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

[0001] The cytoskeleton of skeletal muscle and myocardium cells is unique compared to all other cells. It consists of an almost crystalline network of tightly packed cytoskeleton proteins called sarcomerers. Sarkomer is perfectly organized in the form of a set of alternating thin and thick filaments. Thick filaments are made of myosin, a motor protein responsible for transforming the chemical energy coming from ATP hydrolysis into strength and directed movement. Thin filaments are constructed of spirally-placed actin monomers. Four regulatory proteins are associated with actin filaments, which allow the regulation of contraction by calcium ions. The inflow of intracellular calcium initiates muscle contraction; thick and thin filaments move in relation to each other as a result of repetitive interaction of myosin motor domains with thin actin filaments. [0002] Of the thirteen different classes of myosin found in human cells, Class II myosin is responsible for skeletal muscle, cardiac and smooth muscle contraction. This class of myosin significantly differs in amino acid composition and structure from myosins from the remaining twelve different classes. Myosin II is in the form of homodimers forming two spherical domains that are joined together by means of a long, alpha-helical tail-twisted superhex that forms the core of a thick filament of the sarcomere. These spherical heads have a catalytic domain where actin binding occurs and ATPase activity of myosin takes place. After binding to an actin filament, the release of phosphate (cf. ADP-Pi to ADP) signals a structural change in the conformation of the catalytic domain, which, in turn, causes a change in the orientation of the light chain domain connecting the lever arm that extends from the spherical head; this movement is referred to as a power explosion. This change in the orientation of the myosin head relative to the actin causes the movement of the thick filament of which it is part, relative to the thin actin filament to which it is bound. Disconnection of the spherical head from the actin filament (regulated by Ca This change in the orientation of the myosin head relative to the actin causes the movement of the thick filament of which it is part, relative to the thin actin filament to which it is bound. Disconnection of the spherical head from the actin filament (regulated by Ca This change in the orientation of the myosin head relative to the actin causes the movement of the thick filament of which it is part, relative to the thin actin filament to which it is bound. Disconnection of the spherical head from the actin filament (regulated by Ca²⁺), combined with the return of the catalytic domain and the light chain to their initial conformation / position, ends the catalytic cycle, which is responsible for intracellular motion and muscle contraction.

[0003] Tropomyosin and troponin mediate the effect that calcium has on the effects of actin and myosin. The troponin complex consists of three polypeptide chains: troponin C, which binds calcium ions; troponin I, which binds to actin; and troponin T, which binds to tropomyosin. The troponin-tropomyosin complex of the skeletal muscle simultaneously controls the myosin binding sites extending over several actin units.

[0004] Troponin, a complex of the three polypeptides described above, is an accessory protein that is closely related to actin filaments of vertebrate muscles. The troponin complex works in conjunction with the tropomyosin muscle form, mediating Ca-dependent²⁺ ATPase activity of myosin, and thus, controls muscle spasms. The troponin T, I and C polypeptide names are associated with their activity regarding tropomyosin binding, inhibition and calcium binding, respectively. Troponin T binds to tropomyosin and is believed to be responsible for the location of the troponin complex on a thin muscle filament. Troponin I binds to actin, and the complex, formed by troponin I and T and tropomyosin, inhibits the action of actin and myosin. Troponin C skeletal muscle is able to bind four atoms of calcium. Research suggests that when the calcium level in the muscles is raised, troponin C reveals the binding site for troponin I, keeping it away from actin. This causes the tropomyosin molecule to change position, and thus,

[0005] Human skeletal muscle consists of various types of contractile fibers classified according to the type of myosin and named as fast or slow fibers. Table 1 presents the various proteins that make up these muscle types.

Table 1

<td rowspan="2"></td><td colspan="2">Type of muscle fiber</td>

<td>Skeletal fast</td><td>Skeletal free</td>

<td>Myosin heavy chain</td><td>IIa (IIb *) IIx / d</td><td>Cardiac β</td>

<td>Troponin I (TnI)</td><td>TnI fast SK</td><td>TNI free SK</td>

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

<td>Troponin C (TNC)</td><td>TnC quick SK</td><td>TNC free / cardiac</td>

<td>tropomyosin</td><td>TM-p / TM-a / TPM 3</td><td>^ TM / TM-AS</td>

* MHC IIb does not occur in human muscle, but occurs in rodents and other mammals.

[0006] Most skeletal muscles in healthy people are made of both fast and free fibers, although their proportions depend on the type of muscle. Free skeletal fibers, often called Type I fibers, are structurally more similar to the myocardium and, as a rule, are mainly used to control the correct posture. They usually have a greater oxidative ability and are more resistant to prolonged fatigue. Fast skeletal muscle fibers, often called Type II fibers, are classified as quick oxygen fibers (IIa) and rapid glycolytic fibers (type IIx / d). Although these muscle fibers contain different types of myosin, they have many common elements, including troponin and tropomyosin regulatory proteins. Fast skeletal muscle fibers give more strength,

[0007] Muscle spasm and force generation is regulated by stimulation of the nervous system by innervation of motor neurons. Each motor neuron can innervate many (about 100-380) muscle fibers with different shrinkage, which we define as a motor unit. When muscle contraction is required, motor neurons send stimuli in the form of nerve impulses (action potentials) from the brain stem or spinal cord to each fiber within the motor unit. The area of ​​contact between the nerve and muscle fibers is a specialized synapse called the neuromuscular plate (NMJ). It is the depolarization of the membrane, leading to the emergence of a functional potential in the nerve, which translates into an impulse in the muscle fibers by the release of the acetylcholine neurotransmitter (ACh). ACh triggers the second action potential in the muscle,²⁺ in the sarcoplasmic reticulum (SR) of the muscle through the dihydropyridine (DHPR) receptor. DHPR stimulation triggers the second Ca channel²⁺ w SR, receptor rianodynowy, uwalniając Ca²⁺ from SR tanks to the muscle cytoplasm, where it can interact with the troponin complex, initiating muscle contraction. If muscle stimulation is stopped, calcium is rapidly withdrawn to SR by an ATP-dependent Ca pump²⁺, HEART'S.

[0008] Muscle function may be limited during disease as a result of multiple mechanisms. Such examples include frailty associated with old age (referred to as sarcopenia) and wasting syndromes associated with diseases such as malignant neoplasms, heart failure, chronic obstructive pulmonary disease (COPD) and chronic kidney disease / dialysis. Severe muscle dysfunction may be due to neuromuscular diseases (such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and myasthenia gravis) or muscle myopathy (eg muscular dystrophy). In addition, muscle function may be reduced due to rehabilitation deficiencies, such as those associated with post-operative recovery (eg muscle weakness after surgery), prolonged bedtime or rehabilitation after a stroke.

[0009] US2007 / 197507 discloses substituted urea derivatives that are useful for the treatment of systolic heart failure. US2007 / 197505 discloses substituted urea derivatives that are useful for the treatment of obesity, sarcopenia, wasting syndrome, frailty, muscle contraction, cachexia, neuromuscular diseases (e.g., amyotrophic lateral sclerosis, spinal muscular atrophy, hereditary or acquired myopathy or muscular dystrophy) ), post-operative and post-traumatic muscle weakness and other diseases.

[0010] In view of the above, there is a need for new compounds that regulate skeletal muscle contractility. There remains a current need for measures that use new mechanisms of action, and which can provide better results in terms of symptom alleviation, safety and mortality in both short- and long-term therapy, and may have a better therapeutic index.

[0011] The invention provides a compound according to claim 1 wherein Or a pharmaceutically acceptable salt thereof.

[0012] The invention also provides a pharmaceutically acceptable composition comprising a compound described herein or a pharmaceutically acceptable salt thereof.

The invention also relates to compounds described herein for use in methods of treating a disease or condition susceptible to regulating contractility of skeletal muscle sarcomas, e.g., regulating a troponin complex with a sarcomere of fast skeletal muscles with one or more myosins, actin, tropomyosin, troponin C, troponin I, troponin T building fast skeletal fibers and their fragments and isoforms.

[0014] The following words and expressions used in the present specification generally have the meanings given below, except those whose context of use suggests otherwise.

References to compounds herein include ionic, polymorphic, pseudopolymorphic forms, amorphous forms, solvates, multicomponent crystals, chelates, tautomers and / or isotopes thereof. The terms "crystal form", "polymorphic" and "new form" can be used interchangeably herein and are intended to include all crystalline and amorphous forms of this compound, including, for example, polymorphic, pseudopolymorphic forms, solvates (including hydrates). ), multi-component crystals, unsolvated polymorphic forms (including anhydrides), conformational polymorphic forms, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is mentioned. In some embodiments, references to the compounds of the present invention include polymorphic forms, solvates, multicomponent crystals and / or tautomers. In some embodiments, references to compounds herein include their polymorphic forms, solvates and / or multicomponent crystals. In some embodiments, references to compounds herein include tautomers. In some embodiments, references to compounds herein include their solvates. Similarly, the term "salts" includes the solvates of the salts of the compounds. In some embodiments, references to compounds herein include their solvates. Similarly, the term "salts" includes the solvates of the salts of the compounds. In some embodiments, references to compounds herein include their solvates. Similarly, the term "salts" includes the solvates of the salts of the compounds.

[0016] "Optional" or "optionally" means that the event or circumstance described above may or may not occur, and that such description includes the cases in which it occurs and cases in which the event or circumstance does not occur. For example, "optionally substituted alkyl" includes both "alkyl" as defined herein and "substituted alkyl". It will be understood by those skilled in the art that, with respect to any group containing one or more substituents, such groups are not intended to introduce any substitutions or substitution patterns that are spatially impractical, synthetically impossible to perform, and / or inherently unstable. .

[0017] If a range of values ​​is given (e.g., C1-6 alkyl), it includes each value in this range as well as all intermediate ranges. For example, "C1-6 alkyl" includes C1, C2,^C3^{, C}4^{, C}5^{, C}6^{, C}1-6^{, C}2-6^{, C}3-6^{, C}4-6^{, C}5-6^{, C}1-5^{, C}2-5^{, C}3-5^{, C}4-5^.C1-4, C2-4, C3-4, C1-3, C2-3 and C1-2 alkyl.

[0018] When the residue is defined as optionally substituted, it may be substituted in itself or form part of another residue. For example, when R^x is defined as "C1-6 alkyl or OC1-6alkyl, wherein C1-6alkyl is optionally substituted with halogen" is both the C1-6alkyl itself and C1-6alkyl, which is part of a group.

OC1-6alkyl may be substituted with a halogen atom.

[0019] The term "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 1-6 alkyl includes alkyls with both straight and branched chains of 1 to 6 carbon atoms. Where the name of an alkyl residue having the specified number of carbon atoms is given, it includes all branched and straight chain versions containing that number of carbon atoms; thus, for example, "propyl" includes n-propyl and isopropyl; and "butyl" includes n-butyl, sec-butyl, isobutyl and t-butyl. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. "Lower alkyl" refers to alkyl groups having from 1 to 6 carbon atoms.

[0020] "Fluoroalkyl" includes straight and branched carbon chains having the indicated number of carbon atoms (e.g., from 1 to 6 carbon atoms) substituted with at least one halogen atom. In cases where the haloalkyl group contains more than one halogen atom, halogen atoms can (e.g. dichloromethyl) or different (e.g., examples of haloalkyl groups include, without limitation, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 2) -fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl,

2,2-dichloroethyl, 2,2,2-trichloroethyl, pentachloroethyl and pentafluoroethyl.

be the same chlorofluoromethyl)

2-chloroethyl,

1,2-dichloroethyl, &amp; quot; Alkenyl &amp; quot; refers to an unsaturated branched or straight chain alkyl group having the specified number of carbon atoms (e.g., from 2 to 8 or from 2 to 6 carbon atoms) and at least one double bond carbon-carbon, formed by the removal of one hydrogen molecule from adjacent carbon atoms of the corresponding alkyl. Such a group may have a cis or trans configuration (Z or E configuration) around the double bond (s). Alkenyl groups include, without limitation, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1ene-2-yl, prop-2-en-1-yl (allyl), prop-2-ene) 2-yl) and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1) -yl, but-2-en-1-yl, but-2-en-2-yl, butyl-1,3-dien-1-yl, butyl-1,3-diene-2-yl). "Lower alkenyl" refers to alkenyl groups having from 2 to 6 carbon atoms.

[0022] "Alkynyl" refers to an unsaturated branched or straight chain alkyl group having the specified number of carbon atoms (e.g., from 2 to 8 or from 2 to 6 carbon atoms) and at least one carbon-carbon triple bond formed by removal of two hydrogen molecules from adjacent carbon atoms of the corresponding alkyl. Alkynyl groups include, without limitation, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2yn-1-yl) and butynyl (e.g., but-1-yn-1-yl, but-1- yn-3-yl, but-3-yn-1-yl). "Lower alkynyl" refers to alkynyl groups having from 2 to 6 carbon atoms.

[0023] "Cycloalkyl" means a non-aromatic, fully saturated carbocyclic ring having the specified number of carbon atoms, for example, from 3 to 10 or from 3 to 8 or from 3 to 6 ring carbon atoms. Cycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl as well as groups with bridged and cluster ring systems (e.g., norbornan, bicyclo [2.2.2] octane). In addition, one ring of the cyclic alkyl cycloalkyl group may be aromatic as long as the polycyclic cycloalkyl group is bonded to the parent structure through a non-aromatic carbon atom. For example, a 1,2,3,4-tetrahydronaphthalen-1-yl group (where the remainder is attached to the parent structure through a non-aromatic carbon atom), is a cycloalkyl group, while 1,2,3,4-tetrahydronaphthalen-5-yl (where the residue is attached to the parent structure through an aromatic carbon atom) is not considered to be a cycloalkyl group. Examples of polycyclic cycloalkyl groups containing a cycloalkyl group fused to an aromatic ring are described below.

[0024] "Cycloalkenyl" means a non-aromatic carbocyclic ring having the specified number of carbon atoms (e.g., from 3 to 10 or from 3 to 8 or from 3 to 6 carbon atoms in the ring) and at least one carbon-carbon double bond resulting from removal one hydrogen molecule from adjacent carbon atoms of the corresponding cycloalkyl. Cycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl, as well as groups with a bridged and cluster ring system (e.g., bicyclo [2.2.2] octene). In addition, one ring of a cyclicalkenyl cycloalkenyl group can be aromatic as long as the polycyclic cycloalkenyl group is bonded to the parent structure through a non-aromatic carbon atom.

For example, inden-1-yl (where the residue is attached to the parent structure through a non-aromatic carbon) is considered to be cycloalkenyl, while inden-4-yl (where the residue is attached to the parent structure via an aromatic carbon atom) , is not considered to be a cycloalkenyl group. Examples of polycyclic cycloalkenyl groups consisting of a cycloalkenyl group fused to an aromatic ring are described below.

[0025] "Aryl" means an aromatic carbon ring having the specified number of carbon atoms, for example, from 6 to 12 or from 6 to 10 carbon atoms. Aryl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some cases, both rings of the polycyclic aryl group are aromatic (e.g., naphthyl). In other cases, the polycyclic aryl groups may contain a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to the aromatic ring, provided that the polycyclic aryl is attached to the parent structure via an aromatic ring atom. Thus, a 1,2,3,4-tetrahydronaphthalen-5-yl group (where the residue is attached to the parent structure through an aromatic carbon atom) is considered to be an aryl group while 1,2,3, 4-tetrahydronaphthalen-1-yl (where the residue is attached to the parent structure through a non-aromatic carbon) is not considered to be an aryl group. Similarly, a 1,2,3,4-tetrahydroquinolin-8-yl group (where the residue is attached to the parent structure through an aromatic carbon atom) is considered to be an aryl group while the 1,2,3,4-tetrahydroquinoline groups are 1-yl, (where the remainder is attached to the parent structure through a non-aromatic nitrogen atom) is not considered to be an aryl group. However, the term "aryl" does not cover or does not coincide with the "heteroaryl" referred to herein, regardless of the point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some cases, aryl is phenyl or naphthyl. In some cases, aryl is phenyl. Additional examples of aryl groups containing an aromatic carbon ring attached to a non-aromatic ring are described below. [0026] "Arylalkyl" refers to a residue having the specified number of carbon atoms (eg, from 7 to 12 or from 7 to 10 carbon atoms) in which the aryl group is attached to the parent structure through the alkyl group. The alkyl group may be straight or branched. Examples include benzyl, phenethyl, 1-phenylethyl. The alkyl group may be straight or branched. Examples include benzyl, phenethyl, 1-phenylethyl. The alkyl group may be straight or branched. Examples include benzyl, phenethyl, 1-phenylethyl.

[0027] "Het eroaryl" means an aromatic ring containing a specified number of atoms (e.g., 5 to 12 or 5 to 10 membered heteroaryl), made up of one or several heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S, and other atoms in the carbon ring. The 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 does not exceed 2. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 1. Unless specified otherwise, heteroaryl groups may be attached to the parent structure by a carbon atom or a nitrogen atom, so long as valence allows. "pyridyl" includes the group

For example, 3-pyridyl

2-pyridyl

4-pyridyl, "pyrrolyl" includes the group

1-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl. When nitrogen is present in the heteroaryl ring, it may be in the oxidized state (i.e.⁺-ABOUT^-), if the nature of neighboring atoms and groups allows this. Furthermore, when sulfur is present in the heteroaryl ring, it may be in the oxidized state (i.e.⁺-O- or SO2), as the nature of adjacent atoms and groups allows. The heteroaryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).

[0028] In some cases, the heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g. 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g. , 2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g. 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g. 1,2,4-triazine, 1,3,5-triazine) and tetrazine.

[0029] In some cases, both rings of the polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzisothiazole, benzothiadiazole,

1H-pyrrolo [2,3-b] pyridine,

1H-pyrazolo [3,4-b] pyridine,

3H-imidazo [4,5-b] pyridine, 3H- [1,2,3] triazolo [4,5-b] pyridine,

1H-pyrrolo [3,2-b] pyridine,

1H-pyrazolo [4,3-b] pyridine,

1H-imidazo [4,5-b] pyridine, 1H- [1,2,3] triazolo [4,5-b] pyridine,

1H-pyrrolo [2,3-c] pyridine,

1H-pyrazolo [3,4-c] pyridine,

3H-imidazo [4,5-c] pyridine, 3H- [1,2,3] triazolo [4,5-c] pyridine,

1H-pyrrolo [3,2-c] pyridine,

1H-pyrazolo [4,3-c] pyridine,

1H-imidazo [4,5-c] pyridine, 1H- [1,2,3] triazolo [4,5-c] pyridine, furo [2,3-b] pyridine, oxazolo [5,4-b] pyridine , isoxazolo [5,4-b] pyridine, [1,2,3] oxadiazolo [5,4-b] pyridine, furo [3,2-b] pyridine, oxazolo [4,5-b] pyridine, isoxazole [ 4,5-b] pyridine, [1,2,3] oxadiazolo [4,5-b] pyridine, furo [2,3-c] pyridine, oxazolo [5,4-c] pyridine, isoxazole [5,4 -c] pyridine, [1,2,3] oxadiazolo [5,4-c] pyridine, furo [3,2-c] pyridine, oxazolo [4,5-c] pyridine, isoxazole [4,5-c] pyridine, [1,2,3] oxadiazolo [4,5-c] pyridine, thieno [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, isothiazolo [4,5-b] pyridine, [1,2 , 3] thiadiazolo [4,5-b] pyridine, thieno [2,3-c] pyridine, thiazolo [5,4-c] pyridine, isothiazolo [5,4-c] pyridine, [1,2,3] thiadiazolo [5,4-c] pyridine, thieno [3,2-c] pyridine, thiazolo [4,5-c] pyridine, isothiazolo [4,5-c] pyridine, [1,2,3] thiadiazolo [4,5-c] pyridine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (e.g.

1,7-naphthyridine, 1,6-naphthyridine,

2,7-naphthyridine, 2,6-naphthyridine), imidazo [1,2-a] pyridine, 1H-pyrazolo [3,4-d] thiazole, 1H-pyrazolo [4,3-d] thiazole and imidazo [2 1-b] thiazole.

examples, the polycyclic groups include a non-aromatic cycloalkenyl ring, heterocycloalkyl, fused to a heteroaryl ring, provided the polycyclic heteroaryl group is attached to the parent structure by

1,8-naphthyridine,

1,5-naphthyridine, [0030] In others, heteroaryl may (e.g., cycloalkyl, heterocycloalkenyl) an aromatic ring atom. For example, a group

4,5,6,7-tetrahydro-benzo [d] thiazol-2-yl, (where the residue is attached to the parent structure through an aromatic carbon atom), is considered a heteroaryl group whereas the 4,5,6,7-tetrahydrobenzo group [d] thiazol-5-yl, (where the residue is attached to the parent structure through a non-aromatic carbon) is not considered a heteroaryl group. Examples of polycyclic heteroaryl groups containing a heteroaryl ring fused to a non-aromatic ring are described below.

[0031] "Heterocycloalkyl" means a non-aromatic, fully saturated ring containing the specified number of atoms (e.g., 3- to 10- or 3- to 7-membered heterocycloalkyl), made up of one or several heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S atoms, and from the remaining atoms in the ring being carbon atoms. Heterocycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. When nitrogen is present in the heterocycloalkyl ring, it may be in the oxidized state (i.e.⁺-ABOUT^-), if the nature of neighboring atoms and groups allows this. Examples include piperidinyl N-oxide and morpholinyl N-oxide. Furthermore, when sulfur is present in the heterocycloalkyl ring, it may be in an oxidized state (i.e.⁺-ABOUT^- or -SO2-), as the nature of adjacent atoms and groups permits. Examples include thiomorpholine S-oxide and thiomorpholine S, S-dioxide. In addition, one ring of a polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkyl is bonded to the parent structure through a non-aromatic carbon atom or a nitrogen atom. For example, a 1,2,3,4-tetrahydroquinolin-1-yl group (where the residue is attached to the parent structure through a non-aromatic nitrogen atom) is considered to be a heterocycloalkyl group, while

1,2,3,4-tetrahydroinolin-8-yl, (where the residue is attached to the parent structure through an aromatic carbon atom), is not considered to be a heterocycloalkyl group. Examples of polycyclic heterocycloalkyl groups containing heterocycloalkyl fused to an aromatic ring are described below.

[0032] "Heterocycloalkenyl" means a non-aromatic ring containing the specified number of atoms (e.g., 3- to 10- or 3- to 7-membered heterocycloalkyl), composed of one or several heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) ) selected from N, O and S atoms, and from other atoms in the carbon ring, and from at least one double bond formed by removing one hydrogen molecule from adjacent carbon atoms, adjacent nitrogen atoms or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl. Heterocycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). When nitrogen is present in the heterocycloalkenyl ring, it may be in the oxidized state (i.e.⁺-ABOUT^-), if the nature of neighboring atoms and groups allows this. Furthermore, when sulfur is present in the heterocycloalkenyl ring, it may be in an oxidized state (i.e.⁺-ABOUT^- or -SO2-), as the nature of adjacent atoms and groups permits. Examples of heterocycloalkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrotiophenyl (e.g., 2,3-dihydrotiophenyl, 2,5-dihydrotiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H- pyrrolyl, 2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g., 2,3-dihydro-1H-imidazolyl, pyranyl, dihydropyranyl 3,6-dihydro-2H-pyranyl),

1,2,3,4-tetrahydropyridinyl, and dihydropyridine

1,4-dihydropyridine). Also,

4,5-dihydro-1H-imidazolyl), (e.g. 3,4-dihydro-2H-pyranyl, tetrahydropyridinyl) (e.g., 1,2,3,6-tetrahydropyridinyl) (e.g. 1,2-dihydropyridine, one polycyclic ring) the heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkenyl group is attached to the parent structure through a non-aromatic carbon atom or a nitrogen atom. For example, a 1,2-dihydroquinolin-1-yl group (where the remainder is attached to parent structure through a non-aromatic nitrogen atom), is considered to be a heterocycloalkenyl group while the group is

1,2-dihydroquinolin-8-yl, (where the residue is attached to the parent structure via an aromatic carbon atom), is not considered to be a heterocycloalkenyl group. Examples of polycyclic heterocycloalkenyl groups consisting of a heterocycloalkenyl group fused to an aromatic ring are described below.

Examples of polycyclic rings consisting of an aromatic ring (e.g., aryl or heteroaryl) condensed with a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenylene) include indenyl, 2,3-dihydro-1-indenyl, 1,2,3, 4-tetrahydronaphthalenyl, benzo [1,3] dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo [1,4] dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-1H-indazolyl,

2.3- dihydro-1H-benzo [d] imidazolyl, 2,3-dihydrobenzofuranyl,

1,3- dihydroisobenzofuranyl, 1,3-dihydrobenzo [c] isoxazolyl,

2.3- dihydrobenzo [d] isoxazolyl, 2,3-dihydrobenzo [d] oxazolyl,

2.3- dihydrobenzo [b] thiophenyl, 1,3-dihydrobenzo [c] thiophenyl,

1,3-dihydrobenzo [c] isothiazolyl, 2,3-dihydrobenzo [d] isothiazolyl, 2,3-dihydrobenzo [d] thiazolyl, 5,6-dihydro-4H-cyclopenta [d] thiazolyl, 4,5,6,7-tetrahydrobenzo [ d] thiazolyl, 5,6-dihydro-4H-pyrrolo [3,4-d] thiazolyl, 4,5,6,7-tetrahydrotiazolo [5,4-c] pyridinyl, indolin-2-one, indolin-3- he, isoindolin-1-on,

1H-benzo [d] imidazol-2 (3H) -one, benzofuran-3 (2H) -one, benzo [c] isoxazol-3 (1H) -one, benzo [d] oxazol-2 (3H) -one, benzo [b] thiophen-3 (2H) -one, benzo [c] isothiazol-3 (1H) -one,

1,2-dihydro-indazol-3-one, benzofuran-2 (3H) -one, isobenzofuran-1 (3H) -one, benzo [d] isoxazol-3 (2H) -one, benzo [b] thiophen-2 (3H ) -one, benzo [c] thiophen-1 (3H) -one, benzo [d] isothiazol-3 (2H) -one, benzo [d] thiazol-2 (3H) -one, 4,5-dihydro-pyrrole [3,4-d] thiazol-6-one, 1,2-dihydropyrazolo [3,4-d] thiazol-3-one, quinolin-4 (3H) -one, quinazolin-4 (3H) -one, quinazoline-2 , 4 (1H, 3H) -dione, quinoxalin-2 (1H) -one, quinoxaline-2,3 (1H, 4H) -dione, cinnolin-4 (3H) -one, pyridin-2 (1H) -one, pyrimidin-2 (1H) -one, pyrimidin-4 (3H) -one, pyridazin-3 (2H) -one, 1H-pyrrolo [3,2b] pyridin-2 (3H) -one, 1H-pyrrolo [3, 2-c] pyridin-2 (3H) -one, 1H-pyrrolo [2,3-c] pyridin-2 (3H) -one, 1H-pyrrolo [2,3-b] pyridin-2 (3H) -one, 1 , 2-dihydropyrazolo [3,4-d] thiazol-3-one and 4,5-dihydropyrrolo [3,4-d] thiazol-6-one. As discussed herein, if each ring is considered to be aryl, heteroaryl, cycloalkyl, cycloalkenyl,

[0034] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0035] "And zomers" mean different compounds that have the same molecular formula. "Stereoisomers" mean isomers that differ only in the way atoms are arranged in space. "Enantiomers" mean stereoisomers that are their non-superimposable mirror images. A 1: 1 mixture of a pair of enantiomers is a "racemic" mixture. The symbol '(±)' may be used to designate the racemic mixture, where appropriate. "Diastereoisomers" mean stereoisomers containing at least two asymmetric atoms but which are not mirror images of one another. A "meso compound" or "meso isomer" means an optically inactive member of a stereoisomeric set. The meso isomers contain two or more chiral centers, but are not chiral (i.e. there is a symmetry plane in the molecule). The absolute stereochemistry is determined according to the Cahn-Ingold-Prelog RS rule. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon can be designated as R or S. Separated compounds whose absolute configuration is unknown can be designated as (+) or (-) depending on the direction (right or left-handed) in which they twist the plane of polarized light at the wavelength corresponding to the D line of sodium. Certain compounds disclosed and / or described herein contain one or more asymmetric centers, which can lead to the formation of enantiomers, diastereomers, meso isomers and other stereoisomeric forms. Unless otherwise indicated, the compounds disclosed and / or described herein include all possible enantiomers, diastereoisomers, meso isomers or other stereoisomeric forms, including racemic mixtures, optically pure forms, diastereomers, and intermediates. Enantiomers, meso isomers and other stereoisomeric forms can be obtained using chiral synthons or chiral reagents, or can be separated by conventional techniques. Unless otherwise specified, when the compounds disclosed and / or described herein contain olefinic double bonds or other centers of geometric asymmetry, it is understood that these compounds include both E and Z isomers. or can be separated using conventional techniques. Unless otherwise specified, when the compounds disclosed and / or described herein contain olefinic double bonds or other centers of geometric asymmetry, it is understood that these compounds include both E and Z isomers. or can be separated using conventional techniques. Unless otherwise specified, when the compounds disclosed and / or described herein contain olefinic double bonds or other centers of geometric asymmetry, it is understood that these compounds include both E and Z isomers.

[0036] The stereochemistry shown for the cyclic structures of the meso compounds is not absolute; the stereochemistry is intended to rather indicate the location of the substituents in relation to each other, e.g. the cis or trans configuration.

For example, the formula:

<img file="PL2560653T3_D0001.tif" />

is intended to mean a compound in which the fluorine atom and the pyridyl substituent on the cyclobutyl ring are in the cis configuration relative to each other, while the formula:

<img file="PL2560653T3_D0002.tif" />

is intended to mean a compound in which the fluorine atom and the pyridyl substituent on the cyclobutyl ring are in trans configuration with respect to each other.

[0037] If a compound can exist in the form of one or more meso isomers, it is intended that all possible meso isomers are included within the scope of the invention. For example, the compound {[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} pyrimidin-2-ylamine is intended to include both meso, cis and trans isomers:

<img file="PL2560653T3_D0003.tif" />

and mixtures thereof. Unless otherwise indicated, the compounds disclosed and / or described herein include all possible meso isomers and mixtures thereof.

[0038] "Tauters" are structurally different isomers that go into one another following tautomerism. Tautomerism is a form of isomerization and includes prototropic tautomerism or proton location, which is considered to be part of the chemistry of acids and bases. The prototropic tautomerism or tautomery of the proton location involves the migration of the proton, which is accompanied by changes in the order of bonds, often with the replacement of a single bond into an adjacent double bond. Where tautomerism is possible (e.g. in solution), the chemical balance of the tautomers can be achieved. An example of tautomerism is keto-enol tautomerism. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenolic-ketone tautomeria.

A specific example of phenol-keto tautomerism is the reciprocal conversion of the tetromers of pyridin-4-ol and pyridin-4 (1H) -one. When the compounds described herein contain groups capable of tautomerism, the compounds are intended to include all possible tautomers unless otherwise indicated.

[0039] A "protecting group" has the meaning conventionally linked to it in organic synthesis, i.e. a group that selectively blocks one or more reactive sites in a compound having multiple functional groups, such that the chemical reaction can be selectively carried out in another unprotected reactive place, and such a group can be easily removed after completion of the selective reaction. Various protecting groups have been disclosed, for example in TH Greene and PGM Wuts, Protective Groups in Organic Synthesis, third edition, John Wiley &amp; Sons, New York (1999). For example, a "protected hydroxyl form" includes at least one hydroxyl group protected by a hydroxyl protecting group. Also, amines and other reactive groups can be protected in a similar manner.

[0040] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness 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 Science, January 1977, 66 (1), 1-19. In many cases, the compounds described herein are capable of forming salts with acids and / or bases due to the presence of amino groups and / or carboxyl groups, or groups similar to them. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and with organic acids. Inorganic acids from which salts can be obtained include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. The organic acids from which salts can be obtained include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, 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. Inorganic bases from which salts may be obtained include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum bases. The 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. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium and magnesium salts.

[0041] If a compound described herein is obtained in the form of an acid addition salt, its free base may be obtained by basifying a salt solution formed with an acid. Conversely, if the compound is in the form of the free base, the addition salt, in particular its pharmaceutically acceptable addition salt, can be obtained by dissolving the free base with a suitable organic solvent and treating the solution with an acid according to conventional acid addition salts from basic compounds (see e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Science, January 1977, 66 (1), 1-19). Those skilled in the art will recognize various synthetic methods that can be used to prepare pharmaceutically acceptable addition salts.

[0042] A "solvate" is formed as a result of the interaction of a solvent and a given compound. Suitable solvents include, for example, water and alcohols (e.g., ethanol). Solvates include hydrates with any compound to water ratio, such as monohydrates, dihydrates and hemi-hydrates.

[0043] "Chelate" is formed by coordinating the compound with a metal ion at two (or more) locations. The term "compound" is intended to include chelates of compounds. Similarly, "salts" include salt chelates, and "solvates" include chelates of solvates. [0044] A "non-covalent complex" is formed by the interaction of a compound with another molecule, as a result of which a covalent bond between the compound and the molecule is not formed.

For example, complexation can occur due to van der Waals interactions, hydrogen bonding and electrostatic interactions (also called ion bonding). Such non-covalent complexes are included in the term "compound".

[0045] The term "prodrug" refers to a substance administered in an inactive or inactive form, which is then transformed (e.g., as a result of metabolic processing of the prodrug in the body) into the active compound. The rational justification for administering the prodrug is to optimize the absorption, distribution, metabolism and / or excretion of the drug. Prodrugs can be obtained by derivatization of the active compound (e.g., a compound disclosed and / or described herein) that undergoes the conditions under which it is used (e.g., in the body) to form the active compound. Conversion of the prodrug of the active compound may proceed spontaneously (e.g., as a result of a hydrolysis reaction) or it may be catalyzed or induced by another agent (e.g., an enzyme, light, acid or base and / or temperature). The agent may be endogenous to the conditions of use (e.g., an enzyme present in cells to which the prodrug or acidic conditions are administered in the stomach), or the agent may be supplied externally. Prodrugs can be obtained by converting one or more functional groups of the active compound to another functional group that is then converted back to the original functional group upon administration to the body. For example, the hydroxyl functional group can be converted to a sulfonate, phosphate, ester or carbonate group which, in turn, can be hydrolyzed in vivo back to the hydroxyl group. Similarly, the amine functional group can be converted, for example, to an amide, carbamate, urea, imine, phosphenyl, phosphoryl or sulfenyl functional group, which can be hydrolyzed in vivo back to the amino group. The carboxylic functional group can be converted, for example, to an ester (including silyl esters and thioesters), amide or hydrazide functionality, which can be hydrolyzed in vivo back to the carboxyl group. Examples of prodrugs include, without limitation, phosphate, acetate, formate and benzoate derivatives of functional groups (such as hydroxyl or amine groups) present in the compounds disclosed and / or described herein.

[0046] The compounds disclosed and / or described herein may be isotopically enriched forms e.g. enriched with a content ²H ³H

C

C and / or ¹⁴C.

In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be obtained, for example, according to the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. Such deuterated compounds may improve the efficacy and increase the lifetime of the compounds disclosed and / or described herein. Deuterium-substituted compounds can be synthesized using various methods such as those described in: Deanem, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000; 6 (10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21), 6601-21; and Evans, E. Synthesis of radiolabeled compounds,

J. Radioanal. Chem., 1981, 64 (1-2), 9-32.

[0047] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes all solvents, dispersing agents, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents with pharmaceutically active substances is well known in the art. Except insofar as any conventional medium or agent is incompatible with the active substance, its use in pharmaceutical compositions is contemplated. Additional active ingredients may also be included in the pharmaceutical composition.

[0048] The term "active substance" is used to indicate that the compound has biological activity. In some embodiments, the term "active substance" means a compound having therapeutic utility. In some embodiments, such a compound increases at least one aspect of skeletal muscle activity or activity, such as the output power, skeletal muscle strength, skeletal muscle strength, oxygen consumption, yield and / or calcium sensitivity. In some embodiments, the active ingredient is a compound described herein or a pharmaceutically acceptable salt thereof.

[0049] 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 subject or subject is a human, for example, a human who has been or will be the object of treatment, observation or experiment. The compounds, compositions and methods described herein may be useful both for human treatment and in veterinary applications.

[0050] As used herein, the term "skeletal muscle" includes skeletal muscle tissue as well as components such as skeletal muscle fibers, myofibrils containing skeletal muscle fibers, skeletal muscle sarcomere, which includes myofibrils and various components of skeletal muscle sarcomere described herein the document, including myosin, actin, tropomyosin, troponin C, troponin I, troponin T skeletal muscles and fragments and isoforms thereof. In some embodiments, the &amp; quot; skeletal muscle &amp; quot; includes skeletal muscle tissue composed of fast fibers, as well as components thereof, such as fast skeletal muscle fibers, myofibrils containing fast skeletal muscle fibers, a sarcomnet of fast skeletal muscle fibers, which includes myofibrils and various components of the herein described sarcomere of fast skeletal muscle fibers, including myosin, actin, tropomyosin, troponin C, troponin I, troponin T of fast skeletal muscle fibers and fragments thereof, and isoforms. Skeletal muscle does not include cardiac muscle or a combination of sarcomer components that are present in such a combination entirely in the myocardium. [0051] The term "therapeutic" as used herein refers to the ability to regulate rapid skeletal muscle contractility. As used herein, the term "regulation" (and related terms, such as "regulate", "regulated", "regulate") refers to a change in the action or performance of one or more components of the skeletal muscle sarcomer, including myosin, actin, tropomyosin, troponin C, troponin I and troponin T of rapid skeletal muscle, including fragments and isoforms, as a direct or indirect reaction for the presence of a compound described herein, relative to the activity of the rapid skeletal muscle sarcomer present in the absence of a compound. This change may be an increase in activity (increase) or decrease in activity (inhibition) and may result from the direct interaction of the compound with the sarcomere, or may result from the interaction of the compound with one or more other factors that in turn affect the sarcomere or one. or a few of its ingredients. In some embodiments, regulation means increasing the activity or fitness of one or more components of the skeletal muscle sarcomer, including myosin, actin, tropomyosin, troponin C, troponin I and troponin T rapid skeletal muscles, including fragments and isoforms. Regulation can occur according to any mechanism and at any physiological level, for example, by sensitization of the fast skeletal muscle sarcomer to shrinkage at lower Ca concentrations.²⁺. The term "fitness" or "muscle efficiency" as used herein means the ratio of mechanical work done to total metabolic cost.

[0052] The term "therapeutically effective amount" or "effective amount" refers to that amount of a compound disclosed and / or described herein that is sufficient to affect the treatment described herein when administered to a patient in need of such treatment. The therapeutically effective amount of the compound may be in an amount suitable for the treatment of diseases responsive to the regulation of skeletal muscle fast. The therapeutically effective amount will vary depending on, for example, the condition of the patient and the disease being treated, the patient's weight and age, the severity of the disease, the particular compound, the dosing schedule to be followed, the time of administration, the mode of administration, all of which can be easily determined by a specialist in the field.

[0053] The term "treatment" (and related terms, such as "treat", "treated", "treatment") includes one or more actions: preventing the onset of a disease or disorder (i.e., the clinical symptoms of the disease or disorder do not arise; a) inhibiting the disease or disorder; slowing or stopping the development of clinical symptoms of the disease or disorder; and / or relieving the disease or disorder (i.e., regression or regression of clinical symptoms). The term includes situations in which the disease or disorder has already occurred in the patient, as well as situations where the disease or disorder has not occurred at the moment, but is expected to occur. The term includes both total and partial alleviation or prevention of a disorder or disorder, and total or partial reduction of clinical symptoms of the disease or disorder. Thus, the compounds described and / or disclosed herein can prevent the progression of an existing disease or disorder, help to treat a disease or disorder, or alleviate or eliminate a disease or disorder. When used in prophylactic form, the compounds disclosed and / or described herein may prevent the development of a disease or disorder, or reduce the severity of the disease or disorder that may occur. As used herein, the term muscle "strength" means work / cycle time and can be scaled in PoLo units / cycle time based on muscle properties. Power can be adjusted by changing, for example, activating parameters during cyclic length changes,

[0054] "ATPase" refers to an enzyme that hydrolyzes ATP. ATPases include proteins that are motor molecules, such as myosin.

[0055] As used herein, the term "selective binding" or "selectively bind" refers to selective binding to a target protein in one type of muscle or muscle fiber; unlike other types. For example, the compound selectively binds to troponin C fast skeletal fibers if the compound preferentially binds to troponin C in the troponin complex of rapid skeletal muscle fiber or sarcomere, compared to troponin C in the troponin complex of free muscle fiber or sarcomere, or to troponin C in the troponin complex of the cardiac sarcomere.

[0056] The invention also provides a compound selected from:

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

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

4-fluoro-3-[2-({[3-fluoro-1-(3-fluoro-(2-pirydylo))cyklobutylo]metylo}amino)pirymidyn-5-ylo]benzamidu;

{4-fluoro-3- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] phenyl} -N-metylokarboksyamidu;

{4-fluoro-3- [2 - ({[trans-3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] phenyl} -N-metylokarboksyamidu;

4-fluoro-3- (2 - ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -2-hydroxybenzamide;

3- (2 - ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -4-hydroxy-N-methylbenzamide;

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

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

4- [2 - ({[trans-3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] pyridine-2-carboxamide or a pharmaceutically acceptable salt thereof;

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

1- [2 - ({[trans-3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] pyrazole-4-carboxamide;

1- (2 - ((3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -1H-pyrrole-3-carboxamide;

1- (2 - (((trans) -3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -1H-pyrrole-3-carboxamide;

2- [2 - ({[(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] -1,3-thiazole-5-carboxamide;

2- (2- (2 - ((1- (3-chloropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -thiazol-5-yl) acetamide; and

2- (2 - ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) thiazole-5-carboxamide;

or a pharmaceutically acceptable salt thereof.

[0057] The compounds and compositions described and / or disclosed herein control the shrinkage of the skeletal muscle sarcomere. In particular, these compounds regulate the troponin complex of the rapid skeletal muscle sarcomer through one or more myosins, actin, tropomyosin, troponin C, troponin I, troponin T, rapid skeletal fibers, and fragments and isoforms thereof. The term "regulate" used in this context means increasing or decreasing activity. In some cases, the compounds described and / or disclosed herein enhance the activity (i.e., increase the activity) of one or more myosins, actin, tropomyosin, troponin C, troponin I, troponin T of quick skeletal fiber and fragments thereof and isoforms. In other cases, the compounds described and / or disclosed herein, inhibit the activity (i.e.

[0058] In both preclinical and clinical studies, troponin complex activators of fast skeletal muscle have been shown to enhance the response of fast skeletal muscles to nerve stimulation, which results in increased muscle strength at submaximal muscle activation (see, e.g., Russell et al., "The Fast Skeletal Troponin Activator, CK2017357, Increases Skeletel Muscle Force in vitro and in situ ", 2009 Experimental Biology Conference, New Orleans, LA, April 2009). The troponin complex of rapid skeletal muscle has been shown to increase the sensitivity to calcium of skeletal muscle fibers separated from the skin, and in working muscles, the frequency of stimulation, which in any case leads to increased muscle strength at submaximal muscle activation. It was also shown^th Cachexia Conference, Barcelona, ​​Spain, December 2009; Hinken et al., "The Fast Skeletal Troponin Activator, CK2017357, 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). An increase in muscle strength in response to a nervous stimulus has also been demonstrated in healthy volunteers (see, e.g., Hansen et al., "CK-2017357, and Novel Activator of Fast Skeletal Muscle, Increases Isometric Force, Evoked by Electrical Stimulation of Anterior. Tibialis Muscle in Healthy Male Subjects ", Society for Neuroscience 40^th Annual Meeting: Neuroscience 2010, November 2010). A study of additional preclinical models of muscle activity suggests that troponin complex activators of fast skeletal fibers also increase muscle power and / or strength. These pharmacological properties indicate that this mechanism of action may be applicable, for example, under conditions in which neuromuscular functions are attenuated.

Ujawniono sposoby zwiększania sprawności szybkich mięśni szkieletowych u pacjenta, który tego wymaga, obejmujące podawanie wspomnianemu pacjentowi skutecznej ilości związku lub kompozycji opisanych i/lub ujawnionych w niniejszym dokumencie, które selektywnie wiążą kompleks troponinowy szybkich włókien mięśni szkieletowych lub sarkomeru. W niektórych wykonaniach, związek ujawniony i/lub opisany w niniejszym dokumencie aktywuje szybkie włókna mięśni szkieletowych i sarkomery. W niektórych wykonaniach, podawanie związku ujawnionego i/lub opisanego w niniejszym dokumencie powoduje wzrost mocy szybkich mięśni szkieletowych. W niektórych wykonaniach, podawanie związku ujawnionego i/lub opisanego w niniejszym dokumencie powoduje zwiększoną wrażliwość szybkich włókien mięśni szkieletowych i sarkomerów na jony wapnia, w stosunku do szybkich włókien mięśni szkieletowych i sarkomerów nieleczonych tym związkiem. W niektórych wykonaniach, podawanie związku ujawnionego i/lub opisanego w niniejszym dokumencie prowadzi do zmniejszenia stężenia jonów wapnia, powodującego, że miozyna szybkiego mięśnia szkieletowego wiąże się z aktyną. W niektórych wykonaniach, podawanie związku ujawnionego i/lub opisanego w niniejszym dokumencie powoduje, że szybkie włókna mięśni szkieletowych generują większą siłę przy submaksymalnym poziomie aktywacji mięśni.

[0059] Ujawniono również sposób uwrażliwiania szybkich włókien mięśni szkieletowych na wytwarzanie siły w odpowiedzi na niskie stężenie jonów wapnia, obejmujący doprowadzenie do kontaktu między szybkim włóknem mięśnia szkieletowego i związkiem lub kompozycją opisanymi i/lub ujawnionymi w niniejszym dokumencie, które selektywnie wiążą się z kompleksami troponinowymi w sarkomerze szybkich mięśni szkieletowych. W niektórych wykonaniach, doprowadzenie do kontaktu między szybkim włóknem mięśni szkieletowych i związkiem powoduje aktywację szybkich włókien mięśni szkieletowych przy niższym stężeniu jonów wapnia niż w przypadku nieleczonych szybkich włókien mięśni szkieletowych. W niektórych wykonaniach, doprowadzenie do kontaktu między szybkim włóknem mięśni szkieletowych i związkiem powoduje wytworzenie większej siły przy niższym stężeniu jonów wapnia w porównaniu z nieleczonym szybkim włóknem mięśni szkieletowych.

[0060] Uj awniono także sposób wydłużenia czasu do wystąpienia zmęczenia szybkich mięśni szkieletowych u pacjenta potrzebującego takiego działania, obejmujący doprowadzenie do kontaktu między szybkimi włóknami mięśni szkieletowych i związkiem lub kompozycją opisanymi i/lub ujawnionymi w niniejszym dokumencie, które selektywnie wiążą się z kompleksami troponinowymi szybkich włókien mięśni szkieletowych. W niektórych wykonaniach, związek wiąże się tworząc kompleksy ligand-troponina-jon wapnia, które aktywują szybkie włókna mięśni szkieletowych. W niektórych wykonaniach, utworzenie kompleksów i/lub aktywacja szybkich włókien mięśni szkieletowych prowadzi do zwiększenia siły i/lub wydłużenia czasu do wystąpienia zmęczenia w porównaniu z nieleczonymi szybkimi włóknami mięśni szkieletowych, które poddano działaniu podobnego stężenia jonów wapnia.

[0061] Związki i kompozycje farmaceutyczne opisane i/lub ujawnione w niniejszym dokumencie są zdolne do regulowania kurczliwości sarkomeru w warunkach in vivo i szybkich mięśni szkieletowych mogą mieć zastosowanie zarówno w chorobach ludzi jak i zwierząt. Takie regulowanie byłoby pożądane w licznych schorzeniach lub chorobach, w tym bez ograniczenia: 1) zaburzeniach nerwowo-mięśniowych, takich jak stwardnienie zanikowe boczne (ALS), rdzeniowy zanik mięśni (SMA), neuropatie obwodowe i miastenia rzekomoporaźna; 2) zaburzeniach mięśni zależnych od woli, w tym w dystrofiach mięśniowych, miopatiach i schorzeniach związanych z utratą mięśni, takich jak sarkopenia i zespoły wyniszczenia (np. zespół wyniszczenia spowodowany chorobami, takimi jak nowotwory złośliwe, niewydolność serca, przewlekła obturacyjna choroba płuc (POChP) i przewlekła choroba nerek/dializy), brakami rehabilitacyjnymi, takimi jak te związane z rekonwalescencją pooperacyjną (np. pooperacyjne osłabienie mięśni), długotrwałe leżenie w łóżku lub rehabilitacja po udarze; 3) zaburzeniach ośrodkowego układu nerwowego (OUN), w których głównymi objawami są osłabienie mięśni, atrofia i zmęczenie, takich jak stwardnienie rozsiane, choroba Parkinsona, udar mózgu i uraz rdzenia kręgowego; oraz 4) objawach mięśniowych wynikających z zaburzeń ogólnoustrojowych, w tym chorobie naczyń obwodowych (PVD) lub chorobie tętnic obwodowych (PAD) (np. chromania), zespole metabolicznym, syndromie chronicznego zmęczenia, otyłości i wątłości wynikającej ze starzenia się.

[0062] Związki i kompozycje opisane i/lub ujawnione w niniejszym dokumencie mogą być stosowane do leczenia chorób nerwowo-mięśniowych, czyli chorób, które wpływają na dowolną część jednostki nerwowo-mięśniowej. Choroby nerwowo-mięśniowe obejmują, na przykład: 1) choroby związane z jednostką motoryczną, w tym, bez ograniczenia, stwardnienie zanikowe boczne (ALS), w tym postać opuszkową i pierwotną stwardnienia bocznego (PLS); rdzeniowy zanik mięśni typu 1-4; zespół Kennedy'ego; zespół post-polio; neuropatie motoryczne, w tym, na przykład, polineuropatię stanu krytycznego; wieloogniskową neuropatię ruchową z blokiem przewodzenia; chorobę

Charcota-Mariego-Tootha i inne dziedziczne neuropatie motoryczne i sensoryczne; i zespół Guillaina-Barrego, 2) zaburzenia połączeń nerwowo-mięśniowych, w tym miastenię rzekomoporaźną, zespół miasteniczny Lamberta-Eatona i przedłużoną blokadę nerwowo-mięśniową wywołaną narkotykami lub toksynami; i 3) neuropatie obwodowe, takie jak ostra zapalna poliradikuloneuropatia demielinizacyjna, neuropatia cukrzycowa, przewlekła zapalna poliradikuloneuropatia demielinizacyjna, uszkodzenia urazowe nerwów obwodowych, neuropatia wywołana trądem, neuropatia naczyniowa, zapalenie skórno-mięśniowe/zapalenie wielomięśniowe i neuropatia wywołana ataksją Friedricha.

[0063] Związki i kompozycje opisane i/lub ujawnione w niniejszym dokumencie mogą być stosowane do leczenia zaburzeń mięśni zależnych od woli. Zaburzenia mięśni zależnych od woli obejmują: 1) dystrofie mięśniowe (w tym, na przykład,

Beckera, obręczowo-kończynową, obręczowo-kończynową, i wrodzone dystrofie dystrofię Duchenne'a, twarzowo-łokietkowo-ramienną,

Emery'ego-Dreyfusa, oczno-gardłową mięśniowe); oraz 2) miopatie, takie jak miopatia nemalinowa, choroby centralnego rdzenia, wrodzone miopatie, miopatie mitochondrialne, miopatia ostra; miopatie zapalne (takie jak zapalenie skórno-mięśniowe/zapalenie wielomięśniowe i wtrętowe zapalenie mięśni), miopatie w chorobach układu wewnątrzwydzielniczego (takie jak te związane z nadczynnością lub niedoczynnością tarczycy), zespół Cushinga lub Addisona, lub choroby i zaburzenia gruczołów przysadki, miopatie metaboliczne (takie jak choroby spichrzeniowe glikogenu, np. choroba McArdle'a, choroba Pompego, itp.), miopatię polekową (statyny, leki antyretrowirusowe, miopatia sterydowa), chorobę restrykcyjną płuc, sarkoidozę, zespół Schwartza-Jampela, ogniskowe zaniki mięśni i miopatie dystalne.

[0064] Związki i kompozycje opisane i/lub ujawnione w niniejszym dokumencie mogą być stosowane do leczenia stwardnienia zanikowego bocznego (ALS). ALS jest chorobą, która zwykle pojawia się w późniejszym okresie życia (wiek 50+) oraz szybko postępuje; od początkowej słabości kończyn do porażenia i śmierci. Przeciętna długość życia po rozpoznaniu wynosi 3-5 lat. Przyczyna choroby u większości pacjentów z ALS jest nieznana (określana jako forma samoistna), a niewielki odsetek pacjentów ma odziedziczoną postać choroby (genetyczną). Schorzenie powoduje postępującą śmierć neuronów motorycznych, której przyczyny nie są jasne. Jednostki motoryczne, które przetrwały, próbują zrównoważyć jednostki umierające przez unerwienie większej liczby włókien (zwane tworzeniem), ale może to tylko częściowo poprawić działanie mięśni, ponieważ mięśnie są, w konsekwencji, bardziej podatne na problemy koordynacyjne i zmęczenie. Ostatecznie, neurony motoryczne, które przetrwały, umierają, co prowadzi do całkowitego paraliżu zaatakowanych mięśni. Choroba jest często śmiertelna poprzez ostateczną utratę unerwienia przepony, co prowadzi do niewydolności oddechowej. Obecne możliwości leczenia ALS są ograniczone.

[0065] Związki i kompozycje opisane i/lub ujawnione w niniejszym dokumencie mogą być stosowane do leczenia rdzeniowego zaniku mięśni (SMA). SMA jest chorobą genetyczną, która powstaje na skutek mutacji białka SMN1, które wydaje się być niezbędne do przetrwania i normalnego działania neuronów motorycznych. Choroba występuje najczęściej u dzieci, jako że większość pacjentów dożywa tylko do 11-12 roku życia. Leczenie SMA nie jest obecnie dostępne.

[0066] Związki i kompozycje opisane i/lub ujawnione w niniejszym dokumencie mogą być stosowane do leczenia miastenii rzekomoporaźnej. Miastenia jest przewlekłą autoimmunologiczną chorobą nerwowo-mięśniową, w której organizm wytwarza przeciwciała, które blokują, zmieniają lub niszczą białka uczestniczące w przekazywaniu sygnału w połączeniach nerwowo-mięśniowych, co zapobiega wystąpieniu skurczu mięśni. Białka te obejmują receptor nikotynowy acetylocholiny (AChR) lub, rzadziej, mięśniowo-specyficznej kinazy tyrozynowej (MuSK), uczestniczący w tworzeniu klastrów AChR (patrz, np. Drachman, N. Eng. J. Med., 330: 1797-1810, 1994). Choroba charakteryzuje się różnym stopniem osłabienia mięśni szkieletowych (zależnych od woli) ciała. Cechą charakterystyczną miastenii jest osłabienie mięśni, które zwiększa się w okresach aktywności i zmniejsza po okresie spoczynku. Chociaż miastenia może mieć wpływ na wszelkie mięśnie zależne od woli, niektóre mięśnie, takie jak te, które kontrolują ruch oczu i powiek, wyraz twarzy, żucie, mowę i połykanie, są często, ale nie zawsze, objęte tym zaburzeniem. Może ono mieć również wpływ na mięśnie, które kontrolują oddychanie i ruch szyi oraz kończyn. W większości przypadków pierwszym objawem jest widoczne osłabienie mięśni oka. W innych przypadkach, pierwszymi oznakami mogą być trudności w przełykaniu i zaburzenia mowy. Stopień osłabienia mięśni objętych miastenią różni wśród pacjentów; od postaci miejscowej, ograniczonej do mięśni oka (miastenia oczna), do ciężkiej i uogólnionej postaci, która dotyczy wielu mięśni w tym czasami tych, które kontrolują oddychanie. Objawy, które różnią się pod względem rodzaju i nasilenia, mogą obejmować opadanie jednej lub obu powiek (ptoza), niewyraźne lub podwójne widzenie (diplopia) wynikające z osłabienia mięśni, które kontrolują ruchy gałek ocznych, niestabilny lub kołyszący chód, osłabienie ramion, rąk, palców, nóg i szyi, zmiany wyrazu twarzy, trudności w połykaniu i duszność, i zaburzenia mowy (dyzartria). Uogólnione osłabienie rozwija się u około 85% pacjentów.

[0067] The compounds and compositions described and / or disclosed herein can be used to treat sarcopenia, e.g., sarcopenia associated with aging and disease (e.g., HIV infection). Sarcopenia is characterized by loss of mass, quality and resistance of skeletal muscles. Clinically, a decrease in skeletal muscle mass (muscle wasting) contributes to the frailty of older people. In men aged 50 to 80, muscle mass decreases by one third. In elderly people, prolonged hospital stay can lead to further deepening of atrophy, leading to a possible loss of the ability to live independently and to an avalanche reduction of physical fitness. In addition, the process of physical aging deeply affects the structure of the body, including a significant reduction in lean body mass and an increase in the amount of adipose tissue in the middle part of the body. Changes in the overall amount and distribution of adipose tissue appear to be important factors in many diseases commonly associated with age, such as hypertension, glucose intolerance, diabetes, dyslipidemia, atherosclerosis and cardiovascular diseases. In addition, it is possible that age-related loss of muscle mass, and then strength and endurance, may be a critical factor in the loss of fitness, dependence and disability. Muscle weakness is also an important factor in making older people prone to falls and the resulting morbidity and mortality. Changes in the overall amount and distribution of adipose tissue appear to be important factors in many diseases commonly associated with age, such as hypertension, glucose intolerance, diabetes, dyslipidemia, atherosclerosis and cardiovascular diseases. In addition, it is possible that age-related loss of muscle mass, and then strength and endurance, may be a critical factor in the loss of fitness, dependence and disability. Muscle weakness is also an important factor in making older people prone to falls and the resulting morbidity and mortality. Changes in the overall amount and distribution of adipose tissue appear to be important factors in many diseases commonly associated with age, such as hypertension, glucose intolerance, diabetes, dyslipidemia, atherosclerosis and cardiovascular diseases. In addition, it is possible that age-related loss of muscle mass, and then strength and endurance, may be a critical factor in the loss of fitness, dependence and disability. Muscle weakness is also an important factor in making older people prone to falls and the resulting morbidity and mortality. and then strength and endurance, can be a critical factor in the loss of fitness, dependence and disability. Muscle weakness is also an important factor in making older people prone to falls and the resulting morbidity and mortality. and then strength and endurance, can be a critical factor in the loss of fitness, dependence and disability. Muscle weakness is also an important factor in making older people prone to falls and the resulting morbidity and mortality.

[0068] The compounds and compositions described and / or disclosed herein can be used to treat cachexia. Cachexia is a condition often associated with malignancy or other serious diseases or diseases (eg chronic obstructive pulmonary disease, heart failure, chronic kidney disease, renal dialysis), which is characterized by progressive weight loss, muscular dystrophy and fatigue resulting from impoverishment in adipose tissue and skeletal muscles.

[0069] The compounds and compositions described and / or disclosed herein can be used to treat muscular dystrophies. Muscular dystrophy is characterized by progressive muscle weakness, destruction and regeneration of muscle fibers, and the possible replacement of muscle fibers with fibrous or fat connective tissue.

[0070] The compounds and compositions described and / or disclosed herein can be used to treat post-operative muscle weakness, which means reducing the strength of one or more muscles as a consequence of a surgical operation. This weakness can be generalized (i.e., weakening of the whole body) or located in a specific area, side of the body, limb or muscle.

[0071] The compounds and compositions described and / or disclosed herein can be used to treat post-traumatic muscle weakness, which means reducing the strength of one or more muscles resulting from injury (e.g., injury). This weakness can be generalized (i.e., weakening of the whole body) or located in a specific area, side of the body, limb or muscle.

[0072] 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 artery disease (PAD). Peripheral vascular disease is a disease or disorder of the circulatory system, outside the brain and the heart. Peripheral arterial disease (PAD), also known as peripheral arterial occlusive disease (PAOD), is a form of PVD in which a partial or complete obstruction of the artery, usually that leading to the thigh or arm, occurs. PVD and / or PAD may be the result of, for example, atherosclerosis, an inflammatory process leading to stenosis, embolism / thrombus or damage to blood vessels resulting from disease (e.g., diabetes), infection or injury. PVD and / or PAD may cause acute or chronic ischemia; usually legs. Symptoms of PVD and / or PAD include pain, weakness, numbness or muscle spasms resulting from decreased blood flow (claudication), muscle pain, soreness, cramps, numbness or fatigue that occurs during movement and subsides after a short rest period (intermittent claudication) , pain during rest (resting pain) and loss of biological tissue (gangrene). Symptoms of PVD and / or PAD often occur in the calf muscles, but symptoms can also be observed in other muscles, such as the muscles of 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 with ischemic heart disease, or after a heart attack or stroke, they usually develop PVD and / or PAD at an increased frequency. The troponin complex of rapid skeletal muscle activators has been shown to reduce muscle fatigue and / or prolong the overall time to fatigue in a model of in vitro and in-vitro failure of blood vessels (see, e.g., Russell et al., The Fast Skeletal Troponin Activator, CK2017357, Increases Skeletel Muscle Force and Reduces Muscle

Fatigue in vitro and in situ ", 5^th Cachexia Conference, Barcelona, ​​Spain, December 2009; Hinken et al., "The Fast Skeletal Troponin Activator, CK2017357, Reduces Muscle Fatigue in an In-Situ Model of Vascular Insufficiency", Society for Vascular Medicine's 2010 Annual Meeting: 21^stAnnual Scientific Sessions, Cleveland, OH, April 2010). [0073] The compounds and compositions described and / or disclosed herein can be used to treat the symptoms of frailty, e.g., aging-related frailty. Stool is characterized by one or more of the following symptoms: unintentional weight loss, muscle weakness, slow gait, fatigue and limited physical activity. [0074] The compounds and compositions described and / or disclosed herein may have weakness and / or fatigue in cachexia, which is unintentional weight loss with fever and diarrhea. In no

<td>be</td><td>used to</td><td>treatment</td>

<td>muscles</td><td>resulting</td><td>from the team</td>

<td>the state</td><td colspan="2">characterized by</td>

<td>the body</td><td>connected with</td><td>chronic</td>

<td>tórych</td><td>cases</td><td>patients with</td>

Wasting syndrome loses 10% of their original body weight in one month.

[0075] The compounds and compositions described and / or disclosed herein can be used to treat muscle diseases and diseases 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, with inclusion bodies), myotonic syndromes, diseases affecting muscular ion channels, malignant hyperthermia, metabolic myopathies, congenital myasthenic syndromes, sarcopenia, muscle atrophy and cachexia.

[0076] The compounds and compositions described and / or disclosed herein can be used to treat diseases and conditions caused by muscle dysfunction resulting from neuronal dysfunction or neuronal conduction, including amyotrophic lateral sclerosis, spinal muscular atrophy, hereditary ataxia, hereditary motor neuropathies and sensory, hereditary paraplegia, stroke, multiple sclerosis, brain injuries with motor deficits, spinal cord injuries, Alzheimer's disease, Parkinson's disease with motor deficits, myasthenia gravis and Lambert-Eaton syndrome.

[0077] The compounds and compositions described and / or disclosed herein can also be used to treat diseases and conditions caused by the CNS, spinal cord and muscle dysfunction resulting from endocrine and / or metabolic disorders, including thyroid chromania, diabetes, and disease peripheral arteries, hyperactivity or hypoparathyroidism, adrenal dysfunction, pituitary function abnormalities, and acid-base imbalance disorders.

[0078] 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 abovementioned disorders.

[0079] The compounds and compositions described and / or disclosed herein can be combined with one or more other therapies for the treatment of 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 for treating a subject suffering from ALS.

[0080] The compounds and compositions described and / or disclosed herein can be combined with one or more other therapies for post-operative myasthenia gravis. Examples of suitable therapies include the administration of anticholinesterase drugs (e.g., neostigmines, pyridostigmines) that help increase neuromuscular function and increase muscle strength; administration of immunosuppressive drugs (e.g., prednisone, cyclosporin, azathioprine, mycophenolate mofetil) that improve muscle endurance by inhibiting the production of abnormal antibodies; tymctomy (ie surgical removal of the thymus, which is often abnormal in patients with myasthenia gravis); plasmapheresis; and intravenous immunoglobulins.

[0081] The compounds and compositions described and / or disclosed herein can be combined with one or more other therapies for the treatment of PVD or PAD (e.g., claudication). Treatment of PVD and PDA, in general, aims to increase arterial blood flow, for example, by quitting smoking, controlling blood pressure, controlling diabetes and exercising. Treatment may also include medications such as medicines that help to extend walking distance without experiencing pain (eg cilostazol, pentoxifylline), antiplatelet agents (eg aspirin, ticlopidine, clopidogrel) anticoagulants (eg heparin, low molecular weight heparin, warfarin, enoxaparin), thrombolytics , blood pressure-lowering agents (e.g., diuretics, angiotensin-converting enzyme inhibitors, calcium channel blockers, beta-blockers, angiotensin II receptor antagonists), as well as cholesterol-lowering agents (e.g., statins). Some patients may require angioplasty, stenting or surgery (eg, coronary artery bypass surgery or surgical removal of atherosclerotic plaque).

[0082] Suitable therapeutic agents include, for example, anti-obesity agents, anti-sarcopenia agents, anti-wasting agents, anti-frailty agents, anti-cachectic agents, anti-muscular contractures, anti-post-operative and post-traumatic muscle weakening agents and anti-neuromuscular agents.

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

Other suitable therapeutic agents include TRH, diethylstilbesterol, theophylline, enkephalins, E series prostaglandins, compounds disclosed in U.S. Patent No. 3,239,345 (e.g., zeranol), compounds disclosed in U.S. Patent No. 4,036,979 (e.g., sulbenox), peptides disclosed in the patent No. 4,411,890, growth hormone secretagogues, such as GHRP-6, GHRP-1 (disclosed in U.S. Patent No. 4,411,890 and 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 analogs and somatomedins including IGF-1 and IGF -2, alpha-adrenergic agonists such as clonidine agonists or 5-HTD serotonin, 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).

[0085] That is, 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). [0086] Other suitable therapeutic agents include anabolic agents such as selective androgen receptor modulators (SARMs); antagonists of the activin receptor pathway, such as myostatin antibodies or soluble decoy receptor receptors, including ACE 031 (Acceleron Pharmaceuticals, type of soluble antagonist of type IIB activin receptor), MYO-027 / PFE-3446879 (Wyeth / Pfizer, myostatin antibody inhibitor), AMG-745 (Amgen, myostatin inhibitor peptide antibody) and ActRIIB decoy receptor (see, Zhou et al. in, Cell, 142, 531-543, August 20, 2010); and anabolic steroids.

[0087] That is, other suitable therapeutic agents include aP2 inhibitors, such as those disclosed in US Patent No. 6,548,529, PPAR gamma antagonists, PPAR-delta agonists, beta 3 adrenergic receptor agonists such as AJ9677 (Takeda / Dainippon), L750355 (Merck ) or CP331648 (Pfizer), other beta 3 adrenergic receptor agonists disclosed in US Patent No. 5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064, a lipase inhibitor such as orlistat and ATL-962 a serotonin reuptake inhibitor such as sibutramine, topiramate (Johnson &amp; amp; Johnson) or aksokinę (Regeneron), a thyroid beta receptor drug, such as the thyroid receptor ligand disclosed (Alizyme), (and dopamine), vitronectin, hydroxy prostanoids, inhibitors

tibolone

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

[0088] That is, other suitable therapeutic agents include those used in HIV and AIDS therapy such as indinavir sulphate, saquinavir, saquinavir messenger, ritonavir, lamivudine, zidovudine, the combination of lamivudine / zidovudine, zalcitabine, didanosine, stavudine and megestrol acetate.

[0089] That is, other suitable therapeutic agents include antiresorptives, hormone therapies, vitamin D analogs, elemental calcium and calcium supplements, cathepsin K inhibitors, MMP inhibitors, antagonists of the Src SH.sub.2 antagonists,

H⁺-ATP-ases, ipryflawone, fluoride, hydroxysteroid dehydrogenase inhibitors and Src kinase inhibitors.

[0090] The foregoing therapeutic agents, if used in combination with the compounds and compositions disclosed and / or described herein, can be used, for example, in the amounts indicated in the Physicians' Desk Reference (PDR) or otherwise determined by a specialist in the field.

[0091] The compounds and compositions disclosed and / or described herein are administered at a therapeutically effective dose, e.g. a dose sufficient to provide treatment for the disease state. Although human dosage levels still need to be optimized for the compounds described herein, in general, the daily dose ranges from about 0.05 to 100 mg / kg body weight; in some embodiments, from about 0.10 to 10.0 mg / kg of body weight, and transdermal, vaginal, in some embodiments from about 0.15 to 1.0 mg / kg of body weight. Thus, when administered to a 70 kg person, in some embodiments, the dosage range should be about 3.5 to 7,000 mg per day; in some embodiments, from 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 chemical substance to be administered will depend, for example, on the patient and severity of the disease being treated, the severity of the disease, the manner and schedule of administration, and the judgment of the prescribing physician. For example, the exemplary dosage range for oral administration is from about 70 mg to about 700 mg per day, and the example intravenous dose is from about 70 mg to about 700 mg per day, in each case, depending on the pharmacokinetics of the compound.

[0092] The administration of the compounds and compositions disclosed and / or described herein may include any acceptable mode of administration of therapeutic agents including, without limitation, oral, sublingual, subcutaneous, parenteral, intravenous, nasal, topical, intraperitoneal, intramuscular, rectal or intraocular administration . In embodiments, the compound or composition is administered orally or intravenously. In some embodiments, the compound or composition disclosed and / or described herein is administered orally.

intra-pleated, some [0093] Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as a tablet, capsule, powder, liquid, suspension, suppository or aerosol. The compounds disclosed and / or described herein can also be administered in a sustained or controlled release dosage form and / or administration (e.g., controlled / sustained release tablets, depot solution, osmotic pumps or transdermal patches (including , electrotransport)) for a long time, pulse at a certain rate. In some embodiments, the compositions are in unit dose form suitable for single administration of the precise dose.

[0094] The compounds disclosed and / or described herein can be administered alone or in combination with one or more conventional pharmaceutical carriers and excipients (e.g. mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose) , gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition may also contain small amounts of non-toxic excipients, such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, acetate triethanolamine, triethanolamine oleate). In general, depending on the intended mode of administration, the pharmaceutical composition will contain about 0, 005% to 95% or about 0.5% to 50% by weight of the compound disclosed and / or described herein. Current methods for preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0095] In some embodiments, the compositions are in the form of a pill or tablet, and thus the composition may contain, in addition to the compounds disclosed and / or described herein, one or more diluents (e.g., lactose, sucrose, dicalcium phosphate), lubricants (e.g. magnesium stearate) and / or binders (e.g. starch, acacia, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives). Other solid dosage forms include powder, fine sphere particles made with a marumerizer, solution or suspension (e.g., propylene carbonate, vegetable oils or triglycerides) enclosed in a gelatin capsule.

[0096] Liquid pharmaceutical compositions for administration may, for example, be prepared by dissolving, dispersing or suspending etc. a compound disclosed and / or described herein and optional pharmaceutical additives in a vehicle (e.g., 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 in such parenteral compositions depends, for example, on the physical nature of the compound, on the activity of the compound and on the needs of the patient. However, percentages from 0 are used,

In some embodiments, the composition contains in a solution from about 0.2 to 2% of a compound disclosed and / or described herein.

[0097] Pharmaceutical compositions containing compounds disclosed and / or described herein can also be administered to the respiratory system as an aerosol or as a spray solution or as a particulate powder for insufflation, alone or in combination with an inert carrier such as lactose. In this case, the particles of the pharmaceutical composition have a diameter of less than 50 microns or, in some embodiments, less than 10 microns.

[0098] In addition, the pharmaceutical compositions may contain a compound disclosed and / or described herein and one or more additional therapeutic agents, pharmaceuticals, adjuvants, and the like. Suitable therapeutic and pharmaceutical agents include those described herein.

[0099] The following examples serve to describe the invention described in this document in more detail. It is understood that these examples in no way limit the actual scope of the invention and are provided for purposes of illustration only.

Example 1: Preparation of (S) -2- (4-fluorophenyl) propan-1-amine (reference example)

<img file="PL2560653T3_D0004.tif" />

[0100] [0101] (S) -4-Benzyl-3- (2- (4-fluorophenyl) acetyl) oxazolidin-2-one. To a cooled (-78 ° C) solution of (S) -4-benzyloxazolidin-2-one (10 g, 58 mmol, 1.0 eq) in 100 mL of THF, n-BuLi (40 mL, 1.6 M in hexanes, 64 mL) was added dropwise. mmol, 1.1 eq.). After stirring for 30 minutes, 4-fluorophenylacetyl chloride (10 g, 58 mmol, 1.0 eq.) Was added dropwise. After an additional 30 minutes of stirring, the reaction mixture was allowed to warm to room temperature. The reaction was quenched with saturated aqueous NH 4 Cl, extracted with dichloromethane and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Purification with silica gel (EtOAc / hexanes 10-20%) afforded the title compound as a viscous oil (14.7 g, 81%).

<img file="PL2560653T3_D0005.tif" />

[0102] (S) -4-Benzyl-3 - ((S) -2- (4-fluorophenyl) propanoyl) oxazolidin-2-one. To a solution of (S) -4-benzyl-3- (2- (4-fluorophenyl) acetyl) oxazolidin-2-one (5.1 g, 16.3 mmol, 1.0 eq) in dry THF (100 mL) was added via iodomethane syringe (1.0 ml, 16.2 mmol, 1.0 equiv.) at room temperature. The resulting mixture was cooled to -78 ° C and added dropwise through a NaHMDS syringe (8.15 mL, 2 M in THF, 16.3 mmol, 1.0 equiv). After 15 minutes of stirring at -78 ° C, the reaction mixture was allowed to warm to room temperature. The reaction was quenched with saturated aqueous NH 4 Cl and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo.

<img file="PL2560653T3_D0006.tif" />

[0103] (S) -2- (4-Fluorophenyl) propan-1-ol. To a solution of (S) -4-benzyl-3 - ((S) -2- (4-fluorophenyl) propanoyl) oxazolidin-2-one (1.8 g, 5.5 mmol, 1.0 eq) in THF (18 mL) ) at room temperature a solution of NaBH4 (1.0 g, 26.4 mmol, 4.8 eq) in water (6.0 mL) was added. The reaction mixture was stirred for 3 h at room temperature and then the reaction was stopped, careful addition of 1 M aqueous HCl. The reaction mixture was diluted with water and ethyl acetate. The layers were separated and the organic layer was then washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by chromatography on silica gel (EtOAc / hexanes 10-75%) afforded the title compound (0.824 g, 97%).

<img file="PL2560653T3_D0007.tif" />

[0104] (S) -2- (2- (4-Fluorophenyl) propyl) isoindoline-1,3-dione.

To a solution of (S) -2- (4-fluorophenyl) propan-1-ol (0.82 g, 5.35 mmol, 1.0 eq), phthalimide (0.82 g, 5.6 mmol, 1.05 g). equivalent) and triphenylphosphine (2.1 g, 8.03 mmol, 1.5 eq.) in dry THF (18 mL) was added dropwise diethyl azodicarboxylate (3.6 mL, 15% in toluene 8.0 mmol, 1.5 eq.). . The reaction mixture was stirred for 72 h, and then concentrated under reduced pressure. Purification by chromatography on silica gel (EtOAc / hexanes 15-25%) gave the title compound (0.9 g, 59%).

<img file="PL2560653T3_D0008.tif" />

[0105] (S) -2- (4-Fluorophenyl) propan-1-amine. To a solution of (S) -2- (2- (4-fluorophenyl) propyl) isoindoline-1,3-dione (900 mg, 3.2 mmol, 1.0 eq) in toluene (14 mL) at room temperature was added via hydrazine hydrate syringe (1.4 ml, 45 mmol, 14 equivalents). The resulting mixture was heated to 80 ° C for 30 minutes and then cooled to room temperature. The resulting solution was decanted from the solid present in the reaction mixture, and the solid was washed with an additional portion of toluene. The organic layers were combined and concentrated under reduced pressure to give the title compound (491 mg, 99%) which was used without further purification.

Example 2: Preparation of 2- (4-fluorophenyl) -2-methylpropan-1-amine (Reference Example) [0106]

<img file="PL2560653T3_D0009.tif" />

To a solution of 4-fluorophenyl acetonitrile (50 g, 370 mmol, 1.0 eq) and iodomethane (70 mL, 1.1 mole, 3 eq) in THF (370 mL) solid potassium t-butoxide (124 g) was added in portions. , 1.1 moles, 3 eq.), So that the temperature of the reaction mixture does not exceed 50 ° C. The reaction mixture was stirred overnight and then the reaction was quenched with brine. The mixture was diluted with ethyl acetate and washed twice with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give 2- (4-fluorophenyl) -2-methylpropanenitrile as a yellow oil (57 g, 94%) that 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 eq). The mixture was heated to reflux overnight then the reaction mixture was allowed to cool to room temperature and worked up according to Fieser and Fieser (300 μΐ water / mmol, 1.0 ml 3N NaOH / mmol, 300 μΐ water / mmol). Filtration of the resulting precipitate gave the title compound as an orange oil (57 g, 92%).

Example 3: Preparation of (1- (4-fluorophenyl) cyclobutyl) methanamine (reference example)

<img file="PL2560653T3_D0010.tif" />

A solution of 4-fluorophenyl acetonitrile (6.7 g, 75 mmol, 1.5 eq), 1,3-dibromopropane (10 mL, 50 mmol, 1 eq), KOH (10.2 g, 150 mmol, 3, 0 eq.) 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. Silica gel chromatography using an EtOAc / hexanes gradient of 0-30% yielded a partially purified product, which was further purified by distillation using a Kugelrohr apparatus at 200 ° C, yielding 3.76 g (22 mmol) of the intermediate nitrile product in the form of oil. The residue was dissolved in dry THF (22 ml) and treated with a solution of lithium aluminum hydride (27 ml, 2 M in ether, 55 mmol, 2.5 eq). The mixture was stirred at 0 ° C for 2 hours, followed by treatment according to

Fiesera and Fieser (38 μΐ water / mmol, 118 μΐ 3N NaOH / mmol, 38 μΐ water / mmol). The organic layer was concentrated to dryness to afford the desired product (3.6 g, 40% overall yield) as a yellow oil.

Example 4: Preparation of (1- (6-methoxypyridin-2-yl) cyclobutyl) methanamine (reference example) [0110]

<img file="PL2560653T3_D0011.tif" />

[0111] 2- (3-Fluoropyridin-2-yl) acetonitrile. To a solution of 2-chloro-3-fluoropyridine (3.0 g, 23 mmol, 1.0 eq) and acetonitrile (1.3 ml, 25 mmol, 1.1 eq) in toluene cooled to 0 ° C (50 ml) sodium hexamethyldisilazide (NaHMDS) (2.0 M in THF, 13 ml, 25 mmol, 1.1 eq.) 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 NaCl solution, dried over Na2SO4 and concentrated under reduced pressure to give the desired crude product as an oil which was used without further purification.

Example 5: Preparation of (1- (6-methoxypyridin-2-yl) cyclobutyl) methanamine (reference example)

<img file="PL2560653T3_D0012.tif" />

[0113] 1- (6-Fluoropyridin-2-yl) cyclobutanecarbonitrile.

According to the same procedure as for the above 2- (3-fluoropyridin-2-yl) acetonitrile, using 2,6-difluoropyridine (5.0 g, 43 mmol, 1.0 eq), cyclobutyl carbonitrile (3.5 g, 43 mmol, 1.0 eq.) And NaHMDS (2.0 M in THF, 24 mL, 47 mmol, 1.1 eq.) In toluene (100 mL) afforded the desired product (4.9 g, 64%) as a colorless oil, purification on silica gel using 25% EtOAc / hexanes as the eluent.

<img file="PL2560653T3_D0013.tif" />

[0114] 1- (6-Methoxypyridin-2-yl) cyclobutanecarbonitrile.

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

<img file="PL2560653T3_D0014.tif" />

[0115] (1- (6-Methoxypyridin-2-yl) cyclobutyl) methanamine.

To a stirred solution of 1- (6-methoxypyridin-2-yl) cyclobutanecarbonitrile (1.7 g, 8.8 mmol, 1.0 eq) in THF (20 mL) was added a solution of lithium aluminum hydride (1.0 M in THF, 11). ml, 11 mmol, 1.1 eq.). The mixture was heated at 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 times with 0.43 ml of water (treatment according to Fieser and Fieser). The resulting mixture was filtered through diatomaceous earth and washed with THF. The combined organic phases were dried over Na2SO4 and concentrated to dryness to afford the desired product (1.6 g, 97%) as a viscous oil.

Example 6: Preparation of 1- (3-fluoropyridin-2-yl) cyclobutanamine [0116]

<img file="PL2560653T3_D0015.tif" />

[0117] 1- (3-Fluoropyridin-2-yl) cyclobutanecarboxamide.

To a 250 mL round bottom flask containing DMSO (60 mL) was added 1- (3-fluoropyridin-2-yl) cyclobutanecarbonitrile (2.96 g, 16.8 mmol, 1.0 eq) and the mixture was stirred until homogeneous. Potassium carbonate (7.0 g, 50.4 mmol, 3.0 eq) was then added and the reaction mixture was cooled to 0 ° C, followed by addition of a 35% solution of hydrogen peroxide (6.5 ml). The reaction mixture was stirred at 0 ° C for 30 minutes and then warmed to room temperature. At this time, the reaction mixture was diluted with water (50 mL) and ethyl acetate (100 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (3 x 50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give a crude solid,

<img file="PL2560653T3_D0016.tif" />

[0118] Methyl 1- (3-fluoropyridin-2-yl) cyclobutyl carbamate. 1- (3-Fluoropyridin-2-yl) cyclobutanecarboxamide (1.92 g, 9.88 mmol, 1.0 eq) was dissolved in methanol (20 mL) and potassium hydroxide (1.11 g, 19.8 mmol) was added, 2.0 eq.). The mixture was sonicated to homogeneity, followed by the addition of iodo-benzene diacetate (4.77 g, 14.8 mmol, 1.5 eq). The reaction mixture was stirred for 20 minutes and then diluted with water (100 mL) and ethyl acetate (125 mL). After transferring to a separatory 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 dried over Na2SO4, filtered and concentrated to give a crude oil which was purified by silica gel chromatography (40% EtOAc / hexanes),

<img file="PL2560653T3_D0017.tif" />

[0119] 1- (3-Fluoropyridin-2-yl) cyclobutanamine. To a 20 ml microwave reaction tube was added methyl 1- (3-fluoropyridin-2-yl) cyclobutylcarbamate (1.47 g, 6.56 mmol, 1.0 eq), ethanol (12 ml) and a 3N aqueous sodium hydroxide solution (7 ml). ). The reaction mixture was heated in a microwave reactor at 150 ° C for 30 min. The ethanol was evaporated under reduced pressure and the mixture was extracted with ethyl acetate (30 ml). The aqueous layers were then extracted with ethyl acetate (2 x 30 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to give 1- (3-fluoropyridin-2-yl) cyclobutanamine (1.01 g, 93%) as a crude yellow oil which was used in the next reaction step without further purification.

Example 7: 5- (2- (2- (4-Fluorophenyl) -2-methylpropylamino) pyrimidin-5-yl) -1H-indazole-3-amine (reference example)

<img file="PL2560653T3_D0018.tif" />

[0121] 5-Bromo-N- (2- (4-fluorophenyl) -2-methylpropyl) pyrimidin-2-amine. 2-chloro-5-bromopyridine (440 mg, 2.3 mmol, 1.1 eq), 2- (4-fluorophenyl) -2-methylpropan-1-amine (350 mg, 2.1 mmol) were placed in a 20 dram vial.

1.0 eq.), DIPEA (1.0 mL, 5.7 mmol, 2.7 eq) and toluene (5 mL). The vial was heated in an oil bath at 80 ° C and stirred for 12 h, concentrated and purified by silica gel column chromatography (0-30% EtOAc / hexanes) to yield 270 mg (40%) of 5-bromo-N- ( 2- (4-fluorophenyl) -2-methylpropyl) pyrimidine-2-amine as a white solid.

<img file="PL2560653T3_D0019.tif" />

[0122] 2-Fluoro-5- (2- (2- (4-fluorophenyl) -2-methylpropylamino) pyrimidin-5-yl) benzonitrile. 5-bromo-N- (2- (4-fluorophenyl) -2-methylpropyl) pyrimidine-2-amine (267 mg, 0.8 mmol, 1.0 eq), 3-cyanoacetate were added to a 5 mL microwave reaction vessel. 4-fluorophenylboronic acid (203 mg, 1.2 mmol, 1.5 eq), Cl₂Pd (dppf) (60 mg, 82 μmol, 0.1 eq.), Potassium carbonate (1.2 ml of a 2 N aqueous solution, 2.4 mmol, 3.0 eq) and dioxane (4 ml). The reaction mixture was heated in a microwave reactor at 120 ° C for 20 min. The aqueous layer was removed from the reaction mixture, and the organic layer was directly purified by reverse phase column chromatography, yielding 220 mg (73%) of 2-fluoro-5- (2- (2- (4-fluorophenyl) -2-methylpropylamino) pyrimidine. 5-yl) benzonitrile as a white solid.

<img file="PL2560653T3_D0020.tif" />

[0123] 5- (2- (2- (4-Fluorophenyl) -2-methylpropylamino) pyrimidin-5-yl) -1H-indazole-3-amine. To 5 ml of the microwave reaction vessel was added 2-fluoro-5- (2- (2- (4-fluorophenyl) -2-methylpropylamino) pyrimidin-5-yl) benzonitrile (220 mg, 0.6 mmol), hydrazine (500 μΐ). and isopropanol (5 ml). The reaction mixture was heated to 120 ° C and stirred for 3 h. The reaction mixture was concentrated and purified by reverse phase chromatography to yield 95 mg (42%) of 5- (2- (2- (4-fluorophenyl) -2-methylpropylamino) pyrimidine. -5-yl) -1H-indazol-3-amine as a white solid (m / z [M + H] = 377.1).

Example 8: Preparation of Methyl 2- (2- (4-fluorophenyl) -2-methylpropylamino) pyrimidine-5-carboxylate (Reference Example) [0124]

<img file="PL2560653T3_D0021.tif" />

[0125] A methyl 2-chloropyrimidine-5-carboxylate (250 mg, 1.4 mmol, 1.0 eq), 2- (4-fluorophenyl) -2-methylpropan-1-amine (468 mg, 2) was placed in a dram vial. 8 mmol, 2.0 eq.), DIPEA (1.0 mL, 5.6 mmol,

4.0 eq.) And toluene (5 ml). The vial was heated in an oil bath at 60 ° C and stirred for 20 min, concentrated and purified by silica gel column chromatography (0-50% EtOAc / hexanes) to obtain 325 mg (77%) of 2- (2- (4) methyl-fluorophenyl) -2-methylpropylamino) pyrimidine-5-carboxylate in the form of a white solid (m / z [M + H] = 304.1).

Example 9: Preparation of 3- (2- (2- (4-fluorophenyl) -2-methylpropylamino) pyrimidin-5-yl) benzamide (Reference Example) [0126]

<img file="PL2560653T3_D0022.tif" />

[0127] 5-Bromo-N- (2- (4-fluorophenyl) -2-methylpropyl) pyrimidin-2-amine. To a solution of 5-bromo-2-fluoropyrimidine (1.0 g, 5.6 mmol, 1.0 eq) and 2- (4-fluorophenyl) -2-methylpropan-1-amine (1.05 g, 6.3 mmol, 1.1 eq.) In isopropanol (12 ml) in a microwave reaction vial, equipped with a magnetic stirrer, potassium carbonate (3.68 g, 11.2 mmol, 2.0 eq) was added. The vial was provided with a vial cap for microwave reactions and heated at 120 ° C for 45 min. The reaction mixture was filtered to remove solid potassium carbonate and concentrated in vacuo. After dissolving the residue in EtOAc and water, the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo.

<img file="PL2560653T3_D0023.tif" />

[0128] 3- (2- (2- (4-Fluorophenyl) -2-methylpropylamino) pyrimidin-5-yl) benzamide. In a microwave reaction vial equipped with a stirrer, 5-bromo-N- (2- (4-fluorophenyl) -2-methylpropyl) pyrimidine-2-amine (75 mg, 0.23 mmol, 1.0 eq) was added, solid 3- acid (carboxamino) phenylboronic acid (25 mg, 0.35 mmol, 1.5 eq.) and solid PdCl2 (dppf) (18 mg, 0.23 mmol, 1.0 eq). The vial was closed with a rubber stopper and rinsed with a nitrogen stream for 5 min. The syringe was charged with nitrogen purged dioxane (1 mL) and a 2 N K 2 CO 3 aqueous solution (0.5 mL) and the rubber stopper was quickly replaced with the lid of the microwave reaction vial. The reaction mixture was heated in a microwave reactor for 30 min at 125 ° C, and LCMS analysis indicated the consumption of aryl bromide. The reaction mixture was diluted with EtOAc. The organic layer was washed once with a saturated aqueous solution of NaHCO 3 and once with brine. The combined aqueous layers were washed once with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by chromatography on silica gel (3% -10% MeOH / DCM) afforded the title compound as a yellow solid (44 mg, 52%), (m / z [M + H] = 365.3).

Example 10: Preparation of (1- (3-fluoropyridin-2-yl) cyclobutyl) methanamine

<img file="PL2560653T3_D0024.tif" />

[0130] 1- (3-Fluoropyridin-2-yl) cyclobutanecarbonitrile.

To a 0 ° C-cooled solution of 2-chloro-3-fluoropyridine (80.0 g, 611 mmol, 1.0 eq) and cyclobutanecarbonitrile (49.5 g, 611 mmol, 1.0 eq) in toluene (500 ml) was added dropwise. Sodium hexamethyldisilazide (2.0 M in THF, 306 ml, 612 mmol, 1.0 eq.). The resulting mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction was then quenched with water (500 ml) and the organic layer was separated from the aqueous layer. The aqueous layer was extracted with EtOAc (2 x 300 mL) and the combined organic phases were washed with saturated brine (2 x 400 mL), dried over Na 2 SO 4 and concentrated to give a crude yellow oil, followed by chromatography on silica gel (2-10% EtOAc / hex. ) to give 1- (3-fluoropyridin-2-yl) cyclobutanecarbonitrile (88 g, 83%) as a light yellow oil.

<img file="PL2560653T3_D0025.tif" />

[0131] (1- (3-Fluoropyridin-2-yl) cyclobutyl) methanamine.

To a 0 ° C solution of 1- (3-fluoropyridin-2-yl) cyclobutanecarbonitrile (88 g, 500 mmol, 1.0 eq) in THF (400 mL) was added LAH (2M in THF, 575 mL, 1) dropwise. 15 moles) in one hour. The reaction mixture was then warmed to room temperature and stirred for 15 min. After completion of the reaction, it was cooled back to 0 ° C and water (43 ml), 3 N NaOH (43 ml) and water (125 ml) were added slowly. The interrupted reaction was stirred for 30 min and then filtered through celite. The filtrate was concentrated and dried in vacuo to afford (1- (3-fluoropyridin-2-yl) cyclobutyl) methanamine (80 g, 88%) as a crude yellow oil that was used without further purification.

Example 11: Preparation of 2- (6- (difluoromethoxy) pyridin-2-yl) propan-2-amine (Reference Example) [0132]

<img file="PL2560653T3_D0026.tif" />

[0133] 2- (6-Fluoropyridin-2-yl) -2-methylpropanenitrile.

To a 0 ° C solution of 2,6-difluoropyridine (69.6 g, 605 mmol, 1.0 eq.) And isobutyronitrile (41.7 g, 610 mmol, 1.0 eq.) In toluene (500 ml) was added dropwise. Sodium hexamethyldisilazide (2.0 M in THF, 302 ml, 605 mmol, 1.0 eq.). The resulting mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction was then quenched with water (500 ml) and the organic layer was separated from the aqueous layer. The aqueous layer was extracted with EtOAc (2 x 300 mL) and the combined organic phases were washed with saturated brine (2 x 400 mL), dried over Na 2 SO 4 and concentrated to give a crude yellow oil and chromatographed on silica gel (2-10% EtOAc / hex), yielding 2- (6-fluoropyridin-2-yl) -2-methylpropanenitrile (55.7 g, 56%) as a colorless oil.

<img file="PL2560653T3_D0027.tif" />

[0134] 2- (6-Methoxypyridin-2-yl) -2-methylpropanenitrile.

To a solution of 2- (6-fluoropyridin-2-yl) -2-methylpropanenitrile (10 g) in methanol (30 ml) was added sodium methoxide (50 ml 30% solution in methanol). The reaction mixture was then heated at reflux for 1 h, cooled to room temperature, poured into ethyl acetate (400 mL) and washed with brine (3 x 200 mL). The organic layer was dried over Na2SO4 and concentrated to give 2- (6-methoxypyridin-2-yl) -2-methylpropanenitrile (9.8 g, 92%) as a light yellow oil.

<img file="PL2560653T3_D0028.tif" />

[0135] 2-Methyl-2- (6-oxo-1,6-dihydropyridin-2-yl) propanenitrile. In a vial of 20 drams, 2- (6-methoxypyridin-2-yl) -2-methylpropanenitrile (7 g, 40 mmol) and 4 N HCl in dioxane (15 mL) were added to the microwave reactions. The reaction mixture was closed and heated in a microwave reactor at 190 ° C for 30 min. This reaction was repeated six times using the above procedure. The products of these reactions were combined and filtered. The resulting white precipitate was washed with 20% EtOAc / hexanes and then dried under reduced pressure to give 2-methyl-2- (6-oxo-1,6-dihydropyridin-2-yl) propanenitrile (24.7 g, 77%) as a yellow solid. white sediment.

<img file="PL2560653T3_D0029.tif" />

[0136] 2- (6- (Difluoromethoxy) pyridin-2-yl) -2-methylpropanenitrile. To a 100 mL round bottom flask was added 2-methyl-2- (6-oxo-1,6-dihydropyridin-2-yl) propanenitrile (8.2 g, 51 mmol, 1.0 eq), methyl chlorodifluoroacetate (14.9 g, 103). mmol, 2.0 eq.), cesium carbonate (23.3 g, 71 mmol, 1.4 eq) and DMF (100 mL). The reaction mixture was heated at 95 ° C and stirred for 3 hours. The reaction was then quenched with water (100 mL) and diluted with EtOAc (500 mL). The organic layer was separated from the aqueous layer. The aqueous layer was extracted with EtOAc (100 mL) and the combined organic phases were washed with saturated brine (3 x 200 mL), dried over Na2SO4, concentrated and chromatographed on silica gel (2-5% EtOAc / hex.) To afford 2- (6- (difluoromethoxy) pyridin-2-yl) 2-methylpropanenitrile (6.2 g, 57%) as a colorless oil.

<img file="PL2560653T3_D0030.tif" />

[0137] 2- (6- (Difluoromethoxy) pyridin-2-yl) -2-methylpropanamide. To a 1 liter round bottom flask was added 2- (6- (difluoromethoxy) pyridin-2-yl) -2-methylpropanenitrile (19.2 g, 91 mmol, 1 eq.), Potassium carbonate (37.0 g, 270 mmol, 3 eq. ) and DMSO (150 mL). The reaction mixture was cooled to 0 ° C and 30% hydrogen peroxide (25 ml) was added slowly in 2 ml portions over ten minutes. The reaction mixture was then warmed to room temperature and stirred for 1 h. After consumption of the starting material, the reaction mixture was poured into ethyl acetate (600 mL), washed with brine (3 x 300 mL), dried over Na 2 SO 4 and concentrated to afford 2- (6- (difluoromethoxy) pyridin-2-yl) -2-methylpropanamide (20 g, 97%) as a colorless oil.

<img file="PL2560653T3_D0031.tif" />

[0138] Methyl 2- (6- (difluoromethoxy) pyridin-2-yl) propan-2-ylcarbamate. To a 500 mL round bottom flask was added 2- (6- (difluoromethoxy) pyridin-2-yl) -2-methylpropanamide (20.0 g, 91 mmol, 1 equiv) and methanol (150 mL). The mixture was cooled to 0 ° C and a solution of sodium hydroxide (7.3 g dissolved in 150 ml of methanol, 182 mmol, 2.0 eq) was added. The reaction mixture was stirred for 2 minutes and iodobenzene diacetate (40.8 g, 127 mmol, 1.4 eq) was added. The reaction mixture was stirred for 2 hours while warming it slowly to room temperature. The reaction mixture was then poured into ethyl acetate (700 mL), washed with saturated brine (2 x 400 mL), dried over Na 2 SO 4, concentrated and chromatographed on silica gel (10-20%).

EtOAc / hex.) To give methyl 2- (6- (difluoromethoxy) pyridin-2-yl) propan-2-yl-carbamate (12.4 g, 55%) as a white solid.

<img file="PL2560653T3_D0032.tif" />

[0139] 2- (6- (Difluoromethoxy) pyridin-2-yl) propan-2-amine.

To a solution of 2- (6- (difluoromethoxy) pyridin-2-yl) propan-2-ylcarbamate (12.4 g, 48 mmol) in acetonitrile (50 ml) was added TMSI (10 ml). The reaction mixture was stirred for 30 min and then poured into methanol (100 mL) and water (5 mL). The mixture was concentrated, dissolved in ethyl acetate (200 ml) and washed with 1 N NaOH (2 x 30 ml). The organic layer was separated, dried over Na2SO4, concentrated and chromatographed on silica gel (50% EtOAc / hex. Followed by 5-20% MeOH / CH2Cl2) to give 2- (6- (difluoromethoxy) pyridin-2-yl). ylo) propane-2-amine (8.8 g, 92%) as a yellow oil.

Example 12: Preparation of trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methanamine

<img file="PL2560653T3_D0033.tif" />

[0141] Carbonitrile

1- (3-Fluoropyridin-2-yl) -3-methylene-cyclobutano into a solution of 3-methylene-cyclobutanecarbonitrile (150 g, 1.61 mol, 1 eq.) And 2-chloro-3-fluoropyridine (212 g, 1.61 mmol, 1 eq. ) in toluene (1 L), NaHMDS (2M in THF, 885 mL, 1.1 eq) was added at 0-10 ° C. After the addition was complete, the reaction mixture was warmed to room temperature, stirred overnight and quenched with saturated NH4Cl solution. The organic layer was washed with water (2 x 500 mL) and brine (500 mL), dried over Na2SO4, 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="PL2560653T3_D0034.tif" />

[0142] 1- (3-Fluoropyridin-2-yl) -3-oxocyclobutanecarbonitrile. To a mixture of 1- (3-fluoropyridin-2-yl) -3-methylenecyclobutanecarbonitrile (272 g, 1.45 moles) and

RuCl3'H₂O (9.0 g, 0.044 mole) in a mixture of DCM (1 L), acetonitrile (1 L) and water (1.5 L) was added in portions solid NaIO 4 (1235 g, 5.8 moles) at 10 ° C. 30 ° C. After the addition was complete, the reaction mixture was stirred for 1 h at 15 ° C and overnight at room temperature. The solid precipitate was filtered and washed with DCM (2 x 1000 mL). The organic layer was washed with water (2 x 500 mL) and brine (500 mL), dried over Na2SO4 and concentrated to give the crude title compound as a dark solid (238 g, 86.3%). LRMS (M + H⁺) m / z 191.1.

<img file="PL2560653T3_D0035.tif" />

[0143] 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 L) and MeOH (200 mL) was added NaBH4 in portions at -78 ° C. The reaction mixture was stirred at -78 ° C for 1 h and quenched with methanol / water (1/1). The organic layer was washed with water (500 mL x 3), dried over Na2SO4 and concentrated. The residue was purified on silica gel (50% EtOAc / hexanes) to give the title compound as an amber oil (185.8 g, 77.5%) LRMS (M + H).⁺) m / z 193.2.

<img file="PL2560653T3_D0036.tif" />

[0144] trans-3-Fluoro-1- (3-fluoropyridin-2-yl) cyclobutanecarbonitrile. To a solution of 1- (3-fluoropyridin-2-yl) -3-hydroxycyclobutanecarbonitrile (185 g, 0.96 mol) in DCM (1 L) was added in portions DAST at 0-10 ° C. After the addition was complete, the reaction mixture was heated to reflux for 6 hours. The reaction mixture was cooled to room temperature and poured into a saturated solution of NaHCO 3. The mixture was separated and the organic layer was washed with water, dried over Na2SO4 and concentrated. The residue was purified on silica gel (100% DCM) to give the title compound as a brown oil (116 g, 62%) which was a 8: 1 mixture of trans: cis. The above brown oil (107 g) was dissolved in toluene (110 ml) and hexane (330 ml) at 70 ° C. The solution was cooled to 0 ° C and stirred at 0 ° C overnight. The precipitate was filtered and washed with hexanes to give the trans isomer as a white solid (87.3 g, 81.6%). LRMS (M + H⁺) m / z 195.1.

FF

<img file="PL2560653T3_D0037.tif" />

[0145] trans-3-Fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methanamine. A mixture of trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutanecarbonitrile (71 g, 0.37 mol) and Raney nickel (~ 7 g) in a 7 N solution of ammonia in methanol (700 ml) was maintained under a hydrogen atmosphere (60 psi) for 2 days. The reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was concentrated under reduced pressure to obtain the title compound as a light green oil (70 g, 97.6%). LRMS (M + H⁺) m / z 199.2.

Example 13: Preparation of t-butyl 5-bromopyrimidin-2-yl ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate [0146]

<img file="PL2560653T3_D0038.tif" />

A mixture of trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methanamine (37.6 g, 190 mmol), 5-bromo-2-fluoropyrimidine (32.0 g, 181 mmol), DIPEA (71 mL, 407 mmol) and NMP (200 mL) was stirred at room temperature overnight. The reaction mixture was then diluted with EtOAc (1500 mL) and washed with saturated sodium hydrogen carbonate solution (500 mL). The organic layer was separated, dried over Na2SO4 and concentrated. The resulting precipitate was dissolved in THF (600 ml), followed by the slow addition of DMAP (14 g, 90 mmol) and Boc2O (117.3 g, 542 mmol). The reaction mixture was heated at 60 ° C and stirred for 3 h. The reaction mixture was concentrated and purified by silica gel chromatography (EtOAc / hex.) To provide 59.7 g of 5-bromopyrimidin-2-yl ((trans-3-fluoro-1). T-butyl (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate as a white solid.

Example 14: Preparation of 1- (2 - (((trans) -3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -1H-pyrrole-3-carboxamide

<img file="PL2560653T3_D0039.tif" />

[0149] Tert-butyl 5- (3-cyano-1H-pyrrol-1-yl) pyrimidin-2-yl (((trans) -3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate . To a solution of t-butyl 1-bromopyrimidin-2-yl ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate (1.0 g, 2.8 mmol) in 15 ml of toluene ( degassed with nitrogen) copper iodide (100 mg, 0.6 mmol), potassium phosphate (1.31 g, 6.2 mmol), trans-N, N'-dimethylcyclohexane-1,2-diamine (320 mg, 2.2 mmol) were added. mmol) and

3-cyanopyrrole (310 mg, 3.6 mmol). The reaction mixture was heated at 100 ° C and stirred for 2 h. The reaction mixture was then concentrated and purified by silica gel chromatography (EtOAc / hexanes) to give 1.1 g of 5- (3-cyano-1H-pyrrole -1-yl) pyrimidin-2-yl (tert-butyl (((trans) -3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate as a colorless oil.

<img file="PL2560653T3_D0040.tif" />

[0150] 1- (2 - (((trans) -3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -1H-pyrrole-3-carboxamide. To a solution of t-butyl 5- (3-cyano-1H-pyrrol-1-yl) pyrimidin-2-yl (((trans) -3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate (1, 1 g, 3.1 mmol) in DMSO (10 ml) was added potassium carbonate (1.3 g, 9.3 mmol). The mixture was cooled to 0 ° C and hydrogen peroxide (3 ml) was added slowly. The reaction mixture was warmed to room temperature and stirred for 90 min. The reaction mixture was diluted with EtOAc (75 mL) and washed three times with brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give a crude solid which was purified by silica gel chromatography (10% MeOH / CH2Cl2) to afford 1, 07 g 1- (2 - ((trans) -3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -1H-pyrrole-3-carboxamide as a white solid. This compound was dissolved in 25% TFA / CH 2 Cl 2 and stirred for 1 h. The reaction mixture was then concentrated, dissolved in ethyl acetate (75 mL) and washed three times with potassium carbonate. The organic layer was dried over Na2SO4, filtered and concentrated to give a crude solid, which was triturated with 75% ethyl acetate / hexanes. The resulting suspension was sonicated and filtered to obtain 500 mg of 1- (2 - (((trans) 3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -1H-pyrrole. -3-carboxamide in the form of a white solid (M + H = 385). dissolved in ethyl acetate (75 ml) and washed three times with potassium carbonate. The organic layer was dried over Na2SO4, filtered and concentrated to give a crude solid, which was triturated with 75% ethyl acetate / hexanes. The resulting suspension was sonicated and filtered to obtain 500 mg of 1- (2 - (((trans) 3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -1H-pyrrole. -3-carboxamide in the form of a white solid (M + H = 385). dissolved in ethyl acetate (75 ml) and washed three times with potassium carbonate. The organic layer was dried over Na2SO4, filtered and concentrated to give a crude solid, which was triturated with 75% ethyl acetate / hexanes. The resulting suspension was sonicated and filtered to obtain 500 mg of 1- (2 - (((trans) 3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -1H-pyrrole. -3-carboxamide in the form of a white solid (M + H = 385).

Example 15: Preparation of 2- (2 - ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) thiazole-5-carboxamide [0151] ο

<img file="PL2560653T3_D0041.tif" />

The t-butyl 5-bromopyrimidin-2-yl ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate (850 mg, 1.95 g) was added to a 20 mL microwave reaction vial. mmol), ethyl thiazole-5-carboxylate (459 mg, 2.92 mmol), Cl2Pd (PPh3) 2 (205 mg, 0.29 mmol), JohnPhos (213 mg, 0.58 mmol), Cs2CO3 (1.9). g, 5.85 mmol) and toluene (8 ml).

The reaction mixture was stirred and heated at 140 ° C for 30 min in a microwave reactor. The reaction mixture was poured into ethyl acetate (100 mL), washed with NaHCO 3 (50 mL), washed with brine (50 mL), then dried over Na 2 SO 4, filtered, concentrated and purified by silica gel chromatography (EtOAc / hexanes), in resulting in 191 mg of 2- (2- (t-butoxycarbonyl ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) amino) pyrimidin-5-yl) thiazole-5-carboxylate methyl. This compound was then dissolved in ethanol (4 ml) and ammonium hydroxide (2 ml) was added. The reaction mixture was heated at 60 ° C and stirred for 30 min. The reaction mixture was then concentrated, dissolved in CH2Cl2 (30 mL), washed with NaHCO3 (10 mL), washed with brine (10 mL), then dried over MgSO4, filtered and concentrated. The crude solid was dissolved in CH 2 Cl 2 (5 mL) and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 30 min, concentrated, and then purified by reverse phase chromatography to give 51 mg.

2- (2 - ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) thiazole-5-carboxamide as a white solid (M + H = 385, 1).

Example 16: Preparation of 4-fluoro-3- (2 - ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -2-hydroxybenzamide [0153]

<img file="PL2560653T3_D0042.tif" />

[0154] 4-Fluoro-3- (2 - ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -2-methoxybenzonitrile. To 250 mL of a round bottom flask was added 5-bromopyrimidin-2-yl ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) carbamate t-butyl (5.0 g, 11.0 mmol), 3-bromo-6-fluoro-2-methoxyphenylboronic acid (2.7 g, 11.0 mmol), (dppf) PdCl2 (0.80 g, 1.1 mmol), dioxane (25 ml, degassed for 10 min at nitrogen atmosphere), K 2 CO 3 (3.0 g, 22 mmol) and water (4 ml). The mixture was heated at 95 ° C and stirred overnight. The reaction mixture was poured into ethyl acetate (200 mL), washed successively with NaHCO 3 (50 mL) and brine (50 mL), then dried over Na 2 SO 4, filtered, concentrated and purified by silica gel chromatography to give 2.4 g (4, 1 mmol) of 5- (3-bromo-6-fluoro-2-methoxyphenyl) -N - ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) pyrimidine-2-amine as a pale yellow sediment. Zinc cyanide (0.76 g, 6.5 mmol), Pd (PPh3) 4 (2.9 g, 2.5 mmol) and DMF (25 mL) were added to this solid. The mixture was heated at 100 ° C for 2 h, then diluted with EtOAc and washed with saturated aqueous NaHCO 3 solution and brine. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by reverse phase chromatography to afford 1.1 g of 4-fluoro-3- (284- (trans-3-fluoro-1- (3-fluoropyridin-2-y). yl) cyclobutyl) methylamino) pyrimidin-5-yl) -2-methoxybenzonitrile. 5 mmol) and DMF (25 ml). The mixture was heated at 100 ° C for 2 h, then diluted with EtOAc and washed with saturated aqueous NaHCO 3 solution and brine. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by reverse phase chromatography to afford 1.1 g of 4-fluoro-3- (284- (trans-3-fluoro-1- (3-fluoropyridin-2-y). yl) cyclobutyl) methylamino) pyrimidin-5-yl) -2-methoxybenzonitrile. 5 mmol) and DMF (25 ml). The mixture was heated at 100 ° C for 2 h, then diluted with EtOAc and washed with saturated aqueous NaHCO 3 solution and brine. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by reverse phase chromatography to afford 1.1 g of 4-fluoro-3- (284- (trans-3-fluoro-1- (3-fluoropyridin-2-y). yl) cyclobutyl) methylamino) pyrimidin-5-yl) -2-methoxybenzonitrile.

<img file="PL2560653T3_D0043.tif" />

[0155] 4-Fluoro-3- (2 - ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -2-hydroxybenzamide. A mixture of 4-fluoro-3- (2 - ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -2-methoxybenzonitrile (1.0 g, 1.9 mmol) ), K 2 CO 3 (0.8 g, 5.7 mmol) and DMSO (5 mL) were mixed in a round bottom flask and cooled to 0 ° C. H2O2 (8.0 mL of 35% solution) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO 3 solution and brine (three times). The organic layer was dried over sodium sulfate, filtered, concentrated and purified by reverse phase chromatography to give 0, 55 g (1 mmol) 4-fluoro-3- (2 - ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -2-methoxybenzamide as a white solid . This compound was mixed with pyridine (6 ml) and LiI (1.22 g, 9 mmol) and heated in a microwave reactor at 125 ° C for 15 min. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO 3 and brine. The organic layer was dried over sodium sulfate, filtered, concentrated and purified by reverse phase chromatography to give the title compound.

163 mg of 4-fluoro-3- (2 - ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -2-hydroxybenzamide as a white solid (M + H); )⁺ = 430.1.

Example 17: Preparation of 2- (2- (2 - ((1- (3-chloropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) thiazol-5-yl) acetamide

<img file="PL2560653T3_D0044.tif" />

[0157] To a 50 ml round bottom flask was added t-butyl 5-bromopyrimidin-2-yl ((1- (3-chloropyridin-2-yl) cyclobutyl) methyl) carbamate (1.0 g, 2.2 mmol), Pd (PPh 3 ) 4 (0.25 g, 0.22 mmol), hexamethyldicine (0.92 mL, 2.2 mmol), LiCl (0.25 g, 5.9 mmol) and dioxane (10 mL). The mixture was heated at 90 ° C for 1 h. To a resulting dark brown solution was added 2- (2-bromothiazol-5-yl) acetonitrile (0.89 g, 4.4 mmol), Pd (PPh 3) 4 (0.076 g, 0.066 g). mmol) and CuI (4.2 g, 22.2 mmol). The reaction mixture was stirred at 90 ° C for 1 h. Then the reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and filtered through celite. The filtrate was washed with water (30 ml) and brine (30 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (EtOAc / hex.) to afford 222 mg (1- (3-chloropyridin-2-yl) cyclobutyl) methyl (5- (5- (cyanomethyl) thiazol-2-yl; amount of t-butyl pyrimidine-286 yl) carbamate in the form of a viscous brown oil. Potassium carbonate (185 mg, 1.3 mmol) and DMSO (3 mL) were added to this compound. The mixture was cooled to 0 ° C and hydrogen peroxide (0.5 ml) was added slowly. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was diluted with EtOAc (75 mL) and washed three times with brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give a crude solid which was purified by reverse phase chromatography, to obtain 48 mg of t-butyl 5- (5- (2-amino-2-oxoethyl) thiazol-2-yl) pyrimidin-2-yl ((1- (3-chloropyridin-2-yl) cyclobutyl) methyl) carbamate in white form sediment. This compound was dissolved in 25% TFA / CH 2 Cl 2 and stirred for 10 min. The reaction mixture was then concentrated, dissolved in ethyl acetate (75 mL) and washed three times with saturated sodium bicarbonate. The organic layer was dried over Na2SO4, filtered and concentrated to give 39 mg of 2- (2- (2 - (1- (3-chloropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) thiazol-5-yl) acetamide in the form white solid (M + H =

415.1).

Example 18: Preparation of 3- (2 - ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -4-hydroxy-N-methyl-benzamide [0158]

<img file="PL2560653T3_D0045.tif" />

[0159] 3- (2 - ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -4-hydroxybenzoic acid. The 5-bromo-N - (((trans) -3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methyl) pyrimidin-2-amine (1.2 g, 3) was added to a 20 mL microwave reaction tube, 8 mmol), methyl 4-hydroxy-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (1.1 g, 4.0 mmol), (dppf) PdCl 2 (0.25 g, 0.38 mmol), dioxane (15 mL), K 2 CO 3 (1.4 g, 10.1 mmol) and water (3 mL). The mixture was heated at 135 ° C and stirred for 15 min. The reaction mixture was poured into ethyl acetate (200 mL), washed with brine (50 mL) and dried over Na 2 SO 4, filtered, concentrated and purified by silica gel chromatography (EtOAc / hexane) to afford 0, 65 g of methyl 3- (2 - ((trans3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -4-hydroxybenzoate as a brown solid. This compound was dissolved in methanol (7 ml) and KOH (2 ml of 3N aqueous solution) was added. The reaction mixture was stirred at 80 ° C for 1 h and then concentrated. The crude residue was purified by reverse phase chromatography to give 0.24 g of 3- (2 - (trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) acid - 4-hydroxybenzoic acid in the form of a white solid.

<img file="PL2560653T3_D0046.tif" />

[0160] 3- (2 - ((trans-3-Fluo -1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -4-hydroxy-N-methylbenzamide. 3- (2 - ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) -4-hydroxybenzoic acid (147 mg, 0.36) was added to a 50 mL round bottom flask. mmol)

HATU (204 mg, 0.54 mmol), HOBT (72 mg, 0.54 mmol), methylamine hydrochloride (239 mg, 3.6 mmol), DIPEA (187 μΐ, 1.1 mmol) and DMF (1.5 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by reverse phase chromatography to yield 93 mg of 3- (2 - ((trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) 4- hydroxy-N-methylbenzamide in the form of a white solid (M + H = 418.1).

Example 19: Preparation of 6- (2- (2- (3-chloropyridin-2-yl) propan-2-ylamino) pyrimidin-5-yl) imidazo [2,1-b] thiazole-3-carboxamide (reference example) [0161]

<img file="PL2560653T3_D0047.tif" />

[0162] 2-Bromo-1- (2- (2- (3-chloropyridin-2-yl) propan-2-ylamino) -pyrimidin-5-yl) ethanone. To a stirred solution of dioxane (50 mL, degassed) was added 5-bromo-N- (2- (3-chloropyridin-2-yl) propan-2-yl) pyrimidin-2-amine (3.0 g, 12 mmol), Cl2Pd ( PPh3) 2 (0.65 g, 1.2 mmol) and tributyl (1-ethoxyvinyl) tin (2.66 mL, 13.8 mmol). The reaction mixture was heated at 90 ° C and stirred for 2 h. The reaction mixture was then concentrated, followed by EtOAc (100 mL) and potassium fluoride (50 mL of a saturated aqueous solution). The mixture was stirred for 10 min and then filtered through a pad of celite. The filtrate was concentrated and then dissolved in THF (20 mL) and water (20 mL). NBS (4.9 g, 27.6 mmol) was added and the reaction mixture was stirred for 20 min at room temperature. The reaction mixture was poured into ethyl acetate (200 ml),

<img file="PL2560653T3_D0048.tif" />

[0163] 6- (2- (2- (3-Chloropyridin-2-yl) propan-2-ylamino) pyrimidin-5-yl) imidazo [2,1-b] thiazole-3-carboxamide.

In a 20 dram vial, 2-bromo-1- (2- (2- (3-chloropyridin-2-yl) propan-2-ylamino) pyrimidin-5-yl) ethanone (103 mg, 0.28 mmol) was added. -ethylaminothiazole-4-carboxylate (48 mg, 0.28 mmol) and methyl ethyl ketone (2 ml). The mixture was heated at 90 ° C in a sealed tube and stirred overnight. The reaction mixture was then concentrated and purified by silica gel chromatography (EtOAc / hex.) To yield 33 mg of 6- (2- (2- (3-chloropyridin-2-yl) propan-2-ylamino) pyrimidin-5-yl) imidazo [Ethyl-2,1-b] thiazole-3-carboxylate as a brown solid. This compound was dissolved in methanol (1 mL) and ammonium hydroxide (3 mL) was added. The resulting mixture was heated in a microwave reactor at 135 ° C and stirred for 15 min. The reaction mixture was concentrated, then HBTU (68 mg, 179 μη ^ ί), HOBt (24 mg, 179 μmol), NH was added.₄Cl (48 mg, 1.1 mmol), DIPEA (78 μL 441 μmol) and NMP (2 mL). The reaction mixture was stirred for 2 h and then directly purified by reverse phase chromatography to yield 18 mg of 6- (2- (2- (3-chloropyridin-2-yl) propan-2-ylamino) pyrimidin-5-yl ) imidazo [2,1-b] thiazole-3-carboxamide in the form of an off-white solid (M + H = 414.1).

Example 20: Preparation of 4- (2 - (((cis) -3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) picolineamide [0164]

<img file="PL2560653T3_D0049.tif" />

[0165] 4- (2-Chloropyrimidin-5-yl) picolinonitrile.

4-Bromopicolinonitrile (11.8 g, 74.5 mmol), 2-chloropyrimidin-5-ylboronic acid (15.0 g, 82.0 mmol), (dppf) PdCl2 (5.5 g, 7.45 mmol) , dioxane (150 ml, degassed with nitrogen) and 2 N aq. K 2 CO 3 solution (33 ml) were mixed and heated in a round bottom flask at 100 ° C overnight. The hot mixture was filtered through a pad of celite, diluted with ethyl acetate, washed with water, concentrated and purified by silica gel chromatography to give 4- (2-chloropyrimidin-5-yl) picolinonitrile as a brown solid (2.1 g, 13%). ).

<img file="PL2560653T3_D0050.tif" />

[0166] 4- (2 - (((cis) -3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino) pyrimidin-5-yl) picolinamide. 4- (2-Chloropyrimidin-5-yl) picolinonitrile (0.9 g, 4.2 mmol), (3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methanamine (1.0 g, 5.0) mmol), DIPEA (1 mL) and ACN (20 mL) were mixed and heated at 90 ° C for 4 h. The reaction mixture was concentrated, diluted with EtOAc and washed with saturated aqueous NaHCO 3 and brine. The organic layer was dried over sodium sulfate, filtered, concentrated and purified by reverse phase chromatography to give 4- (2 - ((cis) -3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino). pyrimidin-5-yl) picolinonitrile as a colorless oil (the cis isomer is eluted earlier). This compound was then treated with DMSO (3 ml), K 2 CO 3 (200 mg) and H 2 O 2 (2 ml). The reaction mixture was stirred for 4 h, then diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by reverse phase chromatography to afford 93 mg of 4- (2 - (((cis) -3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl) methylamino. ) pyrimidin-5-yl) picolinamide in the form of an off-white solid (m / z [M + H] = 397.2).

Example 21: Preparation and analysis of fast skeletal muscle myofibrils [0167] Preparation of fast skeletal muscle myofibrils.

Rabbit skeletal muscle microfibrils were prepared based on the method of Herrmann et al. (Biochem. 32 (28): 7255-7263 (1993). Myofibrils were obtained from the lumbar muscle of a rabbit purchased from Pel-Freez Biologicals (Arkansas) within days of ordering and stored in ice. Ground muscle was homogenized in 10 volumes of ice-cold buffer " standard "(50 mM Tris, pH = 7.4, 0.1 M potassium acetate, 5 mM KCl, 2 mM DTT, 0.2 mM PMSF, 10 pM leupeptin, 5 pM pepstatin, 0.5 mM sodium azide) containing 5 mM EDTA and 0.5% Triton X-100, using an OmniMacro homogeniser. Myofibrils were recovered by low speed centrifugation (3000 rpm for 10 minutes) and washed 2 times in buffer containing Triton X-100 to ensure that they were removed After washing with Triton, the myofibrils were washed in "standard" times buffer containing 2 mM magnesium acetate. A final wash was carried out in assay buffer (12 mM PIPES, pH = 6.8, 60 mM KCl, 1 mM DTT) and sucrose was added to a concentration of 10% for rapid freezing in liquid nitrogen and stored at -80 ° C.

[0168] Activation of fast skeletal muscle myofibrils.

Quick fiber activators were identified by measuring the enzymatic activity of muscle myofibril preparations using the proprietary PUMA test system^™ (see, e.g., U.S. Patent Nos. 6,410,254, 6,743,599, 7,202,051 and 7,378,254). Mylofibril preparations consisted of rabbit skeletal muscle (about 90% of fast fibers) that were mechanically homogenised and washed with detergent (Triton X-100) to remove cell membranes. This formulation contained all the sarcomer components in the native conformation and the enzymatic activity was still regulated by calcium. The compounds were tested using a suspension of myofibrils and calcium at a level sufficient to increase the enzymatic activity of myofibrils by 25% of their maximum rate (referred to as pCa25). Enzymatic activity was monitored by means of a conjugated pyruvate kinase enzyme system and lactate dehydrogenase. This test refers to the reconstitution of ATP from the ADP-mediated myosin by NADH oxidation, which gives a change in absorbance at 340 nm. The buffer was 12 mM Pipes, 2 mM MgCl 2, 1 mM DTT, pH = 6.8 (PM 12 buffer). Data are given as AC1.4, which is the concentration at which the compound has increased its enzymatic activity by 40%. The results are summarized in the following Table 2.

Example 22: Preparation and analysis of skeleton muscle sarcomere proteins

Powder preparation [0169]

1. The volumes are given for about 1000 g of ground muscle.

2. Cut out the gauze and cook it for 10 minutes in water. Filter and dry.

3. Grind the chicken breast in a chilled meat grinder.

4. Extract with stirring in 2 liters of 0.1 M KCl, 0.15 M potassium phosphate, pH = 6.5 for 10 min at 4 ° C. Centrifuge at 5000 rpm, 10 min, 4 ° C at JLA. Collect the pellet.

5. Extract the pellet with 2 liters of 0.05 M NaHCO3 for 5 min. Centrifuge at 5000 rpm, 10 min, 4 ° C at JLA. Collect the pellet. Repeat the extraction one more time.

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

7. Extract with 2 liters of H2O for 5 min with stirring. Centrifuge at 10000 rpm, 15 min, 4 ° C at JLA. Carefully collect the pellet, part of which will be loose and gelatinous.

8. Extract 5 times with acetone (2 liters of acetone for 10 min each time with stirring). Squeeze gently through the gauze. All acetone extractions are carried out at room temperature. The acetone should be cooled to 4 ° C.

9. Drying: Place the filtered residue on a large glass tray and leave it overnight under the hood. When the residue is dry, place in a plastic bottle with a wide outlet and store at 20 ° C.

Alternative powder formulation [0170] (See Zot &amp; Potter (1981) Prep. Biochem. 11 (4), pp.

381-395)

1. Separate the left ventricles of the heart muscle. Remove as much pericardium and fat as possible. Grind in a chilled meat grinder. Weigh.

2. Prepare 5 volumes of extraction buffer (see below). Homogenize the meat in a blender, 4 times for 15 seconds of mixing with 15 seconds between. Do this with 1 volume (weight / volume) of buffer taken from the previously prepared 5 volumes. Add the homogenate back to the extraction buffer and mix until well mixed (5 minutes).

3. Filter through a gauze in a large polypropylene strainer. Resuspend in 5 volumes of extraction buffer as above.

4. Repeat Step 3 four more times. Finally, do not suspend in the extraction buffer, but go to Step 5. Pellets should be yellow and white.

5. Suspend in 3 volumes (according to the original weight) 95% cold ethanol. Stir for 5 minutes and squeeze through the gauze as above, repeat twice.

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

7. Repeat Step 6 three more times.

8. Leave overnight as a single layer on gas, on a glass tray.

9. After drying, collect the powder, weigh and store in a wide outlet jar at 4 ° C.

EXTRACTIVE BUFFER: 50 mM KCl, 5 mM Tris pH = 8.0, prepared as 50-fold concentrated. For 2 liters: 250 mM Tris, pH = 8.0. Tris base (121.14 g / mol, 60.6 g), bring the pH to 8.0 with concentrated HCl, and then add 2.5 M KCl (74.55 g / mol, 372 g).

Actin preparation [0171]

1. Extract the powder (described above) with 20 ml buffer A (see below, add BME and ATP immediately before use, in each of the next steps) per gram of powder (200 ml per 10 g). Use a large 4-liter beaker for 150 g of powder. Mix vigorously to dissolve the powder. Stir at 4 ° C for 30 min.

2. Separate the extract from the hydrated powder by pressing through several layers of gauze. The gas should be pre-wet-sterilized using microwave radiation for 1-2 min.

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

4. Centrifuge in the JLA10 rotor (s) for 1 hour. at 10K rpm (4 ° C). Collect the supernatant through 2 layers of gauze.

5. Add ATP to 0.2 mM and MgCl2 to obtain mM. Stir on the stirrer at 4 ° C for 60 minutes to allow the polymerization / formation of actin para-crystals.

6. Slowly add solid KCl to 0.6 M (45 g / l). Stir at 4 ° C for 30 min.

7. Centrifuge in the JLA10 rotor at 10K rpm within 1 hour.

8. Depolymerization: Quickly wash the surface of the pellets with buffer A and remove the washings. Soften the pellets by pre-incubating on ice with a small amount of buffer A in each tube (use less than half of the total final volume used for resuspension in all tubes). Re-suspend first by hand scraping cells and combine the pellets. Wash the tubes with the additional buffer using a 25 ml pipette and an automatic pipettor, aggressively removing the actin from the walls of the tube. Homogenize in a large Dounce homogenizer, in cold buffer A, on ice. Use 3 ml / g of the originally extracted powder.

9. Dialyze against buffer A with 4 changes within 48 hours.

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

11. Collect the supernatant (G-actin). Keep the sample for gel analysis and protein determination.

12. To polymerize G actin for storage, add KCl to 50 mM (from 3 M stock), MgCl 2 to obtain 1 mM and NaN 3 to obtain 0.02% (from the 10% stock solution). Store at 4 ° C. Do not freeze.

Buffer A: 2 mM Tris / HCl, 0.2 mM CaCl₂, 0.5 mM (36 μΥΥ 2-mercaptoethanol, 0.2 mM Na 2 ATP (added fresh) and 0.005% sodium azide, pH = 8.0.

Purification of skeletal muscle myosin [0172] (See, Margossian, SS and Lowey, S. (1982) Methods Enzymol. 85, 55-123; and Goldmann, WH and Geeves, MA (1991)

Anal. Biochem. 192, 55-58)

Solution A: 0.3 M KCl, 0.15 M potassium phosphate, 0.02 M EDTA, 0.005 M MgCl 2, 0.001 mM ATP, pH = 6.5.

Solution B pH = 6.5. Solution C Solution D Solution E Solution F pH = 6.5. Solution G

M KCl, 0.025 M EDTA, 0.06 M potassium phosphate,

0.6 M KCl, 0.025 M potassium phosphate, pH = 6.5.

0.6 M KCl, 0.05 M potassium phosphate, pH = 6.5.

0.15 M potassium phosphate, 0.01 M EDTA, pH = 7.5.

0.04 M KCl, 0.01 M potassium phosphate, 0.001 M DTT,

M KCl, 0.01 M potassium phosphate, pH = 6.5.

All procedures were carried out at 4 ° C.

1. Obtain approx. 1000 g of skeletal muscle, such as rabbit skeletal muscles.

2. Divide twice; extract with 2 liters of solution A while stirring for 15 min; add 4 liters of cold H2O, filter through gauze; dilute with cold H2O to obtain an ionic strength of 0.04 (about 10 times); allow the precipitate to settle for 3 h; collect the precipitate at 7000 rpm in the GSA rotor for 15 min.

3. Suspend the precipitate in 220 ml of solution B; dialyzed overnight against 6 liters of solution C; slowly add a volume of ~ 400 ml of cold distilled H2O; stir for 30 min; centrifuge at 10000 rpm for 10 min in the GSA rotor.

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

5. Dilute the supernatant to obtain an ionic strength of 0.04 (~8-fold); leave my son to fall through the night; collect about 5-6 l of fluffy myosin precipitate by centrifugation at 10,000 rpm for 10 min in a GSA rotor.

6. Resuspend the pellet in the minimum volume of G solution; dialyzed overnight against 2 liters of solution D;

centrifuge at 19,000 rpm for 2 h in cellulose nitrate tubes; pierce the test tubes and separate myosin from fat and insoluble pellets.

7. Dilute the supernatant to 5-10 mg / ml and dialyze to a large extent against solution E, load onto the DEAE-Sephadex column.

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

9. Myosin is then cleaved with chymotrypsin or papain in the presence of EDTA to form a S1 fragment that is soluble under conditions of low salt concentration that is optimal for ATPase activity (Margossian, supra).

Preparation and Test [0173] The mint was obtained by precipitation from the rabbit lumbar sacrum extracts, and the soluble fraction S1 was obtained by digestion with chymotrypsin (Margossian and Lowey, 1982).

[0174] The actin was purified by first obtaining ethereal heart muscle powder (Zot HG and Potter JD (1981) Preparative Biochemistry 11: 381-395) as described above. Then, the actin was subjected to cyclic changes between the filamentous and soluble form through the centrifugation steps and

100 dialysis (Spudich JA and Watt S. (1971), J. Biol. Chem. 246: 4866-4871).

[0175] Tropomyosin was extracted from the ethereal powder and separated from the other proteins, based on pH-dependent precipitation followed by salting out 53% and 65% ammonium sulfate (Smillie LB. (1981) Methods Enzymol. 85 Pt B: 234-41 ). Troponin was isolated as an intact TnC, TnT and TnI complex. The ether powder was extracted in a buffer with high salt concentration. A further 30% ammonium and 45% ammonium sulfate was recovered; the precipitate was dissolved by dialysis into a low salt buffer, then further purified on a Toyopearl DEAE column with a 25-350 mM KCl gradient. None of the components has a measurable ATPase activity, except for myosin, which naturally has very low basal ATPase activity in the absence of actin.

[0176] Prior to performing the assays, actin, tropomyosin and troponin complex were mixed together in the required ratio (e.g., 7: 1: 1) to achieve maximal regulation of the actin filament with calcium. The test is carried out at a concentration that gives 25% activation. This calcium concentration is in the physiological range that occurs during muscle contraction.

[0177] To measure the production of ADP during the reaction, a coupled enzyme kinase system of pyruvate kinase / lactate dehydrogenase / NADH (PK / LDH) is added to the actin. Myosin is kept separate and added to adjustable, thin filaments to initiate the reaction. Oxidation of NADH is monitored in real time, so that kinetic curves are obtained.

101

The compounds are dissolved in DMSO and applied to the bottom of 384-well plates at a final concentration of 10 to 40 g / ml.

[0178] By using procedures similar to those described herein, using reagents and commercially available intermediates (e.g., Sigma-Aldrich), or those that can be easily synthesized by a person skilled in the art, the compounds shown in the present invention were characterized, characterized, and tested. in Table 2. AC1.4 values ​​were determined according to the procedure described in Example 21, and the observed mean AC1.4 values ​​are as follows: A = &lt;1 μM; B = 1-10 μM; C = 10-20 μM; D =&gt; 20 μM.

Table 2 * Indicates the reference example)

102

Relationship m / z (M + H)

4- (2 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} pyrimidin-5-yl) benzamide *

Structure

<img file="PL2560653T3_D0051.tif" />

365.3

Average

AC1.4

B

3- (2 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} pyrimidin-5-yl) benzamide *

5- (2 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} pyrimidin-5-yl) pyridine-3-carbonitrile *

<img file="PL2560653T3_D0052.tif" />

365.3

348.3

B m / z

Average

103

Relationship (M + H)

AC1.4

5- (2 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} pyrimidin-5-yl) pyridine-3-carboxamide *

Structure

<img file="PL2560653T3_D0053.tif" />

366.3

3- (2-aminopyrimidin-5-yl) benzamide *

<img file="PL2560653T3_D0054.tif" />

215.3 [2- (4-fluorophenyl) -2-methylpropyl] -5,6,7,8-tetrahydropyridine [4,3-d] pyrimidin-2-ylamine *

<img file="PL2560653T3_D0055.tif" />

301.0

D m / z

Average

Relationship

Methyl 2 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} pyrimidine-5-carboxylate *

104 (M + H)

AC1.4

N- [2- (4-fluorophenyl) -2-methylpropyl] (2 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} pyrimidin-5-yl) carboxamide *

Structure

<img file="PL2560653T3_D0056.tif" />

304.1

439.1

1 - [(2 - [[2- (4-fluorophenyl) -2-methylpropyl] amino} pyrimidin-5-yl) carbonylamino] cyclopropanecarboxylate *

<img file="PL2560653T3_D0057.tif" />

401.1

D m / z

Average

105

Relationship

Structure (M + H)

AC1.4 2 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} pyrimidine-5-carboxylic acid *

<img file="PL2560653T3_D0058.tif" />

289.0 (5-bromopyrimidin-2-yl) [2- (4-fluorophenyl) -2-methylpropyl] -amine *

<img file="PL2560653T3_D0059.tif" />

324.0 1 - [(2 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} pyrimidin-5-yl) carbonylamino] cyclopropanecarboxylic acid *

<img file="PL2560653T3_D0060.tif" />

373.1

D

106

Relationship

1 - [(2 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} pyrimidin-5-yl) carbonylamino] cyclopropanecarboxamide *

Structure

<img file="PL2560653T3_D0061.tif" />

m / z (M + H)

373.1

Average

AC1.4

5- (2 - {[2- (4-fluorophenyl) -2-methyl-propyl] amino} pyrimidin-5-yl) -3-hydrobenzimidazol2-one *

378.1

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

<img file="PL2560653T3_D0062.tif" />

343.0

D

107

Relationship m / z (M + H)

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

Structure

<img file="PL2560653T3_D0063.tif" />

379.0

Average

AC1.4

B [2- (4-fluorophenyl) -2-methylpropyl] (6-methyl (5,6,7,8-tetrahydropyridine [4,3-d] pyrimidin-2-yl)) amine *

<img file="PL2560653T3_D0064.tif" />

315.0

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

<img file="PL2560653T3_D0065.tif" />

301.0

D

108

Relationship

2- (2 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} (5,6,7,8-tetrahydropyridine [4,3-d] pyrimidin-6-yl)) - 2-oxoacetamide *

Structure

<img file="PL2560653T3_D0066.tif" />

m / z (M + H)

372.0

Average

AC1.4

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

<img file="PL2560653T3_D0067.tif" />

344.0

2- (2 - {[2- (4-fluorophenyl) -2-methylpropyl] amino} (5,6,7,8-tetrahydropyridine [3,4-d] pyrimidin-7-yl)) - 2-oxoacetamide *

<img file="PL2560653T3_D0068.tif" />

372.0

D m / z

Average

109

Relationship (M + H)

AC1.4

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

Structure

<img file="PL2560653T3_D0069.tif" />

379.0 [5- (3-amino (1H-indazol-5-yl)) pyrimidin-2-yl] [2- (4-fluorophenyl) -2-methylpropyl] -amine *

<img file="PL2560653T3_D0070.tif" />

377.1

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

<img file="PL2560653T3_D0071.tif" />

382.1

AND

110

Relationship m / z (M + H)

4- (2 - {[(4-fluorophenyl) cyclobutyl] amino} pyrimidin-5-yl) pyridine-2-carbonitrile *

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

4- (2 - {[(3-fluoro-2-pyridyl) cyclobutyl] amino} pyrimidin-5-yl) pyridine-2-carbonitrile *

Structure

<img file="PL2560653T3_D0072.tif" />

346.1

381.1

Average

AC1.4

C

347.1

D m / z

Average

Relationship

111 (M + H)

AC1.4

4- (2 - {[(3-fluoro-2-pyridyl) cyclobutyl] amino} pyrimidin-5-yl) pyridine-2-carboxamide *

4- (2 - {[(4-fluorophenyl) cyclobutyl] amino} pyrimidin-5-yl) pyridine-2-carboxamide * (5- (1H-indazol-5-yl) pyrimidin-2-yl) [(3 fluoride) (2-pyridyl)) cyclobutyl] amine *

Structure

<img file="PL2560653T3_D0073.tif" />

365.1

364.1

361.1

B m / z

Average

Relationship

112 (M + H)

AC1.4

5- (2 - {[(3-fluoro-2-pyridyl) cyclobutyl] amino} pyrimidin-5-yl) -1H-indazole-3-carbonitrile *

5- (2 - {[(3-fluoro-2-pyridyl) cyclobutyl] amino} pyrimidin-5-yl) -1H-indazole-3-carboxamide * [5- (6-fluoro (1H-indazol-5-yl) )) pyrimidin-2-yl] [(3-fluoro- (2-pyridyl)) cyclobutyl] amine *

Structure

<img file="PL2560653T3_D0074.tif" />

386.1

404.1

379.1

B m / z

Average

Relationship

113 (M + H)

AC1.4

6-fluoro-5- (2 - {[(3-fluoro- (2-pyridyl)) cyclobutyl] amino} pyrimidin-5-yl) -1H-indazole-3-carbonitrile *

6-Fluoro-5- (2 - {[(3-fluoro- (2-pyridyl)) cyclobutyl] amino} pyrimidin-5-yl) -1H-indazole-3-carboxamide * (5-bromopyrimidin-2-yl) [( 4-fluorophenyl) cyclobutyl] amine *

Structure

<img file="PL2560653T3_D0075.tif" />

404.1

422.1

322.0

D

(5-Bromopyrimidin-2-yl) [(3-fluoro-2-pyridyl)) cyclobutyl] -amine (6-bromochinazolin-2-yl) [(3-fluoro-2-pyridyl)] cyclobutyl] -amine.

2 - {[(3-fluoro-2-pyridyl) cyclobutyl] amino} quinazolin-6-carbonitrile *

114 m / z (M + H)

Average

AC1.4 [(3-fluoro- (2-pyridyl)) cyclobutyl] quinazolin-2-ylamine *

Structure

<img file="PL2560653T3_D0076.tif" />

323.0

373.0

320.1

295.1

115

Relationship m / z (M + H)

2 - {[(3-fluoro-2-pyridyl) cyclobutyl] amino} quinazolin-6-carboxamide *

2 - {[(3-fluoro-2-pyridyl) cyclobutyl] amino} pyrimidine-5-carbonitrile *

2 - {[(4-fluorophenyl) cyclobutyl] amino} pyrimidine-5-carbonitrile * (5-bromopyrimidin-2-yl) [1- (4-fluorophenyl) isopropyl] -amine *

Structure

<img file="PL2560653T3_D0077.tif" />

338.1

270.1

269.1

Average

AC1.4

D

310.0

C

116

Relationship m / z (M + H)

2 - {[(4-fluorophenyl) cyclobutyl] amino} pyrimidin-4-carboxamide *

2 - {[(4-fluorophenyl) cyclobutyl] amino} pyrimidin-4-carbonitrile * [(4-fluorophenyl) cyclobutyl] pyrazolo [5,4-d] pyrimidin-6-ylamine *

2 - {[(4-fluorophenyl) cyclobutyl] amino} pyrimidine-5-carboxamide *

Structure

<img file="PL2560653T3_D0078.tif" />

287.1

269.1

284.1

287.1

Average

AC1.4

C

Relationship

2 - {[(3-fluoro-2-pyridyl) cyclobutyl] amino} pyrimidine-5-carboxamide *

2 - {[(4-fluorophenyl) cyclobutyl] amino] -4- (trifluoromethyl) pyrimidine-5-carboxamide *

117 m / z (M + H)

Average

AC1.4 2 - {[(4-fluorophenyl) cyclobutyl] amino] -4 (trifluoromethyl) pyrimidine-5-carboxylic acid * [(4-fluorophenyl) cyclobutyl] [4- (trifluoromethyl) pyrimidin-2-yl] -amine *

Structure

<img file="PL2560653T3_D0079.tif" />

288.1

355.1

356.1

312.1

Relationship

118 m / z

Average (M + H)

AC1.4

N - [(4-fluorophenyl) cyclobutyl] (2 - {[(4-fluorophenyl) cyclobutyl] amino} -4- (trifluoro-methyl) pyrimidin-5-yl) carboxamide *

2 - {[(3-fluoro- (2-pyridyl)) cyclobutyl] amino} -4- (trifluoromethyl) pyrimidine-5-carboxamide *

Structure

<img file="PL2560653T3_D0080.tif" />

503.1

356.1

357.1 2 - {[(3-Fluoro- (2-pyridyl)) cyclobutyl] amino] -4- (trifluoromethyl) pyrimidine-5-carboxylic acid *

119

Compound m / z (M + H) [(3-fluoro (2-pyridyl)) cyclobutyl] [4 (trifluoromethyl) pyrimidin-2-yl] -amine *

Ethyl 1- [2 - (([(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] pyrazole-4-carboxylate *

Structure

<img file="PL2560653T3_D0081.tif" />

313.1

397.3

368.3

Average

AC1.4

D

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

Relationship

120 m / z

Average (M + H)

AC1.4 1- [2 - ({[(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] pyrazole-4-carboxylic acid *

Structure

<img file="PL2560653T3_D0082.tif" />

369.2

2- [2 - (([(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] -1,3-thiazole-4-carboxamide *

<img file="PL2560653T3_D0083.tif" />

385.1

<img file="PL2560653T3_D0084.tif" />

385.1

2- [2 - (([(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] -1,3-thiazole-5-carboxamide

121

Relationship

Ethyl 2- [2 - (([(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] -1,3-thiazole-4-carboxylate *

Structure

<img file="PL2560653T3_D0085.tif" />

m / z (M + H)

414.2

Average

AC1.4 2- [2 - (([(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] -1,3-thiazole-4-carboxylic acid *

386.2

2- [2 - ({1- [6- (difluoromethoxy) (2-pyridyl)] amino} isopropyl) pyrimidin-5-yl] -1,3-thiazole-5-carboxamide *

<img file="PL2560653T3_D0086.tif" />

407.2

122

Relationship m / z (M + H)

2- (2 - {[(2-pirydylocyklobutylo) methyl] amino} pyrimidin-5-yl) -1,3-thiazole-5-carboxamide *

Structure

<img file="PL2560653T3_D0087.tif" />

367.2

Average

AC1.4

B

2- (2 - {[(2-pirydylocyklobutylo) methyl] amino} pyrimidin-5-yl) -1,3-thiazole-5-carbonitrile *

<img file="PL2560653T3_D0088.tif" />

349.2

<img file="PL2560653T3_D0089.tif" />

367.2

2- [2 - (([(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] -1,3-thiazole-5-carbonitrile *

123 m / z

Average

Relationship

2- (2 - ([1- (4-methoxy-2-yl) isopropyl] amino} pyrimidin-5-yl) -1,3-thiazole-5-carboxamide *

Structure

<img file="PL2560653T3_D0090.tif" />

(M + H)

372.1

AC1.4 {4- [6 - ({[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyridazin-3-yl] pyrimidin-2-yl} (methylsulfonyl) amine *

<img file="PL2560653T3_D0091.tif" />

430.3

<img file="PL2560653T3_D0092.tif" />

2 - (([(3-Fluoro-2-pyridyl) cyclobutyl] methyl} amino) thiophene [2,3-d] pyrimidine-6-carboxylate *

124 m / z

Average

Relationship

2 - (([(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) thiophene [2,3-d] pyrimidine-6-carboxamide * (M + H)

AC1.4 2 - (([(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) thiophene [2,3-d] pyrimidine-6-carboxylic acid *

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

Structure

<img file="PL2560653T3_D0093.tif" />

358.1

358.1

384.1

Relationship

125 m / z

Average (M + H)

AC1.4

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

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

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

Structure

<img file="PL2560653T3_D0094.tif" />

396.1

366.1

378.2

AND

126

Relationship m / z (M + H)

Average

AC1.4

3- [2 - ({1- [6- (difluoromethoxy) (2-pyridyl)] amino} isopropyl) pyrimidin-5-yl] -4-fluorobenzamide *

3- [2 - ({1- [6- (difluoromethoxy) (2-pyridyl)] amino} isopropyl) pyrimidin-5-yl] benzamide *

3- (2 - {[1- (3-fluoro- (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) benzamide *

Structure

<img file="PL2560653T3_D0095.tif" />

418.2

400.3

352.3

Relationship

127 m / z

Average (M + H)

AC1.4

5 - ({[(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) -1,3-thiazolo [5,4-d] pyrimidine-2-carboxamide * 5 - ({[(3-fluoro-2-acid) pyridyl) cyclobutyl] methyl} amino) -1,3-thiazole [5,4-d] pyrimidine-2-carboxylic acid *

Structure

<img file="PL2560653T3_D0096.tif" />

359.1

360.1

4-fluoro-3- (2 - {[1- (3-fluoro- (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) benzamide *

370.1

B

128

Relationship m / z (M + H)

N - {[4- (2 - {[1- (3-fluoro- (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) phenyl] methyl} acetamide * [5- (2-aminopyrimidin-5-yl) ylo) pyrimidin-2-yl] [(3-fluoro- (2-pyridyl)) - isopropyl] -amine

2- (2 - {[1- (3-fluoro- (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,3-thiazole-5-carboxamide *

Structure

<img file="PL2560653T3_D0097.tif" />

380.2

326.1

359.1

Average

AC1.4

D

2- (2 - {[2- (3-fluoro- (2-pyridyl)) - 2-methylpropyl] amino} pyrimidin-5-yl) pyrimidine-4-carboxamide *

368.2

C

129 m / z

Average

Relationship

Methyl 2- [4-fluoro-3- (2 - {[1- (3-fluoro-2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) phenyl] acetate *

N - {[3- (2- [1- (3-fluoro- (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) phenyl] methyl} acetamide *

3- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) benzamide * (M + H)

AC1.4

Structure

<img file="PL2560653T3_D0098.tif" />

399.1

380.1

368.1

3- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -4fluorobenzamid *

386.1

AND

Relationship

130 m / z

Average (M + H)

AC1.4

1- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) pyrazole-4-carbonitrile *

1- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) pyrazole-4-carboxamide *

2- [4-fluoro-3- (2 - {[1- (3-fluoro- (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) phenyl] acetamide;

2- (2 - {[1- (3-fluoro- (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) pyrimidine-4-carboxamide *

Structure

<img file="PL2560653T3_D0099.tif" />

340.1

358.1

384.1

354.1

D

131 m / z

Average

{5- [5- (Aminomethyl) (1,3-thiazol-2-yl)] pyrimidin-2-yl} [1- (3-fluoro-2-pyridyl)) isopropyl] -amine.

N - {[2- (2 - {[1- (3-fluoro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,3-thiazol-5-yl] methyl} acetamide;

2-Amino-N - {[2- (2 - {[1- (3-fluoro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) (1,3-thiazol-5-yl)] methyl} acetamide *

N - {[2- (2 - {[1- (3-fluoro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) (1,3-thiazol-5-yl)] methyl} imidazol-5-ilokarboksyamid *

Structure

<img file="PL2560653T3_D0100.tif" />

<img file="PL2560653T3_D0101.tif" />

<img file="PL2560653T3_D0102.tif" />

402.2

<img file="PL2560653T3_D0103.tif" />

(M + H)

345.2

387.1

AC1.4

439.1

D

132 m / z

Average

Relationship

N - {[2- (2 - {[1- (3-fluoro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) (1,3-thiazol-5-yl)] methyl} (2-hydroksyimidazol- 5-yl) carboxamide * (aminocyclopropyl) -N - {[2- (2 - {[1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) (1,3-thiazol-5-yl) ) methyl} carboxamide * ((2R) pyrrolidin-2-yl) -N- [2- (2 - {[1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) (1.3) -thiazol-5-yl)] methyl} carboxamide * ((2S) -pyrrolidin-2-yl) -N- [2- (2 - {[1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidine -5ylo) (1,3-thiazol-5-yl)] methyl} carboxamide *

Structure

<img file="PL2560653T3_D0104.tif" />

<img file="PL2560653T3_D0105.tif" />

428.1

442.2 (M + H)

455.1

AC1.4

442.2

C

133 m / z

Average

Relationship

N - {[2- (2 - {[1- (3-fluoro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,3-thiazol-4-yl] methyl} acetamide;

2- [2- (2 - {[1- (3-Fluoro-(2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,3-thiazol-4-yl] acetamide *

Structure

<img file="PL2560653T3_D0106.tif" />

387.3

<img file="PL2560653T3_D0107.tif" />

373.3 (M + H)

AC1.4

1- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) pyrrole-3-carboxamide *

<img file="PL2560653T3_D0108.tif" />

357.1

1- (2 - {[1- (3-fluoro- (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) pyrazole-4-carboxamide *

<img file="PL2560653T3_D0109.tif" />

342.2

D

134

Compound m / z (M + H) {5- [4- (aminomethyl) (1,3-thiazol-2-yl)] pyrimidin-2-yl} [1- (3-fluoro- (2-pyridyl)) isopropyl] -amine *

2- (2 - [[l- (3-fluoro- (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,3-thiazole-4karbonitryl *

2- (2 - {[1- (3-fluoro- (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,3-thiazole-4-carboxamide *

Structure

<img file="PL2560653T3_D0110.tif" />

345.3

341.3

Average

AC1.4

D

<img file="PL2560653T3_D0111.tif" />

359.3

Relationship

135 m / z

Average (M + H)

AC1.4

2-Amino-N - {[2- (2 - {[1- (3-fluoro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) (1,3-thiazol-4-yl)] methyl} acetamide * ((2S) pyrrolidin-2-yl) -N- [2- (2- [1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) (1,3-thiazol-4-yl) )] methyl} carboxamide *

Structure

<img file="PL2560653T3_D0112.tif" />

402.2

442.3

Relationship m / z (M + H)

Average

AC1.4 ((2R) -pyrrolidin-2-yl) -N- [2- (2- [1- (3-fluoro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) (1,3-thiazole -4-yl)] methyl} carboxamide *

2- (2 - {[1- (3-fluoro- (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,3-thiazole-5-carbonitrile *

2- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,3-thiazole-5-carboxamide *

Structure

<img file="PL2560653T3_D0113.tif" />

442.3

341.2

375,2 m / z

Average

Relationship (M + H)

AC1.4 1- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) pyrazole-4-carboxylic acid *

N- (2-carbamoylethyl) [1- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -pyrazol-4-yl] carboxamide *

Structure

<img file="PL2560653T3_D0114.tif" />

359.1

<img file="PL2560653T3_D0115.tif" />

429.1 [1- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -pyrazol-4-yl] -N- (2-hydroxyethyl) carboxamide *

2- [1- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) pyrazol-4-yl] propan-2-ol *

<img file="PL2560653T3_D0116.tif" />

402.1

<img file="PL2560653T3_D0117.tif" />

373.1

138 m / z

Average

Relationship

5- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) isoxazole-3-carboxamide *

Structure

<img file="PL2560653T3_D0118.tif" />

(M + H)

359.2

AC1.4 [1- (3-chloro (2-pyridyl)) isopropyl] (5-pyrazol-4-yl-pyrimidin-2-yl) -amine *

<img file="PL2560653T3_D0119.tif" />

315.1

5- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) pyridine-3-carboxamide * 5- (2 - {[1- (3-chloro-2-yl) acid pyridyl)) isopropyl] amino} pyrimidin-5-yl) thiophene-2-carboxylic acid *

<img file="PL2560653T3_D0120.tif" />

369.1

<img file="PL2560653T3_D0121.tif" />

375.0

139

Relationship m / z (M + H)

5- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) thiophene-2-carboxamide * (5-bromopyrimidin-2-yl) [1- (3-fluorine) (2-pyridyl)) - isopropyl] -amine *

Structure

<img file="PL2560653T3_D0122.tif" />

374.1

Average

AC1.4

B

<img file="PL2560653T3_D0123.tif" />

311.0

2 - {[1- (3-Chloro (2-pyridyl)) isopropyl] amino} pyrimidine-5-carbonitrile * (5-bromopyrimidin-2-yl) [1- (3-chloro (2-pyridyl)) isopropyl] -amine

<img file="PL2560653T3_D0124.tif" />

274.1

<img file="PL2560653T3_D0125.tif" />

328.1

D m / z

Average

140

Relationship

2- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,3-oxazole-4-carboxamide *

Structure (M + H)

AC1.4

<img file="PL2560653T3_D0126.tif" />

Ν

<img file="PL2560653T3_D0127.tif" />

<img file="PL2560653T3_D0128.tif" />

359.2 2- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,3-oxazole-4-carboxylic acid *

<img file="PL2560653T3_D0129.tif" />

360.2

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

<img file="PL2560653T3_D0130.tif" />

397.3

B

141

Relationship m / z (M + H)

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

4- [2 - ({[(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] pyridine-2-carboxamide [1- (3-chloro (2-pyridyl)) isopropyl] 5 pyrrolone 3,2-b] pyridin-6-yl-pyrimidin-2-yl) amine *

Structure

<img file="PL2560653T3_D0131.tif" />

397.3

379.3

Average

AC1.4

B

365.2

AND

142 m / z

Average

Relationship

2- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,3-oxazol-5-carboxamide *

4- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) pyridine-2-carboxamide *

Structure

<img file="PL2560653T3_D0132.tif" />

(M + H)

359.2

AC1.4

4- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,3-thiazol-2-carboxamide *

<img file="PL2560653T3_D0133.tif" />

369.3

375.2

2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidine-5-carboxamide *

<img file="PL2560653T3_D0134.tif" />

'-Ν

Cl '

292.1

D m / z

Average

Relationship

143 (M + H)

AC1.4 [5- (3-amino (1H-indazol-5-yl)) pyrimidin-2-yl] [1- (3-chloro (2-pyridyl)) isopropyl] -amine *

Structure

<img file="PL2560653T3_D0135.tif" />

380.1

3- (2 - {[1-methyl-1- (4-methylthiophenyl) ethyl] amino} pyrimidin-5-yl) benzenecarbonitrile *

3- (2 - {[1-methyl-1- (2-methylthiophenyl) ethyl] amino} pyrimidin-5-yl) benzenecarbonitrile *

<img file="PL2560653T3_D0136.tif" />

361.2

361.2

Relationship

144 m / z

Average (M + H)

AC1.4

5- (2- {1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) pyrazole-3-carboxamide *

Structure

<img file="PL2560653T3_D0137.tif" />

358.1

3- (2- (2- (4- (methylsulfinyl) phenyl) propan-2-ylamino) -pyrimidin-5-yl) benzamide *

3- [2 - ({1-methyl-1- [4- (methylsulfonyl) phenyl] ethyl} amino) pyrimidin-5-yl] benzamide *

3- [2 - ({1-methyl-1- [2- (methylsulfonyl) phenyl] ethyl} amino) pyrimidin-5-yl] benzamide *

<img file="PL2560653T3_D0138.tif" />

395.2

411.2

411.2

D

Relationship

145 m / z

Average (M + H)

AC1.4

3- [2 - ({1-methyl-1- [3- (methylsulfonyl) (2-pyridyl)] ethyl} amino) pyrimidin-5-yl] benzamide *

2- (2 - {[1- (3-Chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,3-thiazole-4-carboxamide * 2- (2 - {[1- (3-acid) -chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,3-thiazole-4-carboxylic acid * 2- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino acid } pyrimidin-5-yl) -1,3-oksazolo5-carboxylic acid *

Structure

<img file="PL2560653T3_D0139.tif" />

<img file="PL2560653T3_D0140.tif" />

<img file="PL2560653T3_D0141.tif" />

412.2

375.2

376.2

360,2 m / z

Average

Relationship

146 (M + H)

AC1.4

3- (2 - {[1-methyl-1- (3-methylthio (2-pyridyl)) ethyl] amino} pyrimidin-5-yl) benzenecarbonitrile *

3- (2 - ([1-methyl-1- (2-methylthiophenyl) ethyl] amino} pyrimidin-5-yl) benzamide *

3- (2- (2- (2- (methylsulfinyl) phenyl) propan-2-ylamino) -pyrimidin-5-yl) benzamide *

Structure

<img file="PL2560653T3_D0142.tif" />

362.2

379.3

395.2

Οm / from

Average

Relationship

147 (M + H)

AC1.4 [1- (3-chloro (2-pyridyl)) - isopropyl] pyrimidin-2-ylamine *

3- (2 - {[1-methyl-1- (3-methylthio (2-pyridyl)) ethyl] amino} pyrimidin-5-yl) benzamide *

3- (2- (2- (3- (methylsulfinyl) pyridin-2-yl) propan-2-ylamino) -pyrimidin-5-yl) benzamide *

Structure

<img file="PL2560653T3_D0143.tif" />

249.2

380.2

396.2 m / z

Average

Relationship

3- [2 - ({1-methyl-1- [3- (methylsulfonyl) (2-pyridyl)] ethyl} (hydroxyamino)) pyrimidin-5-yl] benzamide *

148 (M + H)

AC1.4

Structure

<img file="PL2560653T3_D0144.tif" />

428.2

3- [2 - ({1- [3- (difluoromethyl) (2-pyridyl)] amino} isopropyl) pyrimidin-5-yl] -4fluorobenzenokarbonitryl *

<img file="PL2560653T3_D0145.tif" />

3- [2 - ({1- [3- (difluoromethyl) (2-pyridyl)] amino} isopropyl) pyrimidin-5-yl] -4fluorobenzamid *

<img file="PL2560653T3_D0146.tif" />

402.1

B m / z

Average

Relationship

149 (M + H)

AC1.4 (5- (5H-1,2,3,4-tetrazol-5-yl) pyrimidin-2-yl) [1- (3-chloro (2-pyridyl)) isopropyl] -amine

Structure

<img file="PL2560653T3_D0147.tif" />

317.1

Ethyl 5- {2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,3,4-oxadiazole-2-carboxylate *

5- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,3,4-oxadiazol-2-carboxamide *

<img file="PL2560653T3_D0148.tif" />

<img file="PL2560653T3_D0149.tif" />

389.1

D

150

Relationship m / z (M + H)

Methyl 4- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) thiophene-2-carboxylate *

Average

AC1.4

D

5- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,3-thiazol-2-carboxamide *

Structure

<img file="PL2560653T3_D0150.tif" />

340.2

375.2

5- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,3,4-thiadiazole-2-carboxamide *

<img file="PL2560653T3_D0151.tif" />

376.3

D

151

Relationship

Methyl 4- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1-methylimidazole-2-carboxylate *

Structure

<img file="PL2560653T3_D0152.tif" />

387.2 m / z (M + H)

Average

AC1.4

6- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) pyridine-2-carboxamide *

<img file="PL2560653T3_D0153.tif" />

369.1

3- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -1,2,4-oxadiazol-5-carboxamide *

Ethyl 5- {2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,2,4-oxadiazole-3-carboxylate *

<img file="PL2560653T3_D0154.tif" />

<img file="PL2560653T3_D0155.tif" />

360.3

389.1 m / z

Average

152

Relationship (M + H)

AC1.4 [5- (3-amino (1H-indazol-5-yl)) pyrimidin-2-yl] [1- (3-fluoro-2-pyridyl)) isopropylamine *

Structure

<img file="PL2560653T3_D0156.tif" />

364.2

4- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) thiophene-2-carboxamide *

<img file="PL2560653T3_D0157.tif" />

374.1 [1- (3-chloro (2-pyridyl)) isopropyl] (5- (1,2,4-oxadiazol-5-yl) pyrimidin-2-yl) -amine *

<img file="PL2560653T3_D0158.tif" />

¹-Ν

cl

317.1

D m / z

Average

Relationship

4-fluoro-3- (2 - {[1- (3-methoxy- (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) benzenecarbonitrile *

153

Structure

<img file="PL2560653T3_D0159.tif" />

(M + H)

364.1

AC1.4

4-fluoro-3- (2 - {[1-methyl-1- (3-methyl- (2-pyridyl)) ethyl] amino} pyrimidin-5-yl) benzamide *

<img file="PL2560653T3_D0160.tif" />

366.1

4-fluoro-3- (2 - {[1- (3-methoxy- (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) benzamide *

<img file="PL2560653T3_D0161.tif" />

F

382.1

C m / z

Average

154

{5- [5- (Aminomethyl) (1,3-thiazol-2-yl)] pyrimidin-2-yl} [1- (3-chloro (2-pyridyl)) isopropyl] -amine.

N- [2- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1,3-thiazol-5-yl] methyl} acetamide;

Structure

<img file="PL2560653T3_D0162.tif" />

<img file="PL2560653T3_D0163.tif" />

<img file="PL2560653T3_D0164.tif" />

(M + H)

361.0

403.1

AC1.4

N- [2- (2- [1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) (1,3-thiazol-5-yl)] methyl} -2-hydroxy -2-methylpropanamide *

447.1

C

Relationship

155 m / z

Average (M + H)

AC1.4

N - {[2- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) (1,3-thiazol-5-yl)] methyl} (2-hydroksyimidazol- 4-yl) carboxamide *

Structure

<img file="PL2560653T3_D0165.tif" />

471.1

3- (2 - {[1- (3-chloro-6-hydroxy (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) benzamide *

<img file="PL2560653T3_D0166.tif" />

3- (2 - {[1- (3-chloro-6-methoxy (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) benzamide *

<img file="PL2560653T3_D0167.tif" />

398.1

A m / z

Average

156

Relationship (M + H)

AC1.4 [1- (3-chloro (2-pyridyl)) isopropyl] (5- (1,3-thiazol-2-yl) pyrimidin-2-yl) -amine *

Structure

<img file="PL2560653T3_D0168.tif" />

332.1

2- [4- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) pyrazolyl] ethan-1-ol *

<img file="PL2560653T3_D0169.tif" />

359.1

<img file="PL2560653T3_D0170.tif" />

2- [4- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) pyrazolyl] acetic acid

373.1

D

157

Relationship

M / z structure

Average (M + H)

AC1.4

2- [4- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) pyrazolyl] acetamide;

<img file="PL2560653T3_D0171.tif" />

372.1

2- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) pyridine-4-carbonitrile *

<img file="PL2560653T3_D0172.tif" />

351.1

2- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) pyridine-4-carboxamide *

N - {[1- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino) pyrimidin-5-yl) pyrazol-4-yl] methyl} acetamide *

<img file="PL2560653T3_D0173.tif" />

<img file="PL2560653T3_D0174.tif" />

369.1

386.1

158

Relationship

M / z structure

Average (M + H)

AC1.4

4-fluoro-3- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] benzamide

<img file="PL2560653T3_D0175.tif" />

414.3

3- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] benzamide *

<img file="PL2560653T3_D0176.tif" />

396.3

6- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -2-pyrroline [3,2-b] pyridin-2-one *

<img file="PL2560653T3_D0177.tif" />

381.1

D m / z

Average

159

Relationship

6- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) imidazo [2,1-b] -1,3-thiazoline-2-carboxamide * [5- ( 2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) (1H-indazol-3-yl)] (methylsulfonyl) amine * (M + H)

AC1.4

<img file="PL2560653T3_D0178.tif" />

Structure

<img file="PL2560653T3_D0179.tif" />

414.1 [1- (3-chloro (2-pyridyl)) isopropyl] (4- (1,3-thiazol-2-yl) pyrimidin-2-yl) -amine *

<img file="PL2560653T3_D0180.tif" />

458.1

<img file="PL2560653T3_D0181.tif" />

332.2

D

160

Relationship m / z (M + H)

Average

AC1.4 {1- [6- (difluoromethoxy) (2-pyridyl)] isopropyl} (4- (1,3-thiazol-2-yl) pyrimidin-2-yl) amine *

5- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -1-methylpyrazole-3-carboxamide *

3- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1-methylpyrazole-5-carboxamide *

Structure

<img file="PL2560653T3_D0182.tif" />

<img file="PL2560653T3_D0183.tif" />

364.2

372.2

372.2

161

Relationship m / z (M + H)

6- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) imidazo [2,1-b] -1,3tiazolino-3-carboxamide *

Structure

<img file="PL2560653T3_D0184.tif" />

414.1

Average

AC1.4

B

5- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -2-methoxypyridine-3-carbonitrile *

5- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -2-methoxypyridine-3-carboxamide *

<img file="PL2560653T3_D0185.tif" />

<img file="PL2560653T3_D0186.tif" />

381.1

399.1 m / z

Average

162

Relationship

5- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -2-oksohydropirydyno-3-carboxamide *

Structure

<img file="PL2560653T3_D0187.tif" />

(M + H)

385.1

AC1.4

2 - [(tert-butoxy) carbonylamino] -N - {[1- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -pyrazol-4-yl] methyl} acetamide;

<img file="PL2560653T3_D0188.tif" />

501.1

<img file="PL2560653T3_D0189.tif" />

2-amino-N - {[1- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) pyrazol-4-yl] methyl} acetamide *

401.1

B

163

Relationship m / z (M + H)

Average

AC1.4

3 - [(tert-butoxy) carbonylamino] -N - {[1- (2 - {[(3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) pyrazol-4-yl] methyl } propanamide *

3-amino-N - {[1- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -pyrazol-4-yl] methyl} propanamide *

1Struktura

<img file="PL2560653T3_D0190.tif" />

<img file="PL2560653T3_D0191.tif" />

515.1

415.1

1- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] pyrazole-4-carbonitrile *

<img file="PL2560653T3_D0192.tif" />

368.2

C

164

Compound m / z (M + H) {[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} pyrimidin-2-ylamine *

Structure

<img file="PL2560653T3_D0193.tif" />

277.2

Average

AC1.4

D

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

<img file="PL2560653T3_D0194.tif" />

382.3

3- (2 - {[2- (3-chloro (2-pyridyl)) - 2-methylpropyl] amino} pyrimidin-5-yl) benzamide *

<img file="PL2560653T3_D0195.tif" />

382.3

AND

165

Relationship m / z (M + H)

Average

AC1.4

3- (2 - {[2- (3-chloro (2-pyridyl)) - 2-methylpropyl] amino} pyrimidin-5-yl) -4-fluorobenzamide *

2- (2 - {[(1R) -1- (3-chloro (2-pyridyl)) - 2-methylpropyl] amino} pyrimidin-5-yl) -1,3tiazolo-5-carbonitrile *

2- (2 - {[(1S) -1- (3-chloro (2-pyridyl)) - 2-methylpropyl] amino} pyrimidin-5-yl) -1,3tiazolo-5-carbonitrile *

Structure

<img file="PL2560653T3_D0196.tif" />

400.2

371.2

371.2

166

Relationship

2- (2 - {[(1R) -1- (3-chloro (2-pyridyl)) - 2-methylpropyl] amino} pyrimidin-5-yl) -1,3tiazolo-5-carboxamide *

2- (2 - {[(1S) -1- (3-chloro (2-pyridyl)) - 2-methylpropyl] amino} pyrimidin-5-yl) -1,3tiazolo-5-carboxamide *

Ethyl 3- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) isoxazole-5-carboxylate *

<img file="PL2560653T3_D0197.tif" />

m / z (M + H)

389.2

389.2

Average

AC1.4

D

388.2

D m / z

Average

167

Relationship

3- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) isoxazole-5-carboxamide *

Structure

<img file="PL2560653T3_D0198.tif" />

(M + H)

359.2

AC1.4 (5- (1H-indazol-5-yl) pyrimidin-2-yl) [1- (3-chloro (2-pyridyl)) - isopropyl] -amine

365.1

N- [5- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -1H-indazol-3-yl] acetamide;

<img file="PL2560653T3_D0199.tif" />

422,1 ο

Relationship

168 m / z

Average

Structure (M + H)

AC1.4

3- [2 - ({[1- (3-chloro (2-pyridyl)) - 3-fluorocyclobutyl] methyl} amino) pyrimidin-5-yl] -fluorobenzamide *

3- [2 - ({[1- (3-chloro (2-pyridyl)) - 3-fluorocyklobutylo] methyl} amino) pyrimidin-5-yl] -4-fluorobenzamide *

4-fluoro-3- (2 - {[(3-fluoro-1- (2-pyridyl) cyclobutyl) methyl] amino} pyrimidin-5-yl) benzamide *

<img file="PL2560653T3_D0200.tif" />

430.2

430.2

396.2 m / z

Average

Relationship

169

Structure (M + H)

AC1.4

4-fluoro-3- (2 - {[(3-fluoro-1- (2-pyridyl) cyclobutyl) methyl] amino} pyrimidin-5-yl) benzamide *

396.2

<img file="PL2560653T3_D0201.tif" />

370.2

<img file="PL2560653T3_D0202.tif" />

6- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) pyrimidine-4-carboxamide *

Methyl 6- {2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) pyrimidine-4-carboxylate *

385.2

D m / z

Average

170

Relationship (M + H)

AC1.4

3- {2 - [(tert-butyl) amino] pyrimidin-5-yl} benzamide *

Structure

<img file="PL2560653T3_D0203.tif" />

271.3 [5- (3-amino (1H-indazol-5-yl)) pyrimidin-2-yl] (tert-butyl) amine *

<img file="PL2560653T3_D0204.tif" />

283.3

3- (2 - {[1- (3-chloro (2-pyridyl)) - 3-fluorocyklobutylo] amino} pyrimidin-5-yl) -4-fluorobenzamide *

<img file="PL2560653T3_D0205.tif" />

416.2

AND

Relationship

171 m / z

Average (M + H)

AC1.4

3- [2 - ({[(3-chloro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -4-fluorobenzamide *

Structure

<img file="PL2560653T3_D0206.tif" />

412.2

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

<img file="PL2560653T3_D0207.tif" />

394.3

3- (2 - {[(2-pirydylocyklobutylo) methyl] amino} pyrimidin-5-yl) benzamide *

<img file="PL2560653T3_D0208.tif" />

360.3

B

Relationship

172 m / z

Average (M + H)

AC1.4

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

3- [2 - ({[(3-chloro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -4-fluorobenzenokarbonitryl *

3- [2 - ({[(3-chloro-2-pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] benzenecarbonitrile *

Structure

<img file="PL2560653T3_D0209.tif" />

378.3

394.2

376.2

A m / z

Average

Compound {[(3-chloro (2-pyridyl)) cyclobutyl] methyl} pyrimidin-2-ylamine *

3- (2 - {[1- (2-chloro (3-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) -4-fluorobenzamide *

173 (M + H)

AC1.4 6- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) imidazo [2,1b] -1,3-thiazoline-3-carboxylic acid *

Structure

<img file="PL2560653T3_D0210.tif" />

HO '"O

275.2

386.2

415.0

B m / z

Average

174

2- (2 - {[1- (3-Chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -4-hydro-imidazo [1,2-a] pyridine-6-carboxylic acid compound *

2- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -4-hydroimidazo [1,2-a] pyridine-6-carboxamide * (M + H)

AC1.4

Structure

<img file="PL2560653T3_D0211.tif" />

409.1

408.1

Methyl 1- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] pyrrole-3-carboxylate *

400.3

D

175

Relationship

M / z structure

Average (M + H)

AC1.4 1- [2 - ({[3-fluoro-1- (3-fluoro-2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] pyrrole-3-carboxylic acid

<img file="PL2560653T3_D0212.tif" />

OH

386.3

1- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] pyrrole-3-carboxamide

<img file="PL2560653T3_D0213.tif" />

nh₂

385.3

2- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -4hydroimidazo [1,2-a] pyridine-8-carboxamide *

<img file="PL2560653T3_D0214.tif" />

408.1

B

176 m / z

Average

Relationship

2- (2 - {[1- (3-chloro (2-pyridyl)) isopropyl] amino} pyrimidin-5-yl) -4hydroimidazo [1,2-a] pyridine-7-carboxamide *

5- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) pyridazine-3-carboxamide *

N- (tert-butyl) [5- (2 - {[1- (3-chloro (2-pyridyl)) - isopropyl] amino} pyrimidin-5-yl) pyridazin-3-yl] carboxamide * (M + H)

AC1.4 {3- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] phenyl} -N- (methylsulfonyl) carboxamide *

Structure

<img file="PL2560653T3_D0215.tif" />

408.1

370.2

426.2

474.1

AND

177

Relationship

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

Structure

<img file="PL2560653T3_D0216.tif" />

m / z (M + H)

381.2

Average

AC1.4

2- {2- [2 - ({[(3-chloro-2-pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] -1,3-thiazol-5-yl} acetamide

<img file="PL2560653T3_D0217.tif" />

415.1

3- [2 - ({[1- (3-chloro (2-pyridyl)) - 3,3-difluorocyclobutyl] methyl} amino) pyrimidin-5-yl] -4fluorobenzamid *

<img file="PL2560653T3_D0218.tif" />

448.2

AND

178

Relationship

3- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) -4-methyl-5-yl] benzamide *

Structure

<img file="PL2560653T3_D0219.tif" />

410,1 m / z (M + H)

Average

AC1.4

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

<img file="PL2560653T3_D0220.tif" />

399.2

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

<img file="PL2560653T3_D0221.tif" />

417.1

B

179

Relationship

M / z structure

Average (M + H)

AC1.4 (tert-butoxy) -N - ({2- [2 - ({[(3-fluoro (2-pyridyl)] cyclobutyl] methyl} amino) pyrimidin-5-yl] (1,3-thiazol-5-yl) } methyl) carboxamide *

<img file="PL2560653T3_D0222.tif" />

471,2 {5- [5- (aminomethyl) (1,3-thiazol-2-yl)] pyrimidin-2-yl} {[(3-fluoro (2-pyridyl)] cyclobutyl] methyl} amine *

<img file="PL2560653T3_D0223.tif" />

371.1

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

<img file="PL2560653T3_D0224.tif" />

¹-Ν m / z

Average

180

(Tert-Butoxy) -N - ({2- [2 - ({[(3-chloro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] (1,3-thiazol-5-yl)} methyl ) carboxamide *

Structure

<img file="PL2560653T3_D0225.tif" />

(M + H)

AC1.4 {5- [5- (aminomethyl) (1,3-thiazol-2-yl)] pyrimidin-2-yl} {[(3-chloro (2-pyridyl)] cyclobutyl] methyl} amine *

N - ({2- [2 - ({[(3-chloro-2-pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] -1,3-thiazol-5-yl} methyl) acetamide;

<img file="PL2560653T3_D0226.tif" />

387.1

429.1

AND

Compound m / z (M + H) ({2- [2 - ({[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] (1,3-thiazol-5-yl) } methyl) (methylsulfonyl) amine *

2- {2- [2 - ({[1- (3-chloro (2-pyridyl)) - 3fluorocyklobutylo] methyl} amino) pyrimidin-5-yl] -1,3-thiazol-5-yl} acetamide;

Structure

<img file="PL2560653T3_D0227.tif" />

449.1

433.2 (tert-butoxy) -N - {[2- (2 - {[(2-pyridylcyclobutyl) methyl] amino} pyrimidin-5-yl) (1,3-thiazol-5-yl)] methyl} carboxamide *

<img file="PL2560653T3_D0228.tif" />

Average

AC1.4

B

182

[2 - ({[(3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N-isoxazol-3-ylcarboxamide * m / z Medium (M + H) AC1.4

Structure

<img file="PL2560653T3_D0229.tif" />

369.2 B [2 - ({[(3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N- (1,3-thiazolyl) carboxamide *

385.2

B

183

Relationship

M / z structure

Average (M + H)

AC1.4

2 - ({[(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyrimidine-5-carboxamide *

302,2 [2 - ({[(3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N-methylcarboxamide *

<img file="PL2560653T3_D0230.tif" />

316.2

Relationship

184 m / z

Average (M + H)

AC1.4

N-ethyl-N- [2 - ({[(3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] carboxamide *

Structure

<img file="PL2560653T3_D0231.tif" />

330.2

<img file="PL2560653T3_D0232.tif" />

[2 - ({[(3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N- (2-hydroxyethyl) carboxamide *

346.2

D

185

Relationship

M / z structure (M + H)

Average

AC1.4

N- {2 - [(tert-butoxy) carbonylamino] ethyl} [2- ({[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] carboxamide *

<img file="PL2560653T3_D0233.tif" />

445.2

N- (2 - {[2 - ({[(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] carbonylamino} ethyl) acetamide;

387.2

D

Relationship

186 m / z

Average (M + H)

AC1.4

Methyl 2 {{2 - ({[(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] carbonylamino} acetate * * 3- [2- ({[3-fluoro-1 (3-Fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] phenyl} -N-methylcarboxamide * {4-fluoro-3- [2- ({[3-fluoro-1- (3-fluoro) (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] phenyl} -N-methylcarboxamide

Structure

<img file="PL2560653T3_D0234.tif" />

374.2

410.3

428.3

F m / z

Average

Relationship

187

Structure (M + H)

AC1.4 [2 - ({[(3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N-pyrazol-5-carboxamide *

<img file="PL2560653T3_D0235.tif" />

368.2 5-aminopyrazolyl-2 - ({[(3-fluoro-2-pyridyl)] cyclobutyl] methyl} amino) pyrimidin-5-yl ketone *

<img file="PL2560653T3_D0236.tif" />

'^ = Ν

368.2

188

Compound m / z Medium (M + H) AC1.4 [2 - ({[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N- (3-methylpyrazol-5 yl) carboxamide *

Structure

<img file="PL2560653T3_D0237.tif" />

382.2 D

N- (2-aminoethyl) [2 - ({[(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] carboxamide *

<img file="PL2560653T3_D0238.tif" />

346.2

D

[2 - ({[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N- {2 - [(methylsulfonyl) amino] ethyl} carboxamide *

189 m / z (M + H)

Average

AC1.4 2 - {[2 - ({[(3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] carbonylamino} acetic acid *

Structure

<img file="PL2560653T3_D0239.tif" />

423.2

360.2 {3- [2 - ({[(3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] phenyl} -N-methylcarboxamide *

392.3

B

Relationship

190 m / z

Average (M + H)

AC1.4 {4-fluoro-3- [2 - ({[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] phenyl} -N-methylcarboxamide * [2 - ({[( 3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N-benzamide *

Structure

<img file="PL2560653T3_D0240.tif" />

410.3

378.2 [2 - ({[(3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N- (3-pyridyl) carboxamide *

379.2

C

191

Relationship m / z (M + H)

Average

AC1.4 {3- [2 - ({[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -4-hydroxyphenyl) -N-methylcarbamide]

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

Structure

<img file="PL2560653T3_D0241.tif" />

408.1

394.2 {3- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -4-hydroxyphenyl) -N-methylcarboxamide

426.1

AND

192

Relationship

3- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -4hydroksybenzamid *

Structure

<img file="PL2560653T3_D0242.tif" />

OH m / z (M + H)

412.1

Average

AC1.4 {1- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] pyrrol-3-yl} -N-methylcarboxamide *

<img file="PL2560653T3_D0243.tif" />

399.3 o

m / z

Average

[2 - ({[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N- (1-methylpyrazol-5-yl) carboxamide.

193 (M + H)

AC1.4

Structure

<img file="PL2560653T3_D0244.tif" />

382.2 [2 - ({[(3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N- (4-pyridyl) carboxamide *

379.2

B m / z

Average

Relationship

194 (M + H)

AC1.4 2 - ({[(3-fluoro-2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl-pyrazolyl ketone * [2 - ({[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N- (1,3,4tiadiazol-2-yl) carboxamide *

Structure

<img file="PL2560653T3_D0245.tif" />

353.2

386.2

B

195

Compound m / z Medium (M + H) AC1.4 [2 - ({[(3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N- (2-fluorophenyl) carboxamide *

Structure

<img file="PL2560653T3_D0246.tif" />

396.2 D [2 - ({[(3-fluoro-2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N- (3-fluorophenyl) carboxamide *

396.2

D m / z

Average

[2 - ({[(3-Fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N- (4-fluorophenyl) carboxamide *

196 (M + H)

AC1.4

Structure

<img file="PL2560653T3_D0247.tif" />

396.2 [2 - ({[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N- (6-methoxy (3-pyridyl)) carboxamide *

409.2

D

197

Relationship m / z Average

Structure (M + H) AC 1-4+ 2- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] (4-pyridyl)} -N-methylcarboxamide *

<img file="PL2560653T3_D0248.tif" />

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

<img file="PL2560653T3_D0249.tif" />

400.2

B

198

Relationship

M / z structure

Average (M + H)

AC1.4 [2 - ({[(3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -N-methyl-N- (1,3-thiazol-2-yl) carboxamide *

<img file="PL2560653T3_D0250.tif" />

399.2 {[(3-Fluoro- (2-pyridyl)) cyclobutyl] methyl} (5-imidazol-2-yl-pyrimidin-2-yl) -amine *

<img file="PL2560653T3_D0251.tif" />

325.3

C

199

Compound m / z Medium (M + H) AC1.4

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

<img file="PL2560653T3_D0252.tif" />

385.2 D

7- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] indolin-2-one *

<img file="PL2560653T3_D0253.tif" />

408.3

B

200

Relationship

M / z structure

Average (M + H)

AC1.4 3- [2 - ({[3-fluoro-1- (3-fluoro-2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -4-hydroxybenzoic acid

<img file="PL2560653T3_D0254.tif" />

OH

413.1

Methyl 3- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -4-hydroxybenzoate

<img file="PL2560653T3_D0255.tif" />

427.1

OH

201

1- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -6-oxohydropyridine-3-carboxylic acid compound *

1- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -6oksohydropirydyno-3-carboxamide *

Structure

<img file="PL2560653T3_D0256.tif" />

m / z (M + H)

414.1

Average

AC1.4

413.1

D

202

Compound m / z Medium (M + H) AC1.4

2- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] pyrimidin-4-carbonitrile *

Structure

<img file="PL2560653T3_D0257.tif" />

380,3 B {2- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] pyrimidin-4-yl} -N- methylcarboxamide *

<img file="PL2560653T3_D0258.tif" />

412.3

B

203

Compound m / z Medium (M + H) AC1.4

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

7- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] isoindolin-1-one *

Structure

<img file="PL2560653T3_D0259.tif" />

398.3 B

408.1

B

204

Compound m / z (M + H) {[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} [5- (2-fluorophenyl) pyrimidin-2-yl] -amine *

2- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] benzamide *

2- {2- [2 - ({[3-fluoro-1- (3-fluoro-2-pyridyl) cyclobutyl] methyl} amino) pyrimidin-5-yl] phenyl} acetamide *

Structure

<img file="PL2560653T3_D0260.tif" />

371.3

396.3

410.3

Average

AC1.4

AND

205

Relationship m / z (M + H)

N- {2- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] phenyl} acetamide;

Structure

<img file="PL2560653T3_D0261.tif" />

410.3

Average

AC1.4

D

2- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] benzene-1,4-dicarboxamide *

<img file="PL2560653T3_D0262.tif" />

439.3

4-fluoro-2- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] benzamide *

<img file="PL2560653T3_D0263.tif" />

414.3

206

Relationship

M / z structure

Average (M + H)

AC1.4

2- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] pyridine-4-carbonitrile *

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

<img file="PL2560653T3_D0264.tif" />

379.2

397.3

2- {3- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) -4-methyl-5-yl] phenyl} acetamide;

<img file="PL2560653T3_D0265.tif" />

I-Ν

424.3

207

Relationship

4- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) -4-methyl-5-yl] benzenecarbonitrile *

4- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) -4-methyl-5-yl] benzamide *

6- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] pyridin-3-ol *

Structure

<img file="PL2560653T3_D0266.tif" />

m / z (M + H)

392.3

410.3

Average

AC1.4

370.2

B

208

[5- (5-Amino-pyrazin-2-yl) -pyrimidin-2-yl] - [[3-fluoro-1- (3-fluoro- (2-pyridyl)] cyclobutyl] methyl} -amine.

5- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -2hydroksybenzamid *

Structure

<img file="PL2560653T3_D0267.tif" />

m / z (M + H)

370.1

412.1

Average

AC1.4

2- {4- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) -4-methyl-5-yl] phenyl} acetamide;

424.3

B

209

The compound 2- {4- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) -4-methylpyrimidin-5-yl] phenyl} acetic acid [5- (2- amino-5-methylpyrimidin-4-yl) pyrimidin-2-yl] {[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino} [5- (2-amino-4-methylpyrimidine) 5-yl) -pyrimidin-2-yl] {[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amine *

Structure

<img file="PL2560653T3_D0268.tif" />

m / z (M + H)

425.3

384.3

384.3

Average

AC1.4

210

Relationship m / z (M + H)

3- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] pyridin-2-ol * [5- (6-aminopyridazin) -3-yl) pyrimidin-2-yl] {fluoro-1- (3-fluoro-2-pyridyl)) cyclobutyl] methyl} amino} [5- (2-aminopyrimidin-5-yl) pyrimidin-2-yl ] {fluoro-1- (3-fluoro-2-pyridyl)) cyclobutyl] methyl} amine *

Structure

<img file="PL2560653T3_D0269.tif" />

370.2

370.1

Average

AC1.4

C

370.1

B

211

Relationship

M / z structure

Average (M + H)

AC1.4

5- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] pyridin-2-ol *

<img file="PL2560653T3_D0270.tif" />

370.2 {[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} [5- (6-methoxy) -3-pyridyl] pyrimidin-2-yl] -amine *

<img file="PL2560653T3_D0271.tif" />

ο /

<img file="PL2560653T3_D0272.tif" />

<img file="PL2560653T3_D0273.tif" />

384.3 [5- (6-aminopyrazin-2-yl) pyrimidin-2-yl] {[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amine *

<img file="PL2560653T3_D0274.tif" />

^ι^ = Ν

370,1 m / z

Average

Relationship

212 (M + H)

AC1.4 [5- (2-aminopyrimidin-4-yl) pyrimidin-2-yl] {[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} -amine * [5- (2-) amino-5-fluoro-pyrimidin-4-yl) -pyrimidin-2-yl] {[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amine *

5- {2- [4- (3-fluoro-2-pyridyl) -2-aza [2.1.1] hex-2-yl] pyrimidin-5-yl} pyrimidin-2-ol *

Structure

<img file="PL2560653T3_D0275.tif" />

370.1

388.1

351.2

213

(5-Bromo-4-methoxy-2-yl) {[3-fluoro-1- (3-fluoro-2-pyridyl)) cyclobutyl] methyl} -amine (5-bromo-4-methoxy-2-yl) {[3-fluoro-1- (3fluoro- (2-pyridyl)) cyclobutyl] methyl} amine *

3- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) -4metoksypirymidyn-5-yl] benzamide *

Structure

<img file="PL2560653T3_D0276.tif" />

m / z (M + H)

387.1

387.1

Average

AC1.4

426.3

AND

214

Compound m / z (M + H) 3- [2 - ({[3-fluoro-1- (3-fluoro-2-pyridyl)) cyclobutyl] methyl} amino) -4-hydroxypyrimidin-5-yl] benzoic acid *

3- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) -4hydroksypirymidyn-5-yl] benzamide *

Structure

<img file="PL2560653T3_D0277.tif" />

413.2

412.2

Average

AC1.4

D

5- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] pyrimidin-2-ol *

371.3

D

215

Compound m / z (M + H) {[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} [5- (2-methoxypyrimidin-5-yl) pyrimidin-2-yl] -amine *

6- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] pyridazin-3-ol * {[3-fluoro-1 - (3-fluoro (2-pyridyl)) cyclobutyl] methyl} [5- (6-methoxy-pyridazin-3-yl) pyrimidin-2-yl] -amine *

Structure

<img file="PL2560653T3_D0278.tif" />

385.3

371.2

Average

AC1.4

D

385.2

D

216

Relationship

1- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -4hydroksyhydropirydyn-2-one *

5-Fluoro-6- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} mino) pyrimidin-5-yl] pyridin-3-ol * {3- [2- ( {[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] phenyl} -N- (1-methylazetidin-3-yl) carboxamide *

Structure

<img file="PL2560653T3_D0279.tif" />

m / z (M + H)

386.2

388.2

465.3

Average

AC1.4

217

{4-Fluoro-3- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] phenyl} -N- (1-methylazetidin-3 yl) carboxamide *

N- (1-acetyloazetydyn-3-yl) {3- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] phenyl} carboxamide *

N- (1-acetyloazetydyn-3-yl) {4-fluoro-3- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] phenyl} carboxamide *

Structure

<img file="PL2560653T3_D0280.tif" />

m / z (M + H)

483.3

493.3

Average

AC1.4

511.3

B

218 m / z

Average

{4-Fluoro-3- [2 - ({[3-fluoro-1- (3-fluoro-2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] phenyl} -N- [1- (methylsulfonyl) azetidin-3-yl] carboxamide * {3- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] phenyl} -N- [1 - (methylsulfonyl) azetidin-3-yl] carboxamide * (M + H)

AC1.4

547.2

529.3 {[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} (4-methoxy-5-phenyl-pyrimidin-2-yl) -amine *

Structure

<img file="PL2560653T3_D0281.tif" />

383.2

B

219

{{3-Fluoro-1- (3-fluoro-2-pyridyl)) cyclobutyl] methyl} (4-methoxy-5-phenylpyrimidin-2-yl) -amine} {[3-fluoro-1- (3-fluoro) (2-pyridyl)) cyclobutyl] methyl} (4-methoxy-5-phenyl-pyrimidin-2-yl) methylamine * {[3-fluoro-1- (3-fluoro-2-pyridyl)) cyclobutyl] methyl} (4-methoxy) -2-yl) amine *

Structure

<img file="PL2560653T3_D0282.tif" />

m / z (M + H)

383.3

397.2

Average

AC1.4

307.1

D

220

Compound m / z (M + H) (4-amino-5-phenyl-pyrimidin-2-yl) {[3-fluoro-1- (3-fluoro-2-pyridyl)) cyclobutyl] methyl} -amine * {[3- fluoro-1- (3-fluoro-2- (pyridyl)) cyclobutyl] methyl} [4- (methylamino) -5-phenyl-pyrimidin-2-yl] -amine * [2 - ({[3-fluoro-1- (3) fluoro (2-pyridyl)) cyclobutyl] methyl} amino) -5-phenyl-pyrimidin-4-yl] dimethylamine *

Structure

<img file="PL2560653T3_D0283.tif" />

368.1

382.1

Average

AC1.4

B

396.1

D

221

[2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) -5-phenylpyrimidin-4-yl] (2-methoxyethyl) -amine.

Structure

<img file="PL2560653T3_D0284.tif" />

m / z (M + H)

426.1

466.3

Average

AC1.4 {3- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] phenyl} -N- (3-hydroxycyclobutyl) carboxamide * {4-fluoro-3- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] phenyl} -N- (3-hydroxycyclobutyl) carboxamide *

484.3

AND

222

Relationship

4-fluoro-3- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -2-hydroxybenzamide

3- [2 - ({[3-fluoro-1- (3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -2-hydroxybenzamide * [5- (2,6-dimethoxypyrimidine) 4-yl) pyrimidin-2-yl] {[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amine *

Structure

<img file="PL2560653T3_D0285.tif" />

m / z (M + H)

430.1

412.1

Average

AC1.4

415.2

D

223

Compound m / z (M + H) [5- (2,4-dimethoxypyrimidin-5-yl) pyrimidin-2-yl] {[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amine*

6- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -l, dihydropyrimidine-2,4-dione *

5- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -1, dihydropyrimidine-2,4-dione *

Structure

<img file="PL2560653T3_D0286.tif" />

415.2

387.2

Average

AC1.4

D

387.2

D

224

Relationship

3-amino-6- [2 - ({[3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] hydropyrazin-2-one * {3- [2 - ({ [3-fluoro-1- (3-fluoro (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] -2-hydroxyphenyl) -N-methylcarboxamide *

Structure

<img file="PL2560653T3_D0287.tif" />

m / z (M + H)

386.2

426.2

Average

AC1.4 [2 - ({[(3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-4-yl] -N-benzamide *

<img file="PL2560653T3_D0288.tif" />

378.3 ^--Ν

225

[2 - ({[(3-fluoro- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-4-yl] -N-methyl-N-benzamide * {[3-fluoro-1- (3-fluoro) compound 2-pyridyl)) cyclobutyl] methyl} [5- (3-methoxy-6-methyl (2-pyridyl)) pyrimidin-2-yl] -amine *

Structure

<img file="PL2560653T3_D0289.tif" />

m / z (M + H)

392.3

398.2

Average

AC1.4 ((1R) -1-phenylethyl) [4- (cyclohexylamino) -6-methylpyrimidin-2-yl] -amine *

<img file="PL2560653T3_D0290.tif" />

311.3

........ III

226

Relationship

M / z structure

Average (M + H)

AC1.4

3- [2 - ({[3-fluoro-1- (3-fluoro-6-methyl- (2-pyridyl)) cyclobutyl] methyl} amino) pyrimidin-5-yl] benzamide *

<img file="PL2560653T3_D0291.tif" />

410.2

[0179] Although the present invention has been described with reference to specific embodiments described herein; it is understood by those skilled in the art that various changes and equivalents can be made without departing from the scope of the invention. In addition, modifications may be made to adapt a particular situation, material, composition and / or process to the object and scope of the present invention as defined in the claims.

228

26640 / EP / 16

EP 2 560 653