EA045787B1 - Trisubstituted Aryl and Heteroaryl Derivatives as Modulators of PI3 Kinase and Autophagy Pathways - Google Patents

Description

The present invention relates to trisubstituted aryl and heteroaryl compounds, to pharmaceutical compositions containing them, and to methods of using them, including methods of modulating the PI3K-AKT-MTOR pathway, methods of activating, enhancing or stimulating autophagy by preventing, reversing, slowing or inhibiting the pathway PI3K-AKT-MTOR, and to methods of treating diseases associated with dysregulation of the PI3K-AKT-MTOR pathway.

State of the art

Autophagy, a fundamental mechanism for the clearance of cellular components, plays important roles in development, cellular differentiation, homeostasis, and cell survival. Dysregulation of autophagy is associated with many different neurodegenerative disorders, including amyotrophic lateral sclerosis, Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Therapeutic agents that activate autophagy may be effective in treating these neurodegenerative disorders (Martinez-Vicente et al. Nat. Neurosci. 2010, 13(5), 567-576).

The PI3K-AKT-mTOR (PI3/Akt kinase/mammalian target of rapamycin kinase) cascade regulates the expression of cell survival genes and cell energetics. This cascade is also a key negative regulator of autophagy (Codogno and Meijer, Cell Death Differ. 2005, 12(S2), 15091518, Bhaskar, et al. Molecular Neurodegeneration 2009, 4, 14; Cherra and Chu, Future Neurol. 2008, 3( 3), 309323). Thus, inhibition of the PI3K-AKT-mTOR pathway may be an ideal way to activate autophagy, enhance cell survival, and treat peripheral degenerative disorders and neurodegenerative disorders.

Intracellular systems that regulate the formation of reactive oxygen and reactive nitrogen species (ROS/RNA), as well as ROS/RNS transformation, are essential for maintaining cellular redox homeostasis. Impaired, unregulated ROS/RNS production leads to enzymatic dysfunction, increased protein misfolding, and activation of pathogenic cellular processes that underlie many neurodegenerative disorders. PI3K plays a central role in regulating ROS/RNS formation through modulating the nitric oxide synthase (NOS) and nicotinamide adenine dinucleotide phosphate (NADP) oxidase (NOX) signaling pathways. Indeed, PI3K inhibition reduces ROS and oxidative stress signaling. Therapeutic agents that inhibit PI3K are likely to be effective for the treatment of neurodegenerative diseases that exhibit a pathogenic mechanism of oxidative stress, including hypoxia-ischemia, traumatic brain injury, synucleopathy, AD, HD, spinal cord injury, and seizures.

In addition, the PI3K/AKT pathway has recently been identified as a clinically relevant target in inflammatory diseases, including dermatological disorders. Modulators of the PI3K/AKT pathway may find use in the treatment of dermatological disorders such as atopic dermatitis, rosacea, acne and psoriasis.

There remains a need for compounds that affect autophagy and have the required pharmaceutical properties. The present invention provides certain trisubstituted aryl and heteroaryl compounds that have been found to inhibit the PI3K-AKT-MTOR pathway. These compounds inhibit phosphorylation of AKT and mTOR. Consequently, these compounds also increase the levels of autophagy markers and enhance the clearance of toxic protein aggregates from cells. Thus, these compounds may be useful for the treatment of neurodegenerative disorders and other disorders associated with the PI3K-AKT-mTOR signaling cascade, such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, PD dementia, multiple system atrophy , Huntington's disease, amytrophic lateral sclerosis, cancer, infection, dermatological disorders, Crohn's disease, heart disease, Paget's disease, Charcot-Marie-Tooth disease, macular degeneration, cardiomyopathy and aging.

Disclosure of the Invention

In one aspect of the present invention there is provided a compound of formula (I):

- 1 045787 where R ¹ represents -(CR ^a R ^b )m-C6-18aryl, -CH=CH-C6-18aryl, -(CR ^c R ^d )n-(5-12-membered heteroaryl), -( CR ^e R ^f )o-(3-10 membered heterocycloalkyl) or -(CR ^s R ^h )p-C _3-6 cycloalkyl;

m, n, o and p are each independently equal to 0, 1 or 2;

R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ^g and R ^h are each independently H, halogen or C _1-4 alkyl, or R ^a and R ^b together with a carbon atom, to which they are attached form a C3-6cycloalkyl ring, or R ^a and R ^b together form =CH2 or =O;

each aryl, heteroaryl, heterocycloalkyl or cycloalkyl present in R ¹ is unsubstituted or substituted with one or two R ^x substituents;

where each substituent R ^x independently represents halogen, C1-4alkyl, C3.bcycloalkyl, -Cl.2-haloalkyl, -OH, -OC1-4alkyl, -O-C1-2-haloalkyl, cyano, -C(O)C1 -4alkyl, -C(O)NR ¹ R', -SO2C _1-4 alkyl, -SO ₂ NR ^k R ^l , -NR ^q R ^r , -C(O)-C _3-6 cycloalkyl, -C(O )-Sat. ₁₈ aryl, unsubstituted or substituted with methyl or halogen, -CO ₂ C _1-4 alkyl, -CO ₂ -Cb- ₁₈ aryl, -C(O)CH ₂ -Cb- ₁₈ aryl, unsubstituted or substituted with methyl or halogen, -CH ₂ -Cb- ₁₈ aryl, unsubstituted or substituted with methyl or halogen, or monocyclic 4-6-membered heterocycloalkyl, unsubstituted or substituted with methyl, -C(O)C _1-4 alkyl or -CO ₂ C _1-4 alkyl;

where R ¹ , Rj, R ^k and Rl are each independently H, C _1-4 alkyl, -C ₁ _ ₄ alkyl-OH or -C _1-4 alkyl-O-C _1-4 alkyl, where R ^q and R ^r are each independently H, C _1-4 alkyl, -C ₁ _ ₄ alkyl-OH, -C _1-4 alkyl-O-C _1-4 alkyl, -C(O)C _{1- 4} alkyl, -CO ₂ C _1-4 alkyl or -SO ₂ C _1-4 alkyl;

L represents -S(O) ₂ -, -CIO)-, -O-, -CF ₂ -, -C(=CH ₂ )- or -CRsRt-; where R ^s and Rt are each independently H or C _1-4 alkyl;

X represents O, S, NH, N(CO ₂ C _1-4 alkyl), N(SO ₂ C _1-4 alkyl), N(SO ₂ -C _3-6 cycloalkyl) or CH ₂ ;

Y1, Y ₂ and Y ₃ are each independently CH or N; where at most one of Y1, Y ₂ and Y ₃ represent N; moreover, if L is different from -S(O) ₂ -, then each Y ₂ and Y ₃ represents CH;

G2 is N or CR ² ;

G ₃ represents N or CR ³ ;

G ₄ represents N or CR ^4a ;

G ₅ represents N or CR ⁵ ; And

G ₆ represents N or CR ⁶ ;

wherein R ² , R ³ , R ^4a , R ⁵ and R ⁶ are each independently hydrogen, halogen, -OH, -C _1-4 alkyl, -O-C _1-4 alkyl, -C _1-2 haloalkyl , -O-C _1-2 haloalkyl or -NR ^u R ^v ;

R ^u represents H or C _1-4 alkyl;

R ^v is H, C _1-4 alkyl, monocyclic C _3-6 cycloalkyl, -C(O)C _1-4 alkyl or -C(O)NR ^w R ^y ;

wherein each alkyl present in R ^v is unsubstituted or substituted with a -OH, -NH2, -NH(C _1-4 alkyl) or -N(C _1-4 alkyl) ₂ group,

R ^w and R ^y are each independently H or C1-4 alkyl;

Where

is not unsubstituted phenyl; And

R ⁷ and R ⁸ are each independently hydrogen or C _1-4 alkyl, or R ⁷ and R ⁸ together form -CH2CH2-;

wherein each heteroaryl contains 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulfur; and each heterocycloalkyl contains 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (I) is a compound selected from those described or exemplified in the detailed description of the present invention.

In some embodiments of formula (I), or any variants thereof, R ¹ is -(CR ^a R ^b )m-aryl. In some embodiments, R ¹ is (CR ^c R ^d )n-heteroaryl. In some embodiments, R ¹ is (CR ^e R ^f )o-heterocycloalkyl or (CR ^s R ^h )p-cycloalkyl.

In some embodiments of formula (I), or any variations thereof, L is -S(O) ₂ -. In some embodiments, L is -C(O)-, -CF2-, -C(=CH ₂ )-, or -CRsRt-. In other embodiments, L is -C(O)-, -O-, -CF2-, -C(=CH ₂ )-, or -CRsRt-. In other aspects, compounds of formula (II) are provided:

- 2 045787

where X represents O, S, NH, N(CO ₂ C ₁ . ₄ alkyl), N(SO ₂ C _1-4 alkyl), N(SO ₂ -C ₃ . ₆ cycloalkyl) or

CH2;

Y1, Y2 and Y ₃ are each independently CH or N;

G2 is N or CR ² ;

G ₃ represents N or CR ³ ;

G4 is N or CR ^4a ;

G5 is N or CR ⁵ ; And

G ₆ represents N or CR ⁶ ;

wherein R ² , R ³ , R ^4a , R ⁵ and R ⁶ are each independently hydrogen, halogen, -OH, -C _1-4 alkyl, -O-C _1-4 alkyl, -C _1-2 haloalkyl , -O-C _1-2 haloalkyl or -NR ^u R ^v ;

R ^u represents H or C _1-4 alkyl;

R ^v is H, C _1-4 alkyl, monocyclic C _3-6 cycloalkyl, -C(O)C _1-4 alkyl or -C(O)NR ^w R ^y ;

wherein each alkyl present in R ^v is unsubstituted or substituted with a -OH, -NH2, -NH(C _1-4 alkyl) or -N(C _1-4 alkyl) ₂ group, and

R ^w and R ^y are each independently H or C _1-4 alkyl;

Where

G< θ6 >>

is not unsubstituted phenyl;

R ⁷ and R ⁸ are each independently hydrogen or C _1-4 alkyl, or R ⁷ and R ⁸ together form -CH2CH2-;

R ^9a and R ^9b are each independently hydrogen or halogen;

R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently hydrogen, halogen, -OH, -CN, -C _1-4 alkyl, -O-C ₁ . ₄ alkyl, -C ₁ . ₂ haloalkyl, 4-6 membered heterocycloalkyl, -O-C ₁ . ₂ haloalkyl, -SO ₂ C ₁ . ₄ alkyl or -NR ^aa R ^bb ;

R ^aa represents hydrogen, C1. ₄ alkyl or -C ₁ . ₄ alkyl-OH;

R ^bb represents hydrogen or C1. ₄ alkyl;

wherein each heteroaryl contains 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulfur; and each heterocycloalkyl contains 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur;

or pharmaceutically acceptable salts thereof.

In other aspects, compounds of formula (III) are provided:

And

Ri y θδ

Υ ₃ ^Υι

Q r ⁷ ^x^r ⁸ (III) where R ¹ represents -(CR ^a R ^b )m-C6.18aryl, -CH=CH-C6.18aryl, (CR ^{c Rd} )n-(5-12 -membered heteroaryl), (CR ^e R ^f )o-(3-10 membered heterocycloalkyl) or (CR ^g R ^h )pC ₃ . ₆ cycloalkyl, and if L represents SO ₂ , then the heteroaryl and heterocycloalkyl present in R ¹ are monocyclic;

m is 0 or 2;

n, o and p are each independently equal to 0, 1 or 2;

R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ^g and R ^h are each independently H, halogen or C1. ₄ alkyl, or R ^a and R ^b together with the carbon atom to which they are attached form a C3.6 cycloalkyl ring, or R ^a and R ^b together form =CH2 or =O;

each aryl, heteroaryl, heterocycloalkyl or cycloalkyl present in R ¹ is unsubstituted or substituted with one or two R ^x substituents;

where each substituent R ^x independently represents halogen, C1.4alkyl, C3.6cycloalkyl, -C1.2-haloalkyl, -OH, -OC1.4alkyl, -O-C1.2-haloalkyl, cyano, -C(O)C1 .4alkyl, -C(O)NR ⁱ R ^j , -SO2C ₁ . ₄ alkyl, -SO ₂ NR ^k Rl, -NR ^q R ^r , -C(O)-C ₃ . ₆ cycloalkyl, -C(O) _-C6 . ₁₈ aryl, unsubstituted or substituted with methyl or halogen, -CO2C _1-4 alkyl, -CO ₂ -C _b - ₁₈ aryl, -C(O)CH ₂ -C _b _ ₁₈ aryl, unsubstituted or substituted with methyl or halogen, -CH ₂ -C _b _ ₁₈ aryl, unsubstituted or substituted with methyl or halogen, or monocyclic 4-membered heterocycloalkyl, unsubstituted or substituted with methyl,

-C(O)C _1-4 alkyl or -CO ₂ C1_ ₄ alkyl;

where R ¹ , Rj, R ^k and R ¹ are each independently H, C1-4alkyl, -C1_4alkyl-OH or -C1.4alkyl-O-C1.4alkyl, where ^Rq and ^Rr are each independently is H, C1-4 alkyl, -C1_ ₄ alkyl-OH, -C ₁ . ₄ alkyl-O-C ₁ . ₄ alkyl, -C(O)C _1-4 alkyl, -CO ₂ C1_ ₄ alkyl or -SO ₂ C ₁ . ₄ alkyl;

or R ¹ represents

where R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently hydrogen, halogen, -OH, -CN, _-C1-4 alkyl, -O- _C1-4 alkyl, _-C1-2 haloalkyl , 4-membered heterocycloalkyl, -O-C1- ₂ haloalkyl, -SO ₂ C ₁ . ₄ alkyl or -NR ^aa R ^bb ;

R ^aa is hydrogen, C _1-4 alkyl or -C 1_ ₄ alkyl-OH;

R ^bb represents hydrogen or C _1-4 alkyl;

L represents -S(O) ₂ -, -C(O)-, -O-, -CF2-, -C(=CH ₂ )- or -CR ^s Rt-; where R ^s and Rt are each independently H or C _1-4 alkyl;

X represents O, S, NH, N(CO ₂ C ₁ . ₄ alkyl), N(SO ₂ C ₁ . ₄ alkyl), N(SO ₂ -C ₃ . ₆ cycloalkyl) or CH ₂ ;

Y1, Y2 and Y ₃ are each independently CH or N; moreover, if L is different from -S(O) ₂ -, then each Y2 and Y3 represents CH;

G2 is N or CR ² ;

G3 is N or CR ³ ;

G4 is N or CR ^4a ;

G ₅ represents N or CR ⁵ ; And

G6 is N or CR6;

wherein R ² , R ³ , R ^4a , R ⁵ and R6 are each independently hydrogen, halogen, -OH, -C1- ₄ alkyl, -O-C1_ ₄ alkyl, -C1_ ₂ haloalkyl, -O-C1_ ₂ haloalkyl or -NR ^u R ^v ;

R ^u represents H or C _1-4 alkyl;

R ^v represents H, C _1-4 alkyl, monocyclic C _3-b cycloalkyl, -C(O)C ₁ . ₄ alkyl or -C(O)NR ^w R ^y ;

wherein each alkyl present in R ^v is unsubstituted or substituted with a -OH, -NH ₂ , -NH(C ₁ . ₄ alkyl) or -N(C ₁ . ₄ alkyl) ₂ group,

R ^w and R ^y are each independently H or C _1-4 alkyl;

Where

is not unsubstituted phenyl; And

R ⁷ and R ⁸ are each independently hydrogen or C _1-4 alkyl, or R ⁷ and R ⁸ together form -CH2CH2-;

wherein each heteroaryl contains 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulfur; and each heterocycloalkyl contains 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur;

or pharmaceutically acceptable salts thereof.

In some embodiments, in any of the compounds of formula (I), (II), or (III), Y1, Y2, and _Y3 are each CH. In some embodiments, Y1 is N, and Y2 and _Y3 are each CH. In some embodiments, Y2 is N, and Y1 and _Y3 are each CH. In some embodiments, Y ₃ is N, and Y1 and Y2 are each CH.

In some embodiments, in any of the compounds of formula (I), (II), or (III), X is O. In some embodiments, X is NH, N(CO ₂ C ₁ . ₄ alkyl), N( SO ₂ C1_ ₄ alkyl) or N(SO ₂ cycloalkyl).

In some embodiments, in any of the compounds of formula (I), (II) or (III), G2 and _G4 are each N, and G6 is CR6. In some embodiments, in any of the compounds of formula (I), (II) or (III), G ₃ is CR ³ and G ₅ is CR ⁵ . In some embodiments, in any of the compounds of formula (I), (II), or (III), one of G2 and G4 is N.

In some embodiments, in any of the compounds of formula (I), (II) or (III), R6 is -NR ^u R ^v . In a further aspect of the present invention there is provided a pharmaceutical composition containing at least one compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions, according to the proposed embodiments, may additionally contain a pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition is provided comprising: (a) at least one compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient.

The present invention also provides a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof for use as a drug. In some aspects, a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of formula (I), (II) or (III), is used to treat a disease or medical condition associated with autophagy or the PI3K-AKT-MTOR cascade. In some embodiments, the disease or medical condition is a neurodegenerative disorder. In other embodiments, the disease or medical condition is a peripheral degenerative disorder. In some embodiments, the disease or medical condition is Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, dementia associated with Parkinson's disease, multiple system atrophy, Huntington's disease, amyotrophic lateral sclerosis, cancer, infection, disease Crohn's, heart disease, Paget's disease, Charcot-Marie-Tooth disease, macular degeneration, cardiomyopathy and aging. In some embodiments, the disease or medical condition is a dermatological disorder. In some embodiments, the dermatological disorder is selected from rosacea, acne, psoriasis, and atopic dermatitis.

In another aspect of the present invention, there is provided a method of treating a disease or medical condition associated with autophagy or the PI3K-AKT-mT0R cascade, comprising administering to a subject in need of such treatment an effective amount of at least one compound of formula (I), (II) or ( III) or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or medical condition is a neurodegenerative disease or condition. In other embodiments, the disease or medical condition is a peripheral degenerative disorder. In some embodiments, the disease or medical condition is Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, dementia associated with Parkinson's disease, multiple system atrophy, Huntington's disease, amyotrophic lateral sclerosis, cancer, infection, disease Crohn's, heart disease, Paget's disease, Charcot-Marie-Tooth disease, macular degeneration, cardiomyopathy and aging. In some embodiments, the disease or medical condition is a dermatological disorder. In some embodiments, the dermatological disorder is selected from rosacea, acne, psoriasis, and atopic dermatitis.

The present invention provides the use of a compound of formula (I), (II) or (III) for the preparation of a medicament for the treatment of such diseases and medical conditions, as well as the use of such compounds and salts for the treatment of such diseases and medical conditions. In some embodiments, the use of at least one compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula (I), (II) or (III) for the production of a medicinal product is provided. for the treatment of a disease or medical condition associated with autophagy or the PI3K-AKT-MTOR cascade. In some embodiments, the disease or medical condition is a neurodegenerative disorder. In other embodiments, the disease or medical condition is a peripheral degenerative disorder. In some embodiments, the disease or medical condition is Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, dementia associated with Parkinson's disease, multiple system atrophy, Huntington's disease, amyotrophic lateral sclerosis, cancer, infection, disease Crohn's, heart disease, Paget's disease, Charcot-Marie-Tooth disease, macular degeneration, cardiomyopathy or aging. In some embodiments, the disease or medical condition is a dermatological disorder. In some embodiments, the dermatological disorder is selected from rosacea, acne, psoriasis, and atopic dermatitis.

In another aspect of the present invention, there is provided a method of interfering with the autophagy process in a cell to modulate, activate, enhance or stimulate autophagy in the cell or to prevent, reverse, slow or inhibit the PI3K-AKT-mTOR cascade, comprising contacting said cell with an effective amount of at least one compound of formula (I), (II) or (III) or a salt thereof, and/or at least one pharmaceutical composition in accordance with the proposed embodiments, wherein said contacting is carried out in vitro, ex vivo or in vivo .

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Additional embodiments, features and advantages of the present invention will become apparent from the following detailed description and practice of the present invention.

Detailed description

The present invention relates to aryl and heteroaryl compounds, to pharmaceutical compositions containing them, and to methods of using them, including methods of modulating, activating, enhancing or stimulating autophagy by preventing, reversing, slowing or inhibiting the PI3K-AKT-MTOR pathway, as well as methods for treating diseases associated with the regulation of autophagy.

It should be understood that the present invention is not limited to the specific embodiments described, as they may, of course, vary. It should also be understood that the terminology used herein is intended to describe specific implementations only and should not be construed as limiting.

As used herein and in the appended claims, the singular forms include the plural forms unless the context clearly indicates otherwise. Additionally, it should be noted that the claims may be drafted to exclude any optional element. Thus, this statement is intended as a preliminary basis for the application of exclusionary terminology such as exclusively, only, etc., in relation to the enumeration of the elements of the claims, or for the application of a negative limitation.

As used herein, the terms including, containing and including are used in an open, non-limiting sense.

To make the description more brevity, some quantitative expressions presented herein are not designated by the term approximately. However, it should be understood that whether the term approximate is used or not, each amount presented herein refers to the actual given value and also refers to the approximation of the given value that is reasonable to assume based on general knowledge in the art. including equivalents and approximations due to experimental and/or measurement conditions for a given value. If the yield is expressed as a percentage, then the reported yield refers to the mass of the substance for which the yield is given, relative to the maximum amount of the same substance that can be obtained under specific stoichiometric conditions. Concentrations expressed as percentages refer to mass fractions unless otherwise stated.

Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention relates. Any methods or materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention. All publications mentioned herein are incorporated herein by reference with respect to the disclosure and description of methods and/or materials in connection with which such publications are mentioned.

Unless otherwise indicated, the methods and techniques of the proposed embodiments are generally carried out in accordance with standard methods known in the art, as well as in accordance with methods described in various general and more specific references cited and discussed herein. . See, for example, Loudon, Organic Chemistry, ^4th edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, ^5th edition, Wiley-Interscience, 2001.

The nomenclature used herein for the names of the subject compounds is presented in the examples provided. Compound names were generally generated using commercially available ChemBioDraw Ultra software version 13.0.2.3021.

It should be understood that certain features of the present invention, which are described in the context of individual embodiments for clarity, may also be presented in combination within a single embodiment. Conversely, certain features of the present invention, which for brevity are described in the context of a single embodiment, may also be presented individually or in any suitable subcombination. All combinations of embodiments relating to the chemical groups represented by the variables are specifically contemplated by the present invention and are described herein as if each and every combination were described separately and explicitly, to the extent that such combinations include compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of chemical groups listed in the embodiments describing such variables are also specifically contemplated by the present invention and are described herein as if any and every such subcombination of chemical groups were described herein individually and explicitly. .

Terms.

Unless otherwise specified, the following terms have the following meanings.

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Terms that are not defined have the meaning generally accepted in the art.

The term alkyl refers to a saturated straight or branched hydrocarbon group containing from 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl (tBu), pentyl, isopentyl, t-pentyl, hexyl, isohexyl, and groups that in light of standard knowledge in the art and the instructions presented herein, are considered equivalent to any of the above examples. In some cases, the alkyl groups are _{C1_4} alkyl.

Haloalkyl refers to an alkyl group, as described above, in which one or more hydrogen atoms of the alkyl group are replaced by a halogen group. Examples of such groups include, but are not limited to, fluoroalkyl groups such as fluoroethyl, trifluoromethyl, difluoromethyl, trifluoroethyl and the like.

The term oxo refers to the carbonyl oxygen atom. For example, cyclopentyl substituted with an oxo group is cyclopentanone.

Aryl or Ar refers to a monovalent aromatic carbocyclic group containing from 6 to 18 ring carbon atoms, having a single ring (such as found in the phenyl group) or a ring system containing multiple fused rings (examples of such aromatic ring systems include naphthyl, anthryl and indanyl ), and said fused rings may or may not be aromatic, provided that the point of attachment is at an atom of the aromatic ring. The term includes, by way of example, phenyl and naphthyl.

Cycloalkyl refers to cyclic hydrocarbon groups containing from 3 to 10 carbon atoms, having one or more cyclic rings, including fused, bridged and spiro ring systems. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like. Such cycloalkyl groups include, by way of example, single-ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like, or multi-ring structures such as adamantanyl and the like. In some cases, the cycloalkyl is a monocyclic ring. In some cases, the cycloalkyl is a 3-6 membered ring.

The term heteroaryl refers to a monocyclic, fused bicyclic or fused polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen and sulfur) having from 5 to 12 ring atoms per heterocycle . Such heteroaryl groups contain at least one ring in said ring system which is aromatic, provided that the point of attachment is at an atom of the aromatic ring. In some embodiments, the ring nitrogen and/or sulfur atom(s) in the heteroaryl group are optionally oxidized to form N-oxide (N^O), sulfinyl, or sulfonyl moieties. In some cases, heteroaryl groups are 5-, 6-, 8-, 9-, or 10-membered ring systems.

Examples of heteroaryls include, but are not limited to, pyrrole, furan, thiophenyl, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, benzofuran, benzothiophene, indazole , benzimidazole, benzothiazole, benzoxazole, indolysine, isoindole, purine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, phenoxazine, phenothiazine, phthalimide, etc. .P.

Heterocycloalkyl refers to a saturated or partially unsaturated group containing one ring or more fused rings, including fused, bridged or spiro ring systems, and containing from 3 to 20 ring atoms, including from 1 to 10 heteroatoms. Said ring atoms are selected from the group consisting of carbon, nitrogen, sulfur or oxygen, and in fused ring systems one or more rings may be cycloalkyl, aryl or heteroaryl, provided that the point of attachment is on a non-aromatic ring. In some embodiments, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to form N-oxide moieties, -S(O)- or -SO2-. Examples of heterocycloalkyls include, but are not limited to, azetidine, oxetane, tetrahydrofuran, pyrrolidine, piperazine, piperidine, morpholine, thiomorpholine, 1,1-dioxothiomorpholinyl, dihydroindole, indazole, quinolysine, imidazolidine, imidazoline, indoline, 1,2,3,4 -tetrahydroisoquinoline, thiazolidine, etc. In some cases, heterocycloalkyl groups are 4-, 5-, or 6-membered rings. In some cases, heterocycloalkyl contains a fused phenyl ring.

Cyano belongs to the -CN group.

Halo or halogen refers to fluorine, chlorine, bromine and iodine.

Hydroxy or hydroxyl refers to the -OH group.

In addition to the description provided herein, the term substituted, as used to modify a particular group or radical, means that one or more hydrogen atoms of a particular group or radical, each independently of the other, are substituted with the same or different groups of substituents, as described below . Substituent groups include, but are not limited to, alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halogen, hydroxyl, nitro , carboxyl, thiol, thioalkyl, cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl, heterocyclyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy, etc. The term unsubstituted means that the specified group has no substituents. The term optionally substituted means that the specified group is unsubstituted or substituted with one or more substituents. When using the term substituted to describe a structural system, the substitution can occur at any position of the system allowed by valence. If a group or moiety contains more than one substituent, it will be understood that the substituents may be the same or different from each other. In some embodiments, the substituted group or moiety contains from one to five substituents. In some embodiments, the substituted group or moiety contains one substituent. In some embodiments, the substituted group or moiety contains two substituents. In some embodiments, the substituted group or moiety contains three substituents. In some embodiments, the substituted group or moiety contains four substituents. In some embodiments, the substituted group or moiety contains five substituents.

Any formula depicted herein is intended to denote a compound of that structural formula as well as certain variants or forms. For example, the formula provided herein includes the racemic form or one or more enantiomeric, diastereomeric or geometric isomers, or a mixture thereof. In addition, any formula given herein also refers to a hydrate, solvate or polymorph of the compound, or a mixture thereof.

Any formula presented herein is intended to also denote the unlabeled and isotopically labeled forms of the indicated compounds. Isotopically tagged compounds have structures depicted by the formulas presented herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as ^2H , ^3H , ^PS , ^13C , ^14C , ^15N , ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl and ¹²⁵ I, respectively. Such isotopically tagged compounds are useful for metabolic studies (preferably with ¹⁴ C), reaction kinetics studies (for example with ² H or ³ H), detection or imaging technologies [such as positron emission tomography (PET) or single photon emission computed tomography (SEM). SPECT)], including drug or substrate tissue distribution assays, or for radioactive treatment of patients. In particular, a compound labeled ¹⁸ F or 11 C may be particularly preferred for PET or SPECT studies. PET and SPECT studies can be performed as described, for example, in Brooks, DJ, Positron Emission Tomography and Single-Photon Emission Computed Tomography in Central Nervous System Drug Development, NeuroRx 2005, 2(2), 226-236, and in the references cited therein. In addition, replacement with heavier isotopes such as deuterium (ie ^2H ) may provide certain therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life, or reduced dosage requirements. The isotopically tagged compounds of the present invention and their prodrugs can generally be prepared by the methods described in the Schemes or in the Examples and Preparation Methods below by replacing the untagged reagent with an available isotopically tagged reagent.

The nomenclature Ci.j, where j is greater than i, used herein to designate a class of substituents, refers to embodiments of the present invention for which each and all possible numbers of carbon atoms from i to j, including i and j, are individually implemented. For example, the term C independently refers to embodiments that have one carbon atom (C1), embodiments that have two carbon atoms (C2), and embodiments that have three carbon atoms ( _C3 ).

In the context of this document, any reference to a dissubstitute includes various options for joining when more than one such possibility exists. For example, reference to the disubstituent -A-B-, where A ^ B, in this context refers to such a disubstitute in which A is attached to the first substituted element, and B is attached to the second substituted element, and also refers to such a disubstitute in which A is attached to the second substituted element, and B is attached to the first substituted element.

With respect to any groups described herein that contain one or more substituents, it is of course understood that such groups do not contain substituents or substitution modes that are sterically and/or synthetically impracticable. In addition, the subject compounds include all stereochemical isomers resulting from substitution of said compounds.

The present invention also includes pharmaceutically acceptable salts of the compounds represented by formula (I), preferably the compounds described above and the specific compounds exemplified herein, as well as pharmaceutical compositions containing such salts and methods of using said salts .

Pharmaceutically acceptable salt means a salt of the free acid or base of a compound provided herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See, in general, S.M. Berge, et al., Pharmaceutical Salts, J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues or body of a subject without undue toxicity, irritation or allergic reaction. The compound described herein may contain a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one group of each type and, accordingly, can react with a variety of inorganic or organic bases and inorganic or organic acids to form a pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates , oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butine-1,4-dioates, hexine-1,6-dioates, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates , besylates, xylene sulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, edisylates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates and mandelates. A list of other suitable pharmaceutically acceptable salts is provided in Remington, Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pennsylvania, 1985.

For a compound of formula (I) which contains a basic nitrogen atom, a pharmaceutically acceptable salt may be prepared by any suitable method known in the art, for example by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid , nitric acid, boric acid, phosphoric acid and the like, or an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid , valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidylic acid such as glucuronic acid or galacturonic acid, alpha hydroxy acid such as mandelic acid , citric acid or tartaric acid, amino acid such as aspartic acid or glutaric acid, aromatic acid such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid, sulfonic acid such as lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid acid, ethanesulfonic acid, ethanesulfonic acid, or any compatible mixture of acids, such as those described in the examples presented herein, and any other acid and mixture thereof that are considered equivalent or acceptable substitutes in light of the general state of knowledge in the technology.

Solvate refers to a complex formed by combining solvent molecules with solute molecules or ions. The solvent may be an organic compound, an inorganic compound, or a mixture thereof. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide and water. If the solvent is water, then the solvate formed is a hydrate.

Stereoisomer and stereoisomers refer to compounds that have the same order of atoms joining but different arrangements of atoms in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers and diastereomers.

Tautomer refers to alternative forms of a molecule that differ only in the electronic bonding of atoms and/or the position of the proton, such as enol-ketone and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing a ring group of atoms -N=C(H)-NH- , such as pyrazoles, imidazoles, benzimidazoles, triazoles and tetrazoles. Those skilled in the art will appreciate that other tautomeric arrangements of ring atoms are possible.

The term or salt or solvate or stereoisomer thereof should be understood to include all permutations of salts, solvates and stereoisomers, for example, solvate of a pharmaceutically acceptable salt or stereoisomer of the compound in question.

Connections

The compounds and their salts (such as pharmaceutically acceptable salts) are described in detail herein, including the summary of the invention and the accompanying claims. Also provided are the uses of all of the compounds described herein, including salts and solvates of the compounds described herein, as well as methods for preparing such compounds. Any compound described herein may also be referred to as a drug compound.

In one aspect, compounds of formula (I) are provided:

θΓ θ6 and r ¹ Η Ί ^G5

Υ3^-Υι Λ r ⁷ ^x^r ⁸ _(ι) where R ¹ represents -(CR ^a R ^b )m-aryl, -CH=CH-aryl, -(CR ^c R ^d )n-heteroaryl, - (CR ^e R ^f )o-heterocycloalkyl or -(CR ^g R ^h )p-cycloalkyl; where m, n, o and p are each independently equal to 0, 1 or 2;

R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ^g and R ^h are each independently H, halogen or C ₁ . ₄ alkyl, or R ^a and R ^b together with the carbon atom to which they are attached form a cycloalkyl ring, or R ^a and R ^b together form =CH ₂ or =O;

each aryl, heteroaryl, heterocycloalkyl or cycloalkyl present in R ¹ is unsubstituted or substituted with one or two R ^x substituents;

where each substituent R ^x independently represents halogen, C1.4alkyl, cycloalkyl, -C1.2-haloalkyl, -OH, -OC1.4alkyl, -O-C1.2-haloalkyl, cyano, -C(O)C1.4alkyl , -C(O)NR ¹ R ^j , -SO2C ₁ . ₄ alkyl, -SO ₂ NR ^k Rl, -NR ^q R ^r , -C(O)-cycloalkyl, -C(O)-aryl (optionally substituted with methyl or halogen), -CO ₂ C ₁ . ₄ alkyl, -CO ₂ aryl, -C(O)CH ₂ -aryl (optionally substituted with methyl or halogen), -CH ₂ -aryl (optionally substituted with methyl or halogen) or monocyclic heterocycloalkyl (optionally substituted with methyl, -C(O) C _1.4 alkyl or -CO _{2 C 1.4 alkyl} ) _;

where Ri, R ^j , R ^k and Rl are each independently H, C1-4 alkyl, -C1-4 alkyl-OH or -C1.4 alkyl-O-C1.4 alkyl, where R ^q and R ^r are each independently , represent H, C1. ₄ alkyl, -C ₁ . ₄ alkyl-OH, -C ₁ . ₄ alkyl-O-C ₁ . ₄ alkyl, -C(O)C ₁ . ₄ alkyl, -CO ₂ C ₁ . ₄ alkyl or -SO ₂ C ₁ . ₄ alkyl;

L is absent and represents -S(O) ₂ -, -C(O)-, -O-, -CH ₂ -, -CF2-, C(CH ₃ ) ₂ , -C(=CH ₂ )- or - CR ^s Rt-; where R ^s and Rt independently represent H or alkyl, or R ^s and Rt together with the carbon atom to which they are attached form a cycloalkyl ring;

X represents O, S, NH, N(CO ₂ C ₁ . ₄ alkyl), N(SO ₂ C _1-4 alkyl), N(SO ₂ cycloalkyl) or CH ₂ ;

Y1, Y ₂ and Y ₃ are each independently CH or N; moreover, if L is different from -S(O) ₂ -, then each Y ₂ and Y ₃ represents CH;

G ₂ represents N or CR ² ;

G ₃ represents N or CR ³ ;

G ₄ is N, NR ^4b or CR ^4a ;

G ₅ represents N or CR ⁵ ; And

G6 is N or CR ⁶ ;

wherein R ² , R ³ , R ^4a , R ⁵ and R ⁶ are each independently hydrogen, halogen, -OH, -alkyl, -O-alkyl, -haloalkyl, -O-haloalkyl or -NR ^u R ^v ;

or R ^4b together with R ⁶ and the atoms to which they are attached form a heteroaryl or heterocyclic ring; wherein the heteroaryl ring containing R ^4b and R ⁶ contains no more than one N and is optionally substituted with alkyl, and the heterocyclic ring containing R ^4b and R ⁶ is optionally substituted with an oxo group,

R ^u represents H or C ₁ . ₄ alkyl;

R ^v represents H, C _1-4 alkyl, monocyclic cycloalkyl, -C(O)C ₁ . ₄ alkyl or -C(O)NR ^w R ^y ;

_wherein each alkyl present in R ^v is unsubstituted or substituted with a -OH, -NH ₂ , -NH(C _1-4 alkyl) or -N(C _1.4 alkyl) ₂ group,

R ^w and R ^y are each independently H or C ₁ . ₄ alkyl;

where ^G ₂

G^ Ge >>

% ^G 5 is not unsubstituted phenyl; And

R ⁷ and R ⁸ are each independently hydrogen or C _1-4 alkyl, or R ⁷ and R ⁸ together form -CH2CH2-;

or pharmaceutically acceptable salts thereof.

In some embodiments of formula (I), R ¹ is -(CR ^a R ^b )m-aryl, -CH=CH-aryl, or -(CR ^c R ^d )n-heteroaryl, each of which is unsubstituted or substituted by one or two R ^x substituents. In some embodiments, R ¹ is

- 10 045787

-(CR ^e R ^f )o-heterocycloalkyl or -(CR ^s R ^h )p-cycloalkyl, each of which is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -(CR ^a R ^b )m-aryl, where R ^a and R ^b are each independently H, halogen or C1-4 alkyl, and m is 0, 1 or 2, and wherein the aryl present in R ¹ is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -(CR ^a R ^b )m-aryl, wherein R ^a and R ^b together with the carbon atom to which they are attached form a cycloalkyl, or R ^a and R ^b together form =CH2 or =O, and the aryl present in R ¹ is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is aryl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -CH2-aryl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -CH2CH ₂ -aryl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -(CR ^a R ^b )m-aryl, wherein said aryl is phenyl or naphthyl, each of which is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is phenyl. In other embodiments, R ¹ is naphthyl. In some embodiments, R ¹ is aryl, -CH2-aryl, -CH ₂ CH ₂ -aryl, -CH=CH-aryl, each of which is unsubstituted or substituted with one or two R ^x substituents independently selected from the group, consisting of halogen, C1.4alkyl, -C1.2-haloalkylα, -OH, -OC1-4alkyl, -O-C1.2-haloalkyl, cyano, -NR ^q R ^r and monocyclic heterocycloalkyl (optionally substituted with methyl, -C( O)C1- ₄ alkyl or -CO ₂ C ₁ _ ₄ alkyl), where R ^q and R ^r are each independently H, C1.4alkyl, -C1.4alkyl-OH, -C1.4alkyl-O-C1 .4alkyl, -C(O)C1.4alkyl, -CO2C1.4alkyl or -SO2C1.4alkyl. In some embodiments, R ¹ is phenyl, -CH2-phenyl, -CH ₂ CH ₂ -phenyl, -CH=CH-phenyl, naphthyl, -CH ₂ -naphthyl, -CH ₂ CH ₂ -naphthyl, or -CH= CH-naphthyl. In some embodiments, R ¹ is phenyl, -CH2-phenyl, -CH2CH2-phenyl, -CH=CH-phenyl, naphthyl, -CH2-naphthyl, -CH2CH2-naphthyl, or -CH=CH-naphthyl, each of which substituted with one or two R ^x substituents independently selected from the group consisting of F, Cl, -CF3, -OCF ₃ , cyano, -CH ₃ , -OCH ₃ , -NHC(O)CH ₃ , -NHCY ₂ C(CH ₃ ) ₂ OH, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl and -NHS(O) ₂ CH ₃ .

In some embodiments, R ¹ is -(CR ^c R ^d )n-heteroaryl, wherein R ^c and R ^d are each independently H, halogen, or C1. ₄ αlkyl, and n is 0, 1 or 2, the heteroaryl present in R ¹ being unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is heteroaryl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -CH2-heteroaryl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -CH2CH2-heteroaryl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -(CR ^c R ^d )n-heteroaryl, wherein said heteroaryl is a monocyclic heteroaryl. In some embodiments, R ¹ is -(CR ^c R ^d )n-heteroaryl, wherein said heteroaryl is a bicyclic heteroaryl. In any of these embodiments, the heteroaryl contains one or two nitrogen ring members. In some embodiments, R ¹ is -(CR ^c R ^d )n-heteroaryl, wherein said heteroaryl is pyrrole, furan, thiophenyl, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, oxadiazole, thiadiazole, tetrazole , pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, benzofuran, benzothiophene, benzimidazole, benzothiazole or benzoxazole, each of which is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -CH2-heteroaryl or -CH2CH2-heteroaryl, each of which is unsubstituted or substituted with one or two R ^x substituents independently selected from the group consisting of halogen, C1. ₄ αlkyl, -C ₁ . _2- haloalkyl, -OH, -OS _1-4 alkyl, -OC ₁ . ₂ -haloalkyl, cyano, -NR ^q R ^r and monocyclic heterocycloalkyl (optionally substituted with methyl, -C(O)C1.4 alkyl or -CO2C1.4 alkyl), wherein R ^q and R ^r are each independently H, C1. ₄ alkyl, -C ₁ . ₄ αlkyl-OH, -C ₁ . ₄ alkyl-O-C ₁ . ₄ alkyl, -C(O)C ₁ . ₄ alkyl, -CO ₂ C ₁ . ₄ alkyl or -SO ₂ C ₁ . ₄ alkyl. In some embodiments, R ¹ is pyrrole, furan, thiophenyl, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, benzofuran, benzothiophene , benzimidazole, benzothiazole or benzoxazole. In some embodiments, R ¹ is pyrrole, furan, thiophenyl, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, benzofuran, benzothiophene , benzimidazole, benzothiazole or benzoxazole, each of which is substituted with one or two R ^x substituents independently selected from the group consisting of F, Cl, -CF ₃ , -OCF ₃ , cyano, -CH ₃ , -OCH ₃ , -NHC( O)CH ₃ , -NHCH ₂ C(CH ₃ ) ₂ OH, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl and -NHS(O) ₂ CH ₃ .

In some embodiments, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, wherein R ^e and R ^f are each independently H, halogen, or C1. ₄ alkyl, o is 0, 1 or 2, and heterocyclic

- 11 045787 loalkyl present in R ¹ is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is heterocycloalkyl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -CH2-heterocycloalkyl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -CH2CH ₂ -heterocycloalkyl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, wherein said heterocycloalkyl is monocyclic, and in some embodiments, said heterocycloalkyl is a 4-6 membered ring. In some embodiments, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, wherein said heterocycloalkyl is azetidine, tetrahydrofuran, pyrrolidine, tetrahydropyran, piperidine, piperazine, morpholine, thiomorpholine, 1,1-dioxothiomorpholine, azepine, or diazepine . In some embodiments, said heterocycloalkyl is attached to the remainder of the structure via a carbon atom (C-linked heterocycloalkyl). In some embodiments, R ¹ is -CH2-heterocycloalkyl or -CH2CH2-heterocycloalkyl, each of which is unsubstituted or substituted with one or two R ^x substituents independently selected from the group consisting of halogen, C1. ₄ alkyl, -C ₁ . _2- haloalkyl, -OH, -OC ₁ _ ₄ alkyl, -OC ₁ . _2- haloalkyl, cyano, -NR ^q R ^r and monocyclic heterocycloalkyl (optionally substituted with methyl, -C(O)C1-4 alkyl or -CO2C1_4 alkyl), wherein R ^q and R ^r are each independently H, C1. ₄ αlkyl, -C ₁ . ₄ alkyl-OH, -C ₁ . ₄ alkyl-O-C ₁ . ₄ αlkyl, -C(O)C ₁ . ₄ alkyl, -CO ₂ C ₁ . ₄ alkyl or -SO ₂ C ₁ . ₄ alkyl. In some embodiments, R ¹ is azetidine, tetrahydrofuran, pyrrolidine, tetrahydropyran, piperidine, piperazine, morpholine, thiomorpholine, 1,1-dioxothiomorpholine, azepine, or diazepine. In some embodiments, R ¹ is azetidine, tetrahydrofuran, pyrrolidine, tetrahydropyran, piperidine, piperazine, morpholine, thiomorpholine, 1,1-dioxothiomorpholine, azepine, or diazepine, each of which is substituted with one or two R ^x substituents independently selected from the group , consisting of F, Cl, -CF ₃ , -OCF ₃ , cyano, -CH ₃ , -OCH ₃ , -NHC(O)CH ₃ , -NHCH ₂ C(CH ₃ ) ₂ OH, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl and -NHS(O)2CH ₃ .

In some embodiments, R ¹ is -(CR ^s R ^h )p-cycloalkyl, where R ^g and R ^h are each independently H, halogen, or C1. ₄ alkyl, and p is 0, 1 or 2, and the cycloalkyl present in R ¹ is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is cycloalkyl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -CH2-cycloalkyl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -CH2CH ₂ -cycloalkyl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -(CR ^s R ^h )p-cycloalkyl, wherein said cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R ¹ is cycloalkyl, -CH2-cycloalkyl, or -CH ₂ CH ₂ -cycloalkyl, each of which is unsubstituted or substituted with one or two R ^x substituents independently selected from the group consisting of halogen, C1.4αalkyl , -C1.2-haloalkyl, -OH, -OC1.4-alkyl, -O-C1.2-haloalkyl, cyano, -NR ^q R ^r and monocyclic heterocycloalkyl (optionally substituted with methyl, -C(O) _C1.4 alkyl or -CO ₂ C ₁ . ₄ alkyl), with R ^q and R ^r each independently representing H, C1.4alkyl, -C1.4αalkyl-OH, -C1.4alkyl-O-Smalkyl, -C(O)C1 .4alkyl, -CO2C1.4alkyl or -SO2C1.4αalkyl. In some embodiments, R ¹ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R ¹ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or two R ^x substituents independently selected from the group consisting of F, Cl, -CF3, -OCF ₃ , cyano, -CH ₃ , -OSH ₃ , -NHC(O)CH ₃ , -NHCH ₂ C(CH ₃ ) ₂ OH, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl and -NHS(O) ₂ CH ₃ .

In some embodiments, R ¹ is phenyl, naphthyl, dihydrobenzofuran, benzofuran, benzyl, indolylmethyl, phenethyl, 1,1-difluoro(phenyl)methyl, imidazolylmethyl, benzimidazolylmethyl, pyridinylmethyl, cyclohexyl, cyclohexylmethyl, azetidine, tetrahydrofuran, tetrahydrofuranylmethyl, pyrrolidine , tetrahydropyran, tetrahydropyranylmethyl or piperidine, each of which is unsubstituted or substituted with one or two R ^x substituents.

In each case, R ¹ is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, there is one R ^x substituent, and in others there are two R ^x substituents.

In some embodiments, each R ^x is independently halogen, C1.4alkyl, cycloalkyl, -C1.2-haloalkyl, -OH, -OC1.4alkyl, -O-C1.2-haloalkyl, cyano, -C(O) C1.4alkyl, -C(O)NR'R', -SO2C1.4alkyl, -SO2NR ^k R ^l , -NR ^q R ^r , -C(O)-cycloalkyl, -C(O)-aryl (optionally substituted with methyl or halogen), -CO2C ₁ . ₄ αlkyl, -C(O)CH ₂ -aryl (optionally substituted with methyl or halogen), -CH ₂ -aryl (optionally substituted with methyl or halogen) or monocyclic heterocycloalkyl (optionally substituted with methyl, -C(O)C ₁ . ₄ alkyl or -CO ₂ C _1.4 αlkyl) _. Somehow

- 12 045787 In many embodiments, each R ^x is independently halogen, C1-4alkyl, cycloalkyl, -C1-2-haloalkyl, -OH, -OC1-4alkyl, -O-C1-2-haloalkyl, cyano, -C( O)C1-4alkyl, -C(O)NR'R ^j , -SO2C _1-4 alkyl, -SO2NR ^k R ^l , -NR ^q R ^r , -C(O)-cycloalkyl, -C(O)-aryl (optionally substituted with methyl or halogen), -CO2C1_4alkyl, -CO2aryl, -C(O)CH2-aryl (optionally substituted with methyl or halogen), -CH2-aryl (optionally substituted with methyl or halogen) or monocyclic heterocycloalkyl (optionally substituted with methyl, - C(O)C1_4αalkyl or -CO2 C1-4alkyl). In some embodiments, each R ^x independently represents a halogen (such as fluorine, chlorine, bromine) _, methyl, ethyl, propyl, isopropyl, -C(O)NH2, -C(O)NHC _{1_4} alkyl, -C (O)NMe ₂ , acetyl, -C(O)ethyl, -C(O)-isopropyl, -C(O)-tert-butyl, -C(O)-cyclopropyl, -CO ₂ -tert-butyl, - C(O)CH ₂ -phenyl, -C(O)phenyl, -C(O)NHC ₁ . ₂ alkyl-OSH ₃ , boc-piperidinyl, isopropyl, tetrahydropyranyl, cyano, morpholinyl, fluorine, chlorine, -CF ₃ , methoxy, -NHSO2CH3, 2-hydroxy-2-methyl-1-aminopropyl, -NH-acetyl or -OCF3 . In some embodiments, each R ^x is independently tetrahydrofuranyl, tetrahydropyranyl, or pyridinyl, each of which is optionally substituted. In each case, the aryl and heterocycloalkyl groups are optionally substituted as described above.

In some embodiments, R ¹ and Rj are each independently H, C ₁ - ₄ αlkyl, -C ₁ . ₄ alkyl-OH or -C ₁ _ ₄ alkyl-O-C ₁ . ₄ alkyl. In some embodiments, Ri and Rj are each independently H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, 2-hydroxy-2-methylpropyl, methoxymethyl, or methoxyethyl.

In some embodiments, R ^k and R ¹ are each independently H, C1_4alkyl, -C1.4αalkyl-OH, -C1.4alkyl-O-C1.4alkyl, -C(O)C1.4alkyl, -CO2C1. 4alkyl or -SO2C1_4αalkyl. In some embodiments, R ^k and R ^l are each independently H, methyl, ethyl, propyl, isopropyl, -C1. ₄ alkyl-OH, acetyl or -CO ₂ -tert-butyl.

In some embodiments of formula (I), X is O. In some embodiments, X is S. In some embodiments, X is NH, N(CO ₂ C ₁ . ₄ alkyl), N(SO ₂ C _1.4 alkyl) or N(SO ₂ cycloalkyl) _. In some embodiments, X is CH ₂ .

In some embodiments of formula (I), Y1, Y2, and _Y3 are each CH. In some embodiments, Y1, Y2, and Y ₃ are each N. In some embodiments, Y1 is N, and Y2 and Y ₃ are each CH. In some embodiments, Y2 is N, and Y1 and _Y3 are each CH. In some embodiments, Y ₃ is N, and Y1 and Y2 are each CH. In some embodiments, Y1 and Y2 are each N, and _Y3 is CH. In some embodiments, Y1 and Y ₃ are each N and Y2 is CH. In some embodiments, Y2 and Y ₃ are each N and Y1 is CH.

In some embodiments of formula (I) or any variant thereof, L is absent -S(O) ₂ -, -CIO)-, -CH2-, -CF2-, C(CH ₃ ) ₂ , -C(=CH ₂ ) - or -CR ^s Rt-; wherein R ^s and R' independently represent H or alkyl, or R ^s and R' together with the carbon atom to which they are attached form a cycloalkyl ring; and R ¹ , R ² , R ³ , R ^4a , R ^4b , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, Y _b Y2, Y3, G ₂ , G3, G4, G ₅ , G ₆ , R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , R ^h , R ¹ , R j , R ^k , R ¹ , R ^q , R ^r , R ^u , R ^v , R ^w , R ^x , ^Ry , m, n, o and p are as described for formula (I) or any variation or implementation thereof.

In some embodiments of formula (I), L is -S(O) ₂ -. In some embodiments, L is absent. In some embodiments, L is -CIO)-, -O-, -CH ₂ -, -CF2-, C(CH ₃ ) ₂ , -C(=CH ₂ )-, or -CR ^s Rt-. In some embodiments, L is -CIO)-, -CH2-, -CF2-, C(CH3)2, -C(=CH2)-, or -CR ^s Rt-. In some embodiments, L is absent and is -CIO)-, -CH2-, -CF2-, C(CH ₃ ) ₂ , -C(=CH ₂ )- or -CR ^s Rt-; and each Y2 and _Y3 represents CH.

In some embodiments of Formula (I), G2 is CR ² , G3 is CR ³ , G4 is CR ^4a , G5 is CR ⁵ , and G6 is CR ⁶ . In some embodiments, one of G2, G3, G4, G5, and G6 is N. In some embodiments, more than one of G2, G3, G4, G5, and G6 is N. In some embodiments, two of G2, G3, G4, G5, and G6 are N. In some embodiments, G2 is N, G3 is CR ³ , G4 is CR ^4a , G5 is CR ⁵ , and G6 is CR ⁶ . In some embodiments, G ₂ is CR ² , G3 is CR ³ , G4 is CR ^4a , G ₅ is N, and G ₆ is CR ⁶ . In some embodiments, G2 and G4 are each N, G3 is CR ³ , G5 is CR ⁵ , and G6 is CR ⁶ . In some embodiments, G4 and G5 are each N, G2 is CR ² , G3 is CR ³ , and G ₆ is CR ⁶ .

In some embodiments, in which none of G2, _G3 , _G4 , _G5 , and _G6 is N, _G4 is N or ^NR4b , and at least one of ^R2 , ^R3 , R ^4a , R ⁵ and R ⁶ are not hydrogen. In some embodiments, G ₄ is NR ^4b In some embodiments, R ^4b together with R ⁶ and the atoms to which they are attached form a heteroaryl or he

- 13 045787 terocyclic ring. In some embodiments, the heteroaryl ring containing R ^4b and R ⁶ contains at most one N. In some embodiments, the heteroaryl ring containing R ^4b and R ⁶ is optionally substituted with alkyl, and the heterocyclic ring is optionally substituted with oxo. In some embodiments, none of G2, _G3 , _G4 , _G5 , and _G6 is N, _G4 is N or ^NR4b , and at least one of R2, ^R3 , ^R4a , R ⁵ and R ⁶ represents halogen, -OH, -alkyl, -O-alkyl, -haloalkyl, -O-haloalkyl or -NR ^u R ^v .

In some embodiments of Formula (I), R ⁷ and R ⁸ are each hydrogen. In some embodiments, one of R ⁷ and R ⁸ is hydrogen and the other is C1.4alkyl. In some embodiments, both R ⁷ and R ⁸ are C1. ₄ alkyl. In some embodiments, R ⁷ and R ⁸ together form -CH2CH2-.

In some embodiments of formula (I), L is -S(O) ₂ -, and R ¹ is -(CR ^a R ^b )m-aryl, wherein R ^a and R ^b are each independently H, halogen or C1. ₄ alkyl, and m is 0, 1 or 2, and wherein aryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, L is -S(O)2-, and R ¹ is -(CR ^c R ^d )n-heteroaryl, wherein R ^c and R ^d are each independently H, halogen, or C1_4 alkyl , and n is 0, 1 or 2, and wherein the heteroaryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, L is -S(O)2-, and R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, wherein R ^e and R ^f are each independently H, halogen, or C1. ₄ αlkyl, and o is 0, 1 or 2, and heterocycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is -S(O)2-, and R ¹ is -(CR ^s R ^h )p-cycloalkyl, wherein R ^g and R ^h are each independently H, halogen, or C ₁ . ₄ alkyl, and p is 0, 1 or 2, and wherein the cycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is -S(O)2-, and R ¹ is -CH=CH-aryl.

In some embodiments, L is -S(O) ₂ -, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, and X is O. In some embodiments, L is -S(O)2-, R ¹ is -(CR ^c R ^d )n-heteroaryl, and X is O. In some embodiments, L is -S(O) ₂ -, R ¹ is is -(CR ^e R ^f )o-heterocycloalkyl, and X is O. In other embodiments, L is -S(O)2-, R ¹ is -(CR ^s R ^h )p-cycloalkyl, and X represents O.

In some embodiments, L is -S(O) ₂ -, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and none of G2, G3 , G4, G5, and G6 are not N. In some embodiments, L is -S(O)2-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and one of G2, _G3 , _G4 , _G5 and _G6 is N. In some embodiments, L is -S(O)2-, ^R1 is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and two of G2, G3, G4, G5, and G6 are N. In some embodiments, L is -S(O)2-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, each G2 and G ₄ is N, G ₃ is CR ³ , G5 is CR ⁵ , and G6 represents CR ⁶ .

In some embodiments, L is -S(O) ₂ -, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and none of G2, G3, G4, G5, and G6 is N. In some embodiments, L is -S(O)2-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and one of G2, G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is -S(O)2-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and two of G2 , G3, G4, G5, and G6 are N. In some embodiments, L is -S(O)2-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, each G2 and G ₄ is N, G ₃ is CR ³ , G5 is CR ⁵ , and G6 is CR ⁶ . In some embodiments, L is -S(O)2-, R ¹ is -(CR ^e R ^f ')o-heterocycloalkyl, X is O, and none of G2, G ₃ , G ₄ , G ₅ and G ₆ is not N. In some embodiments, L is -S(O) ₂ -, R ¹ is -(CR ^e R ^f ')o-heterocycloalkyl, X is O, and one of G2 , G3, G4, G5, and G6 are N. In some embodiments, L is -S(O)2-, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, and two of G2, _G3 , _G4 , _G5 and _G6 are N. In some embodiments, L is -S(O) _2- , ^R1 is -(CR ^e R ^f ) _o -heterocycloalkyl, X is O, G2 and G ₄ are each N, G ₃ is CR ³ , G5 is CR ⁵ , and G6 is CR ⁶ .

In certain embodiments of formula (I), L is -C(O)-, and R ¹ is -(CR ^a R ^b )m-aryl, wherein R ^a and R ^b are each independently H, halogen or C1. ₄ alkyl, and m is 0, 1 or 2, and wherein aryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, L is -C(O)-, and R ¹ is -(CR ^c R ^d )n-heteroaryl, wherein R ^c and R ^d are each independently H, halogen, or C1_4 alkyl, and n is 0, 1 or 2, and wherein heteroaryl is unsubstituted or substituted by one or two

- 14 045787 with placeholders R ^x . In some embodiments, L is -C(O)-, and R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, wherein R ^e and R ^f are each independently H, halogen, or C1-4αalkyl , and o is 0, 1 or 2, and the heterocycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is -C(O)- and R ¹ is -(CR ^s R ^h )p-cycloalkyl, wherein R ^g and R ^h are each independently H, halogen or C1-4 alkyl , and p is 0, 1 or 2, and the cycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is -C(O)-, and R ¹ is -CH=CH-aryl.

In some embodiments, L is -C(O)-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, and X is O. In some embodiments, L is is -C(O)-, R ¹ is -(CR ^c R ^d )n-heteroaryl, and X is O. In some embodiments, L is -C(O)-, R ¹ is -( CR ^e R ^f ) _o -heterocycloalkyl, and X is O. In other embodiments, L is -C(O)-, R ¹ is -(CR ^s R ^h )p-cycloalkyl, and X is O .

In some embodiments, L is -C(O)-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and none of G2, G3, G4, G5, and G6 are not N. In some embodiments, L is -C(O)-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and one of G ₂ , G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is -C(O)-, R ¹ is -(CR ^a R ^b )m -aryl or -CH=CH-aryl, X is O, and two of G2, G3, G4, G5, and G6 are N. In some embodiments, L is -C(O)-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, G2 and G4 are each N, G ₃ is CR ³ , G5 is CR ⁵ , and G6 is CR ⁶ .

In some embodiments, L is -C(O)-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and none of G2, G3, G4, G5, and G6 is is N. In some embodiments, L is -C(O)-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and one of G ₂ , G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is -C(O)-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and two of G2, G3 , G4, G5, and G6 are N. In some embodiments, L is -C(O)-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, G2 and G4 are each N, G ₃ is CR ³ , G5 is CR ⁵ , and G6 is CR ⁶ . In some embodiments, L is -C(O)-, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, and none of G2, G3, G4, G5, and G6 is is N. In some embodiments, L is -C(O)-, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, and one of G ₂ , G ₃ , G ₄ . G ₅ and G ₆ is N. In some embodiments, L is -C(O)-, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, and two of G2, G3 , G4, G5, and G6 are N. In some embodiments, L is -C(O)-, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, each G2 and G ₄ is N, G ₃ is CR ³ , G5 is CR ⁵ , and G6 is CR ⁶ .

In some embodiments of Formula (I), L is -O-. In some embodiments, L is -O-, and R ¹ is -(CR ^c R ^d )n-heteroaryl, wherein R ^c and R ^d are each independently H, halogen, or C1. ₄ alkyl, and n is 0, 1 or 2, and wherein the heteroaryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, L is -O-, and R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, wherein R ^e and Rf are each independently H, halogen, or C1. ₄ alkyl, and o is 0, 1 or 2, and heterocycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is -O- and R ¹ is -(CR ^s R ^h )p-cycloalkyl, wherein R ^g and R ^h are each independently H, halogen or C1. ₄ αlkyl, and p is 0, 1 or 2, and the cycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is -O- and R ¹ is -CH=CH-aryl.

In some embodiments, L is -O-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, and X is O. In some embodiments, L is -O -, R ¹ is -(CR ^c R ^d )n-heteroaryl, and X is O. In some embodiments, L is -O-, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, and X is O. In other embodiments, L is -O-, R ¹ is -(CR ^s R ^h )p-cycloalkyl, and X is O.

In some embodiments, L is -O-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and none of G2, G3, G4, G5 and G6 is not N. In some embodiments, L is -O-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and one of G2 , G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is -O-, R ¹ is -(CR ^a R ^b ) _m -aryl, or

-CH=CH-aryl, X is O, and two of G2, _G3 , _G4 , _G5 , and _G6 are N. In some embodiments, L is -O-, ^R1 is -( CR ^a R ^b ) _m -aryl or -CH=CH-aryl,

X is O, G2 and _G4 are each N, _G3 is ^CR3 , G5 is ^CR5 , and G6 is ^CR6 .

In some embodiments, L is -O-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and none of G2, G3, G4, G5, and G6 is N. In some embodiments, L is -O-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and one of G2, G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is -O-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and two of G2, G3, G4, G5 and G6 are N. In some embodiments, L is -O-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, each G2 and G ₄ is N, G ₃ is CR ³ , G5 is is CR ⁵ , and G6 is CR ⁶ . In some embodiments, L is -O-, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, and none of G2, G3, G4, G5, and G6 is N. In some embodiments, L is -O-, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, and one of G2, G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is -O-, R ¹ is

-(CR ^e R ^f ) _o -heterocycloalkyl, X is O, and two of G2, G ₃ , G ₄ , G ₅ and G ₆ are N. In some embodiments, L is -O-, R ¹ represents

-(CR ^e R ^f ) _o -heterocycloalkyl, X is O, G2 and _G4 are each N, _G3 is ^CR3 , G5 is ^CR5 , and G6 is ^CR6 .

In some embodiments of formula (I), L is -CH2-, -CF2-, C(CH ₃ ) ₂ , -C(=CH ₂ )- or -CRsRt-, and R ¹ is -(CR ^a R ^b )m-aryl, wherein R ^a and R ^b are each independently H, halogen or C1-4 alkyl, and m is 0, 1 or 2, and wherein aryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, L is -CH2-, -CF2-, C(CH3)2, -C(=CH2)-, or -CRsRt-, and R ¹ is -(CR ^c R ^d )n-heteroaryl, wherein R ^c and R ^d are each independently H, halogen or C1-4alkyl, and n is 0, 1 or 2, and heteroaryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, L is -CH2-, -CF2-, C(CH3) ₂ , -C(= _CH2 )-, or -CRsRt-, and ^R1 is -(CR ^e R ^f )o-heterocycloalkyl wherein R ^e and R ^f are each independently H, halogen or C1-4 alkyl, and o is 0, 1 or 2, and wherein heterocycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is -CH2-, -CF2-, C(CH3)2, -C(=CH2)-, or -CRsRt-, and R ¹ is -(CR ^s R ^h )p-cycloalkyl; wherein R ^g and R ^h are each independently H, halogen or C1-4 alkyl, and p is 0, 1 or 2, and wherein the cycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is -CH2-, -CF2-, C(CH3) ₂ , -C(= _CH2 )-, or -CRsRt-, and ^R1 is -CH=CH-aryl.

In some embodiments, L is -CH2-, -CF2-, -C(CH ₃ ) ₂ -, -C(=CH ₂ )-, or -CRsRt-, R ¹ is -(CR ^a R ^b )m -aryl or -CH=CH-aryl, and X is O. In some embodiments, L is -CH2-, -CF2-, C(CH3)2, -C(=CH2)- or -CRsRt-, R ¹ is -(CR ^c R ^d )n-heteroaryl, and X is O. In some embodiments, L is -CH2-, -CF2-, C(CH ₃ ) ₂ , -C(=CH ₂ )- or -CRsRt-, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, and X is O. In other embodiments, L is -CH2-, -CF2-, C(CH3)2, -C(=CH2)- or -CRsRt-, R ¹ is -(CR ^g R ^h )p-cycloalkyl, and X is O.

In some embodiments, L is -CH2-, -CF2-, C(CH3)2, -C(=CH2)- or -CRsRt-, R ¹ is -(CR ^a R ^b )m-aryl or - CH=CH-aryl, X is O, and none of G2, G3, G4, G5, and G6 is N. In some embodiments, L is -CH2-, -CF2-, -C(CH3) 2-, -C(=CH2)- or -CRsRt-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and one of G2, G ₃ , G ₄ , G ₅ , and G ₆ are N. In some embodiments, L is -CH2-, -CF2-, C(CH ₃ ) ₂ , -C(=CH ₂ )- or -CRsRt-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and two of G2, G3, G4, G5 and G6 are N. In some embodiments, L is - CH2-, -CF2-, C(CH3)2, -C(=CH2)- or -CRsRt-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is Oh, G2 and _G4 are each N, _G3 is ^CR3 , G5 is ^CR5 , and G6 is ^CR6 .

In some embodiments, L is -CH2-, -CF2-, -C(CH ₃ ) ₂ -, -C(=CH ₂ )-, or -CRsRt-, R ¹ is -(CR ^c R ^d )n -heteroaryl, X is O, and none of G2, G3, G4, G5, and G6 is N. In some embodiments, L is -CH2-, -CF2-, -C(CH3)2-, -C(=CH2)- or -CRsRt-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and one of G2, G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L represents

- 16 045787 is -CH2-, -CF2-, C(CH ₃ ) ₂ , -C(=CH ₂ )- or -CR ^s R'-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and two of G2, G3, G4, G5, and G6 are N. In some embodiments, L is -CH2-, -CF2-, C(CH3)2, -C(=CH2)- or -CRsRt-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, each G2 and G ₄ is N, G ₃ is CR ³ , G5 is CR ⁵ , and G6 is is CR ⁶ . In some embodiments, L is -CH2-, -CF2-, -C(CH3)2-, -C(=CH2)-, or -CRsRt-, R ¹ is -(CR ^e R ^f ')o- heterocycloalkyl, X is O, and none of G2, _G3 , _G4 , _G5, and _G6 is N. In some embodiments, L is _-CH2- , _-CF2- , -C( CH ₃ ) ₂ -, -C(=CH ₂ )- or -CR ^s R ^t -, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, and one of G2, G3, G4 , G5 and G6 is N. In some embodiments, L is -CH2-, -CF2-, C(CH3)2, -C(=CH2)- or -CRsRt-, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, and two of G2, G ₃ , G ₄ , G ₅ and G ₆ are N. In some embodiments, L is -CH2-, -CF2-, C( CH ₃ ) ₂ , -C(=CH ₂ )- or -CRsRt-, R ¹ is -(CR ^e R ^f ) _o -heterocycloalkyl, X is O, each G2 and G ₄ is N, G ₃ is is CR ³ , G5 is CR ⁵ , and G6 is CR ⁶ .

In some embodiments of formula (I), L is absent and R ¹ is -(CR ^a R ^b )m-aryl, wherein R ^a and R ^b are each independently H, halogen or C1-4 alkyl, and m is 0, 1 or 2, and wherein aryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, L is absent and R ¹ is -(CR ^c R ^d )n-heteroaryl, wherein R ^c and R ^d are each independently H, halogen, or C 1-4 alkyl, and n is 0.1 or 2, and wherein the heteroaryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, L is absent and R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, wherein R ^e and Rf are each independently H, halogen, or C1-4 alkyl, and o is 0, 1, or 2, and wherein the heterocycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is absent and R ¹ is -(CR ^s R ^h )p-cycloalkyl, where R ^g and R ^h are each independently H, halogen or C1-4α alkyl, and p is 0.1 or 2, and wherein the cycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is absent and R ¹ is -CH=CH-aryl.

In some embodiments, L is absent, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, and X is O. In some embodiments, L is absent, R ¹ is -( CR ^c R ^d )n-heteroaryl, and X is O. In some embodiments, L is absent, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, and X is O. In other embodiments, L is absent, R ¹ is -(CR ^s R ^h )p-cycloalkyl, and X is O.

In some embodiments, L is absent, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and none of G2, G3, G4, G5 and G6 is is N. In some embodiments, L is absent, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and one of G2, G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is absent, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and two of G2, G3, G4, G5, and G6 are N. In some embodiments, L is absent, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, each G2 and G ₄ is is N, G ₃ is CR ³ , G5 is CR ⁵ , and G6 is CR ⁶ .

In some embodiments, L is absent, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and none of G2, G3, G4, G5, and G6 is N. In some embodiments , L is absent, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and one of G2, G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is absent, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and two of G2, G3, G4, G5 and G6 are N. In some embodiments, L is absent, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, G2 and G ₄ are each N, G ₃ is CR ³ , G5 is CR ⁵ , and G6 is CR ⁶ . In some embodiments, L is absent, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, and none of G2, G3, G4, G5, and G6 is N. In some embodiments , L is absent, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, and one of G2, G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is absent, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, and two of G2, G3, G4, G5 and G6 are N. In some embodiments, L is absent, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, G2 and _G4 are each N, _G3 is ^CR3 , G5 is ^CR5 , and G6 is ^CR6 .

In another aspect, compounds of formula (II) are provided:

- 17 045787

where X represents O, S, NH, N(CO ₂ C ₁ - ₄ αlkyl), N(SO ₂ C _1-4 alkyl), N(SO2 cycloalkyl) or CH2;

Y1, Y2 and Y ₃ are each independently CH or N;

G2 is N or CR ² ;

G ₃ represents N or CR ³ ;

G4 is N, NR ^4b or CR ^4a ;

G5 is N or CR ⁵ ; And

G ₆ represents N or CR ⁶ ;

wherein R ² , R ³ , R ^4a , R ⁵ and R ⁶ are each independently hydrogen, halo, -OH, -alkyl, -O-alkyl, -haloalkyl, -O-haloalkyl or -NR ^u R ^v ;

or R ^4b together with R ⁶ and the atoms to which they are attached form a heteroaryl or heterocyclic ring; wherein the heteroaryl ring containing R ^4b and R ⁶ contains no more than one N and is optionally substituted with alkyl, and the heterocyclic ring containing R ^4b and R ⁶ is optionally substituted with an oxo group,

R ^u represents H or C _{1_4} alkyl _;

R ^v is H, C ₁ _ ₄ alkyl, monocyclic cycloalkyl, -C(O)C ₁ _ ₄ αalkyl or -C(O)NR ^w R ^y ;

wherein each alkyl present in R ^v is unsubstituted or substituted with a -OH, -NH ₂ , -NH(C ₁ _ ₄ alkyl) or -N(C ₁ _ ₄ alkyl) ₂ group, and

R ^w and R ^y are each independently H or C _{1_4} αlkyl _;

where ^G 6 and

H ^G 5 is not unsubstituted phenyl;

R ⁷ and R ⁸ are each independently hydrogen or C _{1_4} alkyl, or R ⁷ and R ⁸ together _form -CH2CH2-;

R ^9a and R ^9b are each independently hydrogen or halogen;

R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently hydrogen, halogen, -OH, -CN, -alkyl, -O-alkyl, -haloalkyl, heterocycloalkyl, -O-haloalkyl, -SO ₂ C ₁ _ ₄ alkyl or -NR ^aa R ^bb ;

_R ^aa is hydrogen, C _{1_4} alkyl or -C _{1_4} alkyl-OH _;

R ^bb represents hydrogen or C _{1_4} alkyl _;

or R ^9a together with R ¹⁰ and intermediate atoms form a heteroaryl or heterocyclic ring;

or R ¹¹ together with R ¹² and the atoms to which they are attached form a heteroaryl or heterocyclic ring;

or pharmaceutically acceptable salts thereof.

In some embodiments of Formula (II), Y1, _Y2 , and _Y3 are each CH. In some embodiments, Y1, Y ₂ and Y ₃ are each N. In some embodiments, Y ₁ is N, and Y ₂ and Y ₃ are each CH. In some embodiments, Y ₂ is N, and Y ₁ and Y ₃ are each CH. In some embodiments, Y ₃ is N, and Y ₁ and Y ₂ are each CH. In some embodiments, Y1 and Y2 are each N, and Y3 is CH. In some embodiments, Y ₁ and Y ₃ are each N and Y ₂ is CH. In some embodiments, Y ₂ and Y ₃ are each N and Y ₁ is CH.

In some embodiments of formula (II), X is O. In some embodiments, X is S. In some embodiments, X is NH, N(CO ₂ C _{1_4} alkyl), N(SO _{2 C 1} _ ₄ alkyl) or N(SO ₂ cycloalkyl). In some embodiments, X is CH ₂ .

In some embodiments of Formula (II), G ₂ is CR ² , G3 is CR ³ , G4 is CR ^4a , G5 is CR ⁵ , and G6 is CR ⁶ . In some embodiments, one of G2, G3, G4, G5, and G6 is N. In some embodiments, more than one of _G2 , _G3 , _G4 , G5 _, and _G6 is N. In some embodiments, two of G ₂ , G ₃ , G ₄ , G ₅ , and G ₆ are N. In some embodiments, G ₂ is N, G ₃ is CR ³ , G4 is CR ^4a , G5 is CR ⁵ , And

- 18 045787

G6 is CR6. In some embodiments, G2 is CR2, G3 is CR3, G4 is CR ^4a , G5 is N, and G6 is CR6. In some embodiments, G2 and G4 are each N, G3 is CR3, G5 is CR ⁵ , and G6 is CR ⁶ . In some embodiments, G4 and G5 are each N, G2 is CR ² , G3 is CR ³ , and G ₆ is CR ⁶ .

In some embodiments in which none of G2, G3, G4, G5, and G6 is N, G4 is N, or NR ^4b , at least one of R2, R3, R ^4a , R ⁵ , and R6 is not represents hydrogen. In some embodiments, G4 is NR ^4b . In some embodiments, R ^4b together with R 6 and the atoms to which they are attached form a heteroaryl or heterocyclic ring. In some embodiments, the heteroaryl ring containing R ^4b and R ⁶ contains at most one N. In some embodiments, the heteroaryl ring containing R ^4b and R ⁶ is optionally substituted with alkyl, and the heterocyclic ring is optionally substituted with oxo.

In some embodiments of formula (II), R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each hydrogen. In some embodiments, at least one of R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ is not hydrogen. In some embodiments, at least one of R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ is selected from the group consisting of halogen, -OH, -CN, -alkyl, -O-alkyl, -haloalkyl, heterocycloalkyl , -O-haloalkyl, -SO 2C1-4alkyl or -NR ^aa R ^bb . In some embodiments, R ¹⁰ is selected from the group consisting of halogen, -OH, -CN, -alkyl, -O-alkyl, -haloalkyl, heterocycloalkyl, -O-haloalkyl, -SO2C _1-4 alkyl, or -NRaaRbb. In some embodiments, R ¹² is halogen, and R ¹⁰ , R ¹¹ , R ¹³ , and R ¹⁴ are each hydrogen. In some embodiments, at least one of R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ is heterocycloalkyl. In some embodiments, at least one of ^R10 , ^R11 , ^R12 , ^R13 , and ^R14 is a heterocycloalkyl selected from the group consisting of aziridinyl, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl and pyranyl, each of which is optionally substituted. In some embodiments, at least one of R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ is heterocycloalkyl selected from the group consisting of morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyridinyl, each of which is optionally substituted.

In some embodiments of formula (II), R ^9a together with R ¹⁰ and intermediate atoms form a heteroaryl or heterocyclic ring. In some embodiments, R ¹¹ together with R ¹² and the atoms to which they are attached form a heteroaryl or heterocyclic ring.

In some embodiments of Formula (II), R ⁷ and R ⁸ are each hydrogen. In some embodiments, one of R ⁷ and R ⁸ is hydrogen and the other is C1-4alkyl. In some embodiments, both R ⁷ and R ⁸ are C1-4 alkyl. In some embodiments, R ⁷ and R ⁸ together form -CH2CH2-.

In some embodiments of formula (II), Y1, Y2, and Y3 are each CH, R ^9a and R ^9b are each hydrogen, X is O, and none of G2, G3, G4, G5, and G6 are N. In some embodiments, Y1, Y2, and Y3 are each CH, ^R9a and ^R9b are each hydrogen, X is O, and one of G2, _G3 , _G4 , _G5, and _G6 is N. In some embodiments, Y1, Y2, and Y3 are each CH, R ^9a and R ^9b are each hydrogen, X is O, and two of G2, G3, G4, G5, and G6 are N. In some embodiments, In embodiments, Y1, Y2 and Y3 are each CH, R ^9a and R ^9b are both hydrogen, X is O, and R ^4b together with R ⁶ and the atoms to which they are attached form a heteroaryl or heterocyclic ring.

In another aspect, compounds of formula (III) are provided:

where R ¹ represents -(CR ^a R ^b )m-arul, -CH=CH-aryl, -(CR ^c R ^d )n-heteroaryl, -(CR ^e R ^f )o-heterocycloalkyl or (CR ^g R ^h )p-cycloalkyl, and if L represents SO2, then the heteroaryl and heterocycloalkyl present in R ¹ are monocyclic;

m is 0 or 2;

n, o and p are each independently equal to 0, 1 or 2;

R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ^g and R ^h are each independently H, halogen or C _1-4 alkyl,

- 19 045787 or R ^a and R ^b together with the carbon atom to which they are attached form a cycloalkyl ring, or R ^a and R ^b together form =CH2 or =O;

each aryl, heteroaryl, heterocycloalkyl or cycloalkyl present in R ¹ is unsubstituted or substituted with one or two R ^x substituents;

where each substituent R ^x independently represents halogen, C1.4αalkyl, cycloalkyl, -C1.2-haloalkyl, -OH, -OC1_4alkyl, -O-C1.2-halogenalkyl, cyano, -C(O)C1-4 alkyl, -C(O)NR'R', -SO2C1.4alkyl, -SO2NR ^k R ^l , -NR ^q R ^r , -C(O)-cycloalkyl, -C(O)-aryl (optionally substituted with methyl or halogen), -CO2C ₁ . ₄ αlkyl, -CO2 aryl, -C(O)CH ₂ -aryl (optionally substituted with methyl or halogen), -CH ₂ -aryl (optionally substituted with methyl or halogen) or monocyclic heterocycloalkyl (optionally substituted with methyl, -C(O)C _1.4 αlkyl or -CO ₂ C _{1.4 alkyl} ) _;

where Ri, Rj, R ^k and Rl, each independently, represent H, C1.4alkyl, -C1.4alkyl-OH or -C1.4alkyl-O-C1.4alkyl, where ^Rq and ^Rr , each independently, represent is H, C1. ₄ alkyl, -C ₁ . ₄ alkyl-OH, -C ₁ _ ₄ alkyl-O-C ₁ _ ₄ alkyl, -C(O)C ₁ . ₄ alkyl, -CO ₂ C ₁ - ₄ alkyl or -SO ₂ C ₁ . ₄ alkyl;

or R ¹ represents

where R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently hydrogen, halogen, -OH, -CN, -alkyl, -O-alkyl, -haloalkyl, heterocycloalkyl, -O-haloalkyl, - SO ₂ C ₁ . ₄ alkyl or -NR ^aa R ^bb ;

R ^aa represents hydrogen, C ₁ . ₄ αlkyl or -C ₁ . ₄ alkyl-OH;

R ^bb represents hydrogen or C ₁ . ₄ alkyl;

or R ¹⁰ together with R ¹¹ and the atoms to which they are attached form a heteroaryl or heterocyclic ring;

or R ¹¹ together with R ¹² and the atoms to which they are attached form a heteroaryl or heterocyclic ring;

L is absent and represents -S(O) ₂ -, -C(O)-, -O-, -CH ₂ -, -CF2-, C(CH ₃ ) ₂ , -C(=CH ₂ )- or - CR ^s R ^t -; wherein R ^s and R' independently represent H or alkyl, or R ^s and R' together with the carbon atom to which they are attached form a cycloalkyl ring;

X represents O, S, NH, N(CO ₂ C _1-4 alkyl), N(SO ₂ C _1-4 alkyl), N(SO ₂ cycloalkyl) or CH ₂ ;

Y1, Y ₂ and Y ₃ are each independently CH or N; moreover, if L is different from -S(O) ₂ -, then each Y ₂ and Y ₃ represents CH;

G2 is N or CR ² ;

G ₃ represents N or CR ³ ;

G4 is N, NR ^4b or CR ^4a ;

G ₅ represents N or CR ⁵ ; And

G ₆ represents N or CR ⁶ ;

wherein R ² , R ³ , R ^4a , R ⁵ and R ⁶ are each independently hydrogen, halo, -OH, -alkyl, -O-alkyl, -haloalkyl, -O-haloalkyl or -NR ^u R ^v ;

or R ^4b together with R ⁶ and the atoms to which they are attached form a heteroaryl or heterocyclic ring; wherein the heteroaryl ring containing R ^4b and R ⁶ contains no more than one N and is optionally substituted with alkyl, and the heterocyclic ring containing R ^4b and R ⁶ is optionally substituted with an oxo group,

R ^u represents H or C ₁ . ₄ αlkyl;

R ^v represents H, C ₁ . ₄ alkyl, monocyclic cycloalkyl, -C(O)C ₁ . ₄ alkyl or -C(O)NR ^w R ^y ;

wherein each alkyl present in R ^v is unsubstituted or substituted with a -OH, -NH2, -NH(C ₁ . ₄ alkyl) or -N (C ₁ . ₄ α alkyl) ₂ group,

R ^w and R ^y are independently H or C ₁ . ₄ alkyl;

Where

is not unsubstituted phenyl; And

R ⁷ and R ⁸ are each independently hydrogen or C ₁ . ₄ αlkyl, or R ⁷ and R ⁸ together form -CH2CH2-;

or pharmaceutically acceptable salts thereof.

In some embodiments of Formula (I), R ¹ is -(CR ^a R ^b )m-aryl, -CH=CH-aryl, or -(CR ^c R ^d )n-heteroaryl, each of which is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is

- 20 045787

-(CR ^e R ^f )o-heterocycloalkyl or -(CR ^s R ^h )p-cycloalkyl, each of which is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -(CR ^a R ^b )m-aryl, wherein R ^a and R ^b are each independently H, halogen, or C1-4 alkyl, and m is 0 or 2, wherein said aryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -(CR ^a R ^b )2-aryl, wherein R ^a and R ^b together with the carbon atom to which they are attached form a cycloalkyl, or R ^a and R ^b together form =CH2 or =O, and the aryl present in R ¹ is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is aryl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -CH2CH2-aryl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is phenyl, naphthyl, -(CR ^a R ^b )2-phenyl, or -(CR ^a R ^b )2-naphthyl, each of which is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is phenyl. In other embodiments, R ¹ is naphthyl. In some embodiments, R ¹ is aryl, -CH2CH ₂ -aryl, or -CH=CH-aryl, each of which is unsubstituted or substituted with one or two R ^x substituents independently selected from the group consisting of halogen, C1.4alkyl , -C1.2-haloalkylα, -OH, -OC1.4alkyl, -O-C1.2-haloalkylα, cyano, -NR ^q R ^r and monocyclic heterocycloalkyl (optionally substituted with methyl, -C(O) _C1.4alkyl or -CO ₂ C _1.4 alkyl), and R ^q and R ^r , each independently _, represent H, C1.4alkyl, -C1.4alkyl-OH, -C1_4alkyl-O-C1_4alkyl, -C(O)C1.4αalkyl , -CO2C1.4alkyl or -SO2C1.4alkyl. In some embodiments, R ¹ is phenyl, -CH2CH ₂ -phenyl, -CH=CH-phenyl, naphthyl, -CH ₂ CH ₂ -naphthyl, or -CH=CH-naphthyl. In some embodiments, R ¹ is phenyl, -CH2CH2-phenyl, -CH=CH-phenyl, naphthyl, -CH2CH2-naphthyl, or -CH=CH-naphthyl, each of which is substituted with one or two R ^x substituents independently selected from the group consisting of F, Cl, -CF3, -OCF ₃ , cyano, -CH ₃ , -OCH ₃ , -NHC(O)CH ₃ , -NHCY ₂ C(CH ₃ ) ₂ OH, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl , pyridinyl and -NHS(O) ₂ CH ₃ .

In some embodiments, R ¹ is -(CR ^c R ^d )n-heteroaryl, wherein R ^c and R ^d are each independently H, halogen, or C1. ₄ alkyl, and n is 0, 1, or 2, wherein said heteroaryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is heteroaryl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -CH2-heteroaryl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -CH2CH ₂ -heteroaryl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -(CR ^c R ^d ) _n -heteroaryl, wherein said heteroaryl is a monocyclic heteroaryl. In some embodiments, R ¹ is -(CR ^c R ^d )n-heteroaryl, wherein said heteroaryl is a bicyclic heteroaryl. In any of these embodiments, the heteroaryl contains one or two nitrogen ring members. In some embodiments, R ¹ is -(CR ^c R ^d )n-heteroaryl, wherein said heteroaryl is pyrrole, furan, thiophenyl, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, oxadiazole, thiadiazole, tetrazole , pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, benzofuran, benzothiophene, benzimidazole, benzothiazole or benzoxazole, each of which is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -CH2-heteroaryl or -CH2CH2-heteroaryl, each of which is unsubstituted or substituted with one or two R ^x substituents independently selected from the group consisting of halogen, C1. ₄ alkyl, -C ₁ . ₂ -haloalkyl, -OH, -OC ₁ . ₄ alkyl, -OC ₁ . ₂ -haloalkyl, cyano, -NR ^q R ^r and monocyclic heterocycloalkyl (optionally substituted with methyl, -C(O)C1_ ₄ alkyl or -CO ₂ C ₁ . ₄ alkyl), wherein R ^q and R ^r are each independently H, C _1-4 alkyl, -C ₁ . ₄ alkyl-OH, -C ₁ _ ₄ alkyl-O-C ₁ _ ₄ alkyl, -C(O)C _1-4 alkyl, -CO ₂ C ₁ . ₄ alkyl or -SO ₂ C ₁ . ₄ alkyl. In some embodiments, R ¹ is pyrrole, furan, thiophenyl, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, benzofuran, benzothiophene , benzimidazole, benzothiazole or benzoxazole. In some embodiments, R ¹ is pyrrole, furan, thiophenyl, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, benzofuran, benzothiophene , benzimidazole, benzothiazole or benzoxazole, each of which is substituted with one or two R ^x substituents independently selected from the group consisting of F, Cl, -CF3, -OCF3, cyano, -CH3, -OCH3, -NHC(O)CH3, -NHCY2C(CH3)2OH, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl and -NHS(O)2CH3.

In some embodiments, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, wherein R ^e and R ^f are each independently H, halogen or C1-4 alkyl, o is 0, 1 or 2, wherein said heterocycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is heterocycloalkyl, unsubstituted or substituted

- 21 045787 with one or two R ^x substituents. In some embodiments, R ¹ is -CH2-heterocycloalkyl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -CH2CH2-heterocycloalkyl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, wherein said heterocycloalkyl is monocyclic, and in some embodiments, wherein said heterocycloalkyl is a 4-6 membered ring. In some embodiments, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, wherein said heterocycloalkyl is azetidine, tetrahydrofuran, pyrrolidine, tetrahydropyran, piperidine, piperazine, morpholine, thiomorpholine, 1,1-dioxothiomorpholine, azepine, or diazepine . In some embodiments, said heterocycloalkyl is attached to the remainder of the structure via a carbon atom (C-linked heterocycloalkyl). In some embodiments, R ¹ is -CH2-heterocycloalkyl or -CH ₂ CH ₂ -heterocycloalkyl, each of which is unsubstituted or substituted with one or two R ^x substituents independently selected from the group consisting of halogen, C1.4αalkyl, - C1.2-haloalkyl, -OH, -OC1.4-alkyl, -O-C1.2-haloalkyl, cyano, -NR ^q R ^r and monocyclic heterocycloalkyl (optionally substituted with methyl, -C(O)C1_ ₄ alkyl or -CO ₂ C ₁ _ ₄ alkyl), wherein R ^q and R ^r are each independently H, C1-4alkyl, -C1_4alkyl-OH, -C1_4alkyl-O-C1_4alkyl, -C(O)C1_4alkyl, -CO2C1_4alkyl or -SO2C1. 4alkil. In some embodiments, R ¹ is azetidine, tetrahydrofuran, pyrrolidine, tetrahydropyran, piperidine, piperazine, morpholine, thiomorpholine, 1,1-dioxothiomorpholine, azepine, or diazepine. In some embodiments, R ¹ is azetidine, tetrahydrofuran, pyrrolidine, tetrahydropyran, piperidine, piperazine, morpholine, thiomorpholine, 1,1-dioxothiomorpholine, azepine, or diazepine, each of which is substituted with one or two R ^x substituents independently selected from the group , consisting of F, Cl, -CF3, -OCF ₃ , cyano, -CH ₃ , -OCH ₃ , -NHC(O)CH ₃ , -NHCH2C(CH ₃ )2OH, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl and -NHS (O)2CH ₃ .

In some embodiments, R ¹ is -(CR ^s R ^h )p-cycloalkyl, where R ^g and R ^h are each independently H, halogen, or C1. ₄ αlkyl, and p is 0, 1 or 2, and wherein said cycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is cycloalkyl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -CH2-cycloalkyl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -CH2CH ₂ -cycloalkyl, unsubstituted or substituted with one or two R ^x substituents. In some embodiments, R ¹ is -(CR ^s R ^h )p-cycloalkyl, wherein said cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R ¹ is cycloalkyl, -CH2-cycloalkyl, or -CH2CH2-cycloalkyl, each of which is unsubstituted or substituted with one or two R ^x substituents independently selected from the group consisting of halogen, C1-4alkyl, -C1 .2-haloalkyl, -OH, -OC1.4-alkyl, -O-C1.2-haloalkyl, cyano, -NR ^q R ^r and monocyclic heterocycloalkyl (optionally substituted with methyl, -C(O) _C1.4 αlkyl or -CO ₂ C ₁ _ ₄ alkyl), wherein R ^q and R ^r are each independently H, C _1-4 alkyl, -C ₁ _ ₄ alkyl-OH, -C ₁ . ₄ alkyl-O-C ₁ . ₄ alkyl, -C(O)C ₁ - ₄ alkyl, -CO ₂ C ₁ _ ₄ alkyl or -SO ₂ C ₁ . ₄ alkyl. In some embodiments, R ¹ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R ¹ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or two R ^x substituents independently selected from the group consisting of F, Cl, -CF3, -OCF3, cyano, -CH3, -OCH3, -NHC(O)CH3, -NHCH2C(CH3)2OH, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl and -NHS(O)2CH3.

In some embodiments, R ¹ is phenyl, naphthyl, dihydrobenzofuran, benzofuran, benzyl, indolylmethyl, phenethyl, 1,1-difluoro(phenyl)methyl, imidazolylmethyl, benzimidazolylmethyl, pyridinylmethyl, cyclohexyl, cyclohexylmethyl, azetidine, tetrahydrofuran, tetrahydrofuranylmethyl, pyrrolidine , tetrahydropyran, tetrahydropyranylmethyl or piperidine, each of which is unsubstituted or substituted with one or two R ^x substituents.

In each case, R ¹ is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, there is one R ^x substituent, and in others there are two R ^x substituents.

In some embodiments, each R ^x is independently halogen, C1.4alkyl, cycloalkyl, -C1.2-haloalkyl, -OH, -OC1-4alkyl, -O-C1.2-haloalkyl, cyano, -C(O) C1-4alkyl, -C(O)NR'R', -SO2C1.4alkyl, -SO2NR ^k R ^l , -NR ^q R ^r , -C(O)-cycloalkyl, -C(O)-aryl (optionally substituted with methyl or halogen), -CO2C ₁ . ₄ αlkyl, -C(O)CH ₂ -aryl (optionally substituted with methyl or halogen), -CH ₂ -aryl (optionally substituted with methyl or halogen) or monocyclic heterocycloalkyl (optionally substituted with methyl, -C(O)C ₁ - ₄ alkyl or -CO ₂ C ₁ - ₄ alkyl). In some embodiments, each R ^x is independently a halogen, C ₁ . ₄ alkyl, cycloalkyl, -C ₁ . ₂ -haloalkyl, -OH, -OC ₁ . ₄ αlkyl, -OC ₁ . ₂ -haloalkyl, cyano, -C(O)C ₁ _ ₄ alkyl, -C(O)NR'R', -SO ₂ C ₁ . ₄ alkyl, -SO ₂ NR ^k Rl, -NR ^q R ^r , -C(O)-cycloalkyl, -C(O)-aryl (optionally substituted with methyl

- 22 045787 or halogen), -CO2C _1- 4alkyl, -CO2aryl, -C(O)CH2-aryl (optionally substituted with methyl or halogen), -CH2-aryl (optionally substituted with methyl or halogen) or monocyclic heterocycloalkyl (optionally substituted with methyl , -C(O)C _1.4 alkyl or _-CO2C1.4 alkyl) _. In some embodiments, each R ^x independently represents halogen (such as fluorine, chlorine, bromine), methyl, ethyl, propyl, isopropyl, -C(O)NH ₂ , -C(O)NHC ₁ . ₄ αlkyl, -C(O)NMe2, acetyl, -C(O)ethyl, -C(O)-isopropyl, -C(O)-tert-butyl, -C(O)-cyclopropyl, -CO ₂ -tert -butyl, -C(O)CH ₂ -phenyl, -C(O)phenyl, -C(O)NHC ₁ . ₂ alkyl-OSH ₃ , Boc-piperidinyl, isopropyl, tetrahydropyranyl, cyano, morpholinyl, fluorine, chlorine, -CF ₃ , methoxy, -NHSO2CH3, 2-hydroxy-2-methyl-1-aminopropyl, -NH-acetyl or -OCF ₃ . In some embodiments, each R ^x is independently tetrahydrofuranyl, tetrahydropyranyl, or pyridinyl, each of which is optionally substituted. In each case, the aryl and heterocycloalkyl groups are optionally substituted as described above.

In some embodiments, R ¹ and Rj are each independently H, C _1-4 alkyl, -C 1- ₄ alkyl-OH, -C ₁ . ₄ alkyl-O-C ₁ . ₄ alkyl. In some embodiments, Ri and Rj are each independently H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, 2-hydroxy-2-methylpropyl, methoxymethyl, or methoxyethyl.

In some embodiments, R ^k and R ¹ are each independently H, C1_4alkyl, -C1.4αalkyl-OH, -C1.4alkyl-O-C1.4alkyl, -C(O)C1_4alkyl, -CO2C1.4alkyl, or -SO2C1.4αlkyl. In some embodiments, R ^k and R ¹ are each independently H, methyl, ethyl, propyl, isopropyl, -C1. ₄ alkyl-OH, acetyl or -CO ₂ -tert-butyl.

In some embodiments of formula (III), R ¹ is

R ¹³

R ¹ 3 Ш ¹⁴

R ¹¹

R ¹⁰

In some embodiments, R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ are each independently hydrogen, halogen, -OH, -CN, -alkyl, -O-alkyl, -haloalkyl, heterocycloalkyl, -O -haloalkyl, -SO ₂ C ₁ . ₄ alkyl or -NR ^aa R ^bb . In some embodiments, R ¹⁰ together with R ¹¹ and the atoms to which they are attached form a heteroaryl or heterocyclic ring. In some embodiments, R ¹¹ together with R ¹² and the atoms to which they are attached form a heteroaryl or heterocyclic ring. In some embodiments, R ¹⁰ together with R ¹¹ form a 5- or 6-membered heteroaryl or heterocyclic ring. In some embodiments, R ¹⁰ combines with R ¹¹ to form furanyl, pyridinyl, oxazolyl, oxadiazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydrothiophenyl, oxathiolanyl, sulfolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxane silt, tianil, dithianyl, trithianyl, morpholinyl or thiomorpholinyl ring. In some embodiments, R ¹⁰ together with R ¹¹ forms a furanyl ring. In some embodiments, R ¹⁰ together with R ¹¹ forms a tetrahydrofuranyl ring.

In some embodiments, R ¹¹ together with R ¹² form a 5- or 6-membered heteroaryl or heterocyclic ring. In some embodiments, R ¹¹ combines with R ¹² to form furanyl, pyridinyl, oxazolyl, oxadiazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydrothiophenyl, oxathiolanyl, sulfolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxane silt, tianil, dithianyl, trithianyl, morpholinyl or thiomorpholinyl ring. In some embodiments, R ¹¹ together with R ¹² forms a furanyl ring. In some embodiments, R ¹¹ together with R ¹² forms a tetrahydrofuranyl ring.

In some embodiments of formula (III), X is O. In some embodiments, X is S. In some embodiments, X is NH, N(CO ₂ C ₁ . ₄ alkyl), N(SO ₂ C _1.4 alkyl) or N(SO ₂ cycloalkyl) _. In some embodiments, X is CH ₂ .

In some embodiments of formula (III), Y1, Y2, and _Y3 are each CH. In some embodiments, Y1, Y2, and Y ₃ are each N. In some embodiments, Y1 is N, and Y2 and Y ₃ are each CH. In some embodiments, Y2 is N, and Y1 and _Y3 are each CH. In some embodiments, Y ₃ is N, and Y1 and Y2 are each CH. In some embodiments, Y1 and Y2 are each N, and _Y3 is CH. In some embodiments, Y1 and Y ₃ are each N and Y2 is CH. In some embodiments, Y2 and Y ₃ are each N and Y1 is CH.

In some embodiments of Formula (III) or any variant thereof, L is absent and is -S(O) _2- , -C(O)-, -CH2-, -CF2-, C( _CH3 ) ₂ , -C (=CH ₂ )- or -CRsRt-; where R ^s and K independently represent H or alkyl, or R ^s and K together with the carbon atom to which they are attached form a cycloalkyl ring; and R ¹ , R ² , R ³ , R ^4a , R ^4b , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, Y1, Y ₂ , Y 3, G2, G ₃ , G ₄ , _{G 5 ,} G6 , R ^a , R ^b ,

R ^c , R ^d , R ^e , R ^f , R ^g , R ^h , R ¹ , R j , R ^k , k ¹ , R ^q , R ^r , R ^u , R ^v , R ^w , R ^x , R ^y , m, n, o and p are as described for formula (III) or any variant or implementation thereof.

- 23 045787

In some embodiments of Formula (III), L is -S(O)2-. In some embodiments, L is absent. In some embodiments, L is -C(O)-, -O-, -CH ₂ -, -CF ₂ -, C(CH ₃ ) ₂ , -C(=CH ₂ )- or -CR ^s R' -. In some embodiments, L is -C(O)-, -CH2-, -CF2-, C(CH ₃ ) ₂ , -C(=CH ₂ )-, or -CRsRt-. In some embodiments, L is absent and is -C(O)-, -CH2-, -CF2-, C( _CH3 ) ₂ , -C(= _CH2 )-, or -CRsRt-; and each Y2 and _Y3 represents CH.

In some embodiments of formula (II), G2 is CR ² , G3 is CR ³ , G4 is CR ^4a , G5 is CR ⁵ , and G6 is CR ⁶ . In some embodiments, one of G2, G3, G4, G5, and G6 is N. In some embodiments, one of G2, G3, G4, G5, and G6 is N. In some embodiments, two of G2, G3 , G4, G5, and G6 are N. In some embodiments, G2 is N, G3 is CR ³ , G4 is CR ^4a , G5 is CR ⁵ , and G6 is CR ⁶ . In some embodiments, G2 is CR ² , G3 is CR ³ , G4 is CR ^4a , G5 is N, and G ₆ is CR ⁶ . In some embodiments, G2 and G ₄ are each N, G ₃ is CR ³ , G5 is CR ⁵ , and G6 is CR ⁶ . In some embodiments, G4 and G5 are each N, G2 is CR ² , G3 is CR ³ , and G ₆ is CR ⁶ .

In some embodiments, in which none of G2, _G3 , _G5 , and _G6 is N, _G4 is N, or ^NR4b , at least one of ^R2 , ^R3 , ^R4a , R ⁵ and R ⁶ is not hydrogen. In some embodiments, G ₄ is NR ^4b In some embodiments, R ^4b together with R ⁶ and the atoms to which they are attached form a heteroaryl or heterocyclic ring. In some embodiments, the heteroaryl ring containing R ^4b and R ⁶ contains at most one N. In some embodiments, the heteroaryl ring containing R ^4b and R ⁶ is optionally substituted with alkyl, and the heterocyclic ring is optionally substituted with oxo.

In some embodiments of Formula (III), R ⁷ and R ⁸ are each hydrogen. In some embodiments, one of R ⁷ and R ⁸ is hydrogen and the other is C1-4 alkyl. In some embodiments, both R ⁷ and R ⁸ are C1-4 alkyl. In some embodiments, R ⁷ and R ⁸ together form -CH2CH2-.

In certain embodiments of formula (III), L is -S(O) ₂ -, and R ¹ is -(CR ^a R ^b )m-aryl, wherein R ^a and R ^b are each independently H, halogen or C1-4alkyl, and m is 0, 1 or 2, and wherein aryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, L is -S(O)2-, and R ¹ is -(CR ^c R ^d )n-heteroaryl, wherein R ^c and R ^d are each independently H, halogen, or C1- 4alkyl, and n is 0, 1 or 2, and wherein heteroaryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, L is -S(O)2-, and R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, wherein R ^e and R ^f are each independently H, halogen, or C1- 4αalkyl, and o is 0, 1 or 2, and heterocycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is -S(O)2-, and R ¹ is -(CR ^s R ^h )p-cycloalkyl, wherein R ^g and R ^h are each independently H, halogen, or C1- 4alkyl, and p is 0, 1, or 2, and wherein the cycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is -S(O) ₂ -, and R ¹ is -CH=CH -aryl.

In some embodiments, L is -S(O) ₂ -, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, and X is O. In some embodiments, L is -S(O)2-, R ¹ is -(CR ^c R ^d )n-heteroaryl, and X is O. In some embodiments, L is -S(O)2-, R ¹ is is -(CR ^e R ^f )o-heterocycloalkyl, and X is O. In other embodiments, L is -S(O)2-, R ¹ is -(CR ^s R ^h )p-cycloalkyl, and X represents O.

In some embodiments, L is -S(O) ₂ -, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and none of G2, G3 , G4, G5, and G6 are not N. In some embodiments, L is -S(O)2-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and one of G ₂ , G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is -S(O) ₂ -, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and two of G2, G3, G4, G5 and G6 are N. In some embodiments, L is -S(O)2-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, each G2 and G ₄ is N, G ₃ is CR ³ , G5 is CR ⁵ , and G6 is CR ⁶ .

In some embodiments, L is -S(O)2-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and none of G2, G3, G4, G5, and G6 is N. In some embodiments, L is -S(O)2-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and one of G ₂ , G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is -S(O)2-, R ¹ is

-(CR ^c R ^d ) _n -heteroaryl, X is O, and two of G2, G ₃ , G ₄ , G ₅ and G ₆ are N. In some embodiments, L is -S(O) ₂ -, R ¹ represents

-(CR ^c R ^d ) _n -heteroaryl, X is O, G2 and G ₄ are each N, G ₃ is CR ³ , G5 is CR ⁵ , and G6 is CR ⁶ . In some embodiments, L is -S(O) ² -, R ¹ is -(CR ^e R ^f ') _o -heterocycloalkyl, X is O, and none of G2, G ₃ , G ₄ , G ₅ and G ₆ is not N. In some embodiments, L is -S(O) ₂ -, R ¹ is -(CR ^e R ^f ')o-heterocycloalkyl, X is O, and one of G2 , G3, G4, G5, and G6 is N. In some embodiments, L is -S(O)2-, R ¹ is -(CR ^e R ^f ')o-heterocycloalkyl, X is O, and two of G2, _G3 , _G4 , _G5 and _G6 are N. In some embodiments, L is -S(O) _2- , ^R1 is -(CR ^e R ^f ') _o -heterocycloalkyl , X represents O, G2 and G ₄ each represent N, G ₃ represents CR ³ , G5 represents CR ⁵ , and G6 represents CR ⁶ .

In certain embodiments of formula (I), L is -C(O)-, and R ¹ is -(CR ^a R ^b )m-aryl, wherein R ^a and R ^b are each independently H, halogen or C1-4alkyl, and m is 0, 1 or 2, and wherein aryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, L is -C(O)-, and R ¹ is -(CR ^c R ^d )n-heteroaryl, wherein R ^c and R ^d are each independently H, halogen, or C1-4 alkyl, and n is 0, 1 or 2, and wherein heteroaryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, L is -C(O)-, and R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, wherein R ^e and Rf are each independently H, halogen, or C1-4αalkyl, and o is 0, 1 or 2, and wherein heterocycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is -C(O)- and R ¹ is -(CR ^s R ^h )p-cycloalkyl, wherein R ^g and R ^h are each independently H, halogen or C1-4 alkyl , and p is 0, 1 or 2, and the cycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is -C(O)-, and R ¹ is -CH=CH-aryl.

In some embodiments, L is -C(O)-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, and X is O. In some embodiments, L is is -C(O)-, R ¹ is -(CR ^c R ^d )n-heteroaryl, and X is O. In some embodiments, L is -C(O)-, R ¹ is -( CR ^e R ^f )o-heterocycloalkyl, and X is O. In other embodiments, L is -C(O)-, R ¹ is -(CR ^s R ^h )p-cycloalkyl, and X is O .

In some embodiments, L is -C(O)-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and none of G2, G3, G4, G5, and G6 are not N. In some embodiments, L is -C(O)-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and one of G2, _G3 , _G4 , _G5 , and _G6 is N. In some embodiments, L is -C(O)-, ^R1 is -(CR ^a R ^b )m- aryl or -CH=CH-aryl, X is O, and two of G2, G3, G4, G5 and G6 are N. In some embodiments, L is -C(O)-, R ¹ is - (CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, G2 and G ₄ are each N, G ₃ is CR ³ , G5 is CR ⁵ , and G6 is CR ⁶ .

In some embodiments, L is -C(O)-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and none of G2, G3, G4, G5, and G6 is is N. In some embodiments, L is -C(O)-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and one of G2, _G3 , _G4 , G ₅ and G ₆ is N. In some embodiments, L is -C(O)-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and two of G2, G3, G4, G5, and G6 are N. In some embodiments, L is -C(O)-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, each G2 and G ₄ is is N, G ₃ is CR ³ , G5 is CR ⁵ , and G6 is CR ⁶ . In some embodiments, L is -C(O)-, R ¹ is -(CR ^e R ^f ')o-heterocycloalkyl, X is O, and none of G2, G3, G4, G5, and G6 is N. In some embodiments, L is -C(O)-, R ¹ is -(CR ^e R ^f ')o-heterocycloalkyl, X is O, and one of G2, G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is -C(O)-, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, and two of G2, G3, G4, G5, and G6 are N. In some embodiments, L is -C(O)-, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, each G2 and G ₄ is N, G ₃ is CR ³ , G5 is CR ⁵ , and G6 is CR ⁶ .

In some embodiments of Formula (III), L is -O-, and R ¹ is -(CR ^a R ^b )m-aryl, wherein R ^a and R ^b are each independently H, halogen, or C1. ₄ alkyl, and m is 0, 1 or 2, and aryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, L is -O- and R ¹ is -(CR ^c R ^d )n-heteroaryl, wherein R ^c and R ^d are each independently H, halogen or C1-4 alkyl, and n is 0, 1 or 2, and the heteroaryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, L is -O- and R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, wherein R ^e and R ^f are each independently H, halogen or C1-4α alkyl, and o is 0, 1 or 2, and the heterocycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is -O- and R ¹ is -(CR ^s R ^h )p-cycloalkyl, wherein R ^g and R ^h are each independently H, halogen or C1-4 alkyl, and p is 0, 1 or 2, and the cycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is -O- and R ¹ is -CH=CH-aryl.

In some embodiments, L is -O-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, and X is O. In some embodiments, L is -O -, R ¹ is -(CR ^c R ^d )n-heteroaryl, and X is O. In some embodiments, L is -O-, R ¹ is -(CR ^e R ^f ')o-heterocycloalkyl , and X is O. In other embodiments, L is -O-, R ¹ is -(CR ^s R ^h )p-cycloalkyl, and X is O.

In some embodiments, L is -O-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and none of G2, G3, G4, G5 and G6 is not N. In some embodiments, L is -O-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and one of G2 , G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is -O-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and two of G2, G3, G4, G5, and G6 are N. In some embodiments, L is -O-, R ¹ is -(CR ^a R ^b )m-aryl, or -CH =CH-aryl, X is O, G2 and _G4 are each N, _G3 is ^CR3 , G5 is ^CR5 , and G6 is ^CR6 .

In some embodiments, L is -O-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and none of G2, G3, G4, G5, and G6 is N. In some embodiments, L is -O-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and one of G2, G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is -O-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and two of G2, G3, G4, G5 and G6 are N. In some embodiments, L is -O-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, G2 and G4 are each N, G ₃ is CR ³ , G5 is CR ⁵ , and G6 is CR ⁶ . In some embodiments, L is -O-, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, and none of G2, G3, G4, G5, and G6 is N. In some embodiments, L is -O-, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, and one of G2, G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is -O-, R ¹ is

-(CR ^e R ^f ) _o -heterocycloalkyl, X is O, and two of G2, G ₃ , G ₄ , G ₅ and G ₆ are N. In some embodiments, L is -O-, R ¹ represents

-(CR ^e R ^f ) _o -heterocycloalkyl, X is O, G2 and _G4 are each N, _G3 is ^CR3 , G5 is ^CR5 , and G6 is ^CR6 .

In some embodiments of formula (III), L is -CH2-, -CF2-, C(CH ₃ ) ₂ , -C(=CH ₂ )- or -CRsRt-, and R ¹ is -(CR ^a R ^b )m-aryl, wherein R ^a and R ^b are each independently H, halogen or C1-4 alkyl, and m is 0, 1 or 2, and wherein aryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, L is -CH2-, -CF2-, C(CH3)2, -C(=CH2)-, or -CRsRt-, and R ¹ is -(CR ^c R ^d )n-heteroaryl, wherein R ^c and R ^d are each independently H, halogen or C1-4 alkyl, and n is 0, 1 or 2, and wherein heteroaryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, L is -CH2-, -CF2-, C(CH3) ₂ , -C(=CH ₂ )-, or -CRsRt-, and R ¹ is -(CR ^e R ^f ')o- heterocycloalkyl, wherein R ^e and Rf are each independently H, halogen or C1-4 alkyl, and o is 0, 1 or 2, and wherein heterocycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is -CH2-, -CF2-, C(CH3)2, -C(=CH2)-, or -CRsRt-, and R ¹ is -(CR ^s R ^h )p-cycloalkyl; wherein R ^g and R ^h are each independently H, halogen or C1-4 alkyl, and p is 0, 1 or 2, and wherein the cycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is -CH2-, -CF2-, C(CH ₃ ) ₂ , -C(=CH ₂ )- or -CRsRt-, and R ¹ is -CH=CH-aryl.

In some embodiments, L is -CH ₂ -, -CF2-, -C(CH ₃ ) ₂ -, -C(=CH ₂ )-, or -CRsRt-, R ¹ is -(CR ^a R ^b ) _m is aryl or -CH=CH-aryl, and X is O. In some embodiments, L is -CH ₂ -, -CF2-, C(CH ₃ ) ₂ , -C(=CH ₂ )- or -CRsRt-, R ¹ is -(CR ^c R ^d ) _n -heteroaryl, and X is O. In some embodiments, L is -CH2-, -CF2-, C( _CH3 ) ₂ , -C(=CH ₂ )- or -CRsRt-, R ¹ is

-(CR ^e R ^f ) _o is heterocycloalkyl, and X is O. In other embodiments, L is -CH2-, -CF2-, C( _CH3 ) ₂ , -C(= _CH2 )- or - CRsRt-, R ¹ is -(CR ^s R ^h ) _p -cycloalkyl, and X is O.

In some embodiments, L is -CH ₂ -, -CF ₂ -, C(CH ₃ ) ₂ , -C(=CH ₂ )- or -CRsRt-, R ¹ is -(CR ^a R ^b )m -aryl or -CH=CH-aryl, X is O, and none of G2, G3, G4, G5, and G6 is N. In some embodiments, L is -CH2-, -CF2-, - C(CH3)2-, -C(=CH2)- or -CRsRt-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and one of G2 , G ₃ , G ₄ , G ₅ , and G ₆ is N. In some embodiments, L is -CH2-, -CF2-, C( _CH3 ) ₂ , -C(= _CH2 )-, or -CRsRt -, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and two of G2, G3, G4, G5 and G6 are N. In some embodiments, L is -CH2-, -CF2-, C(CH3)2, -C(=CH2)- or -CRsRt-, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl , X represents O, G2 and G4 each represent N, G ₃ represents CR ³ , G5 represents CR ⁵ , and G6 represents CR ⁶ .

In some embodiments, L is -CH2-, -CF2-, -C(CH ₃ ) ₂ -, -C(=CH ₂ )-, or -CRsRt-, R ¹ is -(CR ^c R ^d )n -heteroaryl, X is O, and none of G2, G3, G4, G5, and G6 is N. In some embodiments, L is -CH2-, -CF2-, -C(CH3)2-, -C(=CH2)- or -CRsRt-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and one of G2, G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is -CH2-, -CF2-, C(CH ₃ ) ₂ , -C(=CH ₂ )- or -CRsRt-, R ¹ is -(CR ^c R ^d )n -heteroaryl, X is O, and two of G2, G3, G4, G5, and G6 are N. In some embodiments, L is -CH2-, -CF2-, C(CH3)2, -C(= CH2)- or -CRsRt-, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, each G2 and G ₄ is N, G ₃ is CR ³ , G5 is CR ⁵ , and G6 is CR ⁶ . In some embodiments, L is -CH2-, -CF2-, -C(CH3)2-, -C(=CH2)-, or -CRsRt-, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl , X is O, and none of G2, G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is -CH ₂ -, -CF ₂ -, -C(CH ₃ ) ₂ -, -C(=CH ₂ ) or -CRsRt-, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, and one of G2, G3, G4, G5 and G6 is is N. In some embodiments, L is -CH2-, -CF2-, C(CH3)2, -C(=CH2)- or -CRsRt-, R ¹ is -(CR ^e R ^f )o- heterocycloalkyl, X is O, and two of G2, _G3 , _G4 , _G5 , and _G6 are N. In some embodiments, L is -CH2-, -CF2-, C( _CH3 ) ₂ . -C(=CH ₂ )- or -CRsRt-, R ¹ is -(CR ^c R ^d CR ^e R ^f ) _o -heterocycloalkyl, X is O, each G2 and G ₄ is N, G ₃ is CR ³ , G5 is CR ⁵ , and G6 is CR ⁶ .

In some embodiments of formula (III), L is absent and R ¹ is -(CR ^a R ^b )m-aryl, wherein R ^a and R ^b are each independently H, halogen or C1-4 alkyl, and m is 0, 1 or 2, and wherein aryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, L is absent and R ¹ is -(CR ^c R ^d )n-heteroaryl, wherein R ^c and R ^d are each independently H, halogen, or C 1-4 alkyl, and n is 0.1 or 2, and wherein the heteroaryl is unsubstituted or substituted with one or two R ^x substituents. In some embodiments, L is absent and R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, wherein R ^e and Rf are each independently H, halogen, or C1-4 alkyl, and o is 0, 1, or 2, and wherein the heterocycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is absent and R ¹ is -(CR ^s R ^h )p-cycloalkyl, where R ^g and R ^h are each independently H, halogen or C1-4 alkyl, and p is 0.1 or 2, and wherein the cycloalkyl is unsubstituted or substituted with one or two R ^x substituents. In other embodiments, L is absent and R ¹ is -CH=CH-aryl.

In some embodiments, L is absent, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, and X is O. In some embodiments, L is absent, R ¹ is -( CR ^c R ^d )n-heteroaryl, and X is O. In some embodiments, L is absent, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, and X is O. In other embodiments, L is absent, R ¹ is -(CR ^s R ^h )p-cycloalkyl, and X is O.

In some embodiments, L is absent, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and none of G2, G3, G4, G5 and G6 is is N. In some embodiments, L is absent, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and one of G2, G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is absent, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, and two of G2, G3, G4, G5, and G6 are N. In some embodiments, L is absent, R ¹ is -(CR ^a R ^b )m-aryl or -CH=CH-aryl, X is O, each G2 and G ₄ are - 27 045787 is N, G ₃ is CR ³ , G5 is CR ⁵ , and G ₆ is CR ⁶ .

In some embodiments, L is absent, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and none of G2, G3, G4, G5, and G6 is N. In some embodiments , L is absent, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and one of G2, G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is absent, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, and two of G2, G3, G4, G5 and G6 are N. In some embodiments, L is absent, R ¹ is -(CR ^c R ^d )n-heteroaryl, X is O, G2 and G ₄ are each N, G ₃ is CR ³ , G5 is CR ⁵ , and G ₆ is CR ⁶ . In some embodiments, L is absent, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, and none of G2, G3, G4, G5, and G6 is N. In some embodiments , L is absent, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, and one of G2, G ₃ , G ₄ , G ₅ and G ₆ is N. In some embodiments, L is absent, R ¹ is -(CR ^e R ^f ) _o -heterocycloalkyl, X is O, and two of G2, G ₃ , G ₄ , G ₅ and G ₆ are N. In some embodiments, L is absent, R ¹ is -(CR ^e R ^f )o-heterocycloalkyl, X is O, G2 and G4 are each N, G3 is CR ³ , G5 is CR ⁵ , and G6 is CR ⁶ .

In any embodiment or example of the invention, ^R1 , R2, ^R3 , R4a, ^R4b , ^R5 , ^R6 , ^R7 , ^{R8 ,} L, X, Y1, Y2, Y3, G2, G3, G4, G5, G6, R ^a , R ^b , R ^c , R ^d , R ^e , Rf, R ^g , R ^h , Ri, R ^j , R ^k , R ¹ , R ^q , R ^r , R ^s , Rt, R ^u , ^Rv , ^Rw , ^Rx , Ry, ^m , n, o and p presented herein can be combined with each other embodiment or embodiment of ^R1 , ^R2 , ^R3 , ^R4a , ^R4b , R ⁵ , R ⁶ , R ⁷ , R ⁸ , L, X, Y1, Y ₂ , Y3, G2, G3, G4, G5, G ₆ , R ^a , R ^{b , R c ,} R ^d , R ^e , Rf, ^Rg , Rh, Ri, ^Rj , ^Rk , ^Rl , ^Rq , Rr, ^Rs , ^Rt , Ru, ^Rv , ^Rw , ^Rx , ^{Ry ,} m, n, o and p, as if each combination were specifically and separately described.

It should be understood that, unless otherwise indicated, any embodiments described herein, such as those described with respect to Formula (I), Formula (II), and Formula (III), also apply to any other formulas described in herein, including formula (I), formula (II) and formula (III).

In some embodiments, provided herein are the compounds and their salts set forth in Table. 1.

- 28 045787

Connection no. Structure Chemical name 1 04 T Z >=* Μ ъ 5 -(3 -morpholino-5 - (phenylsulfonyl)phenyl)pyrimidin-2-amine 2 .N_,OMe o, _z o g ii u φ 0 4-(3 -(2-methoxypyrimidin-5 -yl)-5 (phenylsulfonyl)phenyl)morpholine 3 Qo ₄ /=C° VJ ² vJ 0^z “ _z =< zz M 5 -(3-morpholino-5 -(phenylsulfonyl)phenyl)-4(trifluoromethyl)pyrimidin-2-amine 4 iCo 'ω ъ Ν,N-dimethyl-5 -(3-morpholino-5 (phenylsulfonyl)phenyl)pyrimidin-2-amine 5 N_,OMe a-° Г I Q ^s I^i 0 4-(3 -(6-methoxypyridin-3-yl)-5 (phenylsulfonyl)phenyl)morpholine 6 Q, z z 5 -(3-morpholino-5 -(phenylsulfonyl)phenyl)-4(trifluoromethyl)pyridin-2-amine 7 ^n nh ₂ 0* ,p Г T ν ν 0 5 -(3 -morpholino-5 -((3 - (trifluoromethyl)phenyl)sulfonyl)phenyl)pyrimidine n-2-amine 8 U z z 5 -(3 -((4-fluorophenyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 9 .n^nh ₂ Si φ 0 5 -(3 -morpholino-5 -(naphthalene-2ylsulfonyl)phenyl)pyrimidin-2-amine

- 29 045787

10 .N^NHz O _{h Z} O r IT I j Ύ j 0 4-((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)benzonitrile eleven ωζ z !? 5 -(3 -((3-chloro-4-fluorophenyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 12 O _x /0 and ψ 0 4-(3 -(3 -methylpyridin-4-yl)-5 (phenylsulfonyl)phenyl)morpholine 13 ^-o o z 3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)benzonitrile 14 CM zz >= ^Z x M Ul- z ^z □ O ₄ ⁴ — ^/ 'ω '4 5 -(3 -morpholino-5 -((4- (trifluoromethyl)phenyl)sulfonyl)phenyl)pyrimidine n-2-amine 15 J^NH ₂ 0 0 fl „суА 0 5 -(3 -morpholino-5 -((4- (trifluoromethoxy)phenyl)sulfonyl)phenyl)pyrimidine-2-amine 16 9, ω; /—\ ⁴ ° *=< zz / Ν-μοτηπ-5 -(3-morpholino-5 (phenylsulfonyl)phenyl)pyrimidin-2-amine 17 ,n^nh ₂ 0, _z or IT .Lrch 0 4-((3-(2-amino-4-(trifluoromethyl)pyrimidin-5-yl)5-morpholinophenyl)sulfonyl)benzonigril 18 ,n^nh ₂ 1J IJ I Nc^^ ³ 0 4-((3 -(6-amino-4-(grifluoromethyl)pyr idin-3 -yl)-5 morpholinophenyl)sulfonyl)benzonitrile 19 kJ XT 0 2-((5-(3 -morpholino-5 - (phenylsulfonyl)phenyl)pyrimidin-2yl)amino)ethan-1-ol

- 30 045787

20 and ψ 0 N-cyclopropyl-5 -(3-morpholino-5 (phenylsulfonyl)phenyl)pyrimidin-2-amine 21 _x N^NH ₂ ο. _z o \ II 1J Ύ J 0 5 -(3-morpholino-5-tosylphenyl)pyrimidin-2-amine 22 .N^NHa ΛίΤΧ 0 N-(4-((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)phenyl)acetamide 23 8 ^S H Z 1? 5 -(3 -(benzylsulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 24 n^,nh ₂ O _h ,0 G N and φ 0 Ν Vos 1ret-butyl-4-(3-(2-aminopyrimidin-5-yl)-5(phenylsulfonyl)phenyl)piperazine-1-carboxylate 25 Q, ω' Ζ m 5 -(3 -(phenylsulfonyl)-5 -(piperidin-1 yl)phenyl)pyrimidin-2-amine 26 ^F ^\ _x n^nh ₂ Xb4XU F dХ 0 5 -(3 -((2,4-difluorobenzyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 27 ζ about 8 ωζ X ζ 3 -(((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)methyl)benzonitrile 28 ί °Α ζ 5 -(3 -((4-methoxybenzyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 29 X? 5 -(3 -((4-fluorobenzyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine

- 31 045787

thirty Η Ο.,Ο 6 Υ D and φ 0 Ν-(5-(3 -morpholino-5 - (phenylsulfonyl)phenyl)pyrimidin-2yl)acetamide 31 Ρ ΖΙ / 5 -(3 -(benzylsulfonyl)-5-morpholinophenyl)-Nmethylpyrimide in-2-amine 32 tH ρ-Ό° ο=ω=ο 8 5 -(3 -(benzylsulfonyl)-5 -morpholinophenyl)-4(1fluoromethyl)pyridin-2-amine 33 X ζ /=Υί \з o=w=o 8 5 -(3 -(benzylsulfonyl)-5 -morpholinophenyl)-4(1fluoromethyl)pyrimidin-2-amine 34 ΟΛ^ΥιΥ atf ⁴ ' 0 4-(3 -(benzylsulfonyl)-5 -(2-methylimidazo[1,2a]pyrimidin-6-yl)phenyl)morpholine 35 Η Ckx^XI 0 2-((5-(3 -(benzylsulfonyl)-5 - morpholinophenyl)pyrimidin-2-yl)amino)ethane-1 ol 36 0 A A ζ 5 -(3 -morpholino-5 -((4- morpholinophenyl)sulfonyl)phenyl)pyrimidine-2amine 37 _{l Λ} /Ν^ΝΗ ₂ °\/° ίΓ Υ ί J Ύ J Ν φ 14(4-((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)phenyl)amino)-2- methylpropan-2-ol 38 0—. 0 ^Ν ΝΗ ₂ -Ν «Ι/Υ 0 5 -(3-morpholino-5 -(((tetrahydrofur an-3 yl)methyl)sulfonyl)phenyl)pyrimidin-2-amine 39 ο /Ν ,ΝΗ ₂ 9 1 ιι C Υ 0 5 -(3-morpholino-5 -(((tetrahydro-2H-pyran-4yl)methyl)sulfonyl)phenyl)pyrimidin-2-amine

- 32 045787

40 0 1-ethyl-3-(3'-((4-fluorobenzyl)sulfonyl)-3-methoxy5'-morpholino-[1, G-biphenyl]-4-yl)urea 41 μ ο=ω=ο κ° \_/ ι 3'-((4-fluorobenzyl)sulfonyl)-5'-morpholino-[1, Gbiphenyl]-3-ol 42 0 7-(3 -((4-fluorobenzyl)sulfonyl)-5 - morpholinophenyl)-2H-benzo[b][1,4]oxazin-3(4H)one 43 ^F T1 η ΓΤ°' ^Μβ 0 3'-((4-fluorobenzyl)sulfonyl)-4-methoxy-5'morpholino-[1,1'-biphenyl]-3-amine 44 about MeCL,N. ,ΝΗ ₂ 0 5 -(3 -((4-fluorobenzyl)sulfonyl)-5 morpholinophenyl)-6-methoxypyridin-2-amine 45 Oh ^y. 0 7-(3-((4-fluorobenzyl)sulfonyl)-5 morpholinophenyl)-3,4-dihydro-2Hbenzo[b][1,4]oxazine 46 F _3% 0 4-(5 -((4-fluorobenzyl)sulfonyl)-3'(trifluoromethoxy)-!1,1'-biphenyl]-3-yl)morpholine 47 CM Z $ IZ >= ^z )o 3 N1 -(5 -(3 -((4-fluorobenzyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-yl)ethane-1,2diamine 48 po ο=ω=ο z i? 5 -(3 -(((lH-indol-3-yl)methyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine

- 33 045787

49 τ ζ >= ^{ζ ζ} \ /° ο=ω=ο b 5 -(3 -(cyclohexylsulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 50 ~ρ ο=ω=ο ^ζ =< ζ 5-(3 -((2-fluorobenzyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 51 ο ___ΝΗ ₂ ιι g Τ <zhr% 0 5-(3-morpholino-5 -((tetrahydrofuran-3 yl)sulfonyl)phenyl)pyrimide in-2-amine 52 ο ___ΝΗ ₂ ιι \ Τ Ν ΥϋΧρΥ 0 (R)-5 -(3-morpholino-5 -((tetrahydrofuran-3 yl)sulfonyl)phenyl)pyrimidin-2-amine 53 ο ___ΝΗ ₂ ιι g Τ _Ν OaQ 0 (S)-5 -(3-morpholino-5 -((tetrahydrofuran-3 yl)sulfonyl)phenyl)pyrimidin-2-amine 54 ο ΝΗ ₂ ιι C Υ Sun ° 0 tert-butyl-3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)azetidine-1 carboxylate 55 \ /= ^ζ \ °-ο /Zb·^ /° Ο=ω=ο 4-(3 -((4-fluorobenzyl)sulfonyl)-5 -(5 methoxypyridin-3-yl)phenyl)morpholine 56 CM X Ζ ζ y νΖ^ ^-h CD° °< δ. 5 -(3 -(((Ш-indol-5 -yl)methyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 57 MsHN. o>° ΟΥ)=/ Q N-(4-(((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)methyl)phenyl)methanesulfonamide

- 34 045787

58 0 oX? τ Ύ 5 -(3 -morpholino-5 -((4- morpholinobenzyl)sulfonyl)phenyl)pyrimidine2-amine 59 Ν ΝΗ ₂ I τ <'Υ ό'Ύ^ ην-' 0 5 -(3 -(((1H-imidazol-4-yl)methyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 60 9, Υ ζ 5 -(3 -((cyclohexylmethyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 61 ο ΝΗ ₂ -AcP 0 5 -(3 -(azetidin-3 -ylsulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 62 ο _Χ Ν___ΝΗ ₂ ιι \ Υ ,S. .Ν ΟΓψ^ 0 5 -(3-morpholino-5 -((tetrahydro-2H-pyran-4yl)sulfonyl)phenyl)pyrimidin-2-amine 63 .Ν. .ΝΗ ₂ Ο if η ⁽ _Ν ^υ ° χγ Η 1 0 5-(3-(((1 H-benzo[d]imidazol-5 yl)methyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 64 F ^f Oj^ /=Ν ΟΥυ* Ω 5-(3-(((4,4-difluorocyclohexyl)methyl)sulfonyl)5 -С21H26F2N4O3 8morpholinophenyl)pyrimidine2-amine 65 0 Υ^ ^νη 2 ιι ( Υ yYTiTj 0 5 -(3 -((1 -isopropyl azetidin-3 -yl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 66 ο Μ νη ₂ II X Υ ,ςτΥΎ 0 5 -(3 -morpholino-5 -((1 -(tetrahydro-2H-pyran-4yl)azetidin-3-yl)sulfonyl)phenyl)pyrimidin-2amine 67 ζ Ω ^ζ > ^Η Υ ζ^Ω> O=OT=O 0 8 SP tert-butyl-4-(3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)azetidine-1 - yl)piperidine-1-carboxylate

- 35 045787

68 0 .N^NH ₂ γ^ρ^- 0 1 -(3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)azetidin-1 -yl)ethan1-one 69 0 _n ^^nh ₂ ^МрЛ 0 tert-butyl-3 -((3 -(5 -aminopyrazin-2-yl)-5 morpholinophenyl)sulfonyl)azetidine-1 carboxylate 70 and g ιΓ -dapr^0 5 -(3-morpholino-5 -((tetrahydrofuran-3 yl)sulfonyl)phenyl)-4-(trifluoromethyl)pyridin2-amine 71 O ^f 3C^^.NH ₂ «k# ³ 0 (R)-5 -(3-morpholino-5 -((tetrahydrofuran-3 yl)sulfonyl)phenyl)-4-(trifluoromethyl)pyridin2-amine 72 o/? ^thirty 5 -(3-morpholino-5 -((tetrahydrofuran-3 yl)sulfonyl)phenyl)-4- (trifluoromethyl)pyrimidin-2-amine 73 0 n^^ ^NH 2 R/* 0 5 -(3 -(benzylsulfonyl)-5 morpholinophenyl)pyrazin-2-amine 74 Ο n^^ ^NH2 crapA ¹ * 0 5 -(3-morpholino-5 -((tetrahydrofuran-3 yl)sulfonyl)phenyl)pyrazin-2-amine 75 ο /N___,NH ₂ and g T /\/S. >^.N 'v^aip' ⁰ 1 0 1 -(3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)azetidin-1 yl)propan-1-one 76 o NH ₂ ⁰ I 0 1 -(3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)azetidin-1 -yl)-2methylpropan-1 -one 77 o NH ₂ ¹¹ X v<xhV^ ^{N g} 0 (3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)azetidin-1 yl)(cyclopropyl)methanone

-36045787

78 0 NH ₂ ii\ii lOkg ^F ' 0 1 -(3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)azetidin-1 -yl)-2-(4fluorophenyl)ethan-1 -one 79 0 ^n nh ₂ P o (3 -((3 -(2-aminopyrimide in-5 -yl)-5 morpholinophenyl)sulfonyl)azetidin-1 -yl)(4fluorophenyl)methanone 80 ^F \^O NH ₂ 0 5-(3-(( 1-(4-fluorobenzyl)azetidin-3-yl)sulfonyl)5-morpholinophenyl)pyrimidin-2-amine 81 o ,N^NH ₂ ⁰ 1 0 3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)azetidine-1 carboxamide 82 0 5 -(3 -((4-fluorophenethyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 83 °v° ABOUT 1 -(4-((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)piperidin-1 yl)ethan-1-one 84 ^H0 >L^ Ol>° ^3 ^- C o' “ 1 -((4-(((3 -(2-aminopyrimidin-5 -yl)-5 - morpholinophenyl)sulfonyl)methyl)phenyl)amino)2-methylpropan-2-ol 85 Auxr 0 5-(3-(((2K,68)-2,6-dimethylte1rahydro-2H-pyran-4yl)sulfonyl)-5-morpholinophenyl)pyrimidin-2amine 86 and „P z 1 -(3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)azetidin-1 -yl)-2,2dimethylpropan-1 -one 87 z >= ^z ₄ V? \p co/w 5-(3-((difluoro(phenyl)methyl)sulfonyl)-5morpholinophenyl)pyrimidin-2-amine

- 37 045787

88 τ ζ >=\ LL. 5 -(3 -((4,4-difluorocyclohexyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 89 Ν'-. Ν .NH ₂ HCI AL'? ΐ τ °χχ 0 5 -(3 -((1-isopropylpyrrolidin-3-yl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine hydrochloride 90 ° _ν ο Ο 5 -(3 -((1 -isopropylpiperidin-4-yl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 91 0=/ Λ-, ,ν_,νη ₂ θ' 0 1 -(3 -((3 -(2-aminopyrrimidin-5-yl)-5 morpholinophenyl)sulfonyl)pyrrolidin-1 yl)ethan-1-one 92 0 ΝΗ ₂ УУ^хХ ⁰ 1 0 3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinofsnyl)sulfonyl)-U-(trstbutyl)azetidine-1-carboxamide 93 ο Νη ₂ χβ /DiiL ^U^ac^ ^{0 1} 0 3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)-M-ethyl azetidin-1 carboxamide 94 0 ,Ν..ΝΗ ₂ u ¹¹ \ ιΐ u-Zg ⁰ τ 0 3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinofsnyl)sulfonyl)-M(methoxymethyl)azetidine-1-carboxamide 95 0 ,Д^ ^Ш 2 i diZ 'UZhts^ ⁰ 1 0 3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)-M,Mdimethylazetidine-1-carboxamide 96 θ=ω=θ X ζ ζ 6-(3 -((2,4-difluorobenzyl)sulfonyl)-5 morpholinophenyl)pyride azin-3-amine

- 38 045787

97 0 nh ₂ ] ii ( T IfCX 0 5 -(3-morpholino-5 -((pyridine-4- ylmethyl)sulfonyl)phenyl)pyrimidin-2-amine 98 % ο=ω=ο °0 z -(3 -((2,4-difluorobenzyl)sulfonyl)-5 morpholinophenyl)pyr idin-3-amine 99 <N I z \=z M )° °*r β- 6-(3 -((2,4-difluorobenzyl)sulfonyl)-5 morpholinophenyl)-5-methylpyrid azin-3-amine 100 °^o ₇ „ S' CF ₃ 0 (R)-5 -(3-morpholino-5 -((tetrahydrofuran-3 yl)sulfonyl)phenyl)-3-(trifluoromethyl)pyridin2-amine 101 / ^N o (R)-5 -(3-morpholino-5 -((tetrahydrofuran-3 yl)sulfonyl)phenyl)pyridin-2-amine 102 H 0 ^N _l II\TV ⁰ 1 0 cyclopropyl(3 -((3 -(2- (cyclopropylamino)pyrimidin-5-yl)-5 morpholinophenyl)sulfonyl)azetidin-1 yl)methanone 103 H <F|4 0 K[-cyclopropyl-5 -(3-morpholino-5 ((tetrahydrofuran-3 yl)sulfonyl)phenyl)pyrimidin-2-amine 104 Q ° fVv Ws _x Al ^v sQ 0 5 -(3 -(benzylsulfonyl)-5 -morphol inophenyl)-Mcyclopropylpyrimidin-2-amine 105 aOu vlpFj 0 (R)-5 -(3-morpholino-5 -((tetrahydrofuran-3 yl)sulfonyl)phenyl)-6-(trifluoromethyl)pyridin2-amine

- 39 045787

106 o f^^nh ₂ and Υ ϊ vjyiQj 0 (C)-4-fluoro-5-(3-morpholino-5-((tetrahydrofuran3-yl)sulfonyl)phenyl)pyridin-2-amine 107 o ci\^^NH ₂ and YT °uyTQT^ 0 (R)-4-xnop-5 -(3-morpholino-5 -((tetrahydrofuran-3 yl)sulfonyl)phenyl)pyridin-2-amine 108 Q ο=ω=ο z=r Φ (R)-N-methyl-5-(3-morpholino-5-((τeτpahydropyran3-yl)sulfonyl)phenyl)pyridin-2-amine 109 0 /N^NHa A\ II Г T 4nYv O ^J 0 0 5 -(3 -(benzofuran-3 -ylsulfonyl)-5 morpholinophenyl)pyrimidin-2-amine BY r~n 0 NH ₂ Ш 0 5 -(3 -(benzofuran-7-ylsulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 111 C^° 0=0)=0 O^Q Hz ^z =< z 5 -(3 -((2,3-dihydrobenzofuran-7-yl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 112 0 ^N_NH ₂ II\T n .N OOTQ> 0 5 -(3 -(benzofuran-6-ylsulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 113 M Z Y ^z zp z( \з °< (E)-2-(2-((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)vinyl)phenol 114 o.fO __/ ^v o O^O Hz H z 5= 5 -(3 -((III-indol-3-yl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine

-40045787

115 cm T Z z 2 '°'b 5-(6-morpholino-4-(phenylsulfonyl)pyridin-2yl)pyrimidin-2-amine 116 t Z k* Z y /””4— Z e °\/^ ^x — ^/ “S 5 -(3 -((2,3-dihydrobenzofuran-6-yl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 117 .NH, О _h /° Г Т 0 5-(4-morpholino-6-(phenylsulfonyl)pyridin-2yl)pyrimide in-2-amine 118 .N. .NH ₂ zXJQ u γ 0 5-(2-morpholino-6-(phenylsulfonyl)pyridin-4yl)pyrimide in-2-amine 119 .N___NH ₂ Οχ/9 Hn _: 5 -(3 -((2,3 -dihydrobenzofuran-3 -yl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 120 P O 5-(6-morpholino-4-phenoxypyridin-2yl)pyrimide in-2-amine 121 z (K)-4-methyl-5 -(3-morpholino-5 -((tetrahydrofuran3-yl)sulfonyl)phenyl)pyrimidin-2-amine 122 nh ₂ N^NV Π XL ⁰ k/θ (2-(2-aminopyrimidin-5-yl)-6- morpholinopyridin-4-yl)(phenyl)methanone

- 41 045787

123 0 5-(4-(difluoro(phenyl)methyl)-6-morpholinopyridin2-yl)pyrimide in-2-amine 124 nh ₂ N^N ψ a XX 5 -(4-benzyl-6-morpholinopyridin-2yl)pyrimide in-2-amine 125 nh ₂ V a xx Cx° 5-(6-morpholino-4-(1-phenylethyl)pyridin-2yl)pyrimide in-2-amine 126 nh ₂ nC _n X^Q 5-(6-morpholino-4-(1-phenylvinyl)pyridin-2yl)pyrimide in-2-amine 127 nh ₂ N^NV a X a 5 -(6-morpholino-4-( 1 -phenylcyclopropyl)pyridin2-yl)pyrimide in-2-amine 128 X\ 0 5-(4-(4-chloro-3-(trifluoromethyl)phenoxy)-6morpholinopyridin-2-yl)pyrimidin-2-amine 129 0 ⁰ 1 aXx n*Ch ₂ (3 -((2-(2-aminopyrimidin-5-yl)-6morpholinopyridin-4-yl)oxy)azetidin-1 yl)(cyclopropyl)methanone 130 A °G ^z <4 o about 5 -(6-morpholino-4-((te1rahydrofuran-3 yl)oxy)pyridin-2-yl)pyrimidin-2-amine

-42 045787

131 °\O (2-(2-aminopyrimidin-5-yl)-6- morpholinopyridin-4-yl)(tetrahydro-2H-pyran-4yl)methanone 132 X Z \ ^z ύ o H 5-(4-(4-chloro-3-(trifluoromethyl)phenoxy)-6morpholinopyridin-2-yl)pyrimidin-2-amine 133 νη ₂ Ν^Ν V ι^Ν i 1 L if ^FF 5-(4-(difluoro(tetrahydro-2H-pyran-4-yl)methyl)-6morpholinopyridin-2-yl)pyrimidin-2-amine 134 y o SG ^b 5-(4-(2-chlorophenoxy)-6-morpholinopyridin-2yl)pyrimide in-2-amine 135 o ζ Α Υ ^ζ 5-(4-(2-methoxyphenoxy)-6-morpholinopyridin-2yl)pyrimide in-2-amine 136 0 F ₃ C' ^Ν^ΝΗ ₂ 5 -(6-morpholino-4-(2- (trifluoromethoxy)phenoxy)pyridin-2yl)pyrimide in-2-amine 137 0 ςν%. ^Me ^Χνη ₂ 5-(6-morpholino-4-(o-tolyloxy)pyridin-2yl)pyrimide in-2-amine 138 0 ΟυόχτιΓ^ιί^ ^Ν 01 0 X -ίΧ Ν ΝΗ ₂ (2-(2-aminopyrimidin-5-yl)-6- morpholinopyridin-4-yl)(2-chlorophenyl)methanone 139 0 9xXq Ν ΝΗ ₂ 5-(4-((2-chlorophenyl)sulfonyl)-6- morpholinopyr idin-2-yl)pyrimidin-2-amine

- 43 045787

140 t Z /H \ ^z (I 5-(4-(3,4-dihydroquinolin-1(2H)-yl)-6- morpholinopyridin-2-yl)pyrimidin-2-amine 141 with Υ|1 Ν ΝΗ ₂ 5-(4-(chroman-4-yl)-6-morpholinopyridin-2yl)pyrimide in-2-amine 142a η 0 ΝΗ ₂ Γ ,ί 0 (8)-5-(6-morpholino-4-((te1rahydrofuran-3- yl)sulfonyl)pyridin-2-yl)pyrimidin-2-amine 142b ζόΥΧιΓ ο; ζ ΥΥ 0 (K)-5-(6-morpholino-4-((tetrahydrofuran-3- yl)sulfonyl)pyridin-2-yl)pyrimidin-2-amine 143 ιΥ ^Η2 I' 5-(4-(chroman-4-ylsulfonyl)-6- morpholinopyr idin-2-yl)pyrimidin-2-amine 144 0 6-morpholino-4-(phenylsulfonyl)-4'- (1fluoromethyl)-[2,3'-bipyridine]-6'-amine 145 V Λτν 0 N-(5-(6-morpholino-4-(phenylsylphonyl)pyridin2-yl)pyrimidin-2-yl)acetamide 146 and rg 0 N-cyclopropyl-5-(6-morpholino-4(phenylsulfonyl)pyridin-2-yl)pyrimidin-2amine 147 Μ___ΝΗ ₂ Ο _4/ Ο 6 Τ ΚΎ 5 -(4-((2,3-dihydrobenzofuran-3-yl)sulfonyl)-6morpholinopyridin-2-yl)pyrimidin-2-amine 148 γ<_α ^ΝΗ 0 5-(6-morpholino-4-((te1rahydro-2H-pyran-4yl)sulfonyl)pyridin-2-yl)pyrimidin-2-amine 149 Ν ΝΗ ₂ zJLUCT °CmQj 0 (2-(2-aminopyrimidin-5-yl)-6- morpholinopyridin-4-yl)(te1rahydrofuran-3yl)methanone 150 _Λ ,Ν. ^ΝΗ, W Г ¥ and XX Χλ 5-(6-(2,6-dimethylmorpholino)-4- (phenylsulfonyl)pyr idin-2-yl)pyrimidin-2amine 151 „ ,Ν _ΝΗ ₂ ¥ν%Χΐ and ττ 6 5 -(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4(phenylsulfonyl)pyridin-2-yl)pyrimidin-2amine

and pharmaceutically acceptable salts thereof.

Any formula or compound presented herein, for example, formula (I),

- 44 045787 (II) or (III), or compounds from table. 1 are intended to denote compounds having the structures depicted by this structural formula, as well as certain variations or forms. In particular, compounds of any formula presented herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of compounds of the given general formula, as well as mixtures thereof in any ratio, are considered to be within the scope of the specified formula. Thus, any formula provided herein is intended to denote a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. If the connection from the table 1 is depicted in a specific stereochemical configuration, this document also provides any alternative stereochemical configuration of a given compound, as well as mixtures of stereoisomers of a given compound in any ratio. For example, if the connection from the table. 1 has a stereocenter that is in the stereochemical configuration S, then this document also provides an enantiomer of this compound in which the specified stereocenter is in the stereochemical configuration R. Likewise, if the compound from Table. 1 has a stereocenter that is in configuration R, then this document also provides an enantiomer of this compound in stereochemical configuration S. Also provided are mixtures of the compound in stereochemical configuration S and R. In addition, if the compound from Table. 1 has two or more stereocenters, then any enantiomers or diastereomers of this compound are also represented. For example, if the connection from the table. 1 contains a first stereocenter and a second stereocenter with stereochemical configurations R and R, respectively, stereoisomers of this compound are also presented having first and second stereocenters with stereochemical configurations S and S, respectively, with stereochemical configurations S and R, respectively, and with stereochemical configurations R and S, respectively. If the connection from the table 1 contains a first stereocenter and a second stereocenter with stereochemical configurations S and S, respectively, stereoisomers of this compound are also presented having first and second stereocenters with stereochemical configurations R and R, respectively, with stereochemical configurations S and R, respectively, and with stereochemical configurations R and S, respectively. If the connection from the table 1 contains a first stereocenter and a second stereocenter with stereochemical configurations S and R, respectively, stereoisomers of this compound are also presented having first and second stereocenters with stereochemical configurations R and S, respectively, with stereochemical configurations R and R, respectively, and with stereochemical configurations S and S, respectively. Similarly, if the connection from the table. 1 contains a first stereocenter and a second stereocenter with stereochemical configurations R and S, respectively, stereoisomers of this compound are also presented having first and second stereocenters with stereochemical configurations S and R, respectively, with stereochemical configurations R and R, respectively, and with stereochemical configurations S and S, respectively. In addition, some structures may exist in the form of geometric isomers (ie, cis and trans isomers), tautomers, or atropisomers. In addition, any compound from the table. 1 is intended to mean a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. In addition, some structures may exist as geometric isomers (ie, cis and trans isomers), tautomers, or atropisomers. In addition, any formula presented herein, such as formula (I), (II) or (III), is intended to denote hydrates, solvates and amorphous forms of such compounds and mixtures thereof, even if such forms are not expressly listed . In some embodiments, the solvent is water and the solvates are hydrates.

The compounds of formula (I), (II) or (III) can be prepared and/or formulated in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts are non-toxic salts of a compound in free base form that have the desired pharmacological activity of said free base. In some embodiments, pharmaceutically acceptable salts include acid addition salts made with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or prepared with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butine-1,4-dioates, hexine-1,6-dioates, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propyl sulfonates, besylates, xylene sulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, edisylates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates and mandelates. In some embodiments, pharmacists

- 45 045787 commercially acceptable salts are formed by replacing the acidic proton present in the parent compound with a metal ion, for example an alkali metal ion, an alkaline earth metal ion or an aluminum ion; or when it coordinates with an organic base. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2- diethylaminoethanol, tromethamine, trimethamine, dicyclohexylamine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-ethylglucamine, N-methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, amino acids such as lysine , arginine, histidine, etc. Examples of pharmaceutically acceptable base addition salts include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like. In some embodiments, the organic non-toxic bases are L-amino acids such as L-lysine and L-arginine, tromethamine, N-ethylglucamine and N-methylglucamine. Suitable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide and the like. A list of other suitable pharmaceutically acceptable salts is provided in Remington, Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pennsylvania, 1985.

For a compound described herein that contains a basic nitrogen atom, a pharmaceutically acceptable salt may be prepared by any suitable method known in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid acid, nitric acid, boric acid, phosphoric acid and the like, or an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidylic acid such as glucuronic acid or galacturonic acid, alpha hydroxy acid such as mandelic acid acid, citric acid or tartaric acid, amino acid such as aspartic acid or glutaric acid, aromatic acid such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid, sulfonic acid such as lauryl sulfonic acid, p-toluene sulfonic acid, methanesulfonic acid, benzenesulfonic acid, ethanesulfonic acid or ethanedisulfonic acid, or any compatible mixture of acids, such as the mixtures described in the examples presented herein, and any other acid and mixture thereof that are considered equivalent or acceptable substitutes in light of the general state of knowledge in this technology.

The provided embodiments also provide pharmaceutically acceptable prodrugs of the compounds described herein, as well as methods of treatment using said pharmaceutically acceptable prodrugs.

The term prodrug means a precursor of the specified compound, which, upon administration to a subject, forms the specified compound in vivo through a chemical or physiological process, such as solvolysis or enzymatic degradation, or under physiological conditions (for example, when the prodrug is exposed to physiological pH, it is converted into a compound of formula (I) ). A pharmaceutically acceptable prodrug is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject. Exemplary methods for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. N. Bundgaard, Elsevier, 1985.

The proposed embodiments also relate to pharmaceutically active metabolites of the compounds described herein and to the use of such metabolites in the methods provided herein. Pharmaceutically active metabolite means a pharmacologically active product of metabolism in the body of a compound described herein or a salt thereof. Prodrugs and active metabolites of a compound can be determined using standard techniques known or available in the art. For example, see Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86(7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design of Products (Elsevier Press, 1985); and Larsen, Design and Application of Products, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

Pharmaceutical compositions.

For use in treatment, the pharmaceutical composition of the present invention contains at least one compound of formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions may further contain one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipient

- 46 045787 is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate the administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, coloring agents, fillers, emulsifiers or flavor modifying agents. In some embodiments, the pharmaceutical compositions of the present embodiments are sterile compositions. Pharmaceutical compositions can be prepared using compounding techniques known or available to those skilled in the art.

Sterile compositions are also contemplated by the proposed embodiments, including compositions that comply with national and local regulations establishing requirements for such compositions.

The pharmaceutical compositions and compounds described herein may be formulated in dosage forms of solutions, emulsions, dispersions or inclusion complexes, such as inclusion complexes of cyclodextrins, in suitable pharmaceutical solvents or carriers, or in the form of pills, tablets, troches, suppositories, sachets , dragees, granules, powders, powders for reconstitution or capsules, together with solid carriers in accordance with standard methods known in the field of obtaining various dosage forms. Pharmaceutical compositions, according to the proposed embodiments, can be administered by a conventional route of delivery, such as oral, parenteral, rectal, nasal, topical or ophthalmic route of administration, or by inhalation. In some embodiments, the compositions are formulated for intravenous or oral administration.

For oral administration, the compounds according to the proposed embodiments may be presented in solid form, such as a tablet or capsule, or in the form of a solution, emulsion or suspension. For the preparation of oral compositions, the compounds according to the proposed embodiments can be formulated to provide a dose of, for example, from about 0.01 to about 50 mg/kg per day, or from about 0.05 to about 20 mg/kg per day, or from about 0.1 to about 10 mg/kg per day. Tablets for oral administration may contain the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrants, binding agents, lubricants, sweeteners, flavorings, coloring agents and preservatives. Suitable excipients include sodium calcium carbonate, sodium calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol and the like. Exemplary liquid oral excipients include ethanol, glycerin, water, and the like. Exemplary disintegrants are starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose and alginic acid. Binding agents may include starch and gelatin. The lubricant, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption from the gastrointestinal tract, or may be coated with an enteric coating.

Oral capsules include hard and soft gelatin capsules. To prepare hard gelatin capsules, the active ingredient(s) may be mixed with a solid, semi-solid or liquid diluent. Soft gelatin capsules can be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono- and diglycerides of short-chain fatty acids, polyethylene glycol 400 or propylene glycol.

Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups, or may be lyophilized and presented in dry product form for reconstitution with water or other suitable carrier before use. Such liquid compositions may optionally contain: pharmaceutically acceptable excipients such as suspending agents (eg, sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous vehicles, such as oil (eg, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if necessary, flavoring or coloring agents.

The compositions of the present invention may be formulated for rectal administration in the form of suppositories. For parenteral administration, including intravenous, intramuscular, intraperitoneal, intranasal or subcutaneous routes of administration, the agents, according to the proposed embodiments, can be presented in sterile aqueous solutions or suspensions, buffered to a suitable pH and isotonicity, or in a parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride solution. Such forms may be presented in single dosage form, such as ampoules or single-use injection devices, or in multi-dose forms, such as vials from which the appropriate dose can be extracted, or in solid form or in the form of a preconcentrate, which can be used to obtain a dosage form for injection. Exemplary infusion doses range from about 1 to 1000 mcg/kg/min. agent mixed with a pharmaceutical carrier for a period of time ranging from several minutes to several days.

For nasal, inhalation or oral administration, the pharmaceutical compositions of the present invention can be administered using, for example, a spray dosage form also containing a suitable carrier.

For topical use, the compounds according to the proposed embodiments are preferably formulated in the form of creams or ointments, or a similar carrier suitable for topical use. For topical administration, the compounds of the present invention can be mixed with a pharmaceutical carrier at a concentration of from about 0.1% to about 10% of the drug compound relative to the carrier. Another method of administering agents according to the proposed embodiments may use a patch dosage form to provide transdermal delivery.

As used herein, the terms treat or treatment include both preventive and curative treatment. Preventive treatment means delaying the development of a disease, symptom of a disease or medical condition, suppressing symptoms that may occur, slowing the worsening or progression of a disease, disorder or symptom, or reducing the risk of developing or relapse of a disease or symptom. Curative treatment involves reducing the severity or controlling the worsening of an existing disease, symptom, or condition. Thus, treatment includes alleviating or preventing the worsening of existing symptoms of a disease, preventing the occurrence of additional symptoms, alleviating or preventing underlying systemic causes of symptoms, slowing down the disorder or disease, e.g., stopping the progression of the disorder or disease, alleviating the disorder or disease, initiating regression of the disorder or disease, relief of a condition caused by a disease or disorder, or cessation of symptoms of a disease or disorder.

The term subject refers to a mammalian patient in need of such treatment, such as a human.

Exemplary neurodegenerative diseases that may be therapeutic targets for PI3K-AKT-mTOR pathway modulators include Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, PD dementia, multiple system atrophy, Huntington's disease, and amytrophic lateral sclerosis. In addition to neurodegenerative disorders, compounds that modulate the PI3K-AKT-mTOR pathway may also have applications in the treatment of cancer (particularly prostate, colon, pancreatic, and kidney), infections, Crohn's disease, heart disease, and aging.

In one aspect, the compounds and pharmaceutical compositions of the present invention specifically target PI3K, AKT and/or mTOR. Thus, these compounds and pharmaceutical compositions, by preventing, reversing, slowing or inhibiting the PI3K-AKT-mTOR pathway, can provide treatment for degenerative neurological diseases associated with or caused by dysregulation of autophagy, for example, such as insufficient clearance of protein aggregates and/or damaged organelles , insufficient activation of the survival mechanism of gene expression and/or insufficiency of cellular energy balance. Preferably, the methods of the present invention are directed to neurodegenerative diseases associated with the PI3K-AKT-mTOR cascade. In preferred embodiments, the proposed methods of treatment are directed to Parkinson's disease, Alzheimer's disease, Lewy body disease, multiple system atrophy or Huntington's disease. In other embodiments, the methods of the present invention are directed at peripheral degenerative disorders associated with the PI3K-AKT-mTOR cascade. In some embodiments, the proposed methods of treatment are directed at Paget's disease, Charcot-Marie-Tooth disease, macular degeneration, or cardiomyopathy. The compounds, compositions and methods of the present invention are also useful in reversing autophagy-inhibitory detrimental effects such as insufficient clearance of protein aggregates or damaged organelles. Although the present invention is not limited to any particular mechanism of action, dysregulation of autophagy is believed to be due to alpha-synuclein and/or beta-amyloid.

In the methods of the proposed embodiments, an effective amount of a PI3K-AKT-mTOR modulator means an amount sufficient to alter the phosphorylation of components of the PI3K-AKT-mTOR pathway, alter the expression of survival genes regulated by the pathway, improve the energy balance of the cell, increase autophagy markers, and/ or reducing the accumulation of protein aggregates. Measurement of one or more of these PI3KAKT-mTOR pathway modulation markers can be accomplished by standard analytical methods, such as those described below, which are suitable for many conditions, including in vitro assays.

- 48 045787

In methods of treatment according to the proposed embodiments, an effective amount means an amount or dose generally sufficient to achieve the desired therapeutic effect in subjects in need of such treatment. Effective amounts or doses of active compounds, according to the proposed embodiments, can be determined by standard methods, such as modeling, dose escalation studies, or clinical trials, taking into account conventional factors, for example, the mode or route of administration or delivery of the drug compound, pharmacokinetics of the agent, severity and the course of the infectious disease, the subject's health status, the subject's pathological condition and weight, and the decisions of the attending physician. An exemplary dose is from about 1 μg to 2 mg of active agent per kilogram of subject body weight per day, preferably from about 0.05 to 100 mg/kg/day, or from about 1 to 35 mg/kg/day, or from about 0. 1 to 10 mg/kg/day. The total dose may be administered as a single dose or in divided doses (eg, BID, TID, QID).

Once relief of the patient's illness occurs, the dose may be adjusted to provide preventive or maintenance treatment. For example, depending on the symptoms, the dose or frequency of administration, or both, can be reduced to a level that maintains the desired therapeutic or prophylactic effect. Of course, if the symptoms are reduced to an appropriate level, then treatment can be stopped. However, patients may require intermittent treatment on a long-term basis for any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.

Combinations of drugs.

The compounds of the present invention described herein can be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients for the treatment of neurodegenerative disorders. For example, additional active ingredients are those that are known or developed compounds effective for the treatment of neurodegenerative disorders, including compounds active against another target associated with said disease, such as, but not limited to, a) compounds that act against protein misfolding (such as drugs that reduce the production of such proteins, thereby increasing their clearance, or that alter their aggregation and/or distribution); b) compounds that treat symptoms of such disorders (eg, dopamine replacement therapy, cholinesterase inhibitors and precognitive glutamatergic drugs); and c) drugs that act as neuroprotectors through a complementary mechanism (eg, those that target autophagy, those that are antioxidants, and those that act through other mechanisms such as adenosine A2A antagonists).

For example, additional active ingredients are those that are known or established to be effective in the treatment of neurodegenerative disorders, including those that are active against another target associated with the disease, such as, but not limited to, a) compounds that target various protein misfolding mechanisms (such as aggregation and/or propagation); b) compounds that treat symptoms of such disorders (eg, dopamine replacement therapy); and c) drugs that act as neuroprotectors through a complementary mechanism (eg, those targeting autophagy, antioxidants, and adenosine A2A antagonists).

For example, the compositions and dosage forms of the proposed embodiments, as well as methods of treatment, may further include other drugs or pharmaceuticals, such as other active agents, suitable for treating or ameliorating a degenerative neurological disease associated with or caused by protein aggregation, e.g. aggregation of synuclein, beta-amyloid and/or tau protein, for example Parkinson's disease, Alzheimer's disease (AD), Lewy body disease (LBD) and multiple system atrophy (MSA), or related symptoms or pathological conditions. In this regard, the compositions and dosage forms of the exemplary and specific compounds described herein are useful in methods of treating Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, PD dementia, multiple system atrophy, Huntington's disease, amyotrophic lateral sclerosis , cancer, infection, Crohn's disease, heart disease, Paget's disease, Charcot-Marie-Tooth disease, macular degeneration, cardiomyopathy and aging. Pharmaceutical compositions, according to the proposed embodiments, may further contain one or more such active agents, and methods of treatment may further include administering an effective amount of one or more such active agents. In some embodiments, the additional active agents may be antibiotics (e.g., antibacterial or bacteriostatic peptides or proteins), e.g., those effective against gram-positive or negative bacteria, liquid preparations, cytokines, immunoregulatory agents, anti-inflammatory agents, complement-activating agents , such as peptides or proteins containing collagen-like domains or fibrinogen-like domains (eg, fiolin), carbohydrate-binding domains, etc., as well as combinations thereof. Additional active agents include those useful in

- 49 045787 such compositions and methods, and exclude dopamine therapy drugs, catechol-Omethyltransferase inhibitors, monoamine oxidase inhibitors, cognitive function correctors (such as acetylcholinesterase inhibitors or memantine), adenosine 2A receptor antagonists, beta-secretase inhibitors or gamma-secretase inhibitors. In specific embodiments, at least one compound according to the proposed embodiments can be combined in a pharmaceutical composition or method of treatment with one or more drugs selected from the group consisting of: tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon ), galantamine (Reminyl), physostigmine, neostigmine, icopesil (CP-118954, 5,7-dihydro-3-[2-[1-(phenylmethyl)-4piperidinyl]ethyl]-6H-pyrrolo-[4,5-G ]-1,2-benzisoxazol-6-one maleate), ER-127528 (4-[(5,6-dimethoxy-2fluoro-1-indanone)-2-yl]methyl-1-(3-fluorobenzyl)piperidine hydrochloride ), zanapezil (TAK-147; 3-[1(phenylmethyl)piperidin-4-yl]-1 -(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propane fumarate ), metrifonate (T-588; (-)-R-alpha-[[2-(dimethylamino)ethoxy]methyl]benzo[b]thiophene-5-methanol hydrochloride), FK-960 (N-(4-acetyl- 1-piperazinyl)-p-fluorobenzamide hydrate), TSN-346 (N-methyl-N-2pyropinyldibenz[b,f]oxepin-10-methanamine), SDZ-220-581 ((S)-alpha-amino-5- (phosphonomethyl)-[1,1'biphenyl]-3-propionic acid), memantine (Namenda/Exiba) and 1,3,3,5,5-pentamethylcyclohexan-1amine (Neramexane), tarenflurbil (Flurizan), tramiprosate (Alzhemed ), clioquinol, PBT-2 (8-hydroxyquinilone derivative), 1-(2-(2-naphthyl)ethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, huperzine A, posatyrelin, leuprolide or its derivatives, ispronicline, (3-aminopropyl)(nbutyl)phosphinic acid (SGS-742), N-methyl-5-(3-(5-isopropoxypyridinyl))-4-penten-2-amine (ispronicline), internal salts of N-(2-hydroxy-3-sulfopropyl)-N-methyl-N-octyl-1-decanaminium (zt-1), salicylates, aspirin, amoxyprin, benorylate, cholinemagnesium salicylate, diflunisal, faislamin, methyl salicylate, magnesium salicylate , salicyl salicylate, diclofenac, aceclofenac, acemetacin, bromfenac, etodolac, indomethacrine, nabumetone, sulindac, tolmetin, ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketoprofen, ketorolac, loxoprofen, naproxen, tiaprofen acid, suprofen, mefenamic acid, meclofenamic acid, phenylbutazone, azapropazone, metamizole, oxyphenbutazone, sulfinprazone, piroxicam, lornoxicam, meloxicam, tenoxicam, celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, nimesulide, arylalkanoic acids, 2-arylpropionic acids (profens), N- arylanthranilic acids (phenamic acids ), pyrazolidine derivatives, oxicams, COX-2 inhibitors, sulfonanilides, essential fatty acids and minozac (2-(4-(4-methyl-6-phenylpyridazin-3-yl)piperazin-1yl)pyrimidine dihydrochloride hydrate). Such a combination may serve to increase efficacy, alleviate other symptoms of a disease, reduce one or more side effects, or reduce the required dose of a compound of this invention. The additional active ingredients may be administered in a separate pharmaceutical composition, separate from the compound of the embodiments, or they may be included in the same pharmaceutical composition with the compound of the embodiments. Additional active ingredients can be administered simultaneously, before or after administration of the compound of formula (I).

Methods of application

The compounds and pharmaceutical compositions described herein can be used to treat or prevent a disease or condition in an individual. In some embodiments, methods are provided for treating a disease or condition associated with autophagy or the PI3K-AKT-MTOR cascade, comprising administering to an individual in need thereof a compound of formula (I), (II) or (III) or a compound from Table 1 , or a pharmaceutically acceptable salt of any of them. In some embodiments, methods are provided for treating a disease or condition associated with autophagy or the PI3K-AKTMTOR cascade, comprising administering to a subject a therapeutically effective amount of at least one chemical compound described herein.

In some embodiments, compositions are provided containing one or more of the compounds of formula (I), (II) or (III) or a compound from table. 1, or a pharmaceutically acceptable salt of any of them, for use in the treatment of a disease or pathological condition associated with autophagy or the PI3K-AKT-MTOR cascade. In some embodiments, compositions are provided containing at least one chemical compound described herein for use in treating a disease or condition associated with autophagy or the PI3K-AKT-MTOR cascade. In some embodiments, the disease or medical condition is a neurodegenerative disorder. In other embodiments, the disease or medical condition is a peripheral degenerative disorder. In some embodiments, the disease or medical condition is Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Lewy body dementia, PD dementia, multiple system atrophy, Huntington's disease, amyotrophic lateral sclerosis, cancer, infection, Crohn's disease, heart disease , Paget's disease, Charcot-Marie-Tooth disease, macular degeneration, cardiomyopathy or aging.

Also provided herein is the use of a compound of formula (I), (II) or (III) or

- 50 045787 compounds from table. 1, or pharmaceutically acceptable salts thereof, for the production of a medicament for the treatment of a disease or pathological condition associated with autophagy or the PI3K-AKT-MTOR cascade. In some embodiments, the use of at least one chemical compound described herein is provided for the production of a medicament for treating a disease or condition associated with autophagy or the PI3K-AKT-MTOR cascade.

In some embodiments, the disease or medical condition is a neurodegenerative disorder. In other embodiments, the disease or medical condition is a peripheral degenerative disorder. In some embodiments, the disease or condition is selected from Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Lewy body dementia, PD dementia, multiple system atrophy, Huntington's disease, amyotrophic lateral sclerosis, cancer, infection, Crohn's disease, heart disease , Paget's disease, Charcot-Marie-Tooth disease, macular degeneration, cardiomyopathy and aging.

Also provided are methods of interfering with the PI3K-AKT-MTOR cascade in a cell or modulating, preventing, slowing, reversing or inhibiting the PI3K-AKT-MTOR cascade in a cell, which include contacting the cell with an effective amount of at least one of the compounds of formula (I ), (II) or (III) or compounds from table. 1, or a pharmaceutically acceptable salt thereof. In some embodiments, methods are provided for interfering with the PI3KAKT-MTOR cascade in a cell or modulating, preventing, slowing, reversing, or inhibiting the PI3K-AKT-MTOR cascade in a cell, which comprise contacting the cell with an effective amount of at least one chemical compound, described in this document.

Also provided herein are compositions containing one or more of the compounds of formula (I), (II) or (III) or a compound from Table. 1, or a pharmaceutically acceptable salt of any of them, for use in interfering with the PI3K-AKT-MTOR cascade in a cell or modulating, preventing, delaying, reversing or inhibiting the PI3K-AKT-MTOR cascade in a cell. In some embodiments, compositions are provided comprising at least one chemical compound described herein for use in interfering with the PI3KAKT-MTOR cascade in a cell or modulating, preventing, delaying, reversing, or inhibiting the PI3K-AKT-MTOR cascade in a cell .

This document further provides the use of at least one chemical compound described herein, such as a compound of formula (I), (I) or (III) or a compound from table. 1, or a pharmaceutically acceptable salt of any of them, for the manufacture of a medicament for interfering with the PI3K-AKT-MTOR cascade or modulating, preventing, delaying, reversing or inhibiting the PI3K-AKT-MTOR cascade.

Sets.

Also provided are manufactured articles and kits containing any of the compounds and pharmaceutical compositions disclosed herein. A manufactured product may be a container with a label. Suitable containers include, for example, bottles, vials and test tubes. Containers can be made from various materials such as glass or plastic. The container may contain a pharmaceutical composition as provided herein. The label of the container may indicate that the pharmaceutical composition is intended to prevent, treat, or suppress the pathological condition described herein, and may also provide instructions for in vivo or in vitro use.

In one aspect, provided herein are kits containing a compound or composition described herein and instructions for use. The kits may contain instructions for use for treating a disease or condition associated with the PI3K-AKT-MTOR cascade in an individual in need thereof. The kit may further contain any materials or equipment that can be used to administer the compound or composition, such as vials, syringes, or IV infusion bags. The kit may also include sterile packaging.

Chemical synthesis.

The proposed embodiments also relate to methods and intermediates useful for preparing the subject compounds or their salts or solvates or stereoisomers.

There are many general references that present well-known chemical synthesis schemes and conditions applicable to the synthesis of the described compounds (e.g., Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, fifth edition, Wiley-Interscience, 2001).

The compounds described herein can be purified by any methods known in the art, including chromatographic methods such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reverse phases, as well as ion exchange resins. Most often, the described compounds are purified by chromatography on silica gel and/or alumina. See, for example, Introduction to Modern Liquid Chromatography, 2nd ed., ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; And

Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

During any processes for preparing the subject compounds, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the subject molecules. This can be achieved using conventional protecting groups described in standard scientific works such as T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 4th ^ed ., Wiley, New York, 2006. Protecting groups can be removed at a suitable subsequent stage by methods known in the art.

Illustrative chemical compounds suitable for the methods according to embodiments of the present invention are described below with reference to illustrative synthetic schemes intended to describe general methods for their preparation, as well as specific examples presented below. Those skilled in the art will appreciate that for the preparation of the various compounds described herein, the starting materials may be selected to provide the reaction scheme with the resulting substituents required, with or without the use of protection, as appropriate, to obtain the desired product. . Alternatively, in place of the ultimately required substituent, it may be necessary or desirable to use a suitable group that can be used in the reaction scheme and, if necessary, substituted with the desired substituent.

In addition, those skilled in the art will appreciate that the transformations shown in the following diagrams can be performed in any order consistent with the functionality of the particular pendant groups. Each reaction shown in the general diagrams is preferably carried out at a temperature from about 0° C. to the boiling point of the organic solvent used. Unless otherwise stated, all variables are as described above with reference to Formula (I). The isotopically tagged compounds described herein are prepared by the methods described below using appropriate tagged starting materials. Such materials are usually available from commercial suppliers of radiolabeled chemicals.

Exemplary methods for the synthesis of compounds of formula (I) are described in Schemes 1-3 and A-Q, as well as in the specific examples presented below.

In some embodiments, the compounds provided herein can be synthesized according to Scheme 1.

Scheme 1.

where R ¹ , R ⁷ , R ⁸ , Y1, Y ₂ , Y ₃ , G ₂ , G ₃ , G ₄ , G5, G ₆ and X are as described for formula (I), (II), (III ) or any variants thereof described herein, v is 2 or 3, and R is -OH, -O-alkyl or halogen, or -BR _v is

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

- 52 045787

Set it to 4

Scheme A.

Put ί

ABOUT, ,

R ¹ ,O

Cl

1) RRPz, SVg ₄

2) AsZK 3) S1 ₂

R ₍ -OH

Set it to 2

Set it to 3

Na _? SOj,H _? O, MaNSO _3.2 h

R„B

Vg

ABOUT.

R ¹

Vg

O~Na' _______ X

Cu(OAc)g, Oz, _Kg CO _e , DMSO, 2-7 days (34%, 2 stages)

Ar—BR,

R< ^S

Ar where Ar represents

0^2 , ^G 3 ^G 6

G3-Pd-XPhos Xphos K ₃ PO ₄ , THF, eb°s, 1 hour (50-95%) ^5 and R ¹ , G2, G ₃ , G ₄ , G5, G6 and X are as described for formula (I), (II), (III) or any variants thereof described herein, v is 2 or 3, and R is -OH, -O-alkyl or halogen, or -BRv is

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

Scheme B.

Stage 4

a) Ar—BR, 6

GS-Pd-XPhos Xphos, KjPO ₄ , THF, 85 C, 1 Part.

Stage 6 a)AcjO, DIPEA b) ^0(0)0,

DIPEA OR Et ₃ N

C) R ⁴ C(O)R ⁵ , Na(OAc) ₃ BH, DCE

d) R ³ NCO, EbN.flXM

Stage 5 if r'= N-Bqc

TPA, DXM 0“S-room. t-ra, 2 hours.

Stage 6

a) AsgO. DIPEA

b) R ² G(O)GI,

DIPEA OR EbN >.

c) FfCXOjR ⁵ , NafOAchBH. EDC

d) R ^S NGO, EtjN, DXM

R*

aJGS-Pd-XPhos Xphos, KiPO*.

OR

b) Pd(dbab K ₃ PO ₄

OR

c) PDF dppf)QI ₂

KgCO ₅

where Ar represents

and R ¹ , G ₂ , G ₃ , G ₄ , G5 , G ₆ , X, and R ^x are as described for formula (I), (II), (III) or any variants thereof described herein , v is 2 or 3, and R is -OH, -O-alkyl or halogen, or -BR _v is

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

Scheme C.

where Ar represents

and R ¹ , R ^q , R ^r , G _b G3, G4, G5, G6 and X are as described for formula (I), (II), (III) or any variants thereof described herein, v is 2 or 3 and R is -OH, -O-alkyl or halogen, or -BR _v is

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

Scheme D.

where Ar represents

and R ¹ , G ₂ , G ₃ , G ₄ , G ₅ , G6 and X are as described for formula (I), (II), (III) or any variants thereof described herein, v is 2 or 3 and R is -OH, -O-alkyl or halogen, or -BR _v is

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

- 54 045787

Scheme E.

where Ar represents

and R ¹ , G2, G3, G4, G5 and G6 are as described for formula (I), (II), (III) or any variants thereof described herein, v is 2 or 3, and R is is -OH, -O-alkyl or halogen, or -BR _v is

In some embodiments, the compounds presented in be synthesized according to Scheme F.

Scheme F.

this document may

Stage 16

Rt-Br

Stage 15

BuLI

BfOiPrk „ _ —----ii" R,B(OH) _g nz'^

CuSCM,

1,10-phenanthroline

N

Vg

Stage 12a

1) mCPSA

Stage 4c

2) Ag-VYA,

PdfdppnCL k _g so _a ^Rl '/

where Ar represents θ6 ^e ^5 and R ¹ , G ₂ , G ₃ , G4 , G5 and G6 are as described for formula (I), (II), (III) or any variants thereof described herein , v is 2 or 3, and R is -OH, -O-alkyl or halogen, or -BR _v is

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

Scheme G.

- 55 045787 and G2, G ₃ , G4, G5 and G ₆ are as described for formula (I), (II) or (III) or any variants thereof described herein, v is 2 or 3, and R represents -OH, -O-alkyl or halogen, or -BR _v represents where Ar represents ^G ₂

G ₆

I and

Άγ ³⁴

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

Scheme N.

where Ar represents θ3 θ6 γ g ₅ and R ¹ , G ₂ , G ₃ , G4 , G5 , G ₆ , and Y ₁ are as described for formula (I), (II) or (III) or any of them of the embodiments described herein, v is 2 or 3, and R is -OH, -O-alkyl, or halogen, or -BR _v is

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

Scheme I.

where Ar represents

L, ^G 5 and R ¹ , G ₂ , G ₃ , G4, G5 and G6 are as described for formula (I), (II) or (III) or any variants thereof described herein, v is 2 or 3 and R is -OH, -O-alkyl or halogen, or -BR _v is

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

- 56 045787

Scheme J.

where Ar is /G ₂ θΓ ^G 6 yCD" ^G 5 and G2, G3, G4, G5 and G ₆ are as described for formula (I), (II) or (III) or any variants thereof described in herein, v is 2 or 3, and R is -OH, -O-alkyl or halogen, or -BR _v is

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

Scheme K.

where Ar represents

and G ₂ , G ₃ , G4 , G5 , G ₆ and R ¹ are as described for formula (I), (II) or (III) or any variants thereof described herein, v is 2 or 3, and R is -OH, -O-alkyl or halogen, or -BR _v is

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

Scheme L.

where Ar represents

and R ¹ , G ₂ , G ₃ , G4 , G5 and G ₆ are as described for formula (I), (II) or (III) or any variants thereof described herein, n and m, each independently , are equal to 0, 1, 2, 3 or 4, v is equal to

- 57 045787 or 3, and R is -OH, -O-alkyl or halogen, or -BRv is

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

Scheme M.

where Ar represents

G ₃ Ge g G ₅ and R ¹ , G ₂ , G ₃ , G4 , G5 and G ₆ are as described for formula (I), (II) or (III) or any variants thereof described herein, v is 2 or 3 and R is -OH, -O-alkyl or halogen, or -BR _v is

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

Scheme N.

C.I.

Stage 35

1)(PinB} _{2 R}

Pd(PPh ₃ )CI ₂

COAS

Stage 4c

2) RtBf, Pd(dppf)CI _£ , K ₂ CO ₃

Stage 26

3) morpholine, DIPEA

C.I.

Stage 4c

1)Ar-BR _v Pd{dppf)Ck, K ₂ CO _E if Ri= vinyl Venzol

Stage 31 ____2£Pd/C, N _g if R _d = vinylVenzol Stage 36

ABOUT

I NaH

Ar where Ar represents θ6 and G ₂ , G ₃ , G ₄ , G ₅ and G ₆ are as described for formula (I), (II) or (III) or any variants thereof described herein, v is 2 or 3 and R is -OH, -O-alkyl or halogen, or -BR _v is

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

- 58 045787

Scheme O.

where Ar represents

and G2, G3, _G4 , G5 and _G6 are as described for formula (I), (II) or (III) or any variants thereof described herein, v is 2 or 3, and R is is -OH, -O-alkyl or halogen, or -BR _v is

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

Scheme R.

Stage 38

1) PHM(OTf) ₂

where Ar represents

and G ₂ , G ₃ , G ₄ , G5 and G ₆ are as described for formula (I), (II) or (III) or any variants thereof described herein, v is 2 or 3, and R represents -OH, -O-alkyl or halogen, or -BR _v represents

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

Scheme Q.

Stage 8

DBnSH, □foundation

Stage 10

2)A1S1 _E

Stage 11

a) r’-Oh or

b) R ¹ -ranoreH

Stage 12a

TsppSRVA

Stage 4c 2) Ar—BR ₄

Ж ^,)С|2

where Ar represents

and R ¹ , G ₂ , G ₃ , G ₄ , G5 and G ₆ are as described for formula (I), (II) or (III) or any variants thereof described herein, v is 2 or 3 , and R is -OH, -O-alkyl or halogen, or -BR _v is

- 59 045787

In some embodiments, the above methods described in Schemes 1 or AQ further include the step of forming a salt, including a pharmaceutically acceptable salt, of a compound of the present invention. Salt forms can be prepared by standard salt preparation methods known in the art.

Embodiments relate to other methods described herein; and to the product obtained by any of the methods described herein. Specific non-limiting examples are provided below in the Examples section.

Examples

The following examples are provided by way of illustration only, and not limitation, of the compositions, applications, and methods provided herein. The proposed compounds are prepared by the general methods described above.

In the examples given, the following chemical abbreviations are used: AcSK (potassium thioacetate), BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), CDI (1,1'-carbonyldiimidazole), DAST (diethylaminosulfur trifluoride), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DCE (dichloroethane), DCM (dichloromethane), DEAD (diethyl azodicarboxylate), DMAP (4-dimethylaminopyridine), DMF (N,Ndimethylformamide), DMSO ( dimethyl sulfoxide), DIPEA (N,N-diisopropylethylamine), EA (ethyl acetate), EtOH (ethanol), iPrOH (propan-2-ol), mCPBA (meta-chloroperoxybenzoic acid), MeOH (methanol), M0MC1 (chloromethyl methyl ether), NaHMDS (sodium bis(trimethylsilyl)amide), NBS (Nbromosuccinimide), PTSA (p-toluenesulfonic acid), SNAr (nucleophilic aromatic substitution), TEA (trimethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TIPS (triisopropylsilane) and TIPSCl (triisopropylsilyl chloride).

Example 1 5-(3-morpholino-5-(phenylsulfonyl)phenyl)pyrimidin-2-amine (compound 1).

Stage 1 (see scheme A, stage 2): Synthesis of sodium benzenesulfinate from benzenesulfonyl chloride. (Adapted from PCT International Application 2012031199, March 08, 2012; sodium benzene sulfinate is also commercially available).

Sodium sulfite (10.7 g, 85 mmol) was added to 23 ml of water. After complete dissolution, the solution was cooled to 0°C and 5 g of benzenesulfonyl chloride (28.3 mmol) was added dropwise. Sodium bicarbonate (NaHCO ₃ ) was added piecemeal to maintain the alkaline solution (~5.0 g). The reaction mixture was warmed to room temperature and stirred for 2 hours. The water was removed on a rotary evaporator and the residual water was lyophilized overnight. The solid was dissolved in methanol and filtered. The filtrate was concentrated under reduced pressure. The resulting solid was dissolved in methanol and filtered, evaporated and dried under high vacuum and used as such for the next reaction.

Step 2 (see scheme A, step 3): Synthesis of 4-(3-bromo-5-(phenylsulfonyl)phenyl)morpholine. (Tetrahedron Letters, 2004, 45 (16), 3233.).

To a round bottom flask equipped with an air drying tube (filled with Drierite drying agent), add 3-bromo-5-morpholinophenylboronic acid (3.5 g, 12.3 mmol, 1 eq.), 1.1 eq. Cu(OAc) ₂ (2.5 g, 13.5 mmol), 2.3 eq. sodium phenylsulfinate (28.3 mmol), 2 eq. K ₂ CO ₃ (7.82 g, 56.6 mmol) and 4 A molecular sieves (7 g, 200% w/w). DMSO (50 mL, 0.25 M) was added and the mixture was stirred for 72 hours at room temperature, and then filtered through a pad of celite, eluting with dichloromethane. The filtrate was diluted with dichloromethane and saturated aqueous ammonium chloride, and the aqueous layers were extracted with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (0-5% (0.5 M NH ₃ /MeOH)/DCM) to give the desired product (1.58 g, 4.13 mmol, 34% yield). ESI-MS+: 404.1, 406.1 (M+Na) ⁺ , C^H^BrNOsS. 1H NMR (CDCI3, 500 MHz) δ: 7.93 (dd, J=7.5, 1.5 Hz, 2H), 7.59-7.59 (td, J=7.5, 2 Hz, 1H ), 7.53 (td, J=7.5, 1.5 Hz, 2H), 7.45 (t, J=1.5 Hz, 1H), 7.36 (t, J=2 Hz, 1H ), 7.21 (t, J=2.0 Hz, 1H), 3.85-3.83 (m, 4H), 3.20 (dd, J=4.5, 4.5 Hz, 4H) .

Connection 1

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Step 3 (see Scheme A, Step 4): Synthesis of 5-(3-morpholino-5-(phenylsulfonyl)phenyl)pyrimidin-2amine (Chem. Sci., 2013, 4, 916).

A flask equipped with a magnetic stirrer was charged with Xphos (59 mg, 0.12 mmol), G-3 Xphos precatalyst (105 mg, 0.12 mmol), 4-(3-bromo-5-(phenylsulfonyl)phenyl)morpholine ( 1.58 g, 4.12 mmol) and (2aminopyrimidin-5-yl)boronic acid (0.86 g, 6.2 mmol). The flask was sealed with a screw septum and then evacuated and filled with argon. Degassed THF (8.24 mL) and degassed 0.5 M aqueous K ₃ PO ₄ (16.5 mL) were added via syringe and the reaction mixture was stirred at 75° C. for 2.5 hours. The reaction mixture was cooled, then DCM (40 ml) and water (40 ml) were added to the mixture and the aqueous phase was extracted with DCM (3x40 ml). The combined organic phase was dried over Na ₂ SO ₄ , concentrated in vacuo and purified by column chromatography (0-7% (0.5 M NH ₃ /MeOH)/DCM) to give the desired product (compound 1) (1.15 g, 2 .9 mmol, yield 70%). ESI-MS+: 397.5 (M+H), 419.3 (M+Na), C ₁₆ H ₁₆ BrNO ₃ S. ¹ H NMR (DMSO, 500 MHz) δ: 8.61 (s, 2H) , 8.09-8.1 (m, 2H), 7.71-7.64 (m, 1H), 7.64-7.56 (m, 2H), 7.52 (t, J=1, 5 Hz, 1H), 7.38 (t, J=2.0 Hz, 1H), 7.32 (t, J=2.0 Hz, 1H), 6.88 (s, 2H), 3.74 (dd, J=6.1, 3.7 Hz, 4H), 3.27-3.23 (m, 4H).

The following compounds were prepared by methods similar to those described for compound 1 and as described in Scheme A:

Connection no. MS Ή NMR 2 412.5 (M+H), 434.3 (M+Na) (CDCh, 500 MHz) δ: 8.66 (s, 2H), 7.99 - 7.95 (m, 2H), 7.61 7.57 (m, 1H), 7.55 - 7.50 ( m, 2H), 7.49 - 7.46 (m, 2H), 7.10 (dd, J = 2.4, 1.5 Hz, 1H), 4.07 (s, ZN), 3.90 - 3.86 (m, 4H), 3.28 (dd, J = 4.3, 2.6 Hz, 4H). 3 465.5 (M+H), 487.4 (M+Na) (CDC1 ₃ , 500 MHz) δ: 8.33 (s, 1H), 7.95 - 7.91 (m, 2H), 7.61 7.56 (m, 1H), 7.54 - 7.49 (m, 2H), 7.47 (dd, J = 2.5, 1.6 Hz, 1H), 7.30 - 7.28 (m, 1H), 6.90 (t, J = 1.9 Hz, 1H), 5.42 (shs, 2H), 3.88 - 3.82 (m, 4H), 3.26 - 3.19 (m, 4H). 4 425.5 (M+H), 447.3 (M+Na) (CDC1 ₃ , 500 MHz) δ: 8.48 (s, 2H), 7.99 - 7.92 (m, 2H), 7.60 7.54 (m, 1H), 7.55 - 7.47 (m, 2H), 7.45 - 7.37 (m, 2H), 7.05 (dd, J = 2.4, 1.5 Hz, 1H), 3.89 - 3.85 (m, 4H ), 3.27 - 3.21 (m, JN). 5 411.4 (M+H), 433.3 (M+Na), 449.4 (M+K) (CDCh, 500 MHz) δ: 8.32 (dd, J = 4.0, 2.5 Hz, 1H), 7.99 - 7.94 (m, 2H), 7.73 (ddd, J = 8 ,4, 5.8, 2.5 Hz, 1H), 7.60 - 7.54 (m, 1H), 7.53 - 7.47 (m, ZN), 7.43 (dd, J = 2 ,4, 1.5 Hz, 1H), 7.12 (dd, J = 2.5, 1.5 Hz, 1H), 6.82 (d, J = 8.7 Hz, 1H), 3.98 (s, ZN), 3.89 - 3.84 (m, 4H), 3.29 - 3.23 (m, 4H). 6 464.5 (M+H), 486.3 (M+Na), 502.6 (M+K) (CDC13, 500 MHz) δ: 8.01 (s, 1H), 7.95 - 7.91 (m, 2H), 7.59 7.55 (m, 1H), 7.53 - 7.48 ( m, 2H), 7.45 (dd, J = 2.5, 1.6 Hz, 1H), 7.31 (s, 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.79 (s, 1H), 5.16 (s, 2H), 3.88 - 3.81 (m, 4H), 3.24 - 3.18 (m, 4H). 7 465.2 (M+H), 487.3 (M+Na) (CDC13, 500 MHz) δ: 8.48 (s, 2H), 8.33 (d, J = 4.9 Hz, 1H), 8.23 (d, J = 1.8 Hz, 1H), 8 .15 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.44 (t, J = 1.5 Hz, 1H), 7.09 (dd, J = 2.4, 1.5 Hz, 1H), 5.21 (s, 2H), 3.92 - 3.84 ( m, 4H), 3.31 - 3.24 (m, 4H). 8 437.4 (M+Na) (DMSO-s16, 500 MHz) δ: 8.62 (s, 2H), 8.18 - 8.11 (m, 2H), 7.53 (d, J = 1.5 Hz, 1H), 7, 47 - 7.41 (m, 2H), 7.38 (t, J = 1.9 Hz, 1H), 7.33 (t, J = 1.9 Hz, 1H), 6.90 (s, 2H ), 3.74 (dd, J = 6.0, 3.7 Hz, 4H), 3.27 (dd, J = 6.0, 3.8 Hz, 4H).

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9 469.4 (M+Na) (CDC13, 500 MHz) δ: 8.58 (d, J = 1.8 Hz, 1H), 8.48 (s, 2H), 8.01 - 7.97 (m, 1H), 7.95 ( d, J = 8.7 Hz, 1H), 7.90 - 7.84 (m, 2H), 7.67 - 7.58 (m, 2H), 7.49 (dt, J = 6.1, 1.6 Hz, 2H), 7.04 (dd, J = 2.5, 1.5 Hz, 1H), 6.37 (s, 2H), 3.90 - 3.84 (m, 4H), 3.29 - 3.24 (m, 4H). 10 422.3 (M+H), 444.2 (M+Na) (CDC13, 500 MHz) δ: 8.48 (s, 2H), 8.10 - 8.03 (m, 2H), 7.85 7.77 (m, 2H), 7.42 (t, J = 1.5 Hz, 1H), 7.39 (t, J = 2.0 Hz, 1H), 7.09 (t, J = 1.9 Hz, 1H), 5.31 (s, 2H), 3 .90 - 3.85 (m, 4H), 3.29 - 3.25 (m, 4H). eleven 449.1 (M+H), 471.8 (M+Na) (CDC13, 500 MHz) δ: 8.65 (s, 2H), 8.36 (dd, J = 6.9, 2.4 Hz, 1H), 8.12 (dd, J = 8.8, 4 .5, 2.4 Hz, 1H), 7.65 (t, J = 8.9 Hz, 1H), 7.60 (t, J = 1.4 Hz, 1H), 7.39 (dt, J = 14.9, 2.0 Hz, 2H), 6.89 (s, 2H), 3.75 (t, J = 4.9 Hz, 4H), 3.28 (m, 4H). 12 395.5 (M+H), 417.5 (M+Na), 433.5 (M+K) (CDC13, 500 MHz) δ: δ 8.52 (d, J = 20.9 Hz, 2H), 7.99 - 7.89 (m, 2H), 7.61 - 7.55 (m, 1H) , 7.55 - 7.46 (m, ZN), 7.31 - 7.27 (m, 1H), 7.19 (d, J = 5.1 Hz, 1H), 6.92 (t, J = 2.0 Hz, 1H), 3.90 3.81 (m, 4H), 3.30 - 3.23 (m, 4H). 13 422.1 (M+H) (DMSO-s16, 500 MHz) δ: 8.65 (s, 2H), 8.61 (t, J = 1.8 Hz, 1H), 8.38 (dt, J = 8.3, 1.4 Hz, 1H), 8.15 (dt, J = 7.8, 1.3 Hz, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.64 - 7.58 (m , 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.38 (t, J = 2.0 Hz, 1H), 6.91 (s, 2H), 3.79 - 3 .68 (m, 4H), 3.29 (t, J = 4.9 Hz, 4H). 14 465.1 (M+H) (DMSO-s16, 500 MHz) δ: 8.63 (s, 2H), 8.29 (d, J = 8.3 Hz, 2H), 7.98 (d, J = 8.3 Hz, 2H) , 7.57 (d, J = 1.6 Hz, 1H), 7.42 (t, J = 2.0 Hz, 1H), 7.36 (t, J = 2.0 Hz, 1H), 6 .91 (s, 2H), 3.74 (t, J = 4.8 Hz, 4H), 3.28 (t, J = 4.9 Hz, 4H). 15 481.1 (M+H) (DMSO-s16, 500 MHz) δ: 8.63 (s, 2H), 8.23 - 8.19 (m, 2H), 7.59 (dt, J = 7.8, 1.1 Hz, 2H ), 7.57 - 7.55 (m, 1H), 7.41 (t, J = 1.9 Hz, 1H), 7.35 (t, J = 1.9 Hz, 1H), 6.91 (s, 2H), 3.77 - 3.70 (m, 4H), 3.30 - 3.25 (m, 4H). 16 411.1 (M+H) (DMSO-s16, 500 MHz) δ: 8.65 (s, 2H), 8.08 - 8.02 (m, 2H), 7.71 - 7.65 (m, 1H), 7.61 (dd , J = 8.5, 7.0 Hz, 2H), 7.52 (t, J = 1.5 Hz, 1H), 7.40 - 7.35 (m, 2H), 7.32 (t, J = 2.0 Hz, 1H), 3.74 (dd, J = 5.9, 3.8 Hz, 4H), 3.26 (dd, J = 5.9, 3.9 Hz, 4H), 2.84 (d, J = 4.8 Hz, ZN). 17 490.1 (M+H) (DMSO-s16, 500 MHz) δ: 8.41 (s, 1H), 8.17 (d, J = 8.5 Hz, 2H), 8.10 (d, J = 8.5 Hz, 2H) , 7.44 (m, ZN), 7.28 (s, 1H), 7.21 (t, J = 1.9 Hz, 1H), 3.73 (dd, J = 6.0, 3.8 Hz, 4H), 3.24 (dd, J = 5.9, 3.9 Hz, 4H). 18 489.1 (M+H) (DMSO-s16, 500 MHz) δ: 8.19 - 8.14 (m, 2H), 8.11 - 8.07 (m, 2H), 7.96 (s, 1H), 7.42 (t , J = 2.0 Hz, 1H), 7.22 (s, 1H), 7.14 (t, J = 1.9 Hz, 1H), 6.81 (s, 1H), 6.68 (s , 2H), 3.72 (dd, J = 6.1, 3.6 Hz, 4H), 3.23 (dd, J = 5.8, 3.9 Hz, 4H). 19 441.2 (M+H) (DMSO-s16, 500 MHz) δ: 8.64 (s, 2H), 8.07 - 8.03 (m, 2H), 7.71 - 7.65 (m, 1H), 7.61 (dd , J = 8.4, 7.0 Hz, 2H), 7.52 (t, J = 1.4 Hz, 1H), 7.38 (t, J = 2.0 Hz, 1H), 7.35 - 7.30 (m, 2H), 4.68 (t, J = 5.6 Hz, 1H), 3.74 (dd, J = 5.9, 3.7 Hz, 4H), 3.53 ( k, J = 6.1 Hz, 2H), 3.39 (k, J = 6.2 Hz, 2H), 3.28 - 3.23 (m, 4H). 20 437.1 (M+H) (DMSO-s16, 500 MHz) δ: 8.67 (s, 2H), 8.07 - 8.03 (m, 2H), 7.70 - 7.64 (m, 2H), 7.61 (dd , J = 8.4, 7.0 Hz, 2H), 7.53 (t, J = 1.4 Hz, 1H), 7.39 (t, J = 1.9 Hz, 1H), 7.33 (t, J = 2.0 Hz, 1H), 3.74 (dd, J = 6.0, 3.8 Hz, 4H), 3.28 - 3.24 (m, 4H), 2.75 ( tk, J = 7.3, 3.8 Hz, 1H), 0.69 (td, J = 6.9, 4.6 Hz, 2H), 0.51 - 0.47 (m, 2H). 21 411.1(M+H) (DMSO-s16, 500 MHz) δ: 8.60 (s, 2H), 7.95 - 7.89 (m, 2H), 7.51 - 7.48 (m, 1H), 7.40 (d , J = 8.1 Hz, 2H), 7.36 (t, J = 1.9 Hz, 1H), 7.30 (t, J = 1.9 Hz, 1H), 6.89 (s, 2H ), 3.74 (dd, J = 6.0, 3.8 Hz, 4H), 3.29 - 3.22 (m, 4H), 2.36 (s, ZN).

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22 454.2 (M+H) (DMSO-C16, 500 MHz) δ: 10.35 (s, 1H), 8.60 (s, 2H), 7.99 7.93 (m, 2H), 7.82 - 7.71 (m, 2H), 7.47 (t, J = 1.5 Hz, 1H), 7.36 (t, J = 1.9 Hz, 1H), 7.28 (t, J = 1.9 Hz, 1H) , 6.89 (s, 2H), 3.74 (dd, J = 6.0, 3.8 Hz, 4H), 3.25 (dd, J = 5.9, 3.7 Hz, 4H), 2.07 (s, ZN). 23 411.1 (M+H) (DMSO-C16, 500 MHz) δ: 8.56 (s, 2H), 7.42 (d, J = 2.1 Hz, 1H), 7.35 - 7.27 (m, ZN), 7, 25 (d, J = 1.5 Hz, 1H), 7.21 (dd, J = 7.2, 2.3 Hz, 2H), 7.03 (t, J = 1.9 Hz, 1H), 6.89 (s, 2H), 4.69 (s, 2H), 3.74 (t, J = 4.8 Hz, 4H), 3.22 - 3.16 (m, 4H). 24 496.2(M+H) (DMSO-46, 500 MHz) δ: 8.61 (s, 2H), 8.09 - 8.02 (m, 2H), 7.71 - 7.65 (m, 1H), 7.61 (dd , J = 8.4, 7.0 Hz, 2H), 7.52 (t, J = 1.4 Hz, 1H), 7.38 (t, J = 1.9 Hz, 1H), 7.34 (t, J = 1.9 Hz, 1H), 6.90 (s, 2H), 3.46 (t, J = 5.1 Hz, 4H), 3.28 (dd, J = 6.4, 4.0 Hz, 4H), 1.42 (s, 9H). 25 395.1 (M+H) (DMSO-C16, 500 MHz) δ: 8.59 (s, 2H), 8.07 - 8.02 (m, 2H), 7.71 - 7.64 (m, 1H), 7.63 - 7 .57 (m, 2H), 7.43 (t, J = 1.5 Hz, 1H), 7.34 (t, J = 1.9 Hz, 1H), 7.28 (t, J = 1, 9 Hz, 1H), 6.87 (s, 2H), 3.29 (t, J = 5.3 Hz, 4H), 1.61 (dd, J = 7.5, 4.0 Hz, 4H) , 1.56 (k, J = 7.3, 5.9 Hz, 2H). 26 447.1 (M+H) (DMSO-C16, 500 MHz) δ: 8.58 (s, 2H), 7.46 (t, J = 2.0 Hz, 1H), 7.33 - 7.27 (m, 2H), 7. 24 (td, J = 9.6, 2.5 Hz, 1H), 7.10 (td, J = 8.5, 2.6 Hz, 1H), 7.04 (t, J = 2.0 Hz , 1H), 6.90 (s, 2H), 4.72 (s, 2H), 3.81 - 3.68 (m, 4H), 3.23 - 3.15 (m, 4H). 27 436.2 (M+H) (DMSO-s16, 500 MHz) δ: 8.59 (s, 2H), 7.82 (cd, J = 4.4, 3.9, 1.8 Hz, 1H), 7.57 (ddd, J = 5.2, 3.5, 1.4 Hz, ZN), 7.46 (t, J = 1.9 Hz, 1H), 7.28 (d, J = 1.5 Hz, 1H), 7 .00 (t, J = 2.0 Hz, 1H), 6.91 (s, 2H), 4.82 (s, 2H), 3.74 (t, J = 4.8 Hz, 4H), 3 .28 - 3.00 (m, 4H). 28 441.2 (M+H) (DMSO-C16, 500 MHz) δ: 8.56 (s, 2H), 7.42 (t, J = 1.9 Hz, 1H), 7.24 (d, J = 1.5 Hz, 1H) , 7.14 - 7.08 (m, 2H), 7.00 (t, J = 1.9 Hz, 1H), 6.92 - 6.83 (m, 4H), 4.60 (s, 2H ), 3.74 (d, J = 5.0 Hz, 4H), 3.72 (s, ZN), 3.21 - 3.14 (m, 4H). 29 429.1 (M+H) (DMSO-C16, 500 MHz) δ: 8.58 (s, 2H), 7.43 (t, J = 1.9 Hz, 1H), 7.27 (t, J = 1.4 Hz, 1H) , 7.26 - 7.21 (m, 2H), 7.19 - 7.12 (m, 2H), 7.02 (t, J = 1.9 Hz, 1H), 6.91 (s, 2H ), 4.71 (s, 2H), 3.74 (t, J = 4.8 Hz, 4H), 3.23 - 3.16 (m, 4H). thirty 439.2(M+H) (DMSO-C16, 500 MHz) δ: 10.71 (s, 1H), 9.01 (s, 2H), 8.09 8.04 (m, 2H), 7.72 - 7.64 (m, 2H), 7.61 (dd, J = 8.4, 7.0 Hz, 2H), 7.52 (t, J = 2.0 Hz, 1H), 7.42 (t, J = 1.9 Hz, 1H), 3.79 - 3.70 (m, 4H), 3.31 - 3.28 (m, 4H), 2.21 (s, ZN). 31 425.1 (M+H) (DMSO-C16, 500 MHz) δ: 8.60 (s, 2H), 7.42 (t, J = 1.9 Hz, 1H), 7.38 - 7.28 (m, 4H), 7. 28 - 7.23 (m, 1H), 7.23 - 7.17 (m, 2H), 7.03 (t, J = 1.9 Hz, 1H), 4.69 (s, 2H), 3 .74 (t, J = 4.8 Hz, 4H), 3.22 - 3.15 (m, 4H), 2.85 (d, J = 4.8 Hz, ZN). 32 478.2 (M+H) (DMSO-C16, 500 MHz) δ: 7.86 (s, 1H), 7.33 - 7.25 (m, ZN), 7.16 - 7.10 (m, 4H), 6.92 (k , J = 2.0, 1.3 Hz, 1H), 6.80 (s, 1H), 6.66 (s, 2H), 4.65 (s, 2H), 3.72 (dd, J = 5.9, 3.8 Hz, 4H), 3.17 - 3.08 (m, 4H). 33 479.2 (M+H) (DMSO-C16, 500 MHz) δ: 8.33 (s, 1H), 7.43 (s, 2H), 7.34 - 7.24 (m, 4H), 7.18 (t, J = 1 .9 Hz, 1H), 7.16 - 7.10 (m, ZN), 6.97 (t, J = 1.4 Hz, 1H), 4.66 (s, 2H), 3.72 (dd , J = 6.0, 3.7 Hz, 4H), 3.18 - 3.09 (m, 4H). 34 449.2 (M+H) (DMSO-C16, 500 MHz) δ: 9.28 (d, J = 2.5 Hz, 1H), 8.80 (d, J = 2.5 Hz, 1H), 7.69 (d, J = 1.2 Hz, 1H), 7.58 (t, J = 2.0 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.37 - 7.29 (m, ZN), 7.26 - 7.19 (m, 2H), 7.11 (t, J = 1.9 Hz, 1H), 4.73 (s, 2H), 3.79 - 3.72 (m, 4H) , 3.23 (dd, J = 5.9, 3.8 Hz, 4H), 2.40 (s, ZN).

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35 455.4 (M+H), 477.4 (M+Na), 493.6 (M+K) (DMSO-s16, 500 MHz) δ: 8.59 (s, 2H), 7.42 (t, J = 1.9 Hz, 1H), 7.35 - 7.28 (m, 4H), 7. 27 (d, J = 1.4 Hz, 1H), 7.21 (dd, J = 7.2, 2.3 Hz, 2H), 7.03 (t, J = 1.7 Hz, 1H), 4.69 (d, J = 2.1 Hz, ZN), 3.74 (t, J = 4.9 Hz, 4H), 3.53 (k, J = 6.1 Hz, 2H), 3, 39 (k, J = 6.2 Hz, 2H), 3.20 (t, J = 4.8 Hz, 4H). 39 419.4 (M+H) (DMSO-c16, 400 MHz) δ: 8.67 (s, 2H), 7.47 (s, 1H), 7.45 (s, 1H), 7.27 (s, 1H), 6.92 ( s, 2H), 3.77 (m, 6H), 3.36 (m, 2H), 3.28 (m, 6H), 2.09 (m, 1H), 1.71 (m, 2H), 1.34 (m, 2H). 40 528.6 (M+H) (DMSO-s16, 500 MHz) δ: 8.19 (d, J = 8.8 Hz, 1H), 7.97 (s, 1H), 7.42 (t, J = 1.9 Hz, 1H) , 7.27 - 7.21 (m, ZN), 7.20 - 7.09 (m, 4H), 7.06 (t, J = 2.0 Hz, 1H), 6.88 (t, J = 5.4 Hz, 1H), 4.71 (s, 2H), 3.94 (s, ZN), 3.76 (dd, J = 5.9, 3.9 Hz, 4H), 3.22 (dd, J = 5.8, 4.1 Hz, 4H), 3.11 (cd, J = 7.1, 5.1 Hz, 2H), 1.08 - 1.04 (m, ZN). 41 428.4 (M+H) (DMSO-c16, 500 MHz) δ: 9.56 (d, J = 1.4 Hz, 1H), 7.40 (t, J = 2.0 Hz, 1H), 7.29 - 7.20 ( m, 4H), 7.18 - 7.12 (m, 2H), 7.10 (t, J = 1.9 Hz, 1H), 7.05 (dt, J = 7.7, 1.2 Hz , 1H), 7.02 (t, J = 2.1 Hz, 1H), 6.81 (ddd, J = 8.1, 2.5, 0.9 Hz, 1H), 4.72 (s, 2H), 3.80 3.69 (m, 4H), 3.24 - 3.16 (m, 4H). 42 483.4(M+H) (DMSO-s16, 500 MHz) δ: 10.81 (s, 1H), 7.41 (t, J = 1.9 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H) , 7.28 - 7.20 (m, 4H), 7.19 - 7.12 (m, 2H), 7.06 (t, J = 1.9 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 4.71 (s, 2H), 4.63 (s, 2H), 3.78 - 3.69 (m, 4H), 3.24 - 3.16 (m, 4H). 43 457.2 (M+H) (DMSO-s16, 500 MHz) δ: 7.33 (t, J = 1.9 Hz, 1H), 7.26 - 7.22 (m, ZN), 7.18 - 7.12 (m, 2H ), 7.04 (t, J = 2.0 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.82 (dd, J = 8.2, 2.2 Hz, 1H), 4.81 (s, 2H), 4.69 (s, 2H), 3.80 (s, ZN), 3.78 - 3.71 (m, 5H), 3.23 -3.17 (m, 4H). 44 458.2 (M+H) (DMSO-c16, 500 MHz) δ: 7.41 (d, J = 8.1 Hz, 1H), 7.29 (t, J = 1.9 Hz, 1H), 7.25 - 7.19 ( m, ZN), 7.18 - 7.11 (m, 2H), 6.99 (t, J = 2.0 Hz, 1H), 6.14 - 6.08 (m, ZN), 4.64 (s, 2H), 3.77 (s, ZN), 3.74 (dd, J = 6.0, 3.7 Hz, 4H), 3.16 - 3.09 (m, 4H). 45 469.1 (M+H) (DMSO-46, 500 MHz) δ: 7.34 - 7.30 (m, 1H), 7.27 - 7.21 (m, 2H), 7.20 (t, J = 1.5 Hz, 1H ), 7.18 - 7.12 (m, 2H), 7.00 - 6.96 (m, ZN), 6.66 - 6.59 (m, 1H), 6.03 (d, J = 2 .6 Hz, 1H), 4.69 (s, 2H), 4.14 (dd, J = 5.0, 3.7 Hz, 2H), 3.79 - 3.68 (m, 4H), 3 .34 3.32 (m, 2H), 3.21 - 3.12 (m, 4H). 46 496.2 (M+H) (DMSO-c16, 500 MHz) δ: 7.72 (dt, J = 7.9, 1.2 Hz, 1H), 7.65 7.59 (m, 2H), 7.50 (t, J = 2.0 Hz, 1H), 7.42 (ddt, J = 8.2, 2.4, 1.2 Hz, 1H), 7.28 (t, J = 1.4 Hz, 1H), 7, 27 - 7.21 (m, 2H), 7.19 7.12 (m, ZN), 4.74 (s, 2H), 3.79 - 3.72 (m, 4H), 3.26 - 3 .20 (m, 4H). 49 403.2(M+H) (DMSO-ab, 500 MHz) δ: 8.64 (s, 2H), 7.45 (d, J = 1.9 Hz, 1H), 7.37 (d, J = 1.5 Hz, 1H) , 7.19 (t, J = 1.8 Hz, 1H), 6.88 (d, J = 4.3 Hz, 2H), 3.76 (dt, J = 8.7, 4.6 Hz, 4H), 3.31-3.27 (m, 4H), 3.18 (dd, J = 5.9, 3.8 Hz, 1H), 1.93 - 1.81 (m, 2H), 1 .76 (dt, J = 12.9, 3.4 Hz, 2H), 1.36 - 1.04 (m, 6H). 50 429.2(M+H) (DMSO-ab, 500 MHz) δ: 8.56 (s, 2H), 7.45 (t, J = 1.9 Hz, 1H), 7.40 (tdd, J = 7.7, 5.3 , 1.8 Hz, 1H), 7.30 - 7.22 (m, 2H), 7.21 7.12 (m, 2H), 7.03 (t, J = 1.9 Hz, 1H), 6.90 (s, 2H), 4.72 (s, 2H), 3.75 - 3.72 (m, 4H), 3.21-3.18 (m, 4H). 51 391.1 (M+H) (DMSO-ab, 500 MHz) δ: 8.66 (s, 2H), 7.46 (d, J = 1.9 Hz, 2H), 7.27 (t, J = 2.0 Hz, 1H) , 6.90 (s, 2H), 4.31 (tg, J = 8.6, 5.1 Hz, 1H), 4.03 (dd, J = 10.0, 4.8 Hz, 1H), 3.86 - 3.73 (m, 6H), 3.66 (dt, J = 8.4, 6.9 Hz, 1H), 3.32 - 3.28 (m, 4H), 2.23 - 2.14 (m, 1H), 2.09 (dddd, J = 13.1, 9.3, 7.1, 5.8 Hz, 1H).

- 64 045787

55 443.2 (M+H) (DMSO-c16, 500 MHz) 5:8.46 (d, J = 1.9 Hz, 1H), 8.34 (d, J = 2.7 Hz, 1H), 7.59 (t, J = 2.3 Hz, 1H), 7.53 (t, J = 1.9 Hz, 1H), 7.35 (d, J = 1.5 Hz, 1H), 7.28 - 7.20 (m, 2H), 7.19 - 7.09 (m, ZN), 4.74 (s, 2H), 3.92 (s, ZN), 3.75 (dd, J = 5.9, 3.7 Hz , 4H), 3.25-3.18 (m, 4H). 60 417.3 (M+H) (CDC13, 400 MHz) 5: 8.54 (s, 2H), 7.44 (s, 1H), 7.37 (s, 1H), 7.14 (s, 1H), 5.30 (w, 2H), 3.89 (m, 4H), 3.29 (m, 4H), 3.01 (d, J=5.6 Hz, 2H), 2.07 (m, 1H), 1.90 ( m, 2H), 1.63 (m, 2H), 1.361.03 (m, 6H). 62 405.2 (M+H) (DMSO-s16, 500 MHz) 5: 8.65 (s, 2H), 7.48 (t, J = 1.9 Hz, 1H), 7.39 (t, J = 1.3 Hz, 1H) , 7.20 (t, J = 1.9 Hz, 1H), 6.90 (s, 2H), 3.91 (ddd, J = 11.7, 4.7, 1.6 Hz, 2H), 3.79 - 3.73 (m, 4H), 3.64 (tg, J = 12.0, 3.8 Hz, 1H), 3.31 - 3.24 (m, 6H), 1.73 ( ddd, J = 12.6, 4.0, 1.8 Hz, 2H), 1.59 (cd, J = 12.2, 4.7 Hz, 2H). 64 453.4 (M+H) (CDC13, 400 MHz) 5: 8.54 (s, 2H), 7.43 (s, 1H), 7.36 (s, 1H), 7.15 (s, 1H), 5.37 (w, 2H), 3.90 (m, 4H), 3.31 (m, 4H), 3.05 (d, J=6.0 Hz, 2H), 2.22 (m, 1H), 2.07 ( m, 4H), 1.77 (m, 2H), 1.46 (m, 2H). 69 476.3 (M+H) (DMSO-c16, 500 MHz) 5: 8.67 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 1.5 Hz, 1H), 7.85 - 7.80 ( m, 1H), 7.79 (t, J = 1.9 Hz, 1H), 7.27 (t, J = 1.9 Hz, 1H), 6.74 (s, 2H), 4.49 ( tg, J = 8.2, 5.3 Hz, 1H), 4.05 (d, J = 29.5 Hz, 4H), 3.77 (t, J = 4.9 Hz, 4H), 3, 33 - 3.23 (m, 4H), 1.36 (s, 9H). 70 458.2 (M+H) (DMSO-s16, 500 MHz) 5: 8.00 (s, 1H), 7.34 (t, J = 2.0 Hz, 1H), 7.18 (t, J = 1.8 Hz, 1H) , 7.14 (s, 1H), 6.83 (s, 1H), 6.67 (s, 2H), 4.24 (tg, J = 8.6, 5.3 Hz, 1H), 3, 98 (dd, J = 10.1, 4.9 Hz, 1H), 3.82 (dd, J = 10.0, 8.1 Hz, 1H), 3.79 - 3.71 (m, 5H) , 3.65 (dt, J = 8.4, 6.9 Hz, 1H), 3.28 - 3.21 (m, 4H), 2.18 - 2.03 (m, 2H). 72 459.1 (M+H) (DMSO-s16, 500 MHz) δ: 8.46 (s, 1H), 7.44 (s, 2H), 7.36 (t, J = 2.0 Hz, 1H), 7.25 (t, J = 1.9 Hz, 1H), 7.19 (d, J = 1.8 Hz, 1H), 4.24 (tg, J = 9.8, 5.2 Hz, 1H), 4.04 - 3.96 (m, 1H), 3.82 (dd, J = 10.0, 8.1 Hz, 1H), 3.75 (dt, J = 5.8, 3.9 Hz, 5H), 3 .65 (dt, J = 8.3, 6.8 Hz, 1H), 3.26 (t, J = 4.9 Hz, 4H), 2.20 - 2.05 (m, 2H). 73 411.2 (M+H) (DMSO-ab, 500 MHz) δ: 8.57 (d, J = 1.5 Hz, 1H), 7.96 (d, J = 1.5 Hz, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.31 (dd, J = 5.1, 2.0 Hz, ZN), 7.21 (dd, J = 6.3, 2.7 Hz, 2H), 7.02 (t, J = 1.9 Hz, 1H), 6.70 (s, 2H), 4.67 (s, 2H), 3, 75 (t, J = 4.8 Hz, 4H), 3.18 (t, J = 4.9 Hz, 4H). 74 391.2 (M+H) (DMSO-c16, 500 MHz) δ:8.66 (d, J = 1.6 Hz, 1H), 7.99 (d, J = 1.5 Hz, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.77 (t, J = 1.9 Hz, 1H), 7.27 (t, J = 2.0 Hz, 1H), 6.74 (shs, 2H), 4 .27 (tg, J = 9.6, 5.2 Hz, 1H), 4.01 (dd, J = 10.0, 4.8 Hz, 1H), 3.87 - 3.80 (m, 1H ), 3.78 (k, J = 5.0 Hz, 5H), 3.69 - 3.62 (m, 1H), 3.29 (dd, J = 5.9, 3.8 Hz, 4H) , 2.24-1.99 (m, 2H). 85 433.16 (M+H) (CDC13, 400 MHz) δ: 8.55 (w, 2H), 7.38 (s, 1H), 7.31 (s, 1H), 7.17 (s, 1H), 5.31 (w, 2H), 3.91 (m, 4H), 3.43 (m, 2H), 3.30 (m, 4H), 3.23 (m, 1H), 1.91 (m, 2H), 1, 42 (m, 2H), 1.23 (d, J=6.0 Hz, 6H), 88 438.7 (M+H) (DMSO-ab, 400 MHz) δ: 8.66 (s, 2H), 7.49 (s, 1H), 7.39 (s, 1H), 7.21 (s, 1H), 6.94 ( s, 2H), 3.77 (m, 4H), 3.57 (m, 1H), 3.29 (m, 4H), 2.11 (m, 2H), 1.95 (m, 2H), 1.83 (m, 2H), 1.61 (m, 2H), 94 463.1 (M+H) (DMSO-ab, 500 MHz) δ: 8.66 (s, 2H), 7.49 (t, J = 1.9 Hz, 1H), 7.45 (d, J = 1.6 Hz, 1H) , 7.41 (t, J = 6.6 Hz, 1H), 7.26 (t, J = 1.9 Hz, 1H), 6.90 (s, 2H), 4.58 - 4.48 ( m, 1H), 4.40 (d, J = 6.6 Hz, 2H), 4.08 - 3.98 (m, 4H), 3.76 (dd, J = 6.0, 3.6 Hz , 4H), 3.30 (d, 1 = 5.9Hz, 4H), 3.13 (s, ZN).

- 65 045787

95 447.1 (M+H) (DMSO-ab, 500 MHz) δ: 8.66 (s, 2H), 7.47 (dt, J = 6.3, 1.7 Hz, 2H), 7.26 (t, J = 1.9 Hz, 1H), 6.89 (s, 2H), 4.56 (tg, J = 8.5, 5.7 Hz, 1H), 4.19 - 3.97 (m, 4H), 3.76 (dd, J = 6.0, 3.7 Hz, 4H), 3.30 (d, J = 6D Hz, 4H), 2.73 (s, 6H). 96 446.83 (M+H) (DMSSMB, 400 MHz) δ: 7.91 (d, J=9.6 Hz, 1H), 7.79 (m, 1H), 7.76 (s, 1H), 7.34 (m, 1H) , 7.25 (m, 1H), 7.11 (m, 2H), 6.85 (d, J=9.6 Hz, 1H), 6.65 (s, 2H), 4.73 (s, 2H), 3.77 (m, 4H), 3.22 (m, 4H). 103 431.2 (M+H) (DMSSMB, 500 MHz) δ: 8.72 (s, 2H), 7.65 (d, J = 3.6 Hz, 1H), 7.47 (k, J = 1.9 Hz, 2H), 7 .28 (t, J = 2.0 Hz, 1H), 4.38-4.17 (m, 1H), 4.03 (dd, J = 10.0, 4.8 Hz, 1H), 3, 87 - 3.71 (m, 6H), 3.66 (dt, J = 8.2, 6.8 Hz, 1H), 3.34 - 3.27 (m, 4H), 2.83 - 2, 71 (m, 1H), 2.24 - 2.16 (m, 1H), 2.15 - 2.05 (m, 1H), 0.72 - 0.67 (m, 2H), 0.54 - 0.46 (m, 2H). 104 451.2 (M+H) (DMSSMB, 500 MHz) δ: 8.62 (s, 2H), 7.63 (d, J = 3.8 Hz, 1H), 7.43 (dd, J = 2.4, 1.5 Hz, 1H), 7.34 - 7.26 (m, 4H), 7.23 - 7.19 (m, 2H), 7.04 (dd, J = 2.4, 1.5 Hz, 1H), 4 .69 (s, 2H), 3.77 - 3.73 (m, 4H), 3.23 - 3.16 (m, 4H), 2.80 - 2.71 (m, 1H), 0.72 - 0.66 (m, 2H), 0.53 - 0.47 (m, 2H).

Example 2 5-(3-morpholino-5-(((tetrahydrofuran-3-yl)methyl)sulfonyl)phenyl)pyrimidin-2-amine: (tetrahydrofuran-3-yl)methanesulfonyl chloride (compound 38).

Step 1: Triphenylphosphine (7.7 g, 29.4 mmol) was added to a solution of (tetrahydrofuran-3-yl)methanol (2 g, 19.6 mmol) and carbon tetrabromide (7.7 g, 23.5 mmol) in DXM (30 ml) at 0°C. The reaction mixture was stirred for 2 hours at room temperature. The mixture was poured into water (50 ml) and extracted with dichloromethane (50 mlx3). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 3-(bromomethyl)tetrahydrofuran (2.0 g, 62% yield).

Step 2: A solution of 3-(bromomethyl)tetrahydrofuran (2 g, 12.2 mmol) and AcSK (2.7 g, 24.4 mmol) in DMF (10 ml) was stirred overnight at room temperature. The mixture was poured into water (50 ml) and extracted with dichloromethane (50 mlx3). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated to give crude S-(tetrahydrofuran-3yl)methylethanethanioate (2.0 g, quantitative yield), which was used for the next reaction without further purification. The compound was confirmed by LC-MS only: 161.27 (M+H)+, C7H12O2S.

Step 3: Chlorine gas Cl ₂ was bubbled through a mixture of S-(tetrahydrofuran-3yl)methylethanethanioate (2.0 g, 12.5 mmol) in DCM/water (20 ml/20 ml) at 0-5°C for 20 minutes. The DCM layer was separated and the aqueous phase of DCM was extracted (20 mlx2). The organic extracts were combined and concentrated to give crude (tetrahydrofuran-3-yl)methanesulfonyl chloride (1.7 g, 75% yield), which was used for the next reaction without further purification.

Step 4: Synthesis of 5-(3-morpholino-5-(((tetrahydrofuran-3-yl)methyl)sulfonyl)phenyl)pyrimidin2-amine.

4-(3-Bromo-5-((tetrahydrofuran-3-yl)methylsulfonyl)phenyl)morpholine was synthesized by methods similar to those described in example 1 from crude (tetrahydrofuran-3-yl)methanesulfonyl chloride (0.9 g, 17% yield ). The compound was confirmed by LC-MS only: 389.90 (M+H) ⁺ , Q5H20B1NO4S.

Step 5 (see Scheme B, Step 4b): Solution of 4-(3-bromo-5-(((tetrahydrofuran-3yl)methyl)sulfonyl)phenyl)morpholine (300 mg, 0.77 mmol), 5-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)pyrimidin-2-amine (170 mg, 0.77 mmol) and an aqueous solution of potassium phosphate (20 ml, 0.5 M) in THF ( 20 ml) were purged with nitrogen three times. Pd ₂ (dba) ₃ (100 mg) was added and the reaction mixture was heated at 7080°C for 2 hours under a protective atmosphere of N2. The solvent was removed in vacuo and the residue was separated into ethyl acetate (30 ml) and water (30 ml). The organic layer was separated and the aqueous phase was again extracted with ethyl acetate (20 mlx2). The organic extracts were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 5-(3-morpholino-5-(((tetrahydrofuran-3yl)methyl)sulfonyl)phenyl)pyrimidin-2-amine (72 mg, 23% yield). ESI-MS+: 404.97 (M+H). ^1H NMR

- 66 045787 (CDCl3, 400 MHz) δ: 8.54 (s, 2H), 7.44 (s, 1H), 7.36 (s, 1H), 7.16 (s, 1H), 5.33 (w, 2H), 3.96 (m, 1H), 3.88 (m,

4H), 3.85 (m, 1H), 3.76 (m, 1H), 3.54 (m, 1H), 3.31 (m, 4H), 3.22 (m, 2H), 2. 77 (m, 1H), 2.22 (m, 1H), 1.73 (m,

1H).

Example 3. tert-butyl-3-((3-(2-aminopyrimidin-5-yl)-5-morpholinophenyl)sulfonyl)azetidine-1carboxylate (compound 54).

1) The synthesis of tert-butyl-3-((3-(2-aminopyrimidin-5-yl)-5-morpholinophenyl)sulfonyl)azetidine-1-carboxylate from commercially available sodium 1-(tert-butoxycarbonyl)azetidine-3-sulfinate was carried out methods similar to those described previously in example 1 for compound 1 (130 mg, yield 42%, 2 stages). ESI-MS+: 476.3 (M+H). 1H NMR (DMSO-d ₆ , 500 MHz) δ: 8.66 (s, 2H), 7.57-7.42 (m, 2H), 7.27 (t, J=1.9 Hz, 1H) , 6.90 (s, 2H), 4.53 (tt, J=8.2, 5.5 Hz, 1H), 4.23-3.91 (m, 4H), 3.76 (dd, J =6.0, 3.8 Hz, 4H), 3.32-3.29 (m, 4H), 1.36 (s, 9H).

Example 4 5-(3-(azetidin-3-ylsulfonyl)-5-morpholinophenyl)pyrimidin-2-amine (compound 61).

(See Scheme B, Step 5): In a round bottom flask equipped with a magnetic stirrer, cool 5-(3morpholino-5-(phenylsulfonyl)phenyl)pyrimidin-2-amine (313 mg, 0.67 mmol) in 3 mL DCM at 0°C in an argon atmosphere. Trifluoroacetic acid (1 mL, 13.6 mmol) was added dropwise and the mixture was allowed to warm to room temperature and stirred until starting material disappeared as determined by TLC. The solvent and excess trifluoroacetic acid were removed in vacuo. The crude material was further used in TPA salt form. Alternatively, the crude material can be purified by column chromatography (0-10% (0.5 M NH ₃ /MeOH)/DCM) to obtain the free amine. ESI-MS+: 376.3 (M+H). ¹ H NMR (DMSO-d6, 500 MHz) δ: 8.64 (d, J=2.5 Hz, 2H), 7.45 (t, J=2.0 Hz, 1H), 7.40 (d , J=1.7 Hz, 1H), 7.22 (d, J=1.9 Hz, 1H), 6.89 (s, 2H), 4.66-4.57 (m, 1H), 3 .82-3.72 (m, 6H), 3.51 (t, J=8.6 Hz, 2H), 3.30-3.26 (m, 4H), 1.24 (shs, 1H).

Example 5 1-(3-((3-(2-aminopyrimidin-5-yl)-5-morpholinophenyl)sulfonyl)azetidin-1-yl)ethan-1one (compound 68).

(See Scheme B, Step 6a): To a round bottom flask equipped with a stirrer, 5-(3-(azetidin-3-ylsulfonyl)-5-morpholinophenyl)pyrimidin-2-amine, TPA salt (182.2 mg, 0.30 mmol), DCM (3 ml) and N,N-diisopropylethylamine (0.157 ml, 0.9 mmol). Acetic anhydride (0.028 mL, 0.3 mmol) was added dropwise. The reaction mixture was stirred for 2 hours under argon atmosphere. Absence of starting material was observed by TLC. The resulting compound was dissolved in DCM, saturated sodium bicarbonate was added and extracted 3 times with DCM. The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by column chromatography (0-10% (0.5 M NH ₃ /MeOH)/DCM) to give the desired product (76.7 mg, 0.184 mmol, yield 61%). ESI-MS+: 418.2 (M+H). 1H NMR (DMSO- _d6 , 500 MHz) δ: 8.67 (s, 2H), 7.48 (p, J=1.5 Hz, 2H), 7.28 (t, J=1.8 Hz , 1H), 6.90 (s, 2H), 4.55 (ddd, J=13.8, 7.6, 6.0 Hz, 1H), 4.38-4.30 (m, 2H), 4.05 (d, J=6.9 Hz, 2H), 3.76 (t, J=4.8 Hz, 4H), 3.30 (m, 4H), 1.77 (s, 3H).

Example 6 1-(3-((3-(2-aminopyrimidin-5-yl)-5-morpholinophenyl)sulfonyl)azetidin-1-yl)-2,2dimethylpropan-1-one (compound 86).

- 67 045787

Compound 86 (See Scheme B, Step 6b): To a flask equipped with a stirrer, 5-(3(azetidin-3-ylsulfonyl)-5-morpholinophenyl)pyrimidin-2-amine TPA salt (54 mg, 0.093 mmol), DCM (1.2 ml) and triethylamine (0.036 ml, 0.26 mmol). Pivaloyl chloride (0.012 mL, 0.1 mmol) was added dropwise. The reaction mixture was stirred overnight under argon. The resulting compound was dissolved in DCM, saturated sodium bicarbonate solution was added, and the organic layer was separated. The aqueous layer was extracted 2 more times with DCM. The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by column chromatography (0-7% (0.5 M NH ₃ /MeOH)/DCM) to give the desired product (35.9 mg, 0.084 mmol, yield 90%). ESI-MS+: 460.2 (M+H). ¹ H NMR (DMSO-d6, 500 MHz) δ: 8.66 (s, 2H), 7.54-7.42 (m, 2H), 7.28 (t, J=2.0 Hz, 1H) , 6.90 (s, 2H), 5.75 (s, 1H), 4.55 (p, J=7.3, 6.7 Hz, 2H), 4.02 (s, 2H), 3, 76 (dd, J=5.9, 3.8 Hz, 4H), 3.31-3.26 (m, 4H), 1.06 (s, 9H).

Example 7 5-(3-((1-isopropylazetidin-3-yl)sulfonyl)-5-morpholinophenyl)pyrimidin-2-amine (compound 65).

Compound 65 (See Scheme B, Step 6c): To a flask equipped with a stirrer, 5-(3(azetidin-3-ylsulfonyl)-5-morpholinophenyl)pyrimidin-2-amine TPA salt (34 mg, 0.06 mmol), sodium triacetoxyborohydride (22 ml), acetone (0.076 ml) and EDC (1 ml). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM and saturated sodium bicarbonate solution was added. After separating the organic layer, the aqueous layer was extracted with DCM 2 times. The combined organic phase was washed with brine, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (0-10% (0.5 M NH ₃ /MeOH)/DCM) to give the desired product (16.8 mg, 0.040 mmol, yield 67%). ESI-MS+: 418.1 (M+H). ¹ H NMR (DMSO-06, 500 MHz) δ: 8.65 (s, 2H), 7.45 (t, J=2.0 Hz, 1H), 7.40 (d, J=1.7 Hz , 1H), 7.22 (t, J=2.0 Hz, 1H), 6.89 (s, 2H), 4.36 (p, J=7.3 Hz, 1H), 3.76 (t , J=4.9 Hz, 4H), 3.36 (t, J=7.9 Hz, 2H), 3.303.25 (m, 6H), 2.31 (p, J=6.2 Hz, 1H ), 0.82 (d, J=6.2 Hz, 6H).

Example 8. (3-((3-(2-aminopyrimidin-5-yl)-5-morpholinophenyl)sulfonyl)azetidin-1-yl)(cyclopropyl)methanone (compound 77).

Connection 77

Step 1 (See Scheme B, Step 5): Tert-butyl 3-((3-bromo-5-morpholinophenyl)sulfonyl)azetidine-1carboxylate, which was synthesized as described in Example 3, was deprotected using TPA in DCM in the same manner as described in Example 4. The resulting TPA salt was used in its crude form after drying under vacuum overnight.

Step 2 (See Scheme B, Step 6b): To a round bottom flask equipped with a stirrer, 4-(3-(azetidin-3-ylsulfonyl)-5-bromophenyl)morpholine, TPA salt (376 mg, 0. 65 mmol), DCM (6.5 ml) and triethylamine (0.292 ml, 2.15 mmol). Cyclopropanecarbonyl chloride (0.088 mL, 0.975 mmol) was added dropwise. The reaction mixture was stirred overnight under argon. The resulting compound was dissolved in DCM, saturated sodium bicarbonate was added and the mixture was separated. The aqueous layer was extracted 2 more times with DCM. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by column chromatography (0-7% (0.5 M NH ₃ /MeOH)/DCM) to give (3-((3-bromo -5morpholinophenyl)sulfonyl)azetidin-1-yl)(cyclopropyl)methanone (267.1 mg, 0.62 mmol, 96%). IERMS ⁺ : 429.1, 431.1.

Stage 3 (see diagram B, stage 4a): This stage was carried out using the Suzuki combination method,

- 68 045787 as previously described in example 1, in step 3, starting from 303 mg (0.705 mmol) (3-((3-bromo-5morpholinophenyl)sulfonyl)azetidin-1-yl)(cyclopropyl)methanone, to obtain 128, 9 mg (0.289 mmol) (3-((3-(2-aminopyrimidin-5-yl)-5-morpholinophenyl)sulfonyl)azetidin-1-yl)(cyclopropyl)methanone in 41% yield. ESI-MS+: 445.3 (M+H). ^1H NMR ( _CDCl3 , 500 MHz) δ: 8.51 (s, 2H), 7.41 (s, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.17 ( t, J=1.8 Hz, 1H), 5.29 (s, 2H), 4.69 (dd, J=9.1, 4.6 Hz, 1H), 4.47 (t, J=8 .4 Hz, 1H), 4.29 (dd, J=9.2, 4.3 Hz, 1H), 4.20-4.04 (m, 2H), 3.89 (t, J=4, 8 Hz, 4H), 3.30 (dd, J=5.9, 3.8 Hz, 4H), 1.36 (tt, J=8.2, 4.6 Hz, 1H), 0.97 ( k, J=3.9, 3.4 Hz, 2H), 0.79 (tm, J=7.7, 3.2 Hz, 2H).

Example 9 3-((3 -(2-aminopyrimidin-5 -yl)-5 -morpholinophenyl)sulfonyl)-N-ethyl azetidin-1 carboxamide (compound 93). O

O o II G T

0'0" 0

Connection 93

Step 1 (see Scheme B, Step 6d): To a flask equipped with a stirrer, 4-(3-(azetidin-3-ylsulfonyl)-5-bromophenyl)morpholine, TPA salt (64 mg, 0.11 mmol), DCM (1.4 ml) and triethylamine (0.031 ml). Ethyl isocyanate (0.0163 mL, 0.206 mmol) was added dropwise. The reaction mixture was stirred for 2 hours at room temperature until the disappearance of the starting material, as determined by TLC. The resulting compound was dissolved in DCM, water and saturated sodium bicarbonate solution were added and the mixture was separated. The aqueous layer was extracted two more times with DCM. The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by column chromatography (0-5% (0.5 M NH ₃ /MeOH)/DCM) to give 3-((3bromo-5- morpholinophenyl)sulfonyl)-N-ethyl azetidin-1-carboxamide (32.4 mg, 0.075 mmol, 68% yield). ESI-MS+: 432.1, 434.1.

Step 2: This step was carried out using the Suzuki coupling method as described previously in example 1, in step 3, starting from 3-((3-bromo-5-morpholinophenyl)sulfonyl)-K-ethyl azetidin-1carboxamide (32.4 mg , 0.075 mmol), yielding 23.3 mg (0.052 mmol) of 3-((3-(2-aminopyrimidin-5yl)-5-morpholinophenyl)sulfonyl)-N-ethyl azetidin-1-carboxamide in 69% yield. ESI-MS+: 447.1, 448.1, 449.0. 1H NMR (DMSO- _d6 , 500 MHz) δ: 8.66 (s, 2H), 7.48 (t, J=1.9 Hz, 1H), 7.44 (d, J=1.5 Hz , 1H), 7.25 (t, J=1.9 Hz, 1H), 6.90 (s, 2H), 6.45 (d, J=5.6 Hz, 1H), 4.51 (tm , J=8.1, 5.5 Hz, 1H), 4.06-3.87 (m, 4H), 3.76 (dd, J=6.0, 3.7 Hz, 4H), 3, 30 (s, 4H), 2.99 (cd, J=7.1, 5.4 Hz, 2H), 0.98 (t, J=7.1 Hz, 3H).

The following compounds were prepared by methods similar to those described for compounds 54, 61, 68, 65, 77 and 93, and as described in scheme B:

Connection no. MS Ή NMR 66 460.3 (M+H) (DMSO-ab, 500 MHz) δ: 8.65 (s, 2H), 7.45 (d, J = 2.2 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H) , 7.23 (t, J = 2.1 Hz, 1H), 6.89 (s, 2H), 4.42 (p, J = 7.4 Hz, 1H), 3.82 - 3.65 ( m, 6H), 3.37 (m, 4H), 3.30 - 3.21 (m, 6H), 2.27 (m, 1H), 1.64 - 1.42 (m, 2H), 1 .07 (m, 2H). 67 559.3 (M+H) (DMSO-ab, 500 MHz) 5: 8.64 (s, 2H), 7.43 (dt, J = 6.2, 1.7 Hz, 2H), 7.24 (t, J = 2.0 Hz, 1H), 6.89 (s, 2H), 4.37 (k, J = 7.0 Hz, 1H), 3.80 - 3.69 (m, 4H), 3.45 (dt, J = 12.8, 4.9 Hz, 2H), 3.37 (d, J = 7.3 Hz, 4H), 3.30 - 3.26 (m, 4H), 2.90 (s, 2H) , 2.23 (d, J = 8.7 Hz, 1H), 1.52 (dd, J = 10.9, 5.6 Hz, 2H), 1.37 (s, 9H), 1.04 - 0.93 (m, 2H). 75 432.2 (M+H) (CDCh, 500 MHz) δ: 8.52 (s, 2H), 7.40 (d, J = 1.5 Hz, 1H), 7.32 (t, J = 2.0 Hz, 1H), 7 .17 (t, J = 1.8 Hz, 1H), 5.31 (s, 2H), 4.54 (dd, J = 9.3, 5.2 Hz, 1H), 4.37 - 4, 25 (m, 2H), 4.16 - 4.00 (m, 2H), 3.93 - 3.83 (m, 4H), 3.30 (dd, J = 5.9, 3.9 Hz, 4H), 2.11 (dk, J = 11.1, 7.7 Hz, 2H), 1.11 (t, J = 7.5 Hz, ZN), 76 446.15 (M+H) (CDC1 ₃ , 500 MHz) δ: 8.51 (s, 2H), 7.40 (d, J = 1.5 Hz, 1H), 7.33 (t, J = 2.0 Hz, 1H), 7.17 (t, J = 1.9 Hz, 1H), 5.22 (s, 2H), 4.58 (dd, J = 9.4, 5.0 Hz, 1H), 4.37 (t , J = 8.7 Hz, 1H), 4.27 (dd, J = 10.2, 5.1 Hz, 1H), 4.14 4.00 (m, 2H), 3.93 - 3.85 (m, 4H), 3.30 (dd, J = 5.8, 3.9 Hz, 4H), 2.41 (p, J = 6.8 Hz, 1H), 1.09 (dd, J = 12.2, 6.8 Hz, 6H). 78 512.2 (M+H) (DMSO-ab, 500 MHz) δ: 8.67 (s, 2H), 7.49 (dt, J = 6.6, 1.7 Hz, 2H), 7.29 - 7.20 (m, ZN ), 7.16 - 7.05 (m, 2H), 6.91 (s, 2H), 4.59 (p, J = 6.9 Hz, 1H), 4.43 (d, J = 6, 8 Hz, 2H), 4.08 (d, J = 6.8 Hz, 2H), 3.76 (t, J = 4.8 Hz, 4H), 3.45 (s, 2H), 3.31 -3.28 (m, 4H).

- 69 045787

79 498.2 (M+H) (DMSOMB, 500 MHz) δ: 8.65 (s, 2H), 7.76 - 7.61 (m, 2H), 7.49 (dt, J = 8.0, 1.6 Hz, 2H), 7.36 - 7.18 (m, ZN), 6.90 (s, 2H), 4.72 - 4.59 (m, 2H), 4.48 (s, 1H), 4.28 (s, 2H), 3.75 (t, J = 4.8 Hz, 4H), 3.29 (dd, J = 7.1, 4.4 Hz, 4H). 80 484.2 (M+H) (DMSO-yb, 500 MHz) δ: 8.64 (s, 2H), 7.46 (t, J = 1.9 Hz, 1H), 7.42 (t, J = 1.4 Hz, 1H) , 7.27 - 7.21 (m, ZN), 7.11 - 7.05 (m, 2H), 6.89 (s, 2H), 4.45 (p, J = 7.2 Hz, 1H ), 3.76 (t, J = 4.8 Hz, 4H), 3.56 (s, 2H), 3.42 (d, J = 7.2 Hz, 4H), 3.28 (t, J = 4.9 Hz, 4H). 81 419.1 (M+H) (DMSO-ab, 500 MHz) δ: 8.66 (s, 2H), 7.48 (t, J = 1.9 Hz, 1H), 7.46 7.42 (m, 1H), 7.25 (t, J = 1.9 Hz, 1H), 6.90 (s, 2H), 6.04 (s, 2H), 4.51 (tg, J = 8.4, 5.4 Hz, 1H) , 4.02 - 3.93 (m, 4H), 3.76 (dd, J = 5.8, 3.8 Hz, 4H), 3.32 - 3.22 (m, 4H). 92 475.2 (M+H) (DMSOMB, 500 MHz) b: 8.66 (s, 2H), 7.48 (t, J = 2.0 Hz, 1H), 7.44 (t, J = 1.5 Hz, 1H), 7 .25 (t, J = 1.9 Hz, 1H), 6.90 (s, 2H), 5.84 (s, 1H), 4.49 (tg, J = 8.4, 5.4 Hz, 1H), 4.01 - 3.87 (m, 4H), 3.81 - 3.74 (m, 4H), 3.31 3.28 (m, 4H), 1.21 (s, 9H). 102 484.2 (M+H) (DMSO-ab, 500 MHz) δ: 8.73 (s, 2H), 7.65 (d, J = 3.5 Hz, 1H), 7.50 (d, J = 1.8 Hz, 2H) , 7.30 (t, J = 1.9 Hz, 1H), 4.65 - 4.53 (m, 1H), 4.53 - 4.42 (m, 2H), 4.07 (d, J = 6.8 Hz, 2H), 3.76 (dd, J = 6.0, 3.8 Hz, 4H), 3.34 3.30 (m, 4H), 2.76 (tk, J = 7 ,2, 3.8 Hz, 1H), 1.60 - 1.53 (m, 1H), 0.76 0.60 (m, 6H), 0.53 - 0.47 (m, 2H).

5-(3-morpholino-5-((4-morpholinophenyl)sulfonyl)phenyl)pyrimidin-2-amine (compound Example 10. Introduction 36).

Stage 1

(See Scheme C, Step 7): Synthesis of 4-(3-bromo-5-(4-morpholinophenylsulfonyl)phenyl)morpholine.

Morpholine (1.25 g, 14.4 mmol) and Cs ₂ CO ₃ (2.93 g, 9.0 mmol) were added sequentially to the stirred solution of 4-(3-bromo-5-((4-fluorophenyl)sulfonyl) phenyl)morpholine (1.2 g, 3.0 mmol) in DMF (10 ml). The reaction mixture was heated at 110-120°C overnight. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (20 ml x 3). The organic extracts were combined, washed with brine (15 mLx2), dried over anhydrous sodium sulfate and concentrated to give crude 4-(3-bromo-5-(4-morpholinophenylsulfonyl)phenyl)morpholine (0.9 g, 64% yield) , which was used for the next reaction without further purification. The compound was confirmed only by LC-MS: 467.27 (M+H)+, C ₂₀ H ₂₃ BrN ₂ O ₄ S.

Step 2 (see Scheme C, Step 4b): 5-(3-morpholino-5-((4-morpholinophenyl)sulfonyl)phenyl)pyrimidin-2-amine was synthesized as described for compound 38 in example 2 (45 mg , yield 4.8%). ESI-MS+: 482.5 (M+H). Ή NMR (CDCl3, 400 MHz) δ: 8.48 (s, 2H), 7.81 (d, J=9.2 Hz, 2H), 7.42 (s, 1H), 7.39 (s, 1H), 7.02 (s, 1H), 6.88 (d, J=9.2 Hz, 2H), 5.31 (w, 2H), 3.87 (m, 4H), 3.83 ( m, 4H), 3.27 (m, 8H).

The following compounds were prepared by methods similar to those described for compound 36 and as described in Scheme C:

Connection no. MS II NMR 37 484.4 (M+H) (DMSO-ab, 400 MHz) δ: 8.59 (s, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.41 (s, 1H), 7.31 (s, 1H), 7.23 (s, 1H), 6.90 (s, 2H), 6.72 (d, J=8.8 Hz, 2H), 6.52 (t, J=5.6 Hz, 1H), 4.51 (s, 1H), 3.74 (m, 4H), 3.24 (m, 4H), 2.99 (d, J=6.0 Hz, 2H), 1.12 ( s, 6H).

Example 11 (R)-5-(3-morpholino-5-((tetrahydrofuran-3-yl)sulfonyl)phenyl)pyrimidin-2-amine (compound 52).

Step 1 (See Scheme D, Step 8): Synthesis of Benzyl(3,5-dibromophenyl)sulfane Phenylmethanethiol (19.8 g, 0.16 mol) was added to a solution of sodium hydride (7.04 g, 0.18 mol, purity 60 % in mineral oil) in DMF (300 ml) at 0°C. The reaction mixture was stirred for 15 minutes at room temperature

- 70 045787 tour and added 1,3,5-tribromobenzene (50 g, 0.16 mol). The reaction mixture was stirred for another 2 hours at room temperature. The solution was poured into ice water (500 ml) and extracted with ethyl acetate (300 ml x 3). The organic extracts were combined, washed with brine (300 ml x 2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether) to give benzyl(3,5-dibromophenyl)sulfane. (50.1 g, 88% yield). The compound was confirmed by LC-MS only: 379.10 (M+Na)+, C ₁₃ H ₁₀ Br ₂ S.

Br Br

Step 2 (see Scheme D, Step 9): Synthesis of 4-(3-(benzylthio)-5-bromophenyl)morpholine Pd ₂ dba ₃ (5 g) was added to a mixture of benzyl(3,5-dibromophenyl)sulfane (50 g , 0.14 mmol), BINAP (7.9 g, 12.6 mmol), t-BuONa (20.16 g, 0.21 mol), DBU (19.2 g, 0.126 mol) and morpholine (12, 2 g, 0.14 mol) in toluene (400 ml) under a protective nitrogen atmosphere. The reaction mixture was heated at 95°C for 2 hours. The mixture was cooled to room temperature and poured into water (500 ml). The mixture was extracted with ethyl acetate (300 mlx3). The organic extracts were combined, washed with brine (200 mlx2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30:1) to give 4-(3-(benzylthio)-5bromophenyl)morpholine (21.3 g, 42% yield) as a yellow solid. The compound was confirmed only by LC-MS: 364.30 (M+H) ⁺ , C ₁₇ H ₁₈ BrNOS.

Br Br

Step 3 (See Scheme D, Step 10): Synthesis of 3-bromo-5-morpholinobenzenethiol Anhydrous AlCl ₃ (60.7 g, 0.45 mol) was added to the 4-(3-(benzylthio)-5-bromophenyl) solution morpholine (33 g, 0.09 mol) in toluene (500 ml). The reaction mixture was heated at 50°C for 2 hours. The mixture was quenched by carefully adding ice water (500 ml) and extracted with ethyl acetate (500 ml x 3). The organic extracts were combined, washed with brine (300 mlx2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1) to give crude 3-bromo-5-morpholinobenzenethiol (21.6 g, 87% yield), which was used for the next reaction without further purification. The compound was confirmed by LC-MS only: 276.22 (M+H)+, C ₁₀ H ₁₂ BrNOS.

Step 4 (See Scheme D, Step 11a): Synthesis of 4-[3-bromo-5-[(3R)-tetrahydrofuran-3yl]sulfanylphenyl]morpholine DEAD (9.88 g, 56.7 mmol) was added to the PPh solution ₃ (14.9 g, 56.7 mmol) in toluene (100 ml) at 0°C. The solution was stirred for 0.5 hour at 0°C and a solution of (S)tetrahydrofuran-3-ol (5.0 g, 56.7 mmol) in toluene (10 ml) was added. After stirring for another 0.5 hour at 0° C., a solution of 3-bromo-5-morpholinobenzenethiol (15.56 g, 56.75 mmol) in toluene (20 ml) was added. The reaction mixture was stirred for another 1 hour at room temperature. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 mlx3). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate and concentrated to give a yellow solid. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1) to give 4-[3-bromo-5-[(3R)-tetrahydrofuran-3yl]sulfanylphenyl]morpholine (11.6 g, 59% yield) in the form of a pale yellow oily substance. The compound was confirmed by LC-MS: 344.35 (M+H)+, C ₁₄ H ₁₈ O ₂ SBrN.

Step 5 (See Scheme D, Step 12a): Synthesis of 4-[3-bromo-5-[(3R)-tetrahydrofuran-3yl]sulfonylphenyl]morpholine mCPBA (23.3 g, 0.13 mol) was added portionwise to a solution of 4-[3-bromo-5[(3R)-tetrahydrofuran-3-yl]sulfanylphenyl]morpholine (11.6 g, 33.7 mmol) in dichloromethane (250 ml). The mixture was stirred at room temperature for 2 hours. Add 4,4,4',4',5,5,5',5'octamethyl-2,2'-bi(1,3,2-dioxaborolane) (34.2 g, 0.13 mol) and stir the resulting mixture for 0.5 hours at room temperature. The reaction mixture was washed with saturated Na ₂ CO ₃ solution (200 mlx3), saturated saline solution (100 ml), dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1) to give the title compound, 4-[3-bromo-5-[(3R)-tetrahydrofurαn-3yl]sulfonylphenyl]morpholine (5.0 g, yield 39%) in the form of a colorless oily substance. The compound was confirmed by LC-MS: 376.53 (M+H)+, C ₁₄ H ₁₈ NO ₄ SBr.

Connection 52

Step 6 (see Scheme D, Step 4c): Mixture of 4-[3-bromo-5-[(3R)-tetrahydrofuran-3yl]sulfonylphenyl]morpholine (3.0 g, 8.0 mmol), 5-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrimidin-2-amine (3.53 g, 16.0 mmol), K2CO3 (2.20 g, 16.0 mmol) and Pd (dppf)Cl ₂ (651 mg, 0.8 mmol) in 1,4-dioxane (15 ml) and H2O (5 ml) was stirred at 95 °C for 1 hour under a protective atmosphere of N ₂ . The mixture was poured into water (50 ml) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=50:1) to give (R)-5-(3-morpholino-5-((tetrahydrofuran-3-yl)sulfonyl)phenyl)pyrimidin-2-amine (compound 52) (1.65 g, 53% yield) as an off-white solid. ESI-MS+: 391.5 (M+H). ^1H NMR (DMSO-d^400 MHz) δ: 8.67 (s, 2H), 7.46 (s, 2H), 7.27 (s, 1H), 6.92 (s, 2H), 4 .33 (m, 1H), 4.04 (m, 1H), 3.80 (m, 2H), 3.77 (m, 4H), 3.68 (m, 1H), 3.31 (m, 4H), 2.18 (m, 1H), 2.09 (m, 1H).

The following compounds were prepared by methods similar to those described for compound 52 and as described in Scheme D:

Connection no. MS Shchyamr 48 (as TPA salt) 450.3 (M+H) (DMSO-s16, 400 MHz) δ: 11.19 (w, 1H), 8.55 (s, 2H), 7.41 (d, J=7.6 Hz, 1H), 7.35 (m, 2H), 7.27 (s, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.03 (m, 2H), 6.89 (m, 1H), 4.815 (s, 2H), 3.71 (m, 4H), 3.11 (m, 4H). 53 390.82 (M+H) (DMSO-c16, 400 MHz) δ: 8.67 (s, 2H), 7.47 (s, 2H), 7.27 (s, 1H), 6.93 (s, 2H), 4.31 ( m, 1H), 4.02 (m, 1H), 3.73-3.87 (m, 6H), 3.66 (m, 1H), 3.30 (m, 4H), 2.17 (m , 1H), 2.09 (m, 1H). 56 450.2 (M+H) (MeOD, 400 MHz) δ: 8.35 (s, 2H), 7.27 (m, 4H), 7.12 (s, 1H), 6.94 (m, 1H), 6.77 (d, J=l,2 Hz, 1H), 6.37 (d, J=2.8 Hz, 1H), 4.55 (s, 2H), 3.72 (m, 4H), 2.96 (m, 4H). 57 (as TPA salt) 503.6 (M+H) (DMSO-c16, 400 MHz) δ: 9.86 (s, 1H), 8.66 (s, 2H), 7.45 (s, 1H), 7.31 (s, 1H), 7.13 ( m, 5H), 7.02 (s, 1H), 4.64 (s, 2H), 3.74 (m, 4H), 3.20 (m, 4H), 2.98 (s, ZN). 58 495.53 (M+H) (DMSO-s16, 400 MHz) δ: 8.56 (s, 2H), 7.41 (s, 1H), 7.22 (s, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.95 (s, 1H), 6.91 (s, 2H), 6.85 (d, J=8.8 Hz, 2H), 4.54 (s, 2H), 3.72 ( m, 8H), 3.17 (m, 4H), 3.07 (m, 4H). 59 (as TPA salt) 401.3 (M+H) (MeOD, 400 MHz) δ: 8.95 (s, 1H), 8.70 (s, 2H), 7.46 (s, 1H), 7.42 (m, 2H), 7.27 (s, 1H), 4.80 (s, 2H), 3.84 (m, 4H), 3.29 (m, 4H). 63 450.9 (M+H) (MeOD, 400 MHz) δ: 8.37 (s, 2H), 8.19 (s, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.34 (s, 1H) , 7.29 (m, 1H), 7.12 (m, 2H), 6.86 (s, 1H), 4.63 (s, 2H), 3.72 (m, 4H), 3.01 ( m, 4H). 71 458.2 (M+H) (CDC1 ₃ , 500 MHz) δ: 8.08 (s, 1H), 7.39 (d, J = 1.9 Hz, 1H), 7.28 (s, 1H), 7.03 (s, 1H ), 6.86 (s, 1H), 5.01 (s, 2H), 4.16 (dd, J = 10.1, 5.8 Hz, 1H), 3.96 (dd, J = 10, 1, 7.9 Hz, 1H), 3.92 - 3.75 (m, 6H), 3.26 (dd, J = 5.9, 3.8 Hz, 4H), 2.41 (dk, J = 13.1, 6.1 Hz, 1H), 2.18 (ddd, J = 13.2, 9.3, 6.7 Hz, 1H), 1.97-1.86 (m, 1H). 82 442.86 (M+H) (DMSO-s16, 400 MHz) δ: 8.66 (s, 2H), 7.43 (d, J=9.2 Hz, 2H), 7.25 (m, ZN), 7.05 (m, 2H), 6.92 (s, 2H), 3.76 (m, 4H), 3.71 (m, 2H), 3.29 (m, 4H), 2.92 (d, J=8.0 Hz, 2H).

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83 446.4 (M+H) (CDC1 ₃ , 400 MHz) δ: 8.54 (s, 2H), 7.38 (s, 1H), 7.29 (s, 1H), 7.17 (s, 1H), 5.38 (w , 2H), 4.75 (m, 2H), 3.97 (m, 1H), 3.90 (m, 4H), 3.30 (m, 4H), 3.14 (m, 1H), 3 .07 (m, 1H), 2.50 (m, 1H), 2.15 (m, 1H), 2.08 (s, ZN), 1.99 (m, 1H), 1.89 (m, 2H), 1.65 (m, 2H). 84 497.8 (M+H) (CDC1 ₃ , 400 MHz) δ: 8.22 (s, 2H), 7.21 (s, 1H), 7.06 (s, 1H), 6.91 (d, >8.0 Hz, 2H) , 6.64 (s, 1H), 6.56 (d, >8.0 Hz, 2H), 4.23 (s, 2H), 3.89 (m, 4H), 3.76 (m, 2H ), 3.40 (s, 1H), 3.24 (m, 4H), 3.08 (s, 2H), 2.01 (m, 1H), 1.32 (s, 6H). 89 432.3 (M+H) (DMSO-46, 400 MHz) δ: 12.04 (w, 1H), 9.07 (w, 2H), 7.62 (w, 2H), 7.36 (m, 1H), 4.48 ( w, 1H), 3.78 (m, 5H), 3.46 (m, ZN), 3.34 (m, 4H), 3.11 (m, 1H), 2.26 (m, 2H), 1.27 (m, 6H). 90 446.6 (M+H) (DMSO-ab, 400 MHz) δ: 8.66 (s, 2H), 7.51 (s, 1H), 7.38 (s, 1H), 7.19 (s, 1H), 6.95 ( s, 2H), 3.77 (m, 4H), 3.36 (m, ZN), 3.30 (m, 4H), 2.93 (w, 2H), 1.73-2.21 (w , 5H), 0.82-1.39 (w, 6H). 91 431.90 (M+N) (DMSO-ab, 400 MHz) δ: 8.74 (s, 2H), 7.54 (m, 2H), 7.32 (m, 1H), 7.01 (s, 2H), 4.36 ( m, 1H), 3.83 (m, 4H), 3.79 (m, 1H), 3.52 (m, 2H), 3.37 (m, 5H), 2.32 (m, 2H), 1.92 (m, ZN). 97 412.01 (M+N) (DMSO-ab, 400 MHz) δ: 8.59 (s, 2H), 8.52 (m, 2H), 7.46 (s, 1H), 7.32 (s, 1H), 7.22 ( m, 2H), 7.05 (s, 1H), 6.94 (s, 2H), 4.82 (s, 2H), 3.74 (m, 4H), 3.21 (m, 4H). 98 446.5 (M+H) (CDC1 ₃ , 400 MHz) δ: 8.54 (s, 2H), 7.38 (s, 1H), 7.29 (s, 1H), 7.17 (s, 1H), 5.38 (w , 2H), 4.75 (m, 1H), 3.97 (m, 1H), 3.90 (m, 4H), 3.30 (m, 4H), 3.14 (m, 1H), 3 .07 (m, 1H), 2.50 (m, 1H), 2.15 (m, 1H), 2.08 (s, ZN), 1.99 (m, 1H), 1.65 (m, 2H). 99 461.6 (M+H) (DMSO-ab, 400 MHz) δ: 7.37 (s, 1H), 7.34 (m, 1H), 7.22 (m, 1H), 7.17 (s, 2H), 7.08 ( m, 1H), 6.66 (s, 1H), 6.41 (s, 2H), 4.73 (s, 2H), 3.75 (m, 4H), 3.18 (m, 4H), 2.09 (s, ZN). 100 458.35 (M+H) (DMSO-ab, 400 MHz) δ: 8.62 (s, 1H), 8.09 (s, 1H), 7.50 (s, 2H), 7.27 (s, 1H), 6.73 ( s, 2H), 4.34 (m, 1H), 4.03 (m, 1H), 3.75-3.85 (m, 6H), 3.67 (m, 1H), 3.30 (m , 4H), 2.11-2.19 (m, 2H). 101 390.4 (M+H) (DMSO-ab, 400 MHz) δ: 8.33 (s, 1H), 7.79 (m, 1H), 7.40 (m, 2H), 7.23 (s, 1H), 6.53 ( d, >8.4 Hz, 1H), 6.22 (s, 2H), 4.31 (m, 1H), 4.02 (m, 1H), 3.84 (m, 2H), 3.76 (m, 4H), 3.65 (m, 1H), 3.30 (m, 4H), 2.15 (m, 2H). 105 458.43 (M+H) (DMSO-ab, 400 MHz) δ: 7.50 (d, 1H), 7.33 (s, 1H), 7.16 (s, 1H), 7.11 (s, 1H), 6.73 ( d, 1H), 6.66 (s, 2H), 4.24 (m, 1H), 3.97 (m, 1H), 3.81 (m, 1H), 3.75 (m, 5H), 3.64 (m, 1H), 3.25 (m, 4H), 2.13 (m, 2H). 106 408.6 (M+H) (CDC1 ₃ , 400 MHz) δ: 8.13 (d, >10.4 Hz, 1H), 7.43 (s, 1H), 7.35 (s, 1H), 7.19 (s, 1H) , 6.31 (d, >12.0 Hz, 1H), 4.89 (w, 2H), 4.20 (m, 1H), 3.774.03 (m, 8H), 3.28 (m, 4H ), 2.44 (m, 1H), 2.20 (m, 1H). 107 424.37 (M+H) (CDC1 ₃ , 400 MHz) δ: 8.00 (s, 1H), 7.37 (m, 2H), 7.12 (s, 1H), 6.66 (s, 1H), 4.81 (s , 2H), 4.18 (m, 1H), 3.80-4.00 (m, 8H), 3.29 (m, 4H), 2.44 (m, 1H), 2.20 (m, 1H). 108 404.7 (M+H) (DMSO-ab, 400 MHz) δ: 8.31 (s, 1H), 7.70 (m, 1H), 7.45 (s, 1H), 7.29 (m, 1H), 7.21 ( s, 1H), 6.50 (d, >8.8 Hz, 1H), 6.26 (w, 1H), 4.19 (m, 1H), 3.77-3.98 (m, 8H) , 3.29 (m, 4H), 2.98 (s, ZN), 2.44 (m, 1H), 2.19 (m, 1H). 114 436.5 (M+H) (DMSO-ab, 400 MHz) δ: 12.25 (w, 1H), 8.56 (s, 2H), 8.23 (s, 1H), 7.87 (dd, >6.8 Hz, 2 .0 Hz, 1H), 7.53 (s, 1H), 7.49 (m, 1H), 7.38 (s, 1H), 7.26 (s, 1H), 7.21 (m, 2H ), 6.89 (s, 2H), 3.73 (m, 4H), 3.23 (m, 4H). 121 404.7 (M+H) (CDC1 ₃ , 500 MHz) δ: 8.11 (s, 1H), 7.35 (dd, J - 2.5, 1.6 Hz, 1H), 7.25 (t, J - 1.5 Hz , 1H), 6.98 (dd, J - 2.5, 1.4 Hz, 1H), 5.20 (s, 2H), 4.18 (dd, J 10.1, 5.7 Hz, 1H ), 3.99 - 3.90 (m, 2H), 3.90 - 3.86 (m, 4H), 3.86 - 3.78 (m, 2H), 3.27 (dd, J = 5 ,9, 4.0 Hz, 4H), 2.46 - 2.39 (m, 1H), 2.33 (d, J = 1.8 Hz, ZN), 2.20 (m, 1H).

Example 12 5-(3-((difluoro(phenyl)methyl)sulfonyl)-5-morpholinophenyl)pyrimidin-2-amine (compound 87).

Step 1 (See Scheme D, Step 11b): Synthesis of 4-(3-(benzylthio)-5-bromophenyl)morpholine (Bromomethyl)benzene (1.25 g, 7.33 mmol) was mixed with 3-bromo-5- morpholinobenzenethiol (2 g, 7.33 mmol) and Cs ₂ CO ₃ (4.8 g, 14.66 mmol) in acetonitrile (30 ml). The reaction mixture was stirred for 1 hour at room temperature. The insoluble precipitate was filtered off and washed with acetonitrile (20 ml). The filtrate and washing solution were combined and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1) to give 4-(3-(benzylthio)-5bromophenyl)morpholine (1.2 g, 45% yield) as an off-white solid. The compound was confirmed by LC-MS only: 366.14 (M+H)+, C ₁₇ H ₁₈ BrNOS.

Vg Vg

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Step 2 (See Scheme D, Step 12a): Synthesis of 4-(3-(benzylsulfonyl)-5-bromophenyl)morpholine.

4-(3-(Benzylthio)-5-bromophenyl)morpholine (1.2 g, 3.3 mmol) was oxidized with mCPBA as described in Example 11 for compound 52 to give 4-(3-(benzylsulfonyl)-5 -bromophenyl)morpholine (0.6 g, 46% yield) as a white solid. The connection was confirmed only using LC-MS:

397.50 (M+H)+, C17H16BrF2NO3S.

Stage (see

13):

D, stage diagram

Synthesis

4-(3-Bromo-5(difluoro(phenyl)methylsulfonyl)phenyl)morpholine NaHMDS (2.68 mL, 5.36 mmol, 2M in THF) was added to a solution of 4-(3-(benzylsulfonyl)-5-bromophenyl) morpholine (0.53 g, 1.34 mmol) in THF (50 ml) at 0°C. The reaction mixture was stirred for 1 hour at 0°C. Ν-Φτορ-Ν(phenylsulfonyl)benzenesulfonamide (1.69 g, 5.36 mmol) was added and the reaction mixture was stirred for an additional 1 hour at 0°C. The mixture was poured into ice water (200 ml) and extracted with ethyl acetate (200 ml x 3). The organic extracts were combined and washed with saturated sodium carbonate solution (100 mlx2). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3:1) to give 4-(3-bromo5-((difluoro(phenyl)methyl)sulfonyl)phenyl)morpholine (0.22 g, 38% yield) as off-white solid. The compound was confirmed only by LC-MS: 434.23 (M+H) ⁺ , C ₁₇ H ₁₆ BrF ₂ NO ₃ S.

Step 4 (see Scheme D, Step 4c): Synthesis of 5-(3-((difluoro(phenyl)methyl)sulfonyl)-5morpholinophenyl)pyrimidin-2-amine:

As a result of the reaction with nyl)phenyl)morpholine (220 mg,

Suzuki between 0.51 mmol) and

4-(3-bromo-5-((difluoro(phenyl)methyl)sulfo5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrimidin-2-amine (110 mg, 0 .51 mmol), as described in example 11 for compound 52, gave 5(3-((difluoro(phenyl)methyl)sulfonyl)-5-morpholinophenyl)pyrimidin-2-amine (93 mg, 41% yield) as dirty -white solid ESI-MS+: 447.2 (M+H) 1H NMR (DMSO-Y6, 400 MHz) δ: 8.59 (s, 2H), 7.71 (m, 1H), 7 .61 (m, 5H), 7.37 (s, 1H), 7.17 (s, 1H), 6.99 (s, 2H), 3.77 (m, 4H), 3.28 (m, 4H).

Example 13 N ¹ -(5-(3-((4-fluorobenzyl)sulfonyl)-5-morpholinophenyl)pyrimidin-2-yl)ethane-1,2diamine (compound 47).

Step 1 (see Scheme E, Step 10): Synthesis of 3,5-dibromobenzenethiol Debenzylation of benzyl(3,5dibromophenyl)sulfane (26 g, 73.0 mmol) with anhydrous AlCl3 (48 g, 0.36 mol) was carried out as follows: described in Example 11 for compound 52, yielding 3,5-dibromobenzenethiol (10.7 g, 55% yield), which was used for the next reaction without further purification. The compound was confirmed by LC-MS only: 266.82 (M-H) ^- , C ₆ H ₄ Br ₂ S.

Step 2 (See Scheme E, Step 11b): Synthesis of (3,5-dibromophenyl)(4-fluorobenzyl)sulfane 3,5 Dibromobenzenethiol (5 g, 18.8 mmol) was treated with 4-fluorobenzyl chloride (3.0 g, 20. 7 mmol) and Cs ₂ CO ₃ (12.3 g, 37.6 mmol) in acetonitrile (300 ml). The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was filtered and washed with acetonitrile (20 ml). The filtrate and wash solution were combined and concentrated to give crude (3,5dibromophenyl)(4-fluorobenzyl)sulfane (6.9 g, 98% yield) as a colorless oil, which was used in the next step without further purification. GC-MS: 376. 1H NMR ( _CDCl3 , 400 MHz) δ: 7.45 (s, 1H), 7.31 (s, 2H), 7.27 (m, 2H), 7.00 (m, 2H), 4.09 (s, 2H).

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Step 3 (see Scheme E, Step 12b and Step 11): Synthesis of 4-(3-bromo-5-(4fluorobenzylsulfonyl)phenyl)morpholine.

A solution of KMnO ₄ (3.79 g, 24.0 mmol) in water (225 ml) was added to a solution of (3,5-dibromophenyl)(4fluorobenzyl)sulfane (6 g, 16.0 mmol) in acetic acid (350 ml) . The reaction mixture was stirred for 1 hour. A 10% Na ₂ SO ₃ solution (30 ml) was added. The resulting precipitate was filtered and washed with water (50 ml). The filter cake was dissolved in ethyl acetate (100 ml) and washed with saturated sodium bicarbonate solution (30 ml). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to give the crude intermediate (6.5 g, quantitative yield). The crude intermediate (6.5 g, 16.0 mmol) was dissolved in toluene (200 ml). Pd ₂ db ₃ (0.5 g), BINAP (0.1 g, 0.18 mmol), t-BuONa (2.3 g, 24.0 mol), DBU (2.2 g, 14.4 mol) and morpholine (1.4 g, 16.0 mol) under a protective nitrogen atmosphere. The reaction mixture was heated at 95°C for 5 hours. The mixture was cooled to room temperature and poured into water (500 ml). The mixture was extracted with ethyl acetate (300 mlx3). The organic extracts were combined, washed with brine (200 mlx2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 6:1) to give 4-(3bromo-5-((4-fluorobenzyl)sulfonyl)phenyl)morpholine (0.7 g, 11% yield) as a yellow solid substances. The compound was confirmed only by LC-MS: 415.75 (M+H) ⁺ , C ₁₇ H ₁₇ BrFNO ₃ S.

Step 4 (see Scheme E, Step 7): Synthesis of tert-butyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrimidin-2-ylamino)ethylcarbamate .

A solution of 5-bromo-2-chloropyrimidine (0.84 g, 4.4 mmol), tert-butyl-2-aminoethylcarbamate (0.7 g, 4.4 mmol) and DIPEA (1.1 g, 8.8 mmol ) in isopropyl alcohol (30 ml) was heated at 80°C for 3 hours. iPrOH was removed in vacuo. The residue was suspended in water (30 ml) and extracted with ethyl acetate (30 mlx3). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated to give crude tert-butyl (2-((5-bromopyrimidin-2-yl)amino)ethyl)carbamate (0.75 g, 54% yield), which was used for following reaction without further purification. Tert-butyl-2(5-bromopyrimidin-2-ylamino)ethylcarbamate was confirmed by LC-MS only: 317.16 (M+H)+, C11H17BrN4O2.

(See Chart E, Step 14): Mixture of tert-butyl-(2-((5-bromopyrimidin-2-yl)amino)ethyl)carbamate (0.75 g, 2.4 mmol), 4,4,4 ',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.67 g, 2.6 mmol), potassium acetate (0.46 g, 4.7 mol) and Pd(dppf)Cl ₂ (0.2 g, 0.24 mmol) in 1,4-dioxane (30 ml) were heated at 115°C for 3 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (50 ml). Insoluble materials were filtered off and washed with ethyl acetate (5 ml). The filtrate and wash solution were combined, washed with water (30 ml x 2), brine (30 ml x 2), dried over anhydrous sodium sulfate and concentrated. The residue was washed with petroleum ether/ethyl acetate (40 ml, 20:1) to give crude tert-butyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrimidin- 2-ylamino)ethylcarbamate (0.93 g, quantitative yield), which was used for the next reaction without further purification. The connection was confirmed only by LCMS: 365.00 (M+H) ⁺ , C ₁₇ H ₂₉ BN ₄ O ₄ .

Step 5 (see Scheme E, Step 4c): By Suzuki reaction between 4-(3-bromo-5-(4fluorobenzylsulfonyl)phenyl)morpholine (200 mg, 0.48 mmol) and tert-butyl-2-(5- (4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)pyrimidin-2-ylamino)ethylcarbamate, as described in example 11 for compound 52, gave tert-butyl-(2-((5- (3-((4-fluorobenzyl)sulfonyl)-5-morpholinophenyl)pyrimidin-2yl)amino)ethyl)carbamate (130 mg, 47% yield) as a white solid. The compound was confirmed only by LC-MS: 572.47 (M+H) ⁺ , C ₂₈ H ₃₄ FN ₅ O ₅ S.

n. HCl (gas)/EA (15 ml) was added as a solution to tert-butyl-(2-((5-(3-((4fluorobenzyl)sulfonyl)-5-morpholinophenyl)pyrimidin-2-yl)amino)ethyl) carbamate (130 mg, 0.23 mmol) in methanol (15 ml). The reaction mixture was stirred for 1 hour at room temperature. The solvent was removed in vacuo and the residue was washed with methanol (1 mlx3) to obtain N ¹ -(5-(3-((4fluorobenzyl)sulfonyl)-5-morpholinophenyl)pyrimidin-2-yl)ethane-1,2-diamine hydrochloride ( compound 47 hydrochloride (79 mg, 68% yield) as a yellow solid. ESI-MS+: 472.4 (M+H). 1H NMR (DMSO-d6, 400 MHz) δ: 8.76 (s, 2H), 8.07 (b, 3H), 7.69 (b, 1H), 7.47 (s, 1H), 7. 31 (s, 1H), 7.24 (m, 2H),

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7.17 (m, 2H), 7.07 (s, 1H), 4.74 (s, 2H), 3.75 (m, 4H), 3.60 (m, 2H), 3.22 (m , 4H), 3.072 (m, 2H).

Example 14 5-(3-(benzofuran-3-ylsulfonyl)-5-morpholinophenyl)pyrimidin-2-amine (compound

109).

Br B(OH) ₂

Step 1 (See Scheme F, Step 15): Synthesis of benzofuran-3-ylboronic acid n-BuLi (8.12 mmol) was added dropwise to a solution of 3-bromobenzofuran (800 mg, 4.06 mmol) and triisopropyl borate (2, 29 g, 12.2 mmol) in THF (15 ml) at minus 78°C in an atmosphere of N ₂ . The reaction mixture was stirred for 1 hour at minus 78°C. The reaction was quenched with a saturated solution of NH4Cl and extracted with ethyl acetate (20 mlx3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated to give benzofuran-3-ylboronic acid (657 mg, quantitative yield) as a pale yellow solid, which was used for the next reaction without further purification. The compound was confirmed only by LC-MS: 162.90 (M+H)+, C8H7O3B.

Step 2 (see Scheme F, Step 16): Synthesis of 4-[3-(benzofuran-3-ylsulfanyl)-5bromophenyl]morpholine.

A solution of benzofuran-3-ylboronic acid (660 mg, 4.08 mmol), 3-bromo-5-morpholinobenzenethiol (1.57 g, 5.71 mmol), CuSO ₄ -5H ₂ O (51 mg, 0.20 mmol ), 1,10-phenanthroline monohydrate (40 mg, 0.20 mmol) and n-Bu ₄ NOH in EtOH (12 ml) were stirred overnight at room temperature under O ₂ atmosphere. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1) to give 4-[3-(benzofuran-3-ylsulfanyl)-5-bromo-phenyl]morpholine (520 mg, 33% yield) as yellow oily substance. The compound was confirmed by LC-MS only: 390.25 (M+H) ⁺ , C18H16O2NSBr.

Connection 109

Step 3 (see Scheme F, Step 12a): Synthesis of 4-[3-(benzofuran-3-ylsulfonyl)-5bromophenyl]morpholine.

Oxidation of 4-[3-(benzofuran-3-ylsulfanyl)-5-bromophenyl]morpholine (520 mg, 1.33 mmol) was carried out as described in example 11 for compound 52 to obtain 4-[3-(benzofuran- 3-ylsulfonyl)5-bromophenyl]morpholine (500 mg, 89% yield) as a pale yellow solid. The compound was confirmed only by LC-MS: 422.34 (M+H) ⁺ , C ₁₈ H ₁₆ BrNO ₄ S.

Step 4 (see Scheme F, Step 4c): Reaction of 4-[3-(benzofuran-3-ylsulfonyl)-5bromophenyl]morpholine (300 mg, 0.71 mmol) and 5-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2yl)pyrimidin-2-amine (157 mg, 0.71 mmol) was carried out as described in Example 11 for compound 52 to give 5-(3-(benzofuran-3- ylsulfonyl)-5-morpholinophenyl)pyrimidin-2-amine (compound 109) (150 mg, 48% yield) as an off-white solid. ESI-MS+: 437.34 (M+H). 1H NMR (DMSO, 400 MHz) δ: 8.94 (s, 1H), 8.61 (s, 2H), 7.90 (d, 1H), 7.75 (d, 1H), 7.63 ( s, 1H), 7.4-7.49 (m, 4H), 6.91 (s, 2H), 3.75 (m, 4H), 3.25 (m, 4H).

The following compounds were prepared by methods similar to those described for compound 109 and as described in Scheme F:

Connection no. MS N NMR BY 437.44 (M+H) (DMSO-ab, 400 MHz) δ: 8.58 (s, 2H), 8.25 (s, 1H), 8.03 (d, 1H), 7.96 (d, 1H), 7.58 ( s, 1H), 7.49 (d, 2H), 7.41 (s, 1H), 7.12 (d, 1H), 6.91 (s, 2H), 3.75 (m, 4H), 3.25 (m, 4H). 111 439.6 (M+H) (DMSO-C16, 400 MHz) δ: 8.57 (s, 2H), 7.65 (d, J=7.6 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H) , 7.47 (s, 1H), 7.40 (s, 1H), 7.37 (s, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.89 (s, 2H), 4.68 (t, J = 8.8 Hz, 2H), 3.76 (m, 4H), 3.25 (m, 6H). 112 437.6 (M+H) (DMSO-ab, 400 MHz) δ 8.63 (s, 2H), 8.42 - 8.38 (m, 1H), 8.28 (d, J = 2.2 Hz, 1H), 7.92 (dd, J = 8.2, 1.6 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.59 (d, J = 1.5 Hz, 1H), 7 .40 - 7.35 (m, 2H), 7.11 (dd, J = 2.2, 1.0 Hz, 1H), 6.91 (s, 2H), 3.74 (dd, J - 6 ,0, 3.7 Hz, 4H), 3.27 (t, J - 4.9 Hz, 4H).

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Example 15. (E)-2-(2-((3-(2-aminopyrimidin-5-yl)-5-morpholinophenyl)sulfonyl)vinyl)phenol (compound 113).

Step 1 (See Scheme G, Step 17): Synthesis of 2-bromo-1-(2-(triisopropylsilyloxy)phenyl)ethanone.

TIPSCl (33.8 g, 0.18 mol) was added dropwise to a solution of 1-(2-hydroxyphenyl)ethanone (20 g, 0.15 mmol), DIPEA (32.8 g, 0.32 mol) and DMAP ( 36.2 g, 0.29 mmol) in dichloromethane (300 ml) at 0°C. The reaction mixture was stirred for 2 hours at room temperature. The solution was poured into water (500 ml) and the pH of the aqueous phase was adjusted to 4-5 using citric acid. The mixture was extracted with dichloromethane (300 mlx3). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 100:1) to give the TIPS-protected ketone (29.1 g, 67% yield). TIPS-protected ketone (20 g, 68.5 mmol) was mixed with PTSA (1.3 g, 6.9 mmol). While stirring, NBS (12.1 g, 68.5 mmol) was added piecemeal. The mixed solid was stirred overnight. The solid was suspended in water (200 ml) and extracted with dichloromethane (200 mlx3). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 200:1) to give 2-bromo-1-(2-(triisopropylsilyloxy)phenyl)ethanone (14.2 g, 55% yield) as a colorless oil. The compound was confirmed only by LC-MS: 373.64 (M+H)+, C ₁₇ H ₂₇ BrO ₂ Si.

Step 2 (See Scheme G, Step 18): Synthesis of (2-(2-bromo-1-chloroethyl)phenoxy)triisopropylsilane.

A solution of 2-bromo-1-(2-(triisopropylsilyloxy)phenyl)ethanone (14 g, 37.8 mmol) in THF (50 ml) was added to a solution of sodium borohydride (1.73 g, 45.5 mmol) in THF ( 200 ml). The reaction mixture was stirred for 2 hours at 50°C. The mixture was cooled to room temperature, diluted with water (300 ml) and then extracted with ethyl acetate (300 ml x 3). The organic extracts were combined, washed with brine (300 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50:1) to give the alcohol (10 g, 71% yield) as a colorless oil. The resulting alcohol (10 g, 26.9 mmol) was dissolved in thionyl chloride (50 ml) and refluxed for 1 hour. The solvent was removed in vacuo and evaporated together with dichloromethane twice to give (2-(2-bromo1-chloroethyl)phenoxy)triisopropylsilane (10.3 g, quantitative yield).

Step 3 (see Scheme G, step 19): Synthesis of 2-bromo-1-(2-(triisopropylsilyloxy)phenyl)ethyl nitrate.

AgNO3 (9.57 g, 56.4 mmol) was added to a solution of (2-(2-bromo-1-chloroethyl)phenoxy)triisopropylsilane (10 g, 25.6 mmol) in acetonitrile (50 ml). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was suspended in water (100 ml) and extracted with dichloromethane (100 mlx3). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated to give crude 2-bromo-1-(2(triisopropylsilyloxy)phenyl)ethyl nitrate (9.3 g, 94% yield).

Step 4 (See Scheme G, Step 20): Synthesis of (E)-2-(2-(3-bromo-5-morpholinophenylthio)vinyl)phenol.

A solution of 3-bromo-5-morpholinobenzenethiol (0.8 g, 2.9 mmol) and a solution of TBAF-THF (4.8 mL, 1M in THF) were added sequentially to the solution of bromo-1-(2-(triisopropylsilyloxy)phenyl) ethyl nitrate (2 g, 4.8 mmol) in THF (100 ml) at minus 78°C. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (200 ml x 3). The combined organic layers were washed with brine (50 mlx2), dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1) to give (E)-2-(2-(3-bromo-5morpholinophenylthio)vinyl)phenol (0.47 g, 25% yield). The compound was confirmed only by LC-MS: 394.87 (M+H) ⁺ , C ₁₈ H ₁₈ BrNO ₂ S.

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Connection 113

Step 5 (see Scheme G, Step 12a): Synthesis of (E)-2-(2-((3-(2-aminopyrimidin-5-yl)-5morpholinophenyl)sulfonyl)vinyl)phenol.

Oxidation with mCPBA was carried out as described in Example 11 for compound 52 to give (E)-2-(2-(3-bromo-5-morpholinophenylsulfonyl)vinyl)phenol (270 mg, 55% yield). LC-MS: 426.29 (M+H)+, C ₁₈ H ₁₈ BrNO ₄ S. 1H NMR (DMSO-d ₆ , 400 MHz) δ: 7.83 (d, J=15.2 Hz, 1H) , 7.53 (m, 1H), 7.39 (m, 2H), 7.29 (m, 2H), 7.14 (d, J=15.6 Hz, 1H), 6.94 (m, 1H), 6.84 (m, 1H), 3.88 (m, 4H), 3.24 (m, 4H).

Step 6 (see Scheme G, Step 4c): Mixture of (E)-2-(2-(3-bromo-5morpholinophenylsulfonyl)vinyl)phenol (270 mg, 0.64 mmol), 5-(4,4,5 ,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyrimidin-2-amine (282 mg, 1.28 mmol), K ₂ CO ₃ (176 mg, 1.28 mmol) and Pd(dppf)Cl ₂ (52 mg, 0.06 mmol) in 1,4-dioxane (9 ml) and H2O (3 ml) were stirred at 95°C for 2 hours under N ₂ atmosphere. The reaction mixture was poured into water (50 ml) and extracted with dichloromethane (50 mlx3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=50:1) to give (E)-2-(2-((3-(2-aminopyrimidin-5-yl)-5morpholinophenyl)sulfonyl)vinyl)phenol (120 mg, yield 43%). ESI-MS+: 439.1 (M+H). 1H NMR (DMSO-d6, 400 MHz) δ: 10.46 (s, 1H), 8.64 (s, 2H), 7.79 (d, J=15.6 Hz, 1H), 7.41- 7.65 (m, 4H), 7.29 (m, 2H), 6.90 (m, 3H), 6.84 (m, 1H), 3.76 (m, 4H), 3.28 (m , 4H).

Example 16 5-(3-((2,3-dihydrobenzofuran-3-yl)sulfonyl)-5-morpholinophenyl)pyrimidin-2-amine (compound 119).

Step 1 (see scheme H, step 21): Synthesis of methyl 2-(2-(methoxymethoxy)phenyl) acetate.

Concentrated H ₂ SO ₄ (1.32 ml) was added to a solution of 2-(2-hydroxyphenyl)acetic acid (10 g, 65.8 mmol) in methanol (132 ml). The reaction mixture was heated at 90°C for 1.5 hours. The solvent was removed and the residue was poured into ice water (100 ml). The resulting mixture was extracted with ethyl acetate (100 mlx2). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated to give the crude methyl ester (12.9 g, quantitative yield). A portion of the crude ester (3.6 g, 21.7 mmol) was dissolved in acetone (15 ml). Potassium carbonate (12 g, 87.0 mmol) was added and the mixture was stirred for 10 minutes at room temperature. The mixture was then cooled to 0°C and MOMCl (10 mL, 0.13 mol) was added dropwise. The reaction mixture was stirred overnight at room temperature. The potassium carbonate was filtered off and washed with acetone. The filtrate and wash solution were combined and concentrated in vacuo. The residue was dissolved in ethyl acetate (100 ml) and washed successively with water (50 ml) and brine (50 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50:1) to give methyl 2-(2-(methoxymethoxy)phenyl)acetate (2.8 g, 62% yield). С11Н14О4. ^1H NMR ( _CDCl3 , 400 MHz) δ: 7.23 (m, 2H), 7.09 (d, J=8.0 Hz, 1H), 6.97 (m, 1H), 5.19 ( s, 2H), 3.68 (s, 3H), 3.63 (s, 2H), 3.45 (s, 3H).

Vg

Step 2 (see scheme H, step 22): Synthesis of methyl 2-(3-bromo-5-morpholinophenylthio)-2-(2(methoxymethoxy)phenyl)acetate.

A solution of methyl 2-(2-(methoxymethoxy)phenyl) acetate (1.73 g, 8.2 mmol), 3-bromo-5morpholinobenzenethiol (4.5 g, 16.4 mmol), potassium carbonate (1.36 g , 9.9 mmol) and p-Bu ₄ NHSO ₄ (0.56 g, 1.6 mmol) in DMSO (30 ml) were stirred overnight at 60°C under O ₂ atmosphere. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (60 ml x 3). The combined organic layers were washed with brine (50 mlx2), dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20:1) to give methyl 2-((3-bromo-5-morpholinophenyl)thio)-2-(2(methoxymethoxy)phenyl)acetate (2.6 g, yield 66%). The compound was confirmed by LC-MS only: 484.21 (M+H)+, C ₂₁ H ₂₄ BrNO ₅ S.

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Step 3 (see Scheme H, Step 23): Synthesis of 2-(3-bromo-5-morpholinophenylthio)-2-(2(methoxymethoxy)phenyl)ethanol LiAlH ₄ (410 mg, 10.8 mmol) was added portionwise to a solution of the resulting methyl 2-((3-bromo-5-morpholinophenyl)thio)-2-(2-(methoxymethoxy)phenyl)acetate (2.6 g, 5.4 mmol) in THF (50 ml) at 0° WITH. The reaction mixture was stirred at 0°C for 30 minutes. The mixture was slowly poured into ice water (100 ml) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated. The residue was purified (ether/ethyl acetate = 5:1) with column chromatography on silica gel (petroleum

2-(3-bromo-5-morpholinophenylthio)-2-(2by (methoxymethoxy)phenyl)ethanol (1.1 g, 45% yield). LC-MS: 455.77 (M+H)+, C ₂₀ H ₂₄ BrNO ₄ S. 1H NMR (CDCl ₃ , 400 MHz) δ: 7.30 (m, 1H), 7.23 (m, 1H) , 7.12 (m, 1H), 6.96 (m, 2H), 6.84 (s, 1H), 6.71 (s, 1H), 5.21 (s, 2H), 4.85 ( m, 1H), 3.90 (m, 2H), 3.78 (m, 4H), 3.48 (s, 3H), 3.06 (m, 4H).

Step 4 (see scheme H, step 24): Synthesis of 4-(3-bromo-5-(2,3-dihydrobenzofuran-3ylthio)phenyl)morpholine.

n. HCl/dioxane solution (5 ml) was added to a solution of 2-(3-bromo-5-morpholinophenylthio)-2-(2(methoxymethoxy)phenyl)ethanol (1.1 g, 2.4 mmol) in dioxane (5 ml) . The reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (20 ml) and washed with saturated sodium bicarbonate solution (10 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated to give the phenol analog (1.02 g, quantitative yield). The resulting phenol analog (1 g, 2.4 mmol) was dissolved in toluene (5 ml) and added to a solution of triphenylphosphine (640 mg, 2.4 mmol) and DEAD (425 mg, 2.4 mmol) in toluene (5 ml) at 0°C. The reaction mixture was then stirred for 1 hour at room temperature. The mixture was poured into water (20 ml) and extracted with ethyl acetate (20 mlx2). The organic extracts were combined, washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20:1) to give 4-(3-bromo-5-(2,3-dihydrobenzofuran-3-ylthio)phenyl)morpholine (630 mg, 67% yield). LC-MS: 393.98 (M+H) ⁺ , C18H18BrNO2S. ^1H NMR (CDCl3, 400 MHz) δ: 7.27 (m, 1H), 7.18 (m, 1H), 6.99 (s, 1H), 6.91 (m, 2H), 6.79 (d, J=84 Hz, 1H), 6.69 (s, 1H), 4.91 (m, 1H), 4.79 (m, 1H), 4.55 (m, 1H), 3.81 (m, 4H), 3.07 (m, 4H).

Connection 119

Step 5 (see Scheme H, Step 12a): Synthesis of 5-(3-((2,3-dihydrobenzofuran-3-yl)sulfonyl)-5morpholinophenyl)pyrimidin-2-amine

Oxidation of 4-(3-bromo-5-(2,3-dihydrobenzofuran-3-ylthio)phenyl)morpholine with mCPBA as shown in Example 11 for compound 52 afforded 4-(3-bromo-5-( 2,3-dihydrobenzofuran-3ylsulfonyl)phenyl)morpholine (500 mg, 46% yield). The compound was confirmed only by LCMS: 426.37 (M+H) ⁺ , C18H18BrNO4S.

Step 6 (see Scheme H, Step 4c): The Suzuki reaction between 4-(3-bromo-5-(2,3dihydrobenzofuran-3-ylsulfonyl)phenyl)morpholine (500 mg, 1.2 mmol) and 5- (4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyrimidin-2-amine (287 mg, 1.3 mmol) as described in Example 11 for compound 52 gave 5-(3 -((2,3-dihydrobenzofuran-3-yl)sulfonyl)-5-morpholinophenyl)pyrimidin-2-amine (139 mg, 27% yield) as a white solid. ESI-MS+: 439.10 (M+H). 1H NMR (DMSO- _d6 , 400 MHz) δ: 8.54 (s, 2H), 7.47 (s, 1H), 7.33 (m, 1H), 7.27 (m, 1H), 7 .22 (s, 1H), 6.97 (m, 2H), 6.92 (s, 2H), 6.77 (d, J=8.0 Hz, 1H), 5.50 (m, 1H) , 4.89 (m, 1H), 4.69 (m, 1H), 3.73 (m, 4H), 3.18 (m, 4H).

Example 17 5-(6-morpholino-4-(phenylsulfonyl)pyridin-2-yl)pyrimidin-2-amine (compound 115).

Step 1 (See Scheme I, Step 25): Synthesis of 2,6-dichloro-4-(phenylthio)pyridine Pd ₂ (dba) ₃ (0.17 g, 0.18 mmol) was added to the 2,6-dichloro mixture -4-iodopyridine (1 g, 3.66 mmol), thiophenol (0.44 g, 4.03 mmol),

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Xantphos (0.21 g, 0.37 mmol) and DIPEA (0.94 g, 7.32 mmol) in dioxane (20 ml) under N ₂ atmosphere. The reaction mixture was heated at 110°C for 2 hours. The mixture was cooled to room temperature, poured into water (20 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether) to give 2,6-dichloro-4(phenylthio)pyridine (0.78 g, 83% yield) as an off-white solid. The compound was confirmed by LC-MS only: 256.16 (M+H)+, CnH ₇ Cl ₂ NS.

Step 2 (see scheme I, step 12a): Synthesis of 2,6-dichloro-4-(phenylsulfonyl)pyridine.

Oxidation of 2,6-dichloro-4-(phenylthio)pyridine with mCPBA as described in Example 11 for compound 52 provided 2,6-dichloro-4-(phenylsulfonyl)pyridine (0.69 g, 90% yield ). The compound was confirmed only by LC-MS: 287.98 (M+H) ⁺ , C11H ₇ Cl ₂ NO ₂ S.

Step 3 (see Scheme I, Step 26): Synthesis of 4-(6-chloro-4-(phenylsulfonyl)pyridin-2-yl)morpholine.

A solution of 2,6-dichloro-4-(phenylsulfonyl)pyridine (0.69 g, 2.40 mmol), morpholine (0.23 g, 2.64 mmol) and DIPEA (0.40 g, 3.13 mmol) in dioxane (20 ml) was heated at 120°C overnight. The reaction mixture was cooled to room temperature and poured into water (100 ml). The mixture was extracted with ethyl acetate (100 mlx3). The organic extracts were combined, dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=60:1) to give 4-(6-chloro-4-(phenylsulfonyl)pyridin-2-yl)morpholine (700 mg, 86% yield). The compound was confirmed only by LC-MS: 339.74 (M+H)+, C ₁₅ H ₁₅ ClN ₂ O ₃ S.

Step 4 (see Scheme I, Step 4c): Synthesis of 5-(6-morpholino-4-(phenylsulfonyl)pyridin-2yl)pyrimidin-2-amine.

The result was a Suzuki coupling between 4-(6-chloro-4-(phenylsulfonyl)pyridin-2-yl)morpholine (338 mg, 1 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)pyrimidin-2-amine (442 mg, 2 mmol) as described in Example 11 for compound 52 gave 5-(6-morpholino-4-(phenylsulfonyl)pyridin-2yl)pyrimidin-2- amine (220 mg, 55% yield). ESI-MS+: 398.27 (M+H). 1H NMR (DMSO- _d6 , 400 MHz) δ: 8.94 (s, 2H), 8.11 (d, J=8.8 Hz, 2H), 7.73 (m, 1H), 7.65 (m, 2H), 7.55 (s, 1H), 7.11 (s, 3H), 3.70 (m, 4H), 3.60 (m, 4H).

The following compounds were prepared by methods similar to those described for compound 115 and as described in Scheme I:

Connection no. MS Ή NMR 150 425.9 (M+H) (DMSO-de, 500 MHz) 8.92 (d, J = 5.3 Hz, 2H), 8.11 (m, 2H), 7.78 (m, 1H), 7.67 - 7.61 ( m, 2H), 7.50 (d, J = 1.1 Hz, 1H), 7.15 (d, J = 1.2 Hz, 1H), 7.07 (s, 2H), 4.31 ( d, J = 12.5 Hz, 1H), 4.04 (td, J = 6.5, 3.4 Hz, 1H), 3.72 (dd, J = 12.8, 3.5 Hz, 1H ), 3.61 (m, 2H), 3.36 (m, 1H), 1.19 (d, J = 6.2 Hz, ZN), 1.16 (d, J = 6.4 Hz, ZN ). 151 423.9 (M+H) (DMSSMB, 500 MHz) δ 8.92 (s, 2H), 8.10 (m, 2H), 7.72 (m, 1H), 7.63 (m, 2H), 7.51 (d, J = 1.1 Hz, 1H), 7.08 (s, 2H), 7.00 (d, J = 1.2 Hz, 1H), 4.45 (dk, J = 4.1, 2.1 Hz , 2H), 3.97 (d, J = 12.5 Hz, 2H), 3.05 (dd, J = 12.5, 2.7 Hz, 2H), 1.83 (dd, J = 8, 4, 4.3 Hz, 2H), 1.73 (k, J = 7.2, 6.4 Hz, 2H).

Example 18 5-(4-morpholino-6-(phenylsulfonyl)pyridin-2-yl)pyrimidin-2-amine (compound 117).

Step 1 (See Scheme J, Step 27): Synthesis of 4-(2-chloro-6-(phenylthio)pyridin-4-yl)morpholine.

Pd ₂ (dba) ₃ (872 mg, 0.95 mmol) was added to a mixture of 2,6-dichloro-4-iodopyridine (2 g, 7.32 mmol), morpholine (764 mg, 8.78 mmol), Xantphos ( 550 mg, 0.95 mmol) and Cs ₂ CO ₃ (3.1 g, 9.52 mmol) in dioxane (50 ml) under N ₂ atmosphere. The reaction mixture was heated at 140°C for 1 hour. The mixture was cooled to room temperature, poured into water (100 ml) and extracted with ethyl acetate (100 ml x 3). United

- 80 045787 the organic layers were washed with brine (100 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3:1) to give 4-(2,6-dichloropyridin-4-yl)morpholine (1.19 g, 70% yield). LCMS: 234.81 (M+H) ⁺ , CH^NO. 'H NMR (CDClj, 400 MHz) δ: 6.60 (s, 2H), 3.82 (t, J=5.0 Hz, 4H), 3.31 (m,

J=5.0 Hz, 4H).

Step 2 (See Chart J, Step 28): Mixture of 4-(2,6-dichloropyridin-4-yl)morpholine (1.1 g, 4.74 mmol), 1,2-diphenyldisulfane (0.62 g, 2.84 mmol) and sodium hydroxide (0.28 g, 7.11 mmol) in DMSO (10 ml) were heated at 120°C overnight. The mixture was cooled to room temperature and poured into water (100 ml). The mixture was then extracted with ethyl acetate (100 mlx3). The organic extracts were combined, washed with brine (50 mlx2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3:1) to give 4-(2-chloro-6-(phenylthio)pyridin-4-yl)morpholine (1.12 g, 77% yield), which was used for the next reaction without further purification. The compound was confirmed only by LC-MS: 306.98 (M+H) ⁺ , C ₁₅ H ₁₅ ClN ₂ OS.

Step 3 (See Scheme J, Step 12a): 5-(4-morpholino-6-(phenylsulfonyl)pyridin-2-yl)pyrimidin2-amine.

As a result of the oxidation of 4-(2-chloro-6-(phenylthio)pyridin-4-yl)morpholine, as described in example 51, 4-(2-chloro-6-(phenylsulfonyl)pyridin-4-yl)morpholine ( 640 mg, yield 58%). The compound was confirmed only by LC-MS: 338.91 (M+H) ⁺ , C ₁₅ H ₁₅ ClN ₂ O ₃ S.

Step 4 (see Scheme J, Step 4c): P (phenylsulfonyl)pyridin-4-yl)morpholine (600 mg, Suzuki coupling reactions, 4-(2-chloro-61.78 mmol) and 5-(4,4 ,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyrimidin-2-amine (432 mg, 1.95 mmol), K ₂ CO ₃ (490 mg, 3.55 mmol) and Pd(dppf) Cl ₂ (145 mg, 0.18 mmol) in 1,4-dioxane (18 ml) and H ₂ O (6 ml) was stirred at 95°C for 1 hour under N 2. The reaction mixture was poured into water (30 ml ) and extracted with ethyl acetate (30 mlx3). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate, concentrated. The crude product was purified by silica gel column chromatography (dichloromethane/methanol = 100:1) and washed with dichloromethane/methanol. (50:1, 10 ml) to give 5-(4-morpholino-6-(phenylsulfonyl)pyridin-2-yl)pyrimidin-2-amine (132 mg, 19% yield): IERMS ⁺ : 397.96 (M +H).'H NMR (DMSO-d6, 400 MHz) δ: 8.81 (s, 2H), 8.03 (d, J=7.2 Hz, 2H), 7.74 (m, 1H) , 7.65 (m, 2H), 7.43 (s, 1H), 7.37 (s, 1H), 7.07 (s, 2H), 3.74 (m, 4H), 3.51 ( m, 4H).

Example 19 5-(2-morpholino-6-(phenylsulfonyl)pyridin-4-yl)pyrimidin-2-amine (compound 118).

Step 1: Synthesis of 5-(2-chloro-6-(phenylthio)pyridin-4-yl)pyrimidin-2-amine: Suzuki coupling on palladium, between 2,6-dichloro-4-iodopyridine (1 g, 3.66 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyrimidin-2-amine (0.97 g, 4.40 mmol) were carried out as described in example 11 for compound 52 to give 5-(2,6-dichloropyridin-4-yl)pyrimidin-2-amine (700 mg, 80% yield). The compound was confirmed only by LC-MS: 240.98 (M+H) ⁺ , C ₉ H ₆ Cl ₂ N ₄ .

Step 2 (see Scheme K, step 29): Mixture of the resulting 5-(2,6-dichloropyridin-4-yl)pyrimidin-2amine (0.7 g, 2.92 mmol), thiophenol (321 mg, 2.92 mmol) and potassium carbonate (483 mg, 3.5 mmol) in DMF (20 ml) were heated at 110°C overnight. The mixture was cooled to room temperature and poured into water (100 ml). The mixture was then extracted with ethyl acetate (100 mlx3). The organic extracts were combined, washed with brine (50 mlx2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 60:1) to give 5-(2-chloro-6-(phenylthio)pyridin-4-yl)pyrimidin-2-amine (0.75 g, 82% yield ). The compound was confirmed only by LC-MS: 314.99 (M+H) ⁺ , C ₁₅ H ₁₁ ClN ₄ S.

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Step 3 (see Scheme K, step 12a): 5-(2-morpholino-6-(phenylsulfonyl)pyridin-4-yl)pyrimidin2-amine.

By oxidizing 5-(2-chloro-6-(phenylthio)pyridin-4-yl)pyrimidin-2-amine (0.75 g, 2.39 mmol) with mCPBA as described in Example 11 for (phenylsulfonyl) pyridin-4-yl)pyrimidin-2-amine (0.25 g, LC-MS only: 346.97 (M+H) ⁺ , C ₁₅ HnClN ₄ O ₂ S.

Step 4 (see Scheme K, step 26): The SNAr reaction of compound 52 gave 5-(2-chloro-6 in 30% yield). The connection was confirmed

5-(2-chloro-6-(phenylsulfonyl)pyridin-4yl)pyrimidin-2-amine (200 mg, 0.58 mmol) with morpholine (503 mg, 5.8 mmol) was carried out as described for compound 115, to give 5-(2-morpholino-6-(phenylsulfonyl)pyridin-4-yl)pyrimidin-2amine (37 mg, 16% yield). ESI-MS+: 398.07 (M+H). Ή NMR (DMSOL, 400 MHz) δ: 8.78 (s, 2H), 7.99 (m, 2H), 7.73 (m, 1H), 7.63 (m, 3H), 7.55 ( s, 1H), 7.14 (s, 2H), 3.64 (m, 4H), 3.50 (m, 4H).

The following compounds were prepared by methods similar to those described for compound 118 and as described in Scheme K:

Connection no. MS Ή NMR 139 432.1 (M+H) (CDCl ₃ +MeOD, 400 MHz) δ: 8.86 (s, 2H), 8.36 (d, J=7.6 Hz, 1H), 7.64 (m, ZN), 7.53 (i , 1H), 7.41 (m, 1H), 7.25 (s, 1H), 7.11 (s, 1H), 3.87 (m, 4H), 3.67 (m, 4H). 144 464.9 (M+H) (DMSO-ab, 500 MHz) δ 8.12 (s, 1H), 8.08 - 8.02 (m, 2H), 7.79 - 7.70 (m, 1H), 7.70 - 7, 61 (m, 2H), 7.18 (d, J = 1.3 Hz, 1H), 7.11 (d, J = 1.2 Hz, 1H), 6.81 (s, 1H), 6, 78 (s, 2H), 3.68 (dd, J = 5.9, 3.9 Hz, 4H), 3.55 (dd, J = 5.8, 3.9 Hz, 4H). 145 439.9 (M+H) (DMSO-ab, 500 MHz) δ 10.76 (s, 1H), 9.29 (s, 2H), 8.21 - 8.08 (m, 2H), 7.79 - 7.69 (m, 2H), 7.69 - 7.62 (m, 2H), 7.24 (d, J = 1.1 Hz, 1H), 3.72 (dd, J = 5.9, 3.7 Hz, 4H ), 3.64 (dd, J = 5.7, 3.8 Hz, 4H), 2.23 (s, ZN). 146 438.0 (M+N) (DMSO-ab, 500 MHz) δ 9.06 - 8.91 (m, 2H), 8.13 - 8.06 (i, 2H), 7.82 (d, J = 3.8 Hz, 1H) , 7.77 - 7.69 (m, 1H), 7.69 - 7.60 (i, 2H), 7.53 (d, J = 1.1 Hz, 1H), 7.11 (d, J = 1.2 Hz, 1H), 3.71 (dd, J = 5.9, 3.9 Hz, 4H), 3.60 (dd, J = 5.8, 3.9 Hz, 4H), 2 .77 (td, J = 7.4, 3.7 Hz, 1H), 0.69 (td, J = 7.0, 4.7 Hz, 2H), 0.53 - 0.47 (m, 2H ).

Example 20 5-(6-morpholino-4-phenoxypyridin-2-yl)pyrimidin-2-amine (compound 120).

Step 1 (see Scheme L, Step 30): Synthesis of 2,6-dichloro-4-phenoxypyridine Mixture of 2,6-dichloro-4iodopyridine (600 mg, 2.20 mmol), phenol (207 mg, 2.20 mmol) and potassium carbonate (455 mg, 3.30 mmol) in DMSO (20 ml) were stirred at 100°C for 3 hours under N2 atmosphere. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine (50 mlx2), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether) to give 2,6-dichloro-4phenoxypyridine (210 mg, 40% yield). The compound was confirmed by LC-MS only: 239.86 (M+H) ⁺ , CiiH7C12NO.

Step 2 (see Scheme L, Step 26): The reaction of SNAr 2,6-dichloro-4-phenoxypyridine (200 mg, 0.84 mmol) and morpholine (218 mg, 2.51 mmol) was carried out as described in the example 17 for compound 115, yielding 4-(6-chloro-4-phenoxypyridin-2-yl)morpholine (180 mg, 74% yield). The compound was confirmed only by LC-MS: 290.75 (M+H) ⁺ , C ₁₅ H ₁₅ ClN ₂ O ₂ .

Step 3 (see Scheme L, Step 4c): Mixture of 4-(6-chloro-4-phenoxypyridin-2-yl)morpholine (180 mg, 0.62 mmol), 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (151 mg, 0.68 mmol), K ₂ CO ₃ (171 mg, 1.24 mmol) and Pd(dppf)Cl ₂ ( 51 mg, 0.06 mmol) in 1,4-dioxane (6 ml) and H2O (2 ml) were stirred at 95°C for 2 hours under N ₂ atmosphere. The reaction mixture was poured into water (20 ml) and extracted with dichloromethane (20 mlx3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1) to give 5-(6morpholino-4-phenoxypyridin-2-yl)pyrimidin-2-amine (150 mg, 69% yield). ESI-MS ⁺ : 350.2 (M+H). ^1H NMR (DMSO-d6, 400 MHz) δ: 8.81 (s, 2H), 7.45 (m, 2H), 7.24 (m, 1H), 7.15 (m, 2H), 6 .97 (s, 2H), 6.81 (s, 1H), 6.16 (s, 1H), 3.68 (m, 4H), 3.43 (m, 4H).

The following compounds were prepared by methods similar to the method described for the compound

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120, and as described in diagram L:

Connection no. MS Ή NMR 128 451.52 (M+H) (DMSO-ab, 400 MHz) δ: 8.86 (s, 2H), 7.76 (d, >8.8 Hz, 1H), 7.61 (s, 1H), 7.45 (m, 1H ), 7.00 (s, 2H), 6.93 (s, 1H), 6.36 (s, 1H), 3.69 (m, 4H), 3.49 (m, 4H). 130 343.8 (M+H) (DMSO-ab, 500 MHz) δ 8.87 (s, 2H), 6.88 (s, 2H), 6.79 (d, J - 1.8 Hz, 1H), 6.18 (d, J = 1.8 Hz, 1H), 5.23 (tg, J = 4.7, 2.0 Hz, 1H), 3.92 (dd, J = 10.2, 4.5 Hz, 1H), 3 .84 (td, J = 8.2, 7.0 Hz, 1H), 3.80 - 3.73 (m, 2H), 3.70 (t, J = 4.9 Hz, 4H), 3, 49 (t, J = 4.9 Hz, 4H), 2.27 (dtd, J = 13.5, 8.3, 6.3 Hz, 1H), 1.99-1.91 (m, 1H) . 132 451.52 (M+H) (DMSO-ab, 400 MHz) δ: 8.86 (s, 2H), 7.76 (d, >8.8 Hz, 1H), 7.61 (s, 1H), 7.45 (m, 1H ), 7.00 (s, 2H), 6.93 (s, 1H), 6.36 (s, 1H), 3.69 (m, 4H), 3.49 (m, 4H). 134 384.2 (M+H) (CDC1 ₃ , 400 MHz) δ: 8.85 (s, 2H), 7.52 (d, >7.6 Hz, 1H), 7.33 (d, >7.6 Hz, 1H), 7, 23 (d, >7.6 Hz, 1H), 7.17 (d, >7.6 Hz, 1H), 6.47 (s, 1H), 6.05 (s, 1H), 5.86 ( w, 2H), 3.81 (m, 4H), 3.52 (m, 4H). 135 380.3 (M+H) (CDC1 ₃ , 400 MHz) δ: 8.83 (s, 2H), 7.26 - 7.19 (m, 1H), 7.11 (dd, J = 7.9, 1.7 Hz, 1H) , 7.07 - 6.94 (m, 2H), 6.51 (d, J - 1.7 Hz, 1H), 6.07 (d, J - 1.6 Hz, 1H), 5.80 ( s, 2H), 3.82 (d, J = 4.8 Hz, 7H), 3.51 (t, J = 4.9 Hz, 4H). 136 434.3 (M+H) (CDC1 ₃ , 400 MHz) δ: 8.84 (s, 2H), 7.39 (m, 1H), 7.33 (m, 1H), 7.28 (m, 1H), 7.19 (m , 1H), 6.53 (s, 1H), 6.08 (s, 1H), 5.49 (w, 2H), 3.82 (m, 4H), 3.53 (m, 4H). 137 364.3 (M+H) (CDC13, 400 MHz) δ: 8.84 (s, 2H), 7.31 (m, 1H), 7.25 (m, 1H), 7.19 (m, 1H), 7.02 (m, 1H), 6.50 (s, 1H), 6.00 (s, 1H), 5.71 (w, 2H), 3.81 (m, 4H), 3.50 (m, 4H), 2, 21 (s, ZN). 138 396.1 (M+H) (CDC1 ₃ , 400 MHz) δ: 8.89 (s, 2H), 7.51 (m, 2H), 7.43 (m, 2H), 7.17 (s, 1H), 6.92 (s , 1H), 5.51 (w, 2H), 3.85 (m, 4H), 3.62 (m, 4H).

Example 21. (3-((2-(2-aminopyrimidin-5-yl)-6-morpholinopyridin-4-yl)oxy)azetidin-1 yl)(cyclopropyl)methanone (compound 129).

Step 1 (see Scheme L, Step 26): Synthesis of 4-(6-chloro-4-iodopyridin-2-yl)morpholine Solution of 2,6dichloro-4-iodopyridine (3 g, 11.0 mmol), morpholine (1 .05 g, 12.1 mmol) and DIPEA (1.86 g, 14.3 mmol) in dioxane (30 ml) were refluxed for 5 hours. The solution was cooled to room temperature and poured into water (100 ml). The mixture was extracted with ethyl acetate (60 mlx3). The organic extracts were combined, washed with brine (30 mlx2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 30:1) to give 4-(6-chloro-4-iodopyridin-2-yl)morpholine (2.5 g, 70% yield). The compound was confirmed by LC-MS only: 324.73 (M+H)+, C9H ₁₀ ClIN2O.

Step 2 (See Scheme L, Step 30): Synthesis of benzyl 3-(2-chloro-6-morpholinopyridin-4yloxy)azetidine-1-carboxylate tBuOK (340 mg, 3.04 mmol) was added to the benzyl-3-hydroxyazetidine-1-carboxylate solution. 1-carboxylate (500 mg, 2.42 mmol) in DMSO (10 ml). The reaction mixture was stirred for 30 minutes and 4-(6-chloro-4-iodopyridin-2-yl)morpholine (650 mg, 2.0 mmol) was added. The reaction mixture was stirred overnight at room temperature under N2 atmosphere. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine (50 mlx2), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20:1) to give benzyl 3-(2-chloro-6-morpholinopyridin-4-yloxy)azetidine-1-carboxylate (280 mg, 35% yield). The compound was confirmed only by LC-MS: 403.93 (M+H) ⁺ , C ₂ oH22C1N304.

Step 3 (see Scheme L, Step 4c): Synthesis of benzyl 3-(2-(2-(tert-butoxycarbonylamino)pyrimidin5-yl)-6-morpholinopyridin-4-yloxy)azetidine-1-carboxylate.

Mixture of benzyl 3-(2-chloro-6-morpholinopyridin-4-yloxy)azetidin-1-carboxylate (280 mg, 0.70 mmol), mixture of tert-butyl 5-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)pyrimidin-2-ylcarbamate and

- 83 045787 its di-Boc analogue (354 mg, ~1.04 mmol), K2CO ₃ (194 mg, 1.40 mmol) and Pd(dppf)Cl ₂ (58 mg, 0.07 mmol) in 1.4 -dioxane (9 ml) and H2O (3 ml) were stirred at 95°C for 2 hours under N2 atmosphere. The reaction mixture was poured into water (20 ml) and extracted with dichloromethane (20 mlx3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to give 3-(2-(2-(tert-butoxycarbonylamino)pyrimidin-5-yl)-6morpholinopyridin-4-yloxy)azetidine-1-carboxylate (50 mg) and its di-Vos analogue (210 mg). Compounds were confirmed by LC-MS only: 3-(2-(2-(tert-butoxycarbonylamino)pyrimidin-5-yl)-6morpholinopyridin-4-yloxy)azetidine-1-carboxylate - 562.2 (M+H)+ , C29H34N6O6; benzyl-3-((2-(2-(diBOC-amino)pyrimidin-5-yl)-6-morpholinopyridin-4-yl)oxy)azetidine-1-carboxylate - 662.2 (M+H)+, C34H42N6 ^O 8.

Step 4 (see Scheme L, Step 31): Solution of benzyl-3-((2-(2-(di-BOC-amino)pyrimidin-5-yl)-6morpholinopyridin-4-yl)oxy)azetidine-1- carboxylate (210 mg, 0.32 mmol) in MeOH (20 ml) was hydrogenated in the presence of Pd/C overnight. Pd/C was filtered off and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 30:1) to give the free amine (30 mg, 18% yield).

Step 5 (see Scheme L, Step 6): The resulting free amine (30 mg, 0.06 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0°C. TEA (0.02 mL, 0.14 mmol) and cyclopropanecarbonyl chloride (12 mg, 0.11 mmol) were added sequentially. The reaction mixture was then stirred for 1 hour at room temperature. The mixture was poured into water (10 ml) and extracted with dichloromethane (10 ml x 3). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated.

The residue was purified by preparative TLC to give cyclopropyl-(3-((2-(2-(di-Vosamino)pyrimidin-5-yl)-6-morpholinopyridin-4-yl)oxy)azetidin-1-yl)methanone (30 mg , yield 89%), which was dissolved in dichloromethane (3 ml) and treated with TFA (0.5 ml) for 1 hour. The solvent was removed in vacuo to give (3-((2-(2-aminopyrimidin-5-yl)-6-morpholinopyridin-4yl)oxy)azetidin-1-yl)(cyclopropyl)methanone-TFA (20 mg, 78% yield ) as a yellow solid. ESI-MS+: 396.95 (M+H). Ή NMR (CDCl ₃ , 400 MHz) δ: 8.86 (s, 2H), 6.43 (s, 1H), 5.88 (s, 1H), 5.34 (s, 2H), 5.06 (m, 1H), 4.66 (m, 1H), 4.42 (m, 1H), 4.34 (m, 1H), 4.10 (m, 1H), 3.84 (m, 4H) , 3.55 (m, 4H), 1.41 (m, 1H), 0.99 (m, 2H), 0.77 (m, 2H).

Example 22. (2-(2-aminopyrimidin-5-yl)-6-morpholinopyridin-4-yl)(phenyl)methanone (compound 122).

C.I.

Step 1 (see scheme M, step 32): Synthesis of (2,6-dichloropyridin-4-yl)(phenyl)methanone.

CDI (3.44 g, 21.2 mmol) was added to a suspension of 2,6-dichloroisonicotinic acid (3.6 g, 18.8 mmol) in dichloromethane (20 ml). The solution was stirred for 2.5 hours at room temperature. N,O-dimethylhydroxylamine HCl (2.74 g, 28.2 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with 1 N. NaOH solution (10 ml) and extracted with dichloromethane (20 mlx3). The organic extracts were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1) to give 2,6dichloro-N-methoxy-N-methylisonicotinamide, 1 (3.8 g, 86% yield) as a white solid. The compound was confirmed only by LC-MS: 235.10 (M+H) ⁺ , C ₈ H ₈ Cl ₂ N ₂ O ₂ .

Step 3 (see Scheme M, Step 33): Phenylmagnesium bromide (24.4 mL, 24.4 mmol, 1M in THF) was added dropwise to a solution of 2,6-dichloro-N-methoxy-N-methylisonicotinamide (3.8 g, 16.2 mmol) in THF (50 ml) at 0°C under a protective nitrogen atmosphere. The reaction mixture was stirred for 2 hours at room temperature. The mixture was quenched with saturated ammonium chloride solution (100 ml) and extracted with ethyl acetate (60 ml x 3). The combined organic layers were washed with brine (50 mlx2), dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20:1) to give (2,6dichloropyridin-4-yl)(phenyl)methanone (3.8 g, 93% yield) as a white solid. The compound was confirmed only by LC-MS: 251.91 (M+H) ⁺ , C ₁₂ H ₇ Cl ₂ NO.

Connection 122

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Step 2 (see Scheme M, step 26): Reaction of SNAr (2,6-dichloropyridin-4-yl)(phenyl)methanone (3.8 g,

15.1 mmol) and morpholine (5.2 g, 59.8 mmol) with DIPEA (7.7 g, 60.1 mmol) were carried out as described in example 17 for compound 115, giving (2-chloro- 6-morpholinopyridin-4-yl)(phenyl)methanone (4.3 g, 94% yield) as a yellow solid. The connection was confirmed only using LC-MS:

303.26 (M+H) ⁺ , C16H15ClN2O2.

Step 3 (see Scheme M, Step 4c): Suzuki Coupling (2-chloro-6-morpholinopyridin-4yl)(phenyl)methanone (500 mg, 1.66 mmol) and 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2amine (360 mg, 1.66 mmol) was carried out as described in Example 11 for compound 52 to give (2(2-aminopyrimidin-5-yl )-6-morpholinopyridin-4-yl)(phenyl)methanone (250 mg, 42% yield) as a yellow solid. ESI-MS+: 362.61 (M+H). ¹ H NMR (DMSO-d6, 400 MHz) δ: 8.92 (s, 2H), 7.84 (d, J=8.0 Hz, 2H), 7.72 (m, 1H), 7.58 (m, 2H), 7.30 (s, 1H), 7.01 (s, 2H), 6.85 (s, 1H), 3.72 (m, 4H), 3.57 (m, 4H) .

The following compounds were prepared by methods similar to those described for compound 122 and as described in Scheme M:

Connection no. MS Ή NMR 131 370.2 (M+H) (CDC1 ₃ , 400 MHz) δ: 8.94 (s, 2H), 7.29 (s, 1H), 6.96 (s, 1H), 5.41 (w, 2H), 4.07 (t , J=6.8 Hz, 1H), 4.05 (t, J=6.4 Hz, 1H), 3.86 (m, 4H), 3.65 (m, 4H), 3.57 (m , 2H), 3.41 (m, 1H), 1.85 (m, 4H). 133 391.91 (M+H) (CDC1 ₃ , 400 MHz) δ: 8.92 (s, 2H), 6.96 (s, 1H), 6.57 (s, 1H), 5.50 (s, 2H), 4.07 - 3 .99 (m, 2H), 3.86 (t, J = 4.9 Hz, 4H), 3.80 (d, J = 4.5 Hz, 1H), 3.63 (t, J = 4, 9 Hz, 4H), 3.35 (td, J = 11.2, 4.7 Hz, 2H), 2.22 (m, 2H), 2.00 (m, 2H). 149 356.3 (M+H) (CDCb, 400 MHz) δ 8.96 (s, 2H), 7.34 (s, 1H), 7.02 (s, 1H), 5.55 (s, 2H), 4.10 (t, J = 8.1 Hz, 1H), 4.03 - 3.89 (m, 4H), 3.87 (t, J = 5.0 Hz, 4H), 3.66 (t, J - 4.9 Hz , 4H), 2.36 - 2.20 (m, 2H).

Example 23 5-(4-(Difluoro(phenyl)methyl)-6-morpholinopyridin-2-yl)pyrimidin-2-amine (compound 123).

Step 1 (see scheme M, step 34): Synthesis of 4-(6-chloro-4-(difluoro(phenyl)methyl)pyridin-2yl)morpholine.

DAST (1.07 g, 6.64 mmol) was added to a solution of (2-chloro-6-morpholinopyridin-4yl)(phenyl)methanone (0.5 g, 1.66 mmol, preparation described in Example 22 for compound 122 ) in dichloromethane (10 ml) at 0°C. The reaction mixture was stirred overnight at room temperature. The solution was slowly poured into ice-cold saturated sodium bicarbonate solution (50 ml) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50:1) to give 4-(6-chloro-4(difluoro(phenyl)methyl)pyridin-2-yl)morpholine (80 mg, 15% yield). The compound was confirmed only by LC-MS: 324.89 (M+H) ⁺ , Ci^C^^O.

Step 2 (see scheme M, step 4c): Synthesis of 5-(4-(difluoro(phenyl)methyl)-6-morpholinopyridin-2yl)pyrimidin-2-amine.

Mixture of 4-(6-chloro-4-(difluoro(phenyl)methyl)pyridin-2-yl)morpholine (80 mg, 0.25 mmol), 5-(4,4,5,5tetramethyl-1,3,2 -dioxaborolan-2-yl)pyrimidin-2-amine (110 mg, 0.49 mmol), K ₂ CO ₃ (103 mg, 0.74 mmol) and Pd(dppf)Cl ₂ (20 mg, 0.03 mmol ) in 1,4-dioxane (6 ml) and H ₂ O (2 ml) were reacted and isolated as described in Example 11 for compound 52 to give 5-(4(difluoro(phenyl)methyl)- 6-morpholinopyridin-2-yl)pyrimidin-2-amine (69 mg, 73% yield). ESI-MS+: 384.2 (M+H). Ή NMR (DMSO-d6, 400 MHz) δ: 8.92 (s, 2H), 7.66 (m, 2H), 7.51 (m, 3H), 7.31 (s, 1H), 7. 03 (s, 2H), 6.84 (s, 1H), 3.71 (m, 4H), 3.55 (m, 4H).

Example 24 5-(6-morpholino-4-(1-phenylvinyl)pyridin-2-yl)pyrimidin-2-amine: 2,6-dichloro-4-(1phenylvinyl)pyridine (compound 126).

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Step 1 (see Scheme N, step 35): Mixture of 2,6-dichloro-4-iodopyridine (5 g, 18.2 mmol), 4,4,5,5tetramethyl-2-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.6 g, 21.9 mmol), KOAc (3.6 g, 36.5 mmol) and Pd( PPh ₃ )Cl ₂ (0.5 g, 0.73 mmol) in DMF (20 ml) was stirred at 100°C for 1 hour under N ₂ atmosphere. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine (100 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 200:1) to give 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyridine (3 .6 g, yield 72%).

Step 2 (see Scheme N, Step 4c): Mixture of (1-bromovinyl)benzene (0.73 mg, 4.01 mmol), 2,6-dichloro-4(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (1.1 g, 4.03 mmol), Pd(dppf)Cl ₂ (68 mg, 0.08 mmol) and potassium carbonate (1.1 g, 8. 0 mmol) in dioxane/water (9 ml/3 ml) was worked up and isolated as described in Example 11 for compound 52 to give 2,6-dichloro-4-(1-phenylvinyl)pyridine (705 mg, yield 71%). The compound was confirmed only by LC-MS: 249.99 (M+H) ⁺ , C ₁₃ H ₉ Cl ₂ N.

Step 3 (See Scheme I, Step 26): A solution of 2,6-dichloro-4-(1-phenylvinyl)pyridine (700 mg, 2.81 mmol), morpholine (490 mg, 5.63 mmol) and DIPEA ( 471 mg, 3.65 mmol) in 1,4-dioxane (20 ml) was worked up and isolated as described in Example 17 for compound 115 to give 4-(6-chloro-4-(1phenylvinyl)pyridine-2 -yl)morpholine (530 mg, 63% yield). The compound was confirmed only by LC-MS: 301.22 (M+H) ⁺ , C ₁₇ H ₂₇ ClN ₂ O.

Step 4 (see Scheme N, Step 4C): Mixture of 2,6-dichloro-4-(1-phenylvinyl)pyridine (200 mg, 0.67 mmol) and 5-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)pyrimidin-2-amine (300 mg, 1.36 mmol) was subjected to Suzuki coupling as described in Example 11 for compound 52 to give 5-(6-morpholino-4- (1phenylvinyl)pyridin-2-yl)pyrimidin-2-amine (98 mg, 41% yield). ESI-MS+: 360.2 (M+H). 1H NMR ( _CDCl3 , 400 MHz) δ: 8.94 (s, 2H), 7.35 (m, 5H), 6.92 (s, 1H), 6.57 (s, 1H), 6.10 (w, 2H), 5.62 (s, 1H), 5.57 (s, 1H), 3.85 (m, 4H), 3.58 (m, 4H).

The following compound was prepared by methods similar to those described for compound 126 and as described in Scheme N:

Connection no.

348.2 (M+H)

Ί1 NMR (DMSO-ab, 400 MHz) 5: 8.84 (s, 2H), 7.31 (m, 4H), 7.20 (m, 1H), 7.13 (s, 1H), 6, 93 (s, 2H), 6.65 (s, 1H), 3.87 (s, 2H), 3.70 (m, 4H), 3.47 (m, 4H).

Example 25 5-(6-morpholino-4-(1-phenylethyl)pyridin-2-yl)pyrimidin-2-amine (compound 125).

(See Diagram L, Step 31): Mixture

5-(6-morpholino-4-(1-phenylvinyl)pyridin-2-yl)pyrimidin-2 amine (25 mg, 0.07 mmol) and Pd/C (5 mg) in methanol (5 ml) were hydrogenated for 1 hour at room temperature and 1 atm. _H2 . Pd/C was filtered and washed with methanol (3 ml). The filtrate and wash solution were combined and concentrated in vacuo to give 5-(6-morpholino-4-(1phenylethyl)pyridin-2-yl)pyrimidin-2-amine (19 mg, 76% yield). ESI-MS+: 362.04 (M+H). 1H NMR (CDCl3, 400 MHz) δ: 8.96 (s, 2H), 7.32 (m, 5H), 6.87 (b, 2H), 6.80 (s, 1H), 6.54 ( s, 1H), 4.10 (k, J=7.1 Hz, 1H), 3.84 (m, 4H), 3.56 (m, 4H), 1.65 (d, J=7.2 Hz, 3H).

Example 26 5-(6-morpholino-4-(1-phenylcyclopropyl)pyridin-2-yl)pyrimidin-2-amine (compound 127).

Step 1 (see Chart N, Step 36): Sodium hydride (62 mg, 60% in mineral oil, 1.55 mmol) at

- 86045787 parts were added to a solution of trimethylsulfoxonium iodide (341 mg, 1.55 mmol) in DMSO (10 ml) at room temperature. The reaction mixture was stirred for 15 minutes and then a solution of 4-(6-chloro-4-(1-phenylvinyl)pyridin-2-yl)morpholine (310 mg, 1.03 mmol) in THF (5 ml) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (50 ml x 3). The organic extracts were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50:1) to give 4-(6-chloro-4-(1-phenylcyclopropyl)pyridin-2-yl)morpholine (184 mg, 56% yield) as white solid matter. The compound was confirmed by LC-MS only: 315.04 (M+H) ⁺ , C18H19ClN2O.

Step 2 (see Scheme N, Step 4c): Mixture of 4-(6-chloro-4-(1-phenylcyclopropyl)pyridin-2yl)morpholine (184 mg, 0.59 mmol), 5-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (259 mg, 1.17 mmol) was subjected to Suzuki coupling as described in Example 11 for compound 52 to give 5-(6 -morpholino-4-(1-phenylcyclopropyl)pyridin-2-yl)pyrimidin-2-amine (130 mg, 59% yield) as a yellow solid. ESI-MS+: 374.08 (M+H). 1H NMR (DMSO- _d6 , 400 MHz) δ: 8.83 (s, 2H), 7.31 (m, 4H), 7.24 (m, 1H), 6.98 (s, 1H), 6 .93 (s, 2H), 6.45 (s, 1H), 3.68 (m, 4H), 3.42 (m, 4H), 1.38 (m, 2H), 1.25 (m, 2H).

Example 27 5-(4-(3,4-Dihydroquinolin-1(2H)-yl)-6-morpholinopyridin-2-yl)pyrimidin-2-amine (compound 140).

Step 1 (see diagram O, step 37): Mixture of 1,2,3,4-tetrahydroquinoline (133 mg, 1 mmol), 4-(6-chloro-4iodopyridin-2-yl)morpholine (324 mg, 1 mmol ), BESTAP (62 mg, 0.1 mmol), t-BuONa (192 mg, 2 mmol) and Pd ₂ dba ₃ (91.6 mg, 0.1 mmol) in toluene (10 ml) were refluxed at within 2 hours. The mixture was cooled to room temperature, diluted with water (30 ml) and extracted with ethyl acetate (30 ml x 3). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC to give 4-(6-chloro-4-(3,4-dihydroquinolin-1(2H)yl)pyridin-2-yl)morpholine (57 mg, 17% yield). The compound was confirmed by LC-MS only: 300.28 (M+H)+, Ci8H2oC1N30.

Step 2 (see Scheme N, Step 4c): Synthesis of 4-(6-amino-4-(3,4-dihydroquinolin-1(2H)-yl)pyridin-2yl)morpholine. A mixture of 4-(6-chloro-4-(3,4-dihydroquinolin-1(2H)-yl)pyridin-2-yl)morpholine (55 mg, 0.17 mmol), 5-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (74 mg, 0.33 mmol), Na ₂ CO ₃ (71 mg, 0.67 mmol) and Pd(dppf)Cl ₂ (27 mg, 0.03 mmol) in 1,4-dioxane (6 ml) and H2O (2 ml) was stirred at 95°C for 2 hours under N2 atmosphere. The reaction mixture was poured into water (10 ml) and extracted with dichloromethane (10 ml x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated. The crude product was purified by preparative TLC to give 4-(6-amino-4-(3,4-dihydroquinolin-1(2H)-yl)pyridin-2-yl)morpholine (11 mg, 81% yield). ESI-MS+: 389.1 (M+H). ^1H NMR ( _CDCl3 , 400 MHz) δ: 8.84 (s, 2H), 7.24 (m, 1H), 7.14 (m, 1H), 7.10 (m, 1H), 6. 94 (m, 1H), 6.84 (s, 1H), 6.29 (s, 1H), 5.37 (w, 2H), 3.84 (m, 4H), 3.69 (m, 2H ), 3.53 (m, 4H), 2.77 (m, 2H), 2.02 (m, 2H).

Example 28 5-(6-morpholino-4-((tetrahydrofuran-3-yl)sulfonyl)pyridin-2-yl)pyrimidin-2-amine (compound 142a).

Step 1 (see Scheme Q, Step 8): Synthesis of 2-chloro-6-morpholinopyridine-4-thiol: Mixture of 4-(6-chloro-4iodopyridin-2-yl)morpholine (0.55 g, 2 mmol), BnSH (0.25 g, 2 mmol) and potassium carbonate (0.41 g, 3 mmol) in DMSO (5 ml) were heated at 55°C for 2 hours. The mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml x 3). The organic extracts were combined, washed with brine (10 mlx2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether) to give 4-(4-(benzylthio)-6-87 045787 chloropyridin-2-yl)morpholine (310 mg, 58% yield). The connection was confirmed only by LCMS: 321.21 (M+H)+, C ₁₆ H ₁₇ ClN ₂ OS.

Step 2 (Scheme Q, Step 10): Deprotection of benzyl group with AlCl ₃ was carried out as described in Example 11 for compound 52 to give 2-chloro-6-morpholinopyridine-4thiol (150 mg, 75% yield ) as an off-white solid. The compound was confirmed only by LC-MS: 179.84 (M+H) ⁺ , C ₉ H _n ClN ₂ OS.

Step 3 (see Scheme Q, Step 11b): Synthesis of (S)-4-(6-chloro-4-(tetrahydrofuran-3-ylthio)pyridin-2yl)morpholine: Mixture of 2-chloro-6-morpholinopyridine-4- thiol (195 mg, 0.85 mmol), (R)-3bromotetrahydrofuran (375 mg, 2.5 mmol) and CsCO ₃ (1.1 g, 3.39 mmol) in acetonitrile (20 ml) were heated at 60°C overnight under a protective nitrogen atmosphere. The solid was filtered and the filtrate was concentrated. The residue was purified by preparative TLC to give (S)-4-(6-chloro-4-(tetrahydrofuran-3ylthio)pyridin-2-yl)morpholine (130 mg, 51% yield). The connection was confirmed only by LCMS: 301.23 (M+H) ⁺ , C13H17ClN2O2S.

Step 4 (see Scheme Q, Step 12a): Synthesis of (S)-5-(6-morpholino-4-((tetrahydrofuran-3yl)sulfonyl)pyridin-2-yl)pyrimidin-2-amine: Oxidation of (S) -4-(6-chloro-4-(tetrahydrofuran-3ylthio)pyridin-2-yl)morpholine with mCPBA was carried out as described in example 11 for compound 52, obtaining (S)-4-(6-chloro- 4-(tetrahydrofuran-3-ylsulfonyl)pyridin-2-yl)morpholine (70 mg, 49% yield) as an off-white solid. The compound was confirmed only by LC-MS: 333.18 (M+H) ⁺ , C13H17QN2O4S·

Step 5 (see Scheme Q, Step 4c): Coupling of (S)-4-(6-chloro-4-(tetrahydrofuran-3ylsulfonyl)pyridin-2-yl)morpholine (70 mg, 0.21 mmol) and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrimidin-2-amine (70 mg, 0.32 mmol) was carried out as described in example 11 for compound 52 to give ( S)-5-(6-morpholino-4-((tetrahydrofuran-3-yl)sulfonyl)pyridin-2-yl)pyrimidin-2-amine (compound 142a) (13 mg, 16% yield). ESI-MS+: 392.2 (M+H). ¹ H NMR (DMSO, 400 MHz) δ: 8.97 (s, 2H), 7.52 (s, 1H), 7.12 (b, 2H), 7.05 (s, 1H), 4.41 (m, 1H), 4.05 (m, 1H), 3.84 (m, 2H), 3.72 (m, 4H), 3.63 (m, 4H), 2.17 (m, 3H) .

The following compounds were prepared by methods similar to those described for compound 142a and as described in Scheme Q:

Example 29 5-(4-(chroman-4-ylsulfonyl)-6-morpholinopyridin-2-yl)pyrimidin-2-amine (compound 143).

Step 1: Synthesis of (6-chloro-4-(chroman-4-ylthio)pyridin-2-yl)morpholine: BH3.SMe ₂ (50 ml, 0.5 mol, 10 M) was added dropwise to the chroman-4 solution -one (10 g, 67.5 mmol) in THF (100 ml) at 0°C. The reaction mixture was stirred for 1 hour at 0°C. The reaction was quenched with methanol (10 ml) and concentrated. The residue was evaporated with DCM (100 ml x 3 ) to give chroman-4-ol (11 g, quantitative yield) as a colorless oil, which was used for the next reaction without further purification. The resulting alcohol (3 g, 20.0 mmol) was dissolved in thionyl chloride (10 ml) and the reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo and evaporated twice with dichloromethane to give 4-chlorochromane (3.3 g, 20.0 mmol),

- 88 045787 which was used in crude form for the next reaction. In the second flask, chloro6-morpholinopyridine-4-thiol (4.6 g, 20.0 mmol, the preparation method is described in example 28, compound 142a) was dissolved in DMF (20 ml) and added to the NaH solution (1.2 mg, 30 .0 mmol, purity 60% in mineral oil) in DMF (5 ml) at 0°C. The reaction mixture was stirred for 5 minutes at 0°C and a solution of the resulting chloride in DMF (3 ml) was added, then KI (100 mg, 0.6 mmol) was added. The reaction mixture was stirred for 3 hours at room temperature. The solution was poured into water (50 ml) and extracted with ethyl acetate (50 ml x 3). The organic extracts were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 30:1 to 15:1) to give 4-(6-chloro-4-(chroman-4-ylthio)pyridin-2-yl)morpholine (5.33 g, yield 74%) as an off-white solid.

The compound was confirmed only by LC-MS: 363.1 (M+H)+, C ₁₈ H ₁₉ ClN ₂ O ₂ S.

Step 2: Synthesis of 4-(6-chloro-4-(chroman-4-ylsulfonyl)pyridin-2-yl)morpholine: mCPBA (11.9 g, 58.8 mmol, 70% purity) was added portionwise to the compound solution 13 (5.33 g, 14.7 mmol) in dichloromethane (100 ml). The mixture was stirred overnight at room temperature. 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (15 g, 58.8 mmol) was added and the mixture was stirred another 30 minutes. The reaction mixture was diluted with dichloromethane (100 ml), washed with saturated Na ₂ CO ₃ solution (100 mlx2), brine (50 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20:1 to 5:1) to give 4-(6-chloro-4-(chroman-4-ylsulfonyl)pyridin-2-yl)morpholine (4.3 g, 74% yield) as a light yellow solid. The compound was confirmed by LC-MS only: 395.7 (M+H)+, C18H19QN2O4S.

Connection 1+3

Step 3: Mixture of 4-(6-chloro-4-(chroman-4-ylsulfonyl)pyridin-2-yl)morpholine (4.3 g, 10.9 mmol), 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (3.6 g, 16.4 mmol), K2CO3 (3 g, 21.8 mmol) and Pd(dppf)Cl ₂ (0 .89 g, 1.09 mmol) in 1,4-dioxane (30 ml) and H ₂ O (10 ml) were stirred at 95°C for 1 hour under N ₂ atmosphere. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (50 mlx2). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated. The crude product was washed successively with petroleum ether/ethyl acetate (30 mlx2; 2:1) and DCM (10 mlx3). Crude compound 143 was redissolved in 10% methanol/dichloromethane and 1 wt/wt was added. equivalent of Silica Thiol MS001 reagent (Shanghai Chiral Chemistry Co., Ltd), and stirred the mixture for 30 minutes at room temperature. Silica Thiol MS001 was filtered and washed with 10% methanol/dichloromethane. The combined filtrate and wash solution were evaporated under reduced pressure to give compound 143 (3.7 g, 75% yield) as an off-white solid. LCMS: 454.4 (M+H)+, C22H23N5O4S. 1H NMR (DMSOL, 400 MHz) δ: 8.96 (s, 2H), 7.51 (s, 1H), 7.36 (m, 1H), 7.30 (m, 1H), 7.14 ( s, 2H), 7.01 (s, 1H), 6.94 (m, 1H), 6.88 (m, 1H), 5.04 (m, 1H), 4.34 (m, 1H), 4.19 (m, 1H), 3.72 (m, 4H), 3.62 (m, 4H), 2.14 (m, 2H).

Example 30 Enantiomeric resolution of 5-(4-(chroman-4-ylsulfonyl)-6-morpholinopyridin-2yl)pyrimidin-2-amine (compound 143).

The racemate of compound 143 was resolved into 2 separate enantiomers using chiral SLC. The racemate of compound 143 (1.3 g) was dissolved in 60 ml of IPA/DMSO and injected in 1.1 ml aliquots (0.024 g per sample injection). The material was separated on a Regis IA column (5 µm, 250 x 21.1 mm) using a 40/60 IPA/CO2 mixture at a flow rate of 32 ml/min. IPA and 80 g/min. CO2. Two peaks were identified. The solvent was removed under reduced pressure at 40°C. Residual DMCo was removed by adding a small amount of water, freezing and lyophilizing. The first fraction eluted, enantiomer 1, is shown arbitrarily as (S) (534 mg, optical rotation [a]20=+104, c=0.1, DMSO). The second eluted fraction, enantiomer 2, is shown arbitrarily as (R) (544 mg, optical rotation [a]20=-112, c=0.1, DMSO).

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Connection no. MS Ή NMR (+)143 453.9 (M+H) (DMSO-ab, 500 MHz) δ 8.95 (s, 2H), 7.49 (d, J = 1.1 Hz, 1H), 7.36 (dd, J = 8.0, 1.7 Hz , 1H), 7.29 (ddd, J = 8.6, 7.2, 1.7 Hz, 1H), 7.11 (s, 2H), 7.00 (d, J = 1.1 Hz, 1H), 6.93 (td, J = 7.5, 1.3 Hz, 1H), 6.88 (dd, J = 8.2, 1.2 Hz, 1H), 5.03 (t, J = 4.3 Hz, 1H), 4.34 (m, 1H), 4.19 (m, 1H), 3.73 (dd, J = 5.7, 4.0 Hz, 4H), 3.61 (dd, J = 5.8, 3.9 Hz, 4H), 2.19 - 2.09 (m, 2H). (-)143 453.9 (M+H) (DMSOlb, 500 MHz) δ 8.95 (s, 2H), 7.49 (d, J = 1.1 Hz, 1H), 7.36 (dd, J = 7.8, 1.7 Hz, 1H ), 7.29 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 7.11 (s, 2H), 7.00 (d, J = 1.2 Hz, 1H) , 6.93 (td, J = 7.5, 1.2 Hz, 1H), 6.88 (dd, J = 8.2, 1.2 Hz, 1H), 5.03 (t, J = 4 .3 Hz, 1H), 4.34 (ddd, J = 11.1, 8.9, 5.8 Hz, 1H), 4.18 (m, 1H), 3.73 (dd, J = 5, 8, 4.0 Hz, 4H), 3.61 (t, J = 5.0 Hz, 4H), 2.16 (u, J = 4.5, 4.1 Hz, 2H).

Additional compounds within the scope of formula (I) can be prepared by methods similar to those described herein. Mass spectrometry (MS) and nuclear magnetic resonance (NMR) characterization data for the compounds described herein are presented in Table. A.

Table A

Connection no. MS Ή NMR 116 438.97 (M+H) (CDCh, 400 MHz) δ: 8.47 (s, 2H), 7.48 (m, 1H), 7.41 (s, 2H), 7.29 (m, 2H), 7.04 (s, 1H), 5.21 (w, 2H), 4.63 (d, J=8.8 Hz, 2H), 3.88 (m, 4H), 3.25 (m, 6H). 141 390.1 (M+H) (CDC1 ₃ , 400 MHz) δ: 8.87 (s, 2H), 7.17 (m, 1H), 6.82-6.91 (m, ZN), 6.78 (s, 1H), 6 .36 (s, 1H), 5.48 (w, 2H), 4.23 (m, 2H), 4.13 (m, 1H), 3.83 (m, 4H), 3.54 (m, 4H), 2.36 (m, 1H), 2.13 (m, 1H). 147 440.3 (M+H) (DMSO-ab, 400 MHz) δ: 8.93 (s, 2H), 7.45 (d, J=7.2 Hz, 1H), 7.34 (m, 2H), 7.19 (m, 2H), 7.05 (m, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.84 (s, 1H), 5.66 (m, 1H), 4.99 ( m, 1H), 4.77 (m, 1H), 3.76 (m, 4H), 3.59 (m, 4H).

Biological example B-1.

Inhibition of PI3Ka.

Quantification of ATP to ADP conversion as a measure of PI3K activity b. Active PI3K b (Life Technologies), in the presence or absence of a PI3K b inhibitor, was coupled with PIP2:PS (Life Technologies), a substrate specifically optimized for use with class I PI3 kinases, and ultrapure ATP (Promega). The conversion of ATP to ADP by PI3K b was measured by the luminescent signal using the Promega ADP-Glo kinase activity assay. The assay was validated using published PI3Ka inhibitors LY294002, PI-103, BYL719, GDC0198, as well as a DMSO vehicle control.

Compounds were prepared at 100X final concentration using a 12-point 1:3 serial dilution in DMSO, with a DMSO control as the ^12th point. The compound was then diluted in solution (25 mM HEPES pH 7.5, 1 mM EGTA, 0.3% CHAPS) before adding to PI3K b. Active PI3K b, diluted to 0.24 ng/μl (1.1 nM) in solution (50 mM HEPES pH 7.5, 6 mM MgCl ₂ , 1 mM EGTA, 200 mM NaCl, 0.03% CHAPS, 8 mM DTT) were incubated with the compound for 0 hours and 3 hours before the reaction began. 25 μM PIP2:PS and 60 μM ATP were diluted from the stock in solution (25 mM HEPES pH 7.5, 1 mM EGTA, 0.3% CHAPS) and added to initiate the PI3K b reaction. The reaction time was 30 minutes. The conversion of ATP to ADP was measured by counting luminescence on a DTX880 plate reader (Beckman Coulter). IC ₅₀ compounds were recorded using GraphPad Prism software. The analytical method used was a 4-parameter non-linear regression curve fitting with a lower fit to validated reference reference samples of PI3Ka inhibitors and no upper fit (floating upper value). The data obtained in the described analysis are presented in table. 2.

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table 2

Connection no. 1С ₅₀ Р13К _а (µM) Connection no. 1С ₅₀ Р13К _а (µM) Connection no. IC ₅ o Р13К _а (µM) 1 0.61 53 0.11 105 1.7 2 5.0 54 0.13 106 0.10 3 2.0 55 12 107 0.067 4 eleven 56 0.26 108 0.69 5 12 57 (as TPA salt) 0.48 109 1.2 6 3.8 58 0.41 BY 0.40 7 1.8 59 (as TPA salt) 0.46 111 0.38 8 1.3 60 0.81 112 2.3 9 1.5 61 0.50 113 1.1 10 0.46 62 0.33 114 2.4 eleven 1.40 63 0.47 115 0.066 12 9.0 64 1.1 116 2.3 13 0.91 65 0.87 117 z, z 14 7.3 66 1.3 118 0.88 15 3.5 67 0.80 119 0.11 16 1.5 68 0.047 120 0.091 17 1.9 69 0.54 121 0.84 18 3.9 70 7.6 122 0.037 19 2.9 71 9.1 123 0.046 20 2.7 72 0.46 124 0.12 21 2.1 73 1.5 125 0.21 22 2.8 74 1.0 126 0.27 23 0.10 75 0.25 127 0.056 24 21 76 0.30 128 1.22 25 thirty 77 0.10 129 0.034 26 0.27 78 0.18 130 0.023 27 0.38 79 0.21 131 0.023 28 0.37 80 0.66 132 1.21 29 0.37 81 0.062 133 0.012 thirty 3.1 82 0.29 134 0.07 31 0.66 83 0.34 135 0.079 32 0.45 84 0.60 136 0.37 33 0.98 85 1.0 137 0.075 34 13 86 0.58 138 0.014 35 1.1 87 0.21 139 0.017 36 1.1 88 0.53 140 0.12 37 2.0 89 2.5 141 0.062 38 0.74 90 7.22 142a 0.0057 39 0.79 91 0.18 142b 0.0068 40 6.5 92 0.15 143 0.0017 41 0.53 93 0.088 (+) 143 0.0045 42 4.7 94 0.11 (-) 143 0.0010 43 eleven 95 0.12 144 0.39 44 13 96 1.4 145 0.39 45 5.9 97 0.51 146 0.37 46 19 98 12 147 0.0070 47 (as HC1 salt) 1.2 99 4.3 148 0.0130 48 (as TPA salt) 0.47 100 1.6 149 0.0140 49 0.49 101 0.88 150 0.45 50 0.28 102 0.54 151 0.83 51 0.12 103 0.68 52 0.13 104 1.3

Biological example B-2.

mTor Analysis Protocol.

The substrate was prepared in the main reaction buffer (20 mM Hepes (pH 7.5), 10 mM _MgCl2 , 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO) and the necessary cofactors were added to the substrate solution. mTor kinase was added to the substrate solution and the solution was carefully mixed. Experimental compounds were dissolved in 100% DMSO to a certain concentration. Serial dilution was performed using Integra Viaflo Assist in DMSO. Compounds were introduced into the kinase reaction mixture using acoustic technology (Echo550; nanoliter range) and the reaction mixture was incubated for 20 minutes at room temperature. 33P-ATP (specific activity 10 μCi/μl) was then added to the reaction mixture to initiate the reaction. The reaction mixture was incubated for 2 hours at room temperature. Radioactivity was read using the filter binding method. Kinase activity data were expressed as the percentage of residual kinase activity in experimental samples compared to reactions with vehicle (dimethyl sulfoxide). IC ₅₀ values were obtained and curves were plotted using Prism (GraphPad Software). The data obtained in the described analysis are presented in table. 3.

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Biological example B-3.

RACT protocol.

Inhibition of the PI3K-AKT-mTOR cascade was measured by quantifying loss of (Ser-473) pAKT using AlphaScreen (Perkin Elmer). B103 cells (rat neuroblastoma) were seeded in serum containing medium (high glucose (-phenol red) DMEM + 10% FBS + 2X Glutamax + 1 mM sodium pyruvate + 10 mM HEPES + 1X nonessential amino acids + 1X penicillin/streptomycin) for treated 96-well tissue culture plate and grown for 20 hours. Cells were then maintained in serum-free medium (high glucose (-phenol red) DMEM + 1X Glutamax + 1 mM sodium pyruvate + 1X penicillin/streptomycin) for 6 hours, followed by a 2-hour pretreatment with inhibitors of the indicated cascade, including reference inhibitor LY294002. These inhibitors were prepared at 200X final concentration using a 6-point 1:3 serial dilution in DMSO, with a DMSO control sample as the ^7th point. Inhibitors were then diluted in experimental medium (high glucose (-phenol red) DMEM + 1X Glutamax + 1 mM sodium pyruvate + 1X penicillin/streptomycin + 25 mM HEPES + 0.1% BSA) and combined with cells at a final concentration of 1X 0.5% DMSO Cells were then stimulated for 20 min with insulin (2.5 μg/ml), an activator of the PI3K-AKT-mTOR pathway and a known agonist (Ser-473) of pAKT. Cells were rapidly lysed in proprietary Perkin Elmer lysis buffer and (Ser-473) pAKT and total AKT in the lysate were measured using AlphaScreen. In AlphaScreen, donor beads were coated with streptavidin to capture one of the antibodies, which is biotinylated. Acceptor beads were coated with protein A to immobilize another antibody. In the presence of a target protein, these two antibodies bring the donor and acceptor beads closer together, creating a signal. The intensity of light emission is directly proportional to the amount of target protein present in the sample. For each inhibitor tested, plot the ratio of measured (Ser-473) pAKT/total AKT in GraphPad Prism as a 7-point, 4-parameter nonlinear regression curve with the lower value tied to the lower value of the reference control sample and an unconstrained upper value value tied to DMSO. IC ₅₀ (Ser-473) pAKT values were calculated and recorded, and the data obtained in the described analysis are presented in table. 3.

Table 3

Example No. pACT (µM) tTog (µM) 1 7.52 2.00 8 7.62 0.83 10 30.70 0.64 eleven 100.00 22.00 12 100.00 100.00 13 28.60 10.00 15 100.00 22.00 17 100.00 100.00 18 100.00 100.00 19 37.00 16.00 20 100.00 10.00 21 37.00 9.39 22 39.00 8.69 23 8.50 3.00 26 6.20 5.30 27 14.00 11.00 28 13.00 7.90 29 10.90 10.90 thirty 18.00 10.90 32 6.30 >33 35 23.49 12.20

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38 9,P 3.60 39 9.90 4.80 41 0.86 4.27 47 (as HC1 salt) 2.18 But. 48 (as TPA salt) >50 6.39 49 31.10 But. 50 >50 2.98 51 2.12 0.46 52 3.46 0.73 53 1.65 0.54 54 2.46 0.59 56 19.76 6.15 57 (as TPA salt) 19.75 3.44 58 41.29 3.95 59 (as TPA salt) 36.09 4.60 60 31.12 But. 62 6.47 1.87 63 3.71 But. 68 4.66 1.21 70 4.02 7.61 71 11.20 But. 72 9.13 But. 75 6.40 But. 76 5.64 But. 77 3.19 But. 78 4.52 But. 79 5.02 But. 81 26.40 But. 82 10.78 But. 83 8.47 But. 87 1.00 1.44 88 6.54 2.46 91 7.33 2.58 92 2.91 But. 93 5.44 0.87 94 19.84 But. 95 5.19 But. 96 1.06 But. 97 12.37 But. 100 48.20 But. 101 8.53 But. 102 6.79 But. 103 5.81 But. 106 4.10 1.46 107 3.70 4.33 108 4.72 But. 109 15.00 But. BY 8.70 9.90 111 14.50 5.40 112 22.30 But. 113 14.30 But. 114 15.30 But. 115 0.57 0.063 116 22.90 But. 117 17.30 But.

118 13.80 But. 119 4.00 4.70 120 0.64 0.48 122 0.48 0.51 123 0.46 0.56 124 0.89 But. 125 0.81 0.27 126 0.49 But. 127 0.38 0.13 129 3.46 2.95 130 0.75 1.75 131 0.56 0.59 133 0.40 0.44 134 0.38 0.45 135 1.62 0.70 136 1.51 2.06 137 0.45 0.37 138 0.19 1.10 139 0.016 But. 140 0.31 But.

But. = not determined.

Claims (29)

1. Compound of formula (I): where R ¹ represents -(CR ^a R ^b )m-C6-18αryl, -CH=CH-C6-18aryl, -(CR ^c R ^d )n-(5-12-membered heteroaryl), -(CR ^e R ^f )o-(3-10 membered heterocycloalkyl) or -(CR ^g R ^h )p-C _3-6 cycloalkyl; m, n, o and p are each independently equal to 0, 1 or 2; R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ^g and R ^h are each independently H, halogen or C _1-4 alkyl, or R ^a and R ^b together with a carbon atom, to which they are attached form a C _3-6 cycloalkyl ring, or R ^a and R ^b together form =CH ₂ or =O; each aryl, heteroaryl, heterocycloalkyl or cycloalkyl present in R ¹ is unsubstituted or substituted with one or two R ^x substituents; where each substituent R ^x independently represents halogen, C1-4alkyl, C3-6cycloalkyl, -C1-2-haloalkyl, -OH, -OC1-4alkyl, -O-C1-2haloalkyl, cyano, -C(O)C1-4alkyl , -C(O)NR ⁱ R ^, , -SO2C _1-4 alkyl, -SO ₂ NR ^k R ^l , -NR ^q R ^r , -C(O)-C _3-6 cycloalkyl, -C(O)- C _6-18 aryl unsubstituted or substituted with methyl or halogen, -CO ₂ C _1-4 alkyl, -CO ₂ -C _6-18 aryl, -C(O)CH ₂ -C _6-18 aryl unsubstituted or substituted with methyl or halogen , -CH ₂ -C _6-18 aryl unsubstituted or substituted with methyl or halogen, or monocyclic 4-6-membered heterocycloalkyl unsubstituted or substituted with methyl, -C(O)C _1-4 alkyl or -CO ₂ C _1-4 alkyl; where R ⁱ , Rj , R ^k and Rl are each independently H, C _1-4 alkyl, -C _1-4 alkyl-OH or -C _1-4 alkyl-O-C _1-4 alkyl, where R ^q and R ^r are each independently H, C _1-4 alkyl, -C _1-4 alkyl-OH, -C _1-4 alkyl-O-C _1-4 alkyl, -C(O)C _{1- 4} alkyl, -CO ₂ C _1-4 alkyl or -SO ₂ C _1-4 alkyl; L represents -S(O) ₂ -, -C(O)-, -O-, -CF2-, -C(=CH ₂ )- or -CR ^s Rt-; where R ^s and Rt are each independently H or C _1-4 alkyl; X represents O, S, NH, N(CO ₂ C _1-4 alkyl), N(SO ₂ C _1-4 alkyl), N(SO ₂ -C _3-6 cycloalkyl) or CH ₂ ; Y1, Y ₂ and Y3 are each independently CH or N; where at most one of Y1, Y ₂ and Y3 are N; moreover, if L is different from -S(O) ₂ -, then each Y ₂ and Y3 represents CH; G2 is N or CR ² ; G3 is N or CR ³ ; G ₄ represents N or CR ^4a ; G5 is N or CR ⁵ ; And G6 is N or CR ⁶ ; wherein R ² , R ³ , R ^4a , R ⁵ and R ⁶ are each independently hydrogen, halogen, -OH, -C _1-4 alkyl, -O-C _1-4 alkyl, -C _1-2 haloalkyl , -O-C _1-2 haloalkyl or -NR ^u R ^v ; R ^u represents H or C _1-4 alkyl; R ^v is H, C _1-4 alkyl, monocyclic C _3-6 cycloalkyl, -C(O)C _1-4 alkyl or -C(O)NR ^w R ^y ; wherein each alkyl present in R ^v is unsubstituted or substituted with a -OH, -NH2, -NH(C _1-4 alkyl) or -N(C _1-4 alkyl) ₂ group, R ^w and R ^y are each independently H or C _1-4 alkyl; where ^G 5 Ό ₆ II .g ₄ is not unsubstituted phenyl; And R ⁷ and R ⁸ are each independently hydrogen or C _1-4 alkyl, or R ⁷ and R ⁸ together form -CH2CH2-; wherein each heteroaryl contains 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulfur; and each heterocycloalkyl contains 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R ¹ represents -(CR ^a R ^b ) _m -C _6-18 aryl. - 94 045787 3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R ¹ is -(CR ^c R ^d ) _n -(5-12 membered heteroaryl). 4. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R ¹ is (CR ^e R ^f )o-(3-10 membered heterocycloalkyl) or (CR ^g R ^h )p-C ₃ . ₆ cycloalkyl. 5. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, characterized in that L represents -S(O) ₂ -. 6. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, characterized in that L represents -C(O)-, -CF2-, -C(=CH ₂ )- or -CR ^s Rt-. 7. A compound according to claim 1, characterized in that it is a compound of formula (II) where X represents O, S, NH, N(CO ₂ C ₁ . ₄ alkyl), N(SO ₂ C ₁ . ₄ alkyl), N(SO ₂ -C ₃ . ₆ cycloalkyl) or CH2; Y1, Y ₂ and Y ₃ are each independently CH or N; G ₂ represents N or CR ² ; G ₃ represents N or CR ³ ; G4 is N or CR ^4a ; G5 is N or CR ⁵ ; And G ₆ represents N or CR ⁶ ; wherein R ² , R ³ , R ^4a , R ⁵ and R ⁶ are each independently hydrogen, halogen, -OH, -C ₁ . ₄ alkyl, -O-C ₁ . ₄ αlkyl, -C ₁ . ₂ haloalkyl, -OC ₁ . ₂ haloalkyl or -NR ^u R ^v ; R ^u represents H or C ₁ . ₄ alkyl; R ^v represents H, C ₁ . ₄ alkyl, monocyclic C ₃ . ₆ cycloalkyl, -C(O)C ₁ . ₄ alkyl or -C(O)NR ^w R ^y ; wherein each alkyl present in R ^v is unsubstituted or substituted with a -OH, -NH ₂ , -NH(C _{1 4} alkyl) or -N(C _1-4 alkyl) ₂ group, and R ^w and R ^y are each independently H or C ₁ . ₄ alkyl; where θ6 >> \ ^G 5 is not an unsubstituted phenyl; R ⁷ and R ⁸ are each independently hydrogen or C ₁ . ₄ alkyl, or R ⁷ and R ⁸ together form -CH ₂ CH ₂ -; R ^9a and R ^9b are each independently hydrogen or halogen; R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently hydrogen, halogen, -OH, -CN, -C _1-4 alkyl, -O-C ₁ . ₄ alkyl, -C _1-2 haloalkyl, 4-6 membered heterocycloalkyl, -O-C ₁ . ₂ haloalkyl, -SO ₂ C ₁ . ₄ αlkyl or -NR ^aa R ^bb ; R ^aa represents hydrogen, C ₁ . ₄ alkyl or -C ₁ . ₄ alkyl-OH; R ^bb represents hydrogen or C ₁ . ₄ αlkyl; wherein each heteroaryl contains 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulfur; and each heterocycloalkyl contains 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur; or a pharmaceutically acceptable salt thereof. 8. A compound according to claim 1, characterized in that it is a compound of formula (III) where R ¹ represents -(CR ^a R ^b )m-C6.18 aryl, -CH=CH-C6.18 aryl, (CR ^c R ^d )n-(5-12-membered heteroaryl), (CR ^e R ^f ) o-(3-10-membered heterocycloalkyl) or (CR ^g R ^h )p-C ₃ . ₆ cycloalkyl, and if L represents SO ₂ , then the heteroaryl and heterocycloalkyl present in R ¹ are monocyclic; - 95 045787 m is equal to 0 or 2; n, o and p are each independently equal to 0, 1 or 2; R ^a , R ^b , R ^c , R ^d , R ^e , Rf , R ^g and R ^h are each independently H, halogen or C _1-4 alkyl, or R ^a and R ^b together with a carbon atom, k to which they are attached form a C _3-6 cycloalkyl ring, or R ^a and R ^b together form =CH ₂ or =O; each aryl, heteroaryl, heterocycloalkyl or cycloalkyl present in R ¹ is unsubstituted or substituted with one or two R ^x substituents; where each substituent R ^x independently represents halogen, C1-4αalkyl, C3-6cycloalkyl, -C1-2-haloalkyl, -OH, -OC1-4alkyl, -O-C1-2-haloalkyl, cyano, -C(O)C1 -4alkyl, -C(O)NR'R', -SO2C1-4alkyl, -SO2NR ^k R ^l , -NR ^q R ^r , -C(O)-C3-6cycloalkyl, -C(O)-C _6-18 aryl unsubstituted or substituted with methyl or halogen, -CO ₂ C _1-4 alkyl, -CO ₂ -C _6-18 aryl, -C(O)CH ₂ -C _6-18 aryl unsubstituted or substituted with methyl or halogen, -CH ₂ -C _6-18 aryl unsubstituted or substituted with methyl or halogen, or monocyclic 4-6-membered heterocycloalkyl unsubstituted or substituted with methyl, -C(O)C _1-4 alkyl or -CO ₂ C _1-4 alkyl; where Ri, Rj, R ^k and Rl are each independently H, C _1-4 alkyl, -C _1-4 alkyl-OH or -C _1-4 alkyl-O-C _1-4 alkyl, where R ^q and R ^r are each independently H, C _1-4 alkyl, -C _1-4 alkyl-OH, -C _1-4 alkyl-O-C _1-4 alkyl, -C(O)C _1-4 alkyl, -CO ₂ C _1-4 alkyl or -SO ₂ C _1-4 alkyl; or R ¹ represents R ¹³ R ¹ ° where R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently hydrogen, halogen, -OH, -CN, -C _1-4 alkyl, -O-C _1-4 alkyl, -C _1-2 haloalkyl, 4-6 membered heterocycloalkyl, -O-C _1-2 haloalkyl, -SO ₂ C _1-4 alkyl or -NR ^aa R ^bb ; R ^aa is hydrogen, C _1-4 alkyl or -C _1-4 alkyl-OH; R ^bb represents hydrogen or C _1-4 alkyl; L represents -S(O) ₂ -, -СУ)-, -О-, -CF2-, -C(=CH ₂ )- or -CRsRt-; where R ^s and Rt are each independently H or C _1-4 alkyl; X represents O, S, NH, N(CO ₂ C _1-4 alkyl), N(SO ₂ C _1-4 alkyl), N(SO ₂ -C _3-6 cycloalkyl) or CH ₂ ; Y _b Y ₂ and Y ₃ are each independently CH or N; moreover, if L is different from -S(O) ₂ -, then each Y ₂ and Y ₃ represents CH; G2 is N or CR ² ; G ₃ represents N or CR ³ ; G ₄ represents N or CR ^4a ; G ₅ represents N or CR ⁵ ; And G ₆ represents N or CR ⁶ ; wherein R ² , R ³ , R ^4a , R ⁵ and R ⁶ are each independently hydrogen, halogen, -OH, -C _1-4 alkyl, -OC _1-4 alkyl, -C _1-2 haloalkyl, - O-C _1-2 haloalkyl or -NR ^u R ^v ; R ^u represents H or C _1-4 alkyl; R ^v represents H, C _1-4 alkyl, monocyclic C _3-6 cycloalkyl, -C(O)C _1-4 αalkyl or -C(O)NR ^w R ^y ; wherein each alkyl present in R ^v is unsubstituted or substituted with a -OH, -NH2, -NH(C _1-4 alkyl) or -N(C _1-4 αalkyl) ₂ group, R ^w and R ^y are each independently H or C _1-4 alkyl; Where is not unsubstituted phenyl; And R ⁷ and R ⁸ are each independently hydrogen or C _1-4 alkyl, or R ⁷ and R ⁸ together form -CH2CH2-; wherein each heteroaryl contains 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulfur; and each heterocycloalkyl contains 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur; or a pharmaceutically acceptable salt thereof. 9. A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, characterized in that each Y _b Y ₂ and Y ₃ represents CH. 10. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, differing - 96 045787 in that Y1 represents N, and each Y2 and Y ₃ represents CH. 11. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, characterized in that Y2 is N and Y1 and Y3 are each CH. 12. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, characterized in that Y ₃ represents N and each Y ₁ and Y ₂ represents CH. 13. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, characterized in that X represents O. 14. A compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof, characterized in that X represents NH, N(CO ₂ C _1-4 alkyl), N(SO ₂ C _1-4 alkyl) or N( SO ₂ -C _3-6 cycloalkyl). 15. A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, characterized in that G2 and G4 are each N and G6 is CR ⁶ . 16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, characterized in that G ₃ is CR ³ and G ₅ is CR ⁵ . 17. A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, characterized in that one of G2 and G4 is N. 18. A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, characterized in that R ⁶ represents -NR ^u R ^v . 19. A compound selected from the table below, or a pharmaceutically acceptable salt thereof: Connection no. Structure Chemical name 1 Q,? с /—\ / ⁼ с° ==< ζ I Μ 5 -(3-morpholino-5 - (phenylsulfonyl)phenyl)pyrimidin-2-amine 2 Ν^,ΟΜβ ο. ,ο G Υ and ΈΤ 0 4-(3 -(2-methoxypyrimidin-5 -yl)-5 (phenylsulfonyl)phenyl)morpholine 3 Qo co' o—z ω Z Z N 5 -(3-morpholino-5 -(phenylsulfonyl)phenyl)-4(trifluoromethyl)pyrimidin-2-amine 4 Φ s z 4—z^\E ъ X,X-dimethyl-5 -(3-morpholino-5 (phenylsulfonyl)phenyl)pyrimidin-2-amine 5 N^^OMe o _xz o Г T w u* 0 4-(3 -(6-methoxypyridin-3 -yl)-5 (phenylsulfonyl)phenyl)morpholine 6 f ₃ c^^^nh ₂ o. .o 1 ll /xS ^N Μ 0 5 -(3-morpholino-5 -(phenylsulfonyl)phenyl)-4(trifluoromethyl)pyridin-2-amine 7 _χ Ν^,ΝΗ ₂ 0 _4Z 0 [ IT LJ XX 0 5 -(3-morpholino-5 -((3 - (trifluoromethyl)phenyl)sulfonyl)phenyl)pyri midin-2-amine 8 _x n^nh ₂ Οχ/0 GP JL J 1X ' 0 5-(3-((4-fluorophenyl)sulfonyl)-5morpholinophenyl)pyrimidin-2-amine - 97 045787 9 _x n^nh ₂ 0..0 Γ II ^Ν υυ ts 0 5-(3-morpholino-5-(naphthalene-2ylsulfonyl)phenyl)pyrimide in-2-amine 10 .Ν^ΝΗζ Ο _{4 Ζ} Ο G II l J Ύ j 0 4-((3-(2-aminopyrimidin-5 -yl)-5morpholinophenyl)sulfonyl)benzonitrile 11 Οχ/Ο Г II ^{c 1 s} a^a^ ⁿ IT Ύ T ' 0 5-(3-((3-chloro-4-fluorophenyl)sulfonyl)-5morpholinophenyl)pyrimidin-2-amine 12 Z=\w ζ E °x Kommersant 4-(3-(3-methylpyridin-4-yl)-5 (phenylsulfonyl)phenyl)morpholine 13 z O 6, ω; /—X /=('° Χζ M z I 3 -((3 -(2-aminopyridimidin-5 -yl)-5 morpholinophenyl)sulfonyl)benzonitrile 14 -N^nh ₂ ο. ,ο G II JL JTJ F ₃ C^^ 0 5 -(3-morpholino-5 -((4- (trifluoromethyl)phenyl)sulfonyl)phenyl)pyri midin-2-amine 15 O about. ω /—X /=( ° ΖΆ *=< z z 5 -(3 -morpholino-5 -((4- (trifluoromethoxy)phenyl)sulfonyl)phenyl)pyr imidin-2-amine 16 Q _? ω' /=( ⁴ ° /А ^zx / ¹ N-methyl-5 -(3-morpholino-5 (phenylsulfonyl)phenyl)pyrimidin-2-amine 17 z o A ^ω \ /— ₄ /_/ o V“O ω Ζ— Ζ I 4-((3 -(2-amino-4-(trifluoromethyl)pyrimidin-5 yl)-5-morpholinophenyl)sulfonyl)benzonitrile 18 _χ ν^νη ₂ 0. ,Ο Г |Г JL JTJ If ³ 0 4-((3-(6-amino-4-(trifluoromethyl)pyridin-3 yl)-5-morpholinophenyl)sulfonyl)benzonitrile 19 Qo ω _χ /—X /=( ° /L z=< ZI $ o I 2-((5 -(3-morpholino-5 - (phenylsulfonyl)phenyl)pyrimidin-2yl)amino)ethan-1-ol - 98 045787 20 Η NN Ο _{χ Ζ} Ο Γ Υ V Μ χχ 0 N-cyclopropyl-5 -(3-morpholino-5 (phenylsulfonyl)phenyl)pyrimidin-2-amine 21 _χ ν^νη ₂ Ο _χ Ό G Π Ν Λ J Ύ J 0 5 -(3-morpholino-5-tosylphenyl)pyrimidine-2amine _{22 _} ^_ _{_} ^_ )phenyl)acetamide 23 ν_,νη ₂ \ ιΙ ο _χ ,ο ΓΗ td 0 5 -(3 -(benzylsulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 24 _Z N _V NH ₂ o. .о G Y and th 0 N Voc tert-butyl-4-(3 -(2-aminopyrimidin-5 -yl)-5 (phenylsulfonyl)phenyl)piperazine-1 carboxylate 25 .N^NHj O _x .0 G Y m xx 5 -(3 -(phenylsulfonyl)-5 -(piperidin-1 yl)phenyl)pyrimidin-2-amine 26 _x n^nh ₂ GN o _4z o G II Ν F 0 5 -(3 -((2,4-difluorobenzyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 27 ,n^nh ₂ \ Il 1 H NC T1 0 3 -(((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)methyl)benzonitrile 28 χΝ^ΝΗ ₂ \ 0 o o f ιι 0 5 -(3 -((4-methoxybenzyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 29 ^F \^\ .n^nh ₂ 1 |] o. _z o [ II ΊίΎ 0 5 -(3 -((4-fluorobenzyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine - 99 045787 30 Η ο _χ ,ο \ ιι Π Μ XT 0 Ν-(5-(3-morpholino-5-(phenylsulfonyl)phenyl)pyrimidin-2yl)acetamide 31 Η 0 / ^Ν ___Ν. Γ 11 and Γ ^^ιιΥίΡ^ ο 0 5 -(3 -(benzylsulfonyl)-5 -morpholinophenyl)M-methylpyrimidin-2-amine 32 0 G 11 II Γϊ ΤΥΐ Ο CF ₃ φ 5 -(3 -(benzylsulfonyl)-5 -morpholinophenyl)4-(trifluoromethyl)pyr idin-2-amine 33 0 ^Ν_ΝΗ ₂ Γ 1 II g Υ Jk .S _x Α-Ν ^ΊΐΥΎϊ ο LA CF ₃ 0 5 -(3 -(benzylsulfonyl)-5 -morpholinophenyl)4-(trifluoromethyl)pyrimidin-2-amine 34 Π II g ' ^πιΤί^ ο Χχ^ 0 4-(3 -(benzylsulfonyl)-5 -(2methylimidazo[1,2-a]pyrimidine-6- yl)phenyl)morpholine 35 Η 0 ^Ύ ^Ν ^ΟΗ ΓΗ II \ Υ ^0Η Τί^ ο ΧΗ 0 2-((5-(3-(benzylsulfonyl)-5morpholinophenyl)pyrimidin-2-yl)amino)ethan-1-ol 36 .ΙΥ DN ₂ Οχ /0 < V ^JsY^JUn ί Υ Υ Υ 0. J Ν Q 5 -(3-morpholino-5 -((4-morpholinophenyl)sulfonyl)phenyl)pyrimidi n-2-amine 37 ,N. ,ΝΗ ₂ °\ /О ίί Ύ x^O ^S O^Tx^N JL J Ύ J ΗΝ^^ ₀ 1 -((4-((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl )phenyl)amino)-2-methylpropan-2-ol 38 Ο-, ο ^Ν ΝΗ ₂ / Ί ιι \ Υ V\,S./x A . Ν ^ΥΙΊιί ο 0 5 -(3-morpholino-5 -(((tetrahydrofuran-3 yl)methyl)sulfonyl)phenyl)pyrimidin-2amine 39 0 ^Ν ΝΗ ₂ 9 1 ιι r Υ ^ΠΙ Ρκ ο 0 5 -(3-morpholino-5 -(((tetrahydro-2H-pyran-4yl)methyl)sulfonyl)phenyl)pyrimidin-2amine 40 9 Η Η 0 Υ^Ν Ν^ γη ¹¹ Γ Υ Υ Τν 0 1 -ethyl-3 -(3 '-((4-fluorobenzyl)sulfonyl)-3 methoxy-5 '-morpholino-[ 1,1 '- biphenyl]-4yl)urea - 100 045787 41 He ABOUT Τι and Ο O 0 3'-((4-fluorobenzyl)sulfonyl)-5'-morpholino[1,1'-biphenyl]-3-ol 42 Η ΰφ^° 0 7-(3-((4-fluorobenzyl)sulfonyl)-5morpholinophenyl)-2H-benzo[b][1,4]oxazin- 3(4H)-on 43 LI U I o VA 0 3'-((4-fluorobenzyl)sulfonyl)-4-methoxy-5'morpholino-[1, G-biphenyl]-3-amine 44 Fk^\ o MeO.___N.___,NH ₂ G II and T ¥ ^¥1YY^ o W 0 5 -(3 -((4-fluorobenzyl)sulfonyl)-5 morpholinophenyl)-6-methoxypyridin-2-amine 45 H ua^^jcxj ΐΠφ^ 0 7-(3-((4-fluorobenzyl)sulfonyl)-5morpholinophenyl)-3,4-dihydro-2Hbenzo[b][1,4]oxazine 46 F ₃ % T 1 ¹¹ G1 ^ΜιΤί^ o Μ#* ¹ 0 4-(5-((4-fluorobenzyl)sulfonyl)-3'(trifluoromethoxy)-[1,1'-biphenyl]-3 yl)morpholine 47 H r .___. NN ____. V ⁴ ! <lp f T ^NHz TA 0 N1 -(5-(3 -((4-fluorobenzyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-yl)ethane-1,2diamine 48 LL 0/ 0 ,N NH ₂ ^ην 0Τ^^ΧΤ IGR o AA 0 5 -(3-(((ΙΗ-indol-3-yl)methyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 49 0 /N_NH ₂ II Г T IT Ύί^ 0 5 -(3 -(cyclohexylsulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 50 O /N^NH ₂ G II II \ II T¥i Yv F O ^l CA Ф 5 -(3 -((2-fluorobenzyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine - 101 045787 51 0 .N^.NH ₂ and \ T 'CMpC' 0 5 -(3-morpholino-5 -((tetrahydrofuran-3 yl)sulfonyl)phenyl)pyrimidin-2-amine 52 ο /N ,NH ₂ ii \ T „ /S. 0 (R)-5 -(3-morpholino-5 -((tetrahydrofuran-3 yl)sulfonyl)phenyl)pyrimidin-2-amine 53 O /N_NH ₂ II \ T /x Λ..Ν °Γν ιιΎίγ K—J 0 0 (S)-5 -(3-morpholino-5 -((tetrahydrofuran-3 yl)sulfonyl)phenyl)pyrimidine-2- amine 54 o z ^N nh ₂ II Г If _{_} _ R Vos ° 0 tert-butyl-3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)azetidine-1 carboxylate 55 F^^, 0 J\ Π II 1 II % Jk Ax .N O 0 4-(3-((4-fluorobenzyl)sulfonyl)-5-(5methoxypyrid in-3-yl)phenyl)morpholine 56 9 Wx _/Ό OQ 4 z M z z KJ 5 -(3-((( Ш-indol-5 -yl)methyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 57 2 w e ΐ ίου ril z^z z X N-(4-(((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)methyl)phenyl)meth ansulfonamide 58 LzNk o>° Н<Он ₂ ^=/ 'ύ-Ν c 5 -(3-morpholino-5 -((4- morpholinobenzyl)sulfonyl)phenyl)pyrimide in-2-amine 59 n^nh ₂ 0 5 -(3-((( 1H-imidazol-4-yl)methyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 60 ,n nh ₂ 0./9 G II ,— ₄ C/ TD 0 5 -(3 -((cyclohexylmethyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine - 102 045787 61 0 /N_NH ₂ II G ¥ ΗνΓΛ 0 5 -(3 -(azetidin-3-ylsulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 62 0 /Ν^ΝΗ ₂ II Г Τ ίΎιιΥη^ 0 5-(3-morpholino-5-((tetrahydro-2H-pyran-4yl)sulfonyl)phenyl)pyrimidin-2-amine 63 _N. _ΝΗ ₂ .ο ί Ύ ⁽ ν^ °ΤΤ Η 1^ 0 5-(3-(((1 H-benzo [d] imidazole-5 and l) methyl l) sul fonyl) -5 - morpholinophenyl)pyrimidine- 2-amine 64 Όν /=Ν \/\Γ ¥ ^νη 2 )= ⁷ ^-Ν ^Ν 0^ 5-(3-(((4,4-difluorocyclohexyl)methyl)sulfonyl)-5morpholinophenyl)pyrimidin-2-amine 65 ο ^Ν ΝΗ ₂ ιι \ ¥ у+УХ^¥ 0 5 -(3-(( 1 -isopropylazetidin-3-yl)sulfonyl)5-morpholinophenyl)pyrimidin-2-amine 66 0 ΝΗ ₂ ιι \ ¥ .ytiy 0 5 -(3-morpholino-5 -((1 -(tetrahydro-2H-pyran-4l) azetidin-3-yl)sulfonyl)phenyl)pyrimidin-2-amine 67 ο /Ν_ΝΗ ₂ II \ ¥ <Y ⁿ ^ZhYj^ Boc'N^J 0 γ 0 tert-butyl-4-(3 -((3 -(2-aminopyrimidin-5 -yl)5 -morpholinophenyl)sulfonyl )azetidine-1 yl)piperidine-1-carboxylate 68 Ο Ν^ΝΗ ₂ уМхА 0 1 -(3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)azetidin-1 yl)ethan-1-one 69 Ο Ν>^ ^ΝΗ 2 and Υ ¥ _R ,nC¥h Boc ^ϋ 0 tert-butyl-3 -((3-(5-aminopyrazin-2-yl)-5 morpholinophenyl)sulfonyl)azetidine-1 carboxylate 70 0 ^F 3C^^^NH ₂ ii g ¥ <Mp¥ 0 5 -(3-morpholino-5 -((tetrahydrofuran-3 yl)sulfonyl)phenyl)-4-(trifluoromethyl)pyridin-2-amine - 103 045787 71 0 F ₃ C^^NH ₂ II TT 0 (R)-5 -(3-morpholino-5 -((tetrahydrofuran-3 yl)sulfonyl)phenyl)-4-(trifluoromethyl)pyridin-2-amine 72 0 F ₃ C_N_NH ₂ II Τ Τ <mg 0 5 -(3-morpholino-5 -((tetrahydrofuran-3 yl)sulfonyl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine 73 Ρ Ο=ω=ο OQ Q ζ ζ 5 -(3 -(benzylsulfonyl)-5 morpholinophenyl)pyrazin-2-amine 74 0 Μ^^ ^ΝΗ ₂ ιι 7 π «mu 0 5 -(3-morpholino-5 -((tetrahydrofuran-3 yl)sulfonyl)phenyl)pyrazin-2-amine 75 0 .N^NHa II G Τ Zhi ⁰ 1 0 1 -(3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)azetidin-1 yl)propan-1 -one 76 0 ^N^NHa / II \ II / a___ ywp ⁰ 1 0 1 -(3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)azetidin-1 -yl)2-methylpropan- 1 -on 77 0 /N^NHa and r ιι r ^N ^o£i 0 (3-((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)azetidin-1 yl)(cyclopropyl)methanone 78 ο /N___NH ₂ and g T ^F *^\===^ N Q 1 -(3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)azetidin-1 -yl)2-( 4-fluorophenyl)ethan-1-one 79 0 ^N^NH ₂ V 0 F XT (3-((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)azetidin-1 -yl)(4-fluorophenyl)methanone 80 o=«=o 'ОХЭ Hz ^z =< zz 5 -(3-(( 1 -(4-fluorobenzyl)azetidin-3 yl)sulfonyl)-5-morpholinophenyl)pyrimidin-2-amine 81 o ^n^nh ₂ ΥΥ ⁰ 1 0 3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)azetidine-1 carboxamide - 104 045787 82 with H Tj ° Gn V Z ζ 5 -(3 -((4-fluorophenethyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 83 V θγΟ' ^ΖΗΓ^ ^ΝΗ * ο—' 1 -(4-((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)piperidin-1 yl)ethan-1-one 84 ο>° ΧΤΧ )= ⁷ / ^- Ν ο— ⁷ 1-((4-(((3-(2-aminopyrimide in-5-yl)-5morpholinophenyl)sulfonyl)methyl)phenyl)amino but)-2 -methylpropan-2-ol 85 ζ ζ >=\ Μ Κζ^Ο Οχ s' Μχ / Ό Ο—ζ 5 -(3 -(((2R, 6S)-2,6-dimethylteΊhydro-2Hπpyran-4-yl)sylphonyl)-5- morpholinophenyl)pyrimidine-2-amine 86 ο ΝΗ ₂ ιι \ Τ 0 1 -(3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)azetidin-1 -yl)-2,2-dimethylpropan-1 -one 87 ^Ν ΝΗ ₂ 0*/ f Υ FWyV^ ⁿ 0 5 -(3 -((difluoro(phenyl)methyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 88 .Ν___ΝΗ ₂ exp Γ Υ 'S. +¾. .Ν 5 -(3 -((4,4-difluorocyclohexyl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 89 ο..ρ ^λ w __/ Ο O~Q ζ ζ Μ Ζ ο 5 -(3-(( 1 -isopropylpyrrolidin-3 yl)sulfonyl)-5-morpholinophenyl)pyrimidin-2-amine hydrochloride 90 ν ^“4Ι^ ^ΝΗ 2 0^ 5 -(3-(( 1 -isopropylpiperidin-4yl)sulfonyl)-5-morpholinophenyl)pyrimidin-2-amine - 105 045787 91 cm X Z Τθ V/ X ο 1 -(3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)pyrrolidine-1 - yl)ethan-1-one 92 ο Ν ΝΗ ₂ θ' TpgST ⁰ 1 0 3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinofsnyl)sulfonyl)-X-(trstbutyl)azetidine-1-carboxamide 93 ο ,Ν ΝΗ ₂ \,й ⁰ τ 0 3 -((3 -(2-aminopyrimidin-5 -yl)-5 - morpholinophenyl)sulfonyl)-M-ethyl azetidin1-carboxamide 94 ο .Ν^ΝΗ ₂ u II Г Τ -о. And ⁰ 1 0 3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl)-M(methoxymethyl)azetidine-1-carboxamide 95 0 / _V ^N H ₂ 'U-LC ⁰ τ 0 3 -((3 -(2-aminopyrimidin-5 -yl)-5 morpholinophenyl)sulfonyl) -N,Νdimethylazetidine-1-carboxamide 96 G || and GT Ί^ιιΤηρ ^N F 0 0 6-(3 -((2,4-difluorobenzyl)sulfonyl)-5 morpholino phenyl)pyride azin-3-amine 97 .,^ 0 NH ₂ Μ II \ II G JX A. _N iiYV o NT 0 5 -(3-morpholino-5 -((pyridin-4-ylmethyl)sulfonyl)phenyl)pyrimidin-2-amine 98 ^F '^\ 0 ^^NH ₂ 1 11 II 1 Ϊ ttiYt ^N F 0 <4 0 6-(3 -((2,4-difluorobenzyl)sulfonyl)-5 morpholino phenyl)pyr idin-3-amine 99 X z \=z M v^ ^-z d/° Ox / G 6-(3-((2,4-difluorobenzyl)sulfonyl)-5 morpholinophenyl)-5 -methylpyridazin-3-amine 100 Rx -O ,„, S' CF ₃ °U Aav=C \ UL //“ ^NH 2 )=/ 4_ _N T ^N w (R)-5 -(3-morpholino-5 -((tetrahydrofuran-3 yl )sulfonyl)phenyl)-3-(1fluoromethyl)pyridin-2-amine - 106 045787 101 ^=/ V- _N O o—' (R)-5 -(3-morpholino-5 -((tetrahydrofuran-3 yl) sulfonyl) phenyl) pyr idin-2-amine 102 Η ο Ν L II \ II V ⁰ 1 s cyclopropyl(3 -((3 -(2-(cyclopropylamino)pyrimidin-5-yl)-5 morpholinophenyl)sulfonyl)azetidin-1 yl)methanone 103 Η <HPSg^ 0 N-cyclopropyl-5 -(3-morpholino-5 ((tetrahydrofuran-3yl)sulfonyl)phenyl)pyrimidin-2-amine 104 Η ^χ ο Ν gn G V X Jk .s. Αχ_Ν ^ν 0 0 5 -(3 -(benzylsulfonyl)-5 -morpholinophenyl)M-cyclopropylpyrimidin-2-amine 105 C.M. 0=03=0 ъ (R)-5 -(3 -morpholino-5 -((tetrahydrofuran-3 yl)sulfonyl)phenyl)-6- (trifluoromethyl)pyridin-2-amine 106 O \^xLN ₂ II g ϊ,— Al, AH <gf ιιΥι V-' O 0 (R)-4-φτop-5-(3-morpholino-5- ((tetrahydrofuran-3 - yl)sulfonyl)phenyl )pyr idin-2-amine 107 o ^C1 x^\A ⁿ 2 and g T /x ,S. ^x 4l. .N cgf ιι^ΓίΓ^ \—- o <A 0 (R)-4-chloro-5-(3-morpholino-5- ((tetrahydrofuran-3 - yl)sulfonyl)phenyl)pyr idin-2-amine 108 n II GT ^Mel ,S. /l Αχ ,Ν °С^ ηΊιί^ ν-- о XX 0 (R)-N-MCTnn-5 -(3-morpholino-5 ((tetrahydrofuran-3yl)sulfonyl)phenyl)pyridin-2-amine 109 _ about ΝΗ ₂ /A and G r \\ /A ^S, Ax,N ^OTG; O-^ O 0 5 -(3 -(benzofuran-3-ylsulfonyl)-5 morpholinophenyl)pyrimidin-2-amine - 107 045787 Software ¥? and Г «\Vs _v/ x Α,Ν P ¹¹ Tv 0 5 -(3 -(benzofuran-7-ylsulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 111 __ O NH ₂ L? II Г ¥ xA/Sk/^Az-n and ¹¹ Tv 0 5 -(3 -((2,3-dihydrobenzofuran-7 yl)sulfonyl)-5-morpholinophenyl)pyrimidin-2-amine 112 0 Ш nh ₂ ii r ¥ ίϊΎΐΐΐΐ 0 5 -(3 -(benzofuran-6-ylsulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 113 /K OH Ιι V .N. ,NH ₂ IAj ιί υ °' ХД 0 (E)-2-(2-((3-(2-aminopyrrimidin-5 -yl)-5 morpholino phenyl)sulfonyl)vinyl) phenol 114 X O7 _/Ό €K) Λ^Ζ z I N> 5 -(3 -((lH-indol-3-yl)sulfonyl)-5 morpholinophenyl)pyrimidin-2-amine 115 CN I z z y CX/'°'b 5-(6-morpholino-4-(phenylsulfonyl)pyridin2-yl)pyrimidin-2-amine 116 8 /4*0 ά z A z x 5-(3-((2,3-dihydrobenzofuran-6- yl)sulfonyl)-5- morpholinophenyl)pyrimidin-2-amine 117 CN T z >= ^z _x V z^~/O 0^ / ' ъ 5-(4-morpholino-6-(phenylsulfonyl)pyridin2-yl)pyrimidin-2-amine 118 X z ¥ ^z _x M Z ⁷ E 0^/ ^zx °'b 5-(2-morpholino-6-(phenylsulfonyl)pyridin4-yl)pyrimidin-2-amine - 108 045787 119 CM TZ >=\ w Οχ / ' Z ^W o' ZY /~O 5 -(3 -((2,3-dihydrobenzofuran-3 yl)sulfonyl)-5-morpholinophenyl)pyrimidin-2-amine 120 nh ₂ N^N aX %,0 5-(6-morpholino-4-phenoxypyridin-2yl)pyrimidin-2-amine 121 „ _n NH ₂ <VP g Y %J IX 0 (K)-4-methyl-5 -(3-morpholino-5 - ((tetrahydrofuran-3 - yl)sulfonyl)phenyl)pyrimidin-2-amine 122 nh ₂ N^N L Π P XI ° χο (2-(2-aminopyrimidin-5 -yl)-6morpholinopyridin-4-yl)(phenyl)methanone 123 nh ₂ N^NL l| H xl FF Xo 5-(4-(difluoro(phenyl)methyl)-6-morpholino pyridin-2-yl)pyrimidin-2-amine 124 nh ₂ N^NLH Π Xi --- Y/° 5-(4-benzyl-6-morpholinopyridin-2yl)pyrimidin-2-amine 125 nh ₂ N^NLH Π xl x° 5 -(6-morpholino-4-( 1 -phenylethyl)pyridin-2yl)pyrimidin-2-amine 126 nh ₂ N^N 5 -(6-morpholino-4-( 1 -phenylvinyl)pyridin-2yl)pyrimidin-2-amine - 109 045787 127 ΛΑ ъаь ^Ζ 5 -(6-morpholino-4-( 1 - phenylcyclopropyl)pyridin-2-yl)pyrimidin2-amine 128 Ο o txh /—Ζ '—Ζ μ 5-(4-(4-chloro-3-(trifluoromethyl)phenoxy)-6morpholino pyr idin-2-yl)pyrimidin-2-amine 129 ό ⁰ 1 ^Ν^ΝΗί (3 -((2-(2-aminopyrimidin-5-yl)-6morpholinopyridin-4-yl)oxy)azetidin-1 yl)(cyclopropyl)methanone 130 Ρ ο 0X3° V ζ I YU 5-(6-morpholino-4-((tetrahydrofuran-3yl)oxy)pyr idin-2-yl)pyrimidin-2-amine 131 ^Ο= \ €Mh C-^ (2-(2-aminopyrimidin-5-yl)-6morpholinopyridin-4-yl)(te1rahydro-2H-pyran-4-yl)methanone 132 CM and s/ o 0 o H LL 5-(4-(4-chloro-3-(1fluoromethyl)phenoxy)-6morpholino pyr idin-2-yl)pyrimidin-2-amine 133 nh ₂ N^N lh Ο'Ά PA I 1 L if ^FF P-0 5-(4-(difluoro(te1rahydro-2H-pyran-4yl)methyl)-6-morpholinopyridin-2yl)pyrimidin-2-amine 134 0 N Cl jlX ci IL N NH ₂ 5-(4-(2-chlorophenoxy)-6-morpholinopyridin-2yl)pyrimidin-2-amine 135 I z \ ^z o 5 5-(4-(2-methoxyphenoxy)-6-morpholinopyridin-2-yl)pyrimidin-2-amine - 110 045787 136 X z /4 \ ^z o O-h 5-(6-morpholino-4-(2-(trifluoromethoxy)phenoxy)pyridin-2yl)pyrimidin-2-amine 137 0 ^Me ^n*%h ₂ 5-(6-morpholino-4-(o-tolyloxy)pyridin-2yl)pyrimidin-2-amine 138 0 N P JLjl ^{Cl 0} (2-(2-aminopyrimidin-5-yl)-6morpholinopyridin-4-yl)(2chlorophenyl)methanone 139 Ox / st O ^z \=x / ₄ y_G^ zx 5-(4-((2-chlorophenyl)sulfonyl)-6-morpholino pyridin-2-yl)pyrimidin-2-amine 140 0 N iS P'N'^ ^x pp ^> N MN^nh ₂ 5-(4-(3,4-dihydroquinolin-1(2H)-yl)-6morpholinopyridin-2-yl)pyrimidin-2-amine 141 0 N jfS OTMCi V|1 N NH ₂ 5-(4-(chroman-4-yl)-6-morpholinopyridin-2yl)pyrimidin-2-amine 142a _n O NH ₂ G ii θ TT Ί VJ 0 (8)-5-(6-morpholino-4-((tetrahydrofuran-3yl)sulfonyl)pyridin-2-yl)pyrimidin-2amine 142b _n O NH ₂ % // \ T 4 = II I 0 (K)-5-(6-morpholino-4-((tetrahydrofuran-3yl)sulfonyl)pyridin-2-yl)pyrimidin-2amine 143_N. .NH ₂ ύ ₀ 5-(4-(chroman-4-ylsulfonyl)-6-morpholinopyridin-2-yl)pyrimidin-2-amine - 111 045787 144 Cho ω V__U Ζ X m 6-morpholino-4-(phenylsulfonyl)-4'- (trifluoromethyl)-[2,3'-bipyridine]-6'-amine 145 I Ζ k ^z ζ y °\ ^x/ O Ν-(5-(6-ΜορφοπΗΗθ-4-(phenylsulfonyl)pyridin-2-yl)pyrimidin-2yl)acetamide 146 n η __ ΥΥΥΙ U φί 0 X-cyclopropyl-5-(6-morpholino-4(phenylsulfonyl)pyridin-2-yl)pyrimidin-2amine 147.N. .ΝΗ ₂ Z? f Υ ϊ Τ ι Ο ί У 5 -(4-((2,3-dihydrobenzofuran-3 yl)sulfonyl)-6-morpholinopyridin-2-yl)pyrimidin-2-amine 148 τ ζ Η\ ζ y 5-(6-morpholino-4-((tetrahydro-2H-pyran-4yl)sulfonyl)pyridin-2-yl)pyrimidin-2amine 149 ⁰ iiV ^H2 from τ τ 0 (2-(2-aminopyrimidin-5-yl)-6-morpholinopyridin-4-yl)(tetrahydrofuran-3yl)methanone 150 Η /=Λ° n ζ Τ 5-(6-(2,6-dimethylmorpholino)-4- (phenylsulfonyl)pyridin-2-yl)pyrimidin-2amine 151 Q, ζ τ 5 -(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4(phenylsulfonyl)pyridin-2-yl)pyrimidin-2- amine 20. Pharmaceutical composition containing: (a) at least one compound according to any one of paragraphs. 1-19 or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable excipient. 21. A method of treating a disease or medical condition associated with autophagy or the PI3K-AKT-MTOR cascade, comprising administering to a subject in need of such treatment an effective amount of at least one compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20. 22. The method of claim 21, wherein the disease or medical condition is Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, dementia associated with Parkinson's disease, multiple system atrophy, Huntington's disease, amyotrophic lateral sclerosis, cancer, infection, Crohn's disease, heart disease, Paget's disease, Charcot-Marie-Tooth disease, macular degeneration, cardiomyopathy or aging. 23. The method of claim 21, wherein the disease or medical condition is rosacea, acne, psoriasis or atopic dermatitis. 24. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for the treatment of a disease or medical condition associated with autophagy or the PI3K-AKTMTOR cascade. 25. Use according to claim 24, characterized in that the disease or medical condition is - 112 045787 is Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with corpuscles Lewy's disease, dementia associated with Parkinson's disease, multiple system atrophy, Huntington's disease, amyotrophic lateral sclerosis, cancer, infection, Crohn's disease, heart disease, Paget's disease, Charcot-Marie-Tooth disease, macular degeneration, cardiomyopathy, or aging. 26. The use of claim 24, wherein the disease or medical condition is rosacea, acne, psoriasis or atopic dermatitis. 27. Use of at least one compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20 for the production of a medicament for the treatment of a disease or medical condition associated with autophagy or the PI3K-AKT-MTOR cascade . 28. The use of claim 27, wherein the disease or medical condition is Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, dementia associated with Parkinson's disease, multiple system atrophy, Huntington's disease, amyotrophic lateral sclerosis, cancer, infection, Crohn's disease, heart disease, Paget's disease, Charcot-Marie-Tooth disease, macular degeneration, cardiomyopathy or aging. 29. The use of claim 27, wherein the disease or medical condition is rosacea, acne, psoriasis or atopic dermatitis.