (3- fluoro (2- pyridyl)) cyclobutyl] methyl } amino) pyrimidin-5- yl] phenyl} -N- [1- (methylsulfonyl) azetidin- 3-yl] carboxamide</td><td>and</td>

<td>{[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl } (4-methoxy-5- phenylpyrimidin-2-yl) amine</td><td> -¿</td>

<td>([3-fluoro-1- (3-fluoro (2- pyridyl)) cyclobutyl] methyl } (4-methoxy-5- phenylpyrimidin-2-yl) amine</td><td>-Q</td>

-261 ([3-fluoro-l- (3-fluoro (2pyridyl)) cyclobutyl] methyl} (4-methoxy-5phenylpyrimidin-2yl) methylamine {[3-fluoro-l- (3-fluoro (2pyridyl)) cyclobutyl] methyl} (4-methoxypyrimidin-2yl) amine

<img file="MX2012012189A_D0262.tif" />

<img file="MX2012012189A_D0263.tif" />

(4-amino-5phenylpyrimidin-2-yl) {[3fluoro-1- (3-fluoro (2piridil)) cyclobutyl] methyl} amine {[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} [4- (methylamino) -5phenylpyrimidin-2-yl] amine [2- ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl lamino) -5-phenylpyrimidin4-yl] dimethylamine

<img file="MX2012012189A_D0264.tif" />

<img file="MX2012012189A_D0265.tif" />

<img file="MX2012012189A_D0266.tif" />

-26210 [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl lamino) -5-phenylpyrimidin4-yl] (2-methoxyethyl) amine {3- [2 - ({[3-fluoro -l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] phenyl} -N- (3hydroxycyclobutyl) carboxa mida {4-fluoro-3- [2 - ({[3fluoro-l- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] phenyl} -N- (3hydroxycyclobutyl) carboxa mide

4-fluoro-3- [2 - ({[3fluoro-l- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -2hydroxybenzamide

<img file="MX2012012189A_D0267.tif" />

<img file="MX2012012189A_D0268.tif" />

<img file="MX2012012189A_D0269.tif" />

<img file="MX2012012189A_D0270.tif" />

-26310

3- [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -2hydroxybenzamide [5- (2,6dimethoxypyrimidin-4yl) pyrimidin-2-yl] {[3fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amine [5- (2,4dimethoxypyrimidin-5yl) pyrimidin-2-yl] {[3fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl ] methyl} amine

6- [2 - ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] 1,3-dihydropyrimidin-2,4dione

<img file="MX2012012189A_D0271.tif" />

<img file="MX2012012189A_D0272.tif" />

<img file="MX2012012189A_D0273.tif" />

<img file="MX2012012189A_D0274.tif" />

-26410

5- [2- ({[3-fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] 1,3-dihydropyrimidin-2,4dione

3-amino-6- [2 - ({[3-fluoro1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] hydropyrazin-2-one {3- [2 - ({[3- fluoro-l- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -2hydroxyphenyl} -Nmethylcarboxamide [2 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-4 -il] -Nbenzamide

<img file="MX2012012189A_D0275.tif" />

<img file="MX2012012189A_D0276.tif" />

<img file="MX2012012189A_D0277.tif" />

<img file="MX2012012189A_D0278.tif" />

-26510 [2 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl lamino) pyrimidin-4-yl] -Nmethyl-N-benzamide {[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl ] methyl} [5- (3-methoxy-6-methyl (2pyridyl)) pyrimidin-2yl] amine ((IR) -1-phenylethyl) [4 (cyclohexylamino) -6methylpyrimidin-2-yl] amine

3- [2- ({[3-fluoro-1- (3fluoro-6-methyl (2pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5yl] benzamide

Table 2 (Continued)

<img file="MX2012012189A_D0279.tif" />

<img file="MX2012012189A_D0280.tif" />

<img file="MX2012012189A_D0281.tif" />

<img file="MX2012012189A_D0282.tif" />

-266-

<td>Compound</td><td>m / z (M + H)</td><td>Half AC1.4</td>

<td>4- (2 - {[2- (4-fluorophenyl) -2- methylpropyl] amino} pyrimidin-5- il) benzamide</td><td> 365, 3</td><td>B</td>

<td>3— (2 - {[2- (4-fluorophenyl) -2- methylpropyl] amino} pyrimidin-5- il) benzamide</td><td> 365, 3</td><td>TO</td>

<td>5- (2 - {[2- (4-fluorophenyl) -2- methylpropyl] amino} pyrimidin-5- il) pyridin-3-carbonitrile</td><td> 348,3</td><td>B</td>

<td>5— (2 - {[2- (4-fluorophenyl) -2- methylpropyl] amino} pyrimidin-5- il) pyridin-3-carboxamide</td><td> 366, 3</td><td>B</td>

<td>3- (2-aminopyrimidin-5- il) benzamide</td><td> 215, 3</td><td>D</td>

<td>[2- (4-fluorophenyl) -2- methylpropyl] -5,6,7,8- tetrahydropyridine [4.3— d] pyrimidin-2-ylamine</td><td> 301, 0</td><td>D</td>

<td>2 - {[2- (4-fluorophenyl) -2- methylpropyl] amino} pyrimidin-5- methyl carboxylate</td><td> 304,1</td><td>D</td>

-267-

<td>Ν- [2- (4-fluorophenyl) -2- methylpropyl] (2 - {[2- (4-fluorophenyl) - 2-methylpropyl] aminoIpirimidin-5- il) carboxamide</td><td> 439,1</td><td>D</td>

<td>1 - [(2 - {[2- (4-fluorophenyl) -2- methylpropyl] amino} pyrimidin-5- il) carbonyllamino] cyclopropanecarbox ethyl ilate</td><td> 401,1</td><td>D</td>

<td>2 - {[2- (4-fluorophenyl) -2- acid methylpropyl] amino} pyrimidin-5- carboxylic</td><td> 289, 0</td><td>D</td>

<td>(5-bromopyrimidin-2-yl) [2— (4 - fluorophenyl) -2-methylpropyl] amine</td><td> 324,0</td><td>D</td>

<td>1 - [(2 - {[2- (4-fluorophenyl) -2- acid methylpropyl] amino} pyrimidin-5- il) carbonyllamino] cyclopropanecarbox ilic</td><td> 373, 1</td><td>D</td>

<td>1- [(2- {[2- (4-fluorophenyl) -2- methylpropyl] amino} pyrimidin-5- il) carbonyllamino] cyclopropanecarbox amide</td><td> 373, 1</td><td>D</td>

<td>5- (2- ([2- (4-fluorophenyl) -2- methylpropyl] amino} pyrimidin-5-yl) - 3-hydrobenzoimidazol-2-one</td><td> 378,1</td><td>B</td>

-268-

<td>6-acetyl-2 - {[2- (4-fluorophenyl) -2- methylpropyl] amino} -5,6,7,8- tetrahydropyridine [4,3-d] pyrimidine</td><td> 343,0</td><td>D</td>

<td>2 - {[2- (4-fluorophenyl) -2- methylpropyl] amino} -6- (methylsulfonyl) -5,6,7,8- tetrahydropyridine [4,3-d] pyrimidine</td><td> 379, 0</td><td>B</td>

<td>[2- (4-fluorophenyl) -2- methylpropyl] (6-methyl (5,6,7,8- tetrahydropyridine [4,3-d] pyrimidin- 2-yl)) amine</td><td> 315,0</td><td>D</td>

<td>2 - {[2- (4-fluorophenyl) -2- methylpropyl] amino) -5,6,7,8- tetrahydropyridine [4,3-d] pyrimidin- 6-carboxamide</td><td> 301,0</td><td>D</td>

<td>2- (2 - ([2- (4-fluorophenyl) -2- methylpropyl] amino} (5,6,7,8- tetrahydropyridine [4,3-d] pyrimidin- 6-yl)) - 2-oxoacetamide</td><td> 372,0</td><td>D</td>

<td>2 - {[2- (4-fluorophenyl) -2- methylpropyl] amino) -5,6,7,8- tetrahydropyridine [3,4-d] pyrimidin- 7-carboxamide</td><td> 344,0</td><td>D</td>

-269-

<td>2- (2 - ([2- (4-fluorophenyl) -2- methylpropyl] amino} (5,6,7,8- tetrahydropyridine [3,4-d] pyrimidin- 7-yl)) - 2-oxoacetamide</td><td> 372,0</td><td>D</td>

<td>2- {[2- (4-fluorophenyl) -2- methylpropyl] amino} -7- (methylsulfonyl) -5, 6,7,8- tetrahydropyridine [3,4-d] pyrimidine</td><td> 379, 0</td><td>C</td>

<td>[5- (3-amino (lH-indazol-5- il)) pyrimidin-2-yl] [2 - (4- fluorophenyl) -2-methylpropyl ·] amine</td><td> 377,1</td><td>TO</td>

<td>4-fluoro-3- (2 - {[(3-fluoro (2- pyridyl)) cyclobutyl] amino} pyrimidin -5-yl) benzamide</td><td> 382,1</td><td>TO</td>

<td>4- (2 - ([(4- fluorophenyl) cyclobutyl] amino} pyrimi din-5-yl) pyridin-2-carbonitrile</td><td> 346, 1</td><td>C</td>

<td>4-fluoro-3 - (2 - {[(4- fluorophenyl) cyclobutyl] amino} pyrimi din-5-yl) benzamide</td><td> 381, 1</td><td>TO</td>

<td>4- (2— {[(3-fluoro-2- pyridyl) cyclobutyl] amino} pyrimidin- 5- yl) pyridin-2-carbonitrile</td><td> 347,1</td><td>D</td>

-270-

<td>4- (2— {[(3-fluoro-2- pyridyl) cyclobutyl] aminoJpirimidin- 5— yl) pyridin-2-carboxamide</td><td> 365,1</td><td>B</td>

<td>4- (2- {[(4- fluorophenyl) cyclobutyl] aminojpirimi din-5-yl) pyridin-2-carboxamide</td><td> 364,1</td><td>B</td>

<td>(5- (lH-indazol-5-yl) pyrimidin-2- il) [(3-fluoro (2- pyridyl)) cyclobutyl] amine</td><td> 361, 1</td><td>B</td>

<td>5- (2 - {[(3-fluoro-2- pyridyl) cyclobutyl] amino} pyrimidin- 5-yl) -lH-indazol-3-carbonitrile</td><td> 386,1</td><td>B</td>

<td>5- (2- {[(3-fluoro-2- pyridyl) cyclobutyl] aminojpyrimidin- 5-yl) -lH-indazol-3-carboxamide</td><td> 404,1</td><td>TO</td>

<td>[5- (6-fluoro (lH-indazol-5- yl)) pyrimidin-2-yl] [(3-fluoro (2- pyridyl)) cyclobutyl] amine</td><td> 379, 1</td><td>B</td>

<td>6-fluoro-5- (2 - {[(3-fluoro (2- pyridyl)) cyclobutyl] amino} pyrimidin -5-yl) -lH-indazol-3-carbonitrile</td><td> 404,1</td><td>B</td>

<td>6-fluoro-5 - (2- {[(3-fluoro (2- pyridyl)) cyclobutyl] amino} pyrimidin -5-yl) -lH-indazol-3-carboxamide</td><td> 422, 1</td><td>TO</td>

-271 -

<td>(5-bromopyrimidin-2-yl) [(4- fluorophenyl) cyclobutyl] amine</td><td> 322,0</td><td>D</td>

<td>(5-bromopyrimidin-2-yl) [(3— fluoro (2-pyridyl)) cyclobutyl] amine</td><td> 323,0</td><td>D</td>

<td>(6-bromoquinazolin-2-yl) [(3- fluoro (2-pyridyl)) cyclobutyl] amine</td><td> 373, 0</td><td>D</td>

<td>2 - {[(3-fluoro-2- pyridyl) cyclobutyl] amino} quinazolin a-6-carbonitrile</td><td> 320,1</td><td>D</td>

<td>[(3-fluoro (2- pyridyl)) cyclobutyl] quinazolin-2- ylamine</td><td> 295,1</td><td>D</td>

<td>2 - {[(3-fluoro-2- pyridyl) cyclobutyl] amino} quinazolin a-6-carboxamide</td><td> 338,1</td><td>D</td>

<td>2 - {[(3-fluoro-2- pyridyl) cyclobutyl] amino} pyrimidin- 5-carbonitrile</td><td> 270, 1</td><td>D</td>

<td>2- {[(4- fluorophenyl) cyclobutyl] amino} pyrimi din-5-carbonitrile</td><td> 269, 1</td><td>C</td>

<td>(5-bromopyrimidin-2-yl) [l— (4 - fluorophenyl) -isopropyl] amine</td><td> 310, 0</td><td>C</td>

-272-

<td>2 - {[(4-fluorophenyl) cyclobutyl] amino} pyrimidin-4-carboxamide</td><td> 287,1</td><td>C</td>

<td>2 - {[(4-fluorophenyl) cyclobutyl] amino} pyrimidin-4-carbonitrile</td><td> 269, 1</td><td>D</td>

<td>[(4-fluorophenyl) cyclobutyl] pyrazolo [5,4-d] pyrimidin-6-ylamine</td><td> 284,1</td><td>D</td>

<td>2 - {[(4-fluorophenyl) cyclobutyl] amino} pyrimidin-5-carboxamide</td><td> 287,1</td><td>D</td>

<td>2 - {[(3-fluoro-2-pyridyl) cyclobutyl] amino} pyrimidin-5-carboxamide</td><td> 288,1</td><td>D</td>

<td>2 - {[(4-fluorophenyl) cyclobutyl] amino} -4- (trifluoromethyl) pyrimidin- 5-carboxamide</td><td> 355, 1</td><td>B</td>

<td>2- {[(4-fluorophenyl) acid cyclobutyl] amino} -4- (trifluoromethyl) pyrimidin-5- carboxylic</td><td> 356, 1</td><td>D</td>

<td>[(4-fluorophenyl) cyclobutyl] [4- (trifluoromethyl) pyrimidin-2- il] amine</td><td> 312, 1</td><td>C</td>

<td>N - [(4-fluorophenyl) cyclobutyl] (2- {[(4-fluorophenyl) cyclobutyl] amino} - 4- (trifluoromethyl) pyrimidin-5- il) carboxamide</td><td> 503, 1</td><td>D</td>

-273-

<td>2- {[(3-fluoro (2- pyridyl)) cyclobutyl] amino} -4- (trifluoromethyl) pyrimidin-5- carboxamide</td><td> 356, 1</td><td>D</td>

<td>2 - {[(3-fluoro (2- pyridyl)) cyclobutyl] amino} -4- (trifluoromethyl) pyrimidin-5- carboxylic</td><td> 357,1</td><td>D</td>

<td>[(3-fluoro (2- pyridyl)) cyclobutyl] [4- (trifluoromethyl) pyrimidin-2- il] amine</td><td> 313, 1</td><td>D</td>

<td>1- [2 - ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5-yl] pyrazol-4-carboxylate from ethyl</td><td> 397,3</td><td>D</td>

<td>1— [2 - ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5-yl] pyrazol-4-carboxamide</td><td> 368,3</td><td>B</td>

<td>1- [2 - ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5-yl] pyrazol-4-carboxylic</td><td> 369, 2</td><td>D</td>

-274-

<td>2- [2 - ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5-yl] -1,3-thiazol-4- carboxamide</td><td> 385,1</td><td>B</td>

<td>2- [2 - ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5-yl] -1,3-thiazol-5- carboxamide</td><td> 385, 1</td><td>TO</td>

<td>2- [2 - ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5-yl] -1,3-thiazol-4- ethyl carboxylate</td><td> 414,2</td><td>D</td>

<td>2- [2 - ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5-yl] -1,3-thiazol-4- carboxylic</td><td> 386, 2</td><td>C</td>

<td>2- [2 - ({1- [6- (difluoromethoxy) (2- pyridyl)] - isopropyl} amino) pyrimidin-5-yl] - 1,3-thiazol-5-carboxamide</td><td> 407,2</td><td>TO</td>

<td>2- (2- ([(2- pyridylcyclobutyl) methyl] aminoJpirim idin-5-yl) -1,3-thiazol-5-carboxamide</td><td> 367,2</td><td>B</td>

-275-

<td>2- (2 - {[(2- pyridylcyclobutyl) methyl] aminojpirim idin-5-yl) -1,3-thiazol-5- carbonitrile</td><td> 349, 2</td><td>D</td>

<td>2- [2- ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5-yl] -1,3-thiazol-5- carbonitrile</td><td> 367,2</td><td>C</td>

<td>2- (2— {[1- (4-methoxypyrimidin-2-yl) - isopropyl] amino} pyrimidin-5-yl) - 1,3-thiazol-5-carboxamide</td><td> 372, 1</td><td>D</td>

<td>{4- [6 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr idazin-3-yl] pyrimidin-2- il} (methylsulfonyl) amine</td><td> 430,3</td><td>D</td>

<td>2 - ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl) amino) thiof ene [2,3-d] pyrimidin-6-carboxylate ethyl</td><td> 387, 1</td><td>D</td>

<td>2 - ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) thiof ene [2,3-d] pyrimidin-6-carboxamide</td><td> 358,1</td><td>C</td>

<td>2 - ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) thiof ene [2,3-d] pyrimidin-6-carboxylic</td><td> 358,1</td><td>D</td>

-276-

<td>4-fluoro-3- (2 - {[2- (3-fluoro (2- pyridyl)) - 2- methylpropyl] amino} pyrimidin-5- il) benzamide</td><td> 384,1</td><td>B</td>

<td>4-fluoro-3- [2— ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin.-5-yl] benzamide</td><td> 396, 1</td><td>TO</td>

<td>3- (2 - {[2- (3-fluoro (2-pyridyl)) -2- methylpropyl] amino} pyrimidin-5- il) benzamide</td><td> 366,1</td><td>B</td>

<td>3- [2 - ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5-yl] benzamide</td><td> 378,2</td><td>TO</td>

<td>3- [2 - ({1- [6- (difluoromethoxy) (2- pyridyl)] - isopropyl} amino) pyrimidin-5-yl] -4- fluorobenzamide</td><td> 418,2</td><td>TO</td>

<td>3- [2 - ({1- [6- (difluoromethoxy) (2- pyridyl)] - isopropyl} amino) pyrimidin-5- il] benzamide</td><td> 400, 3</td><td>TO</td>

<td>3 - (2- {[1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) benzamide</td><td> 352,3</td><td>B</td>

-277-

<td>5- ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) - 1,3-thiazolo [5,4-d] pyrimidin-2- carboxamide</td><td> 359, 1</td><td>C</td>

<td>5 - ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) - 1,3-thiazolo [5,4-d] pyrimidin-2- carboxylic</td><td> 360, 1</td><td>D</td>

<td>4-fluoro-3- (2 - {[1- (3-fluoro (2- pyridyl)) - isopropyl] amino} pyrimidin-5- il) benzamide</td><td> 370, 1</td><td>B</td>

<td>N- {[4- (2- ([1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- yl) phenyl] methyl} acetamide</td><td> 380,2</td><td>D</td>

<td>[5- (2-aminopyrimidin-5- yl) pyrimidin-2-yl] [1- (3-fluoro (2- pyridyl)) - isopropyl] amine</td><td> 326, 1</td><td>D</td>

<td>2- (2- ([1- (3-fluoro (2-pyridyl)) - isopropyl] amino Jpirimidin-5-yl) - 1,3-thiazol-5-carboxamide</td><td> 359, 1</td><td>D</td>

<td>2- (2 - ([2- (3-fluoro (2-pyridyl)) - 2- methylpropyl] amino} pyrimidin-5- il) pyrimidin-4-carboxamide</td><td> 368,2</td><td>C</td>

-278-

<td>2- [4-fluoro-3- (2 - {[1- (3-fluoro (2- pyridyl)) - isopropyl] amino} pyrimidine-5- yl) phenyl] methyl acetate</td><td> 399, 1</td><td>C</td>

<td>N- {[3— (2 - {[1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- yl) phenyl] methyl} acetamide</td><td> 380, 1</td><td>C</td>

<td>3- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) benzamide</td><td> 368,1</td><td>TO</td>

<td>3 - (2- {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -4- fluorobenzamide</td><td> 386, 1</td><td>TO</td>

<td>1- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyrazole-4-carbonitrile</td><td> 340, 1</td><td>D</td>

<td>1- (2- {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyrazole-4-carboxamide</td><td> 358, 1</td><td>B</td>

<td>2- [4-fluoro-3- (2 - {[1- (3-fluoro (2- pyridyl)) - isopropyl] amino} pyrimidin-5- yl) phenyl] acetamide</td><td> 384,1</td><td>B</td>

-279-

<td>2 - (2 - {[1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyrimidin-4-carboxamide</td><td> 354,1</td><td>D</td>

<td>{5- [5- (aminomethyl) (1,3-thiazol-2- yl)] pyrimidin-2-yl} [1- (3-fluoro (2- pyridyl)) - isopropyl] amine</td><td> 345,2</td><td>D</td>

<td>N- {[2- (2- ([1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,3-thiazol-5-yl] methyl} acetamide</td><td> 387, 1</td><td>D</td>

<td>2-amino-N - {[2- (2 - ([1- (3-fluoro (2- pyridyl)) - isopropyl] amino} pyrimidin-5- il) (1,3-thiazol-5- il)] methyl} acetamide</td><td> 402,2</td><td>D</td>

<td>N - {[2- (2 - ([1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) (1,3-thiazol-5- yl)] methyl} imidazol-5-ylcarboxamide</td><td> 439,1</td><td>D</td>

<td>N - {[2- (2 - ([1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- yl) (1,3-thiazol-5-yl)] methyl} (2- hydroxyimidazol-5-yl) carboxamide</td><td> 455, 1</td><td>C</td>

-280-

<td>(aminocyclopropyl) -N - {[2- (2 - ([1- (3- fluoro (2-pyridyl)) - isopropyl] amino) pyrimidin-5- il) (1,3-thiazol-5- il)] methyl} carboxamide</td><td> 428,1</td><td>D</td>

<td>((2R) pyrrolidin-2-yl) -N - {[2- (2 - {[1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) (1,3-thiazol-5- il)] methyl} carboxamide</td><td> 442,2</td><td>D</td>

<td>((2S) pyrrolidin-2-yl) -N- {[2- (2 - {[1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) (1,3-thiazol-5- il)] methyl} carboxamide</td><td> 442,2</td><td>C</td>

<td>N - {[2 - (2- {[1- (3-fluoro (2-pyridyl)) - isopropyl] amino, pyrimidin-5-yl) - 1,3-thiazol-4-yl] metii} acetamide</td><td> 387,3</td><td>D</td>

<td>2- [2- (2 - {[1- (3-fluoro (2-pyridyl)) - isopropyl] amino) pyrimidin-5-yl) - 1,3-thiazol-4-yl] acetamide</td><td> 373, 3</td><td>D</td>

<td>1- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyrrole-3-carboxamide</td><td> 357,1</td><td>B</td>

-281 -

<td>1- (2 - ([1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyrazole-4-carboxamide</td><td> 342,2</td><td>D</td>

<td>{5- [4- (aminomethyl) (1,3-thiazol-2- yl)] pyrimidin-2-yl} [1- (3-fluoro (2- pyridyl)) - isopropyl] amine</td><td> 345,3</td><td>D</td>

<td>2- (2 - ([1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,3-thiazol-4-carbonitrile</td><td> 341,3</td><td>D</td>

<td>2- (2 - {[1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,3-thiazol-4-carboxamide</td><td> 359, 3</td><td>D</td>

<td>2-amino-N - ([2- (2 - ([1- (3-fluoro (2- pyridyl)) - isopropyl] amino} pyrimidin-5- il) (1,3-thiazol-4- il)] methyl} acetamide</td><td> 402,2</td><td>D</td>

<td>((2S) pyrrolidin-2-yl) -N - {[2- (2 - ([1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) (1,3-thiazol-4- il)] methyl} carboxamide</td><td> 442, 3</td><td>D</td>

-282-

<td>((2R) pyrrolidin-2-yl) -Ν - {[2- (2 - {[1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) (1,3-thiazol-4- il)] methyl} carboxamide</td><td> 442, 3</td><td>D</td>

<td>2- (2 - {[1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,3-thiazol-5-carbonitrile</td><td> 341,2</td><td>D</td>

<td>2- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,3-thiazol-5-carboxamide</td><td> 375,2</td><td>B</td>

<td>acid 1— (2 - {[1— (3 — chlorine (2— pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyrazole-4-carboxylic</td><td> 359,1</td><td>D</td>

<td>N- (2-carbamoylethyl) [1- (2- ([1- (3- chlorine (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyrazole-4-yl] carboxamide</td><td> 429, 1</td><td>D</td>

<td>[1- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- yl) pyrazol-4-yl] -N- (2- hydroxyethyl) carboxamide</td><td> 402,1</td><td>D</td>

-283-

<td>2— [1— (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyrazole-4-yl] propan-2-ol</td><td> 373, 1</td><td>D</td>

<td>5- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) isoxazol-3-carboxamide</td><td> 359, 2</td><td>B</td>

<td>[1- (3-chloro (2-pyridyl)) - isopropyl] (5-pyrazol-4-ylpyrimidin- 2-yl) amine</td><td> 315, 1</td><td>B</td>

<td>5- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyridin-3-carboxamide</td><td> 369,1</td><td>B</td>

<td>5- (2- {[1- (3-chloro (2- pyridyl)) - isopropyl] amino} pyrimidin-5- il) thiophene-2-carboxylic</td><td> 375, 0</td><td>D</td>

<td>5- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) thiophene-2-carboxamide</td><td> 374,1</td><td>B</td>

<td>(5-bromopyrimidin-2-yl) [l- (3- fluoro (2-pyridyl)) - isopropyl] amine</td><td> 311, 0</td><td>D</td>

<td>2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- carbonitrile</td><td> 274,1</td><td>D</td>

-284-

<td>(5-bromopyrimidin-2-yl) [1- (3- chlorine (2-pyridyl)) - isopropyl] amine</td><td> 328,1</td><td>D</td>

<td>2- (2- {[1- (3-chloro (2-pyridyl)) - isopropyl] amino) pyrimidin-5-yl) - 1,3-oxazol-4-carboxamide</td><td> 359, 2</td><td>D</td>

<td>2- (2- {[1- (3-chloro (2- pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,3-Oxazol-4-carboxylic</td><td> 360, 2</td><td>D</td>

<td>4— [2 - ({[3-fluoro-1- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] pyridin-2-carboxamide</td><td> 397,3</td><td>B</td>

<td>4— [2 - ({[3-fluoro-1- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] pyridin-2-carboxamide</td><td> 397,3</td><td>B</td>

<td>4- [2 - ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5-yl] pyridin-2-carboxamide</td><td> 379, 3</td><td>B</td>

<td>[1- (3-chloro (2-pyridyl)) - isopropyl] (5-pyrrolo [3,2-b] pyridine- 6-ilpyrimidin-2-yl) amine</td><td> 365,2</td><td>TO</td>

<td>2- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amine} pyrimidin-5-yl) - 1,3-Oxazol-5-Carboxamide</td><td> 359, 2</td><td>D</td>

-285-

<td>4- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyridin-2-carboxamide</td><td> 369, 3</td><td>B</td>

<td>4- (2- ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,3-thiazol-2-carboxamide</td><td> 375,2</td><td>C</td>

<td>2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- carboxamide</td><td> 292, 1</td><td>D</td>

<td>[5- (3-amino (lH-indazol-5- yl)) pyrimidin-2-yl] [1- (3-chloro (2- pyridyl)) - isopropyl] amine</td><td> 380,1</td><td>TO</td>

<td>3- (2 - ([1-methyl-l- (4- methylthiophenyl) ethyl] amino} pyrimidine- 5-yl) benzenecarbonitrile</td><td> 361, 2</td><td>D</td>

<td>3- (2 - {[1-methyl-l- (2- methylthiophenyl) ethyl] aminojpyrimidin- 5-yl) benzenecarbonitrile</td><td> 361,2</td><td>TO</td>

<td>5- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyrazole-3-carboxamide</td><td> 358,1</td><td>C</td>

<td>3- (2- (2- (4- (methylsulfinyl) phenyl) propan-2- ylamino) pyrimidin-5-yl) benzamide</td><td> 395,2</td><td>D</td>

-286-

<td>3- [2 - ({1-methyl-l- [4- (methylsulfonyl) phenyl] ethyl} amino) pyr imidin-5-yl] benzamide</td><td> 411,2</td><td>D</td>

<td>3- [2 - ({1-methyl-1- [2- (methylsulfonyl) phenyl] ethyl} amino) pyr imidin-5-yl] benzamide</td><td> 411,2</td><td>D</td>

<td>3- [2 - ({1-methyl-1- [3- (methylsulfonyl) (2- pyridyl)] ethyl} amino) pyrimidin-5- il] benzamide</td><td> 412,2</td><td>D</td>

<td>2- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,3-thiazol-4-carboxamide</td><td> 375, 2</td><td>C</td>

<td>2- (2 - {[1- (3-chloro (2- pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,3-thiazol-4-carboxylic</td><td> 376,2</td><td>D</td>

<td>2- (2 - {[1- (3-chloro (2- pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,3-Oxazol-5-carboxylic</td><td> 360,2</td><td>D</td>

<td>3- (2 - {[1-methyl-1- (3-methylthio (2- pyridyl)) ethyl] amino} pyrimidin-5- il) benzenecarbonitrile</td><td> 362,2</td><td>B</td>

-287-

<td>3- (2 - ([1-methyl-l- (2- methylthiophenyl) ethyl] amino} pyrimidine- 5-yl) benzamide</td><td> 379, 3</td><td>TO</td>

<td>3- (2- (2- (2- (methylsulfinyl) phenyl) propan-2- ylamino) pyrimidin-5-yl) benzamide</td><td> 395,2</td><td>D</td>

<td>[1- (3-chloro (2-pyridyl)) - isopropyl] pyrimidin-2-ylamine</td><td> 249, 2</td><td>D</td>

<td>3- (2 - ([1-methyl-l- (3-methylthio (2- pyridyl)) ethyl] amino} pyrimidin-5- il) benzamide</td><td> 380,2</td><td>B</td>

<td>3- (2- (2- (3- (methylsulfinyl) pyridine- 2-yl) propan-2-ylamino) pyrimidin-5- il) benzamide</td><td> 396, 2</td><td>D</td>

<td>3- [2 - ({1-methyl-l- [3- (methylsulfonyl) (2- pyridyl)] ethyl) (hydroxyamino)) pyrimi din-5-yl] benzamide</td><td> 428,2</td><td>D</td>

<td>3- [2 - ({1- [3- (difluoromethyl) (2- pyridyl)] - isopropillamino) pyrimidin-5-yl] -4- fluorobenzenecarbonitrile</td><td> 384,1</td><td>B</td>

-288-

<td>3- [2 - ({1- [3- (difluoromethyl) (2- pyridyl)] - isopropyl} amino) pyrimidin-5-yl] -4- fiuorobenzamide</td><td> 402,1</td><td>B</td>

<td>(5- (5H-1,2,3,4-tetraazol-5- yl) pyrimidin-2-yl) [1- (3-chloro (2- pyridyl)) - isopropyl] amine</td><td> 317,1</td><td>D</td>

<td>5- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,3,4-Oxadiazol-2-carboxylate ethyl</td><td> 389, 1</td><td>D</td>

<td>5- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,3,4-Oxadiazol-2-carboxamide</td><td> 389, 1</td><td>D</td>

<td>4- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) methyl thiophene-2-carboxylate</td><td> 340, 2</td><td>D</td>

<td>5- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,3-thiazol-2-carboxamide</td><td> 375, 2</td><td>B</td>

<td>5- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,3,4-thiadiazol-2-carboxamide</td><td> 376, 3</td><td>D</td>

-289-

<td>4- (2- ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -1- methylimidazol-2-carboxylate de methyl</td><td> 387,2</td><td>D</td>

<td>6- (2- ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyridin-2-carboxamide</td><td> 369, 1</td><td>C</td>

<td>3- (2- ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,2,4-Oxadiazol-5-carboxamide</td><td> 360, 3</td><td>D</td>

<td>5- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,2,4-Oxadiazol-3-carboxylate ethyl</td><td> 389, 1</td><td>D</td>

<td>[5- (3-amino (lH-indazol-5- il)) pyrimidin-2-yl] [1- (3-fluoro (2- pyridyl)) - isopropyl] amine</td><td> 364,2</td><td>TO</td>

<td>4- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) thiophene-2-carboxamide</td><td> 374,1</td><td>B</td>

<td>(1- (3-chloro (2-pyridyl)) - isopropyl] (5- (1,2,4-oxadiazol-5- il) pyrimidin-2-yl) amine</td><td> 317,1</td><td>D</td>

-290-

<td>4-fluoro-3- (2 - {[1- (3-methoxy (2- pyridyl)) - isopropyl] amino} pyrimidin-5- il) benzenecarbonitrile</td><td> 364,1</td><td>D</td>

<td>4-fluoro-3- (2 - {[1-methyl-l- (3- methyl (2- pyridyl)) ethyl] amino} pyrimidin-5- il) benzamide</td><td> 366, 1</td><td>B</td>

<td>4-fluoro-3- (2 - {[1- (3-methoxy (2- pyridyl)) - isopropyl] amino} pyrimidin-5- il) benzamide</td><td> 382,1</td><td>C</td>

<td>{5- [5- (aminomethyl) (1,3-thiazol-2- yl)] pyrimidin-2-yl} [1- (3-chloro (2- pyridyl)) - isopropyl] amine</td><td> 361,0</td><td>D</td>

<td>N- {[2- (2- ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) - 1,3-thiazol-5-yl] methyl] acetamide</td><td> 403, 1</td><td>C</td>

<td>N - {[2- (2- ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- yl) (1,3-thiazol-5-yl)] methyl} -2- hydroxy-2-methylpropanamide</td><td> 447,1</td><td>C</td>

-291 -

<td>Ν - {[2- (2- ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- yl) (1,3-thiazol-5-yl)] methyl} (2- hydroxyimidazol-4-yl) carboxamide</td><td> 471, 1</td><td>B</td>

<td>3- (2 - {[1- (3-chloro-6-hydroxy (2- pyridyl)) - isopropyl] amino} pyrimidin-5- il) benzamide</td><td> 384,1</td><td>D</td>

<td>3- (2 - {[1- (3-chloro-6-methoxy (2- pyridyl)) - isopropyl] amino} pyrimidin-5- il) benzamide</td><td> 398, 1</td><td>TO</td>

<td>[1- (3-chloro (2-pyridyl)) - isopropyl] (5- (1,3-thiazol-2- il) pyrimidin-2-yl) amine</td><td> 332,1</td><td>B</td>

<td>2- [4 - (2- {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyrazolyl] ethan-l-ol</td><td> 359, 1</td><td>D</td>

<td>2- [4- (2 - {[1- (3-chloro (2- pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyrazolyl] acetic</td><td> 373, 1</td><td>D</td>

-292-

<td>2— [4— (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyrazolyl] acetamide</td><td> 372, 1</td><td>D</td>

<td>2 - (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyridin-4-carbonitrile</td><td> 351, 1</td><td>C</td>

<td>2- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyridin-4-carboxamide</td><td> 369,1</td><td>B</td>

<td>N- {[1- (2- ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyrazole-4-yl] methyl, acetamide</td><td> 386, 1</td><td>D</td>

<td>4-fluoro-3- [2 - ({[3-fluoro-l - (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] benzamide</td><td> 414,3</td><td>TO</td>

<td>3— [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methylamino) pyr imidin-5-yl] benzamide</td><td> 396, 3</td><td>TO</td>

<td>6- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -2- pyrrolino [3,2-b] pyridin-2-one</td><td> 381, 1</td><td>D</td>

-293-

<td>6- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) imidazo [2, lb] 1,3-thiazolin-2- carboxamide</td><td> 414,1</td><td>D</td>

<td>[5- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) (1H- indazol-3-yl)] (methylsulfonyl) amine</td><td> 458, 1</td><td>TO</td>

<td>[1- (3-chloro (2-pyridyl)) - isopropyl] (4- (1,3-thiazol-2- il) pyrimidin-2-yl) amine</td><td> 332,2</td><td>D</td>

<td>{1- [6- (difluoromethoxy) (2-pyridyl)] - isopropyl] (4- (1,3-thiazol-2- il) pyrimidin-2-yl) amine</td><td> 364,2</td><td>C</td>

<td>5- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -1- methylpyrazol-3-carboxamide</td><td> 372,2</td><td>D</td>

<td>3- (2- ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -1- methylpyrazole-5-carboxamide</td><td> 372,2</td><td>D</td>

<td>6- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) imidazo [2, lb] 1,3-thiazolin-3- carboxamide</td><td> 414,1</td><td>B</td>

-294-

<td>5- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -2- methoxypyridin-3-carbonitrile</td><td> 381,1</td><td>D</td>

<td>5- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -2- methoxypyridin-3-carboxamide</td><td> 399, 1</td><td>B</td>

<td>5- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -2- oxohydropyridin-3-carboxamide</td><td> 385, 1</td><td>B</td>

<td>2 - [(tert-butoxy) carbonylamino] -N- {[1- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- yl) pyrazol-4-yl] methyl} acetamide</td><td> 501,1</td><td>D</td>

<td>2-amino-N- {[1- (2- ([1- (3-chloro (2- pyridyl)) - isopropyl] amino} pyrimidin-5- yl) pyrazol-4-yl] methyl} acetamide</td><td> 401, 1</td><td>B</td>

<td>3 - [(tert-butoxy) carbonylamino] -N- {[1- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyrazol-4-yl] methylJpropanamide</td><td> 515,1</td><td>D</td>

<td>3-amino-N - {[1- (2 - ([1- (3-chloro (2- pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyrazol-4-yl] methylJpropanamide</td><td> 415, 1</td><td>B</td>

-295-

<td>l- [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] pyrazol-4-carbonitrile</td><td> 368,2</td><td>C</td>

<td>([3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} pyrimidin -2-ylamine</td><td> 277,2</td><td>D</td>

<td>1- (2 - (([3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-i1] pyrazole-4-carboxamide</td><td> 382,3</td><td>B</td>

<td>3- (2 - ([2- (3-chloro (2-pyridyl)) - 2- methylpropyl] amino} pyrimidin-5- il) benzamide</td><td> 382,3</td><td>TO</td>

<td>3- (2 - ([2- (3-chloro (2-pyridyl)) - 2- methylpropyl] amino} pyrimidin-5-i1) - 4- fluorobenzamide</td><td> 400, 2</td><td>TO</td>

<td>2- (2 - ([(IR) -1- (3-chloro (2-pyridyl)) - 2-methylpropyl] amino} pyrimidin-5- il) -1,3-thiazol-5-carbonitrile</td><td> 371, 2</td><td>D</td>

<td>2- (2 - ([(1S) -1- (3-chloro (2-pyridyl)) - 2-methylpropyl] amino} pyrimidin-5- il) -1,3-thiazol-5-carbonitrile</td><td> 371,2</td><td>D</td>

<td>2- (2 - ([(IR) -1- (3-chloro (2-pyridyl)) - 2-methylpropyl] amino} pyrimidin-5- yl) -1,3-thiazol-5-carboxamide</td><td> 389,2</td><td>D</td>

-296-

<td>2- (2 - ([(IS) -1- (3-chloro (2-pyridyl)) - 2-methylpropyl] amino} pyrimidin-5- yl) -1,3-thiazol-5-carboxamide</td><td> 389,2</td><td>D</td>

<td>3- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) ethyl isoxazol-5-carboxylate</td><td> 388,2</td><td>D</td>

<td>3- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) isoxazol-5-carboxamide</td><td> 359,2</td><td>C</td>

<td>(5- (lH-indazol-5-yl) pyrimidin-2- yl) [1- (3-chloro (2-pyridyl)) - isopropyl] amine</td><td> 365, 1</td><td>TO</td>

<td>N- [5- (2- {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -1H- indazol-3-yl] acetamide</td><td> 422, 1</td><td>B</td>

<td>3— [2 - ({[1- (3-chloro (2-pyridyl)) - 3- fluorocyclobutyl] methyl} amino) pyrimi din-5-yl] -4-fluorobenzamide</td><td> 430,2</td><td>TO</td>

<td>3 - [2 - ({[1- (3-chloro (2-pyridyl)) - 3- fluorocyclobutyl] methyl} amino) pyrimi din-5-yl] -4-fluorobenzamide</td><td> 430,2</td><td>TO</td>

<td>4-fluoro-3- (2- {[(3-fluoro-1- (2- pyridyl) cyclobutyl) methyl] amino) pyri midin-5-yl) benzamide</td><td> 396, 2</td><td>TO</td>

-297-

<td>4-fluoro-3- (2 - {[(3-fluoro-1- (2- pyridyl) cyclobutyl) methyl] aminojpiri midin-5-yl) benzamide</td><td> 396,2</td><td>B</td>

<td>6— (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyrimidin-4-carboxamide</td><td> 370,2</td><td>B</td>

<td>6- (2- {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyrimidin-4-carboxylate methyl</td><td> 385, 2</td><td>D</td>

<td>3- {2 - [(tert-butyl) amino] pyrimidine- 5-yl} benzamide</td><td> 271, 3</td><td>D</td>

<td>[5- (3-amino (lH-indazol-5- yl)) pyrimidin-2-yl] (tert- butyl) amine</td><td> 283, 3</td><td>B</td>

<td>3- (2 - {[1- (3-chloro (2-pyridyl)) - 3- fluorocyclobutyl] amino} pyrimidin-5- il) -4-fluorobenzamide</td><td> 416,2</td><td>TO</td>

<td>3- [2 - ({[(3-chlorine (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -4-fluorobenzamide</td><td> 412,2</td><td>TO</td>

<td>3 - [2 - ({[(3-chloro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5-yl] benzamide</td><td> 394,3</td><td>TO</td>

-298-

<td>3- (2 - ([(2- pyridylcyclobutyl) methyl] amino} pyrim idin-5-yl) benzamide</td><td> 360,3</td><td>B</td>

<td>4-fluoro-3- (2 - {[(2- pyridylcyclobutyl) methyl] amino} pyrim idin-5-yl) benzamide</td><td> 378,3</td><td>TO</td>

<td>3- [2- ({[(3-chlorine (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -4- fluorobenzenecarbonitrile</td><td> 394,2</td><td>TO</td>

<td>3- [2- ({[(3-chloro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5-yl] benzenecarbonitrile</td><td> 376, 2</td><td>TO</td>

<td>{[(3-chlorine (2- pyridyl)) cyclobutyl] methyl} pyrimidin -2-ylamine</td><td> 275, 2</td><td>D</td>

<td>3 - (2 - {[l- (2-chloro (3-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -4- fluorobenzamide</td><td> 386,2</td><td>B</td>

<td>6- (2- {[1- (3-chloro (2- pyridyl)) - isopropyl] amino} pyrimidin-5- il) imidazo [2,1-b] 1,3-thiazolin-3- carboxylic</td><td> 415, 0</td><td>B</td>

-299-

<td>2- (2 - {[1- (3-chloro (2- pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -4- hydroimidazo [1,2-a] pyridin-6- carboxylic</td><td> 409,1</td><td>D</td>

<td>2- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -4- hydroimidazo [1,2-a] pyridin-6- carboxamide</td><td> 408,1</td><td>C</td>

<td>1— [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] pyrrole-3-carboxylate from methyl</td><td> 400,3</td><td>D</td>

<td>1- [2 - ({[3-fluoro-l- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] pyrrole-3-carboxylic</td><td> 386, 3</td><td>D</td>

<td>1— [2 - ({[3-fluoro-1- (3-fluoro (2-</td><td></td><td></td>

<td>pyridyl)) cyclobutyl] methyl} amino) pyr</td><td> 385, 3</td><td>TO</td>

<td>imidin-5-yl] pyrrole-3-carboxamide</td><td></td><td></td>

<td>2- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -4- hydroimidazo [1,2-a] pyridin-8- carboxamide</td><td> 408,1</td><td>B</td>

-300-

<td>2- (2 - ([1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -4- hydroimidazo [1,2-a] pyridin-7- carboxamide</td><td> 408,1</td><td>D</td>

<td>5- (2— {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyridazine-3-carboxamide</td><td> 370,2</td><td>B</td>

<td>N- (tert-butyl) [5- (2 - ([1- (3-chloro (2- pyridyl)) - isopropyl] amino} pyrimidin-5- il) pyridazin-3-yl] carboxamide</td><td> 426, 2</td><td>D</td>

<td>{3- [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] phenyl} -N- (methylsulfonyl) carboxamide</td><td> 474,1</td><td>TO</td>

<td>2- {2- [2 - ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5-yl] -1,3-thiazol-5- il} ethanonitrile</td><td> 381, 2</td><td>B</td>

<td>2- {2- [2 - ({[(3-chloro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5-yl] -1,3-thiazol-5- il} acetamide</td><td> 415, 1</td><td>TO</td>

-301 -

<td>3 - [2- ({[1- (3-chloro (2-pyridyl)) - 3,3- difluorocyclobutyl] methyl} amino) pyri midin-5-ii] -4-fluorobenzamide</td><td> 448,2</td><td>TO</td>

<td>3- [2- ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) -4- methylpyrimidin-5-yl] benzamide</td><td> 410, 1</td><td>B</td>

<td>2- (2- (2 - (([(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5-yl] -1,3-thiazol-5- il} acetamide</td><td> 399,2</td><td>B</td>

<td>2- (2- [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -1,3-thiazol-5- il} acetamide</td><td> 417,1</td><td>B</td>

<td>(tert-butoxy) -N- ((2- [2- ({[(3- fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] (1,3-thiazol-5- il) (methyl) carboxamide</td><td> 471, 2</td><td>B</td>

<td>{5- [5- (aminomethyl) (l, 3-thiazol-2- il)] pyrimidin-2-yl} {[(3-fluoro (2- pyridyl)) cyclobutyl] methyl (amine</td><td> 371, 1</td><td>C</td>

-302-

<td></td><td>Ν- ({2- [2 - ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5-yl] -l, 3-thiazol-5- il} methyl) acetamide</td><td></td><td>B</td>

<td> 5</td><td>(tert-butoxy) -N - ({2— [2 - ({[(3- chlorine (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] (1,3-thiazol-5- il) Jmethyl) carboxamide</td><td></td><td>TO</td>

<td> 10</td><td>{5- [5- (aminomethyl) (1,3-thiazol-2- yl)] pyrimidin-2-yl} {[(3-chloro (2- pyridyl)) cyclobutyl] methyl Jamin</td><td> 387, 1</td><td>B</td>

<td> 15</td><td>N- ((2- [2 - ({[(3-chloro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5-yl] -1,3-thiazol-5- il} methyl) acetamide</td><td> 429, 1</td><td>TO</td>

<td> 20</td><td>({2- [2- ({[(3-fluoro (2- pyridii)) cyclobutyl] methyl} amino) pyr imidin-5-yl] (1,3-thiazol-5- il) Jmethyl) (methylsulfonyl) amine</td><td> 449, 1</td><td>B</td>

<td></td><td>2- {2— [2 - ({[1- (3-chloro (2-pyridyl)) - 3- fluorocyclobutyl] methyl} amino) pyrimi din-5-yl] -1,3-thiazol-5-yl} acetamide</td><td> 433,2</td><td>B</td>

-303-

<td>(tert-butoxy) -N - {[2- (2 - {[(2- pyridylcyclobutyl) methyl] amino} pyrim idin-5-yl) (1,3-thiazol-5- il)] methyl} carboxamide</td><td></td><td>B</td>

<td>[2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -N-isoxazol-3- ilcarboxamide</td><td> 369, 2</td><td>B</td>

<td>[2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -N- (1,3-thiazol-2- il) carboxamide</td><td> 385,2</td><td>B</td>

<td>2 - ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5-carboxamide</td><td> 302,2</td><td>D</td>

<td>[2— ({[(3-fluoro (2- pyridyl)) cyclobutyl] methy1} amino) pyr imidin-5-yl] -N-methylcarboxamide</td><td> 316, 2</td><td>D</td>

<td>N-ethyl [2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] carboxamide</td><td> 330,2</td><td>D</td>

<td>[2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -N- (2- hydroxyethyl) carboxamide</td><td> 346, 2</td><td>D</td>

-304-

<td>Ν- {2 - [(tert- butoxy) carbonylamino] ethyl} [2 - ({[(3- fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] carboxamide</td><td> 445,2</td><td>D</td>

<td>N— (2 - {[2— ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5- yl] carbonylamino} ethyl) acetamide</td><td> 387,2</td><td>D</td>

<td>2 - {[2 - ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl} amino) pyri midin-5-yl] carbonylamino} acetate methyl</td><td> 374,2</td><td>D</td>

<td>{3- [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl) amino) pyr imidin-5-i1] phenyl} -N- methylcarboxamide</td><td> 410,3</td><td>B</td>

<td>{4-fluoro-3- [2 - ({[3-fluoro-1- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] phenyl} -N- methylcarboxamide</td><td> 428,3</td><td>TO</td>

- 305-

<td>[2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -N-pyrazole-5- ilcarboxamide</td><td> 368,2</td><td>C</td>

<td>5-aminopyrazolyl-2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl ketone</td><td> 368,2</td><td>C</td>

<td>[2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -N- (3-methylpyrazol-5- il) carboxamide</td><td> 382,2</td><td>D</td>

<td>N- (2-aminoethyl) [2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] carboxamide</td><td> 346, 2</td><td>D</td>

<td>[2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methylamino) pyr imidin-5-yl] -N- {2- [(methylsulfonyl) amino] ethyl} carboxam Going</td><td> 423, 2</td><td>D</td>

<td>acid 2 - {[2 - ({[(3-fluoro-2- pyridyl) cyclobutyl] methyl Jamino) pyri midin-5-yl] carbonylamino} acetic</td><td> 360,2</td><td>D</td>

-306 -

<td></td><td>{3 - [2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methylamino) pyr imidin-5-yl] phenyl} -N- methylcarboxamide</td><td> 392,3</td><td>B</td>

<td> 5</td><td>{4-fluoro-3 - [2— ({[(3-fluoro (2- pyridyl)) cyclobutyl] methylamino) pyr imidin-5-yl] phenyl} -N- methylcarboxamide</td><td> 410, 3</td><td>B</td>

<td> 10</td><td>[2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -N-benzamide</td><td> 378,2</td><td>C</td>

<td></td><td>[2 - ({[(3-fluoro (2-</td><td></td><td></td>

<td> 15</td><td>pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -N- (3- pyridyl) carboxamide</td><td> 379, 2</td><td>C</td>

<td></td><td>{3- [2- ({[(3-fluoro (2- pyridii)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -4-hydroxyphenyl} -N- methylcarboxamide</td><td> 408,1</td><td>B</td>

<td> 20</td><td>3- [2 - ({[(3-fluoro (2-</td><td></td><td></td>

<td></td><td>pyridyl)) cyclobutyl] methyl} amino) pyr</td><td> 394,2</td><td>TO</td>

<td></td><td>imidin-5-yl] -4-hydroxybenzamide</td><td></td><td></td>

-307-

<td>{3— [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -4-hydroxyphenyl} -N- methylcarboxamide</td><td> 426,1</td><td>TO</td>

<td>3— [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl (amino) pyr imidin-5-yl] -4-hydroxybenzamide</td><td> 412, 1</td><td>TO</td>

<td>{1- [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] pyrrole-3-yl) -time ti lcarboxamide</td><td> 399, 3</td><td>B</td>

<td>[2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -N- (l-methylpyrazol-5- il) carboxamide</td><td> 382,2</td><td>D</td>

<td>[2 - ({[(3-fluoro (2- pyridii)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -N- (4- pyridyl) carboxamide</td><td> 379, 2</td><td>B</td>

<td>2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl pyrazolyl ketone</td><td> 353, 2</td><td>C</td>

-308-

<td>[2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -N- (1,3,4-thiadiazol-2- il) carboxamide</td><td> 386, 2</td><td>B</td>

<td>[2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -N- (2- fluorophenyl) carboxamide</td><td> 396, 2</td><td>D</td>

<td>[2— ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -N- (3- fluorophenyl) carboxamide</td><td> 396,2</td><td>D</td>

<td>[2- ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -N- (4- fluorophenyl) carboxamide</td><td> 396,2</td><td>D</td>

<td>[2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -N- (β-methoxy (3- pyridyl)) carboxamide</td><td> 409, 2</td><td>D</td>

<td>{2 - [2 - ({[3-fluoro-1- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] (4-pyridyl)} - N- methylcarboxamide</td><td> 411, 3</td><td>B</td>

-309-

<td>{[2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] amino} -N- (1,3-thiazol-2- il) carboxamide</td><td> 400,2</td><td>B</td>

<td>[2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -N-methyl-N- (1,3-thiazole- 2-yl) carboxamide</td><td> 399,2</td><td>D</td>

<td>{[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} (5- imidazol-2-ylpyrimidin-2-yl) amine</td><td> 325, 3</td><td>C</td>

<td>N- [2- ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -1,3-thiazol-2- ilcarboxamide</td><td> 385, 2</td><td>D</td>

<td>7- [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] indolin-2-one</td><td> 408,3</td><td>B</td>

<td>3- [2 - ({[3-fluoro-l- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -4-hydroxybenzoic</td><td> 413, 1</td><td>TO</td>

-310-

<td>3- [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -4-hydroxybenzoate of methyl</td><td> 427,1</td><td>TO</td>

<td>1- [2 - ({[3-fluoro-l- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -6-oxohydropyridin-3- carboxylic</td><td> 414,1</td><td>D</td>

<td>l ^- [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -6-oxohydropyridin-3- carboxamide</td><td> 413, 1</td><td>D</td>

<td>2— [2 - ({[3-fluoro-1- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] pyrimidin-4- carbonitrile</td><td> 380, 3</td><td>B</td>

<td>(2- [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] pyrimidin-4-i1) -N- methylcarboxamide</td><td> 412,3</td><td>B</td>

<td>2— [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methylamino) pyr imidin-5-yl] pyrimidin-4-carboxamide</td><td> 398,3</td><td>B</td>

-311 -

<td>7— [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] isoindolin-l-one</td><td> 408,1</td><td>B</td>

<td>{[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl) [5 - (2 - fluorophenyl) pyrimidin-2-yl] amine</td><td> 371, 3</td><td>TO</td>

<td>2— [2— ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] benzamide</td><td> 396, 3</td><td>C</td>

<td>2- {2- [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] phenyl} acetamide</td><td> 410,3</td><td>C</td>

<td>N- {2- [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] phenyl} acetamide</td><td> 410, 3</td><td>D</td>

<td>2- [2- ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] benzene-1,4- dicarboxamide</td><td> 439, 3</td><td>B</td>

<td>4-fluoro-2- [2 - ({[3-fluoro-1- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] benzamide</td><td> 414,3</td><td>B</td>

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<td>2- (2 - (([3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methylamino) pyr imidin-5-yl] pyridin-4-carbonitrile</td><td> 379, 2</td><td>B</td>

<td>2- (2 - (([3-fluoro-1- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] pyridin-4-carboxamide</td><td> 397,3</td><td>B</td>

<td>2- {3- [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methylamino) -4- methylpyrimidin-5-yl] phenyl} acetamide</td><td> 424,3</td><td>C</td>

<td>4- [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) -4- methylpyrimidin-5- il] benzenecarbonitrile</td><td> 392,3</td><td>D</td>

<td>4— [2 - ({[3-fluoro-1- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) -4- methylpyrimidin-5-yl] benzamide</td><td> 410, 3</td><td>D</td>

<td>6— [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methylamino) pyr imidin-5-yl] pyridin-3-ol</td><td> 370,2</td><td>B</td>

<td>[5- (5-aminopyrazin-2-yl) pyrimidine- 2-yl] {[3-fluoro-1- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amine</td><td> 370, 1</td><td>B</td>

<td>5— [2 - ({[3-fluoro-l- (3-fluoro (2- pyridii)) cyclobutyl] methylamino) pyr imidin-5-yl] -2-hydroxybenzamide</td><td> 412, 1</td><td>TO</td>

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<td>2- {4- [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) -4- methylpyrimidin-5-yl] phenyl} acetamide</td><td> 424,3</td><td>B</td>

<td>2- {4- [2 - ({[3-fluoro-1- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amino) -4- methylpyrimidin-5-yl] phenyl} acetic</td><td> 425, 3</td><td>D</td>

<td>[5- (2-amino-5-methylpyrimidin-4- yl) pyrimidin-2-yl] {[3-fluoro-1- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amine</td><td> 384,3</td><td>D</td>

<td>[5- (2-amino-4-methylpyrimidin-5- yl) pyrimidin-2-yl] {[3-fluoro-1- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amine</td><td> 384,3</td><td>C</td>

<td>3— [2 - ({[3-fluoro-1- (3-fluoro (2-</td><td></td><td></td>

<td>pyridyl)) cyclobutyl] methyl} amino) pyr</td><td> 370, 2</td><td>C</td>

<td>imidin-5-yl] pyridin-2-ol</td><td></td><td></td>

<td>[5- (6-aminopyridazin-3- yl) pyrimidin-2-yl] {[3-fluoro-l- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amine</td><td> 370, 1</td><td>B</td>

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<td>[5- (2-aminopyrimidin-5- yl) pyrimidin-2-yl] {[3-fluoro-l- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amine</td><td> 370, 1</td><td>B</td>

<td>5— [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-i1] pyridin-2-ol</td><td> 370,2</td><td>D</td>

<td>{[3-fluoro-1- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} [5— (6— methoxy (3-pyridyl)) pyrimidin-2- il] amine</td><td> 384,3</td><td>D</td>

<td>[5- (6-aminopyrazin-2-yl) pyrimidine- 2-yl] {[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amine</td><td> 370, 1</td><td>B</td>

<td>[5- (2-aminopyrimidin-4- yl) pyrimidin-2-yl] {[3-fluoro-1- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amine</td><td> 370, 1</td><td>C</td>

<td>[5- (2-amino-5-fluoropyrimidin-4- yl) pyrimidin-2-yl] {[3-fluoro-1- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amine</td><td> 388,1</td><td>B</td>

<td>5- {2- [4- (3-fluoro-2-pyridyl) -2- azabicyclo [2.1.1] hex-2- il] pyrimidin-5-yl} pyrimidin-2-ol</td><td> 351,2</td><td>D</td>

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<td>(5-bromo-4-methoxypyrimidin-2- il) {[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amine</td><td> 387, 1</td><td>D</td>

<td>(5-bromo-4-methoxypyrimidin-2- il) {[3-fluoro-l- (3-fluoro (2- pyridii)) cyclobutyl] methyl} amine</td><td> 387,1</td><td>D</td>

<td>3— [2 - ({[3-fluoro-l- (3-fluoro (2- pyridii)) cyclobutyl] methyl} amino) -4- methoxypyrimidin-5-yl] benzamide</td><td> 426, 3</td><td>TO</td>

<td>3- [2 - ({[3-fluoro-1- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amino) -4- hydroxypyrimidin-5-yl] benzoic</td><td> 413, 2</td><td>D</td>

<td>3— [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methylamino) -4- hydroxypyrimidin-5-yl] benzamide</td><td> 412,2</td><td>B</td>

<td>5— [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methylamino) pyr imidin-5-yl] pyrimidin-2-ol</td><td> 371,3</td><td>D</td>

<td>{[3-fluoro-1- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} [5- (2- methoxypyrimidin-5-yl) pyrimidin-2- il] amine</td><td> 385,3</td><td>D</td>

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<td>6— [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methylamino) pyr imidin-5-yl] pyridazin-3-ol</td><td> 371,2</td><td>D</td>

<td>([3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} [5— (6— methoxypyridazin-3-yl) pyrimidin-2- il] amine</td><td> 385,2</td><td>D</td>

<td>1- [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -4-hydroxyhydropyridin- 2- one</td><td> 386, 2</td><td>D</td>

<td>5-fluoro-6- [2 - ({[3-fluoro-l- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] pyridin-3-ol</td><td> 388,2</td><td>B</td>

<td>{3- [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] phenyl} -N- (1- methylazetidine-3-yl) carboxamide</td><td> 465, 3</td><td>TO</td>

<td>{4-fluoro-3- [2 - ({[3-fluoro-l- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-i1] phenyl} -N- (1- methylazetidine-3-yl) carboxamide</td><td> 483, 3</td><td>B</td>

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<td>Ν- (l-acetylazetidin-3-yl) {3— [2 - ({[3-fluoro-1- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] phenyl [carboxamide</td><td> 493, 3</td><td>B</td>

<td>N- (l-acetylazetidin-3-yl) {4-fluoro- 3- [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] phenyl} carboxamide</td><td> 511, 3</td><td>B</td>

<td>{4-fluoro-3- [2- ({[3-fluoro-1- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] phenyl} -N- [1- (methylsulfonyl) azetidin-3- il] carboxamide</td><td> 547,2</td><td>B</td>

<td>{3- [2 - ({[3-fluoro-1- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] phenyl} -N- [1- (methylsulfonyl) azetidin-3- il] carboxamide</td><td> 529, 3</td><td>B</td>

<td>{[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} (4- methoxy-5-phenylpyrimidin-2-yl) amine</td><td> 383,2</td><td>B</td>

<td>{[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} (4- methoxy-5-phenylpyrimidin-2-yl) amine</td><td> 383, 3</td><td>B</td>

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<td>{[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} (4- methoxy-5-phenylpyrimidin-2- il) methylamine</td><td> 397,2</td><td>D</td>

<td>{[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} (4- methoxypyrimidin-2-yl) amine</td><td> 307,1</td><td>D</td>

<td>(4-amino-5-phenylpyrimidin-2-yl) {[3- fluoro-1- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amine</td><td> 368,1</td><td>B</td>

<td>{[3-fluoro-1- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} [4- (methylamino) -5-phenylpyrimidin-2- il] amine</td><td> 382, 1</td><td>D</td>

<td>[2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) -5- phenylpyrimidin-4-yl] dimethylamine</td><td> 396, 1</td><td>D</td>

<td>[2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) -5- phenylpyrimidin-4-yl] (2- methoxyethyl) amine</td><td> 426,1</td><td>D</td>

<td>(3 - [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] phenyl} -N- (3- hydroxycyclobutyl) carboxamide</td><td> 466, 3</td><td>B</td>

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<td>{4-fluoro-3- [2 - ({[3-fluoro-l- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] phenyl} -N- (3- hydroxycyclobutyl) carboxamide</td><td> 484,3</td><td>TO</td>

<td>4-fluoro-3- [2 - ({[3-fluoro-l- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -2-hydroxybenzamide</td><td> 430, 1</td><td>TO</td>

<td>3— [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -2-hydroxybenzamide</td><td> 412, 1</td><td>TO</td>

<td>[5- (2,6-dimethoxypyrimidin-4- yl) pyrimidin-2-yl] {[3-fluoro-l- (3- fluoro (2- pyridyl)) cyclobutyljmethyl [amine</td><td> 415, 2</td><td>D</td>

<td>[5- (2,4-dimethoxypyrimidin-5- yl) pyrimidin-2-yl] {[3-fluoro-l- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amine</td><td> 415, 2</td><td>D</td>

<td>6— [2 - ({[3-fluoro-1- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -1,3-dihydropyrimidin- 2,4-dione</td><td> 387,2</td><td>B</td>

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<td>5— [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -1,3-dihydropyrimidin- 2,4-dione</td><td> 387,2</td><td>D</td>

<td>3-amino-6- [2 - ({[3-fluoro-l- (3- fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] hydropyrazin-2-one</td><td> 386,2</td><td>B</td>

<td>{3 - [2 - ({[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] -2-hydroxyphenyl} -N- methylcarboxamide</td><td> 426, 2</td><td>B</td>

<td>[2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-4-yl] -N-benzamide</td><td> 378,3</td><td>D</td>

<td>[2 - ({[(3-fluoro (2- pyridyl)) cyclobutyl] methylamino) pyr imidin-4-yl] -N-methyl-N-benzamide</td><td> 392,3</td><td>D</td>

<td>{[3-fluoro-l- (3-fluoro (2- pyridyl)) cyclobutyl] methyl} [5— (3— methoxy-6-methyl (2- pyridyl)) pyrimidin-2-yl] amine</td><td> 398,2</td><td>C</td>

<td>((IR) -1-phenylethyl) [4- (cyclohexylamino) -6- methylpyrimidin-2-yl] amine</td><td> 311,3</td><td>B</td>

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<td>3- [2- ({[3-fluoro-l- (3-fluoro-6- methyl (2- pyridyl)) cyclobutyl] methyl} amino) pyr imidin-5-yl] benzamide</td><td> 410,2</td><td>TO</td>

Although the present invention has been described with reference to the specific embodiments described herein, it should be understood by those skilled in the art that various changes can be made and the equivalents can be substituted without departing from the true spirit and scope of the invention. Furthermore, modifications can be made to adapt a particular situation, material, composition of matter and / or process to the objective, spirit and scope of the present invention.

All of these modifications are intended to be included within the scope of the appended claims.

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