Certain amino-pyridazines, compositions thereof, and methods of their use.

(54) Title: CERTAIN AMINO-PIRIDAZINES, COMPOSITIONS OF THE SAME AND METHODS OF USE THEREOF. (54) Title: CERTAIN AMINO-PYRIDAZINES, COMPOSITIONS THEREOF, AND METHODS OF THEIR USE.

(57) Summary

Compounds of Formula I are provided: (see formula) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, X and m are as defined herein 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.

CERTAIN AMINO-PIRIDAZINES, COMPOSITIONS OF THE SAME AND METHODS

OF USE OF THE SAME

This application claims priority benefit from United States Provisional Applications No. 61 / 327,538, filed on April 23, 2010 and 61 / 412,302 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 closkeletal 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 attached to the actin elements, which allow the contraction to be modulated by calcium ions. An inflow of intracellular calcium initiates muscle contraction; the thick and fine filaments slide across each other driven by repeated interactions of the myosin motor domains with the 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 nucleus of the

-2 sarcoomer 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 (conferring 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 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 catalytic domain and light chain to its starting conformation / 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

-3positioning 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 the 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 ATPase activity.

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>Rapid skeleton</td><td>Slow skeleton</td>

<td>Heavy Chain from myosin</td><td>lia, (llb *), llx / 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 / ΤΜ-α / ΤΡΜ 3</td><td>ΤΜ-β / TM-as</td>

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

-4In healthy human beings, most skeletal muscles are composed 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 fibers (lia) and fast glycolytic fibers (type llx / d). Although these muscle fibers have different types of mlosin, they share many components, including the regulatory proteins of troponin and tropomlosin. 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.

Muscle 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 slnapsis 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 membrane invasions, called T tubules. Tubules T

-5 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 + reserves in the SR into the muscle cytoplasm where it can interact with the troponin complex to initiate 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 skeletal muscle contractility. 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.

-6 A compound of Formula I is provided:

R¹

R² 'N

Z. (CR⁸R⁹)_mR³'' 'iZ N

R⁷

<img file="MX2012012259A_D0001.tif" />

R⁵ R⁶

R⁴

Formula I or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, 5 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 for treating a disease or condition sensitive to modulation of skeletal sarcomere contractility, eg, modulation of the troponin complex of rapid skeletal muscle sarcomere through one or more of myosin, actin, tropomyosin, troponin C , rapid skeletal troponin I and troponin T, and fragments and isomers thereof.

As used herein, the following words and 15 phrases are generally intended to have the meanings set forth below, except to the extent that the context in which they are used Indicate 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, subgenres,

-7 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, N-oxides, S-oxides), esters , prodrugs, isotopes and / or protected forms thereof. Crystalline, polymorphic and novel forms may 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, non-solvated polymorphs ( 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, salts, 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 compound compound 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 experts in the field, with respect to

-8 any group containing one or more substituents, that said groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically infeasible and / or intrinsically unstable.

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

C2-5, C3.5, C4.5, Ci_4, C2-4, C3.4, C-i_3, C2-3 and Ci_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 C ^ -alkyl or C ^ -alkyl, where C ^ -alkyl is optionally substituted with halogen, then both the Ci_alkyl group₆ just like Ci alkyl.₆ which is part of the Oalquilo Ci group.₆ they may 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, C- | alkyl.₆ includes straight or branched chain alkyl of 1 to 6 carbon atoms. When an alkyl moiety having a specified number of carbons is named, it is intended to include all branched and linear chain versions having that number of carbons; therefore, for example, propyl includes n-propyl and isopropyl; and butyl includes n-butyl, secbutyl, 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, 2-pentyl, 3pentyl, isopentyl, neopentyl, hexyl, 2-hexyl , 3-hexyl and 3-methylpentyl. Lower alkyl refers to alkyl groups having 1 to 6 carbons.

Haloalkyl includes straight and branched carbon chains having the indicated number of carbon atoms (eg, 1 to 6 carbon atoms)

-9substituted with at least one halogen atom. In cases 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, 2-chloroethyl , 2,2-dichloroethyl, 2,2,2-trichloroethyl, 1,2-dichloroethyl, pentachloroethyl and pentafluoroethyl.

Alkenyl refers to an unsaturated, straight or branched chain alkyl group having the indicated number of carbon atoms (eg, 2 to 8, or 2 to 6 carbon atoms) and at least one carbon double bond -carbon 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-1-en-1-yl, prop-1-en-215 yl, prop-2-en-1-yl (allyl), prop- 2-en-2-yl) and butenyl (for example, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but- 2-en-1-yl, but-2-en-1-yl, but-2-en-2-ylo, buta-1,3dien-1-yl, buta-1,3-dien-2-yl ). Lower alkenyl refers to alkenyl groups having 2 to 6 carbons.

Alquinyl refers to an unsaturated, straight or branched chain alkyl group having the indicated number of carbon atoms (for example, de2a8ode2a6 carbon atoms) and at least one carbon-carbon triple bond obtained 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-1 -in-1-yl, prop-2-in-1-yl), and butynyl (eg, but-1-in-1- yl, but-1-in-3- 10yl, but-3-in-1-yl). Lower alkynyl refers to alkynyl groups having 2 to 6 carbons.

Cycloalkyl indicates a fully saturated, non-aromatic, carbocyclic ring having the indicated number of carbon atoms, eg, 3 to 10, or 3 to 8, or 3 to 6 carbon atoms in the ring. 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, blcyclo [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-1-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-llo (in which 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 carbocyclic, non-aromatic ring containing the indicated number of carbon atoms (eg, 3 to 10, or 3 to 8, or 3 to 6 carbon atoms in the ring) and at least a double carbon-carbon bond obtained from the removal of a hydrogen molecule from adjacent carbon atoms of the corresponding cycloalkyl. Cycloalkenyl groups can be monocyclic or polycyclic (eg, bicyclic, tricyclic). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and chlorohexenyl, as well as bridged and closed 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-1-io (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 denotes an aromatic carbon ring having the stated number of carbon atoms, for example 6 to 12 or 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, 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-1-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 1,2,3,4-tetrahydroquinolin-1-yl group (in which the remainder is attached to the parent structure through a non-nitrogen atom

- 12 aromatic) 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 (eg, quinolin-5-yl and quinolin-2-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 (eg, de7a12ode7a10 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 1-phenylethyl.

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 contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group is not greater than 2. In some embodiments, the total number of S and O atoms in the heteroaryl group is not greater than 1. Unless otherwise indicated, 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, 2-pyrrolyl, and 3-pyrrolyl groups. When nitrogen is present in a heteroaryl ring, it can exist, when the nature of adjacent atoms and groups permits, in an oxidized state (i.e., N⁺-OR). 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 'o

- 13SO₂). 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 (eg 1,2,3-oxadiazole, 1,2,4 oxadiazole, 1,3,4-oxadiazole), thiophene, sothiazole, thiazole, thiadiazole (eg 1,2,3thiadiazole, 1,2,4 -thiadlazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (eg 1,2,4-triazine, 1,3,5-triazine) and tetrazine.

In some cases, the two rings of a polycyclic heteroaryl group are aromatic. Examples include indole, isoindol, indazole, benzoimidazole, benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole, benzothlofen, benzothiazole, benzoisothiazole, benzothiadiazole, 1H-pyrrolo [2,3-b] pyridine, 1H-prazolo 3,4-b] pyridine, 3H, midazo [4,5-b] pyridine, 3H- [1,2,3] triazolo [4,5-b] pyridine, 1H-pyrrolo [3,2 -b] pyridine, 1H-pyrazolo [4,3-b] pyridine, 1H-imidazo [4,5-b] pyridine, 1H- [1,2,3] tr¡azolo [4,5- b] pyridine, 1Hpyrrolo [2,3-c] pyridine, 1H-pyrazolo [3,4-c] pyridine, 3H-midazo [4,5-c] pyridine, 3H [1.2.3] triazolo [4,5-c] pyridine, 1 Hprrolo [3,2-c] pyridine, 1 H-pyrazolo [4,3-c] pyridine, 1H¡m¡dazo [4,5-c] pyridine, 1H- [1,2,3] triazolo [4,5-c] p¡ ridin, furo [2,3-b] pyridine, oxazolo [5,4bjpyrldine, isoxazolo [5,4-b] plridine, [1,2,3] oxadiazolo [5,4-b] pyridine , furo [3,2-b] pyridine, oxazolo [4,5-b] pyridine, ¡soxazolo [4,5-b] pyridine, [1,2,3] oxadiazolo [4,5-b ] pyridine, furo [2,3cjpyridine, oxazolo [5,4-c] pyridine, isoxazolo [5,4-c] pyridine, [1,2,3] oxadiazole [5,4-c] pyridine, furo [3,2-c] pyridine, oxazolo [4,5-c] pyridine, soxazolo [4,5-c] pyridine, [1,2,3] oxadiazolo [4, 5cjpyridine, tiene [2,3-b] pyridine, thiazolo [5,4-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, isothiazole [4,5bjpyridine, [1,2,3] thiadiazolo [4,5-b] pyridine, thieno [ 2,3-c] p¡ridine, t¡azolo [5,4-c] p¡r¡d¡na, sotiazolo [5,4-c] pyridine, [1,2,3] thiadiazolo [ 5,4-c] pyridine, thieno [3,2-c] pyridine, thiazolo [4,5-14c] pyridine, sotlazolo [4,5-c] pyridine , [1,2,3] thiadiazolo [4,5-c] p¡r¡d¡na, quinoline, ¡soquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (eg 1,8-naphthyridine, 1 , 7naphthyridine, 1,6-naphthridine, 1,5-naphthyrldine, 2,7-naphthyridine, 2,6-naphthyrldine), imidazo [1,2ajpyridine, 1H-pyrazolo [3,4-d] thiazole, 1 Hp ¡Razolo [4,3-d] t¡azol and ¡m¡dazo [2,1-b] t¡azol.

In other cases, 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-tetrahldrobenzo [d] thiazol-2-llo 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.

Heterocycloalkyl indicates a non-aromatic, fully saturated ring having the indicated number of atoms (eg, 3- to 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 atoms of the ring are carbon. Heterocycloalkyl groups can be monocyclic or polycyclic (eg, bicyclic, tricyclic). Examples of heterocycloalkyl groups include oxyranyl, aziridinyl, azetidyl, pyrrolidinyl, imidazolidyl, pyrazolidinyl, piperidinyl, plperazinyl, morpholinyl, and thiomorpholinyl. 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 * -O). Examples include N-oxide

-15 piperidinyl 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⁺-O '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 polycyclic heterocycloalkyl group is attached to the parent structure through a non-aromatic carbon atom or a nitrogen atom . For example, a 1,2,3,4-tetrahydroquinoline-1-yl group (in which the moiety is attached to the parent structure through a non-aromatic nitrogen atom) is considered a heterocycloalkyl group, while the 1,2,3,4-tetrahydroquinolin-8-yl group (in which 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, 3-10ode3a7 membered heterocycloalkyl) consisting of one or more heteroatoms (eg, 1, 2, 3 or 4 heteroatoms) selected from N, O and S and in the that 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, tricyclic). 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⁺-O). Also, when sulfur is present in a ring

- 16heterocycloalkenyl, may exist, when the nature of adjacent atoms and groups allows, in an oxidized state (i.e. S⁺-O 'or -SO₂-). Examples of heterocycloalkenyl groups include dihydrofuranyl (eg, 2,3-dihydrofuranyl, 2,5dihydrofuranyl), dihldrotlophenyl (eg, 2,3-dihldrothiophenyl, 2,5-dihydrotlophenyl), dihydropyrrolyl (eg, 2,3-dihydro -1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl), dihydrolmidazolyl (for example, 2,3-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl, dihydropyranyl ( for example, 3,4-dih¡dro-2H-p¡ran¡lo, 3,6-d¡h¡dro-2H-piran¡lo), tetrahydropyridinyl (eg 1,2,3,4-tetrahydropyrldinyl, 1,2,3,6-tetrahydropyrldinyl) and dihydropyridine (eg 1,2-dihydroplridine, 1,4-dihydropyrldine). 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 via a non-aromatic carbon atom or a nitrogen atom . For example, a 1,2-dihydroquinolin-1-ylo group (in which the moiety is attached to the parent structure through a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, while the 1,2 group -dihydroquinolin-8-yl (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 indenllo, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo [1,3] doxoxyl, tetrahydroqulnolinyl, 2,3-dihydrobenzo [1,4] dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-1H-indazolyl, 2,3dlhldro-1H-benzo [d] lmldazolyl, 2,3-dihydrobenzofuranllo, 1,3-dihydroisobenzofuranllo,

- 171,3-dihydrobenzo [c] lsoxazolyl, 2,3-dihydrobenzo [d] isoxazolyl, 2,3dih¡drobenzo [d] oxazolyl, 2,3-dih¡drobenzo [b] thiophenyl, 1,3-d¡h ¡Drobenzo [c] t¡ofen¡lo, 1,3dih¡drobenzo [c] sotiazolil, 2,3-dih¡drobenzo [d] isothiazolil, 2,3-d¡hidrobenzo [d] t¡azol¡lo, 5,6-dihydro-4H-cyclopenta [d] thiazolyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, 5,6-dihydro-4Hpyrrolo [3,4-d] thiazolyl, 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridinyl, indolin-2-one, indolin-3-one, isoindolin-1-one, 1,2-dihydroindazole-3- ona, 1H-benzo [d] imidazol-2 (3H) -one, benzofuran2 (3H) -one, benzofuran-3 (2H) -one, ¡sobenzofuran-1 (3H) -one, benzo [c] isoxazol-3 (1H ) ona, benzo [d] isoxazol-3 (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) -one, benzo [c] sotiazol-3 (1H) -one, benzo [d] isothiazol-3 (2H) -one, benzo [d] t¡azol-2 (3H) -one, 4,5-dih¡drop¡rrolo [3,4-d] thiazol-6one, 1,2-d¡hidropírazolo [3,4-d ] thiazol-3-one, quinolin-4 (3H) -one, quinazolin-4 (3H) -one, quinoline-2,4 (1H, 3H) -done, quinoxalin-2 (1H) -one, quinoxalin-2,3 (1H, 4H) -done, cannolin-4 (3H) -one, pyridin-2 (1H) - ona, pyrimin-2 (1H) -one, pyridine-4 (3H) -one, pyridazln3 (2H) -one, 1H-pyrrolo [3,2-b] pyridin -2 (3H) -ona, 1H-p¡rrolo [3,2-c] p¡r¡din-2 (3H) -ona, 1Hp¡rrolo [2,3-c] p¡r¡d¡n -2 (3H) -one, 1 Hprrolo [2,3-b] pyridin-2 (3H) -one, 1,2-dlhydropyrrazolo [3,4d] thiazol-3-one and 4,5- dih¡drop¡rrolo [3,4-d] thiazol-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.

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

- 18 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 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.

-19 The stereochemistry represented in cyclic mesocomposite structures is not absolute; rather, stereochemistry is intended to indicate the position of the substituents on each other, eg, c / 's or trans. For example,

F

N

<img file="MX2012012259A_D0002.tif" />

It 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

NH NH \ = N is intended to designate a compound in which the fluorine and pyridyl substituents on the cyclobutyl ring are in 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- [6 ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-l] benzenecarbonitrile Intends to include both cis and trans mesoisomers:

F

N

F

N

<img file="MX2012012259A_D0003.tif" />

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

-20Tautomers 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 phenolcet 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 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

-21 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 the biological efficacy and properties of the compounds described herein and are not biologically, or otherwise, undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66 (1), 1-19. In many cases, the compounds 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, melic 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, p-toluenesulfonic 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 naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. The base examples

-22 organic 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, may be produced by dissolving the free base in a suitable organic solvent, and by treating the solution with an acid, of 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 (eg, ethanol). Solvates include hydrates that have any ratio of compound to water, such as monohydrates, dihydrates, and hemlhydrates.

A chelate is formed by the coordination of a compound with a metallic 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 interactions

-23Waals, 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. They can get preparing a derivative of an active compound (eg, a compound of Formula I or another compound disclosed and / or described herein) that will undergo transformation under 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, by means of a hydrolysis reaction) or it can be catalyzed or induced by another agent (for example, an enzyme, light, acid or base and / or temperature). The agent can be endogenous to the conditions of use (eg, an enzyme present in the cells to which the prodrug is administered or the arid conditions of the stomach) or the agent can be provided exogenously. Prodrugs can be 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 may be converted to a sulfonate, phosphate, ester, or carbonate group, which in turn may be rehydrolyzed to the hydroxyl group in vivo. Similarly, an amyl 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 hydrazide, which can be hydrolyzed in vivo from

-24new to 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 ¹¹C, 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. ef 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 media, coatings, antibacterial and antifungal agents, isotonic and absorption retardant agents, 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.

-25 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 salt.

The terms "patient" and "subject" refer to an animal, such as a mammal, bird, or fish. In some 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 various components of the sarcomere skeletal described herein, including myosin, actin, tropomyosin, troponin C, troponin I, skeletal troponin T and fragments and isoforms thereof. In some embodiments, "skeletal muscle" includes fast skeletal muscle tissue as well as components thereof, such as fast skeletal muscle fibers, myofibrils comprising fast skeletal muscle fibers, rapid skeletal sarcomere comprising myofibrils, and

-26 the various components of the rapid skeletal sarcomere described herein, including 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 that appear in that combination entirely in cardiac muscle.

As used herein, the term "therapeutic" refers to the ability to modulate skeletal muscle contractility rapidly. As used herein, "modulation" (and related terms, such as "modular," "modulated," "modulating") refers to a change in the function or efficacy of one or more components of skeletal muscle sarcoma. Rapid, Including myosin, actin, tropomyosin, troponin C, troponin I and troponin T of rapid skeletal muscle, including fragments and isoforms thereof, in 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 They affect the sarcomere or one or 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⁺. How to use

-27 herein, "efficacy" or "muscle 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 who needs such 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 dosage regimen to be followed, the time of administration, the Administration form, all of which can be easily 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 "treat", "treated", "treating") includes one or more of: preventing a disease or disorder (that is, causing the clinical symptoms of the disease or disorder not to 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

-28 clinical symptoms of a disease or disorder. Therefore, the compounds described and / or disclosed herein can prevent an existing disease or disorder from worsening, aid in the treatment of the disease or disorder, or reduce or eliminate 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, "power output" of a muscle means work / cycle time and its Poio / 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 "selectively binding" refers to preferential binding to a target protein in one type of muscle or muscle fiber as opposed to other types. For example, a compound selectively binds to rapid skeletal troponin C if the compound preferentially binds to troponin C in the troponin complex of a sarcomere or rapid skeletal muscle fiber compared to troponin C in the troponin complex of a sarcomere or slow muscle fiber. or with troponin C in the troponin complex of a cardiac sarcomere.

A compound of Formula I is provided:

-29R¹

<img file="MX2012012259A_D0004.tif" />

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

R¹ is selected from hydrogen, halogen, CN, C ^ alkyl, Ci haloalkyl.₆,

C (O) OR^to, C (O) NR^bR^c, OR^to, NR^bR^c, aryl C₆.₁₀ and 5-10 membered heteroaryl;

R² is selected from cycloalkyl C₃.₈, cycloalkenyl C₃_e, heterocycloalkyl of

3-8 membered, 3-8 membered heterocycloalkenyl, aryl C₆.₁₀, 5-10 membered heteroaryl and NR^bR^c, where each of the cycloalkyl groups C₃.₈, cycloalkenyl C₃.₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆-wy and 5-10 membered heteroaryl is 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^dSO2R^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)_nMR^to, (CH2) nS (O) R^to, (CH2)_nSW₂R^to, (CH2) nSO2NR^bR^c, Cve alkyl, Ci.6 haloalkyl, C alkenyl₂.₆, alkynyl C₂.₆, (CH₂)_ncycloalkyl C₃.₈, (CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_naryl C₆.₁₀ and (CH₂)_n5-10 membered heteroaryl, where each of the C ^ e alkyl, C alkenyl groups₂.₆, alkynyl C₂._6l

-30 (CH₂)_ncycloalkyl C₃._8l (CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_naryl C₆-io and (CH₂)_n5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 R substituents^F;

R³ is selected from hydrogen, halogen, CN, C ^ alkyl, C ^ haloalkyl, C (O) OR^to, C (O) NR^bR^c, OR^to, NR^bR^c, aryl C₆.₁₀ and 5-10 membered heteroaryl;

R⁴ is selected from hydrogen, Ci.6 alkyl, C ^ 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_alkyl_and and C ^ haloalkyl;

or alternatively R⁵ and R⁶ together with the carbon atom to which they are attached they form C3_s cycloalkyl, C3_8cycloalkenyl, 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, Ci_6 alkyl and Ci_ haloalkyl₆;

R⁷ is selected from C3.8 cycloalkyl, C3_s cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6.i0 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 (O) 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, C ^ alkyl, C ^ haloalkyl, C2 alkenyl.₆, alkynyl C₂.₆, cycloalkyl C₃.₈, cycloalkenyl C₃.₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆-i₀, aralkyl C₇.ny heteroaryl 5-10

-31 members, where each of the alkyl groups Ci-₆, alkenyl C₂-6, alkynyl C₂.₆, C3.8 cycloalkyl, C3.8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆.₁₀, aralkyl C₇.ny and 5-10 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 C ^ -alkyl;

X is selected from a bond, - (CH₂)_P-, - (CH₂)_pC (O) (CH₂)_what-, - (CH₂)_pO (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) q-, - (CH2) pNR^dC (O) NR^d(CH2)_what-, (CH₂)_pNR^dSO2 (CH2) q- and - (CH2) pSO2NR^d(CH2)_what-¡ 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, Cv-alkyl ₆, haloalkyl C ^, alkenyl C₂.₆, alkynyl C₂-6, cycloalkyl C₃.₈, cycloalkenyl C₃.₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆-io, aralkyl C₇.ny and 5-10 membered heteroaryl, where each of the Ci_ alkyl groups ₆, alkenyl C₂.₆, alkynyl C₂.₆, cycloalkyl C₃.₈, cycloalkenyl C₃.₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆.₁₀, aralkyl C₇.ny 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, C ^ alkyl, C ^ haloalkyl, C alkenyl₂_6, alkynyl C₂.₆, cycloalkyl C₃.₈,

-32cycloalkenyl C₃.₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆-io. aralkyl C₇.n, 5-10 membered heteroaryl, C (O) R⁹, C (O) OR⁹, C (O) NR'R^j and SO2R⁹, where each of the C ^ alkyl, C2 alkenyl groups.₆, alkynyl C₂.₆, cycloalkyl C₃.₈, cycloalkenyl C₃.₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆-i₀, Cy.n 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 alkyl

Cl-6¡

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

R^F, in each case, is independently selected from halogen, CN, OR^h, OC (O) R^h, OC (O) OR^h, OC (O) NR^¡R^¡, NR^¡R^j, NR^dC (O) R^h, NR^dC (O) OR^h, NR ^ OJNRR *, NR^dC (O) C (O) NR'R^j, NR^dC (S) R^h, NR^dC (S) OR^h, NR^dC (S) NRⁱRⁱ, NR^dC (NR^and) NRⁱRⁱ, NR^dS (O) R^h, NR^dSO2R^h, NR^dSO2NRⁱRⁱ, C (O) R^h, C (O) OR^h, CÍOJNR'Ri C (S) R^h, C (S) OR^h, C (S) NR'R^j, C (NR^and) NR'R^j, MR^h, S (O) R^hSO2R^h, SOzNR'N, C ^ alkyl, C ^ haloalkyl, C2 alkenyl.₆, alkynyl C₂.₆, cycloalkyl C₃.₈, cycloalkenyl C₃.₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆.₁₀, aralkyl C₇.ny and 5-10 membered heteroaryl, where each of the Ci alkyl groups.₆, alkenyl C₂.₆, alkynyl C₂. ₆, cycloalkyl C₃-g, cycloalkenyl C₃.₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆-i₀, aralkyl C₇.ny and 5-10 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

C₃.₈ and 3-8 membered heterocycloalkyl;

-33R⁹, in each case, is independently selected from Ci alkyl._6&gt;haloalkyl Ci.₆, phenyl, naphthyl and aralkyl C₇.n, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, OH, Ci alkoxy.₆, alkyl and haloalkyl Ο_ν6;

R^h, in each case, is independently selected from hydrogen, alkyl Ο_ν6, haloalkyl C ^, alkenyl C₂.₆, Alkylnyl C₂.₆, cycloalkyl C₃.₈, cycloalkenyl C₃.8, 3-8 membered heteroclcloalkyl, 3-8 membered heteroclcloalkenyl, aryl C₆-io, aralkyl C₇.ny and 5-10 membered heteroaryl, where each of the alkyl groups Cv Q, alkenyl C₂-_and, alkynyl C₂-_and, cycloalkyl C₃.₈, cycloalkenyl C₃.₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆-io. aralkyl C₇.n and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 R substituents^k;

each of R 'and R^j, in each case, is independently selected from hydrogen, C ^ -alkyl, C ^ e-haloalkyl, C2_6-alkenyl, C2.6-alkynyl, C3.8-cycloalkyl, C3.8-cycloalkenyl, 3-8-membered hetero-chloralkyl-alkyl members, C6.10 aryl, C7.n aralkyl, 5-10 membered heteroaryl, C (O) R⁹ and C (O) OR⁹, where each of the C ^ e alkyl, C ^ e haloalkyl, C2 alkenyl groups.₆, alkynyl C₂.₆, cycloalkyl C₃.₈, cycloalkenyl C₃.₈, 3-8 membered heteroclcloalkyl, 3-8 membered heteroclcloalkenyl, aryl C₆.₁₀, aralkyl C₇.ny and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN, OH, C ^ -alkoxy, alkyl and haloalkyl Ci ^

R^k, in each case, is independently selected from halogen, CN, OH, Ct.6 alkoxy, NH_2i NH (alkyl Ci.₆), N (something C ^)₂, NHC (O) alkyl C ^, NHC (O) aralkyl

C₇.n, NHC (O) Oalkyl Ci-₆, NHC (O) Oaralqullo C₇.n, OC (O) alkyl C ^, OC (O) aralqullo

C₇_ii, OC (O) Qalqullo Cve, OC (O) Oaralqullo C₇.n, C (O) alkyl C ^ e, C (0) aralkyl C₇.n,

-34C (O) Oalkyl Ci._6l C (O) Oaralqu¡lo C₇.n, alkyl Ci.₆, haloalkyl Ci.₆, alkenyl C₂.6 and alkynyl C₂-6, where each alkyl substituent Ci-₆, alkenyl C₂-6, alkynyl C₂.₆ and aralkyl C₇-n is optionally substituted with 1, 2 or 3 substituents selected from OH, Ci alkoxy._6l NH₂, NH (alkyl Ο ^ θ), N (alkyl Ci ^)₂, NHC (O) alkyl Ci_e, NHC (O) aralkyl

C₇.n, NHC (O) Oalkyl 0) .6 and NHC (O) Oaralkyl 0₇._1Ί;

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; m is 0.1 or 2;

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

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

In some embodiments of compounds of Formula I, when m is 1 and each of R⁵ and R⁶ is methyl, so R⁷ it is not piperidinyl or morpholino. In some embodiments of compounds of Formula I, when m is 1, X is a bond and R² is optionally substituted phenyl, then R⁷ it is not piperidinyl or morpholino. In some embodiments, the compound of Formula I is not 6- (4-chlorophenyl) -5-methyl-N- (2-methyl-2 (piper¡din-1-l) propyl) p¡ridaz¡n-3 -amine, N- (2-methyl-2- (piperidin-1-yl) propyl) -6-phenyl-5propylpindazin-3-amine or N- (2-methyl-2-morpholinopropyl) -6-fenll- 5-propylpyridazin-3-amine.

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

-35R¹

<img file="MX2012012259A_D0005.tif" />

R⁴

Formula II in which 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="MX2012012259A_D0006.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 is hydrogen and the other is C ^ alkyl.

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

In some embodiments of compounds of Formula I, II or III, each of R⁵ and 15 R⁶ it is methyl.

-36 In some embodiments, the compounds are of Formula IV (a) or IV (b), or a pharmaceutically acceptable salt thereof:

R¹

<img file="MX2012012259A_D0007.tif" />

R⁴

Formula IV (a)

R¹

<img file="MX2012012259A_D0008.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 IV (b), R⁷ it is not piperidinyl or morpholinyl.

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_g 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, 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^to,

SW₂R^to, SO₂NR^bR^c, alkyl and haloalkyl C ^.

-37 In some embodiments of compounds of Formula I, II or III, R⁵ and R⁶, together with the carbon to which they are attached, form C3.6 cycloalkyl 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, Cv 6 alkyl and Ci haloalkyl.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 clclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, 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, Ci alkyl.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, 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, C ^ alkyl and C ^ 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 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 (O) R^to, SO2R \ SO2NR^bR^c, CV6 alkyl and haloalkyl C₁₆, 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 (O) R^toSO2R^toSO2NR^bR^c, C ^ alkyl and C ^ haloalkyl, where the

-38 substituent and R⁷ they are in cis 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="MX2012012259A_D0009.tif" />

Formula V (a)

<img file="MX2012012259A_D0010.tif" />

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

In some embodiments of compounds of Formula V (a) or V (b), each of

R^m and Rⁿ it is hydrogen.

-39 In some embodiments, compounds of Formula V (a) or V (b), each of R^m and Rⁿ it is halogen.

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

In some embodiments, compounds of Formula V (a) or 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.

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, 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 and haloalkyl Ci-₆.

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, 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^to, SO₂R^toSO2NR^bR^c, Cv 6 alkyl and C ^ haloalkyl.

-40 In some embodiments of compounds of Formula I, II or III, each of R⁵ and R⁶ is independently Ci-6 alkyl, or R⁵ and R⁶ together with the carbon atom to which they are attached they form C3 cycloalkyl.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, 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^to, SO₂R^toSO2NR^bR^c, Cv 6 alkyl and C ^ 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 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, 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 and haloalkyl C ^.

In some embodiments of compounds of Formula I, II or III, each of R⁵ and R⁶ is independently C ^ -alkyl, 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, 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, Cv alkyl₆ and C ^ 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 to which they are attached, form cyclobutyl optionally substituted with 1,2,3,4 0 5 substituents selected from halogen, CN, oxo, OR^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, Ci_6 alkyl and C ^ haloalkyl.

-41 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, 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 (O) NR^bR °, 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, C ^ alkyl, C ^ haloalkyl, C2 alkenyl.₆, alkynyl C₂.₆, cycloalkyl C₃_₈, cycloalkenyl C₃.₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆-io, aralkyl C₇.ny and 5-10 membered heteroaryl, where each of the Ci_ alkyl groups₆, alkenyl C₂-6, alkynyl C₂.₆, cycloalkyl C₃.₈, cycloalkenyl C₃._8l 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆.₁₀, aralkyl C₇_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, III or IV (b), when each of R⁵ and R⁶ is methyl, R⁷ it is not piperidinyl or morpholinyl.

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^dC (O) R^to, NR^dC (O) OR^to, NR^dC (O) 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 (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, Ci-6-alkyl, Ci-haloalkyl₆, alkenyl C₂-₆, alkynyl C₂-₆, cycloalkyl C₃.₈, cycloalkenyl C₃.₈, 3-8 membered heterocycloalkyl, 3-8 heterocycloalkenyl

-42 members, aryl C₆-io, aralkyl C₇.ny and 5-10 membered heteroaryl, where each of the Ci_ alkyl groups₆, alquenllo C₂-6, alkynyl C₂.₆, cycloalkyl C₃-₈, cycloalkenyl C₃.₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆-io, aralkyl C₇-very 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:

R¹

<img file="MX2012012259A_D0011.tif" />

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

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

R¹

<img file="MX2012012259A_D0012.tif" />

Formula Vll (a)

-43R¹

<img file="MX2012012259A_D0013.tif" />

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

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

<img file="MX2012012259A_D0014.tif" />

<img file="MX2012012259A_D0015.tif" />

-44 Formula Vlll (b) in which each of R^m and Rⁿ is independently selected from hydrogen, halogen, and C ^ 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 Vlll (a) or Vlll (b), each of R^m and Rⁿ it is hydrogen.

In some embodiments made of Formula Vlll (a) or Vlll (b), each of Rm and pn _is h_tolog_andnot.

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

In some embodiments, compounds of Formula Vlll (a) or Vlll (b), one of R^m and Rⁿit 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 some embodiments of such 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 Vlll (a) or Vlll (b), one of R^m and Rⁿit 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, 3,4difluorophenyl, 3,5-difluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,

2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-methylphenyl, 3-methylphenyl, 2,4-45dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2- (hydroxymethyl) phenyl , 3 (hydroxymethyl) phenyl, 4- (hydroxymethyl) phenyl, 2- (aminomethyl) phenyl, 3- (aminomethyl) phenyl, 4 (aminomethyl) phenylo, 2-phenol, 3-phenol, 4-phenol, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,

2-d¡fluorometox¡fen¡lo, 3-d¡fluorometox¡fen¡lo, 4-difluoromethoxyphenyl, 2trlfluorometoxlfenilo, 3-tr¡fluorometox¡fenilo, 4-trifluorometoxlfenllo, 2-cyanophenyl, 3cianofenilo, 4-cyanophenyl, 2- benzamine, 3-benzamide, 4-benzamida, N-methyl-2benzamine, N-methyl-3-benzamide, N-methyl-4-benzamida, 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 5-10 membered heteroaryl 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 (O) 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^dSW₂R^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^to, SO₂NR^bR^c, C- | alkyl.₆, haloalkyl C ^ e, alkenyl C₂. ₆, rent C₂.₆, cycloalkyl C₃.₈, clcloalquenllo C₃_₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆-io, aralkyl C₇_n and 5-10 membered heteroaryl, where each of the Ci alkyl groups.₆, alkenyl C₂.₆, alkynyl C₂.₆, cycloalkyl C₃._8l cycloalkenyl C₃.₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆.io, 5-10 membered Cy.n aralkyl and 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), R⁷ is pyridyl 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 (O) NR^bR^c, NR^dC (O) C (O) NR^bR^c, NR^dC (S) R^to,

-46NR^dC (S) OR^to, NR^dC (S) NR^bR^c, NR^dC (NR^and) NR^bR^c, NR^dS (O) R^to, NR^dSW₂R^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^to, SO₂NR^bR^c, C1-6 alkyl, C ^ haloalkyl, C alkenyl₂-₆, alkynyl C₂.₆, cycloalkyl C₃.₈, cycloalkenyl C₃.₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, aryl C₆-₁₀, aralkyl C₇.ny and 5-10 membered heteroaryl, where each of the Ci alkyl groups._6l alkenyl C₂^, alkynyl C₂-₆, cycloalkyl C₃.₈, cycloalkenyl C₃.₈, 3-8 membered heterocycloalkyl, 3-8 membered copter cycloalkenyl, aryl C₆-io, aralkyl C₇.ny 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), R⁷ is selected from 2-pyridyl, 3-pyridyl and 4-pyridyl, 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 (O) 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^dSW₂R^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, C ^ alkyl, C ^ haloalkyl, C2 alkenyl.₆, alkynyl C₂.6, cycloalkyl C₃.₆, cycloalkenyl C₃_₆, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, phenyl, naphthyl, aralkyl C₇.ny and 5-10 membered heteroaryl, where each of the C alkyl groups_{v 6}, alkenyl C₂^, alkynyl C₂.₆, cycloalkyl C₃.₈, cycloalkenyl C₃.₈, heterocycloalkyl of

3-8 membered, 3-8 membered heterocycloalkenyl, aryl C₆-io, aralkyl C₇.ny 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 IX, or a pharmaceutically acceptable salt thereof:

<img file="MX2012012259A_D0016.tif" />

Formula IX in which r is O, 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 X (a) or X (b), or a pharmaceutically acceptable salt thereof:

<img file="MX2012012259A_D0017.tif" />

R¹

<img file="MX2012012259A_D0018.tif" />

Formula X (b)

-48 where r is O, 1, 2, 3 or 4, and R¹, R², R³, R⁴, R⁸, R⁹, R^F and X are as defined herein.

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

<img file="MX2012012259A_D0019.tif" />

<img file="MX2012012259A_D0020.tif" />

Formula Xl (b) in which each of R^m and Rⁿ is independently selected from hydrogen, halogen, and C ^ 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 Xl (a) or Xl (b), each of

R^m and R is hydrogen.

-49difluoromethyl-pyrid-2-yl, difluoromethyl-pyrid-2-yl,

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

In some embodiments made of Formula Xl (a) or Xl (b), each of R^m and

Rⁿ it's fluorine.

In some embodiments, compounds of Formula Xl (a) or Xl (b), one of R^m and Rⁿit 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 cis configuration with respect to each other in the cyclobutyl ring.

In some embodiments, compounds of Formula Xl (a) or Xl (b), one of R^m and Rⁿit 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-fluoropyrid-2-yl, 6-fluoro-pyrid-2-yl, 3-chloro -pyrid-2-yl, 4-chloro-pyrid-2-yl, 5-chloro-pyrid-2-yl, 6-chloro-pyrid-2-yl, 3-cyano-pyrid-2-yl, 4-cyano-pyrid -2-yl, 5-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-methyl-pyrid-2-yl, 34-difluoromethyl-pyrid-2-yl, 5-difluoromethyl-pyrid-2-yl, 63-trifluoromethyl-pyrid-2-yl, 4-trifluoromethyl-pyrid-2 -ilo, 5trifluoromethyl-pyrid-2-yl, 6-trifluoromethyl-pyrid-2-yl, 3-hydroxymethyl-pyrid-2-yl, 4-hydroxymethylpyrid-2-yl, 5-hydroxymethyl-pyrid-2-yl, 6-hydroxymethyl- pyrid-2-yl, 3-aminomethyl-pyrid-2-yl, 4-aminomethyl-pyrid-2-yl, 5-aminomethyl-pyrid-2-yl, 6-aminomethyl-pyrid-2-yl, 3-hydroxy-pyrid- 2-50¡lo, 4-hydroxy-pyrid-2-yl, 5-hydroxy-pyrid-2-yl, 6-hydroxy-pyrid-2-yl, 3-methoxy-pyrid-2-yl, 4-methoxy- pyrid-2-yl, 5-methoxy-pyrid-2-yl, 6-methoxy-pyrid-2-yl, 3-difluoromethoxy-pyr-d-2-yl, 4difluoromethoxy-pyrid-2-yl, 5-dfluoromethoxy, -p¡r¡d-2-yl, 6-difluoromethoxy-pyrd-2-yl, 3-trifluoromethoxy-pyrid-2-yl, 4-trifluoromethoxy-pyrid -2-yl, 5-trifluoromethoxy-pyrid-2-yl, 65 trifluoromethoxy-pyrid-2-yl, 3-methylthio-pyrid-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-carboxamidapyrid-2-yl, 6-carboxamida-p¡ rd-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-fluoro10 pyrid-3-yl, 6-fluoro-pyrid-3-yl, 2- chloro-pyrid-3-yl, 4-chloro-pyrid-3-yl, 5-chloro-pyrid-3-yl, 6-chloro-pyrid-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- prid-3-ylo, 6-methyl-pyr-d-3-yl, 2-difluoromethyl-pyrid-3-yl, 4-difluoromethi-pyrid-3-ylo, 5-difluoromethyl-p -rid-3- yl, 6difluoromethyl-pyrid-3-yl, 2-trifluoromethyl-pyrid-3-yl, 4-trifluoromethyl-pyrid-3-yl, 515 trifluoromethyl-pyrid-3-yl, 6-trifluoromethyl-pyrid-3-yl, 2-hydroxymethyl-pyrid- 3-yl, 4-hydroxymethylpyrid-3-yl, 5-hydroxymethyl-pyrid-3-yl, 6-hydroxymethyl-pyrid-3-yl, 2-aminomethyl-pyrid-3-yl, 4 aminomethyl-pyrid-3-yl, 5-aminomethyl-pyrid-3-yl, 6-aminomethyl-pyrid-3-yl, 2-hydroxy-pyrid-3-yl, 4-hydroxy-pyrid-3-yl, 5-hydroxy-pyrid-3-ylo , 6-hydroxy-pyrid-3-yl, 2-methoxy-pyrid-3-yl, 4-methoxy-pyrid-3-yl, 5-methoxy-pyrid-3-yl, 6-methoxy-pyrid-3-yl, 2-difluoromethoxy-pyrid-3-yl, 420 difluoromethoxy-pyrid-3-yl, 5-difluoromethoxy-pyrid-3-yl, 6-difluoromethoxy-pyrid-3 -yl, 2trifluoromethoxy-pyrid-3-yl, 4-trifluoromethoxy-pyrid-3-yl, 5-trifluoromethoxy-pyrid-3-yl, 6-trifluoromethoxy-pyrid-3-yl, 2-methyl-pyrid-3-yl -yl, 4-methylthio-p¡r¡d-3-yl, 5-methylthio-pyrid-3-ylo, 6-methylthio-pyrid-3-yl, 2-carboxamide-pyrid-3-ylo, 4 -carboxamide-pyrid-3-yl, 5-carboxamidapyrid-3-yl and 6-carboxamide-pyrid-3-yl.

-51 In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, Vll (a), Vll (b), Vlll (a ), Vlll (b), IX, X (a), X (b), Xl (a) or Xl (b), X is selected from one bond, - (CH₂)_P-, - (CH₂)_pC (O) (CH₂)_what-, - (CH₂)_pO (CH₂)_what-, - (CH₂)_pS (CH₂)_what-, (CH₂)_pNR^d(CH2) q-, - (CH2) pO (CH2) q-, - (CH2) pS (CH2) q -, - (CH2) pNR^dC (O) (CH2)_what-, 5 (CH₂)_pC (O) NR^d(CH2) q-, - (CH2) pNR^dC (O) NR^d(CH2)_what-, - (CH₂)_pNR^dSO2 (CH2) q- and (CH2) pSO2NR^d(CH2)_what-.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a) or Xl (b), X is a bond.

In some embodiments, the compound is of Formula Xll (a), XIl (b), Xll (c), Xll (d), 10 Xll (e), Xll (f), Xll (g), Xll (h), Xll (l), XIIG), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (o), or a pharmaceutically acceptable salt thereof:

R¹

<img file="MX2012012259A_D0021.tif" />

Formula Xll (a)

R¹

<img file="MX2012012259A_D0022.tif" />

R⁴

Formula Xll (b)

-52R¹

<img file="MX2012012259A_D0023.tif" />

Formula Xll (c)

<img file="MX2012012259A_D0024.tif" />

R⁴

Formula Xll (d)

R¹

<img file="MX2012012259A_D0025.tif" />

Formula Xll (e)

<img file="MX2012012259A_D0026.tif" />

Formula Xll (f)

R¹

<img file="MX2012012259A_D0027.tif" />

R¹

<img file="MX2012012259A_D0028.tif" />

Formula Xll (h)

<img file="MX2012012259A_D0029.tif" />

R¹

<img file="MX2012012259A_D0030.tif" />

<img file="MX2012012259A_D0031.tif" />

Formula Xll (k) (u) nx Biniujoj

<img file="MX2012012259A_D0032.tif" />

<img file="MX2012012259A_D0033.tif" />

<img file="MX2012012259A_D0034.tif" />

-ss-56-

<img file="MX2012012259A_D0035.tif" />

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

In some embodiments of compounds of Formula Xll (c), R⁷ it is not piperidinyl or morpholinyl. In some embodiments of compounds of Formula Xll (c), when R² is optionally substituted phenyl, then R⁷ it is not piperidinyl or morpholinyl.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a) or Xl (b), X is -O-.

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

V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a) or Xl (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, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a) or Xl (b), X is -NR^d-,

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

V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a) or Xl (b), X is selected from CH₂NR^d- and -NR^dCH₂-,

-57 In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, Vll (a), Vll (b), Vlll (a) , Vlll (b), IX, X (a), X (b), Xl (a) or Xl (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), 5 V (b), VI, Vll (a), Vll (b), Vlll (a) , Vlll (b), IX, X (a), X (b), Xl (a) or Xl (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, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (i), Xll (j), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (or ), R² is selected from cycloalkyl C₃.₈, cycloalkenyl C₃.₃, 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, (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^dSO2R^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)_nMR^to, (CH2) nS (O) R^to, (CH2)_nSW₂R^to, (CH2) nSO2NR^bR^c, C ^ -alkyl, C2-haloalkyl-alkenyl₆, alkynyl C₂.₆, (CH₂)_ncycloalkyl C₃.₈, (CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_nphenyl, (CH₂)_nnaft¡lo and (CH₂)_n5-10 membered heteroaryl, where each of the C ·) ^ alkyl, C-alkenyl groups₂^, alkynyl C₂.₆, (CH₂)_nchloroalkyl C₃.₈, (CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_nphenyl, (CH₂)_nnaft¡lo and (CH₂)_n5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 R substituents^F.

-58 In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, Vll (a), Vll (b), Vlll (a) , Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll ( e), Xll (f), Xll (g), Xll (h), Xll (l), XIIQ), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (o) , R² it is phenyl optionally 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 (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^dSO2R^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)_nMR^to, (CH2) nS (O) R^to, (CH2)_nSW₂R^to, (CH2) nSO2NR^bR^c, CV alkyl, Ci.6 haloalkyl, C alkenyl₂.₆, alkynyl C₂.₆, (CH2) nC3.8 Cycloalkyl, (CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_nphenyl, (CH₂)_nnaphthyl and (CH₂)_n5-10 membered heteroaryl, where each of the C ^ alkyl, C alkenyl groups₂_₆, alkynyl C₂.₆, (CH₂)_ncycloalkyl CV, (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, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (i), Xll (j), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (or ), R² 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 (O) R^to, (CH2)_nNR^dC (O) OR^to, (CH₂)_nNR^dC (O) NR^bR^c, (CH₂)_nNR^dC (Ó) 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^dSO2R^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,

-59 (CH₂)_nC (S) NR^bR^c, (CH2) nC (NR^and) NR^bR^c, (CH2)_nMR^to, (CH2) nS (O) R^to, (CH2)_nSW₂R^to, (CH2) nSO2NR^bR^c, C ^ -alkyl, C2-haloalkyl-alkenyl._6&gt; alkynyl C₂.₆, (CH₂)_ncycloalkyl C₃.₈, (CH₂)_n3-8 membered heterocycloalkullo, (CH₂)_nphenyl, (CH₂) nnaft¡lo and (CH₂)_n5-10 membered heteroaryl, where each of the C ^ alkyl, C alkenyl groups₂-6, 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 R substituents^F; where at least one substituent is attached at the meta position.

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

V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c),

Xll (d), Xll (e), Xll (f), Xll (g), Xll (h), Xll (i), Xll (j), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (o), R² is phenyl substituted 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 (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 °, (CH₂)_nNR^dS (O) R^to, (CH2) nNR^dSO2R^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)_nMR^to, (CH2) nS (O) R^to, (CH2)_nSW₂R^to, (CH2) nSO2NR^bR^c, Cve alkyl, Ci.6 haloalkyl, C alkenyl₂.₆, alkynyl C₂.₆, (CH₂)_nchloroalkyl C₃.₈, (CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_nphenyl, (CH₂)_nnaphthyl and (CH₂)_n5-10 membered heteroaryl, where each of the C- | alkyl groups.₆, alkenyl C₂.₆, alkynyl C₂. 6, (CH₂)_ncycloalkyl C₃.₈, (CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_nphenylo,

-60 (CH₂)_nnaphthyl and (CH₂)_n5-10 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), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c),

Xll (d), Xll (e), Xll (f), Xll (g), Xll (h), Xll (i), Xllü), Xll (k), Xll (l), Xll (m), Xll ( n) or Xll (o), R² is phenyl substituted with a substituent selected from C (O) OH, C (O) NH₂, C (O) Oalkyl Ci.6, C (O) NHalkyl and C (0) N (Ci ^ alkyl)₂; and optionally substituted with 1, 2 or 3 additional substituents selected from halogen, alkyl and C ^ haloalkyl.

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

V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c),

Xll (d), Xll (e), Xll (f), Xll (g), Xll (h), Xll (i), Xllü), Xll (k), Xll (l), Xll (m), Xll ( n) or Xll (o), R² is 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 (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^dSO2R^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)_nMR^to, (CH2) nS (O) R^to, (CH2)_nSW₂R^to, (CH₂)_nSW₂NR^bR^c, alkyl Ci-₆, haloalkyl C ^, alkenyl C₂.₆, alkynyl C₂.₆, (CH₂)_ncycloalkyl C₃.₈, (CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_nphenyl, (CH₂)_nnaphthyl and (CH₂)_n5-10 membered heteroaryl, where each of the C ^ alkyl, C alkenyl groups₂.₆, Alkylnyl C₂. ₆, (CH₂)_ncycloalkullo C₃.₈, (CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_nphenyl,

-61 (CH₂)_nnaphthyl and (CH₂)_n5-10 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), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (i), Xll (j), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (or ), R² is 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, C ^ alkoxy, CN, Cve alkyl and Cve haloalkyl.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (i), XIIQ), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (o), R² is phenyl substituted at the meta position with a substituent selected from C (O) OH, C (O) NH₂, C (O) or alkyl C_V6, C (O) NHalqu¡lo Ci_₆ y C (O) N (alqull0 C₁^)₂; and optionally substituted with 1, 2 or 3 additional substituents selected from halogen, hydroxyl, C-alkoxy_v6, CN, C ^ alkyl and Ci- haloalkyl₆·

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (i), XIIQ), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (o), R² is phenyl substituted with (CH2) nNR^dC (O) R^to, where R^to it is 38-membered C ^ -alkyl or 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^dC (NR^and) NR^bR^c, (CH₂)_nNR^dS (O) R^to,

-62 (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)_nMR^to, (CH2) nS (O) R^to, (CH2)_nSW₂R^to, (CH₂)_nSW₂NR^bR^c, Cve alkyl, C haloalkyl, ^, C alkenyl₂.₆, alkynyl C₂.₆, (CH₂)_ncycloalkyl C₃.₈, (CH₂)_n3-8 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, (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 °, (CH₂)_nNR^dS (O) R^to, (CH2) nNR^dSO2R^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)_nMR^to, (CH2) nS (O) R^to, (CH2)_nSW₂R^to, (CH₂)_nSW₂NR^bR^c, Cve alkyl, C ^ haloalkyl, C alkenyl₂.₆, alkynyl C₂.₆, (CH₂)_ncycloalkyl C₃.₈, (CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_nphenyl, (CH₂)_nnaphthyl and (CH₂)_n5-10 membered heteroaryl, where each of the Ci alkyl groups.₆, alkenyl C₂.₆, 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 R substituents^F.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (i), Xll (j), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (or ), R² is phenyl substituted with (CH2) nNR^dC (O) R^to, where R^to is selected from C ^ alkyl, C1.6-OH alkyl and Ci.6-NH alkyl_2&gt; each optionally substituted with 1, 2 or 3 additional substituents selected from halogen, CN, oxo, (CH₂)_nOR^to, (CH₂)_nOC (O) R^to,

-63 (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^dSW₂R^to, (CH2) nNR^dSO2NR^bR^c, (CH2) nC (O) R^to, (CH2)_nC (O) OR^to, (CH2) nC (O) NR^bR^c, (CH2)_nMR^to, (CH2) nS (O) R^to, (CH2)_nSW₂R^to, (CH₂)_nSW₂NR^bR^c, C ^ -alkyl, C1-6-haloalkyl, C-alkenyl₂-₆, alkynyl C₂-_6&gt; (CH₂)_ncycloalkullo C₃.8, (CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_nphenyl, and (CH₂)_n5-10 membered heteroarl; 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, (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^dSO2R^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)_nMR^to, (CH2) nS (O) R^to, (CH2)_nSW₂R^to, (CH2) nSO2NR^bR^c, C16-alkyl, Ci-haloalkyl₆, alkenyl C₂.₆, alkynyl C₂.₆, (CH₂)_nchloroalkyl C₃.₈, (CH₂)_n3-8 membered heterocycloalkullo, (CH₂)_nphenyl, (CH₂)_nnaftllo and (CH₂)_n5-10 membered heteroaryl, where each of the Cj.6-alkyl, C-alkenyl groups₂.₆, 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 R substituents^F.

I

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

V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e), Xll (f), Xll (g), Xll (h), Xll (i), Xll (j), XH (k), Xll (l), Xll (m), Xll (n) or Xll (o), R² is selected from 3-benzamlda, N-metll-3-benzamide, N, N-dimethyl-3-benzamide, 4-fluoro3-benzamide, N-methyl-4-fluoro-3-benzamide, N, N-dimethyl -4-fluoro-3-benzamide, 3-64benzolco 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, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (¡), Xll (j), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (or ), R² 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^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^dSO2R^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)_nMR^to, (CH2) nS (O) R^to, (CH2)_nSW₂R^to, (CH₂)_nSW₂NR^bR^c, alkyl C_v6, haloalkyl C_V6, alkenyl C₂-₆, alkynyl C₂_₆, (CH₂)_nclcloalqullo C₃.₈, (CH₂)_n3-8 membered heteroclcloalkyl, (CH₂)_nfenllo, (CH₂)_nnaftllo and (CH₂)_n5-10 membered heteroaryl, where each of the C ^ e alkyl, C alkenyl groups₂.₆, Alkylnyl C₂. 6&gt; (CH₂)_nchloroalkyl C₃^, (CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_nphenylo, (CH₂)_nnaphthyl and (CH₂)_n5-10 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), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (i), Xll (j), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (or ), R² is selected from pyridyl, pyrimldllo, pirazllo, plrldazllo, trlazllo, furanllo, plrrolilo, tiofenllo, tlazolllo, ¡sotlazolllo, tladlazolllo, oxazolllo, isoxazolllo, ólcl, trz 4 substituents

-65 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^dSO2R^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)_nMR^to, (CH2) nS (O) R^to, (CH2)_nSW₂R^to, (CH₂)_nSW₂NR^bR^c, Cve alkyl, C ^ haloalkyl, C alkenyl₂.₆, alkynyl C₂.₆, (CH₂)_ncycloalkyl C₃.₈, (CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_nphenylo, (CH₂)_nnaft¡lo and (CH₂)_n5-10 membered heteroaryl, where each of the C ^ alkyl, C alkenyl groups₂.₆, alkynyl C₂.

6. (CH₂)_ncycloalkyl C₃.₈, (CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_nphenyl, (CH₂)_nnaft¡lo and (CH₂)_n5-10 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), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (i), Xll (j), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (or ), R² is selected from pyridyl, pirlmidyl, pyrazyl, pyridazyl, triazyl, furanyl, plrrolyl, thiophenyl, thiazolyl, isothiazolllo, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionally substituted with 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, 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^dSO2R^to, (CH2) nNR^dSO2NR^bR^c, (CH₂)_nC (O) R^to,

-66 (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^to, (CH2) nSO2NR^bR^c, CV6 alkyl, Ci-6 haloalkyl, C alkenyl₂.₆, alkynyl C₂.₆, (CH₂)_ncycloalkyl C₃.₈₎(CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_nphenyl, (CH₂)_nnaphthyl and (CH₂)_n5-10 membered heteroaryl, where each of the C ^ alkyl, C alkenyl groups₂.₆, alkynyl C₂. 6&gt; (CH₂)_ncycloalkullo 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 R substituents^F.

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

V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c),

Xll (d), Xll (e), Xll (f), Xll (g), Xll (h), Xll (i), Xll (j), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (o), R² is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl, and triazyl, each optionally substituted with (CH₂)_nC (O) NR^bR^c.

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

V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c),

Xll (d), Xll (e), Xll (f), Xll (g), Xll (h), Xll (¡), Xll (j), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (o), R² is selected from furanllo, pyrrolyl, tlophenyl, tlazolllo, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl, and tetrazolyl, each optionally substituted with (CH₂)_nC (O) NR^bR^c.

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

V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e), Xll (f), Xll (g), Xll (h), Xll (i), Xllü), Xll (k ), Xll (l), Xll (m), Xll (n) or Xll (o), R² is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl, and triazyl, each optionally substituted with (CH₂)_nC (O) NH₂.

-67 In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, Vll (a), Vll (b), Vlll (a) , Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll ( e), Xll (f), Xll (g), Xll (h), Xll (i), Xllü), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (o) , R² is selected from furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl, and tetrazolyl, each optionally substituted with (CH₂)_nC (O) NH₂.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (i), Xllü), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (o), R² is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl, and tetrazolyl, each optionally substituted with (CH₂)_nNR^dC (O) R^to, where R^to is alkyl Ci-₆ 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^dC (NR^and) NR^bR^c, (CH2)_nNR^dS (O) R^to, (CH2) nNR^dSO2R^to, (CH2) nNR^dSO2NR^bR^c, (CH2) nC (O) R^to, (CH2)_nC (O) OR^to, (CH2) nC (O) NR^bR °, (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^to, (CH₂)_nSW₂NR^bR^c, Cve alkyl, C haloalkyl_v6, alkenyl C₂.₈, alkynyl C₂.₆, (CH₂)_ncycloalkyl C₃.₈, (CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_nphenyl, (CH₂)_nnaphthyl and (CH₂)_n5-10 membered heteroaryl, where each of the Ci alkyl groups._6l alkenyl C₂.₆, alkynyl C₂_

6. (CH₂)_ncycloalkyl C₃.₈, (CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_nphenyl,

-68 (CH₂)_nnaphthyl and (CH₂)_n5-10 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), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (i), Xll (j), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (or ), R² is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl, and triazyl, each optionally substituted with (CH2) nNR^dC (O) R^to, where R^to is selected from Ci.6 alkyl, C ^ OH alkyl and Ci ^ -NH alkyl₂, 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^bR^c, (CH2) nNR^dC (O) R^to, (CH2)_nNR^dC (O) OR^to, (CH2) nNR^dC (O) NR^bR^c, (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)_nMR^to, (CH2) nS (O) R^to, (CH2)_nSW₂R^to, (CH₂) nSO2NR^bR^c, alkyl Ci__6&gt; C ^ haloalkyl, C alkenyl₂_₆, rent C₂_₆, (CH₂)_ncycloalkyl C₃.₈, (CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_nphenylo, (CH₂)_nnaphthyl and (CH₂)_nheteroary of 5-10 members.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (i), XIIG), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (o), R² is selected from furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl, and tetrazolyl, each optionally substituted with (CH2) nNR^dC (O) R^to, where R^to is selected from Ci-e alkyl, Ci6OH alkyl and ^ alkyl.₆-ΝΗ₂, 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^bR^c, (CH2) nNR^dC (O) R^to, (CH2)_nNR^dC (O) OR^to, (CH2) nNR^dC (O) NR^bR^c, (CH2)_nNR^dSW₂R^to, (CH2) nNR^dSO2NR^bR^c,

-69 (CH₂)_nC (O) R^to, (CH₂)_nC (O) OR^to, (CH2) nC (O) NR^bR^c, (CH2)_nMR^to, (CH2) nS (O) R^to, (CH2)_nSW₂R^to, (CH₂)_nSW₂NR^bR^c, C ^ alkyl, Ci haloalkyl.₆, alkenyl C₂_6, alkynyl C₂.₆, (CH₂)_nchloroalkyl C₃.₈, (CH₂)_n3-8 membered heteroclcloalkullo, (CH₂)_nfenllo, (CH₂)_nnaftllo and (CH₂)_nheteroarllo of 5-10 members.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (¡), XIIG), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (o), R² is selected from ndolllo, ndazolllo, benzoimldazolyl, benzoxazolyl and benzoisoxazolllo, 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 (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 °, (CH2)_nNR^dS (O) R^to, (CH2) nNR^dSO2R^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)_nMR^to, (CH2) nS (O) R^to, (CH2)_nSW₂R^to, (CH2) nSO2NR^bR^c, C ^ alkyl, haloalkyl Ομ6, alkenyl C₂.₆, alkynyl C₂.₆, (CH₂)_nchloroalkyl C₃_₈, (CH₂)_n3-8 membered heteroclcloalkullo, (CH₂)_nfenllo, (CH₂)_nnaftllo and (CH₂)_n5-10 membered heteroarl, where each of the Ci ^ alkyl, C alkenyl groups₂^, alkynyl C₂.₆, (CH₂)_nclcloalqullo C₃_₈, (CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_nfenllo, (CH₂)_nnaphthyl and (CH₂)_n5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 R substituents^F.

In some embodiments of compounds of Formula Ι, II, III, IV (a), IV (b), V (a),

V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c),

Xll (d), Xll (e), Xll (f), Xll (g), Xll (h), Xll (¡), XIIG), XH (k), Xll (l), Xll (m), Xll ( n) or Xll (o), R² is selected from 1H-indazol-6-yl, 1H-indazol-5-llo, 1H-indazol-4-llo, 3-amino (1H-indazol-705-ylo), 3-amino (1H -indazol-6-yl), 3-amino (1H-indazol-7-ylo), 1-methyl (1 H-indazol-6-yl), 3methyl (1H-indazol-6-ylo), 3-amino-1-methyl (1H-indazol-5-yl), 3-cyano (1H-indazol-5-yl), 3carboxamide (1H-indazol-5-ylo), 3-carboxam! d¡na (1H-indazol-5-ylo), 3-vinyl (1 H-indazol-5yl), 3-ethyl (1 H-indazol-5-yl), 3-acetamide (1H-indazol- 5-yl), 3-methylsulfonylamine (1Hindazol-5-yl), 3-methoxycarboxamide (1H-indazol-5-yl), 3-methylamine (1H-indazol-5-yl), 3dimethylamine (1H-indazol-5-ylo), 3-et¡ lamino (1 H-indazol-5-yl), 3- (2-aminoethyl) amino (1H¡ndazol-5-ylo), 3- (2-h¡drox¡etíl) amino (1 H -indazol-5-yl), 3 - [(methylethyl) amino] (1 H-indazole-5-lo), 6-benzoym-dazole-5-ylo, 6- (2-methylbenzoim-dazole -5-yl), 2-aminobenzoimidazol-5-yl, 2-hydroxybenzoimidazol-5-yl, 2-acetamidabenzoim¡dazol-5-ylo, 3-aminobenzo [3,4d] ¡soxazol-5-yl, 3- aminobenzo [d] ¡soxazol-6-lo, 3-aminonozo [d] isoxazol-7-lo, 2-methylbenzoxazol-5-yl and 2-methylbenzoxazol-6-yl.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (¡), XIIQ), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (o), R² is 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^dSO2R^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)_nMR^to, (CH2) nS (O) R^to, (CH2)_nSW₂R^to, (CH2) nSO2NR^bR^c, C ^ alkyl, Ci_6 haloalkyl, C alkenyl₂-6, alkynyl C₂-6, (CH₂)_ncycloalkyl C₃.₈, (CH₂)_n3-8 membered heterocycloalkyl, (CH₂)_nphenyl, (CH₂)_nnaphthyl and (CH₂)_n5-10 membered heteroaryl, where each of the groups

-71 C ^ -alkyl, C-alkenyl₂.₆, 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 R substituents^F.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (¡), Xll (j), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (or ), R² is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, each optionally substituted with 1,2,3,4 0 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 (0) 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^dSO2R^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)_nMR^to, (CH2) nS (O) R^to, (CH2)_nSW₂R^to, (CH2) nSO2NR^bR^c, C ^ g alkyl, Ci_6 haloalkyl, C alkenyl₂^, alkynyl C₂.₆, (CH₂)_ncycloalkyl C₃.₈, (CH₂)_n3-8 membered heteroclcloalkyl, (CH₂)_nfenllo, (CH₂)_nnaftllo and (CH₂)_n5-10 membered heteroaryl, where each of the C ^ alkyl, C alkenyl groups₂^, alkynyl C₂_₆, (CH₂)_ncycloalkullo C₃.₈, (CH₂)_n3-8 membered heteroclcloalkullo, (CH₂)_nfenllo, (CH₂)_nnaftllo and (CH₂)_n5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 R substituents^F.

In some embodiments of compounds of Formula I, ll, III, IV (a), IV (b), V (a), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a) or Xl (b), R² is NR^bR^c, where R^band 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, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a) or Xl (b), R² is NR^bR^c, where

-72one of R^b and R^c is hydrogen and the other is 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, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a) or Xl (b), X is -C (O) - 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, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a) or Xl (b), X is -C (O) - and R² is NR^bR^cwhere one of R^b and R^c is hydrogen and the other is 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, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a) or Xl (b), X is - (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, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a) or Xl (b), X is - (CH₂)_P- and R² is

NR^bR^cwhere one of R^b and R^c is hydrogen and the other is 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 sulfur, and optionally containing one or more double bonds, and optionally substituted with 1, 2, 3, 4 or 5 substituents R^F.

In some embodiments, the compound is of Formula XIII, or a pharmaceutically acceptable salt thereof:

<img file="MX2012012259A_D0036.tif" />

Formula XIII in which 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 pyridazine ring to which it is attached forms a group selected from cinnollna, pyrido [2,3-c] pyridazine, pyrido [3,4-c] pyridazine , pyrido [4,3-c] pyridazine, pyrido [3,210 cjpyridazine, 5,6,7,8-tetrahydrocinnoline, 5,6,7,8-tetrahydropyride [2,3-c] plridazine, 5, 6,7,8tetrahydropyrido [3,4-c] pyridazine, 5,6,7,8-tetrahydropyrido [4,3-c] pyridazine, 5,6,7,8tetrahydropyrido [3,2-c] pyridazine, thieno [3,2-c] pyridazine, thiazolo [4,5-c] pyridazine, 7Hpirrolo [2,3-c] pyridazine, 7H-imidazo [4,5-c] pyridazine, thieno [3,2-c] pyridazine, thiazolo [4,5cjpiridazine, 5H-pyrolo [3,2-c] pyridazine, 5H-imidazo [4,5-c] pirldazine, 1H-plrazolo [4,315 cjpiridazine, 1H-plrazolo [3,4-c] pyridazine, 3H- [ 1,2,3] triazolo [4,5-c] pyridazine, 6,7-dihydro5H-pyrolo [2,3-c] pyridazine, 6,7-dihydro-5H-pyrrolo [3,4-c] pyridazine, 6,7-dihydro-5Hpyrrolo [3,2-c] pyridazine and 6,7-dihydro-5H-cyclopenta [c] pyridazine, each 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, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c),

-74Xll (d), Xll (e), Xll (f), Xll (g), Xll (h), Xll (i), Xllü), Xll (k), Xll (l), Xll (m), Xll (n), Xll (o) or XIII, R¹is selected from hydrogen, halogen, CN, C ^ alkyl, C ^ haloalkyl, C (O) OR^to, C (O) NR^bR^c, OR^to, NR^bR^c, C6-10 aryl and 5-10 membered heteroaryl.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), 5 V (b), VI, Vll (a), Vll (b), Vlll (a) , Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c),

Xll (d), Xll (e), Xll (f), Xll (g), Xll (h), Xll (i), Xllü), Xll (k), Xll (l), Xll (m), Xll ( n), Xll (o) or XIII, R¹is selected from hydrogen, halogen, CN, C ^ alkyl, C ^ haloalkyl, hydroxyl, C ^ alkoxy, NH_2i NHalkyl Ci_₆ and N (alkyl Ci-₆)₂,

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), 10 V (b), VI, Vll (a), Vll (b), Vlll (a) , Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c),

Xll (d), Xll (e), Xll (f), Xll (g), Xll (h), Xll (i), Xllü), Xll (k), Xll (l), Xll (m), Xll ( n), Xll (o) or XIII, R¹ 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, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c),

Xll (d), Xll (e), Xll (f), Xll (g), Xll (h), Xll (i), Xllü), Xll (k), Xll (l), Xll (m), Xll ( n), Xll (o) or XIII, R¹it is hydrogen.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (i), Xllü), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (o), R³ is selected from hydrogen, halogen, CN, C ^ -alkyl, C-, haloalkyl. 6, C (O) OR^to, C (O) NR^bR^c, OR^to, NR^bR^c, aryl C₆.i₀ and 5-10 membered heteroaryl.

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

V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c),

Xll (d), Xll (e), Xll (f), Xll (g), Xll (h), Xll (i), Xllü), Xll (k), Xll (l), Xll (m), Xll ( n) or Xll (o), R³ I know

-75 select from hydrogen, halogen, CN, alkyl Ci_₆, Ci-e haloalkyl, hydroxyl, C1-6 alkoxy. NH₂, NHalquilo Ci_₆, and N (C ^ alkyl)₂,

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (i), Xll (j), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (or ), R³ 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, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (i), XIIQ), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (o), R³ it is hydrogen.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (¡), XIIG), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (o), each of R¹ and R³ it is hydrogen.

In some embodiments of compounds of Formula I, II, III, IV (a), IV (b), V (a), V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (i), XIIG), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (o), R⁴ is selected from hydrogen, C ^ alkyl, C ^ 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, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c), Xll (d), Xll (e ), Xll (f), Xll (g), Xll (h), Xll (i), Xll (j), XU (k), Xll (l), Xll (m), Xll (n) or Xll (or ), R⁴ it is hydrogen.

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

V (b), VI, Vll (a), Vll (b), Vlll (a), Vlll (b), IX, X (a), X (b), Xl (a), Xl (b), Xll (a), Xll (b), Xll (c),

-76Xll (d), Xll (e), Xll (f), Xll (g), Xll (h), Xll (i), XIIQ), Xll (k), Xll (l), Xll (m), Xll (n) or Xll (o), R¹, each of R³ and R⁴ it is hydrogen.

In some embodiments of compounds of Formula I, III, IV (b), V (b), VI, Vll (b), Vlll (b), IX, X (b), Xl (b), Xll (a), Xll (c), Xll (e), Xll (f), Xll (h), Xll (j), Xll (k), Xll (m), Xll (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, Vll (b), Vlll (b), IX, X (b), Xl (b), Xll (a), Xll (c), Xll (e), Xll (f), Xll (h), Xll (j), Xll (k), Xll (m), Xll (o) or XIII, R⁸ and R⁹, in each case, each of is hydrogen.

In some embodiments, the compound is selected from the compounds of the

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, "modular" 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.

-77In both preclinical and clinical situations, activators of the rapid skeletal troponin complex have been shown to amplify the response of the rapid skeletal muscle to nerve stimulation, resulting in increased development of muscle strength to submaximal muscle activation (see, for example, Russell et al., “The Fast Skeletal Troponln Activator, CK-2017357, increases

Skeletal Muscle Forcé in vitro and in sitif, 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 also been shown to reduce muscle fatigue and / or increase the total time to fatigue under normal and low oxygen conditions (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; Hlnken et al., “The Fast Skeletal Troponin Activator, CK-2017357, Reduces Muscle Fatigue in an in situ Model of Vascular Insufficlency, Society for Vascular Medicine's 2010 Annual Meeting: 21 st Annual Scientific Sessions, Cleveland, OH, April 2010) . Increased muscle strength in response to nerve impulse has also been demonstrated in healthy human volunteers (see, for example, Hansen et al., “CK2017357, a Novel Activator of Fast Skeletal Muscle, Increases Isometric Force Evoked by Electrical Stimulation of the Previous 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

-78power and / or muscular 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, administration of a disclosed and / or disclosed compound herein results in an increase in the output power of rapid skeletal muscle. In some embodiments, administration of a disclosed and / or disclosed compound results in an increased sensitivity of calcium ion sarcomeres or skeletal muscle fibers compared to non-sarcomeres or skeletal muscle fibers. treated 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, 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

-79 compound or composition described and / or disclosed herein that selectively binds to troponin complexes in fast skeletal muscle sarcomere. In some embodiments, contacting the rapid skeletal muscle fiber with the compound results in activation of the rapid skeletal muscle fiber at a lower calcium ion concentration than in untreated rapid 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.

Also provided is a method of increasing the time to rapid skeletal muscle fatigue in a patient in need, comprising contacting the rapid skeletal muscle fibers with a compound or composition disclosed and / or disclosed herein that binds selectively to troponin complexes of 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.

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.

-80 (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, Parklnson's disease, stroke and spinal cord injury; and 4) muscle symptoms derived from systemic disorders, including peripheral vascular disease (PVD) or peripheral arterial disease (PAD) (eg, 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) disorders of the neuromuscular junction, including myasthenia gravis, myasthenic syndrome of Lambert-Eaton and

-81 prolonged neuromuscular blockage due to drugs or toxins; and 3) peripheral neuropathies, such as acute Inflammatory skinning polyradiculoneuropathy, diabetic neuropathy, chronic inflammatory skinning polyradiculoneuropathy, traumatic peripheral nerve injury, leprosy neuropathy, vasculitic neuropathy, dermatomyosltls / pollmlosltls, and Ataxia neuropathy.

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, waist, dysfunction, phaloescapulohumeral, waist, Emery-Dreyfus, oculopharyngeal, and congenital dystrophies); and 2) myopathies, such as nemaline myopathy, central body disease, congenital myopathies, mitochondrial myopathies, acute myopathy, inflammatory myopathies (such as inclusion body dermatomyositis / polymylositis), endocrine myopathies (such as those associated with hlper or hlpotlroidism), 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 (sterol disease, anti-retroviral drugs, statuses,) restrictive lung disease, sarcoldosis, Schwartz-Jampel syndrome, focal muscle atrophies and distal myopathies.

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

-82 disease for the majority of 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 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 severe mlastenla. 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 qulinase (MuSK) involved in

-83 AChR clustering (see, eg, Drachman, N. Eng. J. of Med., 330: 17971810, 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 voluntary muscle, certain muscles, such as those that control eye and eyelid movement, 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 compounds and compositions described and / or 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.

-84 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 atrophy of disuse leading to a potential loss of the ability to live independently. already a cascade of physical deterioration. 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 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 is also 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, (for example, 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 the

-85 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.

The 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, numbness, or cramping in the

-86 muscles 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 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: 21 st 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.

-87 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, distal myopathies, other myopathies (eg myofibrillar, inclusion bodies) myotonic syndromes, ion channel muscle diseases, malignant hyperthermia, metabolic myopathies, congenital myastic 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 may also be used to treat diseases and conditions caused by dysfunction of the CNS, spinal cord, or muscle resulting from endocrine and / or metabolic dysregulation, including claudication secondary to arterial disease

Peripheral -88, hypothyroidism, hyper or hypoparathyroidism, diabetes, adrenal dysfunction, pituitary dysfunction, and 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 (that is, the surgical removal of the thymus gland, which is often 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 can also

-89 include medication, such as medicines to help improve walking distance (eg, cilostazol, pentoxifylline), antiplatelet agents (eg, aspirin, ticlopidine, clopidogrel), anticoagulants (eg, heparin, low molecular weight heparin, 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.

Suitable therapeutic agents include, for example, anti-obesity agents, anti-sarcopenia agents, anti-weakening syndrome agents, anti-fragility 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

United States No. 3,239,345 (eg, zeranol), compounds disclosed in

United States Patent No. 4,036,979 (eg, sulbenox), disclosed peptides

-90 in United States Patent No. 4,411,890, growth hormone secretagogues such as GHRP-6, GHRP-1 (disclosed in United States 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 clonidine agonists or 5HT serotonin_d, such as sumatriptan, agents that inhibit somatostatin or its release, such as physostigmine, pyridostigmine, parathyroid hormone, PTH (1-34), 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 anti-myostatin antibodies or soluble 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 lure receptor from ActRIIB (see Zhou et al., Cell, 142, 531-543, August 20 , 2010); and anabolic steroids.

-91 Other suitable additional 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 (Regeneran), a beta thyroid receptor drug, such as a thyroid receptor ligand as disclosed in WO documents

97/21993, WO 99/00353 and GB98 / 284425 and anorectic agents, such as dexamphetamine, phentermine, phenylpropanolamine or mazindol.

Other additional suitable therapeutic agents 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.

-92 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 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 0.0 mg / kg body weight and in some embodiments, from about 0.15 to 1.0 mg / kg 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, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal administration, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal or intraocular. In some embodiments, the compound or composition is administered orally or intravenously.

-93 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 may 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 may be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (eg, 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

-94 are known or will be apparent to those skilled in the art, for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvanla.

In some embodiments, the compositions will take the form of a pill or tablet and therefore the composition may contain, together with a disclosed and / or disclosed compound, one or more of a diluent (eg, lactose, sucrose , dicalcium phosphate), 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 propylene 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 composition will comprise from about 0.2 to 2% of a disclosed and / or disclosed compound in solution.

-95 The pharmaceutical compositions of the disclosed and / or disclosed compounds may 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 agents include those 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 N- (5- (6- (2- (4-Fluorophenyl) -2-methylpropylamino) pyridazin-3yl) -1 H-indazol-3-yl) acetamide

<img file="MX2012012259A_D0037.tif" />

6-Chloro-N- (2- (4-fluorophenyl) -2-methylpropyl) pyridazin-3-amine. A solution of (2- (4-fluorophenyl) -2-methylpropan-1-amine (27 g, 160 mmol, 1.6 equiv.), 3,620 dlchloropirldazlna (15 g, 100 mmol, 1.0 equiv.) And K₂CO₃ (42 g, 302 mmol, 3.0 equiv.) In isopropanol (15 ml) was stirred at 100 ° C for 36 hours. The cooled mixture was partitioned between water and EtOAc and the organic fraction was dried over Na₂SW₄ and concentrated in a vacuum. Partial purification on silica gel using a gradient of 30-75%

-96EtOAc / hexanes gave the desired product (29.6 g, 103%) which was used without further purification.

<img file="MX2012012259A_D0038.tif" />

2-Fluoro-5- (6- (2- (4-fluorophenyl) -2-methylpropylamino) pyridazin-3-yl) benzonitrile.

To a solution of 6-chloro-N- (2- (4-fluorophenyl) -2-methylpropyl) pyridazin-3-amine (5.0 g, 23 mmol, 1.0 equiv.) And K₂CO₃ (9.4 g, 68 mmol, 3.0 equiv.) In dioxane (35 ml) Pd (dppf) CI was added₂ (1.7 g, 2.3 mmol, 0.1 equiv.) And 3-cyano-4-fluorophenylboronic acid (5.0 g, 30 mmol, 1.3 equiv.). The mixture was stirred at 80 ° C for 3 hours, after which it was allowed to cool to room temperature and concentrated in vacuo. The residue was diluted with EtOAc, washed with NaHCO₃ saturated, dried over Na₂SW₄ and evaporated to dryness. The residue was purified by reverse phase HPLC using a CH gradient₃CN / water to give the desired product (5.3g, 63%).

<img file="MX2012012259A_D0039.tif" />

<img file="MX2012012259A_D0040.tif" />

5- (6- (2- (4-Fluorophenyl) -2-methylpropylamino) pyridazin-3-yl) -1H-indazol-3-amine.

To a solution of 2-fluoro-5- (6- (2- (4-fluorophenyl) -2-methylpropylamino) plridazin-3yl) benzonltrile (0.53 g, 1.5 mmol, 1.0 equiv.) In n -butanol (10 ml) was added hydrazoline monohydrate (1.0 ml, 32 mmol, 20 equiv.). The mixture was stirred at 110 ° C for two hours followed by evaporation of the solvents in vacuo. Purification on a preparative TLC plate using 5% MeOH / DCM as eluant gave the desired product (195mg, 36%), m / z = 377.1 [M + H],

<img file="MX2012012259A_D0041.tif" />

<img file="MX2012012259A_D0042.tif" />

N- (5- (6- (2- (4-Fluorophenyl) -2-methylpropylamino) pyridazin-3-yl) -1H-indazol-3yl) acetamide. To a solution of 5- (6- (2- (4-fluorophenyl) -2-methylpropylamino) pyridazin-3-yl) 1H-indazol-3-amine (50 mg, 133 μιτιοΙ) in pyridine (1 ml) was added acetyl chloride (9.5 μΙ, 133 μΓηοΙ). The mixture was stirred for 15 min, concentrated, and purified by reverse phase chromatography using a CH gradient.₃CN / water to provide 25 mg of a white solid, m / z = 419.9 [M + H],

Example 2: Preparation of N- (2- (4-Fluorophenyl) -2-methylpropyl) -6- (1H-pyrazol-1yl) pyridazin-3-amine

<img file="MX2012012259A_D0043.tif" />

Step 1: To a solution of pyrazole (3.69 g, 25 mmol, 1.0 equiv.) In NMP (25 ml) was added sodium hydride (60% dispersion in mineral oil, 1.5 g, 38 mmol , 1.5 equiv.). The mixture was stirred for 15 min, followed by the addition of 3,6-dichloropyridazine (3.02 g, 25 mmol, 1.0 equiv.). The reaction mixture was stirred for 1.5 hr and then 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 Na₂SW₄, filtered, and concentrated to give 3.89 g of 3-chloro-6- (1H-plrazol-1-yl) pyridazine as a crude brown solid that was used directly in the next step .

-98 Stage 2: To a 5 ml microwave vial 3-chloro-6- (1H-pyrazole-1) pldazine (320 mg, 1.8 mmol, 1.0 equiv.) Was added, 2 - (4-fluorophenyl) -2-methylpropan-1-amine (386 mg, 2.3 mmol, 1.3 equiv.), Diisopropylethylamine (620 μΙ, 3.6 mmol, 2.0 equiv.) and NMP (4 mi). The reaction was heated in a microwave reactor at 250 ° C and stirred for

fifteen min. A portion (approximately one third) of the reaction was purified by reverse phase chromatography and then by chromatography on silica gel (10% MeOH / DCM) to give 61 mg of N- (2- (4-fluorophenyl) -2 -methylpropyl) -6- (1 H-pyrazol-1yl) plridazin-3-amine, m / z = 312.1 [M + H],

Example 3: Preparation of 5- (6- (2- (4-fluorophenyl) -2-methylpropylamino) pyridazin-3-yl) 10 1,3,4-oxadiazol-2 (3H) -one

<img file="MX2012012259A_D0044.tif" />

Methyl 6- (2- (4-Fluorophenyl) -2-methylpropylamino) pyridazin-3-carboxylate. To a 25 ml round bottom flask was added methyl 6-chloropyridazyl-3-carboxylate (0.50 g, 2.90 mmol, 1.0 equiv.), 2- (4-fluorophenyl) -2-methylpropan-1-amine (0.60 g,

3.6 mmol, 1.2 equiv.), Potassium carbonate (300 mg, 2.2 mmol, 0.75 equiv.) And isopropanol (3 ml). The reaction mixture was stirred and heated at 120 ° C for 12h. The reaction was then filtered through celite, concentrated, and purified by chromatography on silica gel (0-40% EtOAc / hexanes) to provide 360 ​​mg (43%) of 6- (2- (4-fluorophenyl) ) -2-methylpropylamine) methyl pyridanyl-3-carboxylate in the form of an off-white foam.

<img file="MX2012012259A_D0045.tif" />

5- (6- (2- (4-Fluorophenyl) -2-methylpropylamino) pyridazine-3-yl) -1,3,4-oxadiazol2 (3H) -one. To a 25 ml round bottom flask was added methyl 6- (2- (4-fluorophenll) -2methylpropllamino) p¡r¡daz¡n-3-carboxylate (100 mg, 0.3 mmol, 1 , 0 equlv.), Hldrazine hydrate (1 ml) and ethanol (5 ml)). The reaction was heated at reflux for 2 h and concentrated. Then Ν, Ν'-carbonyldimidazole (100 mg, 0.6 mmol, 2.0 equlv.) And DMF (1 ml) were added to the crude product and the reaction was heated at 90 ° C for 1.5 h . The reaction mixture was directly purified by Reverse phase column chromatography to provide 72 mg (67%) of 5- (6- (2- (4-fluorophenll) -210 methylpropyllamine) pridazln- 3-l) -1, 3,4-oxadiazole-2 (3H) -one as a white solid, m / z = 330.0 [M + H],

Example 4: Preparation of 6- (2-Amino-1H-imidazol-4-yl) -N- (2- (4-fluorophenyl) -2methylpropyl) pyridazin-3-amine

<img file="MX2012012259A_D0046.tif" />

2-Bromo-1 - (6- (2- (4-fluorophenyl) -2-methylpropylamino) pyridazin-3-yl) ethanone. 6-Chloro-N- (2- (4-fluorophenyl) -2-methylpropyl) pyridazine-3-amlin (300mg, 1.1mmol,

1.0 equlv.) And dloxane (5 ml) to a microwave vial and sonication was applied until the mixture was homogeneous. Then tributyl (1-ethoxyvinyl) stannane (475 µΙ,

1.4 mmol, 1.3 equiv.) And trans-dichlorobis (triphenylphosphine) palladium (30 mg, 0.04 mmol, 0.03

-100 equiv.) And the reaction was heated in a microwave reactor at 150 ° C for 20 min. The reaction was concentrated, dissolved in EtOAc (25 ml) and mixed with 2.0M potassium fluoride (5 ml). The mixture was filtered through celite and then washed with water, dried over Na₂SW₄, filtered and concentrated. The crude solid was redissolved in THF at

50% / water (4 ml), followed by the addition of NBS (300 mg, 1.7 mmol, 1.5 equiv.). The reaction mixture was stirred for 1 hr and then diluted with brine (20 ml) and ethyl acetate (20 ml). After transferring to a settling funnel and shaking, the organic layer was separated from the aqueous layer. Then the organic layer was dried over Na₂SW₄, filtered and concentrated to give a brownish oil which was purified by chromatography on silica gel (0-100% EtOAc / hexanes) to provide 270 mg of 2-bromo-1- (6- (2- ( 4-fluorophenyl) -2-methylpropylamino) pyridazin-3-yl) ethanone as an orange oil.

<img file="MX2012012259A_D0047.tif" />

N- (4- (6- (2- (4-Fluorophenyl) -2-methylpropylamino) pyridazin-3-yl) * 1H-imidazol-215 yl) acetamide. To a 3 ml microwave reaction vial, 2-bromo-1 (6- (2- (4-fluorophenyl) -2-methylpropyllamine) pyridazyl-3-l was added. ) ethanone (125 mg, 0.3 mmol, 1.0 equiv.), acetyl guanidine (90 mg, 0.6 mmol, 2.0 equiv.) and acetonitrile (2 ml). The reaction was heated in a microwave reactor at 100 ° C for 13 min. The reaction was filtered and purified directly by Reverse phase column chromatography to provide

N- (4- (6- (2- (4-fluorophenyl) -2-methylpropyllamine) plrdazin-3-il) -1H-imidazol-2-yl) acetamide (70 mg) as a white solid, m / z = 369.2 [M + H] +.

- 101 -

<img file="MX2012012259A_D0048.tif" />

<img file="MX2012012259A_D0049.tif" />

6- (2-Amino-1 H-imidazol-4-yl) -N- (2- (4-fluorophenyl) -2-methylpropyl) pyridazine-3amine. To a 10 ml round bottom flask was added N- (4- (6- (2- (4-fluorophenyl) 2-methylpropyllamine) plridazin-3-l) -1H- ¡M¡dazol-2-l) acetamida (22 mg, 59 pmol), concentrated HCI (100 μΙ) and methanol (1 ml). The reaction was heated at reflux for 12 h and then concentrated, redissolved in EtOAc (10 ml), washed with saturated sodium carbonate (2 x 10 ml) and brine (1x10 ml), dried (Na₂SW₄) and concentrated to produce 8 mg (42%) of 6- (2-amino-1H-imidazol-4-yl) -N- (2- (4-fluorophenyl) -2methylpropyl) pyridazin-3-amine in form of a pale yellow solid, m / z = 327.2 [M + H],

Example 5: Preparation of 6- (5-Amino-1H-pyrazol-3-yl) -N- (2- (4-fluorophenyl) -2methylpropyl) pyridazin-3-amine

<img file="MX2012012259A_D0050.tif" />

2-bromo-1- (6- (2- (4-fluorophenyl) -215 methylpropylamino) pyridazin-3-yl) ethanone (13 mg, 35 pmol, 1.0 equiv.) Was added to a 20-drach vial. , sodium cyanide (25 mg, 500 μητιοΙ, 15.0 equiv.) and ethanol (1 ml). The reaction mixture was heated at 60 ° C for 30 min. After cooling to room temperature, the reaction was filtered. Then, hydrazine hydrate (250 µΙ) was added and the reaction mixture was heated at 100 ° C for 2 h. The reaction was filtered and purified directly by chromatography on

-102 reverse phase column to provide 6- (5-amino-1H-pyrazol-3-yl) -N- (2- (4fluorophenyl) -2-methylpropyl) pyridazin-3-amine (2 mg) as a white solid, m / z = 327.2 [M + H],

Example 6: Preparation of 6-Ethyl-N- (2- (4-fluorophenyl) -2-methylpropyl) pyridazin-3-amine

<img file="MX2012012259A_D0051.tif" />

<img file="MX2012012259A_D0052.tif" />

Step 1: 6-chloroN- (2- (4-fluorophenyl) -2-methylpropyl) pyridazin-3-amine (123 mg, 441 μίτιοΙ, 1.0 equiv.) Was added to a 5 ml microwave reaction vial. ), 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborine (159 mg, 661 pinol, 1.5 equiv.), CI₂Pd (dppf) (54 mg, μίτιοΙ, 0.15 equiv.), Potassium carbonate (182 mg, 1.32 mmol, 3 equiv.) And dioxane (21 ml). The reaction was heated in a microwave reactor at 140 ° C for 12 min and then diluted with water (20 ml) and ethyl acetate (50 ml). After transferring to a settling funnel and stirring, the organic layer was separated from the aqueous layer and then washed with brine (1 x 20 ml). Then the organic layer was dried over Na₂SW₄, filtered, and concentrated to give a crude solid which was purified by silica gel column chromatography (20-50% EtOAc / hexanes) to give 50 mg (46%) of N- (2- (4- fluorophenyl) -2-methylpropyl) -6-vinylpyridazin-3-amine as a white solid.

Step 2: The isolated product from Step 1 was dissolved in ethanol (10 ml) and transferred to a 20 drachm vial. Then palladium (10% on carbon,

10 mg) and the reaction was stirred at 413.68 kPa (60 psi) of hydrogen for 3 days.

The reaction was then filtered, concentrated, and purified by column chromatography.

-103 reverse phase to provide 3 mg (10%) of 6-ethyl-N- (2- (4-fluorophenyl) -2methylpropyl) pyridazin-3-amine as a clear oil, m / z = 274 [M + H],

Example 7: Preparation of 2- (6 - ((1- (3-Fluoropyridin-2L) cyclobutyl) methylamino) pyridazin-3-yl) propan-2-ol

<img file="MX2012012259A_D0053.tif" />

Methyl 6 - ((1- (3-Fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3-carboxylate. Methyl 6-chloropyridazin-3-carboxylate (510 mg, 2.7 mmol, 1.0 equiv.), (1- (3-fluoropinedin-2-yl) cyclobutyl) methanamine ( 738 mg, 4 mmol, 1.5 equiv.), DIPEA (0.7 ml, 4 mmol, 1.5 equiv.) And NMP (2 ml). The reaction was heated at 120 ° C for 40 min and then diluted with water (20 ml) and ethyl acetate (50 ml). After transferring to a settling funnel and stirring, the organic layer was separated from the aqueous layer and then washed with brine (1 x 20 ml). Then the organic layer was dried over Na₂SW₄, filtered, and concentrated to give a crude solid which was purified by silica gel column chromatography (2015 100% EtOAc / hexanes) to give 440 mg (48%) of 6 - ((1- (3- White methyl fluoropyridin-2yl) cyclobutyl) methylamino) pyridazin-3-carboxylate, m / z = 331.1 [M + H] - »-.

<img file="MX2012012259A_D0054.tif" />

<img file="MX2012012259A_D0055.tif" />

2- (6 - ((1- (3-Fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3-yl) propan-2-ol.

A portion of the isolated 6 - ((1- (3-fluoropyridin-2-yl) cyclobutyl) methylamine) pyridazin-3-carboxylic acid (99 mg, 0.3 mmol, 1.0 equiv.) Was dissolved in THF (10 me) and I know

-104 transferred to a vial of 20 drachmas. The mixture was cooled to 0 ° C and MeMgBr (3M in Et₂Or, 0.5 ml, 1.5 mmol, 5 equiv.). The reaction was allowed to warm to rt and was then stirred for 15 min. The reaction mixture was poured into a mixture of EtOAc (30 ml) and saturated ammonium chloride (15 ml). The organic layer was separated, dried over Na₂SW₄, filtered, and concentrated to give a crude solid which was purified by silica gel column chromatography (0-20% MeOH / CH₂CI₂) to give 42 mg (43%) of 2- (6 - ((1 (3-fluoropyridin-2-yl) cyclobutyl) methylamine) p¡r¡daz¡n-3- L) Propan-2-ol in the form of a white powder, m / z = 317 [M + H] +.

Example 8: Preparation of 1 - (6 - ((1 - (3-Fluoropyridin-210 yl) cyclobutyl) methylamino) pyridazin-3-yl) ethanone

<img file="MX2012012259A_D0056.tif" />

6 - ((1- (3-Fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3-carbonitrile. To a vial of 20 drachms 6-chloropyridazin-3-carbonyltril (1.0 g, 7.2 mmol, 1.0 equiv.), (1- (3-fluoropyridin-2-yl) was added cyclobutyl) methanamine (1.36 g, 7.6 mmol, 1.05 equiv.), triethylamine (2.1 ml, 14.4 mmol, 2.0 equiv.) and NMP (2 ml). The reaction was heated at 130 ° C for 12 hr and then diluted with water (20 mL) and ethyl acetate (50 mL). After transferring to a settling funnel and stirring, the organic layer was separated from the aqueous layer and then washed with brine (1 x 20 ml). Then the organic layer was dried over Na₂SW₄, filtered, and concentrated to give a crude solid which was purified by silica gel column chromatography (20-30% EtOAc / hexanes) to give

507 mg (25%) of 6 - ((1- (3-fluorop¡r¡dln-2-yl) cyclobutyl) met¡lam¡no) p¡r¡daz¡n-3-carbon¡tr the.

m / z = 284 [M + H] +.

-105 F

Ν-Ν _ΓNC-? V-ΝΗ

Ν-Ν γ '(Vnh

1- (6 - ((1- (3-Fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3-yl) ethanone. 6 - ((1- (3-Fluoropyridin-2-yl) cyclobutyl) methylamine) pyridazin-3-carbonitrile (500 mg, 1.8 mmol, 1.0 equiv.) Was dissolved in THF (4.5 ml) and it was transferred to a 20 drachm vial. The mixture was cooled to 0 ° C and MeMgBr (1.8 ml, 5.3 mmol of a 3M solution in Et₂O, 2.9 equiv.). The reaction was stirred at this temperature for 15 min. The reaction mixture was poured into ice-cold water, acidified to pH 2 with 2N aqueous hydrochloric acid, and then extracted with EtOAc (30 ml). Then the organic layer was separated, dried over Na₂SW₄, filtered, and concentrated to give a crude solid which was purified by silica gel column chromatography (50% EtOAc / hexanes) to give 104 mg (18%) of 1- (6 - ((1- ( 3-fluoropyridin-2yl) cyclobutyl) methylamino) pyridazine-3-yl) ethanone as a white powder, m / z = 301.1 [M + H] +.

Example 9: Preparation of N- (2- (4-fluorophenyl) -2-methylpropyl) -6- (pyridin-2-yl) pyridazin15 3-amine

<img file="MX2012012259A_D0057.tif" />

2-bromopyridine (500 mg,

3.2 mmol, 1.0 equiv.), Triisopropyl borate (654 mg, 3.5 mmol, 1.1 equiv.) And a mixture of 80% toluene / THF (16 ml). The mixture was cooled to -78 ° C. After shaking for

-106 10 min, n-BuLi (1.7 ml, 3.48 mmol, 1.1 equiv. Of a 2.0 M / hexanes solution) was added slowly over one hour. After the addition was complete, the reaction mixture was stirred for 30 min and allowed to warm to rt and stirred overnight. The reaction was then concentrated at 100 ° C and dried in vacuo for 2 h. 6-Chloro-N- (2- (4-Fluorophenyl) -2-methylpropyl) pyridazin-3-amine (70mg, 0.25mmol) was added to 100mg of this crude solid in a microwave vial. ), PS₂dba₃ (10 mg, 0.011 mmol), PO (íBu)₃ (5 mg, 0.030 mmol), potassium fluoride (43 mg, 0.75 mmol), and dioxane (0.75 ml). The reaction was degassed with nitrogen for 5 minutes and then heated in a microwave reactor at 160 ° C for 15 min. Then, the reaction was concentrated, dissolved in EtOAc (25 ml), washed with water, dried over Na2SO₄, filtered, concentrated, and purified by reverse phase column chromatography to give 5 mg of N- (2- (4-fluorophenyl) -2-methylpropyl) -6- (pyridin-2-yl) pyridazin- 3-amine as a white solid, m / z = 323.1 [M + H] +.

Example 10: Preparation of 6- (6- (2- (4-fluorophenyl) -2-methylpropylamino) pyridazin-315 yljnicotinamide

<img file="MX2012012259A_D0058.tif" />

2-bromo-5-cyanopyridine (182 mg, 1.0 mmol, 1.0 equiv.), Hexamethyldin (639 mg, 1.1 mmol, 1.1 equiv) was added to a 20 drachm vial. .), CI₂Pd (Ph₃P)₂ (91 mg, 0.13 mmol, 0.13 equiv.), Triphenylarsine (34 mg, 0.11 mmol, 0.11 equiv.) And dioxane (7 ml). The reaction mixture was stirred and heated at ° C for 12h. The reaction was then concentrated, followed by the addition of tert-butyl 6-bromopyridazin-3-yl (2- (4-fluorophenyl) -2-methylpropyl) carbamate (423 mg, 1.0

- 107 mmol, 1.0 equiv.), Pd (Ph₃P) 4 (172 mg, 0.15 mmol, 0.15 equiv.) And DMF (3.3 ml). The reaction was stirred and heated at 100 ° C for 3h. After cooling to room temperature, the reaction was diluted with aqueous potassium fluoride (5 ml), extracted with ethyl acetate (20 ml) and washed with brine (20 ml). Then the organic layer was dried (Na₂SW₄), filtered and concentrated to give crude 6- (5-cyanopyridin-2-yl) pyridazine-3-yl (2- (4-fluorophenyl) -2-methylpropyl) carbamate.

To a vial of 20 drachmas was added 6- (5-cyanopyridin-2-yl) pyridazin-3-yl (2- (4-fluorophenyl) -2-methylpropyl) crude tere-butyl carbamate, hydrogen peroxide (2 ml ) and potassium carbonate (150 mg). The reaction was stirred for 30 min and then diluted with water (20 ml) and ethyl acetate (50 ml). After transferring to a settling funnel and stirring, the organic layer was separated from the aqueous layer and then washed with brine (20 ml). The organic layer was then dried over Na2SO₄, filtered and concentrated to give a crude solid which was subsequently treated with 4N HCI / dloxane (1 ml). The reaction was stirred for 1 h at room temperature, concentrated, quenched with aqueous sodium bicarbonate, and extracted with ethyl acetate (20 mL). Then the organic layer was dried (Na₂SW₄), filtered and concentrated to give a crude solid which was purified by reverse phase column chromatography to provide 10 mg of 6- (6- (2- (4-fluorophenyl) -2-methylpropylamino) pyridazin-3yl) nlcotinamide, m / z = 366.1 [M + Hj.

Example 11: Preparation of 6- (2-aminopyridin-3-yl) -N - ((1- (3-fluoropyridin-2yl) cyclobutyl) methyl) pyridazin-3-amine

<img file="MX2012012259A_D0059.tif" />

-108N - ((1- (3-Fluoropyridin-2-yl) cyclobutyl) methyl) -6- (2-methoxypyridin-3-yl) pyridazin-3amine. 6-Chloro-N - ((1- (3-fluoropyridin-2yl) cyclobutyl) methyl) pyridazin-3-amine (1.8 g, 6.23 mmol, 1.0 equiv) was added to a 20 drachm vial. .), 2-methoxypyridin-3-yl-boronic acid (1.0 g, 6.54 mmol, 1.1 equiv.), CI₂Pd (dppf) (350 mg, 0.43 mmol, 0.07 equiv.), 2M potassium carbonate (8 ml, 15.5 mmol, 2.5 equiv.) And dioxane (21 ml). The reaction was stirred and heated at 90 ° C for 2 hr, then diluted with water (20 mL) and ethyl acetate (50 mL). After transferring to a settling funnel and shaking, the organic layer was separated from the aqueous layer and then washed with lithium chloride (1 x 20 ml). Then the organic layer was dried over Na₂SW₄, filtered, and concentrated to give a crude solid which was purified by silica gel column chromatography to give N - ((1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) -6- (2- methoxypyridin-3-yl) pyridazin-3-amine (1.7 g, 77%) as an off-white solid.

<img file="MX2012012259A_D0060.tif" />

6- (2-Chloropyridin-3-yl) -N - ((1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) pyridazin-315 amine. N - ((1- (3-fluoropyridin-2yl) cyclobutyl) methyl) -6- (2-methoxypyridin-3-yl) pyridazin-3-amine (1 , 7 g, 4.7 mmol), concentrated hydrochloric acid (15 ml) and methanol (15 ml). The reaction was heated to 90 ° C and stirred for 12h. The reaction was concentrated, brought to a pH of 11 through the addition of saturated potassium carbonate (20 ml) and then diluted with ethyl acetate (50 ml). After transferring to a settling funnel and stirring, the organic layer was separated from the aqueous layer and washed with lithium chloride (1 x 20 ml). Then the organic layer was dried over Na₂SW₄, filtered and concentrated to give 3- (6 - ((1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3-yl) pyridin-2-ol (1.6 g, 95%) in form of

-109a chestnut powder. The isolated product (1.3 g, 3.7 mmol, 1.0 equiv.) Was transferred to a 100 ml round bottom flask, followed by the addition of a mixture of phosphorous oxychloride (24 ml) and DMF ( 8 mi). The reaction was heated to 90 ° C and stirred for 6h. The reaction was concentrated and carefully quenched with a 50% mixture of saturated sodium bicarbonate and lithium chloride until gas evolution ceased. The mixture was extracted with ethyl acetate (100 ml). The combined organic layers were then dried over Na₂SW₄, filtered, concentrated, and purified by column chromatography on silica gel to give 1.2 g (88%) of 6- (2-chloroplrldn-3yl) -N - ((1- (3-fluorop Ridin-2-yl) cyclobutyl) methyl) pyridazine-3-amine in the form of an off-white solid.

<img file="MX2012012259A_D0061.tif" />

6- (2-Aminopyridin-3-yl) -N - ((1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) pyridazin-3amine. 6- (2-Chloropyridin-3-yl) -N - ((1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) pyridazin-3-amine (750 mg) was added to a 5 ml microwave reaction vessel. , 2.0 mmol), hydrazine hydrate (1 ml) and dioxane (4 ml). The reaction was heated in a microwave reactor at 160 ° C for 15 min, then diluted with ethyl acetate (50 ml) and washed with brine (20 ml). The organic layer was dried over Na₂SW₄, filtered, and concentrated to give a crude solid which was purified by reverse phase column chromatography to give 150 mg of N - ((1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) - 6- (220 hydrazinylpyridin-3-yl) pyridazin-3-amine as an off-white solid.

The isolated product was then dissolved in methanol and added to a vial containing ~ 1 ml of a suspension of Raney nickel in water. Then the mixture was stirred at

344.74 kPa (50 psi) of hydrogen for 2 h. Then the reaction was filtered,

-110 concentrated and was purified by reverse phase column chromatography to give 10 mg (88%) of 6- (2-amynopyrid-3-yl) -N - ((1- (3-fluoropi rddn-2-l) cyclobutyl) metl) pldazin-3-amine in the form of an off-white solid, m / z = 351.1 [M + H ],

Example 12: Preparation of N1- (5- (6 - ((1- (3-Fluoropyridin-25 yl) cyclobutyl) methylamino) pyridazin-3-yl) -1 H-lndazol-3-ll) ethane-1,2 -dlamlna

<img file="MX2012012259A_D0062.tif" />

<img file="MX2012012259A_D0063.tif" />

2- (2-Fluoro-5- (6 - ((1- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyridazin-3-yl) benzamido) ethyl carbamate. 2-fluoro-5- (6 - ((1- (3-fluoropyrid-2-yl) cyclobutll) methalamine) p! Acid was added to a vial of 20 drachmas ridazin-310 yl) benzoic (320 mg, 0.8 mmol, 1.0 eq.), benzylo 2-aminoethylcarbamate (242 mg, 1.0 mmol, 1.3 eq.), HOBt (141 mg, 1.0 mmol, 1.3 equiv.), EDC HCI (200 mg, 1.0 mmol,

1.3 equlv.), DIPEA (550 μΙ, 3.8 equlv.) And CH₂CI₂ (5 mi). The reaction was stirred for 4 hr, then concentrated, and then purified using a column of silica gel (50% -100% EtOAc / hexanes) to provide 230 mg (50%) of 2- (2-fluoro-5 - (6 - ((1- (315 fluoropyrin-2-yl) cyclobutyl) methylamlno) pyridazin-3-l) benzamido) ethylcarbamate of benzyl in the form of a foam of White color.

<img file="MX2012012259A_D0064.tif" />

CbzHN

CbzHN

-111 2- (2-Fluoro-5- (6 - ((1- (3-fluoropyrin-2-yl) cyclobutyl) methylamino) pyridazin-3yl) phenylthioamido) benzyl ethylcarbamate. To a 20-drachm vial containing 2- (2-fluoro-5- (6 - ((1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3yl) benzamido) ethylbenzylcarbamate (230 mg, 0.5 mmol, 1 equiv.) 5 Lawesson's reagent (162 mg, 0.4 mmol, 0.8 equiv.) And dioxane (10 ml) were added. The reaction was heated to 100 ° C and stirred for 1 h, concentrated, and then purified using a column of silica gel (35% -100% EtOAc / hexanes) to give 203 mg (86%) of 2- Benzyl (2-fluoro-5- (6 - ((1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3yl) phenylthioamido) ethylcarbamate as a pale yellow oil.

<img file="MX2012012259A_D0065.tif" />

Benzyl (2- (5- (6 - ((1 - (3-Fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3-yl) -1Hindazol-3-ylamino) ethylcarbamate. Benzyl 2- (2-fluoro-5- (6 - ((1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3-yl) phenylthioamido) ethyl carbamate was transferred into a 20-drach vial , followed by the addition of hydrazine hydrate (0.1 ml) and dioxane (2 ml). The reaction was heated to 100 ° C and stirred for 12 h, concentrated, and then purified using a column of silica gel (5% -10% MeOH / EtOAc) to produce 48 mg (25%) of 2- (5- (6 - ((1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3yl) -1H-indazol-3-ylamino) benzyl ethylcarbamate as a pale yellow oil .

-112-

<img file="MX2012012259A_D0066.tif" />

Ν1 - (5- (6 - ((1 - (3-Fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3-yl) -1 Ηindazol-3-yl) ethane-1,2-diamine. 2- (5- (6 - ((1 - (3-fluoropyrid-n-2yl) cyclobutyl) methalamine) pyrrdazin-3-is dissolved l) -1H-indazol-3-ylamino) benzyl ethyl carbamate (48 mg, 84 pmol) in acetonitrile (5 ml) and TMSI (0.5 ml) was added. The reaction was stirred for 15 min, diluted with methanol (15 ml), concentrated, and purified directly by reverse phase column chromatography to produce 20 mg (88%) of N1- (5- (6 ((1- (3-fluoropyridin-2-yl) cyclobutyl) methylamine) pyridazin-3-yl) -1H-ndazol-3-yl) ethane-1,2-diamine as a colored solid yellow, m / z = 433 [M + H].

Example 13: Preparation of 6- (5-Aminopyridin-2-yl) -N - ((1- (3-fluoropyridin-2yl) cyclobutyl) methyl) pyridazin-3-amine

<img file="MX2012012259A_D0067.tif" />

2-Bromo-5- (2,5-dimethyl-1H-pyrrol-1-yl) pyridine. To a 25 ml round bottom flask, 5-amino-2-bromopyridine (600 mg, 3.5 mmol, 1.0 equiv.), Hexane-2,5-dione (420 mg, 4.2 mmol, 1.2 equiv.), P-toluenesulfonic acid (5 mg) and toluene (3.5 ml). A Dean-Stark trap was attached to the top of the round bottom flask and the reaction mixture was heated under reflux for 2 h. The reaction was then concentrated and purified by column chromatography on silica gel (5% ethyl acetate / hexanes) to give 660 mg (76%) of 2-bromo-5- (2,5-d-methyl -1H20 pyrrole-1-yl) pyridine.

-113-

<img file="MX2012012259A_D0068.tif" />

Boc

6- (5- (2,5-D¡metil-1 H-piryrrol-1 -i I) pi rid i η-2-i I) pi ridazi n-3-il ((1 - (3-fluoropyridin- 2-l) cyclobutyl-l) methyl) ferc-butyl carbamate. THF (8.5 ml) was cooled to -78 ° C under a nitrogen atmosphere. FBuLi (1.7 ml, 2.9 mmol, 2.0 equiv.) Was added, followed by the addition of 2-bromo-5- (2,5-dimethyl-1H-pyrrole-1-yl) pyridine ( 370 mg, 1.47 mmol, 1.0 equiv (dissolved in 2 ml of THF) for 2 min. The reaction was stirred for 45 min at -78 ° C. Zinc chloride (510 mg, 3.75 mmol, 2.5 equiv. dissolved in 5 ml of THF) and the reaction was allowed to warm to rt and stirred for 3 h. (F-Bu were added₃P)₂F-Butyl Pd (41 mg, 0.015 mmol, 0.10 equiv. Dissolved in 5 ml of THF) and 6-chloropyridazin-3-yl - ((1- (310 fluoropyridin-2-yl) cyclobutyl) methyl) carbamate (393 mg, 0.1 mmol, 0.07 equiv. Dissolved in 5 ml of THF) and the reaction was heated at reflux for 4 h followed by dilution with sodium bicarbonate (20 ml) and extraction with ethyl acetate (40 ml). ). The organic layer was dried over Na₂SW₄, filtered, and concentrated to give a crude solid which was purified by silica gel column chromatography (35% EtOAc / hexanes) to give 245 mg (46%) of 6- (5- (2.5- Fercybutyl dimethyl-1H-pyrrole-1-yl) pyridin-2-yl) pyridazin-3-yl ((1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate.

N

<img file="MX2012012259A_D0069.tif" />

Boc

<img file="MX2012012259A_D0070.tif" />

6- (5-Aminopyridin-2-yl) -N - ((1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) pyridazin-3amine. 6- (5- (2,5-Dimethyl-1 H-pyrrol-1-yl) pyridin-2-114yl) pyridazin-3-yl ((1- (3-fluoropyridin- 2-yl) cyclobutyl) methyl) ferc-butyl carbamate (245 mg, 0.5 mmol) and 5 ml of a 50% mixture of TFA and CH₂CI₂. The reaction was stirred for 15 min, concentrated, and then diluted with sodium bicarbonate (20 ml) and extracted with ethyl acetate (40 ml). The organic layer was dried over Na₂SW₄, filtered, and concentrated to give a crude solid which was purified by silica gel column chromatography (60% EtOAc / hexanes) to give 91 mg (46%) of 6- (5- (2.5- dimethyl-1H-pyrrol-1yl) pyridin-2-yl) -N - ((1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) pyridazine-3-amine. This product was transferred to a 100 ml round bottom flask to which hydroxylamine hydrochloride (270 mg), triethylamine (5 ml) and ethanol (20 ml) were added. The reaction mixture was refluxed overnight, and then concentrated, diluted with sodium bicarbonate (20 ml), and extracted with ethyl acetate (40 ml). The organic layer was dried over Na₂SW₄, filtered, and concentrated to give a crude solid which was purified by reverse phase column chromatography to provide 28 mg of 6- (5-aminopyridin2-yl) -N - ((1- (3-fluoropyridine -2-l) cyclobutyl) metl) pyridazine-3-amine, m / z = 351.2 [M + H],

Example 14: Preparation of 3- (6- (2- (4-Fluorophenyl) -2-methylpropylamino) -4methylpyridazin-3-yl) benzamide

<img file="MX2012012259A_D0071.tif" />

6-Chloro-N- (2- (4-fluorophenyl) -2-methylpropyl) -5-methylpyridazin-3-amine. A solution of (2- (4-fluorophenyl) -2-methylpropan-1-amine (5.5 g, 33 mmol, 1.8 equiv.), 3,620 dichloro-4-methylpyridazine (3.0 g, 18 mmol, 1.0 equiv.) and K₂CO₃ (5.1 g, 37 mmol, 2.0 equiv.) In isopropanol (7.5 ml) was stirred at 100 ° C under a nitrogen atmosphere for 18 hours. The cooled mixture was partitioned between water and EtOAc and the organic fraction was concentrated in vacuo. Purification on silica gel using a 20-35% EtOAc / hexanes gradient gave the desired product (0.80 g, 15%) of a yellow oil

-115 which was determined by HPLC analysis to be a 5: 1 mixture of reglolsomers by HPLC.

<img file="MX2012012259A_D0072.tif" />

2-Fluoro-5- (6- (2- (4-fluorophenyl) -2-methylpropylamino) -4-methylpyridazin-35 yl) benzonitrile. To a solution of 6-chloro-N- (2- (4-fluorophenyl) -2-methylpropyl) -5-methylplridazln-3-amlin (0.8 g, 2.7 mmol, 1.0 equiv.) And K₂CO₃ 2M aqueous (2.0 ml, 8.2 mmol, 3.0 equiv.) in dioxane (14 ml) Pd (dppf) CI was added₂ (0.11 g, 0.14 mmol, 0.05 equiv.) And 3-cyanophenylboronic acid (0.48 g, 3.3 mmol, 1.2 equiv.). The mixture was stirred at 80 ° C for 2 hours under a nitrogen atmosphere. This was followed by the addition of another 100 mg (0.68 mmol, 0.25 equiv.) Of botanical acid and 30 mg (0.037 mmol, 0.013 equiv.) Of Pd (dppf) CI₂ and another 1 h of heating to 100 ° C. The mixture was allowed to cool to room temperature and was then diluted with EtOAc. The solution was washed with a 50% NaCI solution, dried over Na₂SW₄ and evaporated to dryness. The residue was purified over silica gel using a stepwise gradient of EtOAc to

twenty - 50% / hexanes to give the desired product (850 mg, 86%) as a single regloisomer.

<img file="MX2012012259A_D0073.tif" />

3- (6- (2- (4-Fluorophenyl) -2-methyl-propylamino) -4-methyl-lp¡r¡dazin-3-l) benzamide.

A 0 ° C solution of 2-fluoro-5- (6- (2- (4-fluorophenyl) -2-methylpropylamino) -420 methylpyridazin-3-yl) benzonitrile (0.80 g, 2.2 mmol, 1.0 equiv.), Hydrogen peroxide at

30% (0.45 ml, 4.4 mmol, 2.0 equiv.) And K₂CO₃ (600 mg, 4.4 mmol, 2.0 equiv.) In DMSO

-116 (9.0 ml) was stirred for 1 hour. The mixture was diluted with EtOAc, washed with saturated NaCI, water and again with saturated NaCI, and then dried over Na₂SW₄. Reverse phase HPLC purification using a CH gradient₃20-70% CN / water gave the desired product (420 mg, 51%) as a yellow solid, m / z =

379.1 [M + H] +.

Example 15: Preparation of 3- (5-Cyano-6- (2- (4-fluorophenyl) -2methylpropylamino) pyridazin-3-yl) benzamide

<img file="MX2012012259A_D0074.tif" />

3,6-Dichloropyridazin-4-carboxamide. An NH solution₄OH (1.1 ml, 17 mmol, 10 1.2 equiv.) And düsopropylethylelamine (6.2 ml, 36 mmol, 2.1 equiv.) In THF (57 ml) were probed until homogeneous, after which DMAP (1.0 g, 14 mmol, 1.0 equiv.) was added. Then, 3,6-dichloropyridazin-4-carbonyl chloride (3.0 g, 14 mmol, 1.0 equiv.) Was added and the solution was stirred at room temperature for 20 minutes. The solution was filtered and partitioned between EtOAc and a 1M KHSO solution₄. The organic layer was washed once more with KHSO₄one M and saturated NaCI, dried over Na₂SW₄, and evaporated to dryness to give the desired product (2.6 g, 96%).

<img file="MX2012012259A_D0075.tif" />

6-Chloro-3- (2- (4-fluorophenyl) -2-methylpropylamino) pyridazin-4-carboxamide.

Using a procedure similar to that used for 6-chloro-N- (2- (4-fluorophenyl) -2-methylpropyl) 20-5-methylplridaz-3-amine in Example 14, 3,6-dlchloropyridadazln were heated -4carboxamlda (2.6 g, 13 mmol, 1.0 equlv.), (2- (4-fluorophenll) -2-metllpropan-1 -amine (2.5 g, mmol, 1.1 equiv.) And düsopropiletllamlna (2.8 ml, 16 mmol, 1.2 equiv.) In CH₃CN (54

-117ml) at 60 - 90 ° C for 48 hours. The product was purified on silica gel with 100% EtOAc to give the desired product (3.4g, 78%) as a yellow foamy solid.

<img file="MX2012012259A_D0076.tif" />

6-Chloro-3- (2- (4-fluorophenyl) -2-methylpropyllamine) pyridazine-4-carbonyltrile. To a portion of 6-chloro-3- (2- (4-fluorophenyl) -2-methylpropylamino) pyridazin-4-carboxamide (3.4 g, 11 mmol, 1.0 equiv.) POCI was added₃ (10 ml) at room temperature. The mixture was stirred at reflux temperature for 3 hours and then quenched by pouring it into ice-cold water containing NaHCO₃. Dioxane and EtOAc were added to facilitate mixing of the layers. The layers were allowed to separate, the aqueous layer was extracted with EtOAc, and the combined organic phases were washed with saturated NaCI. The organic extracts were dried over Na₂SW₄ and evaporated to dryness in vacuo. Purification on silica gel using a gradient of 10-20% EtOAc / hexanes produced the desired product (0.60 g, 19%) as a yellow oil.

<img file="MX2012012259A_D0077.tif" />

3- (5-Cyano-6- (2- (4-fluorophenyl) -2-methylpropylamino) pyridazin-3-yl) benzamide. To a solution of 6-chloro-3- (2- (4-fluorophenyl) -2-methylpropylamino) pyridazin-4-carbonitrile (550 mg, 1.8 mmol, 1.0 equiv.), 3-aminocarbonylphenylboronic acid, pinacol ester (330 mg, 2.0 mmol, 1.1 equiv.) and K₂CO₃ aqueous (2.0 M, 5.0 ml, 5.4 mmol, 3.0 equiv.) in dioxane (18 ml) was added Pd (dppf) CI₂ (150 mg, 0.18 mmol, 0.1 equiv.). The mixture was stirred at 120 ° C for 10 minutes in a microwave and allowed to cool to temperature

-118environment. Solvents were evaporated in vacuo and the residue was dissolved in dichloromethane. The solution was filtered and the solvent was dried over Na₂SW₄. Purification on silica gel using a gradient of 40-80% EtOAc / hexanes gave a yellow solid which was suspended with CH₃CN to give the desired product (30mg, 4.3%) as a yellow solid, m / z = 390.2 [M + H] +.

Example 16: Preparation of (S) -2- (4-Fluorophenyl) propan-1-amine

<img file="MX2012012259A_D0078.tif" />

Bn (S) -4-Benzyl-3- (2- (4-fluorophenyl) acetyl) oxazolidine-2-one. 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) was added dropwise. ml, 1.6M in hexanes, 64 mmol, 1.1 equiv.). After stirring for 30 minutes, 4-fluorophenylacetyl chloride (10 g, 0.58 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 NH₄CI 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%).

<img file="MX2012012259A_D0079.tif" />

(S) -4-Benzyl-3 - ((S) -2- (4-fluorophenyl) propanoyl) oxazolidin-2-one. To a room temperature solution 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) was added iodomethane (1.0 ml, 16.2

-119mmol, 1.0 equiv.) Using a 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, the reaction mixture was allowed to warm to room temperature. The reaction was stopped with NH₄CI 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%).

<img file="MX2012012259A_D0080.tif" />

—Ζ Me Me

Bn (S) -2- (4-Fluorophenyl) propan-1-ol. To a room temperature solution of (S) 10 4-benzyl-3 - ((S) -2- (4-fluorophenyl) 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 careful addition of HCI aq. 1 M. 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 Na₂SW₄, 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="MX2012012259A_D0081.tif" />

<img file="MX2012012259A_D0082.tif" />

(S) -2- (2- (4-Fluorophenyl) propyl) sondolin-1,3-done. To a solution of (S) -2- (420 fluorophenyl) propan-1-ol (0.82 g, 5.35 mmol, 1.0 equiv.), Phthalimide (0.82 g, 5.6 mmol, 1 , 05 equiv.) And triphenylphosphine (2.1 g, 8.03 mmol, 1.5 equiv.) In dry THF (18 ml) was added

- 120 drop by drop diethyl azodicarboxylate (3.6 ml, 15% 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="MX2012012259A_D0083.tif" />

(S) -2- (4-Fluorophenyl) propan-1 -amine. To a room temperature solution of (S) -2- (2- (4-fluorophenyl) propyl) isoindoline-1,3-dione (900 mg, 3.2 mmol, 1.0 equiv.) In toluene (14 ml ) hldrazine hydrate (1.4 ml, 45 mmol, 14 equiv.) was added to it by 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 17: Preparation of 2- (4-Fluorophenyl) -2-methylpropan-1 -amine

<img file="MX2012012259A_D0084.tif" />

Me me

To a solution of 4-fluorophenyllacetonitrile (50 g, 370 mmol, 1.0 equiv.) And iodomethane (70 ml, 1.1 mol, 3 equiv.) In THF (370 ml) was added portionwise KOíBu (124 g, 1.1 mol, 3 equiv.) As a solid 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 was diluted with EtOAc and washed twice with brine. The organic layer was dried over Na₂SW₄, leaked and

-121 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 µΙ of water / mmol, 1.0 ml of 3N / mmol NaOH, 300) was performed. μΙ of water / mmol). Filtration of the resulting solids provided the title compound as an orange oil (57g, 92%).

Example 18: Preparation (1- (4-Fluorophenyl) cyclobutyl) methanamine

<img file="MX2012012259A_D0085.tif" />

A solution of 4-fluorophenylacetonitrile (6.7 g, 75 mmol, 1.5 equiv.), 1,3-dibromopropane (10 ml, 50 mmol, 1 equiv.), KOH (27 g, 150 mmol, 3.0 equiv. ) and tetrabutylammonium bromide (100 mg) in toluene (135 ml) was heated at 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 LAH (27 ml, 2 M in ether, 55 mmol, 2.5 equiv.). The mixture was stirred at 0 ° C for 2 hours followed by a Fieser and Fieser treatment (38 µΙ water / mmol, 118 µΙ NaOH 3

N / mmol, 38 μΙ of water / mmol). The organic layer was concentrated to dryness to

-122 provide the desired product (3.6 g, 40% overall) as a yellow oil.

Example 19: Preparation of (1- (6-Methoxypyridin-2-yl) cyclobutyl) methanamine

<img file="MX2012012259A_D0086.tif" />

1- (6-Fluoropyridin-2-yl) cyclobutanecarbonitrile. Following the same procedure as described for 2- (3-fluoropyridin-2-yl) acetonitrile (Example 18), 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 a colorless oil followed by purification on silica gel using 25% EtOAc / hexanes as eluant.

<img file="MX2012012259A_D0087.tif" />

1- (6-Methoxypyridin-2-yl) cyclobutanecarbonitrile. Sodium metal (~ 1 g) was added to 6.0 ml of anhydrous methanol stirred at 0 ° C under nitrogen atmosphere and the mixture was stirred for 30 minutes. To this was added 1- (6-fluoropyridin-215 yl) cyclobutanecarbonitrile (1.6g, 9.1mmol) and the resulting mixture heated at 75 ° C 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 NaCI, dried over Na₂SW₄ and concentrated in vacuo to give the desired product (1.7g, 97%) as a colorless oil.

- 123-

<img file="MX2012012259A_D0088.tif" />

(1- (6-Methoxypyridin-2-yl) cyclobutyl) methanamine. To a stirred solution of 1- (6methoxy, p-rd-2-yl) cyclobutanecarbonitrile (1.7 g, 8.8 mmol, 1.0 equiv.) In THF (20 ml), he added a solution of lithium aluminum hydride (1.0 M in THF, 11 ml, 11 mmol, 1.1 equiv.). The 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 (Fleser and Fieser treatment). The resulting mixture was filtered through dlatomaceous earth and rinsed with THF. The combined organic extracts were dried over Na₂SW₄ and concentrated to dryness to give the desired product (1.6 g, 97%) as a viscous oil.

Example 20: Preparation of 1- (3-Fluoropyridin-2-yl) cyclobutanamine

<img file="MX2012012259A_D0089.tif" />

1- (3-Fluoropyridin-2-yl) cyclobutanecarboxamide. To a 250 ml round bottom flask containing DMSO (60 ml) was added 1- (3-fluoropyridin-215 yl) cyclobutanecarbonitin (2.96 g, 16.8 mmol, 1.0 equiv.) And the mixture stirred until homogeneous. Then, potassium carbonate (7.0 g, 50.4 mmol, 3.0 equiv.) Was added and the reaction mixture was cooled to 0 ° C, followed by the addition of 35% hydrogen peroxide (6.5 me). The reaction was stirred at 0 ° C for 30 min and then warmed to room temperature. At this time, the 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, filtered and concentrated to

124 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 as a solid White color.

H, N

<img file="MX2012012259A_D0090.tif" />

<img file="MX2012012259A_D0091.tif" />

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) was added , 2.0 equiv.). The mixture was sonicated until it became 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). The combined organic layers were then dried over Na₂SW₄, 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 1- (3-fluoropyridin-2-yl ) methyl cyclobutylcarbamate as a white solid.

<img file="MX2012012259A_D0092.tif" />

H, N

<img file="MX2012012259A_D0093.tif" />

1- (3-Fluoropyridin-2-yl) cyclobutanamine. Methyl 1- (3-fluoropyridin-2-yl) cyclobutylcarbamate (1.47g, 6.56mmol), ethanol (12ml) and 3N aqueous sodium hydroxide were added to a 20ml microwave reaction vial (7 mi). The reaction mixture was heated in the microwave reactor at 150 ° C for 30 min. Ethanol was evaporated under reduced pressure and the mixture was extracted with ethyl acetate (30 ml). Then the cape

-125aqueous was extracted with ethyl acetate (2 x 30 ml). The organic layers were combined, dried over Na₂SW₄, filtered and concentrated to give 1- (3-fluoropyridin-2yl) cyclobutanamine (1.01 g, 93%) as a yellow crude oil which was used in the next reaction step without further purification.

Example 21: Preparation of 2- (3-Fluoropyridin-2-yl) acetonitrile

<img file="MX2012012259A_D0094.tif" />

<img file="MX2012012259A_D0095.tif" />

To a 0 ° C solution of 2-chloro-3-fluoropyridine (3.0 g, 23 mmol, 1.0 equiv.) And acetonitrile (1.3 ml, 25 mmol, 1.1 equiv.) In toluene ( 50 ml) sodium hexamethyldisilazide (NaHMDS) (2.0 M in THF, 13 ml, 25 mmol, 1.1 equiv.) Was added. The resulting mixture was stirred for 2 hours at 0 ° C and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic phases were washed with saturated NaCI, dried over Na₂SW₄ and concentrated in vacuo to provide the desired crude product as an oil which was used without further purification.

Example 22: Preparation of 6-Chloro-N- (2-phenylpropan-2-yl) pyridazin-3-amine

NN

<img file="MX2012012259A_D0096.tif" />

NH

<img file="MX2012012259A_D0097.tif" />

//

DIPEA

NN cU^z *

<img file="MX2012012259A_D0098.tif" />

NH

To a 5 ml microwave reaction vial were added 3,6 dichloropirldazine (544 mg, 3.7 mmol, 1.0 equiv.), Cumilamine (500 mg, 3.7 mmol, 1.0 equiv.) And DIPEA (640 µΙ, 3.7 mmol, 1.0 equiv.). The reaction was heated in a microwave reactor at 225 ° C for 15 min and then diluted with brine (20 ml) and extracted with ethyl acetate (40 ml). The organic layer was dried over Na₂SW₄, filtered, and concentrated to give a crude solid which was purified by column chromatography

- 126 on silica gel (20% EtOAc / hexanes) to produce 48 mg (5%) of 6-chloro-N- (2phenylpropan-2-l) plridazin-3-amine in form of a white solid.

Example 23: Preparation of 2- (2- (6 - ((1- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyridazin-3-yl) thiazol-5-yl) acetamide

HOTBDMSO

5 - ((f-Butyldimethylsilyloxy) methyl) thiazole. Tlazol-5-methanol (65 g, 0.56 mol), mldazol (58 g, 0.85 mol) and CH were added₂CI₂ (700 ml) to a round bottom flask, followed by TBSCI (93 g, 0.62 mol). The reaction was stirred for 20 min and the resulting white solid was removed by filtration. The filtrate was washed with saturated sodium bicarbonate, dried over sodium sulfate, concentrated, and purified by chromatography on silica gel (10% EtOAc / hexanes) to provide 140 g of 5 - ((fbutyldimethylsilyloxy) methyl) thiazole as of a clear oil.

<img file="MX2012012259A_D0099.tif" />

(-Butyl 6- (5 - ((f-butyldimethylsilyloxy) methyl) thiazol-2-yl) pyridazin-3-yl ((1- (3-fluoropyridin-215 yl) cyclobutyl) methyl) carbamate. N-BuLi (244 ml, 0.56 mol) was added dropwise to a stirring mixture of THF (2000 ml) and diisopropylamine (79.3 ml, 0.56 mol) at -78 ° C. After stirring for 20 min at -78 ° C, a solution of 5 - ((f-butyldimethylsilyloxy) methyl) thiazole (110.9 g, 0.49 mol in 300 ml) was added dropwise to the reaction mixture. THF) while maintaining a temperature below -70 ° C. After the addition was complete, the reaction was stirred for an additional 30 min and a solution of zinc bromide (126.6 g, 0.56 mol in 300 ml THF) was added dropwise to the reaction mixture while it was kept at a temperature below -65 ° C. The

-127 reaction was heated to 0 ° C, stirred for 30 min and added to a stirred mixture of 6-chloropyridaz-3-yl ((1- (3-fluoropyrid-2-yl) cyclobutyl) methyl) carbamate o (100 g, 0.26 mol), tetraquisftrlfenllfosflnajpaladlo (0) (56 g, 0.05 mol) and THF (2000 ml) heated to 80 ° C. The reaction mixture was stirred overnight at 80 ° C. The reaction was concentrated and then suspended in ethyl acetate and brine. The resulting solid was filtered off and the filtrate was dried over sodium sulfate, concentrated, and purified twice by chromatography on silica gel (EtOAc / hexanes) to provide 112.5 g of 6- (5 - ((tert- butildlmetils¡lllox¡) metíl) t¡azol-2-¡l) pyridazin-3-¡l ((1- (3fluoroplr¡d¡n-2-¡l) cyclobutyl) metll) carbamate f-butllo in the form of a dark oil.

<img file="MX2012012259A_D0100.tif" />

(1- (3-Fluoropyridin-2-yl) cyclobutyl) methyl (6- (5- (hydroxymethyl) thiazol-2-yl) pyridazin3-yl) t-butyl carbamate. To a solution of 6- (5 - ((tert-butylldimetlllloxi) methyl) thiazol-2l) pirldazin-3-yl ((1- (3-fluoroplr¡din-2- yl) -clclobutyl) methyl) carbamate (112.5 g, 0.19 mol) in THF (1000 ml) was added TBAF (105 ml, 0.29 mol, at 75% w / w) . The reaction was stirred for 30 min followed by the addition of ammonium chloride (200 ml). The organic layer was separated, washed with brine (300 ml x 3) and concentrated (this washing was repeated once more). Ethyl acetate was added to the oil, resulting in a white solid. Filtration of the solid provided 44 g of (1- (3-fluoropyrldin-2¡l) cyclobutll) metyl (6- (5- (hydroxymethyl) thylzol-2-il ) pyridazine-3-l) f-butyl carbamate.

<img file="MX2012012259A_D0101.tif" />

-1286- (5- (Chloromethyl) thiazol-2-yl) pyridazin-3-yl ((1- (3-fluoropyridin-2yl) cyclobutyl) methyl) carbamate. To a solution of f-butyl (1- (3-fluoroplr¡din-2yl) cyclobutyl) methyl (6- (5- (hydroxymethyl) thiazol-2-yl) pyridazin-3-yl) carbamate (44.1 g 93.8 mmol) in dioxane (235 ml) was added tlonllo chloride (27.3 ml, 375.3 mmol). The reaction was stirred until it became homogeneous. The reaction was then slowly quenched by pouring it into a mixture of saturated potassium carbonate solution and ethyl acetate. Then the organic layer was separated, dried over Na₂SW₄, filtered, concentrated, and purified by chromatography on silica gel (EtOAc / hexanes) to provide 33.1 g of 6- (5- (chloromethyl) t-acezol-2-yl) pyridazln- 3-l ((1- (3-fluoropyrid-210 l) cyclobutll) methyl) butyl carbamate in the form of a white solid.

<img file="MX2012012259A_D0102.tif" />

<img file="MX2012012259A_D0103.tif" />

6- (5- (Cyanomethyl) thiazol-2-yl) pyridazin-3-yl ((1- (3-fluoropyridin-2l) cyclobutyl) methyl) t-butyl carbamate. To a solution of 6- (5- (chloromethyl) tlazol-2¡l) pyr¡dazin-3-¡l ((1- (3-fluorop¡r¡d¡n-2-ll) cyclobutyl ) t-butyl methyl) carbamate (33.1 g, 68 mmol) in CH₂CI₂(450 ml) tetrabutylammonium cyanide (36 g, 135 mmol) was added. The reaction was heated to 45 ° C and stirred for 1 hr, followed by concentration and purification by chromatography on silica gel (EtOAc / hexanes) to provide 13.4 g of 6- (5- (cyanomethyl) thiazole -2-yl) pyridaz-3-l ((1- (3-fluoropyridin-2l) cyclobutyl) methyl) f-butyl carbamate in the form of a solid whitish in color.

<img file="MX2012012259A_D0104.tif" />

S

-129 2- (2- (6 - ((1- (3-fluorop¡r¡d¡n-2-¡l) c¡clobut¡l) met¡lam¡no) p¡r¡daz¡n- 3-l) thiazol-5yl) acetamide. To a solution of i-butyl carbamate to 6- (5- (cyanomethyl) thiazol-2-yl) pyridazin-3-yl ((1- (3-fluoropyridin-2-yl) cyclobutll) methyl) carbamate. (12.5g, 26.0mmol) in DMSO (260ml) was added potassium carbonate (14.4g, 104.1mmol). The mixture was cooled to 0 ° C and hydrogen peroxide (86 ml) was added slowly. The reaction was warmed to rt and stirred for 90 min. The reaction was diluted with EtOAc (200 ml) and water (500 ml) and the organic layer was washed three times with brine (150 ml). Then the organic layer was dried over Na₂SW₄, filtered, and concentrated to give a crude solid which was purified by chromatography on silica gel (CH₃CN / CH₂CI₂) to provide 6.2 g of 6- (5- (210 amino-2-oxoethyl) thiazol-2-yl) pyridazin-3-yl ((1- (3-fluoropyridin-2-yl) cyclobutyl) f-Butyl Methyl) Carbamate as a reddish solid. This compound was combined with other batches (15.5g total), dissolved in 25% TFA / CH₂CI₂, and stirred for 1 h. Then, the reaction was concentrated, dissolved in ethyl acetate (75 ml) and washed three times with potassium carbonate. Then the organic layer was dried over Na₂SW₄, filtered and concentrated to give a crude solid which was recrystallized with THF to give 10.8 g of 1- (2 - ((- - 3-fluoro-1- (3-fluoroplridin-2-yl) c Clobutyl) methylamino) pyrimid-5-yl) -1Hpyrrol-3-carboxamide as an off-white solid (M + H = 399.1).

Example 24: Preparation of 2- (2- (6 - ((1 - (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyridazin-3-yl) thiazol-5-yl) -N-methylacetamide

<img file="MX2012012259A_D0105.tif" />

A solution of 6- (5- (cananomethyl) thiazol-2-yl) pirldazin-3-yl ((1- (3-fluoropyridin-2yl) cyclobutll) methyl) f-Butyl carbamate (1g, 2mmol) in HCI (30ml, conc.) was heated to

105 ° C in a microwave reactor and stirred for 15 min. The reaction concentrated

-130 to give 900 mg (2.3 mmol) of a reddish crude solid. To this solid were added methylamine hydrochloride (183mg, 2.7mmol), HOBt (365mg, 2.7mmol), EDC (516mg, 2.7mmol), DMF (30ml) and TEA (1 , 3 ml, 9 mmol). The reaction was stirred at rt overnight. Then, the reaction was poured into ethyl acetate (200 ml), washed with water (3 x 100 ml) and the organic layer was separated, dried over Na₂SW₄, filtered, concentrated, and recrystallized from EtOAc to give 408 mg of 2- (2- (6 - ((1 - (3-Fluoropyridin-2yl) cyclobutyl) methylamine) p¡r Dazin-3-l) tlazol-5-l) -N-methylacetamide in the form of a white solid (M + H = 413.3).

Example 25: Preparation of N - ((2- (6 - ((1- (3-fluoropyridin-210 yl) cyclobutyl) methylamino) pyridazin-3-yl) thiazol-5-yl) methyl) -2-hydroxyacetamide

Cl

<img file="MX2012012259A_D0106.tif" />

<img file="MX2012012259A_D0107.tif" />

or

6- (5- (Azidomethyl) thiazol-2-yl) pyridazin-3-yl ((1- (3-fluoropyridin-2yl) cyclobutyl) methyl) t-butyl carbamate. To a stirred solution of 6- (5 (chloromethyl) thiazol-2-yl) pyridazin-3-yl ((1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate of t15 butyl ( 60.7 g, 124 mmol) in DMF (800 ml) were added sodium azide (22.2 g, 341 mmol) and DIPEA (31.1 ml, 171 mmol). The reaction was heated to 60 ° C and stirred for 1 hr. The reaction was poured into ethyl acetate (2000 ml), washed with water (3 x 400 ml) and the combined organic layers were separated, dried over Na₂SW₄, filtered, concentrated, and purified by chromatography on silica gel (EtOAc / hexanes) to provide 20.0 g of 6- (5- (azidomethyl) thiazol-2-l) pyridazine-3- f-Butyl yl ((1- (3-fluoropyrin-2l) cyclobutll) methyl) carbamate in the form of a yellow oil.

-131 -

<img file="MX2012012259A_D0108.tif" />

Η₂Ν

<img file="MX2012012259A_D0109.tif" />

Boc

6- (5- (Aminomethyl) thiazol-2-yl) pyridazin-3-yl ((1- (3-fluoropyridin-2yl) cyclobutyl) methyl) t-butyl carbamate. Tin (II) Chloride Dihydrate (15.5g, 80mmol) was added to a solution of 6- (5- (azydometyl) tlazol-2-yl) pyridazin-3-yl (( 1- (35-fluoroplridin-2-yl) cyclobutyl) methyl) carbamate (20 g, 40 mmol) in methanol (400 ml) and the reaction was stirred at rt for 30 min. The reaction was poured into ethyl acetate (1000 ml), washed with water (3 x 200 ml) and the combined organic layers were separated, dried over Na₂SW₄, filtered, concentrated, and purified using silica gel column chromatography (9% MeOH / 90% EtOAc / 1% TEA) to give 35 g of 6- (5- (amynomethyl) t-acezol-2-yl) pyridazin-3-yl ((1- (3-fluoropyridin-2yl) cyclobutyl) methyl) carbamate f-butyl in the form of a yellow oil.

h₂n

<img file="MX2012012259A_D0110.tif" />

HO '

<img file="MX2012012259A_D0111.tif" />

OR

N - ((2- (6 - ((1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3-yl) thiazol-5yl) methyl) -2-hydroxyacetamide. T-Butyl 6- (5- (Aminomethyl) thiazol-2-yl) pyridazin-3-yl ((115 (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate (4.8 g, 10 mmol) was added ), glycolic acid (0.9g, 12mmol), HOBt (1.6g, 12mmol), EDC (2.3g, 12mmol), DMF (50ml) and TEA (5.9ml) at 250 ml round bottom flask and the reaction was heated to 60 ° C and stirred for 1 h. The reaction was poured into ethyl acetate (400 ml), washed with water (3 x 100 ml) and the combined organic layers were separated, dried over Na₂SW₄, filtered, concentrated, and purified by chromatography on silica gel

-132 (EtOAc / hexanes) to provide 3.9 g of (1- (3-fluoropyridin-2-yl) cyclobutyl) methyl (6- (5 ((2-hydroxyacetamide) methyl) t-acezol-2-l) p-r¡dazin-3-l) f-butyl carbamate as a white solid. This compound was dissolved in 30% TFA / CH₂CI₂ (30 ml) and stirred for 1 h. The reaction was concentrated, dissolved in EtOAc (200 ml), washed with potassium carbonate (3 x 30 ml), concentrated, and then recrystallized from ethanol to give a white solid which was adlclonally purified by reverse phase chromatography. to give 305 mg of A / - ((2- (6 - ((1- (3-fluoropyridin-2yl) cyclobutyl) methylamine) plrdazin-3-ll) thiazol-5 -il) metyl) -2-hydroxyacetamide in the form of a white solid (M + H = 429.1).

Example 26: Preparation of 1- (6 - ((1- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyridazin-3-yl) -1 H-pyrrole-3-carboxamide

<img file="MX2012012259A_D0112.tif" />

6- (3-Cyan-1H-pyrrole-1-yl) pyridazin-3-yl ((1 - (3-fluoropyridin-2yl) cyclobutyl) methyl) carbamate. To a stirred solution of 6-f-butyl fluoropyridazin-3-yl ((1- (3-fluoropyrid-2-yl) cyclobutyl) methyl) f-butyl carbamate (200 mg, 551 μπιοΙ) in DMF (2 ml) 3-clanoplrrol (61 mg, 661 μίτιοΙ) and potassium carbonate (152 mg, 1.1 mmol) were added. The reaction was heated to 110 ° C and stirred for 30 min. Then, the reaction was poured into ethyl acetate (100 ml), washed with water (3 x 25 ml) and the organic layer was separated, dried over Na₂SW₄, filtered, concentrated and purified by chromatography on silica gel (EtOAc / hexanes) to provide 130 mg of 6- (3-cyano-1H-prol-1-yl) pyridazine-3-l ((1- (3-Fluoropyridin-2l) cyclobutyl) methyl) f-butyl carbamate as a pale yellow solid.

-133-

<img file="MX2012012259A_D0113.tif" />

<img file="MX2012012259A_D0114.tif" />

- (6 - ((1 - (3-Fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3-yl) -1 H-pyrrole-3carboxamide. 6- (3-Cyano-1 H-pyrrol-1-yl) pyridazin-3-yl (f-butyl (1- (3-fluoropyridin-2yl) cyclobutyl) methyl) carbamate (120 mg, 267 pmol) were combined , potassium carbonate (147 mg,

1.1 mmol) and DMSO (3 ml) in a vial and cooled to 0 ° C. Hydrogen peroxide (700 µΙ) was added dropwise and the reaction was warmed to rt and stirred for 1 h. Then, the reaction was poured into ethyl acetate (50 ml), washed with water (3 x 20 ml) and the organic layer was separated, dried over Na₂SW₄, filtered and concentrated. The crude solid was dissolved in 50% TFA / CH₂CI₂ (2 ml) and stirred for 30 min. The reaction was then concentrated and purified using reverse phase chromatography to give 29 mg of 1- (6 - ((1- (3-fluoropyridin-2-yl) cyclobutyl-methylamino) pyridazin-3-yl) - 1H-pyrrole-3carboxamide as a brown solid (M + H = 367.1).

Example 27: Preparation of 2- (6 - ((1 - (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyridazin-3-yl) -4-hydroxy-2,5-dihydrothiazol-5-carboxamide

<img file="MX2012012259A_D0115.tif" />

6-Cyanopyridazin-3-yl ((1 - (3-fluoropyridin-2-yl) cyclobutyl) methyl) fbutyl carbamate. To a solution of 6 - ((1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3carbonitrile (3.3 g, 4.7 mmol) in THF (30 ml) was added dicarbonate of di- f-butyl (2.8g, 13mmol) and DMAP (0.5g, 4.3mmol). The reaction mixture was heated under reflux for 2 h. The reaction was concentrated and then poured into ethyl acetate (150 ml) and

-134 washed with 0.1M HCI (50 ml, aq.) And brine (50 ml). The organic layer was separated, dried over Na₂SW₄, filtered and concentrated to give a crude oil which was purified by silica gel column chromatography (EtOAc / hexanes) to provide 3.9 g of 6-cyanopyridazin-3-yl ((1- ( 3-fluoropyridin-2-l) cyclobutyl) methyl f-butyl carbamate as a white solid.

<img file="MX2012012259A_D0116.tif" />

6-Carbamothioylpyridazin-3-yl ((1- (3-fluoropyrldin-2-yl) cyclobutyl) methyl) carbamate. NMP (40 ml) and DIPEA (10 ml) were added to 6-cyanopyridazin-3-l (((1- (3fluoropyridln-2-yl) cyclobutyl) methyl) carbamate of f -butllo (3.9 g, 10 mmol) and hydrogen sulfide was bubbled through the reaction mixture for 2 h. The reaction was diluted with water, and the resulting yellow solid was filtered and dried in vacuo to give 2.1 g of 6-carbamotyl or lpridazin-3-l ((1- (3-fluoropyridyl- 2-yl) cyclobutyl) methyl f-butyl carbamate as a yellow solid.

<img file="MX2012012259A_D0117.tif" />

OR

2- (6- (f-Butoxycarbonyl ((1 - (3-fluoropyridin-2-yl) cyclobutyl) methyl) amino) pyridazine-3-yl) -4-hydroxy-2,5-dihydrothiazol-5-carboxylate ethyl. 6-Carbamotlo-pyridazin-3-yl ((1 - (3-fluoropyridin-2-yl) cyclobutyl) methyl) f-butyl carbamate (1.0 g, 2.4 mmol), diethyl bromomalonate (2 ml, 12 mmol) and toluene to a round bottom flask, heated to 90 ° C and stirred for 40 min. The reaction was concentrated and purified using reverse phase chromatography to produce 219 mg of 2- (6- (f- 135butox¡carbonyl ((1 - (3-fluorop¡r¡d¡n-2-¡l) c¡ Ethyl clobutyl) methyl) amino) prazin-3-l) -4-hydroxy-2,5-dihydrothiazol-5-carboxylate in the form of an off-white solid.

<img file="MX2012012259A_D0118.tif" />

2- (6- (t-Butoxycarbonyl ((1 - (3-fluoropyridin-25 yl) cyclobutii) methyl) amino) pyridazin-3-yl) -4-methoxy-2,5-dihydrothiazol-5-carboxylic acid. To a stirred solution of 2- (6- (f-butoxycarbonyl ((1- (3-fluoropyridin-2¡l) cyclobutyl) methyl) amine) pridazin-3- ll) -4-hydroxy-2,5-d-hydroxy-acezole-5-carboxylate (350 mg, 0.7 mmol) in DMF (4 ml) methyl iodide was added ( 200 μΙ, 3.3 mmol) and sodium hydride (60% dispersion in mineral oil, 40 mg, 1 mmol). The reaction was stirred at rt for 1 hr and at 40 ° C for 45 min. The reaction was then concentrated and quenched with water (5 mL), poured into ethyl acetate (150 mL), and washed with 0.1M HCl (50 mL, aq.) And brine (50 mL). The organic layer was separated, dried over Na₂SW₄, filtered, concentrated, and purified by column chromatography on silica gel (EtOAc / hexanes) to provide 205 mg of 2- (6- (tert-butoxycarbonll ((1- (315 fluoropyrid-2- L) cyclobutyl) metll) amino) pyridaz-3-l) -4-methoxy-2,5-d-hydroxy-acezole-5-carboxylate. This compound was dissolved in methanol (4 ml) and 1M KOH (aq, 2 ml). The reaction mixture was heated to 75 ° C and stirred for 45 min. The reaction was cooled and the pH was adjusted to 4 using 1M HCI. Then the reaction was poured into ethyl acetate (50 ml), washed with brine (15 ml), dried over Na₂SW₄, filtered and concentrated to give 175 mg of 2- (6- (f-butoxylcarbonll) ((1- (3-fluoropyridin-2l) cyclobutyl) methyl) amine) p! rdaz¡n-3-yl) -4-methoxy-2,5-d¡h¡dr¡¡azol-5-carboxylic in the form of a white foam.

-136-

<img file="MX2012012259A_D0119.tif" />

OR

F-Butyl 6- (5-Carbamoyl-4-methoxy-2,5-dihydrothiazol-2-yl) pyridazin-3-yl ((1- (3fluoropyridin-2-yl) cyclobutyl) methyl) carbamate. 2- (6- (f-Butoxycarbonyl ((1- (3-fluoropyridin-25 yl) cyclobutyl) methyl) amino) pyridazin-3-yl) -4-methoxy-2, was added to a 50-drach vial. 5-dihydrothiazol-5-carboxylic (175 mg, 0.34 mmol), HATU (194 mg, 0.51 mmol), HOAt (70 mg, 0.51 mmol), DIPEA (296 μΙ, 1.7 mmol), NMP (2 ml) and ammonium chloride (180 mg, 3.4 mmol). The reaction was stirred overnight at rt. The reaction was then poured into ethyl acetate (50 ml) and washed with aqueous sodium bicarbonate and brine (50 ml). The organic layer was separated, dried over Na₂SW₄, filtered, concentrated, and purified by silica gel column chromatography (EtOAc / hexanes) to provide 120 mg of 6- (5-carbamoyl-4-methoxy-2,5-dihydrothiazol-2-yl) pyridazin-3- f-Butyl yl ((1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate.

<img file="MX2012012259A_D0120.tif" />

OO

2- (6 - ((1 - (3-Fluoropyrin-2-yl) cyclobutyl) methylamino) pyridazin-3-yl) -4-hydroxy2,5-dihydrothiazol-5-carboxamide. To a stirred mixture of 6- (5-carbamoyl-4-methoxy-2,5-dihydrothiazol-2-yl) pyridazin-3-yl ((1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate f -butyl (60 mg, 0.12 pmol) in CH₂CI₂ (2 mi) BBr was added₃ (140 μΙ, 1.2 mmol). The reaction was stirred at rt for 2 h and then at 60 ° C for 15 min. The reaction

-137 cooled to rt and carefully diluted with methanol (2 ml). The reaction was concentrated, diluted with ethyl acetate (20 ml) and saturated sodium bicarbonate (10 ml) was added. The mixture was stirred and then filtered. The subsequent crude solid was then purified using reverse phase chromatography to give 15 mg of 2- (6 - ((1- (3-fluoropyridin-25 yl) cyclobutyl) methylamino) pyridazin-3-yl) -4-hydroxy -2,5-dihydrothiazol-5-carboxamide as a yellow solid (M + H = 401.3)

Example 28: Preparation of 4-fluoro-3- (6 - (((frans) -3-fluoro-1- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyridazin-3-yl) -2-hydroxybenzamide

<img file="MX2012012259A_D0121.tif" />

6- (3-Bromo-6-fluoro-2-methoxyphenyl) pyridazin-3-yl (((frans) -3-fluoro-1- (3fluoropyridin-2-yl) cyclobutyl) methyl) carbamate. 6-bromopridaz-3-l ((((frans) -3-fluoro-1- (3-fluoropr-din-2-l) cyclobutyl) metl) carbamate of tbutyl (3.0 g, 6.61 mmol), 3-bromo-6-fluoro-2-methoxyphenylboronic acid (1.64 g, 6.61 mmol), (dppf) PdCI₂ (0.48g, 0.66mmol), Nitrogen Sprayed Dioxane (13.2ml) and K₂CO₃ ac. 2N (0.6 ml) and heated in a microwave reactor at 125 ° C. The reaction mixture was diluted with EtOAc and washed with NaHCO₃ ac. sat. and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Chromatography on silica gel provided the title compound as a yellow solid (1.4 g, 37%), (m / z [M + H] = 579.1).

<img file="MX2012012259A_D0122.tif" />

-138 6- (3-clano-6-fluoro-2-methoxyphenyl) p¡r¡dazln-3-¡l (((írans) -3-fluoro-1- (3fluoropyridin-2-yl) cyclobutyl) i-butyl methyl) carbamate. 6- (3-Bromo-6-fluoro-2-methoxyphenyl) pyridaz-3-yl (((frans) -3-fluoro-1- (3-fluoropyridin-2yl) cyclobutyl) methyl) carbamate were combined of f-butyl (1.4 g, 3.0 mmol), zinc cyanide (0.42 g, 3.6 5 mmol), Pd (PPh₃) 4 (1.0 g, 0.9 mmol) and DMF (3 ml) and heated to 100 ° C. The reaction mixture was diluted with EtOAc and washed with NaHCO₃ ac. sat. and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Chromatography on silica gel provided the title compound as a yellow solid (1.0 g, 63%), (m / z [M + H] = 526.2).

<img file="MX2012012259A_D0123.tif" />

6- (3-carbamoyl-6-fluoro-2-methoxyphenyl) pyridazin-3-yl (((frans) -3-fluoro-1 - (3fluoropyridin-2-yl) cyclobutyl) methyl) f carbamate -butyl. 6- (3-Cyano-6-fluoro-2-methoxyphenyl) pyridazin-3-yl (((frans) -3-fluoro-1- (3-fluoropyridin-2l) cyclobutyl) methyl) carbamate were combined of f-butyl (1.0 g, 1.9 mmol), K₂CO₃ (0.8g, 5.8mmol) and 15 DMSO (10ml) in a round bottom flask, cooled to 0 ° C and added H dropwise₂OR₂ (2 ml of a 35% solution). The reaction mixture was diluted with EtOAc and washed with NaHCO₃ ac. sat. and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Chromatography on silica gel gave the title compound as a white solid (0.32 g, 33%), (m / z [M + H] = 545.1).

<img file="MX2012012259A_D0124.tif" />

-139 4-Fluoro-3- (6 - (((frans) -3-fluoro-1- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyridazin-3-yl) -2-hydroxybenzamide. 6- (3-Carbamoyl-6-fluoro-2-methoxyphenyl) pyridazin-3-yl (((frans) -3-fluoro-1- (3-fluoropyridin-2yl) cyclobutyl) methyl) y-butyl carbamate (0 , 32g, 0.59mmol), lithium iodide (0.71g, 5.34mmol) and pyridine (5ml) in a microwave reactor and heated to 125 ° C. The reaction mixture was diluted with EtOAc and washed with NaHCO₃ ac. sat. and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Reverse phase chromatography provided 4-fluoro-3- (6 - (((E) -3-fluoro-1 - (3-f luoropyridi n-2yl) cyclobutyl) methylamino) pyridazin-3-yl) -2-hydroxybenzamide as a white solid (0.024 g, 10%), (m / z [M + H] = 430.1).

Example 29: Preparation of 4-fluoro-5- (6 - (((frans) -3-fluoro-1- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyridazin-3-yl) -2-hydroxybenzamide

<img file="MX2012012259A_D0125.tif" />

<img file="MX2012012259A_D0126.tif" />

6- (5-Bromo-2-fluoro-4-methoxyphenyl) pyridazin-3-yl (((frans) -3-fluoro-1- (3fluoropyridin-2-yl) cyclobutyl) methyl) carbamate f -butyl. Tbutyl 6-bromopyridazin-3-yl (((trans) -3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate (3.0 g, 6.61 mmol), 2- ( 5-bromo-2-fluoro-4-methoxyphenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.2 g, 6.61 mmol), (dppf) PdCI₂ (0.48g, 0.66mmol), Nitrogen Sprayed Dioxane (13.2ml) and K₂CO₃ ac. 2 N (0.6 ml) and heated to 90 ° C. The reaction mixture was diluted with EtOAc and washed with NaHCO₃ ac. sat. and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Chromatography on silica gel gave a light yellow solid (1.7 g, 44%), (m / z [M + H] = 579.1).

- 140 -

<img file="MX2012012259A_D0127.tif" />

F-Butyl 6- (5-Cyano-2-fluoro-4-methoxyphenyl) pyridazin-3-yl (((frans) -3-fluoro-1- (3fluoropyridin-2-yl) cyclobutyl) methyl) carbamate. 6- (5-Bromo-2-fluoro-4-methoxyphenyl) pyridazine-3-yl (((frar? S) -3-fluoro-1- (3-fluoropyridin-25 yl) were combined f-butyl cyclobutyl) methyl) carbamate (1.7g, 3.6mmol), zinc cyanide (0.51g, 4.3mmol), Pd (PPh3)₄ (1.26g, 1.0mmol), DMF (5ml) and heated to 100 ° C. The reaction mixture was diluted with EtOAc and washed with NaHCO₃ ac. sat. and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Chromatography on silica gel gave a yellow solid (1.1 g, 66%), (m / z [M + H] = 526.2).

<img file="MX2012012259A_D0128.tif" />

F-Butyl 6- (5-Carbamoyl-2-fluoro-4-methoxyphenyl) pyridazin-3-yl (((frans) -3-fluoro-1- (3fluoropyridin-2-yl) cyclobutyl) methyl) carbamate. 6- (5-Cyano-2-fluoro-4-methoxyphenyl) pyridazln-3-l ((((frans) -3-fluoro-1- (3-fluoropyridin-2yl) cyclobutyl) were combined f-butyl methyl) carbamate (0.21 g, 0.4 mmol), K₂CO₃ (0.22g, 1.6mmol) and 15 DMSO (4ml) in a round bottom flask, cooled to 0 ° C and added H dropwise₂OR₂ (1.3 ml of a 35% solution). The reaction mixture was diluted with EtOAc and washed with NaHCO₃ ac. sat. and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Chromatography on silica gel gave a white solid (0.10 g, 46%), (m / z [M + H] = 545.1).

-141 -

<img file="MX2012012259A_D0129.tif" />

4-Fluoro-5- (6 - (((frans) -3-fluoro-1- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyridazin-3-yl) -2-hydroxybenzamide. F-Butyl 6- (5-Carbamoyl-2-fluoro-4-methoxyphenyl) plridazin-3-yl (((frans) -3-fluoro-1- (3-fluoropyridin-25 yl) cyclobutyl) methyl) was combined 0.10 g, 0.18 mmol), lithium iodide (0.22 g, 1.65 mmol) and pyrldine (3 ml) in a microwave reactor and heated to 125 ° C. The reaction mixture was diluted with EtOAc and washed with NaHCO₃ ac. sat. and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Reverse phase chromatography provided the title compound as a white solid (0.023 g, 30%), (m / z [M + H] = 430.1).

Example 30: Preparation of 5- (6 - ((1 - (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyridazin-3-yl) -1 H-pyrazol-3-carboxamide

<img file="MX2012012259A_D0130.tif" />

F-Butyl 6- (1-ethoxyvinyl) pyridazin-3-yl ((1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate. 6-Chloropyridazin-3-yl ((1- (3-fluoropyridin-2l) cyclobutyl) methyl) f-butyl carbamate (5.1g, 13.0mmol), tribut L (1-ethoxyvinyl) stannan (6.1 g, 16.9 mmol), (PPh₃)₂PdCI₂ (2.3g, 3.2mmol) and nitrogen sparged dioxane (18ml) and heated in a microwave reactor at 150 ° C. The reaction mixture was diluted with EtOAc and washed with NaHCO₃ ac. sat. and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Chromatography on silica gel gave a light yellow solid (3.9 g, 71%), (m / z [M + H] = 429.2).

-142-

<img file="MX2012012259A_D0131.tif" />

T-Butyl 6-Acetylpyridazin-3-yl ((1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate. F-Butyl 6- (1-ethoxyvinyl) pyridazin-3-yl ((1- (3-fluoropyridin-2yl) cyclobutyl) methyl) carbamate (1.0 g, 2.3 mmol), EtOH (75) were combined ml) and 1N HCI (15 ml) at 0 ° C, heated to 25 ° C and stirred for 1 h. The reaction mixture was concentrated and chromatography on silica gel gave a colorless oil (0.6g, 64%), (m / z [M + H] = 401.1).

<img file="MX2012012259A_D0132.tif" />

Ethyl (5- (6- (tert-Butoxycarbonyl ((1- (3-fluoropyridin-210 iOciclobutiOmetiOaminolpiridazin-S-iO-IH-pyrazole-S-carboxylate).

F-Butyl 6-acetylpyridazin-3-yl ((1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate (2.5g, 6.2mmol) in THF ( 150 ml) with NaOEt (3.44 g, 10.6 mmol, 21% in EtOH). The resulting mixture was then treated with diethyl oxalate (1.7 ml, 12.5 mmol), heated to 45 ° C and stirred for 4 h. The reaction mixture was added to 1N HCI, extracted with EtOAc and washed with NaHCO₃ ac. sat. and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. A portion of the resulting oil was dissolved in AcOH and hydrazine (0.41 g, 13.2 mmol) was added and stirred at 80 ° C. Concentration provided a yellow oil that was purified by reverse phase chromatography to give a solid (0.285g, 62%), (m / z [M + H] = 497.2).

<img file="MX2012012259A_D0133.tif" />

- 143 5- (6 - ((1- (3-Fluoropyrid-2-l) cyclobutyl) methalamine) prrdazn-3-l) -1H-p Razol-3carboxamide. Ethyl 5- (6- (f-butoxycarbonyl ((1- (3-fluoropyridin-2yl) cyclobutyl) methyl) amino) pyridazin-3-yl) -1H-pyrazol-3-carboxylate (0.28 g) was combined , 0.56 mmol) and 7N ammonia in MeOH in a microwave reactor and heated at 110 ° C for 1 h. The reaction mixture was then concentrated, diluted with EtOAc, and washed with NaHCO₃ ac. sat. and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting oil was diluted in 10 ml of DCM and TFA (15 ml) was added. The reaction mixture was then concentrated and purified by reverse phase chromatography to give the title compound as a white solid (18mg,

12%), (m / z [M + H] = 368.1).

Example 31: Preparation of 3- (6 - ((1 - (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyridazin-3-yl) isoxazol-5-carboxamide

<img file="MX2012012259A_D0134.tif" />

T15-Butyl (1- (3-Fluoropyridin-2-yl) cyclobutyl) methyl (6-vinylpyridazin-3-yl) carbamate. Β-Butyl 6-chloropyridazin-3-yl ((1- (3-fluoropyridin-2yl) cyclobutyl) methyl) carbamate (2.5 g, 6.36 mmol), trietenylboroxine complex and pyridine (1.0) were combined g, 4.13 mmol), Pd (PPh₃)₄ (0.3g, 0.25mmol), Nitrogen Sprayed Dioxane (13.2ml) and K₂CO₃ ac. 2 N (0.9 ml) and heated at 110 ° C for 25 min. The reaction mixture was diluted with EtOAc and washed with NaHCO₃ ac. sat. and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Chromatography on silica gel gave a light yellow oil (2.1 g, 86%), (m / z [M + H] = 385.2).

- 144-

<img file="MX2012012259A_D0135.tif" />

Tbutyl (1 - (3-Fluoropyridin-2-yl) cyclobutyl) methyl (6-formylpyridazin-3-yl) carbamate. (1- - (3-Fluoropyridin-2-yl) cyclobutyl) methyl (6-v-lpyridaz-3-yl) y-butyl carbamate (3.4 g, 8.84 mmol) as a solution in dloxane (100 ml) to a mixture of sodium periodate (10.8 g, 50.5 mmol) and 4% solution of osmium tetraoxide (6.5 ml) in H₂Or (30 mi) at 0 ° C. The reaction was stirred for 2h. The reaction mixture was filtered through a cellte layer and washed with EtOAc. The organic layer was washed with NaHCO₃ ac. sat. brine and dried over sodium sulfate, filtered and concentrated. Chromatography on silica gel gave a Colorless oil (1.4 g, 41%), (m / z [M + H]

<img file="MX2012012259A_D0136.tif" />

<img file="MX2012012259A_D0137.tif" />

Methyl 3- (6- (tert-Butoxycarbonyl ((1- (3-fluoropyridin-2yl) cyclobutyl) methyl) amino) pyridazin-3-yl) isoxazol-5-carboxylate. A (1- (3fluoropyrid-2-l) cyclobutyl) methyl (6-formylpldr-3-ll) t-butyl carbamate (1.4 g, 3.6 mmol) in ethanol (10 ml) and water (2 ml) was added to the hydrochloride hydrochloride (0.27 g, 3.8 mmol) followed by sodium acetate (0.32 g, 3.8 mmol) and stirred at 24 ° C for 30 min. The crude reaction mixture was concentrated and diluted with EtOAc. The organic layer was washed with NaHCO₃ ac. sat. and brine, then dried over sodium sulfate, filtered, and concentrated. The crude mixture was then diluted in THF (2 ml) and plrldlna (57 mg, 0.72 mmol) and then treated with NCS (0.58 g, 4.35 mmol) and heated at 40 ° C for 1.5 h. The crude mixture was then treated with methyl proplolate (0.30 g, 3.56 mmol) and TEA (0.36, 3.56 mmol) and the reaction was stirred for 45 min. The mixture of

-145 reaction was concentrated and diluted with EtOAc and then washed with NaHCO₃ ac. sat. and brine. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by reverse phase chromatography to give a white solid (0.53g, 31%).

<img file="MX2012012259A_D0138.tif" />

3- (6 - ((1- (3-Fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3-yl) isoxazol-5carboxamide. Methyl 3- (6- (tert-butoxycarbonyl ((1- (3-fluoropyridin-2¡l) cyclobutyl) methyl) amino) pyridazin-3-yl) isoxazol-5-carboxylate (0.53 g) were combined , 1.1 mmol), methanol (5 ml) and concentrated ammonium hydroxide (8 ml) in a microwave reactor and heated at 100 ° C for 60 min. Then the reaction mixture was concentrated and diluted with EtOAc and washed with NaHCO₃ ac. sat. and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting oil was diluted in 10 ml of DCM, TFA (6 ml) was added and the reaction was stirred for 35 min. The reaction mixture was then concentrated and purified by reverse phase chromatography to give the title compound as a white solid (144 mg, 36%), (m / z [M + H] = 369, one).

Example

32:

Preparation of

2- (6 - ((1 - (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyridazin-3-yl) thiazol-5-carboxamide

Cl

<img file="MX2012012259A_D0139.tif" />

F _ O 's N = N

<img file="MX2012012259A_D0140.tif" />

NBoc

Ethyl ethyl 2- (6- (tert-Butoxycarbonyl ((1- (3-fluoropyridin-2yl) cyclobutyl) methyl) amino) pyridazin-3-yl) thiazol-5-carboxylate. Tere-butyl tere-butyl carbamate (500 mg, 1.27 mmol), thiazole, was combined 6-146chloropyridazin-3-yl ((1 - (3-fluoropyrid-2-yl) cyclobutyl) methyl) carbamate. -5-ethyl carboxylate (300 mg, 1.91 mmol), Pd (OAc)₂ (86 mg, 0.13 mmol), JohnPhos (92 mg, 0.26 mmol) and Cs₂CO₃ (827 mg, 2.54 mmol) in toluene (10 ml) and heated in a microwave reactor for 30 min at 145 ° C. The reaction mixture was filtered through a celite pad and the filtrate was concentrated. The resulting residue was purified on silica gel using a mixture of ethyl acetate and hexanes to provide the title compound as a yellow oil (162 mg, 82% purity, 21%), LRMS (M + H⁺) m / z 514.3,

<img file="MX2012012259A_D0141.tif" />

yl) cyclobutyl) methyl) carbamate. A solution of ethyl 2- (6- (tert-butoxycarbonyl ((1 (3-fluoropyridin-2-yl) cyclobutyl) methyl) amino) pyridazin-3-yl) thiazol-5-carboxylate (162 mg, 0 , 32 mmol) in MeOH (8 ml) was purged with NH gas₃ for 5 min. The reaction mixture was sealed and heated in a microwave reactor for 30 min at 120 ° C. The reaction mixture was concentrated and used in the next step without

<img file="MX2012012259A_D0142.tif" />

<img file="MX2012012259A_D0143.tif" />

2- (6 - ((1- (3-Fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3-yl) thiazol-5carboxamide. To a crude mixture of f-butyl 6- (5-carbamoylthiazol-2-yl) pyridazin-3-yl ((1- (320 fluoropyridin-2-yl) cyclobutyl) methyl) carbamate (141 mg, crude) in DCM (6 ml) TFA (2 ml) was added to rt. The reaction mixture was stirred additionally at rt for

-147 2 h followed by concentration to dryness. The crude mixture was purified on RPHPLC using a mixture of acetonitrile and H₂Or to provide the title compound as a pale yellow solid (98.5 mg, 99% in 2 steps), LRMS (M + H⁺) m / z 385.2,

Example 33: Preparation of 5- (6 - ((1- (3-fluoropyridin-2yl) clclobutyl) methylamine) pyridazine-3-yl) isoxazol-3-carboxamide

<img file="MX2012012259A_D0144.tif" />

<img file="MX2012012259A_D0145.tif" />

Ethyl ethyl 5- (6 - ((1- (3-Fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3-yl) isoxazol-3-carboxylate. I-Butyl A-6- (1-ethoxyvinyl) pyridazin-3-yl ((1 - (3-fluoropyridin-210 yl) cyclobutyl) methyl) carbamate (439 mg, 1.02 mmol) in THF (5.0 ml ) (E) -ethyl 2-chloro-2- (hydroxyimino) acetate (465 mg, 3.06 mmol) and TEA (1.4 ml, 10.2 mmol) were added. The reaction mixture was stirred at rt for 30 min followed by the addition of TFA (5 ml) and then heated under reflux overnight. The mixture was then concentrated and purified by reverse phase chromatography to give 415 mg of the title compound as a colorless oil, LRMS (M + H⁺) m / z 398.3.

<img file="MX2012012259A_D0146.tif" />

<img file="MX2012012259A_D0147.tif" />

5- (6 - ((1- (3-Fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3-yl) isoxazol-3carboxamide. To a solution of ethyl 5- (6 - ((1- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pinedazin-3-yl) isoxazol-3-carboxylate (200 mg 0.40 mmol) in a THF / MeOH mixture (12 mL, 5: 1) LiOH (1M, 1.2 mL) was added at rt. The

-148 reaction mixture was stirred overnight and concentrated. NH was added to this crude mixture₄CI (60 mg, 1.2 mmol), HBTU (246 mg, 0.65 mmol), DIEA (132 μΙ, 0.8 mmol) and DMF (5.0 ml). The mixture was stirred at rt overnight, filtered and purified by Reverse Phase Chromatography to provide the title compound as a white solid (23.2mg, 16%), LRMS (M + H⁺) m / z 369.2,

Example 34: Preparation of 5- (5- (6 - ((1 - (3-Fluoropyridin-2¡l) cyclobutyl) methylamino) pyridazin-3-yl) thiophene-2-yl) -2H-1,2 , 4-triazol-3 (4H) -one

<img file="MX2012012259A_D0148.tif" />

6- (5-Cyanothiophene-2-yl) pyridazin-3-yl ((1- (3-fluoropyridin-210 yl) cyclobutyl) methyl) carbamate. T-Butyl 6-chloropyridazine-3-yl ((1- (3fluoroplryd-2-yl) cyclobutyl) methyl) carbamate (900mg, 2.29mmol, 1 equiv.), 5-cyanotlofen-2-ylboronic acid (390 mg, 2.52 mmol, 1.1 equiv.), (Dppf) PdCI₂ (164 mg, 0.23 mmol, 0.1 equiv.), Dioxane sprayed with nitrogen (6.0 ml) and K₂CO₃ ac. 2N (2.3 ml) and heated in a microwave reactor for 30 min at 140 ° C. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated. The resulting residue was purified on silica gel using a mixture of ethyl acetate and hexanes to provide the title compound as a yellow oil (340 mg, 32%), LRMS (M + H⁺) m / z 466.3,

<img file="MX2012012259A_D0149.tif" />

- 149 (1 - (3-FI uorop ¡rid ¡η-2-yl) cyclobutyl) meti 1 (6- (5- (5-oxo-4,5-di hid ro-1 H-1,2,4tr Azole-3-l) thiophene-2-l) p¡r¡daz¡n-3-l) tert-butyl carbamate. To a solution of 6- (5-cyanotiofen-2-yl) pyridazin-3-yl ((1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) tert-butyl carbamate (340 mg, 0.73 mmol, 1 equiv.) in MeOH (10 ml) was added sodium methoxide (0.59 g, 1.1 mmol, 1.5 equiv.). The reaction mixture was stirred at rt overnight followed by the addition of hydrazine (0.5 ml). The mixture was then heated at reflux for 2 h and concentrated to dryness. The crude mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na₂SW₄, filtered and concentrated. The crude product was dissolved in dioxane (3 ml), combined with CDI (137 mg, 1.46 mmol, 2 equiv.) And heated for 4 h at 100 ° C. The mixture was cooled, filtered, and purified by reverse phase chromatography to give the title compound as a yellow solid (86 mg, 23% in 3 steps), LRMS (M + H⁺) m / z 524.3.

<img file="MX2012012259A_D0150.tif" />

5- (5- (6 - ((1 - (3-Fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3-yl) thiophene-2-yl) 15 2H-1,2,4-triazole-3 (4H) -one. A (1- (3-fluoropyridin-2-yl) cyclobutyl) methyl (6- (5- (5-oxo-4,5-dihydro-1H-1,2,4-triazol-3- yl) thiophene-2-yl) pyridazin-3-yl) tert-butyl carbamate (86 mg, 0.16 mmol) in DCM (6 ml) TFA (2 ml) was added at rt. The reaction mixture was stirred at rt for 2 h followed by concentration to dryness. The crude mixture was purified by reverse phase chromatography to provide the title compound as a pale yellow solid (73.6 mg, quantitative). LRMS (M + H⁺) m / z 424.2.

Example 35: Preparation of 4-fluoro-3- (6 - (((frans) -3-fluoro-1- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyridazin-3-yl) -N-methylbenzamide

-150 -

<img file="MX2012012259A_D0151.tif" />

1- (3-Fluoropyridin-2-yl) -3-methylenecyclobutanecarbonitrile. To a solution of 3-methenochlorobutanecarbonltrile (150 g, 1.61 mol, 1 equiv.) And 2-chloro-3-fluoropyridine (212 g, 1.61 mmol, 1 equiv.) In toluene (1 I) was added drop by drop NaHMDS (2 M 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 solution₄CI_(sat.). The organic layer was washed with water (500 ml x 2) and brine (500 ml), dried over Na₂SW₄, filtered and concentrated to give the crude title compound (272 g, 90%), which was used in the next step without further purification, LRMS (M + H⁺) m / z 189.1.

<img file="MX2012012259A_D0152.tif" />

1- (3-Fluoropyridin-2-yl) -3-oxocyclobutanecarbonitrile. To a mixture of 1- (3fluoropyrin-2-yl) -3-methylenecyclobutanecarbonitrile (272 g, 1.45 mol) and RuCI₃H₂Or (9.0 g, 0.044 mol) in DCM (1 I), acetonitrile (1 I) and water (1.5 I) NalO 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 by filtration and washed with DCM (1 L x 2). The organic layer was washed with water (500 ml x 2) and brine (500 ml), dried over Na₂SW₄ and concentrated to provide the title compound as a crude dark solid (238g, 86.3%), LRMS (M + H⁺) m / z 191.1.

-151 -

<img file="MX2012012259A_D0153.tif" />

1- (3-Fluoropyridin-2-yl) -3-hydroxycyclobutanecarbonitrile. To a solution of 1 (3-fluoropyridin-2-yl) -3-oxocyclobutanecarbonitrile (231 g, 1.22 mol) in a mixture of DCM (2 I) and MeOH (200 ml) was added portionwise NaBH₄ at -78 ° C. The reaction mixture was stirred 1 h at -78 ° C and then quenched with a mixture of methanol and water (1/1). The organic layer was washed with water (500 ml x 3), dried over Na₂SW₄ and concentrated. The residue was purified on silica gel (50% EtOAc in Hexanes) to provide the title compound as an amber oil (185.8 g, 77.5%), LRMS (M + H⁺) m / z 193.2.

<img file="MX2012012259A_D0154.tif" />

<img file="MX2012012259A_D0155.tif" />

Irans-3-Fluoro-1- (3-fluoropyridin-2-yl) cyclobutanecarbonitrile. To a solution of 1- (3-fluoropyridin-2-yl) -3-hydroxy-cyclobutanecarbonyltrile (185 g, 0.96 mol) in DCM (1 I) was added portionwise DAST 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 Na₂SW₄ and concentrated. The residue was purified on silica gel (100% DCM) to provide the title compound as a brownish oil (116 g, 62%) with a trans / cis ratio of 8: 1 as determined by¹H NMR. The above brownish oil (107 g) was dissolved in a mixture of toluene (110 ml) and hexanes (330 ml) at 70 ° C. The solution was cooled to 0 ° C and stirred at 0 ° C overnight. The

-152 precipitate was filtered and washed with hexanes to provide the single trans isomer as a white solid (87.3 g, 81.6%), LRMS (M + H⁺) m / z 195.1.

<img file="MX2012012259A_D0156.tif" />

Irans-3-Fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methanamine. A mixture of 5 frans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutanecarbonitrile (71g, 0.37mol) and Raney nickel (-7g) in 7N ammonia in methanol ( 700 ml) was charged with hydrogen (413.68 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, 98%), LRMS (M + H⁺) m / z 199.2.

<img file="MX2012012259A_D0157.tif" />

F

<img file="MX2012012259A_D0158.tif" />

6-Chloropyridazin-3-yl (((rans) -3-fluoro-1- (3-fluoropyrid-2yl) cyclobutyl) methyl) carbamate. 3-Chloro-6fluoropyridazine (10.11g, 76.30mmol, 1equiv), fra /? S-3-fluoro-1- (3-fluoropyridin-2l) cyclobutyl were heated at reflux ) methanamine (15.10 g, 76.30 mmol, 4: 1 trans / cis ratio) and K₂CO₃ (29.27 g,

304.9 mmol) in CH₃CN (20 mi) during one night. After cooling, water was added to the mixture. The precipitate was collected and dried to give 9.2 g (39%) of the desired product with a trans: cis ratio greater than 20: 1. To this solid (9.2 g) and

DMAP (353 mg, 2.9 mmol) in THF (100 ml) was added (Boc)₂0 (12.8g, 58.7mmol).

The mixture was then heated at reflux for 2 h, cooled, and concentrated. The residue

-153 was purified on silica gel to provide the title compound as a white solid (9g, 75%), LRMS (M + H⁺) m / z 411.2.

<img file="MX2012012259A_D0159.tif" />

3- (6- (f-Butoxycarbonyl (((yrans) -3-fluoro-1- (3-fluoropyrid-25 yl) cyclobutyl) methyl) amino) pyridazin-3-yl) - Methyl 4-fluorobenzoate. A -butyl-6-chloropyridazin3-yl ((((frans) -3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate (30.3 g, 73.9 mmol, 1 equiv.), 2-fluoro-5- (methoxycarbonyl) phenylboronic acid (16.1 g, 81.3 mmol, 1.1 equiv.), (dppf) PdCI₂ (6.0 g, 7.39 mmol, 0.1 equiv.), K₂CO₃ (40.8 g, 296 mmol, 4 equiv.) Dioxane (160 ml) and water (40 ml) were added. The mixture was heated 2 h

80 ° C, cooled and diluted with EtOAc. The organic layer was washed with brine, dried over Na₂SW₄, filtered and concentrated. The residue was purified on silica gel to provide the title compound as a pale orange solid (29.4 g, 75%), LRMS (M + hT) m / z 529.2.

<img file="MX2012012259A_D0160.tif" />

3- (6- (t-Butoxycarbonyl (((frans) -3-fluoro-1 - (3-fluoropyridin-2yl) cyclobutyl) methyl) amino) pyridazin-3-yl) -4-fluorobenzoic acid.

3- (6- (f-butoxycarbonyl (((frans) 3-f I uoro-1 - (3-f luoropyrid in-2-yl cyclobutyl) met) was added to a 500 ml round-bottom flask. I) methyl pyridazin-3-yl) -4-fluorobenzoate (29.4 g, 55.7 mmol, 1 equiv.), THF (200 ml), MeOH (100 ml) and NaOH (74, 2 mi from

- 154 a 3N aqueous solution, 222 mmol). The mixture was heated 30 min at 60 ° C, cooled, acidified to pH 3 with NaHSO₄ (1N) and concentrated. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na₂SW₄, filtered and concentrated to provide the title compound as a pale orange solid (29 g, crude), LRMS (M + H⁺) m / z 515.2.

<img file="MX2012012259A_D0161.tif" />

((frans) -3-Fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methyl (6- (2-fluoro-5 (methylcarbamoyl) phenyl) pyridazin-3-yl) carbamate of f-butyl. A 3- (6- (fbutoxycarbonyl (((fra / 7s) -3-fluoro-1- (3-fluoropyrid-2-yl) cyclobutyl) methyl) amino acid) plrdazin-3-yl) 10 4-fluorobenzoic (29 g, 55.7 mmol, 1 equiv.) In DCM (200 ml), oxalyl chloride (19.4 ml, 222 mmol, 4 equiv.) was added . The reaction was stirred for 1 hr, concentrated, and azeotropically distilled twice with toluene. The crude product was then dissolved in DCM and cooled to 0 ° C. NH was added to this mixture₂Me (2M / THF, 278 ml, 556.8 mmol). The mixture was warmed to rt and stirred at rt for 30 min. The solid was removed by filtration and the filtrate was concentrated. The crude product was purified on silica gel to provide the title compound as a pale yellow solid (28.1g, 96%), LRMS (M + H⁺) m / z 528.2.

<img file="MX2012012259A_D0162.tif" />

-155 4-fluoro-3- (6 - (((frans) -3-fluoro-1- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyridazin-3-yl) -N-methylbenzamide.

((frans) -3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methyl (6- (2-fluoro-5 (methylcarbamoyl) phenyl) pyridazin-3-yl) tere-butyl carbamate (28 0.1 g, 53.3 mmol) in DCM (100 mL) TFA (40 mL, 533 mmol, 10 equiv) was added at rt. The reaction mixture was further stirred at rt for 2 h followed by concentration to dryness. The residue was partitioned between EtOAc and NaHCO₃, The pH was further adjusted to pH 9 with NaOH (1N). The organic layer was washed with brine, dried over Na₂SW₄, filtered, and concentrated to give 25.2 g of a pale yellow solid. The solid dissolved in

EtOH (80 ml), heated to 66 ° C and diluted with water (80 ml) at 66 ° C. The mixture was slowly cooled to rt with stirring. The precipitate was filtered, washed with water and dried to provide the title compound as a white solid (21.2g, 93%), LRMS (M + H⁺) m / z 428.2.

Example 36: Preparation of 6- (5- (1 H-pyrazol-3-yl) thiazol-2-yl) -N - ((1- (3-fluoropyridin-215 yl) cyclobutyl) methyl) pyridazin-3- amine

<img file="MX2012012259A_D0163.tif" />

<img file="MX2012012259A_D0164.tif" />

F-Butyl 6- (5-bromothiazol-2-yl) pyridazin-3-yl ((1- (3-fluoropyridin-2yl) cyclobutyl) methyl) carbamate. To a 100 ml round bottom flask was added (1- (3-fluoropyridin-2-yl) cyclobutyl) methyl (6- (thiazol-2-yl) pyridazin-3-yl) f-butyl carbamate (2 0.0g, 4.6mmol), NBS (1.6g, 9.1mmol) and DMF (20ml). The reaction was heated to

100 ° C and stirred overnight. Then, the reaction mixture was poured into ethyl acetate (200 ml), washed with water (100 ml), dried over Na₂SW₄, filtered, concentrated and purified by chromatography on silica gel (EtOAc / hex) to

-156 provide 1.8 g of f-butyl 6- (5-bromothiazol-2-yl) plridazin-3-yl ((1- (3-fluoroplridin-2yl) cyclobutyl) methyl) carbamate.

<img file="MX2012012259A_D0165.tif" />

6- (5- (1 H-pyrazol-3-yl) thiazol-2-yl) -N - ((1 - (3-fluoropyridin-25 yl) cyclobutyl) methyl) pyridazin-3-amine. To a microwave vial was added 6- (5bromot¡azol-2-¡l) p¡r¡daz¡n-3-¡l ((1- (3-fluorop¡rld¡n-2-¡l) -butyl cyclobutyl) methyl) carbamate (100mg, 0.19mmol), 1H-pyrazole-5-llboronic acid (32mg, 0.29mmol), (dppf) PdCI₂ (16 mg, 0.02 mmol), dioxane (2 ml) and K₂CO₃ (0.2 ml of a 2M aqueous solution, 38 mmol). The mixture was heated to 140 ° C in a microwave reactor and stirred for 20 min.

Then, the reaction mixture was poured into ethyl acetate (50 ml), washed with water (20 ml), dried over Na₂SW₄, filtered, concentrated, and purified by chromatography on silica gel (EtOAc / hex) to provide 38 mg of 6- (5- (1 H-plrazol-3-ll) thizol-2l) pyr! dazin-3-yl ((1- (3-fluoropyrid-2-yl) cyclobutyl) methyl) f-butyl carbamate. This compound was dissolved in CH₂CI₂ (5 mi) and TFA (1 mi). The reaction was stirred for 30 min at rt, concentrated, and then purified using Reverse Phase Chromatography to give 15 mg of 6- (5- (1 H-plrazol-3-yl) thiazol-2-yl) - N - ((1- (3-fluoropyrldin-2l) cyclobutyl) methyl) pyrdazn-3-amine, (M + H = 408.3).

Example 37: Preparation of 6- (6 - ((rans-3-fluoro-1- (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyridazin-3-yl) imidazo [2,1-b] thiazol-3-carboxamide

<img file="MX2012012259A_D0166.tif" />

2-Bromo-1- (6-chloropyridazin-3-yl) ethanone. To a stirred dioxane solution (100 ml, degassed) was added 3,6-dichloropirldazlin (5.0 g, 34 mmol),

- 157CI₂Pd (PPh₃)₂ (2.4 g, 3.4 mmol) and tributyl (1-ethoxylvln) tin (18.2 g, 50 mmol). The reaction was heated to 100 ° C and stirred for 1 hr. 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 30 min and then filtered through a pad of Celite. The filtrate was concentrated and then dissolved in THF (80 ml) and water (80 ml). Then, NBS (18.1 g, 102 mmol) was added and the reaction was stirred for 20 min at rt. The reaction mixture was poured into ethyl acetate (200 ml), washed twice with brine (50 ml), dried over Na₂SW₄, filtered, concentrated, and purified by chromatography on silica gel to provide 4.2 g of 2-bromo-1- (6-chloropyridazin-10-yl) ethanone.

<img file="MX2012012259A_D0167.tif" />

<img file="MX2012012259A_D0168.tif" />

O = &lt;

OEt

Ethyl 6- (6-Chloropyridazin-3-yl) imidazo [2,1-b] thiazol-3-carboxylate. Ethyl 3-chloro-6- (1-ethoxyvinyl) pyridazine (4.2g, 18mmol), ethyl 2-aminothiazol-4-carboxylate (3.1g, 18mmol) and methyl ethyl ketone were added to a 20 drachm vial. 40 mi). The mixture was heated to 90 ° C and stirred overnight. The reaction was then concentrated and purified by chromatography on silica gel (EtOAc / hex) to provide 1.0 g of ethyl 6- (6-chloropyridazin-3-yl) imidazo [2,1-b] thiazol-3 -carboxylate in the form of a yellow solid.

<img file="MX2012012259A_D0169.tif" />

Ethyl 6- (6-Fluoropyridazin-3-yl) imidazo [2,1-b] thiazol-3-carboxylate. 6- (6-Chloropyridazin-3-yl) imidazo [2,1-b] thiazol-3-carboxylate was added to a vial of 20 drachmas

-158 ethyl (1.0 g, 3.2 mmol), 1,8-bls (dlmethylamine) naphthalene (1.4 g, 6.4 mmol) and Et₃N-3HF (30 mi). The reaction was heated in a microwave at 140 ° C and stirred for 1.5 h. The reaction mixture was poured into ethyl acetate (100 ml), washed with water (50 ml), dried over Na₂SW₄, filtered, concentrated, and purified by chromatography on silica gel to provide 760 mg of ethyl 6- (6-fluoropyridazin-3-yl) midazo [2,1-b] thiazol-3-carboxylate as a yellow solid.

<img file="MX2012012259A_D0170.tif" />

<img file="MX2012012259A_D0171.tif" />

Ethyl ethyl 6- (6 - (((frans) -3-Fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin3-yl) imidazo [2,1-b] thiazol-3-carboxylate. Ethyl 6- (6-Fluoropyridazin-3-yl) imidazo [2,110 b] thiazol-3-carboxylate (65 mg, 0.2 mmol), (frans-3-fluoro-1- (3-fluoropyridin-2yl) c ¡Clobutíl) methanamine (56 mg, 0.29 mmol), DIPEA (114 μΙ, 0.66 mmol) and NMP (3 ml). The reaction was heated to 165 ° C and stirred for 2h. The reaction was then directly purified using reverse phase chromatography to give 15 mg of 6- (6 - ((frans-3fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3-yl ) imidazo [2,1-b] thiazol-315 carboxamide.

<img file="MX2012012259A_D0172.tif" />

<img file="MX2012012259A_D0173.tif" />

6- (6 - (((trans) -3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3yl) imidazo [2,1-b] thiazol-3-carboxamide. To a solution of 6- (6 - ((frans-3-fluoro-1- (3fluoropyrin-2-yl) cyclobutyl) methylamino) pyridazin-3-yl) imidazo [2,1-b] thiazole- 3-carboxamide (20

-159mg, 0.05mmol) in dioxane (0.5ml) LiOH (1M, 0.15ml, 0.15mmol) was added. The reaction mixture was stirred at rt for 1 hr and then concentrated. NH was added to this crude mixture₄CI (28mg, 0.5mmol), HATU (28mg, 0.075mmol), HOAt (10mg, 0.075mmol), DIEA (19mg, 0.15mmol) and DMF (1ml). The mixture was stirred at 50 ° C for 30 min and then directly purified by Reverse Phase Chromatography to provide 2 mg of 6- (6 - ((((frans) -3-fluoro-1- (3-fluoroplr¡d¡ n-2¡l) cyclobutyl) methylamino) pldaz¡n-3-l) ¡m¡dazo [2,1-b] t¡azol-3-carboxamida in the form of a white solid (M + H = 442.1).

Example 38: Preparation of 4-Fluoro-3- (6 - (((frans) -3-fluoro-1- (3-fluoropyridin-210 yl) cyclobutyl) methylamino) pyridazin-3-yl) benzamide and 4-fluoro- 3- (6 - (((c / s) -3-fluoro-1- (3fluoropyridin-2-yl) cyclobutyl) methylamino) pyridazin-3-yl) benzamida

<img file="MX2012012259A_D0174.tif" />

To a solution of 4-fluoro-3- (6 - ((3-fluoro-1- (3-fluoropyrldln-2yl) cyclobutyl) methylamino) pridazin-3-yl) benzonyltrile ( 482 mg, 1.22 mmol, cls / trans ratio

95: 5) in DMSO (3 ml) was added potassium carbonate (673 mg, 4.88 mmol). The mixture was cooled to 0 ° C and hydrogen peroxide (0.6 ml) was added slowly. The reaction was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc (75 ml) and water (50 ml) and the organic layer was washed three times with brine (50 ml). Then the organic layer was dried over Na₂SW₄, filtered, concentrated, and purified by Reverse phase chromatography to provide 470 mg of 4-fluoro-3- (6 - (((rans) -3-fluoro-1- (3fluorop¡r¡dln-2-¡ l) cyclobutyl) methylamino) pyridazine-3-l) benzamide and 6 mg of 4-fluoro-3- (6 (((c / s) -3-fluoro- 1- (3-fluoropryrd-2-l) cyclobutyl) methalamine) prdazin-3-l) benzamide in the form of a solid whites (M + H = 414.3).

-160 Example 39: Preparation and testing of fast skeletal myofibrils

Preparation of skeletal myofibrils. Rabbit skeletal myofibrils were prepared based on the method of Herrmann et al. (Blochem. 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 ice cold "conventional" buffer (50 mM Tris, pH 7.4, 0.1 M potassium acetate, 5 mM KCI, 2 mM DTT, 0.2 mM PMSF, 10 μΜ leupeptin, pepstatin 5 μΜ 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 the Triton washes, the myofibrils were washed 3 times in "standard" buffer containing 2mM magnesium acetate. A final wash was performed in assay buffer (12mM PIPES, pH 6.8, 60mM KCI, 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). 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

-161 compounds were tested using a suspension of myofibrils and a level of calcium sufficient to increase the enzymatic activity of the myofibrils to 25% of their maximum rate (called pCa25). Enzymatic activity was tracked by an enzyme system coupled to lactate dehydrogenase and plruvate qulnasa. This assay regenerates mlosin-produced ADP to ATP by oxidizing NADH, producing a change in absorbance at 340 nm. The buffer system was 12 mM Pipes, MgCI₂2 mM, 1mM DTT at pH 6.8 (PM12 buffer). Data was reported as AC1,4, which is the concentration at which the compound increased enzymatic activity by 40%. The results are summarized in Table 2 below.

Example 40: Preparation and Assay of Sarcomeric Skeletal Muscle Proteins

Powder Preparation

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

2. Pre-cut and boil cheesecloth for 10 minutes in water. Drain and pat dry.

3. Chop chicken breast in a pre-chilled meat grinder.

Four. Extract with stirring in 2 I of 0.1 M KCI, 0.15 M potassium phosphate, 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 sediments with stirring with 2 I of NaHCO₃ 0.05M 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 I of 1 mM EDTA, pH 7.0 for 10 minutes with stirring.

- 1627. Extract with 2 I 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 I of acetone for 10 minutes each with stirring). Squeeze through the cheesecloth gently. All acetone extractions are performed at room temperature. Acetone should be pre-cooled 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. 381-395)

one. Dissect the left ventricles of the heart muscle. Remove as much of the pericardial tissue and fat as possible. Grind in a chilled pre15 meat grinder. To weigh.

2. Prepare 5 volumes of extraction buffer (see below). Homogenize the meat in a mixer, 4 times for 15 seconds in mixture with 15 seconds between them. Do this with one volume (weight / volume) of buffer 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 proceed to Stage 5. Sediments should be yellowish-white.

-1635. 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 dlethyl 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: 50 mM KCI, 5 mM Tris pH 8.0. Prepare as concentrate 50 times. For 2 I: 250 mM Tris pH 8.0. Tris base (121.14 g / mol, 60.6 g), pH 8.0 with concentrated HCI, then add 2.5 M KCI (74.55 g / mol, 372 g).

Actin Preparation

one. 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 I 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. The 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.

-1645. Add ATP at 0.2mM and MgCI₂ at 50 mM. Shake on a stir plate at 4 ° C for 60 minutes to allow the actin to polymerize / form para-crystals.

6. Slowly add solid KCI at 0.6M (45 g / l). 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. 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 45T¡ 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 50mM KCI (3M stock), MgCI₂ at 1 mM and NaN₃ to 0.02% (10% reserve). Store at 4 ° C. Do not freeze.

Buffer A: 2 mM Tris / HCI, CaCI₂ 0.2 mM, 2-mercaptoethanol 0.5 mM (36 μΙ / Ι), 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. 85, 55-123; and Goldmann, WH and Geeves, MA (1991) Anal. Biochem. 192, 55-58)

-165 Solution A: KCI 0.3 M, potassium phosphate 0.15 M, EDTA 0.02 M, MgCI₂ 0.005 Μ, ATP 0.001 M, pH 6.5.

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

Solution C: KCI 0.6 M, potassium phosphate 0.025 M, pH 6.5.

Solution D: 0.6 M KCI, 0.05 M potassium phosphate, pH 6.5.

Solution E: 0.15M potassium phosphate, 0.01M EDTA, pH 7.5.

Solution F: KCI 0.04 M, potassium phosphate 0.01 M, DTT 0.001 M, pH 6.5.

Solution G: 3M KCI, 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 I 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 to

7,000 rpm in GSA rotor for 15 minutes.

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

GSA.

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

5. Dilute the supernatant to ionic strength of 0.04 (~ 8 times); let the mlosin sit overnight; collect approximately 5-6 I 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 I of solution D; centrifuge at 19,000 rpm for 2 hours, in tubes

-166 cellulose nitrate; 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 exhaustively, load on DEAE-sephadex 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 0-0.5 M KCI linear gradient in solution E (2 x 1 liter); collect 10 ml fractions; pool myosin fractions (KCI&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 cleaved with chymlotrlpsin or papain in the presence of EDTA to generate the S1 fragment 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 S1 fraction is prepared by digestion with chymlotrlpsin (Margossian and Lowey, 1982).

Actin is purified by first preparing a heart muscle ether powder (Zot HG and Potter J D. (1981) Preparatlve Biochemistry 11: 381-395) as described above. Subsequently, actin alternates between the filamentous and soluble state through cycles of centrifugation and dialysis (Spudlch 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 from TnC, TnT and Tnl. Dust is extracted

- 167 ether 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 with a KCI gradient of 25-350 mM. There is no median 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, Slgma-Aldrich, St. Louis, MO) or readily synthesized by one skilled in the art, the compounds in Table 2 are synthesized, characterized and rehearsed. AC1.4 values ​​were determined according to the procedure described in Example 40 and the indicated median of AC1.4 values ​​are as follows: A = &lt;1 pM; B = 1-10 pM; C = 10-20 pM; D =&gt; 20 pM.

Compound

3- (6 - {[2- (4-fluorophenyl) -25-methylpropyl] amino} pyridaz-3-l) benzamida

4- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazn-3-yl) benzamida

5- (6 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} pyridazin-3-yl) pyridin-3carbonitrile ₁₅ Methyl 5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) pyridin-3-carboxylate

5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) pyridin-320 carboxamide [2- (4-fluorophenyl) -2-methylpropyl] (6-pyrazol-4ylpyridazin -3-yl) amine

-168 Table 2 m / z

Structure (M + H)

<img file="MX2012012259A_D0175.tif" />

365,2

Half

AC1.4

A h₂n // \

<img file="MX2012012259A_D0176.tif" />

365,1

<img file="MX2012012259A_D0177.tif" />

348,1

381,1

366,1

<img file="MX2012012259A_D0178.tif" />

312,1

-169-

<img file="MX2012012259A_D0179.tif" />

NH [2- (4-fluorophenyl) -2-methylpropyl] (6-prop-2enylpyridazin-3-yl) amine

281.6 B [6 - ((1 E) prop-1-en¡l) pyridazin-3-yl] [2- (4fluorophenyl) -2-methylpropyl] amine

F

<img file="MX2012012259A_D0180.tif" />

286.1 B

3- (6 - {[(2S) -2- (410 fluorophenyl) propyl] amino} pyridazin-3yl) benzamide

<img file="MX2012012259A_D0181.tif" />

3- (6 - {[(2R) -2- (4fluorophenyl) propyl] amino} pyridazine-3yl) benzamide ^H’^N

3- (6 - {[2- (4-chlorophenyl) ethyl] amino} pyridazin-3¡l) benzamide h₂n20

3- (6 - {[2- (3-chlorophenyl) ethyl] amino} pridazin-3! L) benzamida h₂n—

<img file="MX2012012259A_D0182.tif" />

or

-170 3- (6 - {[2- (2-chlorophenyl) ethyl] amino} pyridazin-3yl) benzamide

3- (6 - {[2- (4-methylpheni1) ethyl] amino} p¡ridazin-3yl) benzamida

3- (6 - {[2- (4-fluorophenyl) ethyl] amine} pyridazine-3yl) benzamide

3- (6 - {[2- (4-methoxyphenyl) ethyl] amino} pyridazin-3 · yl) benzamide (6 - {[2- (4-fluorophenyl) -2-methylpropyl] amine} pyridazin-3- il) mettan-1-ol

<img file="MX2012012259A_D0183.tif" />

- 171 6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-carboxylate

<img file="MX2012012259A_D0184.tif" />

3- (6 - {[2- (2,4-d-chlorophenyl) et! L] amino} pyridazin3-yl) benzenecarbonyltrile

3- (6 - {[2- (2,4-dichlorophenyl) etl] amino} pyridazin3-l) benzamida

3- (6 - {[2- (3,4-dichlorophenyl) ethyl] amino} pyridazin3-yl) benzamide

3- (6 - {[2- (2,4-difluorophenyl) etl] amino} pyridazin3-yl) benzamida

<img file="MX2012012259A_D0185.tif" />

369,0

387,0

387,0

355.1 or

-172 10

3- (6 - {[2- (3,4-dfluorophenyl) etl] amino} p¡r¡daz¡n3-l) benzamida

3- (6 - {[2- (3,5-d¡fluorophenyl) et¡l] amino} p¡ridaz¡n3-¡l) benzamida

3- {6 - [(2- (4-p¡rid¡l) et¡l) amino] p¡ridaz¡n-3¡IJbenzamida

3- {6 - [(2- (3-p¡r¡d¡l) et¡l) amino] p¡ridaz¡n-3¡l} benzam¡da

3- {6 - [(2- (2-p¡rid¡l) et¡l) amino] p¡r¡daz¡n-3¡IJbenzamida

F

<img file="MX2012012259A_D0186.tif" />

OR

355.1 C

355.1 D

320.1 D

320.1 D

320.1 D

-173 3- {6 - [(2-phenylethyl) amino] pyridazine-3¡IJbenzamide

319.1 D

3- {6 - [(3-met¡lb uti I) am ¡no] p¡ridazi n-3¡IJbenzamida

3- {6 - [(2-phenylpropyl) amino] pyridazine-3¡l} benzamida

3- (6 - {[(4-fluorophenyl) etl] amino} p¡r¡dazin-3¡l) benzamida

3- {6 - [(fen¡let¡l) amíno] p¡r¡daz¡n-3-¡l} benzam¡da

<img file="MX2012012259A_D0187.tif" />

NH,

319.1 D

333.1 B

337.1 C

319.1 D

3- {6 - [(3,3-d-methylbutyl) amino] p¡ridaz¡n-320 il} benzamida

<img file="MX2012012259A_D0188.tif" />

299.2 D

-1743- {6 - [(2-p¡razin-2-¡let¡l) amino] p¡r¡daz¡n-3¡Qbenzamida

3- (6 - {[2- (2-chlorophenyl) -2methylpropyl] amino} pyridazine-3-yl) benzamide

3- (6 - {[2- (4-chlorophenyl) -2methylpropyl] amino} p¡r¡daz¡n-3-¡l) benzamida

3- (6 - {[2- (2,4-dfluorophenyl) -2methylpropyl] amine} p¡r¡daz¡n-3-¡l) benzamida

3- [6 - ({[(4fluorophenyl) cyclopropyl] methyl} amino) p¡ridaz¡n-3 · l] benzamida

<img file="MX2012012259A_D0189.tif" />

F

-175 (6- (1 H-indazol-6-yl) pyridazine-3-yl) [2- (4fluorophenyl) -2-methylpropyl] amine

3- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3yl) benzenecarbonitrile θ (6- (1 Hi ndazol-5-yl) pyridazin-3-yl) (2- (4fluorophenyl) ) -2-methylpropyl] amine

3- (6 - {[2- (2-fluorophenyl) -215 methylpropyl] amino} pyridaz-3-l) benzamide (6- (1 H-indazol-4 -il) pyridazin-3-yl) [2- (4fluorophenyl) -2-methylpropyl] amine

5- [6 - ({[(4fluorophenyl) cyclopropyl] methyl} amino) pyridazin-3 · yl] pyridin-3-carboxamide

<img file="MX2012012259A_D0190.tif" />

-176 5- [6 - ({[(4fluorophenyl) cyclopropyl] methyl} amino) pyridazine-3l] pyridine-3-carbonitrile

6- {[2- (4-fluorophenyl) -2methylpropyl] amine} pridaz-3-carbonitrile

6 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} pyridazin-3-carboxamide

5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} p¡r¡daz¡n-3-¡l) -315 hydrobenzoimidazol-2-one

3- (6 - {[2- (3-fluorophenyl) -2-methylpropyl] amino} pyridazin-3-yl) benzamide (6- (1H-1,2,3,4-tetraazol-5-yl) p ¡Ridaz¡n-3-¡l) [2 (4-fluorophen¡l) -2-met¡lprop¡l] am¡na

<img file="MX2012012259A_D0191.tif" />

- 177 5- (6 - {[2- (2-chlorophenyl) -2methylpropyl] am} no} p¡r¡daz¡n-3-¡l) p¡r¡d¡n- 3carboxamide

5- (6 - {[2- (2-chlorophenyl) -2methylpropyl] amine} p¡r¡daz¡n-3-¡l) p¡rid¡n-3carbonitrile [(6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} pyridazine-3l) metyl] (methersulfonyl) amine

N - [(6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} pyridazyl-3l) methyl] methoxycarboxamide [6- (3 -am¡no (1H-indazol-5-¡l)) p¡ridaz¡n-3-¡l] [2 (4-fluorophenyl) -2-metpropyl] amine

<img file="MX2012012259A_D0192.tif" />

-178 [6- (3-amino (1 H-indazol-7-yl)) pyridazin-3-yl] [2 (4-fluorophenyl) -2-methylpropyl] amine [6- (3-aminobenzo [3,4 -d] isoxazol-5yl) pyridazin-3-yl] [2- (4-fluorophenyl) -2methylpropyl] amine [6- (3-aminobenzo [d] isoxazol-7-yl) pyridazin-3yl] [2- ( 4-fluorophenyl) -2-methylpropyl] amine [2- (2-chlorophenyl) -2-methylpropyl] (6- (3pyridyl) pyridazin-3-yl) amine [2- (2-chlorophenyl) -2-methylpropyl] ( 6-pıririnidin-52Q ilpiridazin-3-yl) amine

<img file="MX2012012259A_D0193.tif" />

- 179 3- [6 - ({[(2chlorophenyl) cyclopropyl] methyl} amine) pridazin-3yljbenzamide

3- (6 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} -5methylp¡ridazin-3-¡l) benzenecarbon¡tr¡lo

3- (6 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} -5methylplidazin-3-l) benzamida

3- (6 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} -4methylpyridazin-3-l) benzenecarbonyltrile

3- (6 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} -4methylpyridaz-3-yl) benzamide [3- (6 - {[2- (4- fluorophenyl) -2methylpropyl] amine} p¡r¡daz¡n-3-¡l) fen¡l] -N- (2h¡drox¡et¡l) carboxam¡da

<img file="MX2012012259A_D0194.tif" />

-180N- (2,3-dih¡droxipropil) [3- (6 - {[2- (4-fluorophenyl) 2-methylpropyl] amino} p¡r¡daz¡n-3¡l ) fen¡l] carboxam¡da

3- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) phenyl piperidyl ketone

3- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} p¡r¡daz¡n-3-¡l) phenyl morpholin4- l ketone

N- (2-amynoethyl) [3- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} p¡r¡daz¡n-3¡l) fen L] carboxamide [3- (6 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} p¡r¡dazin-3-l) phenyl] -N- (2 - {[3 (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} p¡r¡daz¡n-3¡l) fen¡l] carbon¡lam¡no} etíl) carboxamide

<img file="MX2012012259A_D0195.tif" />

F

439.1 B

433.2 B

435.1 B

408.2 A

755.3 B

- 181 4 - {[3- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3¡l) phenyl] carbonyl} terebutyl piperazinecarboxylate

2- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) benzamide

5- [6 - ({[(4fluorophenyl) cyclopropyl] methyl} amino) pyridazin-3yl] -3-hydrobenzoimidazol-2-one [2- (4-fluorophenyl) -2-methylpropyl] [6- (1 - methyl (1 Hindazol-6-yl)) pyridazine-3-yl] amine

3- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) phenyl piperazinyl ketone

<img file="MX2012012259A_D0196.tif" />

-182 1 - [(6 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} p¡r¡daz¡n-3yl) carbonyl] pyrrolidin-2-carboxamide

Ethyl 1 - [(6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3yl) carbonylamino] cyclopropanecarboxylate 6 - {[2- (4-fluorophenyl) -210 methylpropyl] amino } pyridazin-3-carboxylic acid 1 - [(6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3yl) carbonylamino] cyclopropanecarboxylic

3- (6 - {[2- (2-chlorophenyl) pentyl] amino} pyridazin-3yl) benzamide [6- (3-amino-1-methyl (1H-indazol-5-yl)) pyridazin3-yl] [2- (4-fluorophenyl) -2-methylpropyl] amine

<img file="MX2012012259A_D0197.tif" />

-183 3- (6 - {[2- (2-fluorophenyl) -4methoxybutyl] amino} pyridazin-3-yl) benzamide

6 - {[2- (4-Ftuorophenyl) -2-methylpropyl] amino} pyridazin-3-yl morpholin-4-yl ketone

6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl 4methylpiperazinyl ketone

4 - [(6 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} pyridazin-3yl) carbonyl] piperazinecarboxylate tere-butyl

Terebutyl 4-[(6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) carbonyl] -3 (hydroxymethyl) piperazinecarboxylate

<img file="MX2012012259A_D0198.tif" />

- 184 1 - [(6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3l) carbonyl] azetidn-2-carboxam! gives ⁵ 1 - [(6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} pyridaz-3yl) carbonyl] piperidin-2-carboxamide

4- [(6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} p¡r¡daz¡n-310 il) carbon¡l] p¡peraz¡n-2 -ona

5- (6 - {[2- (2-fluorophenyl) -2methylpropyl] amino} p¡r¡daz¡n-3-¡l) -3h¡drobenzo¡m¡dazol-2 -ona

<img file="MX2012012259A_D0199.tif" />

F [6- (3-amino (1H-indazol-6-yl)) p¡r¡daz¡n-3-¡l] [2 (4-fluorophenyl) -2-metpropyl! l] amína

<img file="MX2012012259A_D0200.tif" />

377.0 A [6- (3-aminobenzo [d] ¡soxazol-6-¡l) p¡ridaz¡n-3¡l] [2- (4-fluorophenyl) -2-methylpropyl! ] am¡na

<img file="MX2012012259A_D0201.tif" />

<img file="MX2012012259A_D0202.tif" />

378.0 A

<td colspan="2"> &gt;—</td>

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

-185

3-fluoro-5- (6 - {[2- (4-fluorophenyl) -2-methyl-propyl] amino} pridada-3-yl) benzamide

N- (1 -carbamoyl-3-methylbutyl) (6 - {[2- (4fluorophenyl) -2-methylpropyl] amino} pyridazin-3yl) carboxamide

N - ((1S) -1-carbamo¡l-2-h¡drox¡etil) (6 - {[2- (4fluorofen¡l) -2-met¡lprop¡l] amíno} p¡r¡ dazn-3yl) carboxamide (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazine-3-yl) -N- (pyrazol-3ylmethyl) carboxamide

3- (5-cyano-6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) benzamide

<img file="MX2012012259A_D0203.tif" />

F

-186

6- (3-carbamo¡lfen¡l) -3 - {[2- (4-fluorophen¡l) -2met¡lprop¡l] amino} p¡r¡daz¡n-4-carboxam¡da

5- [6 - ({2- [2- (hydroxymethyl) phenyl] -2methylpropyl} amino) pyridazin-3-yl] -3hydrobenzoimidazol-2-one

1 - [(6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} p¡r¡daz¡n-3¡l) carbon¡l] p¡perid¡n-3- carboxamida (2S.1 R) -2 - [(6 - {[2- (4-fluorophenil) -2methylpropyl] amine} p¡r¡daz¡n-3¡l) carbon¡lam¡no] c¡clopentanocarboxam¡da

N- (2-carbamo¡let¡l) (6 - {[2- (4-fluorophen¡l) -2met¡lprop¡l] amíno} p¡r¡daz¡n-3-¡l) carboxam gives

<img file="MX2012012259A_D0204.tif" />

<img file="MX2012012259A_D0205.tif" />

O. NN

<img file="MX2012012259A_D0206.tif" />

<img file="MX2012012259A_D0207.tif" />

NH NN

408.2 B

390.1 B

400,1

400,1

360,1

- 1874 - [(6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} p¡ridaz¡n-3¡l) carbon¡l] p¡peraz¡n-2-carboxamida

1 - [(6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} p¡r¡daz¡n-3yl) carbon¡l] p¡rrolid¡n-3- carboxamida

<img file="MX2012012259A_D0208.tif" />

1 - [(6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} p¡r¡daz¡n-3¡l) carbonyllamine] cyclopropanecarboxam! gives

<img file="MX2012012259A_D0209.tif" />

5- {6 - [(2,2-d¡metilpropíl) amino] p¡r¡daz¡n-3-¡l} -3h¡drobenzo¡m¡dazol-2-one

3- (6 - {[3- (1,3-dioxolan-2-yl) -2- (2fluorophenyl) propyl] amino} pyridazin-3l) benzamida

<img file="MX2012012259A_D0210.tif" />

6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazn-3-yl piperazinyl ketone

<img file="MX2012012259A_D0211.tif" />

358.0 D

V

- 1884 - [(6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} p¡r¡dazin-3¡l) carbon¡l] p¡perazincarboxam¡da

<img file="MX2012012259A_D0212.tif" />

401.0 D

5- {6 - [(2-metíl-2-fen¡lprop¡l) amino] p¡ridaz¡n-3 · ¡l} -3-h¡drobenzo¡m¡dazol-2-one

<img file="MX2012012259A_D0213.tif" />

360.1 A

5- (6 - {[2- (4-fluorophenyl) -tercbutyl] amino} p¡ridazin-3-¡l) -3h¡drobenzo¡m¡dazol-2-one

<img file="MX2012012259A_D0214.tif" />

F (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) -N-pyrazol-5¡Icarboxamide (6 - {[2- (4-fluorophen) l) -2methylpropyl] amino} pyridazin-3-yl) -N- (2-oxo (3p¡peridíl)) carboxamida

<img file="MX2012012259A_D0215.tif" />

<img file="MX2012012259A_D0216.tif" />

355.1 D

386.1 D

F

-1894 - [(6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3¡l) carbonylamine] p¡peridncarboxamide (6 - {[2- (4-fluorophenyl) -2met Lpropyl] amine} p¡r¡daz¡n-3-yl) -N - [(5oxopyrrolidin-2-yl) methyl] carboxamide

3- (6 - {[2- (2-fluorophenyl) butyl] amino} pyridazin-3 · yl) benzamide (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) -N- (215 oxopyrrolidin-3-yl) carboxamide

N- {3 - [(tert-butoxy) carbonyllamine] propyl} [3- (6 · {[2- (4-fluorophenyl) -2methylpropyl] amino} p¡r¡daz¡n-3il ) phenyl] carboxamide

F

<img file="MX2012012259A_D0217.tif" />

-190 N- (3-aminopropyl) [3- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3yl) phenyl] carboxamide

<img file="MX2012012259A_D0218.tif" />

(6-benzoimidazol-5-ylp¡ridaz¡n-3-yl) [2- (4fluorophenyl) -2-methylpropyl] amine [2- (4-fluorophenyl) -2-methylpropyl] [6 - (2-methylbenzoimidazol-5-yl) pyridazin-3-yl] amine

<img file="MX2012012259A_D0219.tif" />

[6- (2-aminobenzoim¡dazol-5-yl) pyridazin-3yl] [2- (4-fluorophenyl) -2-methylpropyl] amine ²⁰ [3- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) phenyl] -Nmethylcarboxamide

<img file="MX2012012259A_D0220.tif" />

- 191 3- (6 - {[2- (2oxop¡rrolid¡n¡l) prop¡l] amíno} p¡ridaz¡n-3¡IJbenzamida

3- (6 - {[2- (2-oxop¡perid¡l) prop¡l] amino} p¡r¡daz¡n3-¡l) benzam¡da

N- [5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} p¡r¡daz¡n-3-¡l) -2p¡r¡d¡ l] acetamide [2- (4-fluorophenyl) -2-methylpropyl] [6- (2methylbenzoxazole-5-l) p¡r¡daz¡n-3-¡l] amyna

<img file="MX2012012259A_D0221.tif" />

[2- (4-fluorophenyl) -2-methylpropyl] [6- (2methylbenzoxazole-6-l) pridaz-3-l] amine

<img file="MX2012012259A_D0222.tif" />

<img file="MX2012012259A_D0223.tif" />

377.2 B

1 - [(6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} p¡r¡daz¡n-3¡l) carbonyl] p¡perid¡n-4- carboxamida

<img file="MX2012012259A_D0224.tif" />

- 192 N - ((1S) -1-carbamoyl-2-phenylethyl) (6 - {[2- (4fluorophenyl) -2-methylpropyl] amino} pyridazin-3yl) carboxamide

N - ((1R) -1-carbamoyl-2-phenylethyl) (6 - {[2- (4fluorophenyl) -2-methylpropyl] amino} pyridazin-3yl) carboxamide

N- (carbamoylmethyl) (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) carboxamide

F

<img file="MX2012012259A_D0225.tif" />

N- (1,3-dicarbamoylpropyl) (6 - {[2- (4-fluorophenyl) 15 2-methylpropyl] amino} pyridazin-3yl) carboxamide

3- (6 - {[2- (2-fluorophenyl) propyl] amino} pyridazin3-yl) benzamide

3- (6 - {[2- (3-fluoro (2-pyridyl)) - 2-methylpropyl] amino} pyridazin-3-yl) benzamide

436.1 C

<img file="MX2012012259A_D0226.tif" />

OR

-193 3- (6 - {[2- (5-fluoro (2-pyridyl)) - 2-methylpropyl] amino} pyridazin-3-yl) benzamide

3- (6- (3,3-dimethylindol¡n¡l) pyridazin-3¡IJbenzamida

<img file="MX2012012259A_D0227.tif" />

6- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) -310 hydrobenzoxazol-2-one

<img file="MX2012012259A_D0228.tif" />

3- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) phenyl phenyl ketone

4- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) phenyl phenyl ketone [6- (3-amino (1H-indazol-5-yl)) pyridazin-3-yl ] {[(4fluorophenyl) cyclopropyl] methyl} amine

<img file="MX2012012259A_D0229.tif" />

426.2 D

426.2 D

375.3 A

-194 [2- (4-fluorophenyl) -2-methylpropyl] [6- (3-iodine (1Hindazol-5-yl)) pyridazin-3-yl] amine [2- (4-fluorophenyl) ) -2-methylpropyl] (6- (4-1,2,5,6-tetrahydropyridyl) pyridazin-3-yl) amine [2- (4-fluorophenyl) -2-methylpropyl] (6-pyrazol-310 ilpiridaz¡ n-3-yl) amine

1-acetyl-4- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) -1,2,5,6 tetrahydropyridine

Methyl 4- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) -1,2,5,6-tetrahydropyridinecarboxylate

4- (6 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} p-ridazin-3-yl) -1 (methylsulfonyl) -! 2,5,6-tetrahydropyridine

F

<img file="MX2012012259A_D0230.tif" />

F

-195 4- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} p¡ridazin-3-yl) -1,2,5,6 tetrahydropyridinecarboxamide

3- {6 - [(2-piperid¡lprop¡l) amino] p¡r¡daz¡n-3¡IJbenzamida [6- (3-amino (1H-indazol-5-yl)) p ¡Ridaz¡n-3-¡l] (2p¡perídilpropil) amina

3- {6 - [(1,2,3,4tetrahydronaphthylmetyl) amino] p¡r¡daz¡n-3yljbenzamide (tert-butoxy) -N- (2 - {[5- (6- {[2- (4-fluorophenyl) -2-methylpropyl] amino} prazida-3-l) (1H-indazol-3 · l)] amino} etl) carboxamida [2- (4-fluorophenyl) -2-methylpropyl] (6-paraphrolo [3,2b] p¡rid¡n-6-¡lp¡r¡daz¡n-3- L) am

<img file="MX2012012259A_D0231.tif" />

-196 [2- (4-fluorophenyl) -2-methylpropyl] (6-prazrazolo [5.4b] p¡rid¡n-5-¡lp¡ridaz¡n-3-¡l) amyna

5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) -3h¡drobenzoxazol-2-one [6- (3-amino (1H-indazol-5- L)) p¡r¡daz¡n-3-¡l] {[((2fluorophenyl) cyclopropyl] methyl} amine [6- (3-amino (1 H-ndazol-5-l)) pyridaz N-3-yl] {[(215 fluorophenyl) cyclobutyl] methyl} amine [6- (3-amino (1H-indazol-5-l)) pyridazin-3¡ l] [2,2-dfluoro-2- (4-fluorophenyl) etl] amine

3- [6- (¡ndan-2-ilam¡no) p¡r¡daz¡n-3¡IJbcnzamida

F

<img file="MX2012012259A_D0232.tif" />

- 197 3- {6 - [(indanylmethyl) amino] pyridazin-3yljbenzamide (6- {3 - [(2-aminoethyl) amino] (1H-indazol-5yl)} pyridazin-3-yl) [2- (4 -fluorophenyl) -2methylpropyljamine

- (6 - {[2- (4-fIuorophenyl) -2methylpropyl] amino} pyridazin-3-yl) ethan-1-one

4-fluoro-3- (6 - {[2- (4-fluorophenyl) -215 methylpropyl] amino} pyridazin-3-yl) benzamida

3- {6 - [((2S, 1R) -2phenylcyclopropyl) amino] pyridazIN-3yl} benzamide [2- (4-fluorophenyl) -2-methylpropyl] [6- (3-methyl (1Hindazol-6-yl)) pyridazin-3-yl] amine

<img file="MX2012012259A_D0233.tif" />

-198 [6- (3-amino (1H-indazol-5-l)) p¡ridaz¡n-3-¡l] {[(4fluorophenyl) cyclobutyl] metl } am¡na [6- (3-amino (1H-indazol-5-yl)) p¡r¡daz¡n-3-yl] {[(2fluorophenyl) cyclopentyl] metyl } am¡na [6- (3-amíno (1H-indazol-5-¡l)) p¡ridaz¡n-3-¡l] [2metíl-2- (2-met¡lfen¡ l) propyl] amine [6- (3-amino (1 H-indazol-5-i I)) pridazi η-3-yl] {[(4fluorophenyl) cyclhexyl] metyl amine [6- (3-amino (1H-indazol-5-yl)) p¡r¡daz¡n-3yl] [(phenyllclopropyl) methyl] amine [6- (3-amino (1H-ndazol-5-l)) p¡r¡daz¡n-3¡l] [(fen¡lc¡clobut¡l) rnetil] amine

<img file="MX2012012259A_D0234.tif" />

-199 [6- (3-amino (1 H-indazol-5-yl)) pyridazin-3¡l] [(2,2-dimethyl-1-phenyl-cyclopropyl) met! l] amína

5- (6 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} pyridazin-3-II) -1 H-indazol-3carbonitrile [6- (3-amino (1 H-indazol-5- L)) pyridazin-3-yl] {[(410 fluorophenyl!) Cyclopentyl] methyl} amine

5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} p¡r¡daz¡n-3-yl) -1H-indazol-3carboxamide [4- (2- {[6- (3-amino (1H-indazol-5-yl)) p¡ridazin3-il] amino} -terc-butyl) phenyl] methan-1-ol {[4 - (2 - {[6- (3-amino (1H-indazol-5-yl)) p¡ridazin3-yl] amino} -tei'c-butyl) phenyl] methyl} dimethylamine

<img file="MX2012012259A_D0235.tif" />

-200 [2- (4-fluorophenyl) -2-methylpropyl] [6- (3-vinyl (1 Hindazol-5-yl)) pyridazin-3-yl] amine [6- (3-etyl) 1H-indazol-5-yl)) pyridaz-3-yl] [2- (4fluorophenyl) -2-methylpropyl] amine

3- (6 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} pyridazin-3-yl) -1,2,4 oxadiazol-5-carboxamide [6- (3-amino (1H-indazol-5 -yl)) pyridazin-3-yl] [2 (3-fluoro (2-pyridyl)) - 2-methylpropyl] amine [6- (3-amino (1H-indazol-6-yl)) pyridaz N-3-yl] [2 (3-fluoro (2-pyridyl)) - 2-methylpropyl] amine [6- (3-amino (1H-ndazol-5-yl)) p¡r ¡Daz¡n-3-¡l] [2 (5-fluoro (2-pyridyl)) - 2-methylpropyl] amine

<img file="MX2012012259A_D0236.tif" />

-201 [6- (3-amino (1H-indazol-6-¡l)) p¡r¡daz¡n-3-¡l] [2 (5-fluoro (2-p¡r¡d L)) - 2-metpropyl] amine

- [5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} p¡r¡daz¡n-3-¡l) -1 H-indazol-3¡l] ethane-1,2-diol

2-amino-6- (6 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} p¡r¡dazin-3-¡l) -3h¡drop¡r¡m ¡D¡n-4-one

F

<img file="MX2012012259A_D0237.tif" />

N- [6- (2-amino-6-oxoh¡dropirim¡d¡n-4¡l) p¡ridaz¡n-3-¡l] (tert-butox¡) -N- [2- ( 4fluorofen¡l) -2-met¡lprop¡l] carboxam¡da

6- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} p¡r¡daz¡n-3-¡l) -3hydroquinazolin-4-one

<img file="MX2012012259A_D0238.tif" />

-202 [6- (3-amino (1 H-indazol-5-yl)) pyridazin-3-yl] (2-methyl-2- (1,3-oxazol-2-yl) propyl) amine

<img file="MX2012012259A_D0239.tif" />

Ethyl 2-fluoro-5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) benzoate

2-amino-6- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pridazin-3-yl) -3hydroquinazolin-4-one

<img file="MX2012012259A_D0240.tif" />

4- (2 - {[6- (3-amino (1H-indazol-5-yl)) pyridazine-3¡l] amino} -terc-butyl) benzenecarbonyltrile

<img file="MX2012012259A_D0241.tif" />

384.1 A

4- (2 - {[6- (3-amino (1 H-indazol-5-l)) p¡ridazin-3¡l] amino} -terc-butyl) benzamida

<img file="MX2012012259A_D0242.tif" />

402.2 D

-203 [6- (3-amino (1H-indazol-5-yl)) pyridazin-3-yl] {2 [4- (aminomethyl) phenyl] -2-methylpropyl} amine

5- (6 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} pyridazin-3-yl) -1H-indazol-3carboxamidine

2- [4- (2 - {[6- (3-amino (1 H-indazol-5yl)) pyridazin-3-yl] amino} -terc-butyl) phenyl] propan2-ol

<img file="MX2012012259A_D0243.tif" />

388,2

404,1

417.2 [3- (2 - {[6- (3-amino (1 H-indazol-5-yl)) pyridazin3-yl] amino} -terc-butyl) phenyl] methan-1-ol

<img file="MX2012012259A_D0244.tif" />

nh₂

389,2

2- [5- (6 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} pyridazin-3-yl) -1 H-indazol-3¡l] propan-2-ol

<img file="MX2012012259A_D0245.tif" />

F

-204

3- (6 - {[2- (3,5-Difluoro (2-pyridyl)) - 2-methylpropyl] amino} pyridazin-3-yl) benzamide [5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) -1H-indazol-3yl] methan-1-ol {[3- (2 - {[6- (3-amino (1 H-indazol-5-yl)) pyridazin3 -il] amino} -terc-butyl) phenyl] methyl} dimethyl amine

<img file="MX2012012259A_D0246.tif" />

3- (2 - {[6- (3-amino (1H-indazol-5-yl)) pyridazin-3yl] amino} -terc-butyl) benzenecarbonyltrile

3- (2 - {[6- (3-amino (1H-indazol-5-yl)) pyridazin-3yl] amino} -terc-butyl) benzamide

<img file="MX2012012259A_D0247.tif" />

NHj

-2052- [3- (2 - {[6- (3-amino (1 H-indazol-5yl)) p¡ridaz¡n-3-¡l] amino} -terc-butyl ) fen¡l] propan2-ol

<img file="MX2012012259A_D0248.tif" />

[6- (3-amino (1 H-ndazol-5-yl)) p¡r¡daz¡n-3-¡l] [2 (3,5-d¡f1uoro (2-p¡ r¡d¡l)) - 2-metllprop¡l] am¡na [6- (3-amíno (1H-indazol-5-¡l)) pyridazin-3-¡l] {[(3fluoro (2-p¡rid¡l)) cyclobutyl] methyl} amine

3- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amine) pyridaz-3yl] benzamida

N- [5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} p¡r¡daz¡n-3-¡l) -1H-indazol-320 il] acetamide [6- (3-aminoperazolo [5,4-b] pyridine-5¡l) p¡ridaz¡n-3-¡l] [2- (4-fluorophenyl) -2met¡lprop¡l] am¡na

<img file="MX2012012259A_D0249.tif" />

396.0 A

390.0 A

378.2 A

419.1 A

387.3 A

-206 [3- (2 - {[6- (3-amino (1H-indazol-5-yl)) pyridazin3-yl] amino} -terc-butyl) phenyl] -Nmethylcarboxamide [3- (2- { [6- (3-amino (1 H-indazol-5-yl)) p¡r¡daz¡n3-¡] amino} -terc-butyl) phen¡l] -N, Ndimethylcarboxamide [5- ( 6 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} pyridazin-3-yl) (1H-indazol-310 yl)] (methylsulfonyl) amine [2- (2 - {[6- (3-amino (1H-indazol-5-yl)) pyridazin3-yl] amino} -terc-butyl) phenyl] methan-1-ol [6- (3-amino (1H-indazol-5-¡ l)) p¡r¡daz¡n-3-¡l] {2 [3- (aminomethyl) phenyl] -2-methylpropyl} amine {[((4-fluorophenyl) cyclobutyl] methyl] [6- (2-methoxypyrimidine-5-yl) pyridazin-3-yl] amine

OR

<img file="MX2012012259A_D0250.tif" />

-2075- [6 - ({[(4f1uorophenyl) cyclobutyl] methyl} amino) pyridazin-3yl] -3-hydropyridemid-2-one

5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) -1H-indazol-7carboxamide [6- (3-amino (1H-indazol-5-¡ l)) pyridazin-3-yl] [2 (3-methoxyphenyl) -2-methylpropyl] amine [6- (3-amino (1H-indazol-5-yl)) pyridazin-3-yl] [215 methyl -2- (4-methylphenyl) propyl] amine

2- [3- (2 - {[6- (3-amino (1 H-indazol-5yl)) pyridazin-3-yl] amino} -terc-butyl) phenyl] ethan-1ol [6- (3- amino (1H-indazol-5-yl)) pyridazin-3-yl] {[(5-fluoro (2-pyridyl)) cyclobutyl] methyl} amine

<img file="MX2012012259A_D0251.tif" />

-2083- [6 - ({[(5-fluoro-2pir¡d¡l) cyclobutyl] methyl} amino) pyridazin-3¡l] benzamida (tert-butoxy) - N- [6- (2,3-dxoxo (1,4d¡h¡droqu¡noxal¡n-6-¡l)) p¡r¡dazin-3-yl] -N- [2- (4fluorophen L) -2-methylpropyl] carboxamida {2- [3- (2 - {[6- (3-amino (1H-indazol-5¡l)) p¡ridaz¡n-3-¡ l] amino} -tercbutyl) phenyl] ethyl} dimethylamine

3- (2 - {[6- (3-amino (1H-indazol-5-yl)) p¡ridaz¡n-3 · l] amino} -terc-butyl) phenol

<img file="MX2012012259A_D0252.tif" />

<img file="MX2012012259A_D0253.tif" />

NH,

6- (6 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} pyridaz-3-yl) -1,420 d¡h¡droqu¡noxalina-2,3-d¡ona [6 - (3-amino (1 H-indazol-5-i I)) p¡rídaz¡n-3-¡l] {2 [2- (methoxymethyl) phenyl] -2-methylpropyl} amine

<img file="MX2012012259A_D0254.tif" />

-2093- (6 - {(tert-butoxy) -N- [2- (3-fluoro (2-p¡rid¡l)) - 2 · metpropyl] carbon¡lam¡no} p¡ r¡daz¡n-3¡l) benzam¡da (tert-butox¡) -N- [2- (3-fluoro (2-p¡r¡d¡l)) - 2met¡lprop¡l] -N - [6- (2-hdrox¡benzo¡m¡dazol-5¡l) p¡ridazin-3-¡l] carboxam¡da

5- (6 - {[2- (3-fluoro (2-p¡r¡dil)) - 2met¡lprop¡l] amño} p¡r¡daz¡n-3il) benzo¡m¡dazol- 2-ol (6- (1 H-indazol-5-l) p¡ridaz¡n-3-¡l) [2- (3fluoro (2-p¡rid¡l)) - 2-metllprop L] am¡na

<img file="MX2012012259A_D0255.tif" />

N- [6- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} p¡r¡daz¡n-3¡l) benzo¡m¡dazol-2- L] acetam¡da

<img file="MX2012012259A_D0256.tif" />

419.1 A

6- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} p¡ridaz¡n-3-yl} -1,3d¡h¡droqu¡nazol¡n- 2,4-day

<img file="MX2012012259A_D0257.tif" />

-210

4- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3yljbenzamide ³ 4-fluoro-3- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yljbenzamide (6- (1H-indazol-5-yl) pyridazin-3 -il) {[(3-fluoro (210 pyridyl)) cyclobutyl] methyl} amine

2- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-l) pyridin-4carboxamide

6- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) pyridin-2carboxamide

<img file="MX2012012259A_D0258.tif" />

378.0 B

396.2 A

375.0 A

366.0 A

366.1 B

-211

3- (6 - {(tert-butoxy) -N- [2- (4-fluorophenyl) -2methylpropyl] carbonyllamino} p¡r¡daz¡n-3¡l) benzamida

3- (6 - {(tert-butoxy) -N- [2- (4-fluorophenyl) -2methylpropyl] carbonyllamine} p¡r¡dazin-3-yl) -4fluorobenzamide (6 - (1H-¡ndazol-6-¡l) p¡ridaz¡n-3-¡l) {[(3-fluoro (2p¡r¡d¡l)) c¡clobut¡l] met¡l} am ¡A (6- (1H-¡dazol-6-¡l) p¡ridaz¡n-3-¡l) {[((6-methox¡ (2p¡ridil)) cyclobutyl] met¡l} am ¡Na (6- (1H-indazol-5-l) p¡ridaz¡n-3-yl) {[(6-methox¡ (2p¡r¡d¡l)) cyclobutyl] methyl} am ¡Na

<img file="MX2012012259A_D0259.tif" />

-2124-fluoro-3- [6 - ({[(6-methoxy (2pyridyl)) cyclobutyl] methyl} amino) pyridazn-3yljbenzamide

4-ftuoro-3- (6 - {[(2pyridylcyclobutyl) methyl] amino} pyridazin-3yl) benzamide

F

<img file="MX2012012259A_D0260.tif" />

(6- (1H-indazol-5-yl) pyridazin-3-yl) [(2pyridylcyclobutyl) methyl] amine (6- (1H-indazol-6-yl) pyridazin-3-yl) [(2pyridylcyclobutyl) methyl] amine

<img file="MX2012012259A_D0261.tif" />

357,2

357.2 A

2- fluoro-3- [6 - ({[(3-fluoro (215 pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yljbenzamide

3- fluoro-4- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] benzamide 2-fluoro-4- (6 - {[2- (4- fluorophenyl) -2methylpropyl] amine} pyridazin-3-yl) benzoyl

<img file="MX2012012259A_D0262.tif" />

396.0 B

396.0 B

<img file="MX2012012259A_D0263.tif" />

384.1 D

-2133-amino-5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} p¡r¡daz¡n-3-¡l) -1 H¡ndazolcarboxllato methyl

5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} p¡r¡daz¡n-3-¡l) -3 (methoxycarbonyllamine) -1H- Ndazolcarbox, methyl tin

N- [5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} p¡r¡daz¡n-3-¡l) (1H-indazol-3 ¡L)] methoxycarboxamida [3-amino-5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} p¡r¡daz¡n -3-¡l) (1 H15 ¡ndazol¡l)] - N, Nd¡met¡lcarboxam¡da

6 - ({[(6- (1H-indazol-5-l) pyridazin-3l) amino] methyl} cyclobutyl) pyridin-2-ol

6 - ({[(6- (1H-¡ndazol-6-¡l) p¡ridaz¡n-3il) amino] metíl} c¡clobutíl) p¡rid¡n-2-ol

OR-

<img file="MX2012012259A_D0264.tif" />

-2144-fluoro-3- [6 - ({[(6-hydroxy (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] benzamide

2 - ({[(6- (1 H-indazol-5-l) p¡r¡daz¡n-3yl) amino] methyl} cyclobutit) pyridin-4-ol

4-fluoro-3- [6 - ({[(4-methoxy (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] benzamide (6- (1H-indazol-5-yl) p¡ridaz N-3-yl) {[(4-methoxy! (2-pyridyl)) cyclobutyl] methyl} amine (6- (1H-indazol-6-yl) pyridazin-3-ylX [(4-methoxy ( 2pyridyl)) cyclobutyl] methyl} amine

2 - ({[(6- (1H-indazol-6-yl) pyridazin-3yl) amino] methyl} cyclobutyl) pyridin-4-ol

4-fluoro-3- [6 - ({[(4-hydroxy! (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3¡l] benzamida

F

<img file="MX2012012259A_D0265.tif" />

NH₂

HO '

- 215 5- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -3hydrobenzoimidazol-2-one {[(3-fluoro (2-pyridyl) ) cyclobutyl] methyl} (6-pyrazol4-ylpyridazin-3-yl) amine {[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} [6- (1θ-methylprazol-4- yl) pyridazin-3-yl] amine

6- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) -3,3dimethylindolin-2-one

<img file="MX2012012259A_D0266.tif" />

2-amino-7- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) -3hydroquinazolin-4-one

<img file="MX2012012259A_D0267.tif" />

405.1 C

3- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] metii} amino) pyridazine-3yl] benzenesulfonamide

F

<img file="MX2012012259A_D0268.tif" />

414.4 A

-216 {4- [6 - ({[(3-fluoro (2p¡r¡dil)) cyclobutyl] methyl} amino) pyridazn-3¡l] fenü} (met¡lsulfon¡l) amine {3- [6 - ({[(3-fluoro (2p¡r¡dil)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} (methylsulfonyl) amine

<img file="MX2012012259A_D0269.tif" />

3- {6 - [(2-methyl-2-pyrimidin-210 ylpropyl) amino] pyridazin-3-yl} benzamide

4- fluoro-3- [6 - ({[(3-methoxy (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] benzamide

<img file="MX2012012259A_D0270.tif" />

(6- (1 H-indazol-5-yl) pyridazine-3-yl) {[(3-methoxy¡ (2 · p¡r¡dil)) cyclobutyl] methyl} amine

<img file="MX2012012259A_D0271.tif" />

387.2 B ²θ (6- (1 H-ndazol-6-l) pi ridazin-3-yl) {[(3-methoxy (2pyridyl)) cyclobutyl] methyl} amine

<img file="MX2012012259A_D0272.tif" />

387.1 B

-2174-fluoro-3- [6 - ({[(5-methox¡ (2pir¡dil)) cyclobutyl] methyl} amino) pyridazin-3yljbenzamide (6- (1H-indazol-5-yl ) pyridazin-3-yl) {[(5-methoxy (2pyridyl)) cyclobutyl] methyl} amine

<img file="MX2012012259A_D0273.tif" />

(6- (1H-indazol-6-yl) pyridazin-3-yl) {[(5-methoxy (2 pyridyl)) cyclobutyl] methyl} amine

<img file="MX2012012259A_D0274.tif" />

<td colspan="2">&gt; - z</td>

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

387.2 B

3 - {[(6- (1H-indazol-6-l) p¡ridazin-3¡l) amino] metíl} -3- (2-p¡rid¡l) cyclobutan- 1-ol

3 - {[(6- (1H-indazol-6-yl) pyridazin-3yl) amino] methyl} -3- (2-pyridyl) cyclobutan-1-ol

3- [6 - ({[(4fluorophenyl) cyclobutyl] methyl} amino) pyridazin-3yljbenzamide

<img file="MX2012012259A_D0275.tif" />

F

373.1 D

373.2 D

377.3 A

-2183- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) p¡r¡dazin-3-¡l] -4methylbenzamide

<img file="MX2012012259A_D0276.tif" />

6 - ({[(6- (1H-¡ndazol-5-yl) p¡r¡daz¡n-3¡l) amno] metíl} c¡clobutíl) p¡rid¡n- 3-carbonyltrile

<img file="MX2012012259A_D0277.tif" />

382.2 B

1Q 6- [6 - ({[(3-fluoro (2p¡r¡d¡l)) cyclobutyl] methyl} amino) p¡r¡daz¡n-3-¡l] 3,3- d¡met¡l¡ndol¡n-2-one

3- [6 - ({[(4-cyano-2pyr¡d¡l) cyclobutyl] methyl} amino) p¡ridaz¡n-3¡IJbenzamida

2- [({[6- (3-carbamoylphenyl) p¡r¡daz¡n-3il] amine} methyl) cyclobutyl] pyridine-4-carboxamide

3- [6 - ({[(4-cyano (2p¡r¡d¡l)) cyclobutyl] methyl} amino) p¡ridaz¡n-3-¡l] -4fluorobenzamide

<img file="MX2012012259A_D0278.tif" />

-2192 - [({[6- (3-carbamoyl-6-fluorophenyl) pyridazin-3¡l] amino} methyl) cyclobutyl] pyridin-4-carboxamida

2 - ({[(6- (1 H-indazol-5-yl) pyridazin-3yl) amino] methyl} cyclobutyl) pyridin-4-carbonitrile

2 - ({[(6- (1H-indazol-5-yl) pyridazin-3yl) amino] methyl} cyclobutyl) pyridin-4-carboxamide

<img file="MX2012012259A_D0279.tif" />

3- [6 - ({[(6-cyano-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3yljbenzamide

6 - [({[6- (3-carbamo¡lfen¡l) p¡r¡daz¡n-3il] amino} methyl) cyclobutyl] pyridin-2-carboxamide

6 - ({[(6- (1 H-indazol-5-yl) pyridazin-3yl) amino] methyl} cyclobutyl) pyridin-2-carbonitrile

<img file="MX2012012259A_D0280.tif" />

385,1

403,2

382,1

-2206 - ({[(6- (1H-indazol-5-yl) pyridaz-3-yl) amino] methyl} cyclobutyl) pyridin-2-carboxamide (6- (1H-indazol-6 -yl) pyridazin-3-yl) {[(4fluorophenyl) cyclobutyl] methyl} amine (6- (1 H-indazol-5-yl) pyridazin-3-yl) {[(410 fluorophenyl) cyclobutyl] methyl }amine

4-fluoro-3- [6 - ({[(1-methyl-6-oxo (2hydropyridyl)) cyclobutyl] methyl} amino) pyridazin-3yljbenzamide

3- (6 - {[(2-pyridylcyclobutyl) methyl] amino} pyridazin3-yl) benzamide ({[(6- (1H-indazol-5-yl) pyridazin-320 yl) amino] methyl} cyclobutyl) methane -1-ol 1 - ({[6- (3-cyanophenyl) pyridazin-3yl] amino} methyl) cyclobutane carboxylic acid

<img file="MX2012012259A_D0281.tif" />

-221 1 - ({[6- (3-carbamoylphenyl) pyridazin-3yl] amino} methyl) cyclobutane carboxylic acid ³ 1 - ({[6- (3-cyanopheni I) pyridazi n-3yl] amino} methyl) cyclobutanecarboxamide

3- (6 {[(carbamoilciclobut¡l) met¡l] amíno} pindaz¡n-3 ·

1Q l) benzamida

Methyl 3- (3-fluoro (2-pyridyl)) - 3 - {[((6- (1 H-indazol-5yl) pyridazin-3¡l) amino] methyl} azetidincarboxylate

Methyl 3 - ({[6- (3-carbamoylphenyl) pyridazin-3yl] amino} methyl) -3- (3-fluoro (2pyridyl)) azetidinecarboxylate ²⁰ {[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} {6- [3 (methylamine) (1H-indazol-5-l)] pyridazin-3yl} amine

<img file="MX2012012259A_D0282.tif" />

-222 2-fluoro-5- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] benzoic {2-fluoro-5- [6- ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) p¡r¡daz¡n-3il] phenyl} -N-methylcarboxamida

N- {5- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1 Hindazol-3-yl} acetamide

2- amino-N- {5- [6 - ({[(3-fluoro (215 pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1 H-indazol-3-yl)} acetamide {5 - [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1H-indazol-3-yl)} (methylsulfonyl) amine

3- amino-5- [6 - ({[(3-fluoro (2p¡r¡d¡l)) cyclobutyl] methyl} amino) p¡ridazin-3-yl] 1 H-indazolcarboxamide

<img file="MX2012012259A_D0283.tif" />

-223 [6- (3-amynophenyl) p¡r¡daz¡n-3-¡l] {[((3-fluoro (2p¡r¡dil)) cyclobutyl] methyl} amine [6- (4-amynophenyl) pyridazin-3-yl] {[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amine (6- {3 - [(2-amynoetyl) am No] (1H-ndazol-5yl)} pyridazin-3-yl) {[(3-fluoro (210 pyridyl)) cyclobutyl] methyl} amine amino {3- [6 - ({[(3 -fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} carboxannidine amino {4- [6 - ({[(3-fluoro (2p¡r¡d¡l)) cyclobutyl] methyl! } amino) p¡r¡dazin-3yl] phenyl} carboxamidine

3- (6 - {[(pyrazin-220 ylcyclobutyl) methyl] amino} pyridazin-3¡l) benzamida

<img file="MX2012012259A_D0284.tif" />

nh₂ (6- (1H-indazol-6-yl) pyridazin-3-yl) [(pyrazin-2 · ylcyclobutyl) methyl] amine

<img file="MX2012012259A_D0285.tif" />

<img file="MX2012012259A_D0286.tif" />

358.3 C

-22410 (6- (1 H-indazol-5-yl) pyridazin-3-yl) [(pyrazin-2ylcyclobutyl) methyl] amine amino-N- {3- [6 - ({[(3-fluoro (2pyridyl )) cyclob &lt;jtil] methyl} amino) pyridazin-3¡l] phenyl} amide 5- [6 - ({[((3-fluoro-2piridil) cyclobutyl] methyl} amino) pyridazin-3il] benzene -1,3-dicarboxylic

5- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl] amino) pyridazin-3yl] benzene-1,3-dicarboxamide

3- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3yljbenzenecarboxamidine

3- [6 - ({[1-acetyl-3- (3-fluoro (2-pyridyl)) azetidin-3yl] methyl} amino) pyridazin-3-yl] benzamide

<img file="MX2012012259A_D0287.tif" />

<img file="MX2012012259A_D0288.tif" />

358.3 C

393,2

423,2

421,2

377,2

421,2

-2251-acetyl-3- (3-fluoro (2-p¡rid¡l)) - 3 - {[(6- (1Hindazol-5-¡l) p¡ridaz¡n-3¡l) am ¡No] met¡l} azet¡d¡na (6- (1H-indazol-5-¡l) p¡ridaz¡n-3-¡l) {[3- (3fluoro (2-p¡rid¡ l)) azet¡d¡n-3-¡l] met¡l} am¡na

3- [6 - ({[3- (3-fluoro-2-p¡ridil) azet¡d¡n-310 il] metíl} amino) p¡r¡daz¡n-3-¡l ] benzamida

3- (3-fluoro (2-p¡r¡d¡l)) - 3 - {[(6- (1H-indazol-5 · il) p¡ridaz¡n-3-¡l) amino] methyl} -1 (methylsulfonyl) azetidine

3- [6 - ({[3- (3-fluoro (2-p¡r¡d¡l)) - 1 (met¡lsulfon¡l) azet¡d¡n-3¡l] methyl} amino ) p¡r¡daz¡n-3-¡l] benzam¡da (6- (1 H-¡dazol-5-¡l) p¡ridazin-3-¡l) {[3- (3fluoro (2- p¡ridil)) azet¡din-3¡l] metíl} (metilsulfon¡l) amine

<img file="MX2012012259A_D0289.tif" />

-226am¡no {5- [6 - ({[(3-fluoro (2pir¡d¡l)) c¡clobut¡l] met¡i} amino) p¡r¡daz¡n-3¡l ] (1H-¡ndazol-3-yl)} carboxam¡d¡na

3- [6 - ({[3- (4-fluorophenyl) oxetane-3¡l] methyl} amino) p¡r¡daz¡n-3-¡l] benzam¡da [2- (4-fIuorofen ¡L) -2-met¡lprop¡l] (6- {310 [(met¡let¡l) amino) (1 H-ndazol-5-¡l)} p¡ridaz¡n-3¡ l) amína [6- (2-am¡nopirim¡d¡n-5-¡l) piridaz¡n-3-¡l] [2- (4fluorofen¡l) -2-met¡lprop¡l] amına [2- (4-fluorophenyl) -2-methylpropyl] {6- [3 (methylamine) (1H-indazol-5-yl)] p¡r¡daz¡n-3 ¡IJamina [2- (4-fluorophenyl) -2-metylpropyl] [6- (2methoxypyrrmmdn-5-l) pyridazine-3-l] am ¡Na

<img file="MX2012012259A_D0290.tif" />

-227 [2- (4-f1uorophenyl) -2-methylpropyl] [6- (2-methoxy¡ (3p¡r¡d¡l)) pyridaz¡n-3-¡l] am¡na

<img file="MX2012012259A_D0291.tif" />

{6- [3- (ethylamino) (1H-indazol-5-yl)] pyridazin-3yl} [2- (4-fluorophenyl) -2-methylpropyl] amine [2- (4 -fluorophenyl) -2-metylpropyl] (6fenlpridaz-3-l) amine

5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} pyridazine-3-yl) h¡drop¡r¡d¡n-2 [6- ( 2-amino (4-p¡rid¡l)) p¡ridaz¡n-3-¡l] [2- (4fluorophenyl) -2-methylpropyl] amyna [6- (4-aminophenyl) p¡r¡daz¡n-3-¡l] [2- (4fluorophenyl) -2-metpropyl] am¡na

F

<img file="MX2012012259A_D0292.tif" />

-228 [6- (3-amynophenyl) p¡r¡daz¡n-3-¡l] [2- (4fluorophenyl) -2-methylpropyl] amine

3- (6 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} pyridazin-3-yl) pyridin-2-ol

5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} p¡r¡daz¡n-3-¡l) -3h¡drop¡rim¡d¡n-2 -ona

5- (6 - {[2- (4-fluorophenyl) -215 methyl propyl] amino} p¡ridazin-3-yl) -1,3,4 oxadiazolin-2-one [6- (6-amino (3-pyridyl)) pyridazin-3-yl] [2- (4fluorophenyl) -2-methylpropyl] amine

<img file="MX2012012259A_D0293.tif" />

[2- (4-fluorophenyl) -2-methylpropyl] (6vinylpyridazin-3-l) amine

272,0

-22910 [6- (5-aminopyrazol-3-yl) pyridazine-3-yl] [2- (4fluorophenyl) -2-methylpropyl] amine [2- (4- fluorophenyl) -2-methylpropyl] [6- (6-methoxy¡ (2p¡rid¡l)) p¡r¡dazin-3-¡l] amine

N- [4- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} p¡r¡daz¡n-3-yl) midazol-2¡l] acetam gives

5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} p¡ridaz¡n-3-¡l) p¡r¡d¡n-215 carbonitrile [6- ( 2-aminoimidazole-4-yl) pyridazine-3-yl] [2- (4fluorophenyl) -2-methylpropyl] amine

H, N

5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazine-3-l) p¡r¡d¡n-2carboxamide

<img file="MX2012012259A_D0294.tif" />

, N NN _r

X - //

<img file="MX2012012259A_D0295.tif" />

NN r-

<img file="MX2012012259A_D0296.tif" />

<img file="MX2012012259A_D0297.tif" />

327.2 B

353.1 A

369.2 C

348.0 C

327.2 B

366.1 B

-2306- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) pyridin-2-ol {6- [6- (aminomethyl) (3-pyridyl)] pyridaz-3-yl} [2 (4-fluorophenyl) -2-methylpropyl] amine [2- (4-fluorophenyl) -2-methylpropyl] [6- (2-fluorophenyl) pyridazin-3-yl] amine [ 2- (4-fluorophenyl) -2-methylpropyl] [6- (3fluorophenyl) pyridazin-3-yl] amine [2- (4-fluorophenyl) -2-methylpropyl] [6- (4fluorophenyl) pyridazin- 3-l] amine

HO

<img file="MX2012012259A_D0298.tif" />

-231 [6- (2-chlorophenyl) ptridaz¡n-3-¡l] [2- (4-f1uorofen¡l) 2-metllprop¡l] am¡na

<img file="MX2012012259A_D0299.tif" />

356.1 A [6- (3-chlorophenyl) pyridazin-3-yl] [2- (4-fluorophenyl) 2-methylpropyl] amine

<img file="MX2012012259A_D0300.tif" />

356.1 A [6- (4-chlorophenyl) pyridazin-3-yl] [2- (4-fluorophenyl) 2-methylpropyl] amine

4- (6 - {[2- (4-fluorophenyl) -215 methylpropyl] amine} p¡r¡dazin-3¡l) benzenecarbonitrile [2- (4-fluorophenyl) - 2-metylpropyl] (6- (3pir¡d¡l) p¡r¡daz¡n-3-il) am¡na [6- (6-amino (2-p¡rid¡l)) pyridazine-3-yl] [2- (4fluorophenyl) -2-methylpropyl] amine

<img file="MX2012012259A_D0301.tif" />

-232N - {[5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazine-3-yl) -2pyridyl] methyl} acetamide

N - {[5- (6 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} p¡r¡dazin-3-yl) (2pyridyl)] methyl} methoxycarboxamide {6- [3- (et¡lam¡no) (1 H-indazol-5-¡l)] p¡r¡daz¡n-3ilX [(3-fluoro (2-p¡ridil)) cyclobut¡ l] methyl} amine

3- (6 - {[2-methyl-2 (phen¡lmetox¡) prop¡l] amino} p¡r¡daz¡n-3il) benzamide

3- (6 - {[2-methyl-2 (phenylmethoxy!) Propyl] amino} pyridazin-3yl) benzenecarbonyl [2- (4-fluorophenyl) -2-methylpropyl] (6- (2p¡ r¡dÍI) pyr¡dazin-3-yl) amine

N- {4- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3!] Imidazol-2-yl} acetamide

<img file="MX2012012259A_D0302.tif" />

-233 [6- (2-aminoimidazol-4-yl) pyridazin-3-yl] {[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} amine {[(3-fluoro (2-pyridyl)) cyclobutyl ] methyl} (6- {3 [(m eti leti I) ami no] (1 H-indazol-5-yl)} pyridazin-3yl) amine {6- [3- (ethylamino) (1 H-indazol- 5-l)] pyridazine-310 l} [(2-pyridylchlorylbutyl) methyl] amine [6 - ((1 E) prop-1-enyl) pyridazin-3 -il] [2- (4fluorophenyl) -2-methylpropyl] amine

<img file="MX2012012259A_D0303.tif" />

340.1 D

432.2 A

400.2 A

286.0 B [2- (4-fluorophenyl) -2-methylpropyl] [6- (2-methylprop1 -enyl) pyridazin-3-yl] amine

<img file="MX2012012259A_D0304.tif" />

300.0 B [2- (4-fluorophenyl) -2-methylpropyl] [6- (2-methylpropyl) pyridazin-3-yl] amine

<img file="MX2012012259A_D0305.tif" />

302.0 B

Ethyl -2343- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazn-3-yl) propanoate

6- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) pyridin-3carboxamide (6-ethylpyridazin-3-yl) [2- (4-fluorophenyl) -2methylpropyl] amine [ 3- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pyridazin-3-yl) phenyl] methan-115 ol (tert-butoxy) -N - {[3- (6 - {[2- (4-fl uoropheni I) -2methylpropyl] amino} pyridazin-3yl) phenyl] methyl} carboxamide {6- [3- (aminomethyl) phenyl] pyridazin-3-yl} [2- (4fluorophenyl) -2-methylpropyl] amine

F

<img file="MX2012012259A_D0306.tif" />

-235 {[(3-fluoro (2-pyridyl)) cyclobutyl] methylX6- [2 (tr¡fluoromethoxy!) Fen¡l] pyridazin-3-yl} amine {2- [6 - ({[(3 -fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3¡l] phenyl} methan-1-ol [2- (4-fluorophenyl) -2-methylpropyl] [6- (5-methoxy! (2pyridyl) ) pyridazine-3-yl] amine

<img file="MX2012012259A_D0307.tif" />

6- (6 - {[2- (4-fluorophenyl) -215 methylpropyl] amino} pyridazin-3-l) pyridin-3-ol [6- (5-amino (2-pyridyl)) pyridazin -3-yl] {[(3f1uoro (2-pyridyl)) cyclobutyl] methyl} amine [2- (4-fluorophenyl) -2-methylpropy]] ] (1 H-indazol-5-yl)} pyridazin3-yl) amine

<img file="MX2012012259A_D0308.tif" />

-236 [6- (6-amino (3-p¡ridil)) p¡ridaz¡n-3-¡l] {[(3fluoro (2-p¡ridil)) cyclobutyl] met¡ l} amine [6- (4-amino-3-fluorophenyl) pyridaz-3-yl] {[(3fluoro (2-pyridyl)) cyclobutyl] methyl} amine (6-benzotriazol-6-ylp¡r¡daz¡n-3-l)) [[(3-fluoro (2 · 10 pyridyl)) cyclobutyl] methyl} amine

4- [6 - ({[(3-fluoro-2pyridl) cyclobutyl] methyl} amino) pyridaz-3yl] ndolin-2-one (6-benzoimidazole- 5-ilpiridaz¡n-3-¡l) {[(3fluoro (2-p¡rid¡l)) c¡clobut¡l] met¡l} ain¡na

N- {3- [6 - ({[(3-fluoro-220 pyridyl) cyclobutyl] methyl} amine) pyridazin-3¡l] phenyl} acetamide {[(3 -fluoro (2-pyridyl)) cyclobutyl] metyl] [6- (4morpholyn-4-ilphenyl) pyridazin-3-yl] amine

<img file="MX2012012259A_D0309.tif" />

-23710 {[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} [6- (2-methylpyrimidin-5-yl) pyridazin-3-yl] amine [5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amine} p¡r¡daz¡n-3-yl) (1H-indazol-3¡l)] dimethylamine [2 - (4-fluorophenyl) -2-methylpropyl] [6- (3 - {[2 (phenylmethoxy!) Et] l] amino} (1H-indazol-5¡l)) pyridazine- 3-yl] amine

2 - {[5- (6 - {[2- (4-fluorophenyl) -2methylpropyl] amino} pridazin-3-yl) -1H-indazol-3¡l] am¡ no} etan-1-ol {[(3-fluoro (2-p¡r¡d¡l)) c¡clobut¡l] met¡l} (6pir¡mid¡n-2-¡lp¡ridazin-3 -il) am¡na {[(3-fluoro (2-p¡rid¡l)) cyclobutyl] met¡l} (6-p¡razin2-ilpiridazin-3-il) amína

<img file="MX2012012259A_D0310.tif" />

351.2 D

405.2 B

511.2 A

421.2 A

337.0 B

337.0 B

-2386 - ({[(3-fluoro-2p¡r¡dil) cyclobutyl] methyl} amino) p¡ridaz¡n-3-ethylcarboxylate

2- [6 - ({[(3-fluoro-2p¡r¡d¡l) c¡clobut¡l] met¡l} amino) p¡ridaz¡n-3¡l] propan-2-ol {[ (3-fluoro (2-p¡rid¡l)) cyclobutyl] metíl} (610 fen¡lpiridaz¡n-3-il) amína {[(3-fluoro (2-p¡rid¡ l)) cyclobutyl] methyl} (6v¡n¡lp¡ridaz¡n-3-¡l) am¡na (6-et¡lp¡ridaz¡n-3-yl) {[(3-fluoro ( 2p¡r¡d¡l)) c¡clobut¡l] met¡l} am¡na

N- {4- [6 - ({[(3-fluoro-220 p¡r¡d¡l) c¡clobutíl] met¡l} amino) p¡ridaz¡n-3¡l] fen¡l } acetamide [6- (2-am¡nop¡rim¡d¡n-5-¡l) p¡ridazin-3-il] {[((3 · fluoro (2-pyridyl)) cyclobutyl ] met¡l} am¡na

<img file="MX2012012259A_D0311.tif" />

-239N- {5- [6 - ({[(3-fluoro-2pir¡d¡l) cyclobutyl] met¡l} amino) pir¡daz¡n-3il] pirim¡din-2 -il} acetamide

N- {5- [6 - ({[(3-fluoro (2p¡r¡dil)) c¡clobut¡l] met¡l} amino) p¡r¡daz¡n-3¡l] p ¡Rim¡d¡n-2-¡l} metox¡carboxam¡da

1q {[((3-fluoro (2-p¡rid¡l)) cyclobutyl] metíl} [6- (5metox¡ (2-p¡r¡d¡l)) p¡r¡daz¡n -3-l] am¡na

6- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3¡l] p¡rid¡n-3-ol {5- [6 - ({[(3-fluoro ( 2p¡ridil)) cyclobutyl] methyl} amino) p¡r¡dazin-3¡l] p¡rim¡d¡n-2-¡l} (met¡lsulfon¡l) amine [6 - (2,3-d¡fluorofen¡l) p¡ridaz¡n-3-¡l] {[((3-fluoro (2 p¡r¡d¡l)) cyclobutyl] metíl} am¡ na

<img file="MX2012012259A_D0312.tif" />

-240 {[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} [6- (3fluoro (2-pyridyl)) pyridazin-3-yl] amine

3- {6 - [(1-methyl-1-phenylethyl) amino] pyridazin-3¡l} benzamide

5- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-310 yl] indolin-2-one

5- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1 H

2-hydroindazole-3-one

N- {3- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} (methylamino) carboxamide

N- {4- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} (methylamino) carboxyamide

4- {5- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3yl] pyrimidin-2-yl} tert-25 butyl piperazinecarboxylate

<img file="MX2012012259A_D0313.tif" />

-241 2 - ({5- [6 - ({[(3-fluoro-2p¡r¡d¡l) cyclobutyl] metíl} amino) p¡ridaz¡n-3¡l] pirim ¡D¡n-2-¡l} amino) acetam¡da

<img file="MX2012012259A_D0314.tif" />

{6- [2- (am¡nomet¡l) -5-fluorophen¡l] p¡ridaz¡n-3¡IX [(3-fluoro (2-pyridyl)) cyclobutyl] met¡ l} amína {6- [2- (amínometil) fen¡l] p¡ridaz¡n-3-¡IX ((3fluoro (2-p¡rid¡l)) cyclobutyl] methyl } amine {6- [4- (amiomethyl) phenyl] pyridaz-3-l}} [[(3fluoro (2-pyridyl)) cyclobutyl] methyl} amine { [(3-fluoro (2-p¡r¡d¡l)) cyclobutyl] met¡l} [6- (2piperaz¡n¡lp¡rim¡d¡n-5-¡l) p¡r¡ daz¡n-3-¡l] am¡na (6- (1H-indazol-6-¡l) p¡ridaz¡n-3-¡l) (2,2-dfluoro

2- (2-p¡rid¡l) et¡l) am¡na

409.1 C

<img file="MX2012012259A_D0315.tif" />

421.2 D

<img file="MX2012012259A_D0316.tif" />

-2423- {6 - [(2,2-difluoro-2- (2p¡r¡d¡l) et¡l) amino] p¡r¡daz¡n-3-¡l} benzam¡da

356.1 D [6- (3-chloro (2-p¡ridil)) p¡ridaz¡n-3-yl] {[(3-fluoro (2p¡ridil)) cyclobutyl] met L} am¡na

6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridaz-310 carbonitrile

1- [6 - ({[(3-fluoro-2p¡r¡d¡l) c¡clobut¡l] met¡l} amino) p¡ridaz¡n-3il] ethan-1 -one {[ (3-fluoro (2-pyridyl)) cyclobutyl] methyl} [6- (2methyl (3-p¡r¡dil)) p¡ridaz¡n-3-¡l] am¡na

3- [6 - ({[(3-fluoro-22Q p¡r¡dil) cyclobutyl] methyl} amino) p¡ridaz¡n-3¡l] p¡ridin-2-carbonítrilo

370.1 C

284.0 D

301.1 D

350.2 C

361.1 C

3- [6 - ({[(3-fluoro-2p¡r¡d¡l) c¡clobut¡l] met¡l} amino) p¡ridaz¡n-3¡l] p¡rid¡n -2-carboxamida

F

<img file="MX2012012259A_D0317.tif" />

379.2 C

-2433- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3l] methyl pyridine-2-carboxylate

2- {3- [6 - ({[(3-fluoro-2p¡r¡dil) c¡clobut¡l] metíl} amino) p¡ridaz¡n-3-il] -2p¡rid L} Propan-2-ol amino-N- {4- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} amide

2- amine-2- {3- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} acetamide {[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} (6p¡ridaz¡n-4-¡lpiridazin-3-¡l) am¡na

3- [6 - ({[3,3-dfluoro-1- (3-fluoro (220 pyridyl)) cyclobutyl] methyl} amino) pyridazin-3l] benzamide (6- (1H-indazol-5- yl) pyridazin-3-yl) {[3,3-difluoro1- (3-fluoro (2-p¡r¡dil)) cyclobutyl] methyl} amine

<img file="MX2012012259A_D0318.tif" />

F

-2445- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2 (methylethyl) -1H-2-hydroindazol-3-one

5- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -1 (methylethyl) -1H-2-hydroindazol-3-one

3- {6 - [(1-methyl-1-phenylethyl) amino] pyridazin-3θ yljbenzenecarbonitrile

3- {6 - [(tert-butyl) amino] pyridazin-3yljbenzamide

3- [6- (Phenylcarbonylamino) pyridazin-3yl] benzamide {[(3-f1uoro (2-pyril)) cyclobutyl] methyl} (6- (2pyridyl) pyridazin-3-yl )amine

3- {6 - [(1-methyl-1- (2-pyridyl) et¡l) amino] pyridazin3-yl} benzamide

<img file="MX2012012259A_D0319.tif" />

nh₂

-245 {3- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-¡l] -2p¡r¡d¡l} mettan-1-ol

3- (6 - {[(4-fluorophenyl) cyclobutyl] amino} pyridazn3-yl) benzamide (6- (1H-indazol-5-yl) pyridazin-3-y l) [(4fluorophenyl) cyclobutyl] amine

4- {6 - [(1-methyl-1-phenylethyl) amino] pyridazin-3¡l} benzamida (6- (1H-indazol-5-l) pyridazin-3 -¡L) (1-methyl-1phenylethyl) amine [6- (6-amino (3-pyridyl)) pyridazin-3-yl] (1-methyl-1phenylethyl) amine amino-N - {5- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] (220 pyridyl)} amide (1-methyl-1-phenylethyl) ( 6-phenylpyridazin-3-yl) amine

<img file="MX2012012259A_D0320.tif" />

-2461-amino-1 - {4- [6 - ({[(3-fluoro (2p¡ridil)) cyclobutyl] methyl} amino) p¡r¡daz¡n-3¡l] fen¡l} -2-methylpropan-2-ol amino-N- {5- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3¡l] pyrimidine -2-yl} amide (6- (1H-indazol-6-yl) pyridazin-3-yl) {[3,3-difluoro10

1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amine [6- (2-amino (3-pyridyl)) pyridaz-3-yl] {[(3fluoro (2 -p¡rid¡l)) cyclobutyl] metíl} amino [6- (6-amino-5-fluoro (3-pyridyl)) pyridazin-3yl] {[(3-fluoro (2-pyridyl)) cyclobutyl] metyl} amine

6- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methy} amino) pyridazin-3yl] indolin-2-one

<img file="MX2012012259A_D0321.tif" />

422.2 D

395.2 D

411.1 B

351.1 B

369.1 A

390.1 B

-247 [6- (2-aminopyrimidin-5-yl) pyridazine-3-yl] [(4fluorophenyl) cyclobutyl] amine amino-N- [4- (6 - {[(4fluorophenyl) c¡ clobutyl] amino} pyridazin-3yl) phenyl] amide amino-N- {4- [6 - ({[3,3-difluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} amide

3- (6 - {[1 - (4-fluorophenyl) isopropyl] amino} pyridazin-3-yl) benzamide

3- (6 - {[(2-fluorophenyl) cyclobutyl] amino} pyridazin25 3-yl) benzamide

3- (6 - {[1- (3-fluorophenit) isopropyl] amino} pyridazin-3-yl) benzamide

3- (6 - {[(3-fluorophenyl) cyclobutyl] amino} pyridazin3-yl) benzamide

<img file="MX2012012259A_D0322.tif" />

nh₂

-2483- {6 - [(2-hydroxy-tert-butyl) amino] pyridazin-3yljbenzamide

-³ 3- {6 - [(2-p¡rid¡lc¡clobutíl) amino] p¡r¡daz¡n-3¡IJbenzamide (phenylcyclobutyl) (6-phen¡lpiridaz¡n-3-¡l )amine

3- {6 - [(fen¡lc¡clobutíl) amino] p¡r¡daz¡n-3il} benzam¡da

3- (6 - {[(3-fluoro-215 p¡r¡d¡l) cyclobutyl] amino} pyridazin-3¡l) benzamida

3- (6 - {[(5-fluoro-2pyridyl) cyclobutyl] amino} pyridazin-3¡l) benzamida

4-fluoro-3- (6 - {[(4fluorophenyl) cyclobutyl] amino} p¡r¡daz¡n-3yl) benzamide

<img file="MX2012012259A_D0323.tif" />

h₂n ·

OR

-249 [(4-fluorophen¡l) cyclobutyl] [6- (6-methox¡ (2p¡rid¡l)) p¡r¡daz¡n-3-¡l] am¡na (6 -benzo¡midazol-5-¡lp¡ridaz¡n-3-¡l) [(45 fluorophenyl) cyclobutyl] amine [(4-fluorophenyl) cyclobutyl] (6- p¡razol-4¡lp¡ridaz¡n-3-¡l) am¡na

3- {6 - [(1,3-thiazol-2-ylcylbutyl) amino] p¡ridaz¡n

3- l} benzamida

4- fluoro-3- (6 - {[(3-fluoro (2p¡rid¡l)) c¡clobut¡l] amíno} p¡r¡daz¡n-315 ¡l) benzam¡da

4-fluoro-3- (6 - {[1- (4-fluorophenyl) ¡soprop¡l] amino} p¡ridaz¡n-3-¡l) benzamida ²⁰ 3- (6 - {[(4-methoxy-2-pyridyl) cyclobutyl] amino} pyridazin-3¡l) benzamida

<img file="MX2012012259A_D0324.tif" />

-250 [6- (3-fluoro (4-pyridyl)) pyridazine-3-yl] [(4fluorophenyl) cyclobutyl] amine [(4-fluorophenyl) cyclobutyl] (6- (4-pyridyl) pyridazin5

3- il) amine

4- (6 - {[(4-fluorophenyl) cyclobutyl] amino} pyridazin

3- yl) pyridin-2-carbonitrile

4- (6 - {[(4-fluorophenyl) cyclobutyl] amino} pyridazn · 3-l) p¡rid¡n-2-carboxamida [4- (6 - {[(4fluorophenyl ) cyclobutyl] amino} pyridazin-315 yl) phenyl] (methylsulfonyl) amine [(4-fluorophenyl) cyclobutyl] [6- (2-methoxy¡ (3p¡r¡d¡l)) p¡ r¡dazin-3-yl] amine [(4-fluorophenyl) cyclobutyl] {6- [2- (2,2,2tr¡fluoroethoxy) (3-pyridyl)] pyridazin-3-yl} amine

<img file="MX2012012259A_D0325.tif" />

-251 3- (6 - {[(4-chlorophenyl) cyclobutyl] amino} pyridazin3-yl) benzamide

<img file="MX2012012259A_D0326.tif" />

3- (6 - {[(4-cyanophenyl) cyclobutyl] amino} pyridazin3-yl) benzamide

<img file="MX2012012259A_D0327.tif" />

370,1

3- (6 - {[(3-chloro (2pyridyl)) cyclobutyl] amino} pyridaz-3-yl) -41θ fluorobenzamide [3- (6 - {[(4fluorophenyl) cyclobutyl] amino} pyridazin-3yl ) phenyl] (methylsulfonyl) amine

3- (6 - {[(4carbamoylphenyl) cyclobutyl] amino} pyridazin-3yl) benzamide

<img file="MX2012012259A_D0328.tif" />

nh₂ [(4-fluorophenyl) cyclobutyl] [6- (2-methyl (4pyridyl)) pyridazin-3-yl] amine [(4-fluorophenyl) cyclobutyl] [6- (2-methoxy (4pyridyl)) pyridazin-3 -il] amine

<img file="MX2012012259A_D0329.tif" />

-2523- (6 - {[(6-methoxy-2pyridyl) cyclobutyl] amino} pyridazin-3yl) benzamide

4-fluoro-3- (6 - {[(6-methoxy! (2pyridyl)) cyclobutyl] amino} pyridazin-3yl) benzamide [3- (6 - {[(6-methoxy (210 pyridyl)) cyclobutyl] amino } pyridazin-3¡l) phenyl] (methylsulfonyl) amine [3- (6 - {[(3-fluoro (2pyridil)) cyclobutyl] amino} pyridazin-3yl) phenyl] (methylsulfonyl) am¡ na amino-N- [4- (6 - {[(3-fluoro (2pyridyl)) cyclobutyl] amino} pyridazin-3yl) phenyl] amide

<img file="MX2012012259A_D0330.tif" />

-S-NH

OR

<img file="MX2012012259A_D0331.tif" />

nh₂ (6- (1 H-indazol-6-yl) pyridazin-3-yl) [(3-fluoro (2piridyl)) cyclobutyl] amine (6-benzoimidazol-6-ylpyridazin-3-yl) [( 3f1uoro (2-pyridyl)) cyclobutyl] amine

<img file="MX2012012259A_D0332.tif" />

N.

-2533- [6 - ({[6- (Difluoromethoxy) -2pyridyl] cyclobutyl} amino) pyridazin-3yl] benzamide

3- [6 - ({[6- (Difluoromethoxy) (2pyridyl)] cyclobutyl} amino) pyridazin-3-yl] -4fluorobenzamide {3- [6 - ({[6- (Difluoromethoxy) (2pyridyl)] cyclobutyl } amino) pyridazin-3yl] phenyl} (methylsulfonyl) amine 4-fluoro-3- (6 - {[(415 fluorophenyl) cyclobutyl] amino} pyridazin-3yl) benzoic [4-fluoro-3- (6- {[(4fluorophenyl) cyclobutyl] amino} pyridazin-3-yl) phenyl] ·

N- (2-hydroxy-2-methylpropyl) carboxamide

3- (6 - {[(3-bromo (2pyridyl)) cyclobutyl] amino} pyridazin-3-yl) -4fluorobenzamide

<img file="MX2012012259A_D0333.tif" />

412,0

430,1

462,1

382,2

453,2

442,1

-2543- (6 - {[1- (3-chloro (2-pyridyl)) ¡soprop¡l] amino} p¡r¡daz¡n-3-¡l) -4fluorobenzamide

4-chloro-3- (6 - {[(3-fluoro (2piridil)) cyclobutyl] amino} pyridaz-3l) benzamida [4- (6 - {[ (4fluorophenyl) cyclobutyl] amine) p-ridaz-n-3-l) (210 pr-idl)] - N-melilcarboxamida (6- (1H-¡ ndazol-5-l) p¡ridaz¡n-3-¡l) [(3-fluoro (2p¡r¡d¡l)) cyclobutyl] amine [6- (6-fluoro (1 H-¡ ndazol-5-yl)) pyridazin-3-yl] [(3fluoro (2-pyridyl)) cyclobutyl] amine amine-N- [4-fluoro-3- (6 - {[(3-fluoro (2pyr¡dil)) cyclobutyl] amino} pyridazin-3¡l) phenyl] amidane amino [4-fluoro-3- (6 - {[( 3-fluoro (2p¡r¡dil)) cyclobutyl] amine} p¡ridazin-3¡l) phenil] sulfonamide

<img file="MX2012012259A_D0334.tif" />

-255amino [3-fluoro-4- (6 - {[(3-fluoro (2pyridyl)) cyclobutyl] amino} pyridazin-3yl) phenyl] sulfonamide amine-N- [3-fluoro- 4- (6 - {[(3-fluoro (2p¡r¡dil)) cyclobutyl] amino} p¡ridaz¡n-3il) phenyl] amide

<img file="MX2012012259A_D0335.tif" />

4-fluoro-3- (6 - {[1 -methyl-1 - (6-oxo (2h¡drop¡rid¡l)) et¡l] amino} p¡ridaz¡n-3¡l) benzam gives

3- [6 - ({1- [6- (difluoromethoxy) (2-pyridyl)] ¡soprop¡l} amino) p¡r¡daz¡n-3-¡l] -4fluorobenzamida

3- [6 - ({1- [6- (d¡fluorometox¡) (2-p¡rid¡l)] ¡soprop¡l} amino) p¡rldaz¡n-3-¡l] benzam¡ da {3- [6 - ({1- [6- (d¡fluorometox¡) (2-p¡r¡d¡l)] sopropil} amno) p¡r¡daz¡n-3¡l ] fen¡l} (met¡lsulfon¡l) am¡na

<img file="MX2012012259A_D0336.tif" />

-2563- (6 - {[(4-cyano (2pyridyl)) cyclobutyl] amino} pyridazin-3-yl) -4fluorobenzamide

2 - ({[6- (3-carbamo¡l-6-fluorophen¡l) p¡r¡daz¡n-3¡l] amino} cyclobutyl) p¡r¡d¡n-4- carboxamida

3- (6 - {[(5-cyano (2pyridyl)) cyclobutyl] amino} pyridazin-3-l) -4fluorobenzamide

3- (6 - {[(6-cyano (2pyridyl)) cyclobutyl] amino} pyridazin-3-yl) -4fluorobenzamide

6 - ({[6- (3-carbamo¡l-6-fluorophen¡l) p¡r¡daz¡n-3¡l] amíno} c¡clobut¡l) p¡r¡d¡n- 2-carboxamida

4- fluoro-3- (6 - {[(3-hydrox¡ (2p¡r¡d¡l)) cyclobutyl] amino} p¡r¡daz¡n-320 ¡l) benzamide

4-fluoro-3- (6 - {[(3-methox¡ (2pirid¡l)) cyclobutyl] amino} p¡r¡dazin-3¡l) benzamida

<img file="MX2012012259A_D0337.tif" />

-2573- [6 - ({[3- (d¡fluorometox¡) (2p¡r¡d¡l)] c¡clobut¡l} amino) p¡r¡daz¡n-3-¡l] -4 fluorobenzamide

3- [6 - ({[3- (d¡fluorometox¡) -2p¡r¡dil] cyclobutyl} amino) pyr¡dazin-3¡Ijbenzamide {3- [6 - ({[3- ( difluoromethoxy) (2p¡rid¡l)] cyclobutyl} amno) p¡r¡daz¡n-3¡l] fen¡l} (met¡lsulfon¡l) amína

4- fluoro-3- (6 - {[(5-methox¡ (215 pyridyl)) cyclobutyl] amino} p¡r¡dazin-3il) benzamida

3- [6 - ({[5- (difluoromethoxy) (2p¡r¡d¡l)] cyclobutyl} amino) p¡r¡daz¡n-3-¡l] -4fluorobenzamide

4- fluoro-3- (6 - {[(5-h¡drox¡ (2piridil)) ctclobutil] amino} pyridazin-3¡l) benzamida

<img file="MX2012012259A_D0338.tif" />

-258 [(3-fluoro (2-pyridyl)) cyclobutyl] (6-vinyl, lp, ridaz, n3-l) amine

4-fluoro-3- (6 - {[(3-fluoro (25 pyridyl)) cyclobutyl] amino} pyridazine-3¡l) benzenecarbonyltrly [(3-fluoro (2-pyridyl) )) cyclobutyl] (6-phenylpyridazin3-yl) amine (6-cyclohexylplidazin-3-yl) [(3-fluoro (2pyridyl)) cyclobutyl] amine (6-cyclohex-1-enylpyridazin -3-l) [(3-fluoro (2p¡r¡dil)) cyclobutyl] amine (6-cyclohex-1-enylpyridazin-3-ylX [(3-f1uoro (2pyridyl)) cyclobutyl] methyl} amine

4- fluoro-3- {6 - [(methylcyclobutyl) amino] pyridazin · 3-yl} benzamide (6-cyclohexylpyridazin-3-yl) {[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amine

<img file="MX2012012259A_D0339.tif" />

-259 (2E) -3- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] prop-2-enoate (2E) -3- ( Ethyl 6 - {[(3-fluoro (2pyridyl)) cyclobutyl] amino} pyridazin-3-yl) prop-2 · ethoate

Diethyl 2- [6 - ({[(3-fluoro-210 pyridyl) cyclobutyl] methyl} amino) pyridazin-3yl] propane-1,3-dioate (1S, 2S) -2- [6 - ({[( 3-fluoro (215 pyridyl)) cyclobutyl] methyl} amino) pyridazn-3l] cyclopropanecarboxamld (2S, 1R) -2- [6 - ({[(3-fluoro ( 2p¡r¡d¡l)) c¡clobut¡l] metíl} amlno) p¡r¡daz¡n-320 iljclclopropanocarboxamlda amlno-N- {4- [6 - ({[(3-fluoro (2pirid L)) cyclobutll] methyl} amino) p¡r¡daz¡n-3il] cyclohexyl} amide

<img file="MX2012012259A_D0340.tif" />

-260amino-N- {4- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] cyclohexyl} amida

4-fluoro-3- (6 - {[(3-fluoro (2pyridyl)) cyclopentyl] amino} pyridazin-3yl) benzamide amino-N- {3- [6 - ({[(3-fluoro ( 210 p¡r¡d¡l)) cyclobutyl] methyl} amino) p¡ndazin-3yl] cyclobutyl} amide

<img file="MX2012012259A_D0341.tif" />

amino-N- {3- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] cyclobutyl} amide

<img file="MX2012012259A_D0342.tif" />

amino-N- {4- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] cyclohex-3-enyl} amide

3- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3yl] azetidinecarboxylate of phenylmethyl

<img file="MX2012012259A_D0343.tif" />

-261 (6-azetidin-3-ylpyridazin-3-yl) {[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amine

3- [6 - ({[(3-fluoro-2p¡r¡dil) cyclobu1¡l] methyl} amino) p¡ridaz¡n-3il] methyl azetidinecarboxylate

3- [6 - ({[(3-fiuoro-2p¡r¡d¡l) cyclobutyl] met¡l} amino) p¡ridaz¡n-310 ¡l] azet¡d¡ncarboxam¡da

1-acetyl-3- [6 - (([(3-fluoro (2p¡r¡d¡l)) c¡clobut¡l] met¡l} amino) p¡r¡daz¡n-3il] azetidine

5- [6 - ({[(3-fluoro-2pyridl) cyclobutyl] methyl} amino) pyridazin-3yl] ethyl ethyl soxazol-3-carboxylate 5- [6 - ({[ (3-fluoro-22Q pyridyl) cyclobutyl] methyl} amino) pyridazin-3yl] isoxazol-3-carboxylic

5- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3yl] isoxazol-3-carboxamide

<img file="MX2012012259A_D0344.tif" />

-262amino-N- {5- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1 H-indazol-3-yl )} friend

4- [6 - ({[(3-fluoro (2p¡r¡d¡l)) c¡clobut¡l] met¡l} amino) p¡r¡daz¡n-3-¡l] - 1met¡l¡m¡dazol-2-carboxam¡da

4- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amine) pyridazine-3-l] -210 methoxybenzamide

4- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2hydroxybenzamide

5- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl] amine) pyridazn-3-yl] -2methoxybenzamide

5- [6 - ({[(3-fluoro (2pyr¡dil)) cyclobutyl] methyl} amino) pyridazn-3-¡l] -2hydroxybenzamide

<img file="MX2012012259A_D0345.tif" />

-263 4- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2-methoxy benzoic acid 5- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2methoxybenzoic

5- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3oxazol-2-carboxamide

4- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-315 [l] imidazol-2-carboxamide

3- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridaz-3yl] isoxazol-5-carboxamide

3- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3yl] pyrazol-5-carboxamide

<img file="MX2012012259A_D0346.tif" />

-2643- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -1methylpyrazol-5-carboxamide

5- [6 - ({[(3-f! Uoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -1met¡lp¡razol-3-carboxamida

<img file="MX2012012259A_D0347.tif" />

2- [6 - ({[(3-fluoro-210 pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3 · oxazol-5-carboxamide

<img file="MX2012012259A_D0348.tif" />

369.1 B

2- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,315 thiazol-4-carboxamide

<img file="MX2012012259A_D0349.tif" />

1 - [(6 - {[(3-fluoro-2p¡r¡d¡l) cyclobutyl] amino} p¡r¡daz¡n-3¡l) methyl] pyrazol-4-carboxamide

5- [6 - ({[(3-fluoro-2p¡r¡dil) cyclobutyl] methyl} amino) pyridazin-3-yl] 1,2,4-oxadiazol-3-carboxamide

<img file="MX2012012259A_D0350.tif" />

-2652- [6 - ({[(3-fluoro-2p¡r¡dil) cyclobutyl] methyl} amino) pyridazin-3-yl] -2imidazolin-5-carboxamida

2- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -2mm dazolin-5-carboxylate methyl acid 2- [6 - ({[(3 -fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -210 imidazolin-5-carboxylic

2- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3oxazol-4-carboxamide

2- [6 - ({[(3-fluoro-2p¡r¡d¡l) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3thiazol-5-carboxamide

<img file="MX2012012259A_D0351.tif" />

2- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3oxazol-4-carboxylate

<img file="MX2012012259A_D0352.tif" />

-266 {[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} {6- [6 - ({[(3fluoro (2p¡r¡d¡l)) cyclobutyl] methyl} am ¡No) p¡ridaz¡n-3¡l] piridaz¡n-3-il} am¡na

2- [6 - ({[(3-fluoro-2p¡r¡d¡l) cyclobutíl] met¡l} amino) p¡ridaz¡n-3-¡l] -1,3thiazol-4 -methyl carboxylate

2- [6 - ({[(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3oxazol-5-carboxylate of methyl

2- [6 - ({[(3-fluoro-215 pyridyl) cyclobutyl] methyl} amino) pyridazin-3yl] imidazol-4-carboxamide

2- [6 - ({[(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyridazin-320 yl] methyl midazol-4-carboxylate

<img file="MX2012012259A_D0353.tif" />

515,4

400,2

384,2

368,2

383,3

4- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3thiazol-2-carboxamide

<img file="MX2012012259A_D0354.tif" />

-2675- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3thiazol-2-carboxamide

3- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amine) pyridaz-3-ul] 1.2.4- oxadiazol-5-carboxamide ₁₀ 5- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -4H1.2.4- triazol-3-carboxamide

2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -115 methylimidazol-4-carboxylate

2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -1methylimidazol-4-carboxamide

2- [6 - ({[(3-fluoro (2pyridl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -1 methylimidazol-5-carboxamide

<img file="MX2012012259A_D0355.tif" />

-2682- (6 - {[(3-fluoro-2pyridyl) cyclobutyl] amino} pyridazin-3-yl) -1,3thiazol-5-carboxamide

5- (6 - {[(3-fluoro (2pyridyl)) cyclobutyl] amino} pyridazin-3-yl) -2hydroxybenzamide

<img file="MX2012012259A_D0356.tif" />

5- [6 - ({[(3-fluoro-2p¡r¡dil) cyclobutyl] methyl} amino) pyridazin-3¡l] thiophene-2-carboxamide [6- (3-amino (1H- indazol-5-yl)) pyridazin-3-yl] [(3-fluoro (2-pyridyl)) cyclobutyl] amine

5- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] 1,3,4-thiadiazol-2-carboxamide {[(3-fluoro (2 -pyridyl)) cyclobutyl] methyl} (6- (1,3thiazol-2-yl) pyridazin-3-yl) amine (6- (2H-1,2,3,4-tetraazol-5-yl) pyridazin- 3-yl) {[(3 · fluoro (2-pyridyl)) cyclobutyl] methyl} amine

<img file="MX2012012259A_D0357.tif" />

-2695- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] 1,3,4-oxadiazol-2-carboxamide

2- [6 - ({[(3-fluoro (2p¡ridii)) cyclobutyl] methyl} amino) p¡r¡daz¡n-3-¡l] -4methyl-1,3-thiazol-5- carboxamide

2- (6 - {[(4-fluorophenyl) cyclobutyl] amino} pyridazin10

3- l) -1,3-thiazol-5-carboxamide acid 2- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3thiazol-5- carboxylic

5- (6 - {[(3-fluoro-2pyridyl) cyclobutyl] amino} pyridazin-3-yl) thiophene-2carboxamide

5- (6 - {[(4-fluorophenyl) cyclobutyl] amino} pyridazin3-yl) thiophene-2-carboxamide acid 5- (6 - {[(3-fluoro-2pyridyl) cyclobutyl] amino} pyridazin-3- il) thiophene-2 ​​carboxylic

<img file="MX2012012259A_D0358.tif" />

-2702- [6 - ({[(3-f) uoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3thiazol-5-carbonyltril acid 5- [6 - ({ [(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3yl] thiophene-2-carboxylic

2- [6 - ({[(3-fluoro (210 pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -4hydroxy-1,3-thiazol-5-carboxamide

5- [6 - ({[(3-fluoro-2p¡r¡dil) cyclobutyl] methyl] amino) pridazn-3-yl] -3pyrazolino [3,4-d] 1, 3-thiazol-3-one

2- [6 - ({1- [6- (Difluoromethoxy!) (2-pyridyl)] isopropyl} amino) pyridazin-3-yl] -1,3-thiazol-5carboxamide ²⁰ {2- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3t¡azol-5-yl} methan-1 -ol

<img file="MX2012012259A_D0359.tif" />

-271 [6- (5- (21-1-1,2,3,4-tetraazol-5-yl) (1,3-thiazol-2yl)) p¡ridazin-3-yl] {[(3- fluoro (2pyridyl)) cyclobutyl] methyl} amine

<img file="MX2012012259A_D0360.tif" />

5- {2- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3t¡azol-5-yl} -1,3,4-oxad¡ azolin-2-one

<img file="MX2012012259A_D0361.tif" />

Ethyl 3- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -5hydroxypyrazol-4-carboxylate

<img file="MX2012012259A_D0362.tif" />

3- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -315 pyrazolin-5-one

3- {2- [6 - ({[(3-fluoro-2p¡r¡d¡l) cyclobutyl] methyl} amino) p¡ridazin-3-yl] -1,3thiazol-5-yl } -1,2,4-triazolin-5-one ²⁰ 3- {2- [6 - ({[(3-fluoro-2pyridl) cyclobutyl] methyl} amino) pyridaz-3-yl] -1,3ti azole-5-i I } -1,2,4-oxadiazolin-5-one

<img file="MX2012012259A_D0363.tif" />

-2722- [6 - ({[(3-fluoro (2pirid¡l)) cyclobutyl] methyl} amine) p¡r¡daz¡n-3-¡l] -4hydroxy-1 Ethyl 3-thiazol-5-carboxylate

2- (6 - {[2- (3-fluoro (2-pyridyl)) - 2-methylpropyl] amino} pyridazin-3-yl) -1,3-thiazol-5carboxamide

<img file="MX2012012259A_D0364.tif" />

2- [6 - ({[(3-fluoro (2p¡r¡d¡l)) c¡clobut¡l] met¡l} amino) p¡ridazin-3-¡l] -4metox¡-1 , 3-thiazol-5-carboxamide acid 2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazine-3-l] -4methoxy! 1,3-tlazol-5-carboxylic

1- {2- [6 - ({[(3-fluoro-2p¡rid¡l) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3tlazol-5-yl } ethan-1 -ol ₂Q 2,2,2-trifluoro-1 - {2- [6 - ({[(3-fiuoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3l] (1,3-thiazol-5 -il)} ethan-1 -ol

<img file="MX2012012259A_D0365.tif" />

-27325 {2- [6 - ({[(3-fluoro (2p¡r¡dil)) cyclobutyl] methyl} amino) p¡r¡daz¡n-3il] (1,3- thiazol-5-l)} - N- (methyl) carboxamide

2- [6 - ({[(3-fluoro-2p¡rid¡l) c¡clobut¡l] met¡l} amino) p¡ridaz¡n-3-¡l] -1,3thiazol-4 -ethyl carboxylate

2- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -3p¡rrolino [3,4-d] 1,3-thiazol-6-one

1- {2- [6 - ({[(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3t¡azol-5-yl} ethan-1 -one

2- {2- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3t¡azol-5-yl} propan-2-ol

1,1,1-Trifluoro-2- {2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3l] (1,3-t¡azol-5- L)} propan-2-ol

<img file="MX2012012259A_D0366.tif" />

<img file="MX2012012259A_D0367.tif" />

<img file="MX2012012259A_D0368.tif" />

<img file="MX2012012259A_D0369.tif" />

<img file="MX2012012259A_D0370.tif" />

<img file="MX2012012259A_D0371.tif" />

384.2 C

400.3 C

454.2 C

-274 {2- [6 - ({[(3-fluoro (2p¡r¡d¡l)) cyclobutyl] met¡l} amino) pir¡daz¡n-3¡l] (1, 3-thiazol-5-yl)} - N-methylcarboxamide

3- (6 - {[(2-pyridylcyclobutyl) methyl] amino} pyridazine

3-yl) benzenecarbonitrile

3- (6- {metyl [(2pyridylcyclobutyl) methyl] amino} pyridazin-31Q yl) benzamide

6- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3yl] pyrazin-2-carbonitrile

6- [6 - ({[(3-fluoro-2p¡r¡d¡l) c¡clobut¡l] metíl} amino) p¡ridaz¡n-3il] pyrazin-2-carboxamide

2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -4hydroxy-1,3-thiazol-5-carbonitrile

<img file="MX2012012259A_D0372.tif" />

-2752- (6 - {[(2-pyridylcyclobutyl) methyl] amino} pyridazin3- l) -1,3-t¡azol-5-carboxyamide 2- (6 - {[(25 pyridi-Cyclobutyl) methyl ] amino} pyridazin-3-yl) -1,3-thiazol-5-carboxylic

3- {5- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -21Q thienylj-l, 2,4-triazoline-5-one

3- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] 1,2,4-triazolin-5-one amino {2- [6 - ({[ (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl)} methane-1 -thiona

2,2,2-trifluoro-1- {2- [6 - ({[(3-fluoro (220 pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] (1,3-t¡azol-5-¡ l)} ethane-1,1-diol {[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} {6- [5 (2,2,2-trifluoroethyl) (1,3-thiazol-2 -il)] p¡ridazin-3il} amine

<img file="MX2012012259A_D0373.tif" />

-2765- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3yl] thiophene-2-carbonyltrile

2- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3yl] thiophene [2,3-c] 3-pyrrolin-6-one (6- ( 5- (1-amino-2,2,2-trifluoroethyl) (1,3-thiazol-2 · ¹⁰ yl)] pyridazin-3-ylX [(3-fluoro (2pyridyl)) cyclobutyl] methyl} amine [6- (2-aminopyrimidin-4-yl) pyridazin-3-yl] {[(3fluoro (2-pyridyl))) cyclobutyl] methyl} amine

2- {5- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] 1,2,3,4-tetraazol-2-IJacetam ida {6- [2- (2-aminoethyl) (1,2,3,4-tetraazol-5yl)] pyridazin-3-ylX [(3-fluoro (2pyridyl)) cyclobutyl] methyl} amine

<img file="MX2012012259A_D0374.tif" />

-277 [6- (3- (2H-1,2,3,4-tetraazol-5-yl) phenyl) pyridazin3-yl] {[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} amine

2- {[6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3¡l] carbonylamino} phenylmethyl acetate

3- {3- [6 - ({[(3-fluoro-2pryl) cyclobutyl] methyl} amino) pyridaz-3yl] phenyl} -1,2,4-triazolin-5-one

3- {4-fluoro-3- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} -1,2,4-triazolin-5-one { 6- [5- (aminomethyl) (1,3-thiazol-2-yl)] pyridazin-3ylX [(3-fluoro (2-pyridyl)) cyclobutyl] methyl} amine

<img file="MX2012012259A_D0375.tif" />

-278Ν - ((2- (6 - ((1 - (3-fluoropyridin-2yl) cyclobutyl) methylamino) pyridazin-3-yl) thiazol-5yl) methyl) -2-methylpropane-2-sulfinamide {6- [5- (aminoethyl) (1,3-thiazol-2-yl)] pyridazin-3¡IX [(3-fluoro (2-p¡rid¡l)) cyclobutyl] methyl} am¡ na {6- [5- (3-aminooxetan-3-yl) (1,3-thiazol-2yl)] pyridazin-3-yl} {[(3-fluoro (21 n ^or pyridyl)) cyclobutyl] methyl} amine

2- [6 - ({[(3-fiuoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3yl] pyrimidine-4-carboxamide {2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl } amino) pyridazin-3yl] (1.3-thiazol-5-yl)} - N- (2h id roxi eti I) ca rboxa m ida

<img file="MX2012012259A_D0376.tif" />

5-chloro-2- [5-chloro-6 - ({[(3-fluoro (2pyridl)) cyclobutyl] methyl} amino) pyridazin-3-yl] 1,3-thiazol-4- ethyl carboxylate

<img file="MX2012012259A_D0377.tif" />

482.2 D

-279N- {4- [6 - ({[(3-fluoro-2p¡r¡d¡l) cyclobutyl] methyl} amino) p¡ridaz¡n-3¡l] p¡rim¡d ¡N-2-¡l} acetam¡da {4- [6 - ({[(3-fluoro (2p¡r¡d¡l)) c¡clobut¡l] met¡l} amino) pir¡ dazin-3yl] pyrimidin-2-yl} (methylsulfonyl) amine (2E) -3-amino-3- {2- [6 - ({[(3-fluoro (2p¡r¡ d¡l)) cyclobutyl] metyl} am) p¡r¡daz¡n-31θ l] (1,3-t¡azol-5-¡l)} - 2-azaprop-2 -enonitrile

N - ({2- [6 - ({[(3-fluoro-2p¡r¡d¡l) cyclobutyl] methyl} amino) p¡ridaz¡n-3-¡l] -1 , 3t¡azol-5-¡l} methyl) acetam¡da ({2- [6 - ({[(3-fluoro (2p¡r¡d¡l)) c¡clobut¡l] met¡l} am No) p¡r¡daz¡n-3¡l] (1,3-t¡azol-5-il)} metíl) (met¡lsulfon¡l) amína

<img file="MX2012012259A_D0378.tif" />

N - ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-tholzol-5-l l)} met¡l) metox¡carboxam¡da

<img file="MX2012012259A_D0379.tif" />

2,2-dfluoro-1- {2- [6 - ({[(3-fluoro (2p¡r¡d¡l)) cyclobutyl] methyl} amino) p¡r¡daz¡n -3¡l] (1,3-thiazol-5-¡l)} ethan-1 -ol

<img file="MX2012012259A_D0380.tif" />

-280N- (carbamoylmethyl) [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yljcarboxamide

2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl) morpholin-4-yl ketone

N- (2-aminoethyl) {2- [6 - ({[(3-fluoro (210 pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl )} carboxamida

N- (2,3-dihydroxypropyl) {2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazine-315 ü] (1, 3-thiazol- 5-yl)} carboxamide, 0

<img file="MX2012012259A_D0381.tif" />

359,1

441,3

455,3

428,4

459.3 {2- [6 - ({[(3-fluoro (2-pyril)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl)} - N-pyrrolidin-3 -ilcarboxamide

2- {2- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3thiazol-5-l} acetamide

<img file="MX2012012259A_D0382.tif" />

<img file="MX2012012259A_D0383.tif" />

454.3 A

399.3 B

-281 {[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} [6- (5pyrazol-4-yl (1,3-thiazol-2-yl)) pyridazin-3-yl] amine {[(3 -fluoro (2-pyridyl)) cyclobutyl] methyl} [6- (5prazol-3-yl (1,3-thiazol-2-yl)) pyridazin-3-yl] amine

4- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-31Q il] p¡rim¡d¡na-2-carboxamida

6- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3yl] p¡rim¡d¡na-4-carboxamida

<img file="MX2012012259A_D0384.tif" />

408.3 A

408.3 A

380.3 D

380.3 B [6 - ({[(3-fluoro (2-pyril)) cyclobutyl] methyl} amino) pyridazine-3-yl] -Npyrazol-5-ylcarboxamide /^N%,

<img file="MX2012012259A_D0385.tif" />

HN NN

Kh

368.1 B

N- (carbamoylmethyl) {2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl)} carboxamide

4 - ({2- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3-thiazol-5-yl} carbonyl) piperazin-2-carboxamide

<img file="MX2012012259A_D0386.tif" />

-282 [6- (5-chloro (1,3-tlazolino or [5,4-b] pyridin-2yl)) pyridazin-3-yl] {[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amine {[((3-fluoro (2-pyridyl)) cyclobutyl] methyl} (6- (1,3thiazolino [5,4-b] pyridin-2-yl) pyridazin-3-yl) amine [6 - (5-amino (1,3-thiazolino [5,4-b] p¡rid¡n-2¡l)) plridaz¡n-3-¡l] {[(3-fluoro (210 pyridyl)) cyclobutyl ] methyl} amine amino {4-fluoro-3- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} sulfonamide

2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl) 3-hydroxypyrrolidinyl ketone

4 - ({2- [6 - ({[(3-fluoro-220 pyridi I) cyclobuti l] methyl} am ¡no) plridaz¡n-3-¡l] -1,3thiazol-5-¡l} carbonyl ) -1,4-t¡azaperh¡droin-1,1diona

N- (1,1 -d ioxothio the n-3-I) {2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1 , 3-tlazol-5-l)} carboxamida

<img file="MX2012012259A_D0387.tif" />

-283 {2- [6 - ({[(3-fluoro (2pirid¡l)) cyclobutyl] metyl} amine) pyridaz-3l] (1,3- t¡azol-5-¡l)} - N- [2 (methylsulfonyl) ethyl] carboxamida

2- [6 - ({[(3-fluoro (2p¡rid¡l)) cyclobutyl] methyl} amino) p¡r¡daz¡n-3il] (1,3-t¡azol -5-l) 3-hydroxypiperidyl ketone {[((3-fluoro (2-pyridyl)) cyclobutyl] methyl} (6prazolo [5,4-d] 1,3 -thiazol-5-ilp¡r¡daz¡n-310 ¡l) amine

2- [6 - ({[(3-fluoro (2p¡r¡dil)) c¡clobut¡l] met¡l} amino) p¡r¡daz¡n-3¡l] (1,3 -t¡azol-5-¡l) 4-hydroxypiperidyl ketone ¹⁵ 4 - ({2- [6 - ({[(3-fluoro-2p¡r¡dil) cyclobutyl] methyl} amino) p¡ridaz¡n-3-yl] -1.3t¡ azole-5-l} carbonyl) p¡perazin-2-one {2- [6 - ({[(3-fluoro (2p¡r¡d¡l)) c¡clobut¡l] met¡l } amino) pyridazin-320 W¹.3-thiazol-5-yl)} - N- (oxolan-2lmethyl) carboxamide

1 - ({2- [6 - ({[(3-fluoro-2p¡rid¡l) cyclobutyl] metíl} amino) p¡ridazin-3-¡l] -1,3t¡azol -5-l} carbon¡l) p¡perid¡n-3-carboxam¡da

<img file="MX2012012259A_D0388.tif" />

-284 [6- (3- (2H-1,2,3,4-tetraazol-5-yl) phenyl) pyridazin3-yl] [2- (3-fluoro (2-p¡rid¡l)) - 2 -methylpropyl] amine

2- [6 - ({[(3-fluoro-2p¡r¡dil) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3-thiazolino [5,4-b] pyridin-5-carboxamide {[( 3-fluoro (2-pyridyl)) cyclobutyl] methyl} [6- (5methoxy (1,3-t¡azolino [5,4-b] pyridin-2¡l)) pyridazin-3-yl] amine

2- [6 - ({[(3-fluoro-215 pyridyl) cyclobutyl] methyl} am¡ no) pyridazin-3-yl] -1,3t¡azolino or [5,4-b] pyridin-5-ol

<img file="MX2012012259A_D0389.tif" />

391,3

436,1

423,1

409,1

N - ((2R) -2,3-dihydroxypropyl) {2- [6 - ({[(3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3 · yl] (1,3-thiazole -5-yl)} carboxamide

N - ((2S) -2,3-dihydroxypropyl) {2- [6 - ({[(3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3 · yl] (1,3-thiazole -5-yl)} carboxamide

<img file="MX2012012259A_D0390.tif" />

-285N- (2-amino-3,3,3-trifluoropropyl) {2- [6 - ({[(3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5- il)} carboxamide N- (3-amino-2,2-dfluoropropyl) {2- [6 - ({[(35 fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazine-3yl ] (1,3-thiazol-5-yl)} carboxamide {2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) p¡ridazin-3ill (1,3-thiazol-5 -yl)} - N, N-dimethylcarboxamide

N- (2,2-Difluoro-3-hydroxypropylX2- [6 - ({[(3fluoro (2piridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl )} carboxamide {2- [6 - ({[(3-fluoro (215 pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl)} - N- (2-oxopyrrolidin -3il) carboxamide

3- [6 - ({[3-fl uoro-1 - (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3ylbenzamide

4- fluoro-3- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazn-3yljbenzamide

<img file="MX2012012259A_D0391.tif" />

-2862-amino-N - ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazine-3l] (1,3- thiazol-5-l)} metl) acetamide «2S) pyrroyl-n-2-l) -N - ({2- [6 - ({[(3-fluoro (2p¡r ¡D¡l)) cyclobutyl] metíl} amno) p¡ridaz¡n-3¡l] (1,3-t¡azol-5-il)} metíl) carboxam¡da

<img file="MX2012012259A_D0392.tif" />

((2R) p¡rrol¡d¡n-2-¡l) -N - ({2- [6 - ({[(3-fluora (2p¡rid¡l)) cyclobutyl] methyl} amino) pyridazin-3¡l] (1,3-t¡azol-5-¡l)} metíl) carboxam¡da

<img file="MX2012012259A_D0393.tif" />

468.2 A {[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} (6- (3pyrrolino [3,4-d] 1,3-thiazol-2- il) pyridazin-3yl) amine

2- [6 - ({[(3-fluoro (2p¡r¡d¡l)) c¡clobut¡l] met¡l} amino) p¡r¡daz¡n-3-¡l] - 5 (methylsulfonyl) -3-pyrrolino [3,4-d] 1,3-thiazole

N - ({2- [6 - ({[(3-fluoro (2p¡r¡d¡l)) c¡clobut¡l] met¡l} amino) pir¡daz¡n-320 ¡l] (1,3-t¡azol-5-¡l)} metíl) -2-h¡drox¡acetam¡da

<img file="MX2012012259A_D0394.tif" />

383,1

461,1

429,1

2 - [({2- [6 - ({[(3-fluoro-2p¡rid¡l) cyclobutyl] methyl} amino) p¡ridaz¡n-3-yl] -1,3t¡azol-5 -¡L} met¡l) amino] acetam¡da

<img file="MX2012012259A_D0395.tif" />

-287 ((2S) -5-oxopyrrolidin-2-yl) -N - ({2- [6 - ({[(3fluoro (2p¡rid¡l)) c¡clobut¡l] met¡l} am¡ no) pyridaz-3yl] (1,3-thiazol-5-yl)} methyl) carboxamide

N - ({2- [6 - ({[(3-fluoro (25 pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl)} methyl) -2- h idroxy-2methylpropanamide

N - ((3S) pyrrolidin-3-yl) {2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} annino) pyridazin-3yl] (1,3-thiazol-5- il)} carboxamide

N - ((3R) p¡rrol¡d¡n-3-¡l) {2- [6 - ({[(3-fluoro (2p¡rid¡l)) cyclobutyl] met¡l} am¡ no) p¡ridaz¡n-3¡l] (1,3-thiazol-5-¡l)} carboxam¡da

2- [2- (6 - {[1 - (3-fluoro (2-pyridyl)) isopropyl] amine} pyridazin-3-yl) -1,3-t¡azol-5yl] acetamide ( (3S) morpholin-3-yl) -N - ({2- [6 - ({[(3-fluoro (220 pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3 -thiazol-5-yl)} methyl) carboxamide

N - ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} annino) pyridazin-3yl] (1,3-thiazol-5-yl)} methyl) p¡razol-5¡Icarboxamide

<img file="MX2012012259A_D0396.tif" />

-288N - ({2- [6 - ({[(3-fluoro (2p¡r¡dil)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl)} methyl ) imidazol-2ylcarboxamide

N - ({2- [6 - ({[(3-fluoro (25 pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-t¡azol-5-¡l )} methyl) prazol-4ylcarboxamide ((4S) -2-oxoimidazolidin-4-yl) -N - ({2- [6 - ({[(3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin -310 ^¡|](¹, 3-thiazol-5-yl)} methyl) carboxamide ((3S) -6-oxo (3-piperidil)) - N - ({2- [6 - ({[(3fluoro (2piridil))) cyclobutyl] methyl} amino) pyridazin-3¡l] (1,3-t¡azol-5-¡l)} metl) carboxamida

<img file="MX2012012259A_D0397.tif" />

<img file="MX2012012259A_D0398.tif" />

2H-1,2,3-triazol-4-yl-N - ({2- [6 - ({[(3-fluoro (2pirid¡l)) cyclobutyl] methyl} amino) pyridada! n-3yl] (1,3-thiazol-5-yl)} methyl) carboxamide

<img file="MX2012012259A_D0399.tif" />

OR

466.3 (2S) -2-amino-N - ({2- [6 - ({[(3-fluoro (220 p¡r¡d¡l)) cyclobutyl] methyl} am! no) p¡r¡dazin-3il] (1,3-t¡azol-5-yl)} metíl) -3-h¡drox¡propanamida

<img file="MX2012012259A_D0400.tif" />

458.3 A (2R) -2-amino-N - ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3l] (1,3-thiazole -5-yl)} methyl) -3-hydroxypropanamide

<img file="MX2012012259A_D0401.tif" />

-289 ((2S) -4-acetylpiperazin-2-yl) -N - ({2- [6 - ({[(3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3 -thiazol-5-yl)} methyl) carboxyamide [(2S) -4- (methylsulfonyl) piperazin-2-yl] -N - ({2- [6 ({[(3-fluoro (2pyridyl) ) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl)} methyl) carboxamide ((3S) morpholin-3-yl) -N - ({2- [6- ( {[(3-fluoro (2-pyril)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl)} methyl) carboxamide

1H-1,2,4-triazol-5-yl-N - ({2- [6 - ({[(3-fluoro (2p¡r¡d¡l)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl)} methyl) carboxamide ((2R) -6-oxo (2-piperidil)) - N - ({2- [6 - ({[(3fluoro (2piridil) ) cyclobutyl] methyl} amino) pyridazin-3l] (1,3-thiazol-5-yl)} methyl) carboxamide

<img file="MX2012012259A_D0402.tif" />

hn "

OR'

-290N - ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-l)} methyl) imidazol-5ylcarboxamide

2-amino-N - ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-t¡azol-5-yl)} met¡ l) -2-methylpropanamide

<img file="MX2012012259A_D0403.tif" />

(2S) -2-amino-N - ({2- [6 - ({[(3-fluoro (2pir¡d¡l)) cyclobutyl] methyl} amino) pyr¡dazin-3yl] (1 , 3-thiazol-5-yl)} metyl) propanamide

N - ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-t¡azol-5-l)} methyl) (2- hydroxyimidazol-5yl) carboxamide (2S) -2-amino-N - ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-315 yl] (1,3-thiazole -5-yl)} methyl) -3-hydroxy-3-methylbutanamide (2R) -2-amino-N - ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-l)} methyl) propanamida

<img file="MX2012012259A_D0404.tif" />

<img file="MX2012012259A_D0405.tif" />

((3R) -1,1-dioxo (1,4-thiazaperhydroin-3-yl)) - N ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin- 3yl] (1,3-thiazol-5-yl)} methyl) carboxamide

<img file="MX2012012259A_D0406.tif" />

-291 ((2S) -4,4-difluoropyrrolidin-2-yl) -N - ({2- [6 - ({[(3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3 -thiazol-5-yl)} methyl) carboxyamide (2S) -4,4-difluoro-2- [N - ({2- [6 - ({[(3-fluoro (25 pyridyl)) cyclobutyl] methyl } tere-butyl ((2S) -4,4-difluoro-1-formylpyrrolidin-2-yl) -N - ({}) amino) pyridazin-3yl] (1,3-thiazol-5yl)} methyl) carbamoyl] pyrrolidinecarboxylate 2 · [6 - ({[(3-fluoro (2q pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl)} methyl) carboxamide ((2R, 4R) -4-fluoropyrrolidin-2-yl) -N - ({2- [6 - ({[(3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3 -thiazol-5-yl)} methyl) carboxamide ⁵ N - ({2- [6 - ({[(3-fluoro (2p¡r¡dil)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl)} m eti I) -2-methylpropanamide

4-fluoro-3- (6 - {[1- (3-fluoro (2-pyridyl)) isopropyl] amino} pyridazin-3-yl) benzamide amino-N - ({2- [6 - ({[(3 -fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl)} methyl) amide

<img file="MX2012012259A_D0407.tif" />

-292 ((3S) -1,1-dioxo (1,4-thiazaperhydroin-3-yl)) - N ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} am¡ no) pyridazin-3yl] (1,3-thiazol-5-l)} metl) carboxamide

N - ({2- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] 1,3-thiazol-5-yl} methyl) acetamide

N - ({2- [6 - ({[3-fluoro-1- (3-fluoro (210 pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] 1,3-thiazole -5-yl} methyl) acetamide ((2S) pyrrolidin-2-yl) -N - {[2- (6 - {[2- (3-fluoro (2pyridyl)) - 2-methylpropyl] amino} pyridazn-3-yl) (1,3t¡azol-5-yl)] methyl} carboxamide

2- (6 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyridazin-3-yl) -1,3-thiazol-5carboxamide

4-fluoro-3- [6 - ({[3-fluoro-1- (3-fluoro (220 pyridyl)) cyclobutyl] methyl} amino) p¡ridazin-3¡l] benzamida

<img file="MX2012012259A_D0408.tif" />

-2934-fluoro-3- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] benzenecarbonitrile

396,3

3- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -4hydroxybenzamide 4-fluoro-3- [6 - ({[3 -fluoro-1 - (3-fluoro (210 pyridyl)) cyclobutyl] methyl} amino) p¡ridazin-3¡IJbenzoic

412,3

415,3

3- (6 - {[2- (3-chloro (2-pyridyl)) - 215 methylpropyl] amino} pyridazin-3-yl) benzamide

382,2

3- (6 - {[2- (3-chloro (2-pyridyl)) - 2methylpropyl] amino} pyridazin-3-yl) -420 fluorobenzamide

400,3

N - ((2R) -2,3-dihydroxypropyl) {4-fluoro-3- [6 - ({[3 · fluoro-1- (3-fluoro (2piridil)) cyclobutyl] methyl} amino) pyr! daz-3yl] phenyl} carboxamide

<img file="MX2012012259A_D0409.tif" />

488,3

-294

N - ((3R) pyrrolidin-3-yl) {4-fluoro-3- [6 - ({[3-fluoro1- (3-fluoro (2pyr¡dil)) cyclobutyl] methyl} amino) pyridazine -3¡l] fen¡l} carboxam¡da

N - ((3S) pyrroleid-3-yl) {4-fluoro-3- [6 - ({[3-fluoro1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyr! dazin-3yl] phenyl} carboxamide [6- (3- (2H-1,2,3,4-tetraazol-5-yl) phenyl) pyridazin3-yl] {[3-fluoro-1 - (3-fluoro (2p¡r¡d¡l)) cyclobutyl] methyl} amine

3- (6 - {[2- (3-chloro (2-pyridyl)) - 2methylpropyl] amino} pyridazin-3yl) benzenecarbonitrile

3- (6 - {[2- (3-chloro (2-pyridyl)) - 2methylpropyl] amino} pyridazin-3-yl) -4fluorobenzenecarbonitrile

<img file="MX2012012259A_D0410.tif" />

483.3 B

483.3 B

421.1 A

364.2 B

382.2 B

-2952- [6 - ({[(3-fluoro-2p¡rid¡l) cyclobutyl] methyl} amino) pyridazin-3-¡l] -1,3t¡azol-5-sulfonamida

-&gt; (aminocyclopropyl) -N - ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobuti!] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl)} methyl ) carboxamide

(N- {1- [N - ({2- [6 - ({[(3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3¡l] (1, 2-methylpropanoate) 3-thiazol-5-l)} methyl) carbamoyl] isopropyl} carbamoylloxy) ethyl acid 3- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-315 yl] benzoic acid 3- (6 - {[(3-fluoro-1- (2pyridyl) cyclobutyl) methyl] amino} pyridazin-3yl) benzoic acid 3- (6 - {[(3-fluoro- 1- (2pyridyl) cyclobutyl) methyl] amine} pyridazin-3yl) benzoic

<img file="MX2012012259A_D0411.tif" />

-2963- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yljbenzenecarbonitrile

N - ((2S) -2,3-dihydroxypropyl) {4-fluoro-3- [6 - ({[35 fluoro-1 - (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin -3yl] phenyl} carboxamide

4- methyl-fluoro-3- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-310 yl] benzoate {4-fluoro-3- [6- ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} -N-methylcarboxamide {4-fluoro-3- [6 - ({[3-fluoro- 1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} -N- (methylethyl) carboxamide

Methyl 3- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] benzoate

<img file="MX2012012259A_D0412.tif" />

-297

4-fluoro-3- [6 - ({[3-fluoro-1- (3-fluoro (2p¡r¡d¡l)) cyclobutyl] met¡l} amino) pyridazin-3¡IJbenzoate of methylethyl

6- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3yl] imidazo [2,1-b] 1,3-thiazolin-3-carboxamide acid 6- [6- ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazine-310 yl] imidazo [2,1-b] 1,3-thiazolin-3-carboxylic acid

6- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] imidazo [2,1-b] 1,3-thiazolin-3- carboxamide ¹⁵ N - ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amine) pyridazin-3yl] (1,3-thiazol-5-yl)} methyl) {3 [benzylamine] oxetan-3-yl} carboxamide

3- [6 - ({[3-fluoro-1 - (3-fluoro (22θ pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] benzenesulfonamide {5- [6 - ({[3-fluoro-1 - ( 3-fluoro (2piridii)) cyclobutyl] methyl} amino) pyridazine-3yl] (1H-indazol-3-yl)} (methylsulfonyl) amine

<img file="MX2012012259A_D0413.tif" />

-298 {[3-fluoro-1 - (3-fluoro (2pyridyl)) cyclobutyl] methylX6- [3- (methylamino) (1 Hindazol-5-yl)] pyridazin-3-yl} amine {6- [ 3- (ethylamino) (1 Hi ndazol-5-yl)] pyridazine-3, IX [3-fluoro-1 - (3-fluoro (2pyridyl)) cyclobutyl] methyl} amine [6- (3-amino ( 1H-indazol-5-yl)) pyridazin-3-yl] {[3fluoro-1- (3-fluoro (210 pyridyl)) cyclobutyl] methyl} amine

Ethyl 2-fluoro-5- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] benzoate 15 2-fluoro-5- [6- ({[3-fluoro-1 - (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3¡IJbenzoic

2- {4-fluoro-3- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} acetamide

<img file="MX2012012259A_D0414.tif" />

422.3 A

434.3 A

408.3 A

443.3 C

415.3 B

410.1 B

-299

2- {4-fluoro-3- [6 - ({[(3-fluoro (2plrid¡l)) cyclobutyl] methyl} amino) pridazln-3¡l] fenll} methyl acetate

N - ({4-fluoro-3- [6 - ({[3-fluoro-1- (3-fluoro (2p¡rid¡l)) cyclobutyl] methyl} amino) plridazin- 3¡l] fenll} met¡l) acetamlda

N - ({3- [6 - ({[3-fluoro-1- (3-fluoro (2p¡r¡d¡l)) c¡clobut¡l] met¡l} amino) p¡ridaz¡ n-3¡l] fenll} metíl) acetamlda {2-fluoro-5- [6 - ({[3-fluoro-1- (3-fluoro (2píridil)) cyclobutyl] methyl} amino) plr¡daz¡n-3¡l] fenll} -N-metílcarboxam¡da

N-etll {2-fluoro-5- [6 - ({[3-fluoro-1- (3-fluoro (2p¡r¡d¡l)) cyclobutyl] methyl} amino) p¡ridaz¡ n-3¡l] fenll} carboxam¡da

5- [6 - ({[3-fluoro-1 - (3-fluoro (2p¡r¡d¡l)) c¡clobut¡l] metíl} amino) p¡ridaz¡n-3- l] -2 · (methyl (methylamine) benzoate

<img file="MX2012012259A_D0415.tif" />

-3005- [6 - ({[3-fluoro-1 - (3-fluoro (2p¡r¡d¡l)) c¡clobut¡l] met¡l} amino) p¡r¡daz¡n -3-l] -2 (methylamine) ethyl benzoate {3- [6 - ({[3-fluoro-1 - (3-fluoro (2p¡r¡dil)) cyclobutyl] methyl } amino) pyridazin-3yl] phenyl} methan-1-ol

2- [2- (6 - {[2- (3-chloro (2-pyridyl)) - 2methylpropyl] amino} pyridazin-3-yl) -1,3-thiazol-5yljacetamide

2-amino-N - {[2- (6 - {[2- (3-chloro (2-pyridyl)) - 2-methipropyl] amino} p¡r¡dazin-3-¡l) (1,3-t¡ azole-515 yl)] methyl} -2-methylpropanamide ((2S) azetidin-2-yl) -N - ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino ) pyridazin-3yl] (1,3-thiazol-5-l)} metl) carboxamide

2- {2- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3 · thiazol-4-yl} ethyl acetate

<img file="MX2012012259A_D0416.tif" />

-301 2- {2- [6 - ({[(3-fIoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3-thiazol-4-yl} acetamide

6- (6 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyridazin-3-yl) imidazo [2,1 b] 1,3-thiazolin-3-carboxamide

6- (6 - {[2- (3-chloro (2-pyridyl)) - 2methylpropyl] amino} pyridaz-3-yl) ¡m¡dazo [2,1 b] 1,3- thiazolin-3-carboxamide

6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3carboxamide

2- {2- [6 - ({[(3-fluoro (2pyridl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl)} - 2-methylpropanonitrile

2- {2- [6 - ({[(3-fluoro (220 pyridyl)) cyclobutyl] methyl} amine) pyridazin-3yl] (1,3-thiazol-5-l) } -2-methylpropanamide

3- {2- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-l] -1,3t¡azol-5-l} propanamida

<img file="MX2012012259A_D0417.tif" />

302 Acid 3- {2- [6 - ({[(3-fluoro-2pyridl) cyclobutyl] methyl} amino) pyridaz-3-yl] -1,3thiazol-5- il} propanoic

3- {2- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3t¡azol-5-l} methyl propanoate acid 6- ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-310 carboxylic [6 - ({[(3-fluoro (2piridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -Nmethylcarboxamide [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] N, N-dimethylcarboxamide

2-amino-N - ({2- [6 - ({[(3-fluoro (2p¡r¡dil)) cyclobutyl] methyl} amino) pyridazin-320 yl] (1,3-thia zol-5-i I)} met¡ I) -2-met¡l-Nmetilpropanamida

2- {2- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazine-3-yl] 1,3-thiazol-5-yl } acetamide

<img file="MX2012012259A_D0418.tif" />

-303 2- {2- [6 - ({[3-Fluoro-1 - (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] 1,3-thiazol-5-yl }acetic

2- [2- (6 - {[1- (3-chloro (2-p¡rid¡l)) isopropyl] amino} p¡r¡dazin-3-yl) -1,3-thiazol-5 L] acetamide (3-aminooxetan-3-yl) -N - ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3¡l] (1,3 -thiazol-5-l)} methyl) carboxamide {3- [6 - ({[(3-fluoro (2-pyril)) cyclobutyl] methyl} amino) pyridazin-3l] phenil} - N-methylcarboxamida {4-fluoro-3- [6 - ({[(3-fluoro (215 pyridyl)) cyclobutyl] methyl} amino) p¡r¡dazin-3¡l] phenyl} -N- methylcarboxamide

N - ({5- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1.3²⁰ thiazol-2-l} methyl) acetamide

N - ({4- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3thiazol-2-yl} methyl) acetamida

<img file="MX2012012259A_D0419.tif" />

418,1

389,1

470,1

392,3

410,3

413,3

413,3

-3042- {2- [6 - ({[1- (3-chloro (2-pyridyl)) - 3-fluorocyclobutyl] methyl} amino) pyridazine-3-yl] -1,3thiazol-5 -yl} acetamide {3- [6 - ({[3-fluoro-1- (3-fluoro (2pyr¡dil)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} -N-methylcarboxamide

2- {2- [6 - ({[(3-chloro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,310 thiazol-5-yl} acetamide acid 2- {2- [6 - ({ [(3-fluoro-2pyridyl) cyclob util] methyl} amino) pyridazin-3-yl] -1,3 thiazol-5-yl} acetic¹⁵ 2- {2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl)} - N-methylacetamide

2- {2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-320 yl] (1,3-thiazol-5-yl)} - N, N -dimethylacetamide

<img file="MX2012012259A_D0420.tif" />

-305 [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -Nisoxazol-3-ylcarboxamide [6 - ([[3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -N (1,3-oxazol-2-yl) carboxamide [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridaz N-3-yl] -N (1,3-thiazol-2-yl) carboxamide [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -N ( 1,3,4-thiadiazol-2-yl) carboxamide [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -N¡midazol-2- ilcarboxam¡da

<img file="MX2012012259A_D0421.tif" />

-306N - ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl)} methyl) - 2-methyl-2 (methylamino) propanamide [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -N · (1-methyl pi razol-3-i I) carboxam ida

N- (1 H-1,2,4-triazol-5-yl) [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] carboxamide

N- (4-cyanoimidazol-5-yl) [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] carboxamide

N- (4-cyanopyrazol-5-yl) [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] carboxamide

<img file="MX2012012259A_D0422.tif" />

-3074 - {[6 - ({[(3-fluoro (2p¡rid¡l)) cyclobutyl] met¡l} amino) p¡r¡daz¡n-3il] carbonylamine} -1 -ethyl methylimidazole-2-carboxylate

2 - {[6 - ({[(3-fluoro-2p¡r¡d¡l) cyclobutyl] methyl} amino) p¡ridaz¡n-3¡l] carbon¡lam¡no} Ethyl -1,3-oxazol-4-carboxylate

N - ((3S) -2-oxop¡rrol¡din-3-¡l) [6 - ({[(3-fluoro (2p¡rid¡l)) cyclobutíl] metíl} amino) p¡r¡daz¡n-3¡l] carboxam¡da

N - ((3R) -2-oxop¡rrol¡d¡n-3-¡l) [6 - ({[(3-fluoro (2piridil)) cyclobutyl] methyl} amlno) p¡r¡ daz¡n-3il] carboxamlda

N-et¡l {4-fluoro-3- [6 - ({[3-fluoro-1- (3-fluoro (2p¡r¡d¡l)) c¡clobut¡l] met¡l} am¡ no) p¡r¡daz¡n-320 il] phenyl} carboxam¡da

N- (2-fluoroethyl) {4-fluoro-3- [6 - ({[3-fluoro-1- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazine-3yl] phenyl} carboxamida

<img file="MX2012012259A_D0423.tif" />

-308N- (2,2-d¡fluoroethyl) {4-fluoro-3- [6 - ({[3-fluoro-1 (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3l] phenyl} carboxamide {4-fluoro-3- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3¡l] phenyl} -N- (2,2,2-trifluoroethyl) carboxamide {4-fluoro-3- [6 - ({[3-fluoro-1- (3-fluoro (21Q p¡r¡d¡l)) c¡clobutíl] met¡l} amno) p¡r¡daz¡n-3¡l] fen¡l} -N, Nd¡met¡lcarboxam¡ gives 3- [6 - ({[(3-fluoro (2-pyril)) cyclobutyl] methyl} amino) pyridazin-3-yl] -4hydroxybenzoic acid

2 - {[6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3yl] carbonylamino} cyclopentanecarboxamide [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl } amino) pyridazin-3-yl] -N [(5-oxopyrrolidin-2-yl) methyl] carboxamide

<img file="MX2012012259A_D0424.tif" />

-309 [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-l] -N (2-oxo (3-p¡peridyl)) carboxamide

4 - {[6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] carbonyllamine} -1-methylyldazol- 2carboxamide

2- {[6 - ({[(3-fluoro-2p¡r¡d¡l) c¡clobut¡l] metíl} amino) pyridaz¡n-3¡l] carbon¡lam¡no} -1,3-oxazol-4-carboxamida ₁₅ {3- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -4hydroxyphenyl} -N-methylcarboxamide

3- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) p¡r¡daH¡n-3-¡l] -420 hydroxybenzamide, 0

<img file="MX2012012259A_D0425.tif" />

399.3 D

425.3 D

412.3 D

408.3 B

394.3 B

-31025

5 - {[6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3yl] carbonylamino} pyrazol-4-carboxamide

5- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2methoxypyridin-3-carbonitrile

5- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2methoxypyridin-3-carboxamide acid 5- [6 - ({[(3-fluoro ( 2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2oxohydropyridin-3-carboxylic

5- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2oxohydropyridin-3-carboxamide [6 - ({[(3-fluoro (2piridii )) cyclobutyl] methyl} amino) pyridazin-3-yl] -N (pyrazol-5-ylmethyl) carboxamide

<img file="MX2012012259A_D0426.tif" />

411.3 C

391.1 D

409.2 C

396.1 D

395.1 C

382.3 D

-311 [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -N [(1-methylpyrazol-5-yl) methyl] carboxamide ⁵ [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -N [(1-methylprazol-3-yl) methyl] carboxamide [6- ( {[(3-fluoro (210 pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -N [(5-oxopyrrolidin-3-yl) methyl] carboxamide

N - ((3S) -6-oxo (3-piperidyl)) [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazine-315 yl] carboxamide

N - ((3R) -6-oxo (3-piperidyl)) [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amine) pyridazin-3yl] carboxamide [ 6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -N (2-pyridylmethyl) carboxamide

<img file="MX2012012259A_D0427.tif" />

-312 [6 - ({[(3-fluoro (2p¡r¡d¡l)) cyclobutyl] methyl} amino) p¡ridaz¡n-3-yl] -N (3-p ¡R¡d¡lmetil) carboxam¡da [6 - ({[(3-fluoro (2pir¡d¡l)) cyclobutyl] methyl} amino) pyridazin-3-yl] -N (4-p¡r¡d ¡Lmetíl) carboxam¡da [6 - ({[(3-fluoro (210 p¡rid¡l)) ccloclobutl] met¡l} amino) p¡r¡dazin-3-il ] -N (1,3-t¡azol-2-lmethyl) carboxamide [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amine) pir¡daz¡n-3-¡l] -N · met¡lN- (1,3-t¡azol-2-lmet¡l) carboxamida

2 - {[6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amine) pyridaz-3l] carbonyllamine} -1,3-thiazole Ethyl-5-carboxylate

<img file="MX2012012259A_D0428.tif" />

<img file="MX2012012259A_D0429.tif" />

393.3 C

393.3 D

399.3 D

413.2 D

457.3 D ²⁰ 2 - {[6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridaz-3l] carbonyllamine} -1,3-tlazol-4-carboxyllate methyl

<img file="MX2012012259A_D0430.tif" />

-313

2- (2 - {[6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3yl] carbonylamino} -1,3-thiazol-4-yl) acetate ethyl acid 5- [6 - ({[3-fluoro-1 - (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazyl-3-l] -2hydroxybenzoic {3- [6 - ({[3-fluoro-1 - (3-fl uoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} -N- [2-hydroxy-1 (hydroxymethyl) ethyl] carboxamide {5- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-il] -2 · hydroxyphenyl} -N-methylcarboxamide

5- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2 · hydroxybenzamide

<img file="MX2012012259A_D0431.tif" />

-314 {3- [6 - ({[3-fluoro-1- (3-fluoro (2pirid¡l)) cyclobutyl] metif} amino) pyridazin-3-yl] -4hydroxiphenyl} -N-met Lcarboxamide

2 - {[6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazine-3yl] carbonylamino} -1,3-thiazol-4-carboxamide {5- [6 - ({ [(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-l] (2-thienyl)} - N-methylcarboxamide

2- [6 - ({[(3-fluoro-215 pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] 4.5.6-trihydrocyclopenta [1,2-d] 1,3-thiazol-4carboxamide 2- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] 20

4.5.6- tri-hydrocyclopenta [1,2-d] 1,3-thiazol-4-carboxylic {[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} (6- (4,5,6,7tetrah¡ dro-1,3-thiazolo [5,4-c] pyridin-2yl) pyridazin-3-yl) amine

Oh

<img file="MX2012012259A_D0432.tif" />

-315N- {2- [6 - ({[(3-fluoro (2p¡r¡d¡l)) cyclobutyl] methyl} amino) p¡ridazin-3il] (4,5,6 -trihydrocyclopenta [2,3-d] 1,3-thiazol-4¡I)} methoxy rboxa mida

2- [6 - ({[(3-fluoro-2p¡r¡dil) cyclobutyl] methyl} amino) pyridazin-3-¡l] 4.5.6.7- tetrahydro-1,3- thiazolo [5,4-c] p¡rid¡n-5carboxamide

5-acetyl-2- [6 - ({[(3-fluoro (210 pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] 4.5.6.7- tetrahydro-1,3-thiazolo [5.4 -c] pyridine

2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -5 (methylsulfonII) -4,5,6,7-tetrahydro-1,315 thiazolo [5 , 4-c] pyridine {5- [6 - ({[3-fl uoro-1 - (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2hydroxyphenyl} -N, N- dimethylcarboxamide

4- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridaz-3yl] isoindolin-1-one

<img file="MX2012012259A_D0433.tif" />

-3165- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] ¡soindolin-1 -one

<img file="MX2012012259A_D0434.tif" />

F&gt;

408.1 C

6- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] isoindolin-1 -one or

<img file="MX2012012259A_D0435.tif" />

<img file="MX2012012259A_D0436.tif" />

408.1 B [6- (6-amino (4,5,6,7-tetrahydrobenzothiazol-2 · yl)) pyridazin-3-yl] {[(3-fluoro (2pyridyl)) cic! Obut L] met} amine

<img file="MX2012012259A_D0437.tif" />

411.5 D amino-N- {2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3l] (4,5,6, 7-tetrahydrobenzothiazol-6-l)} amida

N- {3-fluoro-4- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} (methylamine) carboxamide

<img file="MX2012012259A_D0438.tif" />

454.3 D

443.3 A

N- {4- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl) amino) pyridazin-3yl] phenyl} -N-methyl (methylamino) carboxamide

<img file="MX2012012259A_D0439.tif" />

-317

N- [4- (carbamoylmethyl) (1,3-thiazol-2-yl)] [6 - ({[(3fluoro (2p¡ridil)) cyclobutyl] methyl} amino) p¡r¡ daz¡n-35 ¡l] carboxam¡da

2- (2 - {[6 - ({[(3-fluoro (2-pyril)) cyclobutyl] methyl} amino) pyridazin-3yl] carbonylamino} (1,3-thiazol-4-yl)) - N-methylacetamide

2- {2- [6 - ({[1- (3-chloro (2-pyridyl)) - 315 fluorocyclobutyl] methyl} amino) pyridazin-3-yl] (1,3t¡azol- 5-l)} - N-met¡lacetam¡da

3- {6- [4- (3-fluoro (2-pyridyl)) - 2azabicyclo [2,1,1] hex-2-yl] pyridazin-3-yl} -4hydroxybenzamide

<img file="MX2012012259A_D0440.tif" />

nh₂

-3182- (5 - {[6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridaz-3yl] carbonylamino} -1,3,4-thiadiazol-2-yl )ethyl acetate

N- [5- (carbamoylmethyl) (1,3,4-thiadiazol-2-yl)] [6 ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] carboxamide

N- {4- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3¡l] phenyl} (methylamino) carboxamide

<img file="MX2012012259A_D0441.tif" />

2- {2- [6 - ({[(3-chloro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl)} - N-methylacetannide

N-cyclopropyl {4-fluoro-3- [6 - ({[3-fluoro-1- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} carboxamide

<img file="MX2012012259A_D0442.tif" />

-3195- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -8hydro-3-pyrazolino [1,5-a] pyrimidin-7-one

7- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -4hydro-4-imidazole [1,2-a] pyrimidin-5-one q {4-fluoro-5- [6 - ({[3-fluoro-1 - (3-fluoro (2piridil)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2h¡droxifen¡l} -N- metcarboxamida

4-fluoro-5- [6 - ({[3-fluoro-1- (3-fluoro (215 pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2hydroxybenzamide

3- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) p¡ridazin-3-yl] -420 methyl-3-p¡razolin-5-one

3- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] 4,4-dimethyl-2-pyrazolin-5-one

<img file="MX2012012259A_D0443.tif" />

-320 {[(3-fluoro (2-p¡r¡dil)) cic! Obutil] methyl} [6benzylpyridazin-3-ylJamina

3- [6- ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) -4-methylpyridazin ·

3-yl] benzenecarbonitrile

3- [6 - ({[(3-fluoro (210 pyridyl)) cyclobutyl] methyl} amino) -4-methylpyridazin ·

3- yl] benzamide

N-cyclobutyl {4-fluoro-3- [6 - ({[3-fluoro-1- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-315 yl] phenyl} carboxamide

4- fluoro-3- [6 - ({[(3-fluoro (2p¡r¡dil)) cyclobutyl] methyl} amino) -4-methyllp¡ridazin

3-yl] benzamide

N- (3,3-Difluorocyclobutyl) {4-fluoro-3- [6 - ({[3fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} carboxamide

<img file="MX2012012259A_D0444.tif" />

-321 4-fluoro-3- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2hydroxybenzamide

2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) -4-methylpyridaz ·

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

3- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) -5-methylpyridazin

3-yl] benzamide

N-cyclopropyl {3- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} carboxamide [6- (2-aminopyrim ¡D¡n-5-¡l) pyridaz¡n-3-¡l] {[3fluoro-1 - (3-fluoro (2piridil)) cyclobutyl] methyl} amine

N-azet¡d¡n-3-¡l {3- [6 - ({[3-fluoro-1- (3-fluoro (220 pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} carboxamide

<img file="MX2012012259A_D0445.tif" />

-322N- (1-acetylazetidin-3-yl) {3- [6 - ({[3-fluoro-1- (3fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} carboxamide {3 - [6 - ({[3-fluoro-1 - (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} -N- [1- (methylsulfonyl) azetidin-3yljcarboxamide {3- [6 - ({[3-fluoro-1 - (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3¡l] phenyl} -N- (2-hydroxy-2methylpropyl) carboxamide {3- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenylJ-N- (1-methylazetidin-3-yl) carboxamide {3- [6 - ({[3-fluoro-1 - (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} -N-oxetane-3-ylcarboxamide acid 2- {2 - [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) -4-methylpyridazin3-yl] -1,3-thiazol-5-yl} acetic

<img file="MX2012012259A_D0446.tif" />

-323 {2- [6 - ({[(3-fluoro (2p¡r¡dil)) cyclobutyl] methyl} amino) -4-methylp¡ridazin 3-yl] -1,3-t¡azo l -5-yl} meta n-1 -ol

2- {2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) -4-methylpyridazin ·

3-yl] (1,3-thiazol-5-yl)} - N-methylacetamide

2- {2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) -4-methylpyridazin ·

3-yl] -1,3-thiazol-5-yl} acetamide {4-fluoro-3- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} -N- (1-methylazetidin-3-yl) carboxamide

N- (1 -acetylazetin-3-yl) {4-fluoro-3- [6 - ({[3fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amine) p¡ r¡dazin-3yl] phenyl} carboxamide {3- [6 - ({[3-fluoro-1 - (3-fluoro (2pirid¡l)) cyclobutyl] methyl} amino) pyridazn-3¡l] phenyl} -N- (3-hydroxycyclobutyl) carboxamide

<img file="MX2012012259A_D0447.tif" />

-324 {[(3-fluoro (2-p¡r¡d¡l)) cyclobutyl] met¡IX6- [5 (piperazinylmethyl) (1,3-t¡azol-2-yl) ] pyridazine-3¡IJamine {[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} {6- [5 (morpholin-4-lmetyl) (1,3-thiazol-2- il)] pyridazin-3¡IJamina

4 - ({2- [6 - ({[(3-fiuoro-2pyridyl) cyclobutyl] methyl} amino) pyridaz-3-yl] -1,3thiazol-5-yl} methyl) -1 , 4-thiazaperhydroin-1,1-dione {[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} (6- {5 - [(4methylpiperazinyl) methyl] (1,3-thiazol-2yl)} pyridazin-3-yl) amine {[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} [6- (5 - {[4 (2,2,2-trif1uoroethyl) piperazin L] methyl} (1,3-t¡azol2-l)) pyridazin-3-yl] amine

-acetyl-4 - ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-l)} methyl) p¡perazina

1 - ({2- [6 - ({[(3-fluoro (2pir¡d¡l)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-t¡azol-5-yl )} metyl) -4 (methylsulfonyl) piperazine

<img file="MX2012012259A_D0448.tif" />

-325 [(2S) -1 - ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) p¡ridazin-3¡l] (1,3-t¡ azole-5-yl)} methyl) piperazin-2-yl] methan-1 ol ⁵ [(2R) -1 - ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazyl-3yl] (1,3- t¡azol-5-¡l)} met¡l) p¡peraz¡n-2-¡l] mettan-1 ol

N- (2H-3,4,5,6-tetrah¡dropiran-4-¡l) {3- [6 - ({[31Q fluoro-1 - (3-fluoro (2pirid¡l)) c¡clobut¡ l] methyl} amino) p¡r¡daz¡n-3¡l] fen¡l} carboxam¡da {3- [6 - ({[3-fluoro-1 - (3-fluoro (2pirid¡l )) cyclobutyl] methyl} am) p¡r¡daz¡n-3¡l] phenyl} -N- (3-hydroxy-315 metallic cyclobutyl) carboxamida

N - ((3S) oxolan-3-yl) {3- [6 - ({[3-fluoro-1- (3fluoro (2pyridl)) cyclobutyl] methyl} amine) pir¡daz¡n-3¡l] fen¡l} carboxam¡da

2Q N - ((3R) oxolan-3-yl) {3- [6 - ({[3-fluoro-1 - (3fluoro (2pir¡d¡l)) cyclobutyl] metyl} am ¡No) p¡ridaz¡n-3¡l] fen¡l} cart&gt; oxam¡da

<img file="MX2012012259A_D0449.tif" />

470.3 B

470.3 C

480.3 B

480.3 B

466.3 B

466.3 B

-326N - ((3S, 4S) -4-hydroxy¡-1,1-d¡oxot¡olan-3-¡l) {3 [6 - ({[3-fluoro-1- (3-fluoro (2p ¡Rid¡l)) c¡clobut¡l] met¡l} amino) p¡ridaz¡n-3¡l] fen¡l} carboxam¡da ⁵ N- (1,1-dioxothiolan-3-yl) {3- [6 - ({[3-fl uoro-1 - (3fluoro (2pir¡d¡l)) cyclobutyl] methyl} amine ) p¡r¡dazin-3il] fen¡l} carboxam¡da

3- [6 - ({[3-fl uoro-1 - (3-fl uoro (2p¡rid¡l)) c¡clobut¡l] met¡l} amino) p¡r¡daz¡n- 3-l] -2hydroxybenzamide

3- [6 - ({[(3-fluoro (2p¡r¡d¡l)) cyclobutyl] methyl} amino) pridazin-3-l] -2hydroxybenzamide

5-amino-3- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3l] benzenecarbonitrile

3- [6 - ({[3-fluoro-1 - (3-fluoro (2p¡rid¡l)) c¡clobut¡l] met¡l} amino) p¡r¡daz¡n-3- L] -5 (tr¡fluoromet¡l) benzamida

<img file="MX2012012259A_D0450.tif" />

-3275-chloro-3- [6 - ({[3-fluoro-1- (3-fluoro (2p¡r¡d¡l)) c¡clobut¡l] met¡l} amino) p¡r Daz¡n-3¡l] benzam¡da

3- [6 - ({[3-fluoro-1 - (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-l] -5hydroxybenzamide

5-amino-3- [6 - ({[3-fluoro-1- (3-fluoro (210 pyridyl)) cyclobutyl] methyl} amino) p¡ridaz¡n-3¡l ] benzamide {3- [6 - ({[3-fluoro-1 - (3-fl uoro (2p¡r¡dil)) cyclobutyl] methyl} amino) p¡ridaz¡n-3- L] -215 h¡droxifen¡l} -N-methylcarboxam¡da

3- [6 - ({[3-fluoro-1 - (3-fluoro (2p¡rid¡l)) clclobutíl] metíl} amino) p¡ridazln-3-¡l] -2hydroxybenzenecarbonitrile ²⁰ 3- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazn-3-l] -2methoxybenzenecarbonitrile

<img file="MX2012012259A_D0451.tif" />

430.1 B

412.1 A

411.2 B

426.2 A

394.1 B

408.1 C

-328 3- [6 - ({[[3-fluoro-1 - (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2 · hydroxybenzoic acid

5- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2methoxybenzamide

N- (1,1-dioxothietan-3-yl) {3- [6 - ({[3-fluoro-1- (310 fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl ] phenyl} carboxamide

4-fluoro-3- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2 · hydroxybenzamide

4-fluoro-5- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2 hydroxybenzamide {3- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] phenyl} -N [(hydroxycyclopropyl) methyl] carboxamide

<img file="MX2012012259A_D0452.tif" />

-329 {3- [6 - ({[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-l] -5methylphenylJ-N-methylcarboxarriide

3- [6 - ({[3-fluoro-1 - (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -5methylbenzamide

3- [6 - ({[(3-fluoro (210 pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2hydroxy-5-methylbenzamide

3- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -215 hydroxy-5-methylbenzenecarbonitrile

5-bromo-3- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2hydroxybenzenecarbonitrile

3- [6 - ({[3-fluoro-1 - (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] -2methoxybenzamide

<img file="MX2012012259A_D0453.tif" />

-330 {5-bromo-3- [6 - ({[3-fluoro-1 - (3-fluoro (2p¡rid¡l)) c¡clobut¡l] met¡l} amino) p¡r ¡Daz¡n-3-il] -2hydroxyphenyl} -N-methylcarboxamida {3- [6- ({[3-fluoro-1 - (3-fluoro (2pir¡dil)) cyclobutyl ] methyl} amino) p¡r¡daz¡n-3-¡l] -2hydroxy-5-methylphenyl} -N-methylcarboxamide

Methyl 5- [6 - ({[3-fluoro-1- (3-fluoro (210 pyridyl)) cyclobutyl] methyl} amino) pyridazin-3¡l] indole-2-carboxylate

5- [6 - ({[3-fluoro-1 - (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] indole-2-carboxamide acid 5- [6 - ({[3-fluoro- 1 - (3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] indole-2-carboxylic {5- [6 - ({[3-fluoro-1 - {3 -fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-320 yl] indole-2-yl} -N-methylcarboxamide [6- (6-amino (3-pyridyl)) pyridazine-3- yl] {[3-fluoro1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amine

<img file="MX2012012259A_D0454.tif" />

-331 {[3-fl uoro-1 - (3-fluoro (2pyridyl)) cyclobutyl] methyl} {6- [6- (methylamino) (3piridyl)] pyridazin-3-yl} amine {6- [6- (cyclopropylamino) (3-pyridyl)] pyridazin-3i IX [3-fl uoro-1 - (3-fluoro (2pyridyl)) cyclobutyl] methyl} amine {6- [6 [N- -amino-5- (trifluoromethyl) (3pyridyl)] pyridazine-3-yl} {[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} amine ({2- [6 - ({[(3-fluoro-2p¡r¡dil) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3-thiazol-5-yl} methyl) carbamoyl] methyl ( 2S) -2-amino-3-methylbutanoate of [N - ({2- [6 ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3-thiazol-5-yl} methyl) carbamoyl] methyl

<img file="MX2012012259A_D0455.tif" />

<img file="MX2012012259A_D0456.tif" />

<img file="MX2012012259A_D0457.tif" />

'0 h₂n

383.3 B

409.3 D

528.2 A

- [N - ({2- [6 - ({[(3fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3-thiazole - 332 (2S) -2-aminopropanoate) -5-l} methyl) carbamoyl] methyl {[3-fluoro-1- (3-fluoro (2pyridyl)) cyclobutyl] methyl} [6- (6-methoxy-5-methyl (3pyridyl)) pyr! dazin-3-yl] amine [6- (6-amino-5-methyl (3-pyridyl)) pyridazin-3-yl] {[3fluoro-1- (3-fluoro (2p¡r¡dil)) cyclobutyl] methyl} amine (2S) -N - ({2- [6 - ({[(3-fluoro (215 pyridyl)) cyclobutyl] methyl} amino) pyridazin-3l] (1,3-thiazole -5-yl)} methyl) -2-h¡droxipropanam¡da (2R) -N - ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-thiazol-5-yl )} methyl) -2-hydroxypropanamide

2 - [({2- [6 - ({[(3-fluoro-2pyridl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3thiazol-5-yl} methyl) amino ] etan-1-ol

<img file="MX2012012259A_D0458.tif" />

- 333N - ({2- [6 - ({[(3-fluoro (2pyridyl)) cyclobutyl] methyl} amino) pyridazin-3yl] (1,3-t¡azol-5-yl)} methyl) - [N - ({2 [6 - ({[(3-Fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyridazin -3-l] -1,3-thiazol-5-yl} methyl) carbamoyl] methyl (2S) -2 - ((2S) -2-amino-3-methylbutane! Lam) 3-methylbutanoate of [ N - ({2- [6 - ({[(3-fluoro-2pyridyl) cyclobutyl] methyl} amino) pyridazin-3-yl] -1,3t¡azol-5-yl} methyl) carbamoyl] methyl

<img file="MX2012012259A_D0459.tif" />

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.

-334-