HK1237779B

HK1237779B - Compositions and methods for the production of pyrimidine and pyridine compounds with btk inhibitory activity

Info

Publication number: HK1237779B
Application number: HK17111860.5A
Authority: HK
Inventors: B‧L‧霍都斯; L‧刘-布加尔斯基; R‧琼斯; D‧班克斯顿; T‧L‧约翰逊; I‧莫恰金; N‧恩古耶; H‧裘; A‧古托普鲁斯; 布鲁格 N.
Original assignee: 默克专利有限公司
Priority date: 2011-06-10
Filing date: 2014-10-22
Publication date: 2020-10-30

Abstract

The present invention provides novel pyrimidine and pyridine compounds of formula , formula (II), formula (III), formula (IV) and formula (V), their preparation and use for the treatment of hyperproliferative diseases, including but not limited to cancer, lupus, allergic diseases, Sjogren's disease and rheumatoid arthritis. In preferred embodiments, the present invention describes irreversible kinase inhibitors, including but not limited to bruton's tyrosine kinase inhibitors.

Description

Compositions and methods for producing pyrimidine and pyridine compounds having BTK inhibitory activity

This invention patent application is a divisional application of the invention patent with international application number PCT/US2012/041803, international application date June 10, 2012, and application number 201280038868.X that has entered the Chinese national phase.

Technical Field

The present invention relates to a series of pyrimidine and pyridine compounds that can be used as therapeutic agents to treat various pathological symptoms in mammals, including (but not limited to) cancer, autoimmune diseases, inflammatory diseases and neurodegenerative diseases. More specifically, the embodiments of the present invention describe irreversible kinase inhibitors, including but not limited to Bruton's tyrosine kinase (hereinafter referred to as "BTK") inhibitors. Also disclosed herein are methods for preparing the above-mentioned compounds and pharmaceutical compositions containing these compounds. Also disclosed herein are methods for using these BTK inhibitors alone or in combination with other therapeutic agents to treat hyperproliferative diseases in mammals, especially humans, and pharmaceutical compositions containing the inhibitors.

Background of the Invention

Protein kinases constitute a large family of structurally related enzymes that control a variety of signal transduction processes within cells (Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book. I and II, Academic Press, San Diego, CA). Kinases can be divided into several families based on the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.). Sequence motifs that generally correspond to each of these families of kinases have been identified (e.g., Hanks, S.K., Hunter, T., FASEB J., 9:576-596 (1995); Knighton, et al., Science, 253:407-414 (1991); Hiles et al., Cell, 70:419-429 (1992); Kunz et al., Cell, 73:585-596 (1993); Garcia-Bustos, et al., EMBO J., 13:2352-2361 (1994)).

Protein kinases can be characterized by their regulatory mechanisms. These mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, and protein-polynucleotide interactions. A single protein kinase may be regulated by more than one mechanism.

By adding a phosphate group to the target protein, kinases can regulate many different cellular processes, including but not limited to proliferation, differentiation, apoptosis, motility, transcription, translation and other signal transduction processes. These phosphorylation events serve as molecular on-off switches that can regulate or adjust the biological function of the target protein. The phosphorylation of the target protein occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environment or nutritional stress, etc. Suitable protein kinases work in signal transduction pathways to activate or passivate (directly or indirectly) such as metabolic enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels or pumps or transcription factors. The uncontrolled signal transduction caused by protein phosphorylation control defects relates to a variety of diseases, including, for example, inflammation, cancer, allergy/asthma, immune system diseases and illness, central nervous system diseases and illness and angiogenesis.

BTK is a member of the Tec family of non-receptor tyrosine kinases and is a signaling enzyme expressed in all hematopoietic cells except T lymphocytes and natural killer cells. BTK plays a well-documented role in the B cell signaling pathway that links cell surface B-cell receptor stimulation with downstream intracellular responses. BTK is also a regulator of B-cell development, activation, signaling, and survival (Kurosaki, Curr Op Imm, 2000, 276-281; Schaeffer and Schwartzberg, Curr Op Imm 2000, 282-288). In addition, BTK plays a physiological role through other hematopoietic cell signaling pathways, such as the production of TNF-a mediated by Toll-like receptors (TLRs) and cytokine receptors in macrophages, the IgE receptor (FcepsilonR1) signaling in mast cells, the inhibition of Fas/APO-1 apoptosis signaling in B-lineage lymphoid cells, and collagen-stimulated platelet aggregation. BTK has an ATP-binding pocket that is very similar to Src-family kinases, such as lymphocyte-specific protein tyrosine kinase (Lck) and Lyn. Comparison of BTK with other kinases revealed the presence of a conserved cysteine residue, Cys-481, in 11 of 491 kinases, particularly members of the Tec and EGFR (epidermal growth factor receptor) kinase families.

BTK plays an important role in the development, differentiation, activation and proliferation of B cells and their production of antibodies and cytokines. In addition, BTK plays a central role in other immune processes such as the production of cytokines through neutrophils, mast cells and monocytes, degranulation of neutrophils and mast cells, and differentiation/activation of osteoclasts. B cell activation, tolerance breakdown and autoantibody production, on the one hand, the pro-inflammatory environment comes from the increased activation of monocytes, neutrophils and mast cells, on the other hand, they are the key causes of autoimmune diseases (including but not limited to rheumatoid arthritis and systemic lupus erythematosus).

Research has been conducted to convert reversible kinase inhibitors into therapeutic compounds. However, these reversible inhibitors have significant drawbacks. Many reversible kinase inhibitors interact with the ATP binding site. Given that the structure of the ATP binding site is highly conserved among kinases, it is difficult to develop a reversible inhibitor that can selectively inhibit the desired (e.g., target) kinase. Furthermore, given that many reversible kinase inhibitors readily dissociate from their target polypeptides, it is difficult to maintain inhibitory effects over extended periods of time. When reversible kinase inhibitors are used as therapeutic agents, near-toxic doses and/or frequent dosing are often required to achieve the desired biological effect.

Therefore, there is a need to provide irreversible kinase inhibitors that covalently bind to one or more of their target polypeptides but do not (substantially) bind to non-target polypeptides and produce undesirable off-target effects.

Summary of the Invention

The present invention provides a series of novel pyrimidine and pyridine kinase inhibitors. In certain embodiments, the kinase inhibitor is an irreversible inhibitor of tyrosine kinase. In preferred embodiments, the irreversible inhibitor inhibits BTK. Although it is not intended to limit the compounds of the present invention to any particular mechanism of action, in some embodiments, the irreversible kinase inhibitor exerts a physiological effect by forming a covalent bond with Cys481 of BTK. In particular, the Cys481 of BTK has homologs found in other kinases. The embodiments of the present invention also describe methods for synthesizing the irreversible kinase inhibitors and methods for using the irreversible kinase inhibitors to treat diseases, including but not limited to cancer, autoimmune diseases/inflammatory diseases and neurodegenerative diseases. Also described are pharmaceutical preparations containing irreversible kinase inhibitors, including pharmaceutically acceptable salts, solvates or prodrugs thereof, which are kinase inhibitors and can be used to treat the above-mentioned diseases.

The pyrimidine and pyridine kinase inhibitors of the present invention are represented by the general formula (I):

Where:

X represents CH or N,

R ¹ represents NH ₂ , CONH ₂ or H,

R ² represents Hal, Ar ¹ or Het ¹ ,

R ³ represents NR ⁵ [C(R ⁵ ) ₂ ] _n Het ² , NR ⁵ [C(R ⁵ ) ₂ ] _n Cyc, Het ² , O[C(R ⁵ ) ₂ ] _n Ar ² , NR ⁵ [C(R ⁵ ) ₂ ] _n Ar ² , O[C(R ⁵ ) ₂ ] _n Het ² , NR ⁵ (CH ₂ ) _p NR ⁵ R ⁶ , O(CH ₂ ) _p NR ⁵ R ⁶ , or NR ⁵ (CH ₂ ) _p CR ⁷ R ⁸ NR ⁵ R ⁶ ,

R ⁴ represents H, CH ₃ or NH ₂ ,

R ⁵ represents H or an alkyl group containing 1, 2, 3 or 4 C atoms,

R ⁶ N(R ⁵ ) ₂ CH ₂ CH＝CHCONH, Het ³ CH ₂ CH＝CHCONH, CH ₂ ＝CHCONH(CH ₂ ) _n , Het ⁴ (CH ₂ ) _n COHet ³ -diyl-CH ₂ CH＝CHCONH, HC≡CCO, CH ₃ C≡CCO, CH ₂ ＝CH-CO, CH ₂ ＝C(CH ₃ )CONH, CH ₃ CH＝CHCONH(CH ₂ ) _n , N≡CCR ⁷ R ⁸ CONH(CH ₂ ) _n , Het ⁴ NH(CH ₂ ) _p COHet ³ -diyl-CH ₂ CH＝CHCONH, Het ⁴ (CH ₂ ) _p CONH(CH ₂ CH ₂ O) _p (CH ₂ ) _p COHet ³ -diyl-CH ₂ CH＝CHCONH, CH ₂ ＝CHSO _2. ACH＝CHCO, CH ₃ CH＝CHCO, Het ⁴ (CH ₂ ) _p CONH(CH ₂ ) _p Het ³ -diyl-CH ₂ CH＝CHCONH, Ar ³ CH＝CHSO ₂ , CH ₂ ＝CHSO ₂ NH or N(R ⁵ )CH ₂ CH＝CHCO,

R ⁷ and R ⁸ together represent an alkylene group containing 2, 3, 4 or 5 C atoms,

Ar ¹ represents a phenyl group or a naphthyl group, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by R ⁶ , Hal, (CH ₂ ) _n NH ₂ , CONHAr ³ , (CH ₂ ) _n NHCOA, O(CH ₂ ) _n Ar ³ , OCyc, A, COHet ³ , OA and/or OHet ³ (CH ₂ ),

Ar ² represents phenyl, naphthyl or pyridyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by R ⁶ , Hal, OAr ³ , (CH ₂ ) _n NH ₂ , (CH ₂ ) _n NHCOA and/or Het ³ ,

Ar ³ represents a phenyl group, which is unsubstituted or mono-, di- or tri-substituted by OH, OA, Hal, CN and/or A,

Het ¹ represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle containing 1 to 4 N, O and/or S atoms, said heterocycle being unsubstituted or mono-, di- or tri-substituted by R ⁶ , O(CH ₂ ) _n Ar ³ and/or (CH ₂ ) _n Ar ³ ,

Het ² represents a monocyclic or bicyclic saturated heterocycle containing 1 to 4 N, O and/or S atoms, said heterocycle being unsubstituted or mono-, di- or tri-substituted by R ⁶ , Het ³ , CycSO ₂ , OH, Hal, COOH, OA, COA, COHet ³ , CycCO, SO ₂ and/or ═O,

Het ³ represents a monocyclic unsaturated, saturated or cyclic aromatic heterocycle containing 1 to 4 N, O and/or S atoms, said heterocycle being unsubstituted or mono-, di- or tri-substituted by Hal, A and/or =O,

Het ⁴ represents a bicyclic or tricyclic unsaturated, saturated or aromatic heterocycle containing 1 to 4 N, O and/or S atoms, said heterocycle being unsubstituted or mono-, di-, tri- or tetra-substituted by A, NO ₂ , Hal and/or ═O,

Cyc represents a cycloalkyl group containing 3, 4, 5 or 6 C atoms, said cycloalkyl group being unsubstituted or mono- or disubstituted by R ⁶ and/or OH, and said cycloalkyl group may contain a double bond,

A represents a straight-chain or branched alkyl group containing 1 to 10 C atoms, of which 1 to 7 hydrogen atoms may be replaced by F and/or Cl, and/or one or two non-adjacent _CH2 and/or CH- groups may be replaced by O, NH and/or by N,

Hal represents F, Cl, Br or I,

n represents 0, 1, 2, 3 or 4,

p means 1, 2, 3, 4, 5 or 6,

and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, are defined.

Generally speaking, all residues that occur more than once may be identical or different, i.e., independent of each other. In other embodiments, unless explicitly stated, the meanings of residues and parameters are as indicated in the general formula.

Other preferred compounds are compounds represented by substructures 1 to 7 of general formula (I), wherein the residues not specified have the meanings indicated for the compounds in the above preferred group and pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein:

In substructure formula 1, Het ¹ represents piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl, benzo-1,3-dioxolyl, indazolyl, azabicyclo[3.2] .1]octyl, azabicyclo-[2.2.2]octyl, imidazolidinyl, azetidinyl, azepanyl, benzo-2,1,3-thiadiazolyl, tetrahydrofuranyl, dioxolanyl, tetrahydrothiophenyl, dihydro-pyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridinyl, dihydropyridinyl or dihydrobenzodioxinyl, each of which is unsubstituted or mono-, di- or tri-substituted by R ⁶ , O(CH ₂ ) _n Ar ³ and/or (CH ₂ ) _n Ar ³ .

In substructure formula 2, Het ¹ represents pyrazolyl, pyridyl, pyrimidinyl, dihydropyridyl or dihydrobenzodioxinyl, each of which is unsubstituted or mono-, di- or tri-substituted by R ⁶ , O(CH ₂ ) _n Ar ³ and/or (CH ₂ ) _n Ar ³ .

In substructure formula 3, Het ² represents piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, azabicyclo[3.2.1]octyl, azabicyclo-[2.2.2]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[4.4]nonyl, 3-azabicyclo[3.1.0]hexyl, 2-azaspiro[3.3]heptyl, 6-azaspiro[3.4]octyl, 7-azaspiro[3.5]nonyl, 5-azaspiro[3.5]nonyl, imidazolidinyl, azetidinyl, azepanyl, tetrahydrofuranyl, dioxolanyl, tetrahydrothiophenyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydropyridinyl, each of which is unsubstituted or replaced by R ⁶ , Het ³ , CycSO ₂ , OH, OA, COA, COHet ³ , CycCO, SO ₂ and/or ═O are mono-, di- or tri-substituted.

In substructural formula 4, Het ³ represents piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, imidazolidinyl, azetidinyl, azepanyl, tetrahydrofuranyl, dioxolane, tetrahydrothienyl, dihydro-pyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridinyl or dihydropyridinyl, each of which is unsubstituted or mono-, di- or tri-substituted by Hal, A and/or =O.

In substructure formula 5, Het ³ represents piperidinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, dihydro-pyrrolyl, dihydropyrazolyl or dihydropyridinyl, each of which is unsubstituted or mono-, di- or tri-substituted by Hal, A and/or =O.

In substructure formula 6, Het ⁴ represents hexahydrothieno[3,4-d]imidazolyl, benzo[c][1,2,5]oxadiazolyl or 5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-4-ium-uidyl, each of which is unsubstituted or mono-, di-, tri- or tetra-substituted by A, NO ₂ , Hal and/or ＝O.

In Substructure 7, the selected substituents of Formula I are further defined such that:

X represents CH or N,

R ¹ represents NH ₂ , CONH ₂ or H,

R ² represents Hal, Ar ¹ or Het ¹ ,

^R4 represents H,

R ⁵ represents H or an alkyl group containing 1, 2, 3 or 4 C atoms,

Ar ² represents a phenyl group or a naphthyl group, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by R ⁶ , Hal, OAr ³ , (CH ₂ ) _n NH ₂ , (CH ₂ ) _n NHCOA and/or Het ³ ,

Het ¹ represents piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl, benzo-1,3-dioxolyl, indazolyl, azabicyclo[3.2 .1]octyl, azabicyclo-[2.2.2]octyl, imidazolidinyl, azetidinyl, azepanyl, benzo-2,1,3-thiadiazolyl, tetrahydrofuranyl, dioxolanyl, tetrahydrothienyl, dihydro-pyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridinyl, dihydropyridinyl or dihydrobenzodioxinyl, each of which is unsubstituted or mono-, di- or tri-substituted by R ⁶ , O(CH ₂ ) _n Ar ³ and/or (CH ₂ ) _n Ar ³ ,

Het ² represents piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, azabicyclo[3.2.1]octyl, azabicyclo-[2.2.2]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[4.4]nonyl, 3-azabicyclo[3.1.0]hexyl, 2-azaspiro[3.3]heptyl, 6-azaspiro[3.4]octyl, 7-azaspiro[3.5]nonyl, 5-azaspiro[3.5]nonyl, imidazolidinyl, azetidinyl, azepanyl, tetrahydrofuranyl, dioxolanyl, tetrahydrothiophenyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydropyridinyl, each of which is unsubstituted or substituted by R ⁶ , Het ³ , CycSO ₂ , OH, OA, COA, COHet ³ , CycCO, SO ₂ and/or ＝O monosubstituted, disubstituted or trisubstituted,

^Het3 represents piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, imidazolidinyl, azetidinyl, azepanyl, tetrahydrofuranyl, dioxolane, tetrahydrothienyl, dihydro-pyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridinyl or dihydropyridinyl, each of which is unsubstituted or mono-, di- or tri-substituted by Hal, A and/or =0,

Het ⁴ represents hexahydrothieno[3,4-d]imidazolyl, benzo[c][1,2,5]oxadiazolyl or 5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-4-ium-uidyl, each of which is unsubstituted or mono-, di-, tri- or tetra-substituted by A, NO ₂ , Hal and/or ＝O,

Cyc represents a cycloalkyl group containing 3, 4, 5 or 6 C atoms, said cycloalkyl group being unsubstituted or monosubstituted by R ⁶ , and said cycloalkyl group may contain a double bond,

Hal represents F, Cl, Br or I,

n represents 0, 1, 2, 3 or 4,

p represents 1, 2, 3, 4, 5 or 6.

In certain embodiments of the present invention, the pyrimidine and pyridine kinase inhibitors of the present invention are represented by the general formula (II):

and pharmaceutically acceptable salts, solvates, salts of solvates, or prodrugs thereof, wherein:

X is H or CH ₃ or NH ₂ ,

Y is H, Hal or does not exist,

B is N or CH,

E is _NH2 or H,

W is NR, O or cyclic amine,

Z is independently CH ₂ , CH ₃ , CH ₂ -CH ₂ , CH-CH ₂ , H, NH or absent,

"Linker" is ( _CH2 ) _n , wherein: _n is 1, 2 or 3 or is an optionally substituted group selected from a benzene ring, an aromatic ring, a heteroaromatic ring, a branched or straight chain alkyl ring, a 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen or oxygen, a 4-7 membered saturated or partially unsaturated heterocycle containing 1-3 heteroatoms independently selected from nitrogen or oxygen, or a 7-10 membered bicyclic saturated or partially unsaturated heterocycle containing 1-5 heteroatoms independently selected from nitrogen or oxygen, or a 7-10 membered bicyclic saturated or partially unsaturated heterocycle containing 1-5 heteroatoms connected to a saturated heterocycle; the linker can also be a cycloalkane optionally substituted with a heteroatom (independently selected from nitrogen or oxygen), a cycloalkane optionally substituted with -NH or OH, a cycloalkane containing a fused or bridged ring, or a cycloalkane containing an optionally substituted spirocycle, wherein the spirocycle optionally contains a heteroatom,

A is a monocyclic or bicyclic aromatic carbocyclic or heterocyclic ring containing 0, 1, 2, 3 or 4 nitrogen and/or oxygen atoms and 5, 6, 7, 8, 9 or 10 backbone carbon atoms, said carbocyclic or heterocyclic ring being unsubstituted or independently monosubstituted, disubstituted or trisubstituted by Hal, OH or OR,

Hal is F, Cl, Br or I,

R is independently hydrogen, oxygen or an optionally substituted group selected from a C _{1-6 straight chain or cyclic aliphatic group, benzyl, phenyl, phenyl optionally substituted by 1, 2 or 3 oxygen atoms, a 4-7 membered heterocycle containing 1-2 heteroatoms independently selected from nitrogen or oxygen, or a 5-6} membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from nitrogen or oxygen, or a monocyclic or bicyclic aromatic carbocyclic or heterocyclic ring containing 0, 1, 2, 3 or 4 nitrogen or oxygen atoms and 5, 6, 7 or 8 backbone carbon atoms, said carbocyclic or heterocyclic ring being unsubstituted or independently mono-, di- or tri-substituted by Hal, A, OH, NH ₂ , nitrile, and/or CH(Hal) ₃ , or a straight or branched linear alkyl group containing 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, one or two of which are CH The ₂ group may be substituted by an O atom or by –NH-, –CO-, –NHCOO-, –NHCONH-, –CONH-, –NHCO- or –CH=CH-, and 1 to 3 hydrogen atoms thereof may be substituted by Hal,

^Rq is selected from -R, -A, halogen, -OR, -O( _CH2 ) _rOR , -R(NH), _-NO2 , -C(O)R, _-CO2R , -C(O)N(R) ₂ , -NRC(O)R, -NRC(O) _NR2 , _-NRSO2R , or -N(R) ₂ ,

r is 1-4,

n is 0-4, and

Q is an electrophilic group as listed in Table 1, wherein the electrophilic group may further comprise a warhead.

The term "warhead" as used herein refers to a portion of a functional group or substituent of a compound claimed in the present invention, wherein the portion of the functional group or substituent is covalently bound to an amino acid (e.g., cysteine, lysine, or any other natural or modified amino acid capable of forming the covalent bond) in a binding region within a given ligand, wherein the warhead binds to the ligand, and wherein the covalent binding between the warhead and the binding region of the target protein occurs under conditions where the physiological function of the protein is irreversibly inhibited.

While it is not intended that the present invention be limited to specific substituents Q (as indicated above under Formula (II)), in certain embodiments, substituents Q are selected from the groups listed in Table 1. All of the compounds within the box in Table 1 are not "warheads" as defined above.

Table 1

wherein represents the binding point between Q and Z in the general formula (II).

In other embodiments, the pyrimidine and pyridine kinase inhibitors of the present invention are represented by the general formula (III):

X is O or NH,

Y is N or CH,

W is H, NH ₂ or CONH ₂ ,

Q is H or NH ₂ ,

^R1 is ^L1 ^–R4 –L2 ^–R5 ^,

^R2 is ^M1 - ^S4 - ^M2 - ^S5

L ¹ is a single bond, a methylene group, or a ring A, which may be mono- or di-substituted by N or NH ₂ ,

R ⁴ is Ar, A or ring A, and the ring A may be mono- or di-substituted by N, -O- or Hal,

R ⁵ is Ar, A or ring A, which may be mono- or di-substituted by N, -O- or Hal, or is absent; in a preferred embodiment, R ⁵ is selected from the group consisting of 2-fluoropyridine, 1-methylpyridin-2(1H)-one and 2-chloropyridine,

L ² is H, -O-, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₄ heteroalkyl, C ₁ -C ₆ alkoxyalkyl, C ₁ -C ₈ alkylaminoalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 4 alkyl(aryl), C ₁ -C ₄ alkyl(heteroaryl), C ₁ -C ₄ alkyl(C _{3 -C} ₈ cycloalkyl), or C ₁ _-C ₄ alkyl(C ₂ -C ₈ heterocycloalkyl); in certain embodiments, L ² is -CH ₂ -O-(C ₁ -C ₃ alkyl), -CH ₂ -N ₍ C ₁ -C ₃ alkyl) ₂ , C ₁ -C ₄ alkyl(phenyl), or C ₁ -C ₄ alkyl(5- or 6-membered heteroaryl); in certain embodiments, L ² is -A-; in certain embodiments, L ² is absent; in certain preferred embodiments of the present invention, L ² is selected from the group consisting of but-3-en-2-one, propan-2-one, (E)-5-(dimethylamino)pent-3-en-2-one, (E)-pent-3-en-2-one, pent-3-yn-2-one, 1-chloropropan-2-one, (methylsulfonyl)ethane, (E)-5-((2-methoxyethyl)(methyl)amino)pent-3-en-2-one or (Z)-pent-3-en-2-one,

^M1 is a single bond,

S ⁴ is Ar, A or ring A, and the ring A may be mono- or di-substituted by N, -O- or Hal; in a preferred embodiment of the present invention, S ⁴ is a 5-6 membered heteroaromatic ring,

M ² O, NH, CH ₂ or not present,

S ⁵ is H, Ar, A or ring A, which may be mono- or disubstituted by N, -O- or Hal; in a preferred embodiment of the present invention, S ⁵ is selected from the group consisting of but-3-en-2-one, benzene, (E)-5-(dimethylamino)pent-3-en-2-one, ethylbenzene, 1-ethyl-2-methoxybenzene, aniline and (E)-5-morpholinopent-3-en-2-one; in certain embodiments of the present invention, S ₅ is absent,

Ar is a monocyclic or bicyclic aromatic carbocyclic or heterocyclic ring containing 0, 1, 2, 3 or 4 N and/or O oxygen atoms and 5, 6, 7, 8, 9 or 10 backbone atoms, said carbocyclic or heterocyclic ring being unsubstituted or independently of one another being mono-, di- or trisubstituted by Hal, A, OH, OA, NH ₂ , NHA, NA ₂ , NO ₂ , CN, OCN, COOH, COOA, CONH ₂ , CONHA, CONA ₂ , NHCOA, NHCONHA, NHCONH, CHO and/or COA, and wherein the ring nitrogen atoms may be substituted by oxygen atoms, thereby forming N-oxide groups, and wherein, in the case of an aromatic bicyclic ring, one of the two rings may be partially saturated,

A is a straight-chain or branched linear alkyl group containing 1, 2, 3 or 4 C atoms, wherein 1, 2 or 3 hydrogen atoms may be replaced by Hal,

Hal is F, Cl, Br or I.

In certain embodiments, the pyrimidine and pyridine kinase inhibitors of the present invention are represented by the general formula (IV):

Z is N or CH,

X is O or NH, and

^R3 is selected from the group consisting of the following structures:

Wherein, "R" represents the binding point with Z in the general formula IV.

In certain embodiments, the pyrimidine and pyridine kinase inhibitors of the present invention are represented by the general formula (V):

in:

X represents CH or N,

R ¹ represents NR ⁵ [C(R ⁵ ) ₂ ] _n Het ² ,

R ² represents Hal, Ar ¹ or Het ¹ ,

R ³ represents NH ₂ ,

R ⁴ represents H, CH ₃ or NH ₂ ,

R ⁵ represents H or an alkyl group containing 1, 2, 3 or 4 C atoms,

Het ¹ represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle containing 1 to 4 N, O and/or S atoms, said heterocycle being unsubstituted or mono-, di- or tri-substituted by R ⁶ , O(CH ₂ ) _n Ar ³ and/or (CH ₂ ) _n Ar,

Het ³ represents a monocyclic unsaturated, saturated or aromatic heterocycle containing 1 to 4 N, O and/or S atoms, said heterocycle being unsubstituted or mono-, di- or tri-substituted by Hal, A and/or ═O,

Hal represents F, Cl, Br or I,

n represents 0, 1, 2, 3 or 4,

p means 1, 2, 3, 4, 5 or 6,

In general, all radicals that occur more than once may be identical or different, i.e., are independent of one another. Above and below, unless expressly stated otherwise, the radicals and parameters have the meanings assigned to the formulae (I), (II), (III), (IV) and (V). The present invention therefore relates in particular to compounds of the formulae (I), (II), (III), (IV) and (V), in which at least one of the radicals has the preferred meanings indicated below.

Unless otherwise stated, the term "substituted" preferably refers to substitution with the above-mentioned substituents, wherein various degrees of substitution are possible.

All physiologically acceptable salts, derivatives, solvates, solvates of the salts and stereoisomers of these compounds, including mixtures thereof in all ratios, also conform to the invention.

The compounds of the general formula (I), (II), (III), (IV) and (V) may have one or more chiral centers. The compounds may therefore occur in various enantiomeric forms and may be racemic or optically active. The present invention therefore also relates to optically active forms (stereoisomers), enantiomers, racemates, diastereomers and hydrates and solvates of these compounds.

Because the pharmaceutical activities of the racemates or stereoisomers of the compounds of the present invention may differ, it may be necessary to use enantiomers. In these cases, the final products or even the intermediates can be separated into enantiomeric compounds using chemical or physical methods known to those skilled in the art or even directly used in the synthesis.

In the case of racemic amines, the mixture can form diastereomers with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as R or S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, and lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline), or various optically active camphorsulfonic acids. Chromatographic resolution of the enantiomers with the aid of optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate, or other carbohydrate derivatives or chirally derivatized methacrylic acid polymers immobilized on silica gel) is also advantageous. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as ethane/isopropanol/nitrile, for example in a ratio of 82:15:3.

An elegant method for resolving racemates containing ester groups (eg acetyl esters) is the use of enzymes, in particular esterases.

It is also contemplated that compounds of formula (I), formula (II), formula (III), formula (IV) and formula (V) include isotopically labeled forms thereof. Isotopically labeled forms of compounds of formula (I), formula (II), formula (III), formula (IV) and formula (V) are identical to the compounds described, differing only in that one or more atoms of the compounds are replaced by one or more atoms having an atomic mass or mass number different from that of the atoms typically occurring in nature. Examples of isotopes that are readily commercially available and can be incorporated into compounds of formula I by known methods include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, ^2H , ^3H , ^13C , ^14C , ^15N , ^18O , ^17O , ^31P , ^32P , ^35S , ^18F and ^36CI , respectively. Compounds of Formula I, prodrugs thereof, or pharmaceutically acceptable salts thereof containing one or more of the aforementioned isotopes and/or isotopes of other atoms are to be understood as part of the present invention. Isotopically labeled compounds of Formula I can be used in a variety of advantageous ways. For example, isotopically labeled compounds of Formula I incorporating radioactive isotopes such as ³ H or ¹⁴ C can be used in drug and/or substrate tissue distribution assays. These two radioactive isotopes, tritium ( ³ H) and carbon-14 ( ¹⁴ C), are particularly preferred due to their ease of preparation and good detectability. Since heavier isotopes, such as deuterium ( ² H), have greater metabolic stability, incorporating such isotopically labeled compounds into compounds of Formula I can be therapeutically beneficial. Higher metabolic stability directly leads to an increased in vivo half-life or a reduced dosage, which in many cases represents a preferred embodiment of the present invention. Isotopically labeled compounds of formula I can generally be prepared by carrying out the procedures disclosed in the synthetic schemes and associated descriptions in the Examples and Preparations sections of this text, substituting a readily available isotopically labeled reactant for a non-isotopically labeled reactant.

In other embodiments, deuterium ( ² H) is contemplated to be incorporated into compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V). Such deuterium-containing compounds can modify the oxidative metabolism of the compound through the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction due to the replacement of an isotopic nucleus, which is caused by a change in the ground state energy required to form a covalent bond after the isotope replacement. Replacement of heavier isotopes typically results in a decrease in the ground state energy of the chemical bond, thereby causing a decrease in the rate of the rate-limiting bond cleavage reaction. If bond cleavage occurs in or near a saddle point region along the coordinates of a multi-product reaction, the product distribution ratio can be significantly altered. The explanation is as follows: If deuterium is bonded to a non-replaceable position on a carbon atom, the rate difference is typically _km /k _d = 2-7. If this rate difference is successfully applied to compounds of formula (I), formula (II), formula (III), formula (IV) and formula (V) that are easily oxidized, the properties of the compound in vivo can be significantly changed, thereby improving the pharmacokinetic properties.

When discovering and developing therapeutic agents, those skilled in the art attempt to optimize pharmacokinetic parameters while maintaining favorable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic properties are susceptible to oxidative metabolism. Existing in vitro liver microsome assays provide valuable information regarding this type of oxidative metabolic process, which allows for the rational design of deuterated compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V) to enhance stability due to their resistance to oxidative metabolism. Consequently, the pharmacokinetic properties of compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V) are significantly improved, as quantitatively demonstrated by an increase in in vivo half-life (t/2), the concentration at which the drug achieves its maximum efficacy ( _Cmax ), the area under the dose-response curve (AUC), and F, as well as by reduced clearance, dosage, and material cost.

While it is not intended that the present invention be limited to any deuterium-containing motif, the following is an example. Compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and Formula (V) have multiple sites of potential oxidative metabolic attack, such as benzylic hydrogen atoms and hydrogen atoms bonded to nitrogen atoms. In these analogs, various combinations of these hydrogen atoms are replaced with deuterium atoms, such that some, most, or all of the hydrogen atoms are replaced with deuterium atoms. Determination of the half-life allows for an advantageous and accurate determination of the degree of improved resistance to oxidative metabolism. In this manner, it has been determined that the half-life of the parent compound can be increased by up to 100% due to this type of deuterium-hydrogen substitution.

Deuterium-hydrogen substitutions in compounds of Formula (I), (II), (III), (IV), and (V) can also be used to advantageously alter the metabolite profile of the starting compound to reduce or eliminate undesirable toxic metabolites. For example, if a toxic metabolite is produced by oxidative carbon-hydrogen (C-H) bond cleavage, it is reasonable to assume that a deuterated analogue will significantly reduce or eliminate the production of the undesirable metabolite, even if that particular oxidation reaction is not the rate-determining step. For more information on the prior art regarding deuterium-hydrogen substitution, see, for example, Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et al., Biochemistry 33(10) 2927-2937, 1994, and Jarman et al. Carcinogenesis 16(4), 683-688, 1993.

The compounds of the present invention may be in the form of prodrug compounds. "Prodrug compound" refers to a derivative that can be converted into the biologically active compound of the present invention under physiological conditions in an organism by, for example, oxidation reaction, reduction reaction, hydrolysis reaction, etc., each reaction can be carried out with or without the participation of an enzyme. Examples of prodrugs are compounds in which the amino group in the compound of the present invention is acylated, alkylated or phosphorylated, for example, eicosylamino, alanylamino, pivaloyloxymethylamino; or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into a boronate ester, for example, acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy; or wherein the carboxyl group is esterified or amidated; or wherein the thiol group forms a disulfide bridge with a carrier molecule (e.g., a peptide) that selectively delivers the drug to the target and/or to the cytosol. These compounds can be prepared from the compounds of the present invention according to known methods. Further examples of prodrugs are compounds in which a carboxylic acid ester in a compound of the invention is converted into, for example, an alkyl-, aryl-, choline-, amino-, acyloxymethyl-, linol-enoyl-ester.

Metabolites of the compounds of the present invention are also within the scope of the present invention.

When tautomerism (e.g., keto-enol tautomerism) occurs in the compounds of the present invention or their prodrugs, protection is claimed for both their individual forms (e.g., keto or enol forms) and mixtures thereof in any proportion. The same applies to their stereoisomers, e.g., enantiomers, cis/trans isomers, conformers, etc.

If necessary, isomers can be separated according to methods known in the art (e.g., liquid chromatography). The same applies to their enantiomers, for example, by separation using a chiral stationary phase. In addition, enantiomers can be separated by conversion into diastereomers, i.e., coupling with an enantiomerically pure auxiliary compound, followed by separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of the compounds of the invention can be obtained by stereoselective synthesis using optically pure starting materials.

The compounds of the present invention may be in the form of pharmaceutically acceptable salts or solvates. The term "pharmaceutically acceptable salt" (also referred to as "pharmaceutically acceptable salt") refers to salts prepared from pharmaceutically non-toxic bases or acids (including inorganic bases or acids and organic bases or acids). In the case where the compounds of the present invention contain one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically usable salts. Therefore, compounds of the present invention containing acidic groups may exist in salt form and, according to the present invention, may be used as, for example, alkali metal salts, alkaline earth metal salts or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts containing ammonia or organic amines (e.g., ethylamine, ethanolamine, triethanolamine or amino acids). Compounds of the present invention containing one or more basic groups (i.e., groups that can be protonated) may exist in salt form and, according to the present invention, may exist in the form of addition salts formed with inorganic or organic acids. The example of suitable acid comprises hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acid known in the art.If the compounds of this invention comprises acidic and basic groups in molecule simultaneously, so except described salt form, the present invention comprises inner salt or betaine (zwitterion) equally.Described each salt can be made by conventional method well known to persons skilled in the art, for example, they are contacted with organic or inorganic acid or alkali in solvent or dispersant, or negatively charged ion or positively charged ion is exchanged with other salt.The present invention comprises the salt of following all the compounds of this invention equally, it is unsuitable for directly using in medicine because of low physiological compatibility, but can be used as for example chemical reaction intermediate or in the preparation of pharmaceutically acceptable salt, use.

In addition, the present invention relates to a pharmaceutical composition comprising as an active ingredient a compound of the present invention or a prodrug compound thereof or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.

"Pharmaceutical composition" refers to one or more active ingredients and one or more inert components constituting a carrier, as well as any product obtained directly or indirectly from the combination, complexation, aggregation of any two or more components, or the dissociation of one or more components, or any other type of reaction or interaction of one or more components. Therefore, the pharmaceutical compositions of the present invention include any composition prepared by mixing a compound of the present invention and a pharmaceutically acceptable carrier.

The pharmaceutical composition of the present invention may additionally contain one or more other compounds as active ingredients, such as one or more additional compounds of the present invention, prodrug compounds or other BTK inhibitors. Pharmaceutical compositions include suitable compositions for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (eye), pulmonary (nasal or buccal inhalation) or nasal administration, and the most suitable route in any known case depends on the nature and severity of the disease to be treated and the nature of the active ingredient. They can be conveniently present in unit dosage form and prepared using any method known in the pharmaceutical field.

In one embodiment, the compounds and pharmaceutical compositions are used to treat cancer, such as brain cancer, lung cancer, colon cancer, epidermoid cancer, squamous cell carcinoma, bladder cancer, stomach cancer, pancreatic cancer, breast cancer, head cancer, neck cancer, kidney cancer, renal cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, uterine cancer, rectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, melanoma, hematological malignancies such as acute myeloid leukemia, multiple myeloma, chronic myeloid leukemia, myeloid leukemia, glioma, Kaposi's sarcoma, or any other type of solid or liquid tumor. Preferably, the cancer treated is selected from breast cancer, colorectal cancer, lung cancer, prostate cancer or pancreatic cancer or glioblastoma.

The present invention also relates to the use of the compounds of the present invention in the preparation of medicaments for treating hyperproliferative diseases associated with BTK overactivity and diseases regulated by the BTK cascade in mammals, or for treating conditions mediated by abnormal proliferation, such as cancer or overactivity of B cells, mast cells, neutrophils and monocytes, such as inflammation.

BRIEF DESCRIPTION OF THE DRAWINGS

Figures 1A and 1B show data for the evaluation of the compound of the present invention [1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one, represented by "CPD.B" in the figure] in an interferon-α accelerated systemic lupus erythematosus (SLE) mouse model.

Figure 2 shows additional data evaluating the compound of the present invention [[1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one, designated "CPD.B" in the figure] in an interferon-α accelerated systemic lupus erythematosus (SLE) mouse model.

Figure 3 shows the data for evaluating the compound of the present invention [1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one, represented by "CPD.A" in the figure] in a rat collagen-induced arthritis model.

Figure 4 shows data for the evaluation of the compound of the present invention [1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one, represented by "CPD.A" in the figure] in an interferon-α accelerated systemic lupus erythematosus (SLE) mouse model.

Figure 5 shows the data for evaluating the compound of the present invention [1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one, represented by "CPD.B" in the figure] in the passive cutaneous anaphylaxis (PCA) mouse model.

Figure 6 shows data evaluating the compound of the present invention [1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one] in vitro anti-IgD-induced CD69 upregulation in mouse whole blood.

DETAILED DESCRIPTION

The present invention also relates to a compound or pharmaceutical composition for treating angiogenesis or angiogenesis-related diseases in mammals, comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, prodrug or hydrate thereof and a pharmaceutically acceptable carrier.

In one embodiment, the compound or pharmaceutical composition can be used to treat the following diseases: tumor angiogenesis, chronic inflammation (e.g., rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, Sjögren's syndrome), atherosclerosis, skin and allergic diseases (e.g., psoriatic arthritis, psoriasis, eczema and scleroderma), asthma and atopic dermatitis, or diseases such as diabetes, diabetic retinopathy, retinopathy of prematurity and age-related macular degeneration.

In one embodiment, BTK inhibitors are preferably used to treat rheumatoid arthritis, given that BTK inhibitors have been experimentally validated and confirmed to be effective in treating collagen antibody-induced arthritis and collagen-induced arthritis [Pan, Z. et al., Discovery of Selective Irreversible Inhibitors of Brunton's Tyrosine Kinase. ChemMedChem 2, 58-61 (2007)]. More specifically, BTK inhibitor treatment has been shown to reduce the incidence and severity of collagen-induced arthritis and K/BxN serum-induced arthritis.

The present invention also relates to a compound or pharmaceutical composition for inhibiting abnormal cell growth in a mammal, comprising an amount of a compound of the present invention or a pharmaceutically acceptable salt or solvate or prodrug thereof and an amount of another anticancer therapeutic drug, wherein the amount of the compound, salt, solvate or prodrug together with the amount of the chemotherapeutic agent is effective for inhibiting abnormal cell growth. Many anticancer therapeutic drugs are currently known in the art. In one embodiment, the anticancer therapeutic drug is a chemotherapeutic agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens. In another embodiment, the anti-cancer therapeutic is an antibody selected from the group consisting of bevacizumab, a CD40-specific antibody, chTNT-1/B, denosumab, zalumab, an IGF1R-specific antibody, lintuzumab, edrecolomab, WX G250, rituximab, tesimumab, trastuzumab, and cetuximab. In another embodiment, the anti-cancer therapeutic is an inhibitor of another protein kinase, such as Akt, Axl, Aurora A, Aurora B, dyrk2, epha2, fgfr3, igf1r, IKK2, JNK3, Vegfr1, Vegfr2, Vegfr3 (also known as Flt-4), KDR, MEK, MET, Plk1, RSK1, Src, TrkA, Zap70, cKit, bRaf, EGFR, Jak2, PI3K, NPM-Alk, c-Abl, BTK, FAK, PDGFR, TAK1, LimK, Flt-3, PDK1, and Erk.

The present invention also relates to a method for inhibiting abnormal cell growth or treating a hyperproliferative disease in a mammal, comprising administering to the mammal an amount of a compound of the present invention or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with radiotherapy, wherein the amount of the compound, salt, solvate or prodrug combined with radiotherapy is effective for inhibiting abnormal cell growth or treating a hyperproliferative disease in the mammal. Techniques for administering radiotherapy are known in the art, and these techniques can be used in the combined therapies described herein. In this combined therapy, the administration of the compounds of the present invention can be determined as described herein. It is generally believed that the compounds of the present invention can make abnormal cells more sensitive to radiotherapy, thereby killing and/or inhibiting the growth of such cells.

Therefore, the present invention also relates to a method for sensitizing abnormal cells in a mammal to radiotherapy, comprising administering to the mammal an amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, effective to sensitize the abnormal cells to radiotherapy. The amount of the compound, salt, or solvate in this method can be determined according to the methods for determining an effective amount of the compound described herein. The present invention also relates to a method for inhibiting the growth of abnormal cells in a mammal, comprising an amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, prodrug, or isotopically labeled derivative thereof, and an amount of one or more agents selected from anti-angiogenic agents, signal transduction inhibitors, and antiproliferative drugs.

In practical applications, the compounds of the present invention as active ingredients can be combined with pharmaceutical carriers in an intimate mixture according to conventional pharmaceutical formulation techniques. The carrier can take a variety of forms depending on the desired dosage form for administration (e.g., oral or parenteral (including intravenous)). When preparing oral dosage compositions, any conventional pharmaceutical medium can be used, for example, water, ethylene glycol, oils, alcohols, flavoring agents, preservatives, colorants, etc. In the case of oral liquid preparations, any conventional pharmaceutical medium can be used, for example, suspensions, elixirs, and solutions; or carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc. In the case of oral solid preparations, the composition can be present in the form of, for example, powders, hard and soft capsules, and tablets, with solid oral dosage forms being preferred relative to liquid dosage forms.

Because tablets and capsules are easy to administer, they represent the most beneficial oral dosage unit forms, in which case solid pharmaceutical carriers can obviously be used. If desired, tablets can be coated by standard aqueous or non-aqueous techniques. The compositions and formulations should contain at least 0.1% active compound. Of course, the percentage of active compound in these compositions can vary and can advantageously range from about 2% to about 60% of the unit weight. The amount of active compound in the therapeutically useful compositions is that amount that will produce an effective dose. The active compound can also be administered intranasally, for example, as liquid drops or sprays.

Tablets, pills, capsules, etc. may also contain: a binder such as gum tragacanth, gum arabic, corn starch, or gelatin; an excipient such as dicalcium phosphate; a disintegrant such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetener such as sucrose, lactose, or saccharin. When the dosage unit is a capsule, it may contain, in addition to the above-mentioned types of materials, a liquid carrier such as a fatty oil.

Various other substances may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. In addition to the active ingredient, a syrup or elixir may contain sucrose as a sweetener, methyl and propylparabens as preservatives, coloring agents, and flavorings (e.g., cherry or orange flavor).

The compounds of this invention can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared by appropriately mixing with a surfactant (e.g., hydroxy-propyl cellulose) in water. Dispersions can be prepared from glycerol, liquid polyethylene glycol, and mixtures thereof in oils. Under normal conditions of storage and use, these preparations may contain preservatives to prevent the growth of microorganisms.

The pharmaceutical form that is suitable for injection use comprises the sterile injection aqueous solution or dispersion and sterile powder for the immediate preparation of sterile injection solution or dispersion.In all cases, this form must be sterile and must have enough mobility to make them easy to inject.In the case of preparation and storage, described form must be stable and must be able to resist the pollution of microorganism (for example antibacterial and fungus).Carrier can comprise solvent or dispersion medium, for example water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), its suitable mixture and vegetable oil.

Any suitable route of administration can provide an effective dose of the compounds of the present invention to mammals (especially humans). For example, the compounds of the present invention can be administered orally, rectally, topically, parenterally, ophthalmically, pulmonary, or nasally. Dosage forms include tablets, buccal tablets, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably, the compounds of the present invention are administered orally.

The effective amount of the active ingredient administered may depend on the specific compound administered, the mode of administration, the condition to be treated, and the severity of the condition to be treated. The dosage can be readily determined by those skilled in the art.

When treating or preventing cancer, inflammation, or other proliferative diseases for which the compounds of this invention are indicated, generally satisfactory results can be obtained with daily doses of about 0.01 mg to about 100 mg/kg of animal body weight, preferably a single daily dose. For large mammals, the total daily dose is about 0.1 mg to about 1000 mg, preferably about 0.2 mg to about 50 mg. In the case of a 70 kg adult, the total daily dose is about 0.2 mg to 200 mg. The dosage regimen can be adjusted to provide the optimal therapeutic response.

The present invention also relates to a kit (set) comprising the following individual packages:

a) an effective amount of a compound of the present invention or a physiologically acceptable salt, solvate or prodrug thereof; and

b) an effective amount of another pharmaceutically active ingredient.

The kit comprises a suitable container, such as a box, an individual bottle, a bag or an ampoule. The kit may include, for example, individual ampoules, each containing an effective amount of a compound of the present invention and/or a pharmaceutically useful derivative, solvate and stereoisomer thereof (including mixtures thereof in all ratios) and an effective amount of another pharmaceutically active ingredient in dissolved or lyophilized form.

Experimental part

Certain abbreviations that may appear in this application are as follows:

abbreviation

The compounds of the present invention can be prepared using appropriate materials according to the methods in the following processes and examples, as further illustrated in the specific examples below. In addition, by using the methods described herein, in combination with conventional techniques in the art, other compounds required herein can be easily prepared. However, the compounds described in the examples should not be construed as being the only types of compounds of the present invention. The examples also provide a detailed description of the preparation of the compounds of the present invention. It will be readily understood by those skilled in the art that known variations of the conditions and processes of the following preparation methods can be used to prepare these compounds.

The compounds of the present invention are usually isolated in the form of their pharmaceutically acceptable salts, such as those described above. The base corresponding to the isolated salt as a free amine can be prepared by neutralizing it with a suitable base, such as sodium bicarbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide aqueous solution, and extracting the released base as a free amine with an organic solvent, followed by evaporation. The free amine isolated in this manner can be further converted into other pharmaceutically acceptable salts by dissolving it in an organic solvent, then adding an appropriate acid, and finally evaporating, precipitating, or crystallizing it.

The present invention is illustrated but not limited by the specific embodiments described in the following schemes and examples.Unless otherwise indicated in a scheme, any variable has the same meaning as described above.

Unless otherwise stated, all starting materials were obtained from commercial suppliers and used without further purification. Unless otherwise stated, all temperatures are expressed in °C and all reactions were performed at room temperature. Compounds were purified by silica chromatography or preparative HPLC.

The present invention also relates to methods for preparing compounds of formula (I), formula (II), formula (III), formula (IV) and formula (V) according to the schemes and working examples described below.

Synthesis method

Process 1

Process 2

Methods related to the reaction steps in Schemes 1 and 2

Method A: Nucleophilic Aromatic Substitution Using Oxygen Nucleophiles

6-(3-aminophenoxy)-5-chloropyrimidin-4-amine

In a 20 mL microwave vial, place 5,6-dichloropyrimidin-4-amine (500.00 mg; 3.05 mmol), cesium carbonate (1.49 g; 4.57 mmol), and 3-aminophenol (499.08 mg; 4.57 mmol) suspended in DMF (12.00 ml). The reaction mixture was microwaved at 160°C for 2 hours. The reaction mixture was allowed to cool to room temperature. The mixture was filtered through a plug of silica gel. The solution was concentrated under reduced pressure and lyophilized overnight to yield 6-(3-aminophenoxy)-5-chloropyrimidin-4-amine as a crude black solid.

Method B: Nucleophilic Aromatic Substitution Using a Nitrogen Nucleophile

tert-Butyl 4-{[(6-amino-5-chloropyrimidin-4-yl)amino]methyl}piperidine-1-carboxylate

In a 10 mL vial was placed 5,6-dichloropyrimidin-4-amine (250.00 mg; 1.52 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (653.40 mg; 3.05 mmol), and N,N-diisopropylethylamine (1.01 mL; 6.10 mmol) suspended in NMP (2.50 mL). The reaction mixture was microwaved at 150°C for 2 hours. The reaction mixture was allowed to cool to room temperature. The mixture was purified by Biotage column chromatography using 50-100% EtOAc/hexane as the eluent. Fractions containing the desired product were combined and concentrated under reduced pressure to yield tert-butyl 4-{[(6-amino-5-chloropyrimidin-4-yl)amino]methyl}piperidine-1-carboxylate as a yellow, viscous oil.

Method C: Suzuki coupling

6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine

In a 20 mL microwave vial, 6-(3-aminophenoxy)-5-chloropyrimidin-4-amine (400.00 mg; 1.69 mmol), (4-phenoxyphenyl)boronic acid (542.62 mg; 2.54 mmol), palladium acetate (18.97 mg; 0.08 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (69.39 mg; 0.17 mmol), and potassium carbonate (700.77 mg; 5.07 mmol) were suspended in dioxane (8.00 ml) and water (0.80 ml). The reaction mixture was microwaved at 140°C for 2 hours. The reaction mixture was allowed to cool to room temperature. _Na₂SO₄ was added to the mixture, _which was then filtered through a plug of silica gel and concentrated under reduced pressure. The crude mixture was purified by Biotage column chromatography using 80-100% EtOAc/hexanes followed by 0-100% MeOH/EtOAc as eluent. Fractions containing the desired product were combined and concentrated under reduced pressure. The residue was lyophilized overnight to afford 6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine as a yellow solid (177.00 mg, 74% yield).

Method D: Deprotection of tert-butyloxycarbonyl (BOC)-protected amines

5-(4-Phenoxyphenyl)-N-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine

In a 20 mL vial was placed tert-butyl 4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidine-1-carboxylate (534.60 mg; 1.12 mmol) dissolved in methanol (4.00 mL). To the mixture was added hydrogen chloride (2.0 M in ether) (5.62 mL). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and lyophilized overnight to provide 5-(4-phenoxyphenyl)-N-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine as a crude yellow solid.

Method E: Amide formation from carboxylic acid

N-(3-{[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]oxy}phenyl)acrylamide

In a 20 mL reaction vial, acrylic acid (0.01 mL; 0.12 mmol), bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (42.04 mg; 0.17 mmol), and N,N-diisopropylethylamine (0.07 mL; 0.41 mmol) suspended in dioxane (3.00 mL) were placed. The reaction mixture was stirred at room temperature for 1 hour. 6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine (40.00 mg; 0.08 mmol) was then added. The reaction mixture was stirred at room temperature overnight. The crude mixture was purified by Biotage column chromatography using 50-100% EtOAc/hexane followed by 0-40% MeOH/EtOAc as eluent. Fractions containing the desired product were combined and concentrated under reduced pressure. The residue was then purified by preparative HPLC using 35-45% _CH3CN in 0.1% aqueous TFA as eluent. Fractions containing the desired product were combined and lyophilized overnight to afford N-(3-{[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]oxy}phenyl)acryloyl as a crude white solid (29.00 mg, 25% yield). HPLC purity: 97%, RT=4.264min. MS: m/z=425[M+H] ⁺ , RT=2.14min. ¹ H-NMR (DMSO-d ₆ )δ10.14 (s, 1H), 8.00 (s, 1H), 7.41 (s, 1H), 7.36-7.30 (m, 5H), 7.22 (t, 1H), 7.09 (t, 1H), 7.03-7.01 (m, 4H), 6.71 (d, 1H), 6.53 (broad s, 2H), 6.34 (dd, 1H), 6.18 (d, 1H), 5.69 (d, 1H).

Method F: Formation of amide from acid chloride in the presence of an inorganic base

N-[(1-Acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine

In a 20 mL reaction vial, place 5-(4-phenoxyphenyl)-N-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine (70.00 mg; 0.19 mmol) and sodium bicarbonate (23.49 mg; 0.28 mmol) suspended in THF (3.00 mL) and water (0.30 mL). The mixture was cooled to 0°C. Acryloyl chloride (0.02 mL; 0.22 mmol) was added. The ice bath was allowed to melt. The reaction mixture was stirred at room temperature overnight. The crude mixture was purified by Biotage column chromatography using 0-50% MeOH/EtOAc as the eluent. Fractions containing the desired product were combined and concentrated under reduced pressure. The residue was lyophilized overnight to provide N-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine as a white solid (30.00 mg, 37% yield). HPLC purity: 97%, RT=3.665min. MS: m/z=430[M+H] ⁺ , RT=1.53min. ¹ H-NMR (DMSO-d ₆ )δ7.93(s, 1H), 7.40(t, 2H), 7.21-7.08(m, 8H), 6.76(dd, 1H), 6.04(d, 1H), 5.61(d, 1H), 5.43(s, 2H), 4 .34 (d, 1H), 3.98 (d, 1H), 3.12 (t, 2H), 2.95 (t, 1H), 2.56 (t, 1H), 1.81 (m, 1H), 1.59 (m, 2H), 0.92 (m, 2H).

Method G: Formation of amide from acid chloride in the presence of an organic base

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide

In a 20 mL vial, 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline (30.00 mg, 0.08 mmol) and N,N-diethylethanamine (0.02 mL, 0.17 mmol) were suspended in 1-methylpyrrolidin-2-one (0.35 mL) and dichloromethane (2.00 mL). The mixture was cooled to 0°C. Acryloyl chloride (0.02 mL, 0.25 mmol) was added. The ice bath was allowed to melt and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by Biotage column chromatography using 0-40% MeOH in EtOAc as eluent. Fractions containing the desired product were combined, concentrated, and purified using preparative HPLC using 25-55% CH ₃ CN in 0.1% aqueous TFA as eluent. Fractions containing the desired product were combined and lyophilized overnight to give N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide as a white solid (12.00 mg, 35% yield). HPLC purity: 100%, RT=4.235 min. MS: m/z=409 [M+H] ⁺ , RT=3.38 min. ¹ H-NMR (DMSO-d ₆ )δ10.23(s, 1H), 8.52(s, 1H), 8.43(d, 1H), 7.95(s, 1H), 7.71(d, 1H), 7.44-7.33(m, 4H), 7.19(d, 2H), 7.13(t, 1H), 7.09(d, 2H), 7.02(d, 2H), 6.80(d, 1H), 6.45(dd, 1H), 6.26(d, 1H), 5.75(d, 1H).

Method H: Nucleophilic Aromatic Substitution Using Aromatic Amines

N4-(3-Aminophenyl)-5-chloropyrimidine-4,6-diamine

In a 20 mL vial was placed 5,6-dichloropyrimidin-4-amine (500 mg, 3.05 mmol), benzene-1,3-diamine (329.72 mg, 3.05 mmol), and a pre-prepared 1:1 mol mixture of TFA:TEA (347.64 mg:308.52 mg) dissolved in DMSO (6 mL). The mixture was heated to 90°C overnight. The reaction mixture was then cooled to room temperature, and the crude mixture was purified by column chromatography using 0-40% MeOH in EtOAc as the eluent. Fractions containing the desired product were concentrated and lyophilized overnight to provide the desired product, N-(3-aminophenyl)-5-chloropyrimidine-4,6-diamine (82% yield), as a brown syrup.

Method I: Nucleophilic Aromatic Substitution Using Nitrogen Nucleophiles

4-(((6-amino-5-chloropyrimidin-4-yl)amino)methyl)piperidin-2-one

In a 20 mL vial was placed 5,6-dichloropyrimidin-4-amine (100 mg, 0.61 mmol), 4-(((6-amino-5-chloropyrimidin-4-yl)amino)methyl)piperidin-2-one (117.24 mg, 0.91 mmol), and DBU (0.18 mL, 1.22 mmol) dissolved in DMF (2 mL). The reaction mixture was stirred at 90°C overnight. The reaction mixture was allowed to cool to room temperature. The crude mixture was purified by column chromatography using 0-100% MeOH in EtOAc as eluent. Fractions containing the desired product were combined, concentrated, and lyophilized overnight to provide the desired product, 4-(((6-amino-5-chloropyrimidin-4-yl)amino)methyl)piperidin-2-one (90% yield), as a yellow solid.

Process 3

Methods related to the reaction steps in Scheme 3

Method S1: Nucleophilic Aromatic Substitution

tert-Butyl 6-((6-amino-5-chloropyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate

To a round-bottom flask containing 5,6-dichloro-pyrimidin-4-ylamine (300.00 mg; 1.83 mmol; 1.00 eq.) and 6-amino-2-aza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (466.02 mg; 2.20 mmol; 1.20 eq.) in NMP (1.00 ml) was added DIPEA (0.91 ml; 5.49 mmol; 3.00 eq.). The reaction mixture was stirred at 155° C. for 4 hours and then concentrated.

Method S2: Suzuki coupling

tert-6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid Butyl ester

To a microwave vial containing tert-butyl 6-(6-amino-5-chloro-pyrimidin-4-ylamino)-2-aza-spiro[3.3]heptane-2-carboxylate (828.00 mg; 2.44 mmol; 1.00 eq.) in dioxane (4.00 ml; 46.94 mmol; 19.27 eq.) and water (0.40 ml; 22.20 mmol; 9.11 eq.) was added cesium carbonate (1190.86 mg; 3.65 mmol; 1.50 eq.), palladium(II) acetate (27.35 mg; 0.12 mmol; 0.05 eq.), 4-phenoxyphenylboronic acid (651.87 mg; 3.05 mmol; 1.25 eq.) and 2-dicyclohexylphosphino-2',6'-dimethoxydiphenyl (100.03 mg; 0.24 mmol; 0.10 eq.). The reaction mixture was stirred at 140°C for 16 hours, then concentrated and separated on a 50 g silica gel column using a gradient of EtOAc/cyclohexane (0-100%) as eluent. Each fraction was concentrated and used in the next step.

Method S3: Deprotection of tert-butyloxycarbonyl-protected amines

5-(4-Phenoxyphenyl)-N ⁴ -(2-azaspiro[3.3]hept-6-yl)pyrimidine-4,6-diamine

To a round bottom flask containing 6-[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-2-aza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (167.23 mg; 0.35 mmol; 1.00 eq.) in methanol (5.00 ml) was added hydrogen chloride (1.80 ml; 3.53 mmol; 10.00 eq.). The reaction mixture was stirred for 16 hours and then concentrated and used in the next step.

Method S3A: Deprotection of tert-butyloxycarbonyl-protected amines

5-(4-Phenoxyphenyl)-N ⁴ -(2-azaspiro[3.3]hept-6-yl)pyrimidine-4,6-diamine

To a round-bottom flask containing tert-butyl 6-[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-2-aza-spiro[3.3]heptane-2-carboxylate (167.23 mg; 0.35 mmol; 1.00 eq.) in methanol (5.00 ml) was added hydrogen chloride (1.80 ml; 3.53 mmol; 10.00 eq.). The reaction mixture was stirred for 16 hours, then concentrated and purified by HPLC. Fractions containing the desired product were lyophilized to afford the title compound as a white solid (50.3 mg, 34%). HPLC purity: 95%. MS: m/z = 374 [M+H] ⁺ . ¹ H NMR (CD ₃ OD) δ 8.25 (s, 1H), 7.10-7.44 (m, 8H), 4.60 (m, 1H), 4.20 (s, 2H), 4.01 (s, 2H), 2.69 (m, 2H), 2.32 (m, 2H).

Method S4A: Amide Generation Using T3P

1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]hept-2-yl) Prop-2-yn-1-one

To a microwave vial containing N-(2-aza-spiro[3.3]hept-6-yl)-5-(4-phenoxy-phenyl)-pyrimidine-4,6-diamine hydrochloride (80.00 mg; 0.20 mmol; 1.00 eq.) in DCM (1.00 ml) was added DIPEA (0.16 ml; 0.98 mmol; 5.00 eq.) and propionic acid (24.20 μl; 0.39 mmol; 2.00 eq.) followed by 2,4,6-tripropyl-[1,3,5,2,4,6]trioxatriphosphinane-2,4,6-trioxide (0.12 ml; 0.29 mmol; 1.50 eq.). The reaction mixture was stirred at room temperature for 1 hour then concentrated and purified by preparative HPLC (0.1% TFA- _H2O /ACN). Fractions containing the desired product were combined and lyophilized overnight to afford 1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]hept-2-yl)prop-2-yn-1-one as a white solid (27.8 mg, 26.1%). HPLC purity: 99%. MS: m/z = 426 [M+H] ⁺ . ¹ H NMR (CD ₃ OD) δ 8.25 (s, 1H), 7.18-7.49 (m, 9H), 4.32 (d, 1H), 4.09 (d, 2H), 3.89 (d, 1H), 2.60 (m, 2H), 2.29 (m, 2H).

Method S4B: Amide Formation Using Acid Chloride in Pyridine

1-((1R,5S)-6-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-azabis(amino)methyl Cyclo[3.1.0]hex-3-yl)prop-2-en-1-one

To a round-bottom flask containing N-[(1S,5R)-1-(3-aza-bicyclo[3.1.0]hexan-6-yl)methyl]-5-(4-phenoxy-phenyl)-pyrimidine-4,6-diamine hydrochloride (259.68 mg; 0.63 mmol; 1.00 eq.) in pyridine (1.00 ml; 12.36 mmol; 19.52 eq.) was added acryloyl chloride (0.05 ml; 0.63 mmol; 1.00 eq.) in DCM (3.00 ml; 46.80 mmol; 73.88 eq.) over 1 hour at 0°C. The reaction mixture was allowed to warm to room temperature and stirred overnight. Concentration and the crude product was purified by preparative HPLC. Fractions containing the desired product were combined and lyophilized overnight to yield 1-((1R,5S)-6-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-azabicyclo[3.1.0]hex-3-yl)prop-2-en-1-one as a white solid (2.1 mg, 0.6%). HPLC purity: 99%. MS: m/z = 428 [M+H] ⁺ . ¹ H NMR (CD ₃ OD)δ8.24(s,1H),7.21-7.46(m,9H),6.53(m,1H),6.22(m,1H),5.74(m , 1H), 3.77(m, 2H), 3.69(m, 1H), 3.41(m, 2H), 1.70(m, 2H), 0.93(m, 2H).

Method S4C: Amide formation using acid chloride in THF

1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin pyridin-1-yl)prop-2-en-1-one

A round-bottom flask containing (3S,4S)-4-{[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-methyl}-piperidin-3-ol hydrochloride (591.95 mg; 1.38 mmol; 1.00 eq.) and DIPEA (0.69 ml; 4.15 mmol; 5.00 eq.) in THF (30.00 ml) was slowly added acryloyl chloride (0.11 ml; 1.38 mmol; 1.00 eq.) in 1 mL of THF over a period of 1 hour. The reaction mixture was concentrated and purified by preparative HPLC. Fractions containing the desired product were combined and lyophilized overnight to afford 1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-en-1-one as a white solid (21.5 mg, 2.7%). HPLC purity: 99%. MS: m/z = 446 [M+H] ⁺ . ¹ H NMR (CD ₃ OD)δ8.25(s,1H),7.10-7.45(m,9H),6.73(dd,1H),6.34(d,1H),5.77(d,1H),4.5(m,1H),4.03(m , 1H), 3.62(m, 1H), 3.50(m, 1H), 3.25(m, 1H), 3.01(m, 1H), 2.57(m, 1H), 1.71(m, 2H), 1.19(m, 1H).

Method S4D: Amide Formation Using BOP-Cl

1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin pyridin-1-yl)prop-2-yn-1-one

To a 20 mL reaction vial were added propionic acid (0.02 ml; 0.37 mmol; 1.10 eq.), bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (171.33 mg; 0.67 mmol; 2.00 eq.), ethyl-diisopropyl-amine (0.28 ml; 1.68 mmol; 5.00 eq.) and 1.0 mL of DMF. The reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture was then added (3S,4S)-4-{[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-methyl}-piperidin-3-ol hydrochloride (144.00 mg; 0.34 mmol; 1.00 eq.) in 1.0 mL of DMF. The reaction mixture was stirred at room temperature overnight and concentrated. The crude product was purified by preparative HPLC. Fractions containing the desired product were combined and lyophilized overnight to afford 1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-yn-1-one as a white solid (35.2 mg, 18.6%). HPLC purity: 99%. MS: m/z = 444 [M+H] ⁺ . ¹ H NMR (CD ₃ OD)δ8.24(s,1H),7.10-7.46(m,9H),4.36(m,2H),4.00(d,1H),3.74(m,1H),3 .52 (m, 1H), 3.25 (m, 1H), 3.00 (m, 1H), 2.64 (m, 1H), 1.76 (m, 2H), 1.30 (m, 1H).

Process 4

Methods related to the reaction steps in Scheme 4

Method AA: Nucleophilic Aromatic Substitution

(4-(6-Amino-5-chloro-pyrimidin-4-ylamino)-phenyl)-acetic acid ethyl ester

To a vial with a stir bar was added 5,6-dichloro-pyrimidin-4-ylamine (1.4 g, 8.537 mmol, 1.0 eq), (4-amino-phenyl)-acetic acid ethyl ester (4.3 g, 23.993 mmol, 2.8 eq), and N,N-diisopropylethylamine (4.5 ml, 25.611 mmol, 3.0 eq) dissolved in n-butanol (100 ml). The reaction mixture was flushed with nitrogen and heated to 115°C for 8 days. The mixture was concentrated in vacuo, dissolved in EtOAc, washed with water (2x) and brine (1x), dried over sodium sulfate, and concentrated in vacuo. The crude mixture was purified by Biotage column chromatography using 30-70% EtOAc/hexanes as eluent. Fractions containing the desired product were combined and concentrated under reduced pressure to provide ethyl (4-(6-amino-5-chloro-pyrimidin-4-ylamino)-phenyl)acetate (1.71 g, 49% yield) as a white solid. MS: m/z = 307 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ ) δ 8.41 (s, 1H), 7.93 (s, 1H), 7.55 (d, 2H), 7.19 (d, 2H), 6.76 (bs, 2H), 4.11 (q, 2H), 1.21 (t, 3H).

Method BB: Suzuki coupling

(4-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-acetic acid ethyl ester

In a microwave vial were placed [4-(6-amino-5-chloro-pyrimidin-4-ylamino)-phenyl]-acetic acid acetate (1.4 g; 3.423 mmol; 1.0 eq.), (4-phenoxyphenyl)boronic acid (1598.9 mg; 7.470 mmol; 2.18 eq.), palladium acetate (38.4 mg; 0.171 mmol; 0.1 eq.), dicyclohexyl-(2',6'-dimethoxy-diphenyl-2-yl)-phosphine (140.5 mg; 0.342 mmol; 0.1 eq.), and potassium carbonate (1419.2 mg; 10.269 mmol; 3.0 eq.) suspended in dioxane (15.0 ml) and water (1.5 ml). The vial was flushed with nitrogen. The reaction vial was microwaved at 150° C. for 3 h. The mixture was filtered, quenched into water, and extracted with EtOAc (3x). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude compound was purified by Biotage column chromatography (50/50% hexanes/EtOAc to 100% EtOAc). Fractions containing the desired product were collected and concentrated to afford ethyl (4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-acetate (1.43 g, 90% yield) as a yellow foam. MS: m/z = 441 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ ) δ 8.06 (s, 1H), 7.45 (t, 4H), 7.34 (d, 2H), 7.16 (dd, 8H), 5.77 (bs, 2H), 4.10 (q, 2H), 3.56 (s, 2H), 1.20 (t, 3H).

Method CC: Ester Hydrolysis

(4-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-acetic acid

To a vial equipped with a stir bar was added ethyl {4-[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-acetic acid (1430.0 mg; 3.084 mmol; 1.0 eq.) and aqueous sodium hydroxide solution (2N, 9.3 ml; 18.504 mmol; 6.0 eq.) dissolved in dioxane (15.0 ml; 176.040 mmol; 57.1 eq.). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction was quenched by addition of water and washed once with EtOAc. The aqueous phase was acidified with 1N hydrochloric acid. The precipitate was filtered and dried under vacuum to provide (4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-acetic acid (1.11 g, 85% yield) as a white solid.

The filtrate was extracted with EtOAc (2x). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to provide (4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-acetic acid (265 mg, 19% yield) as a white solid. MS: m/z = 413 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ ) δ 12.20 (bs, 1H), 8.05 (s, 1H), 7.41-7.39 (m, 4H), 7.34-7.32 (d, 2H), 7.16-7.11 (m, 8H).

Method DD: Weinreb Amide Synthesis

(4-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-N-methoxy-N-methyl-acetyl amine

To a round-bottom flask with a stir bar was added {4-[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-acetic acid (1375 mg; 3.2 mmol; 1 eq.), N,O-dimethylhydroxylamine hydrochloride (344.2 mg; 3.529 mmol; 1.1 eq.), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (922.5 mg; 0.005 mol; 1.5 eq.), 1-hydroxybenzotriazole (HOBT) hydrate (225.4 mg; 1.668 mmol; 0.5 eq.), and N,N-diisopropylethylamine (0.8 ml; 4.812 mmol; 1.5 eq.) dissolved in DMF (20.0 ml). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc and washed with water (2x) and brine (1x). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude compound was purified by Biotage column chromatography (30-100% EtOAc/cyclohexane). The fractions containing the desired product were collected. The solid was dissolved in DCM and washed with water (3x). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to afford (4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-N-methoxy-N-methyl-acetamide (751 mg, 51% yield) as white crystals. MS: m/z=456[M+H] ⁺ , ¹ H-NMR (DMSO-d ₆ )δ7.92 (s, 1H), 7.44 (m, 4H), 7.40 (d, 2H), 7.26 (d, 2H), 7.14 (t, 5H), 6.11 (t, 1H), 5.50 (bs, 2H), 4.52 (d, 2H), 3.50 (s, 3H), 3.23 (s, 3H).

Method EE: Synthesis of Weinreb's Ketone Using 1-Propylenmagnesium Bromide

1-(4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-pent-3-en-2-one

To a round-bottom flask equipped with a stir bar was added 2-{4-[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-methoxy-N-methyl-acetamide (275.0 mg; 0.604 mmol; 1.0 eq.) suspended in THF (2.5 ml; 12.343 mmol; 20.4 eq.). The suspension was cooled to 0°C. 1-Propylenmagnesium bromide (12.1 ml; 6.037 mmol; 10.0 eq.) was added dropwise at this temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 30 minutes. The reaction suspension was quenched with aqueous ammonium chloride and extracted with EtOAc (3x). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was dissolved in DMSO and purified by preparative HPLC to give 1-(4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-pent-3-en-2-one (78 mg, 19%). MS: m/z = 437 [M+H] ⁺ . ^1H -NMR (DMSO-d ₆ ) 8.50 (bs, 1H), 8.29 (s, 1H), 7.46 (t, 2H), 7.39 (d, 2H), 7.27 (d, 2H), 7.21 (m, 6H), 7.09 (bs, 1H), 7.02 (dd, 1H), 6.20 (ss, 1H), 3.86 (s, 3H), 1.89 (d, 3H).

Method FF: Synthesis of Weinreb's Ketone Using 1-Propylenmagnesium Bromide

1-(4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-pent-3-yn-2-one

To a round-bottom flask equipped with a stir bar was added 2-{4-[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-methoxy-N-methyl-acetamide (275.0 mg; 0.604 mmol; 1.0 eq.) suspended in THF (2.5 ml; 30.857 mmol; 51.1 eq.). The suspension was cooled to 0°C. 1-Propylenmagnesium bromide (12.1 ml; 6.037 mmol; 10.0 eq.) was added dropwise at this temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 30 minutes. The reaction suspension was quenched with aqueous ammonium chloride and extracted with EtOAc (3x). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude compound was dissolved in DMSO and purified by preparative HPLC to afford 1-(4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-pent-3-yn-2-one (68 mg, 17% yield) as a light yellow solid. MS: m/z = 435 [M+H] ⁺ . ^1H -NMR (DMSO-d ₆ ) δ 8.43 (bs, 1H), 8.28 (s, 1H), 7.46 (t, 2H), 7.42 (d, 2H), 7.37 (d, 2H), 7.31-7.13 (m, 7H), 6.99 (bs, 2H), 3.87 (s, 2H), 2.04 (s, 3H).

Method GG: Synthesis of Weinreb's ketone using vinylmagnesium bromide

1-(3-((Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-propenone

To a round-bottom flask equipped with a stir bar was added 3-{[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-methyl}-N-methoxy-N-methyl-benzamide (140.0 mg; 0.307 mmol; 1.0 eq.) suspended in THF (2.0 ml; 24.686 mmol; 80.3 eq.). The suspension was cooled to 0°C. At this temperature, a 1.0 M solution of vinylmagnesium bromide in THF (3.1 ml; 3.073 mmol; 10.0 eq.) was added dropwise isothermally. After the addition was complete, the reaction mixture was stirred at room temperature for 30 minutes. The reaction suspension was quenched with aqueous ammonium chloride and extracted with EtOAc (3x). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude compound was dissolved in DMSO and purified by preparative HPLC to give 1-(3-((amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-propenone (20 mg, 10% yield) as a white amorphous solid. MS: m/z = 484 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ ) δ 8.34 (s, 1H), 7.86 (t, 2H), 7.64 (t, 1H), 7.52 (m, 4H), 7.35 (d, 2H), 7.23 (dd, 3H), 7.14 (d, 2H), 7.02 (bs, 2H), 4.65 (d, 2H), 3.21 (t, 2H), 2.96 (t, 2H).

Analytical methods

Analytical LC/MS was performed using the following three methods:

Method 1 : A Discovery ^C18 , 5 μm, 3 x 30 mm column was used at a flow rate of 400 μL/min, with a 5 μL injection loop. The mobile phase (A) was water containing 0.1% formic acid, and the mobile phase (B) was methanol containing 0.1% formic acid. Retention times are in minutes. Method details: (I) Quaternary Pump G1311A (Agilent) equipped with a UV/VIS diode array detector G1315B (Agilent) and a Finnigan LCQ Duo MS detector (ESI+ mode). UV detection was at 254 and 280 nm. Gradient: 15-95% (B) linear gradient over 3.2 minutes, (II) hold at 95% (B) for 1.4 minutes, (III) linear gradient from 95-15% (B) over 0.1 minutes, and (IV) hold at 15% (B) for 2.3 minutes.

Method 2 : A Waters Symmetry ^C₁₈ column, 3.5 μm, 4.6 x 75 mm, was used at a flow rate of 1 mL/min and a 10 μL injection loop. The mobile phase (A) was water containing 0.05% TFA, and the mobile phase (B) was ACN containing 0.05% TFA. Retention times are reported in minutes. Method Details: (I) Binary Pump G1312A (Agilent) equipped with a UV/Vis diode array detector G1315B (Agilent) and an Agilent G1956B (SL) MS detector (ESI+ mode). UV detection was at 254 and 280 nm. Gradient: 20-85% (B) linear gradient over 10 minutes, (II) hold at 85% (B) for 1 minute, (III) linear gradient from 85-20% (B) over 0.2 minutes, and (IV) hold at 20% (B) for 3.8 minutes.

Method 3 : Gradient: 4.2 minutes/flow rate: 2 ml/minute 99:01-0:100 water + 0.1% (volume) TFA; acetonitrile + 0.1% (volume) TFA; 0.0 to 0.2 minutes: 99:01; 0.2 to 3.8 minutes: 99:01→0:100; 3.8 to 4.2 minutes: 0:100; Column: Chromolith Performance RP18e; length 100 mm, diameter 3 mm; wavelength: 220 nm.

HPLC purity determination

Purity was determined using an Agilent HPLC with a Waters Xbridge C8 column (5 μm, 4.6 x 50 mm) and UV detection at 254 nm. Mobile phase A: 0.1% TFA in water. Mobile phase B: 0.1% TFA in acetonitrile. The method involved a gradient of 98% mobile phase A/2% mobile phase B to 100% mobile phase B over 8 minutes at a flow rate of 2 mL/min.

General Methods for Preparative HPLC

Preparative HPLC was performed on a Waters preparative HPLC system using a Waters Sunfire Prep C ₁₈ (5 or 10 μm) column. Mobile phase A: Water containing 0.1% TFA. Mobile phase B: Acetonitrile. Crude compound was loaded using minimal amounts of methanol or DMSO. A typical gradient for separation was 0-50% mobile phase B over 20-25 minutes, with an optional wash step (100% mobile phase B).

Example

The following working examples are intended to illustrate specific embodiments of the present invention and are not intended to limit the scope of the specification or claims in any way. This section provides experimental details for many example compounds of formula (I), formula (II), formula (III), formula (IV) and formula (V).

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en- 1-one (A1)

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 402 [M+H] ⁺ .

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1- one (A2)

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods A, C, D, and F. HPLC purity: 100%. MS: m/z = 417 [M+H] ⁺ .

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (A3)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, benzene-1,3-diamine, (4-phenoxyphenyl)boronic acid, and acryloyl according to Methods H, C, and F. HPLC purity: 100%. MS: m/z = 424 [M+H] ⁺ . ^1H -NMR (DMSO-d ₆ ), δ 10.11 (s, 1H), 8.47 (broad s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.31-6.97 (m, 14H), 6.37 (dd, 1H), 6.19 (d, 1H), 5.69 (d, 1H).

(R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl) prop-2-en-1-one (A4)

(R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 416 [M+H] ⁺ .

N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)acrylamide ( A5)

N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl (pyrrolidin-3-ylmethyl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 97%. MS: m/z = 416 [M+H] ⁺ .

1-(4-(((5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-one (A6)

1-(4-(((5-(4-Phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5-bromo-4-chloropyrimidine, tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods A, C, D, and F. HPLC purity: 92%. MS: m/z = 416 [M+H] ⁺ .

N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)acrylamide (A7)

N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl (piperidin-4-ylmethyl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 430 [M+H] ⁺ .

4-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidine-1-carbonyl)-1- methylpyridin -2(1H)-one (A8)

4-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidine-1-carbonyl)-1-methylpyridin-2(1H)-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid according to Methods B, C, D, and E. HPLC purity: 100%. MS: m/z = 511 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ )δ8.28(s, 1H), 7.69(d, 1H), 7.38(t, 2H), 7.20(d, 2H), 7.14-6.90(m, 8H), 6.19(s, 1H), 6.06(d, 1H), 1.28(d, 1H), 3.47 (d, 1H), 3.35 (s, 3H), 3.18 (s, 2H), 2.90 (t, 1H), 2.61 (t, 1H), 1.76 (s, 1H), 1.58 (d, 1H), 1.48 (d, 1H), 1.04-0.92 (m, 2H).

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)but-2-yn- 1-one (A9)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)but-2-yn-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and but-2-ynoic acid according to Methods A, C, D, and E. HPLC purity: 100%. MS: m/z = 443 [M+H] ⁺ .

5-(4-Phenoxyphenyl)-N4-((1-(vinylsulfonyl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine (A10)

5-(4-Phenoxyphenyl)-N4-((1-(vinylsulfonyl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and 2-chloroethanesulfonyl chloride according to Methods B, C, D, and G. HPLC purity: 89%. MS: m/z = 466 [M+H] ⁺ .

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4- ((2-methoxyethyl)(methyl)amino)but-2-en-1-one (A11)

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-((2-methoxyethyl)(methyl)amino)but-2-en-1-one was synthesized according to Methods B, C, D, and E using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and (E)-4-((2-methoxyethyl)(methyl)amino)but-2-enoic acid. HPLC purity: 99%. MS: m/z = 531 [M+H] ⁺ .

(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(2-fluoropyridin- 3-yl)methanone (A12)

(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(2-fluoropyridin-3-yl)methanone was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and 2-fluoronicotinic acid according to Methods B, C, D, and E. HPLC purity: 100%. MS: m/z = 499 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ )δ8.28(s, 1H), 8.25(d, 1H), 7.92(t, 1H), 7.39-7.36(m, 3H), 7.20-6.90(m, 10H), 4.39(d, 1H), 3.28(d, 1H), 3.19(m, 2H), 2.94(t, 1H), 2.70(t, 1H), 1.78(s, 1H), 1.63(d, 1H), 1.49(d, 1H), 1.05-0.92(m, 2H).

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but- 2-en-1-one (A13)

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and (E)-but-2-enoic acid according to Methods B, C, D, and E. HPLC purity: 100%. MS: m/z = 444 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ ).δ8.27(s, 1H), 7.38(t, 2H), 7.21-6.88(m, 10H), 6.60-6.52(m, 1H), 6.40(d, 1H), 4.27 (m, 1H), 3.96 (m, 1H), 3.16 (m, 3H), 2.87 (m, 1H), 1.75 (d, 4H), 1.53 (m, 2H), 0.88 (m, 2H).

N4-((1-(cyclopropylsulfonyl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine (A14)

N-((1-(cyclopropylsulfonyl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and cyclopropylsulfonyl chloride according to Methods B, C, D, and G. HPLC purity: 96%. MS: m/z = 480 [M+H] ⁺ .

(Z)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but- 2-en-1-one (A15)

(Z)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and but-2-ynoic acid according to Methods B, C, D, and E, and hydrogenation using Lindela's catalyst. HPLC purity: 81%. MS: m/z = 444 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ ).δ8.35(s, 1H), 7.45(t, 2H), 7.28-6.95(m, 10H), 6.06(d, 1H), 5.94-5.86(m, 1H), 4.35(d, 1H), 3 .83 (d, 1H), 3.24 (m, 2H), 2.94 (t, 1H), 2.55 (t, 1H), 1.82-1.74 (m, 4H), 1.61 (d, 2H), 0.96 (m, 2H).

1-(4-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)piperidin-1-yl)prop-2- en-1 -one (A16)

1-(4-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 98%. MS: m/z = 444 [M+H] ⁺ .

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en- 1-one (A17)

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods A, C, and F. HPLC purity: 100%. MS: m/z = 431 [M+H] ⁺ .

N-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)acrylamide (A18)

N-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl (2-aminoethyl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 376 [M+H] ⁺ .

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en- 1-one (A19)

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods A, C, D, and F. HPLC purity: 100%. MS: m/z = 403 [M+H] ⁺ .

N-(1-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)cyclopentyl)acrylamide (A20)

N-(1-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)cyclopentyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl (1-(aminomethyl)cyclopentyl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 99%. MS: m/z = 430 [M+H] ⁺ .

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop -2- en-1 -one (A21)

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods A, C, D, and F. HPLC purity: 100%. MS: m/z = 417 [M+H] ⁺ .

1-(4-(((5-Fluoro-3-(4-phenoxyphenyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)prop-2-en-1- one (A22)

1-(4-(((5-Fluoro-3-(4-phenoxyphenyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 3-bromo-2-chloro-5-fluoropyridine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 99%. MS: m/z = 432 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ ) δ 8.01 (s, 1H), 7.47-7.45 (m, 4H), 7.32 (d, 1H), 7.21 (t, 1H), 7.12-7.09 (m, 4H), 6.82-6.75 (m, 1H), 6.07 (d, 1H), 5.82 (broad s, 1H), 5.64 (d, 1H), 4.39 (d, 1H), 4.02 (d, 1H), 3.18 (d, 2H), 2.99 (t, 1H), 2.59 (t, 1H), 1.92 (s, 1H), 1.68 (m, 2H), 1.00 (m, 2H).

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)ethanone (A23)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)ethanone was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acetic acid according to Methods B, C, D, and E. HPLC purity: 100%. MS: m/z = 418 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ )δ8.36(s, 1H), 7.46(t, 2H), 7.29-7.01(m, 10H), 4.32(d, 1H), 3.78(d, 1H), 3.24(m, 2H ), 2.94(t, 1H), 2.46(t, 1H), 1.97(s, 3H), 1.79(s, 1H), 1.58(t, 2H), 1.07-0.87(m, 2H).

(E)-7-(3-(4-(4-((3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl) amino )-4-oxobut-2-en-1-yl)piperazin-1-yl)-3-oxopropyl)-5,5-difluoro-1,3-dimethyl-5H-dipyrrolo [1,2-c:2',1'-f][1,3,2]diazaborinin-4-ium-5-uide (A24)

Using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, (4-phenoxyphenyl)boronic acid, (E)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)but-2-enoic acid and 7-(2-carboxyethyl)-5,5-difluoro-1,3-dimethyl-5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-4-ium-5-uide, according to methods A, B, E, D (E)-7-(3-(4-(4-((3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)amino)-4-oxobut-2-en-1-yl)piperazin-1-yl)-3-oxopropyl)-5,5-difluoro-1,3-dimethyl-5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-4-ium-5-uide was synthesized with E. HPLC purity: 100%. MS: m/z = 797 [M+H] ⁺ .

1-(4-(((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en- 1-one (A25)

1-(4-(((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5-bromo-4-chloropyrimidin-2-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 430 [M+H] ⁺ .

(S)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl) prop-2-en-1-one (A26)

(S)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (S)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate, 4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods A, C, D, and F. HPLC purity: 100%. MS: m/z = 417 [M+H] ⁺ .

N-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)ethyl)acrylamide (A27)

N-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)ethyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl (2-hydroxyethyl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods A, C, D, and F. HPLC purity: 100%. MS: m/z = 377 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ ).δ8.28(s, 1H), 8.14(t, 1H), 7.43(t, 2H), 7.31(d, 2H), 7.18(t, 1H), 7.11(d, 2H), 7.01(d, 2 H), 6.71(broads, 1.5H), 6.16(dd, 1H), 6.07(d, 1H), 5.57(d, 1H), 4.34(t, 2H), 3.42(q, 2H).

(S)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl) prop-2-en-1-one (A28)

(S)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (S)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 98%. MS: m/z = 416 [M+H] ⁺ .

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2 -methylprop-2-en-1-one (A29)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2-methylprop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and methacrylic acid according to Methods B, C, D, and E. HPLC purity: 100%. MS: m/z = 444 [M+H] ⁺ .

(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclohex-1- en-1-yl)methanone (A30)

(4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclohex-1-en-1-yl)methanone was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and cyclohex-1-enecarboxylic acid according to Methods B, C, D, and E. HPLC purity: 100%. MS: m/z = 484 [M+H] ⁺ .

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl) -3 -methylbut-2-en-1-one (A31)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-3-methylbut-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and 3-methylbut-2-enoyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 458 [M+H] ⁺ .

(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclopent-1- en-1-yl)methanone (A32)

(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclopent-1-en-1-yl)methanone was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and cyclopent-1-enecarboxylic acid according to Methods B, C, D, and E. HPLC purity: 99%. MS: m/z = 470 [M+H] ⁺ .

1-(4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl) prop-2-en-1-one (A33)

1-(4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (1-benzyl-1H-pyrazol-4-yl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 418 [M+H] ⁺ .

1-(4-(((6-amino-5-(4-(3-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1 -yl)prop-2-en-1-one (A34)

1-(4-(((6-amino-5-(4-(3-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-(3-fluorophenoxy)phenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and E. HPLC purity: 100%. MS: m/z = 448 [M+H] ⁺ .

(E)-7-(3-((2-(4-(4-((3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)amino)-4-oxobut-2-en -1-yl)piperazin-1-yl)ethyl)amino)-3-oxopropyl)-5,5-difluoro-1,3- dimethyl - 5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-4-ium-5-uide (A35)

Using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, (4-(3-fluorophenoxy)phenyl)boronic acid, (E)-4-(4-(2-((tert-butoxycarbonyl)amino)ethyl)piperazin-1-yl)but-2-enoic acid and 7-(2-carboxyethyl)-5,5-difluoro-1,3-dimethyl-5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-4-ium-5-uide, according to methods A, C, E (E)-7-(3-((2-(4-(4-((3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)amino)-4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)amino)-3-oxopropyl)-5,5-difluoro-1,3-dimethyl-5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-4-ium-5-uide was synthesized using HPLC purity: 100%. MS: m/z = 840 [M+H] ⁺ .

1-(4-(((6-amino-2-methyl-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1 -yl)prop-2-en- 1-one (A36)

1-(4-(((6-amino-2-methyl-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloro-2-methylpyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and E. HPLC purity: 100%. MS: m/z = 444 [M+H] ⁺ .

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl) prop-2-en- 1-one (A37)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 446 [M+H] ⁺ .

(R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl) prop-2-en-1-one (A38)

(R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods A, C, D, and F. HPLC purity: 96%. MS: m/z = 417 [M+H] ⁺ .

1-(4-(((6-amino-5-(4-(phenylamino)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl) prop-2-en-1-one (A39)

1-(4-(((6-amino-5-(4-(phenylamino)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, N-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 98%. MS: m/z = 429 [M+H] ⁺ .

1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-1H-pyrrol-2(5H)-one (A40)

1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-1H-pyrrol-2(5H)-one was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, (4-phenoxyphenyl)boronic acid, and 2,5-dimethoxy-2,5-dihydrofuran according to Methods A and C. HPLC purity: 93%. MS: m/z = 437 [M+H] ⁺ .

1-(4-(((6-amino-5-(4-benzylphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1- one (A41)

1-(4-(((6-amino-5-(4-benzylphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, 2-(4-benzylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 428 [M+H] ⁺ .

(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclobut-1- en-1-yl)methanone (A42)

(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclobut-1-en-1-yl)methanone was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and cyclobut-1-enecarboxylic acid according to Methods B, C, D, and E. HPLC purity: 99%. MS: m/z = 456 [M+H] ⁺ .

(Z)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)but- 2-en-1-one (A43)

(Z)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)but-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and but-2-ynoic acid according to Methods A, C, D, and E, and hydrogenation using Lindela's catalyst. HPLC purity: 100%. MS: m/z = 445 [M+H] ⁺ .

1-(4-(((6-amino-2-methyl-5-(4-phenoxyphenyl)pyrimidin-4-yl)(methyl)amino)methyl)piperidin- 1-yl)prop-2-en-1-one (A44)

1-(4-(((6-amino-2-methyl-5-(4-phenoxyphenyl)pyrimidin-4-yl)(methyl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloro-2-methylpyrimidin-4-amine, tert-butyl 4-((methylamino)methyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 458 [M+H] ⁺ .

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2-chloroethanone ( A45)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2-chloroethanone was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and 2-chloroacetyl chloride according to Methods B, C, D, and G. HPLC purity: 100%. MS: m/z = 452 [M+H] ⁺ .

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-yn- 1-one (A46)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-yn-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and propionic acid according to Methods B, C, D, and E. HPLC purity: 98%. MS: m/z = 428 [M+H] ⁺ .

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)(methyl)amino)methyl)piperidin-1 -yl)prop-2-en-1-one (A47)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)(methyl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-((methylamino)methyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 444 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ ) δ 8.32 (s, 1H), 7.45 (t, 2H), 7.33 (d, 2H), 7.20 (t, 1H), 7.12 (t, 4H), 6.95 (broad s, 1.5H), 6.77 (dd, 1H), 6.07 (d, 1H), 5.65 (d, 1H), 4.38 (d, 1H), 4.01 (d, 1H), 3.36 (m , 2H), 2.99(t, 1H), 2.68(s, 3H), 2.57(t, 1H), 1.92(s, 1H), 1.50(d, 2H), 0.97(t, 2H).

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1] oct-8-yl)prop-2-en-1-one (A48)

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, 3-(aminomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 456 [M+H] ⁺ .

N-((1S,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclopentyl)acrylamide (A49)

N-((1S,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclopentyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl trans-3-aminocyclopentyl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 416 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ ) δ 8.35 (s, 1H), 8.12 (d, 1H), 7.46 (t, 2H), 7.28-7.15 (m, 7H), 6.92 (broad s, 1.5H), 6.81 (d, 1H), 6.20 (dd, 1H), 6.06 (d, 1H), 5.57 (d, 1H), 4.64 (s, 1 H), 4.21(q, 1H), 2.05-1.91(m, 2H), 1.86-1.71(m, 2H), 1.55-1.34(m, 2H).

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)butyl)acrylamide (A50)

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)butyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, (4-aminobutyl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 404 [M+H] ⁺ .

N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide (A51)

N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl (trans-3-aminocyclohexyl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 431 [M+H] ⁺ .

1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)azepan-1-yl)prop-2-en- 1-one (A52)

1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)azepan-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 3-aminoazepan-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 430 [M+H] ⁺ .

N-(trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide (A53)

N-(trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl (cis-3-aminocyclohexyl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 430 [M+H] ⁺ .

(E)-5-(4-phenoxyphenyl)-N4-((1-(styrylsulfonyl)piperidin-4-yl)methyl)pyrimidine-4,6- diamine (A54)

(E)-5-(4-Phenoxyphenyl)-N4-((1-(styrylsulfonyl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and (E)-2-phenylethenesulfonyl chloride according to Methods B, C, D, and G. HPLC purity: 98%. MS: m/z = 542 [M+H] ⁺ .

N4-((1-(methylsulfonyl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine (A55)

N-((1-(methylsulfonyl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and methanesulfonyl chloride according to Methods B, C, D, and G. HPLC purity: 99%. MS: m/z = 454 [M+H] ⁺ .

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2,3- dihydroxypropan-1-one (A56)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2,3-dihydroxypropan-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F, and a dihydroxylation reaction with osmium tetroxide. HPLC purity: 96%. MS: m/z = 464 [M+H] ⁺ .

4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-2-one (A57)

4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-2-one was synthesized using 5,6-dichloropyrimidin-4-amine, 4-(aminomethyl)piperidin-2-one, and (4-phenoxyphenyl)boronic acid according to Methods I and C. HPLC purity: 100%. MS: m/z = 390 [M+H] ⁺ .

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)ethylenesulfonamide (A58)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)ethylenesulfonamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, (4-phenoxyphenyl)boronic acid, and 2-chloroethanesulfonyl chloride according to Methods A, C, and G. HPLC purity: 77%. MS: m/z = 461 [M+H] ⁺ .

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)propyl)acrylamide (A59)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)propyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl (3-aminopropyl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 390 [M+H] ⁺ .

N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)pyridin-3-yl)acrylamide (A60)

N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)pyridin-3-yl)acrylamide was synthesized using 6-dichloropyrimidin-4-amine, 5-aminopyridin-3-ol, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods A, C, and F. HPLC purity: 97%. MS: m/z = 426 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ ) δ 10.49 (s, 1H), 8.58 (s, 1H), 8.13-8.09 (m, 2H), 7.97 (s, 1H), 7.46-7.40 (m, 4H), 7.17 (t, 1H), 7.12-7.09 (m, 4H), 6.64 (broad s, 1.2H), 6.43 (dd, 1H), 6.30 (d, 1H), 5.83 (d, 1H).

(R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl) prop-2-yn-1-one (A61)

(R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-yn-1-one was synthesized using 6-dichloropyrimidin-4-amine, (R)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and propionic acid according to Methods B, C, D, and E. HPLC purity: 99%. MS: m/z = 414 [M+H] ⁺ .

(R,E)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1- yl)-4-(dimethylamino)but-2-en-1-one (A62)

(R,E)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-one was synthesized according to Methods B, C, D, and E using 6-dichloropyrimidin-4-amine, (R)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and (E)-4-(dimethylamino)but-2-enoic acid. HPLC purity: 100%. MS: m/z = 473 [M+H] ⁺ .

(E)-N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)-4-(dimethylamino )but-2-enamide (A63)

(E)-N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)-4-(dimethylamino)but-2-enamide was synthesized using 6-dichloropyrimidin-4-amine, tert-butyl (cis-3-aminocyclohexyl)carbamate, (4-phenoxyphenyl)boronic acid, and (E)-4-(dimethylamino)but-2-enoic acid according to Methods B, C, D, and E. HPLC purity: 99%. MS: m/z = 487 [M+H] ⁺ .

N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)propiolamide (A64)

N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)propynamide was synthesized using 6-dichloropyrimidin-4-amine, tert-butyl (cis-3-aminocyclohexyl)carbamate, (4-phenoxyphenyl)boronic acid, and propionic acid according to Methods B, C, D, and E. HPLC purity: 100%. MS: m/z = 428 [M+H] ⁺ .

(S)-1-(2-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2- en- 1-one (A65)

(S)-1-(2-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-one was synthesized using 6-dichloropyrimidin-4-amine, (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods A, C, D, and F. HPLC purity: 99%. MS: m/z = 433 [M+H] ⁺ .

(R)-1-(2-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2- en- 1-one (A66)

(R)-1-(2-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-one was synthesized using 6-dichloropyrimidin-4-amine, (R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods A, C, D, and F. HPLC purity: 100%. MS: m/z = 433 [M+H] ⁺ .

N-(3-((6-amino-5-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl) acrylamide (A67)

N-(3-((6-amino-5-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and acryloyl chloride according to Methods A, C, and F. HPLC purity: 100%. MS: m/z = 431 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ )δ10.21(s, 1H), 8.16(s, 1H), 8.03(s, 1H), 7.74(s, 1H), 7.51(s, 1H), 7.42.7.30(m, 3H), 7. 15-7.09 (m, 3H), 7.03-6.61 (m, 2.5H), 6.42 (dd, 1H), 6.25 (d, 1H), 5.57 (d, 1H), 5.40 (s, 2H).

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1] oct-8-yl)prop-2-yn-1-one (A68)

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-yn-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 3-(aminomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate, 4-phenoxyphenyl)boronic acid, and propionic acid according to Methods B, C, D, and E. HPLC purity: 96%. MS: m/z = 454 [M+H] ⁺ .

N-(3-((6-amino-5-(1-(4-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide ( A69)

N-(3-((6-amino-5-(1-(4-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, 4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)benzonitrile, and acryloyl chloride according to Methods A, C, and F. HPLC purity: 97%. MS: m/z = 438 [M+H] ⁺ . H-NMR(DMSO-d ₆ )δ10.21(s, 1H), 8.18(s, 1H), 8.03(s, 1H), 7.82(d, 2H), 7.76(s, 1H), 7.52(s, 1H), 7.42(d, 2H), 7. 40 (d, 1H), 7.30 (t, 1H), 6.89-6.67 (m, 2.5H), 6.42 (dd, 1H), 6.25 (d, 1H), 5.77 (d, 1H), 5.49 (s, 2H).

N-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (A70)

N-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, benzene-1,3-diamine, 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and acryloyl chloride according to Methods H, C, and F. HPLC purity: 99%. MS: m/z = 412 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ )δ10.17(s, 1H), 8.65(s, 1H), 8.26(s, 1H), 8.02(s, 1H), 7.78(s, 1H), 7.61(s, 1H), 7.44-7.03(m, 10H), 6.45(dd, 1H), 6.26(d, 1H), 5.76(d, 1H), 5.39(s, 2H).

(E)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo [3.2.1]oct-8-yl)-4-(dimethylamino)but-2-en-1-one (A71)

(E)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]oct-8-yl)-4-(dimethylamino)but-2-en-1-one was synthesized according to Methods B, C, D, and E using 5,6-dichloropyrimidin-4-amine, tert-butyl 3-(aminomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate, (4-phenoxyphenyl)boronic acid, and (E)-4-(dimethylamino)but-2-enoic acid. HPLC purity: 100%. MS: m/z = 513 [M+H] ⁺ .

N-(3-((6-amino-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl) acrylamide (A72)

N-(3-((6-amino-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, 1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and acryloyl chloride according to Methods A, C, and F. HPLC purity: 99%. MS: m/z = 443 [M+H] ⁺ . H-NMR(DMSO-d ₆ )δ10.21(s, 1H), 8.08(s, 1H), 8.01(s, 1H), 7.70(s, 1H), 7.50(s, 1H), 7.41(d, 1H), 7.33-7.26(m, 3H), 6.90 (d, 2H), 6.83-6.58 (m, 2.5H), 6.40 (dd, 1H), 6.25 (d, 1H), 5.76 (d, 1H), 5.28 (s, 2H), 3.73 (s, 3H).

(R,E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)-4-( dimethylamino)but-2-en-1-one (A73)

(R,E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and (E)-4-(dimethylamino)but-2-enoic acid according to Methods B, C, D, and E. HPLC purity: 99%. MS: m/z = 459 [M+H] ⁺ .

(R,E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)-4-( dimethylamino )but-2-en-1-one (A74)

(R,E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl 3-aminopiperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and (E)-4-(dimethylamino)but-2-enoic acid according to Methods B, C, D, and E. HPLC purity: 100%. MS: m/z = 473 [M+H] ⁺ .

1-(trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-4-hydroxypyrrolidin-1-yl) prop-2-en-1-one (A75)

1-(trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-4-hydroxypyrrolidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, trans-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 418 [M+H] ⁺ .

1-(4-(((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en- 1-one (A76)

1-(4-(((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 3,4-dichloropyridin-2-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC purity: 100%. MS: m/z = 429 [M+H] ⁺ .

1-(4-(((6-amino-5-(4-fluorophenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one (A77)

1-(4-(((6-Amino-5-(4-fluorophenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-fluorophenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 356 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ )δ8.35(s, 1H), 7.40(t, 2H), 7.32(dd, 2H), 7.07(t, 1H), 6.95(s, 2H), 6.78(dd, 1H), 6.07(dd, 1H), 5.65(dd, 1H) , 4.37(d, 2H), 4.01(d, 2H), 3.21(t, 2H), 2.98(t, 1H), 2.67–2.53(m, 1H), 1.82(s, 1H), 1.61(d, 2H), 0.98(d, 2H).

1-(4-(((6-amino-5-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1 -yl)prop-2-en-1-one (A78)

1-(4-(((6-amino-5-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-(trifluoromethoxy)phenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 422 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ )δ8.36(s, 1H), 7.53(d, 2H), 7.41(d, 2H), 7.12(t, 1H), 6.99(s, 2H), 6.78(dd, 1H), 6.07(dd, 1H), 5.65(dd, 1 H), 4.37(d, 1H), 4.02(d, 2H), 3.22(t, 2H), 2.98(t, 1H), 2.58(t, 1H), 1.82(s, 1H), 1.62(d, 2H), 0.97(s, 2H).

1-(4-(((6-amino-5-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin -1-yl)prop-2-en-1-one (A79)

1-(4-(((6-amino-5-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-(4-(trifluoromethyl)phenoxy)phenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 498 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ )δ8.37(s, 1H), 7.79(d, 2H), 7.31(m, 4H), 7.10(bs, 1H), 7.01(bs, 1H), 6.78(dd, 1H), 6.07(dd, 1H), 5.65(dd, 1H) , 4.38(d, 1H), 4.02(d, 1H), 3.25(t, 2H), 3.09–2.90(m, 1H), 2.59(t, 1H), 1.84(m, 1H), 1.63(d, 2H), 0.99(m, 2H).

1-(4-(((6-amino-5-(4-(4-(fluorophenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl) prop-2-en-1-one (A80)

1-(4-(((6-amino-5-(4-(4-(fluorophenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-(4-fluorophenoxy)phenyl)boronic acid, and acryloyl chloride according to the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 448 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ )δ8.35(s, 1H), 7.37–7.24(m, 4H), 7.22–7.11(m, 4H), 7.05(t, 1H), 6.92(bs, 2H), 6.78(dd, 1H), 6.07(dd, 1H), 5.65 (dd, 1H), 4.37 (d, 1H), 4.02 (d, 1H), 3.23 (t, 2H), 3.00 (t, 1H), 2.58 (t, 1H), 1.83 (m, 1H), 1.62 (d, 2H), 0.97 (m, 2H).

1-(4-(((6-amino-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl) prop-2-en-1-one (A81)

1-(4-(((6-amino-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-(trifluoromethyl)phenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 406 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ )δ8.36(s, 1H), 7.92(d, 2H), 7.51(d, 2H), 7.13(t, 1H), 6.99(s, 2H), 6.78(dd, 1H), 6.07(dd, 1H), 5.65(dd, 1H), 4.37(d, 1H), 4.01(d, 1H), 3.26–3.16(m, 3H), 3.04–2.91(m, 1H), 2.65–2.53(m, 1H), 1.83(m, H), 1.62(d, 2H), 1.09–0.86(m, 2H).

1-(4-(((6-amino-5-(3,4-dimethoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl) prop-2-en-1-one (A82)

1-(4-(((6-amino-5-(3,4-dimethoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (3,4-dimethoxyphenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 398 [M+H] ^{. 1} H-NMR (400MHz, CD ₃ OD) δ 8.24 (s, 1H), 7.19 (d, 1H), 6.90 (dd, Hz, 2H), 6.76 (dd, 1H), 6.18 (dd, 1H), 5.73 (dd, 1H), 4.54 (d, 1H), 4.12 (d, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.38 (bs, 2H), 3.10 (t, 1H), 2.71 (t, 1H), 2.04–1.85 (m, 1H), 1.75 (bs, 2H), 1.29 (s, 1H), 1.13 (bs, 2H).

1-(4-(((6-amino-5-(3,4,5-trimethoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1 -yl)prop-2-en-1-one (A83)

1-(4-(((6-amino-5-(3,4,5-trimethoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (3,4,5-trimethoxyphenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 428 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ): δ8.34(s, 1H), 7.17(s, 1H), 6.99(s, 2H), 6.79(dd, 1H), 6.57(s, 2H), 6.07(dd, 1H), 5.65(dd, 1H), 4.37(d, 1H), 4.02(d , 1H), 3.79(s, 6H), 3.76(s, 3H), 3.25(bs, 2H), 2.99(t, 1H), 2.59(t, 1H), 1.85(bs, 1H), 1.65(d, 2H), 1.09–0.90(m, 2H).

1-(4-(((6-amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-4-yl)amino) methyl )piperidin-1-yl)prop-2-en -1-one (A84)

1-(4-(((6-Amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 396 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ )δ8.33(s, 1H), 7.07(d, 1H), 7.04(d, 1H), 6.93(s, 2H), 6.83–6.73(m, 2H), 6.70(dd, 1H), 6.07(dd, 1H), 5.65(dd, 1H), 4.36( d, 1H), 4.30 (s, 3H), 4.01 (d, 1H), 3.22 (s, 3H), 2.98 (t, 1H), 2.66–2.53 (m, 1H), 1.83 (m, 1H), 1.61 (d, 2H), 1.10–0.83 (m, 2H).

1-(4-(((6-amino-5-(4-methoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en- 1-one (A85)

1-(4-(((6-amino-5-(4-methoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-methoxyphenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 368 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ )δ8.34(s, 1H), 7.17(dd, 4H), 6.99(s, 1H), 6.84(s, 1H), 6.78(dd, 1H), 6.07(dd, 1H), 5.65(dd, 1H), 4.37(d, 1H), 4.01 (d, 1H), 3.83 (s, 3H), 3.22 (t, 2H), 2.98 (t, 1H), 2.58 (t, 1H), 1.82 (bs, 1H), 1.60 (d, 2H), 1.07–0.86 (m, 2H).

4-(4-(4-(((1-acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile ( A86)

4-(4-(4-(((1-Acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile was synthesized from 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-cyanophenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 455 [M+H] ^{. 1} H-NMR (400MHz, DMSO-d ₆ )δ8.27(s, 1H), 7.77(d, 2H), 7.48–7.20(m, 5H), 6.76(dd, 1H), 6.18(dd, 1H), 5.73(dd, 1H), 4.56(d, 1H), 4.13(d, 1H), 3.40 (d, 2H), 3.18–3.00 (m, 2H), 2.79–2.63 (m, 1H), 1.96 (bs, 2H), 1.84–1.68 (m, 2H), 1.51 (d, 2H), 1.25–1.04 (m, 2H).

1-(4-(((6-amino-5-(2,5-difluoro-4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1 -yl)prop-2-en-1-one (A87)

1-(4-(((6-amino-5-(2,5-difluoro-4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (2,5-difluoro-4-phenoxyphenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 466 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ )δ8.38(s, 1H), 7.44(dt, 4H), 7.36–7.12(m, 5H), 6.79(dd, 1H), 6.07(dd, 1H), 5.64(dd, 1H), 4.38(d, 1H), 4. 03 (d, 1H), 3.31 (bs, 1H), 3.21 (bs, 1H), 2.99 (t, 1H), 2.58 (t, 1H), 1.84 (bs, 1H), 1.64 (d, 2H), 1.00 (bs, 2H).

1-(4-(((6-amino-5-(2,3-difluoro-4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1 -yl)prop-2-en-1-one (A88)

1-(4-(((6-amino-5-(2,3-difluoro-4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (2,3-difluoro-4-phenoxyphenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 466 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ )δ8.36(s, 1H), 7.47(t, J=8.0Hz, 2H), 7.35(bs, 1H), 7.27–7.05(m, 5H), 6.79(dd, 1H), 6.07(dd, 1H), 5.65(dd, 1H), 4.38 (d, 1H), 4.02 (d, 1H), 3.25 (s, 2H), 3.05–2.92 (t, 1H), 2.60 (t, 1H), 1.84 (bs, 1H), 1.61 (bs, 2H), 1.00 (bs, 2H).

1-(4-(((6-amino-5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)pyrimidin-4-yl)amino)methyl) piperidin-1-yl)prop-2-en-1-one ( A89)

1-(4-(((6-amino-5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-((1-methylpiperidin-4-yl)oxy)phenyl)boronic acid, and acryloyl chloride according to the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 451 [M+H] ^+. 1 H-NMR (400 MHz, DMSO-d ₆ )δ9.79(s, 1H), 8.35(s, 1H), 7.19(m, 5H), 6.93(m, 3H), 6.78(dd, 1H), 6.07 (dd, 1H), 5.65 (dd, 1H), 4.81 (s, 1H), 4.60 (s, 1H), 4.37 (d, 1H), 4.01 (d, 1H) , 3.19(d, 5H), 2.98(t, 1H), 2.85(d, 4H), 2.65–2.53(m, 1H), 2.29(d, 1H), 2. 06 (d, 2H), 1.81 (d, 2H), 1.59 (s, 2H), 1.33–1.16 (m, 1H), 1.06–0.82 (m, 2H).

1-(4-(((6-amino-5-(4-phenoxy-2-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)methyl)piperidin- 1-yl)prop-2-en-1-one (A90)

1-(4-(((6-amino-5-(4-phenoxy-2-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxy-2-(trifluoromethyl)phenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 498 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ )δ8.35(s, 1H), 7.50(dd, 2H), 7.39(m, 2H), 7.28(t, 1H), 7.19(d, J=7.8Hz, 2H), 7.16–7.07(m, 1H), 7.00(bs, 1H), 6.78(dd, 1H), 6.06(dd , 1H), 5.64(dd, 1H), 4.36(d, 1H), 4.01(d, 1H), 3.16(m, 2H), 2.97(t, 1H), 2.65–2.54(t, 1H), 1.78(bs, 1H), 1.58(bs, 2H), 0.97(bs, 2H).

1-(2-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,7-diazaspiro[3.5]non-7-yl)prop- 2-en-1-one (A91)

1-(2-(6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,7-diazaspiro[3.5]non-7-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 442 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ )δ8.31(s, 1H), 7.43(t, 2H), 7.34(d, 2H), 7.18(t, 1H), 7.11(d, 4H), 7.04(bs, 1 H), 6.77(dd, 1H), 6.06(dd, 1H), 5.65(dd, 1H), 3.10–3.90(m, 8H), 1.59(s, 4H).

1-(8-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]dec-2-yl) prop-2-en-1-one (A92)

1-(8-(6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]dec-2-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 456 [M+H] ^{. 1} H-NMR (400MHz, DMSO-d ₆ )δ8.33(s, 1H), 7.44(t, 2H), 7.35(t, 2H), 7.19(t, 1H), 7.10(d, 3H), 6.91(bs, 2H), 6.53 (m, 1H), 6.13 (d, 1H), 5.72–5.60 (m, 1H), 3.70–3.10 (m, 11H), 1.85 (t, 1H), 1.76 (m, 2H).

1-(7-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,7-diazaspiro[4.4]non-2-yl)prop- 2-en-1-one (A93)

1-(7-(6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,7-diazaspiro[4.4]non-2-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 442 [M+H] ^{. 1} H-NMR (400MHz, DMSO-d ₆ )δ8.33(s, 1H), 7.43(t, 2H), 7.35(d, 2H), 7.18(m, 3H), 7.10(d, 2H), 6.97(bs, 2H), 6.54(ddd, 1 H), 6.11(d, 1H), 5.71–5.60(m, 1H), 3.70-3.10(m, 6H), 1.77(t, 1H), 1.68(t, 1H), 1.39(bs, 4H).

1-(4-(((6-amino-5-(4-(4-hydroxyphenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1 -yl)prop-2-en-1-one (A94)

1-(4-(((6-amino-5-(4-(4-hydroxyphenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-(4-hydroxyphenoxy)phenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 446 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ )δ9.39(bs, 1H), 8.31(s, 1H), 7.54(t, 1H), 7.06(dd, 2H), 7.00(d, 2H), 6.94(d, 1H), 6.89 (bs, 1H), 6.79 (d, 2H), 6.72 (bs, 1H), 6.08 (dd, 1H), 5.66 (dd, 1H), 4.38 (d, 1H), 4.01 (d, J 1H), 3.21(d, 2H), 2.97(t, 1H), 2.63–2.54(m, 1H), 1.81(bs, 1H), 1.58(d, 2H), 0.96(bs, 2H).

1-(4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin -1-yl)prop-2-en-1-one (A95)

1-(4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-(3-(trifluoromethyl)phenoxy)phenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 498 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ )δ8.36(s, 1H), 7.68(t, 1H), 7.55(d, 1H), 7.50–7.39(m, 2H), 7.29(dd, 4H), 7.08(bs, 1H), 6.93(bs, 2H), 6.78(dd, 1H), 6.07(dd, 1 H), 5.64(dd, 1H), 4.37(d, 1H), 4.01(d, 1H), 3.24(t, 2H), 3.06–2.91(m, 1H), 2.60(t, 1H), 1.83(bs, 1H), 1.62(d, 2H), 0.98(m, 2H).

1-(4-(((6-amino-5-(4-(pyridin-3-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1 -yl)prop-2-en-1-one (A96)

1-(4-(((6-amino-5-(4-(pyridin-3-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-(pyridin-3-yloxy)phenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 431 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ )δ8.99(d,1H),8.68(d,1H),8.39(d,1H),7.69(d,1H),7.49(m,2H),7.42(s, 2H), 7.34(d, 1H), 7.08(bs, 2H), 6.78(dd, J＝16.6, 10.5Hz, 1H), 6.07(dd, J＝16 .7, 2.3Hz, 1H), 5.65 (dd, 1H), 4.70 (t, 1H), 4.38 (d, 1H), 4.02 (d, 1H), 3.26 (t, 2H), 3.09–2.92(m, 2H), 2.59(t, 1H), 1.84(bs, 2H), 1.64(d, 2H), 0.99(m, 2H).

1-(4-(((6-amino-5-(4-(pyridin-4-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1 -yl)prop-2-en-1-one (A97)

1-(4-(((6-amino-5-(4-(pyridin-4-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-(pyridin-4-yloxy)phenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 431 [M+H] ^{. 1} H-NMR (400MHz, DMSO-d ₆ )δ9.20(s, 1H), 8.90(d, 1H), 8.39(s, 1H), 8.18(m, 2H), 7.55–7.36(m, 4H), 7.03(s, 2H), 6.78(dd, 1H), 6.07(dd, 1H), 5.65(dd, 1H), 4.85(t , 2H), 4.38(d, 1H), 4.02(d, 1H), 3.25(t, 2H), 3.14(t, 2H), 3.06–2.94(m, 2H), 2.65–2.54(m, 1H), 1.84(bs, 1H), 1.62(d, 2H), 1.00(m, 2H).

1-(4-(((6-amino-5-(4-(p-phenylmethyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl) prop-2-en-1-one (A98)

1-(4-(((6-amino-5-(4-(p-phenylmethyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-(p-phenylmethyloxy)phenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 444 [M+H] ^{. 1} H-NMR (400MHz, DMSO-d ₆ )δ8.35(s, 1H), 7.25(m, 4H), 7.12(d, 2H), 7.07(bs, 1H), 7.04(t, 2H), 6.93(bs, 1H), 6.78(dd, 1H), 6.07(dd, 1H), 5.64(dd, 1 H), 4.37 (d, 1H), 4.01 (d, 1H), 3.23 (t, 2H), 2.98 (t, 1H), 2.57 (t, 1H), 2.33 (s, 3H), 1.83 (bs, 1H), 1.62 (d, 2H), 0.98 (m, 2H).

1-(4-(((6-amino-5-(4-(cyclohexyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1 -yl)prop-2-en-1-one (A99)

1-(4-(((6-amino-5-(4-(cyclohexyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-(cyclohexyloxy)phenyl)boronic acid, and acryloyl chloride via the four steps of General Scheme 2 using Methods I, C, D, and G. MS: m/z = 436 [M+H] ^{. 1} H-NMR (400MHz, DMSO-d ₆ )δ8.34(s, 1H), 7.13(dd, 4H), 7.00(t, 1H), 6.95–6.83(bs, 2H), 6.78(dd, 1H), 6.07(d, 1H), 5.64(d, 1H), 4.38(bs, 2H), 4. 01 (d, 1H), 3.22 (t, 2H), 2.98 (t, 1H), 2.58 (t, 1H), 1.97 (bs, 2H), 1.91–1.67 (m, 3H), 1.67–1.21 (m, 8H), 1.07–0.86 (m, 2H).

The example compounds of formula (I) were synthesized using Scheme 3 and methods S1-S4D.

N ⁴ -((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-ylmethyl)-5-(4-phenoxyphenyl)pyrimidine-4, 6-diamine hydrochloride (A100)

N ⁴ -((1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-ylmethyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine hydrochloride was synthesized using 5,6-dichloropyrimidin-4-amine, exo-3-Boc-6-aminomethyl-3-azabicyclo[3,1,0]cyclohexane and (4-phenoxyphenyl)boronic acid according to General Scheme 3 using Methods S1, S2 and S3.

(3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-3-ol hydrochloride ( A101)

(3S,4S)-4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-3-ol hydrochloride was synthesized using 5,6-dichloropyrimidin-4-amine, (3S,4S)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate and (4-phenoxyphenyl)boronic acid according to General Scheme 3 using Methods S1, S2 and S3.

(E)-1-(6-((6-amino-5-chloropyrimidin-4-yl)oxy)-2-azaspiro[3.3]hept-2-yl)-4-(dimethylamino )but-2-en-1-one (A102)

(E)-1-(6-((6-Amino-5-chloropyrimidin-4-yl)oxy)-2-azaspiro[3.3]hept-2-yl)-4-(dimethylamino)but-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate, and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride according to General Scheme 3 using Methods S1, S2, S3, and S4A. HPLC purity: 99%. MS: m/z = 352 [M+H] ⁺ . ¹ H NMR (CD ₃ OD) δ 8.03 (s, 1H), 6.71 (m, 1H), 6.47 (t, 1H), 5.23 (m, 1H), 4.41 (d, 2H), 4.16 (d, 2H), 3.96 (m, 2H), 2.91 (m, 6H), 2.81 (m, 2H), 2.42 (m, 2H).

1-(3-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)azetidin-1 -yl)prop-2-en-1-one (A103)

1-(3-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)azetidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 3-(2-aminoethyl)azetidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acrylic acid according to General Scheme 3 using Methods S1, S2, S3, and S4A. HPLC purity: 99%. MS: m/z = 416 [M+H] ⁺ . ¹ H NMR (CD ₃ OD)δ8.27(s,1H),7.12-7.45(m,9H),6.25(m,2H),5.73(d,1H),4.37(t,1H),4. 12 (dd, 1H), 2.94 (dd, 1H), 3.71 (dd, 1H), 3.49 (t, 2H), 2.69 (m, 1H), 1.88 (m, 2H).

1-(3-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)azetidin-1-yl) prop-2-yn-1-one (A104)

1-(3-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)azetidin-1-yl)prop-2-yn-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 3-(2-aminoethyl)azetidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and propionic acid according to General Scheme 3 using Methods S1, S2, S3, and S4A. HPLC purity: 99%. MS: m/z = 414 [M+H] ⁺ . ¹ H NMR (CD ₃ OD) δ 8.27 (s, 1H), 7.14-7.45 (m, 9H), 4.33 (t, 1H), 4.09 (dd, 1H), 3.91 (m, 2H), 3.68 (dd, 1H), 3.49 (t, 2H), 2.69 (m, 1H), 1.87 (m, 2H).

(E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]hept-2- yl)-4-(dimethylamino)but-2-en-1-one (A105)

(E)-1-(6-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]hept-2-yl)-4-(dimethylamino)but-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate, (4-phenoxyphenyl)boronic acid, and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride according to General Scheme 3 using Methods S1, S2, S3, and S4A. HPLC purity: 99%. MS: m/z = 486 [M+H] ⁺ . ¹ H NMR (CD ₃ OD) δ8.28 (s, 1H), 7.18-7.45 (m, 9H), 6.63 (m, 1H), 6.45 (dd, 1H), 5.25 (m, 1H), 4.32(d,2H), 4.13(d,2H), 4.92(t,2H), 3.81(m,6H), 2.74(m,2H), 2.23(m,2H).

1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]hept- 2-yl)prop-2-en-1-one (A106)

1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate, (1-benzyl-1H-pyrazol-4-yl)boronic acid, and acrylic acid according to General Scheme 3 using Methods S1, S2, S3, and S4A. HPLC purity: 95%. MS: m/z = 417 [M+H] ⁺ . ¹ H NMR (CD ₃ OD)δ8.32(s,1H),7.94(s,1H),7.76(s,1H),7.35(m,5H),6.29(m,2H),5.72(m,1H ), 5.43 (s, 2H), 5.29 (m, 1H), 4.34 (d, 2H), 4.10 (d, 2H), 2.77 (m, 2H), 2.34 (m, 2H).

1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]hept- 2-yl)prop-2-en-1-one (A107)

1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate, (1-benzyl-1H-pyrazol-4-yl)boronic acid, and acrylic acid according to General Scheme 3 using Methods S1, S2, S3, and S4A. HPLC purity: 98%. MS: m/z = 416 [M+H] ⁺ . ¹ H NMR (CD ₃ OD) δ8.21 (s, 1H), 7.84 (s, 1H), 7.58 (s, 1H), 7.41 (m, 5H), 6.29 (m, 2H), 5.72 (m, 1H ), 5.43(s, 2H), 4.56(s, 1H), 4.34(d, 2H), 4.10(d, 2H), 2.58(m, 2H), 2.27(m, 2H).

1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]hept-2-yl) but-2-yn-1-one (A108)

1-(6-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]hept-2-yl)but-2-yn-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate, (4-phenoxyphenyl)boronic acid, and but-2-ynoic acid according to General Scheme 3 using Methods S1, S2, S3, and S4A. HPLC purity: 99%. MS: m/z = 440 [M+H] ⁺ . ¹ H NMR (CD ₃ OD) δ 8.24 (s, 1H), 7.16-7.45 (m, 9H), 4.57 (s, 1H), 4.27 (d, 2H), 4.05 (d, 2H), 2.61 (m, 2H), 2.27 (m, 2H), 2.00 (m, 3H).

1-((3S,4S)-4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-3- hydroxypiperidin-1-yl)prop-2-en-1-one (A109)

1-((3S,4S)-4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (3S,4S)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate, (1-benzyl-1H-pyrazol-4-yl)boronic acid, and acrylic acid according to General Scheme 3 using Methods S1, S2, S3, and S4A. HPLC purity: 99%. MS: m/z = 434 [M+H] ⁺ . ¹ H NMR (CD ₃ OD)δ8.22(s,1H),7.84(s,1H),7.60(s,1H),7.40(m,5H),6.76(m,1H),6.21(d,1H),5.74(d,1H),5.43(s,2H),4.5 3 (m, 1H), 4.08 (m, 1H), 3.61 (m, 2H), 3.03 (m, 1H), 2.72 (m, 1H), 1.89 (m, 1H), 1.72 (m, 2H), 1.21 (m, 1H), 1.01 (m, 1H).

1-((3S,4S)-4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-3- hydroxypiperidin-1-yl)prop-2-yn-1-one (A110)

1-((3S,4S)-4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-yn-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (1-benzyl-1H-pyrazol-4-yl)boronic acid, (3S,4S)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate, and propionic acid according to General Scheme 3 using Methods S1, S2, S3, and S4A. HPLC purity: 99%. MS: m/z = 432 [M+H] ⁺ . ¹ H NMR (CD ₃ OD)δ8.22(s,1H),7.84(s,1H),7.69(s,1H),7.40(m,5H),4.43(m,2H),4.01(d,1H),3.62(m,1H ), 3.61 (m, 1H), 3.29 (m, 1H), 3.03 (m, 1H), 2.60 (m, 1H), 1.76 (m, 3H), 1.24 (m, 1H), 1.21 (m, 1H).

1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]hept- 2-yl)prop-2-yn-1-one (A111)

1-(6-((6-Amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]hept-2-yl)prop-2-yn-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (1-benzyl-1H-pyrazol-4-yl)boronic acid, tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate, and propionic acid according to General Scheme 3 using Methods S1, S2, S3, and S4A. HPLC purity: 95%. MS: m/z = 414 [M+H] ⁺ . ¹ H NMR (CD ₃ OD)δ8.21(s,1H),7.83(s,1H),7.57(s,1H),7.41(m,5H),5.42(s,2H),4.5 4(s, 1H), 4.31(d, 2H), 4.08(d, 2H), 3.88(d, 1H), 2.61(m, 2H), 2.30(m, 2H).

1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]hept- 2-yl)prop-2-yn-1-one (A112)

1-(6-((6-Amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]hept-2-yl)prop-2-yn-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (1-benzyl-1H-pyrazol-4-yl)boronic acid, tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate, and propionic acid according to General Scheme 3 using Methods S1, S2, S3, and S4A. HPLC purity: 95%. MS: m/z = 415 [M+H] ⁺ . ¹ H NMR (CD ₃ OD)δ8.26(s,1H),7.94(s,1H),7.74(s,1H),7.35(m,5H),5.42(s,2H),5.2 2(m,1H), 4.31(d,2H), 4.08(d,2H), 3.88(d,1H), 2.76(m,2H), 2.39(m,2H).

1-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]oct-6-yl) prop-2-en-1-one (A113)

1-(2-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]oct-6-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 2-amino-6-azaspiro[3.4]octane-6-carboxylate, (4-phenoxyphenyl)boronic acid, and acrylic acid according to General Scheme 3 using Methods S1, S2, S3, and S4A. HPLC purity: 99%. MS: m/z = 442 [M+H] ⁺ . ¹ H NMR (CD ₃ OD)δ8.25(s,1H),7.16-7.47(m,9H),6.50(m,1H),6.24(m,1H),5.73(m,1H),4.71(m , 1H), 3.60 (t, 1H), 3.52 (m, 2H), 3.41 (s, 1H), 2.34 (m, 1H), 2.11 (m, 3H), 1.97 (m, 1H).

1-(6-((6-amino-5-(4-(pyridin-4-yloxy)phenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3] hept-2-yl)prop-2-en-1-one (A114)

1-(6-((6-amino-5-(4-(pyridin-4-yloxy)phenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate, (4-(pyridin-4-yloxy)phenyl)boronic acid, and acrylic acid according to General Scheme 3 using Methods S1, S2, S3, and S4A. HPLC purity: 99%. MS: m/z = 430 [M+H] ⁺ . H NMR (CD ₃ OD) δ 8.75 (m, 2H), 8.31 (m, 1H), 7.56 (m, 4H), 7.44 (m, 2H), 6.27 (m, 1H), 5.7 3(m, 1H), 5.24(m, 1H), 4.26(d, 2H), 4.01(d, 2H), 2.73(m, 2H), 2.25(m, 2H).

1-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]octan-6-yl) prop-2-yn-1-one (A115)

1-(2-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]oct-6-yl)prop-2-yn-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 2-amino-6-azaspiro[3.4]octane-6-carboxylate, (4-phenoxyphenyl)boronic acid, and propionic acid according to General Scheme 3 using Methods S1, S2, S3, and S4A. HPLC purity: 99%. MS: m/z = 440 [M+H] ⁺ . ¹ H NMR (CD ₃ OD)δ8.01(s,1H),7.12-7.48(m,9H),4.52(t,1H),3.71(t,1H),3.58(s, 1H), 3.50(dd, 1H), 2.33(m, 2H), 2.05(m, 2H), 1.96(m, 2H), 1.47(s, 2H).

1-(6-((6-amino-5-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2 - azaspiro[3.3]hept-2-yl)prop-2-en-1-one (A116)

1-(6-((6-amino-5-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate, (1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)boronic acid, and acrylic acid according to General Scheme 3 using Methods S1, S2, S3, and S4A. HPLC purity: 99%. MS: m/z = 416 [M+H] ⁺ . ¹ H NMR (CD ₃ OD)δ8.77(m,2H),8.23(s,1H),8.00(s,1H),7.88(m,2H),7.68(s,1H),6.26(m,2H ), 5.75(m, 3H), 4.54(m, 1H), 4.27(d, 2H), 4.11(d, 2H), 2.59(m, 2H), 2.26(m, 2H).

N-(1,3-trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide (A117)

N-(1,3-trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, cis-tert-butyl 3-aminocyclobutylcarbamate, (4-phenoxyphenyl)boronic acid, and acrylic acid according to General Scheme 3 using Methods S1, S2, S3, and S4A. HPLC purity: 99%. MS: m/z = 402 [M+H] ⁺ . ¹ H NMR (CD ₃ OD) δ 8.25 (s, 1H), 7.10-7.46 (m, 9H), 6.26 (m, 2H), 5.63 (d, 1H), 4.77 (m, 1H), 4.24 (m, 1H), 2.42 (m, 2H), 2.27 (m, 2H).

N-((1,3-cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide (A118)

N-((1,3-cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide was synthesized from 5,6-dichloropyrimidin-4-amine, tert-butyl trans-3-aminocyclobutylcarbamate, (4-phenoxyphenyl)boronic acid, and acrylic acid according to General Scheme 3 using Methods S1, S2, S3, and S4A. HPLC purity 99%. MS: m/=402 [M+H] ⁺ . ¹ H NMR (CD ₃ OD) δ 8.23 (s, 1H), 7.10-7.46 (m, 9H), 6.26 (m, 2H), 5.60 (d, 1H), 4.31 (m, 1H), 4.03 (m, 1H), 2.76 (m, 2H), 1.98 (m, 2H).

N ⁴ -(2-((2-chloroethyl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-5-(4-phenoxyphenyl)pyrimidine- 4,6-diamine (A119)

N 4 -(2-((2-Chloroethyl)sulfonyl)-2-azaspiro[3.3]hept-6-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine (10.5 mg, 11.2%) was synthesized from 5,6-dichloropyrimidin- ⁴ -amine, tert-butyl 6-amino-2-aza-spiro[3.3]heptane-2-carboxylate, (4-phenoxyphenyl)boronic acid, and 2-chloro-ethanesulfonyl chloride according to General Scheme 3 using Methods S1, S2, S3, and S4C. HPLC purity 95%. MS: m/z = 501 [M+H] ⁺ . ¹ H NMR (CD ₃ OD)δ8.24(s,1H),7.10-7.47(m,9H),6.70(m,1H),6.19(d,1H),6.01(d , 1H), 4.62(m, 1H), 3.58(s, 2H), 3.13(s, 2H), 2.37(m, 2H), 1.81(m, 2H).

1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]hept-2-yl) prop-2-en-1-one (A120)

1-(6-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 6-hydroxy-2-aza-spiro[3.3]heptane-2-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to General Scheme 3 using Methods S1, S2, S3, and S4C. HPLC purity: 99%. MS: m/z = 429 [M+H] ⁺ . ¹ H NMR (CD ₃ OD) δ 8.36 (s, 1H), 7.09-7.45 (m, 9H), 6.25 (m, 2H), 5.74 (m, 1H), 5.28 (m, 1H), 4.33 (d, 2H), 4.09 (d, 2H), 2.74 (m, 2H), 2.32 (m, 2H).

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-methoxypiperidin-1 -yl)prop-2-en-1-one (A121)

1-(4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-methoxypiperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-aminomethyl-4-methoxypiperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to General Scheme 3 using Methods S1, S2, S3, and S4C. HPLC purity: 99%. MS: m/z = 460 [M+H] ⁺ . ¹ H NMR (CD ₃ OD)δ8.28(s,1H),7.13-7.43(m,9H),6.77(m,1H),6.17(d,1H),5.75(d,1H),4.27(d,1H),3 .85 (d, 1H), 3.62 (s, 2H), 3.83 (m, 1H), 3.22 (s, 3H), 3.04 (m, 1H), 1.79 (m, 2H), 1.44 (m, 2H).

N-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)spiro[3.3]hept-2-yl)acrylamide (A122)

N-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)spiro[3.3]hept-2-yl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl (6-aminospiro[3.3]hept-2-yl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to General Scheme 3 using Methods S1, S2, S3, and S4C. HPLC purity: 95%. MS: m/z = 442 [M+H] ⁺ . ¹ H NMR (CD ₃ OD) δ 8.23 (s, 1H), 7.10-7.46 (m, 9H), 6.23 (m, 1H), 5.66 (m, 1H), 4.59 (m, 1H), 3.69 (m, 1H), 3.19 (d, 1H), 2.54 (m, 2H), 2.08-2.34 (m, 6H).

1-(1-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-7-azaspiro[3.5]non-7-yl) prop-2-en-1-one (A123)

1-(1-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-7-azaspiro[3.5]non-7-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 1-amino-7-azaspiro[3.5]nonane-7-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to General Scheme 3 using Methods S1, S2, S3, and S4C. HPLC purity: 99%. MS: m/z = 456 [M+H] ⁺ . ¹ H NMR (CD ₃ OD) δ8.24 (s, 1H), 7.11-7.50 (m, 9H), 6.73 (m, 1H), 6.18 (d, 1H), 5.71 (d, 1H), 4.53 (m, 1H), 4.21 (m, 1H), 3 .83 (m, 1H), 3.18 (m, 1H), 2.95 (m, 1H), 2.27 (m, 2H), 2.06 (m, 1H), 1.86 (m, 2H), 1.68 (m, 3H), 1.37 (m, 1H).

1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]hept-2-yl) prop-2-en-1-one (A124)

1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to General Scheme 3 using Methods S1, S2, S3, and S4. HPLC purity: 99%. MS: m/z = 428 [M+H] ⁺ . ¹ H NMR (CD ₃ OD) δ 8.24 (s, 1H), 7.13-7.50 (m, 9H), 6.25 (m, 2H), 5.71 (m, 1H), 4.59 (m, 1H), 4.35 (d, 2H), 4.11 (d, 2H), 2.61 (m, 2H), 2.29 (m, 2H).

1-(8-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-azaspiro[3.5]non-5-yl) prop-2-en-1-one (A125)

1-(8-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-azaspiro[3.5]non-5-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 8-amino-5-azaspiro[3.5]nonane-5-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to General Scheme 3 using Methods S1, S2, S3, and S4C. HPLC purity: 95%. MS: m/z = 456 [M+H] ⁺ . ¹ H NMR (CD ₃ OD) δ8.28 (s, 1H), 7.15-7.43 (m, 9H), 6.61 (m, 1H), 6.13 (d, 1H), 5.67 (d, 1H), 4.64 (m, 1H), 3.95 (m , 1H), 3.03(m, 1H), 2.66(m, 1H), 2.30(m, 1H), 2.19(m, 2H), 2.07(m, 1H), 1.80(m, 4H), 1.30(m, 1H).

(E)-1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3- hydroxypiperidin -1-yl)-4-(dimethylamino)but-2-en-1-one (A126)

(E)-1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-4-(dimethylamino)but-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (3S,4S)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride according to General Scheme 3 using Methods S1, S2, S3, and S4D. HPLC purity: 99%. MS: m/z = 503 [M+H] ⁺ . ¹ H NMR (CD ₃ OD) δ8.26 (s, 1H), 7.10-7.45 (m, 9H), 6.91 (d, 1H), 6.67 (m, 1H), 4.54 (m, 1H), 4.02 (m, 1H), 3 .97 (m, 2H), 3.74 (m, 1H), 3.51 (m, 1H), 3.00 (m, 1H), 2.62 (m, 1H), 1.76 (m, 2H), 1.23 (m, 1H).

(E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]hept-2- yl)-4-(dimethylamino)but-2-en-1-one (A127)

(E)-1-(6-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]hept-2-yl)-4-(dimethylamino)but-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate, (4-phenoxyphenyl)boronic acid, and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride according to General Scheme 3 using Methods S1, S2, S3, and S4D. HPLC purity: 99%. MS: m/z=485[M+H] ⁺ . ¹ H NMR (CD ₃ OD) δ8.24 (s, 1H), 7.13-7.50 (m, 9H), 6.75 (m, 1H), 6.46 (dd, 1H), 4.59 (m, 1H), 4.35(d,2H), 4.11(d,2H), 3.91(m,2H), 2.82(d,6H), 2.61(m,2H), 2.29(m,2H).

The example compounds represented by formula (I) were synthesized using Scheme 4 and Method AA-GG.

3-((6-Amino-5-chloro-pyrimidin-4-ylamino)-methyl)-benzoic acid methyl ester (A128)

3-((6-Amino-5-chloro-pyrimidin-4-ylamino)-methyl)-benzoic acid methyl ester (59% yield) was synthesized according to Method AA using 3-aminomethyl-benzoic acid methyl ester. MS: m/z = 293 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ ) δ 7.90 (s, 1H), 7.83 (d, 2H), 7.58 (d, 1H), 7.48 (t, 1H), 7.38 (t, 1H), 6.52 (bs, 2H), 4.62 (d, 2H), 3.85 (s, 3H).

trans-3-(6-amino-5-chloro-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester (A129)

trans-3-(6-Amino-5-chloro-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester (53% yield) was synthesized using trans-methyl-3-aminocyclohexanecarboxylate hydrochloride according to Method AA. MS: m/z = 285 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ ) δ 7.86 (s, 1H), 6.46 (bs, 2H), 5.98 (d, 1H), 4.07-3.98 (s, 3H), 2.00-1.43 (bm, 9H).

(1R,3S)-3-(6-Amino-5-chloro-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester (A130)

(1R,3S)-3-(6-Amino-5-chloro-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester (42% yield) was synthesized according to Method AA using (1R,3S)-3-amino-cyclohexanecarboxylic acid methyl ester hydrochloride. MS: m/z = 285 [M+H] ⁺ . ^1H -NMR (DMSO-d ₆ ) δ 7.86 (s, 1H), 6.45 (bs, 2H), 6.24 (d, 1H), 4.05-3.92 (bm, 1H), 3.59 (s, 3H), 2.47-2.41 (bm, 1H), 2.01-2.00 (bm, 1H), 1.83-1.77 (bm, 3H), 1.45-1.17 (bm, 4H).

3-((6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-benzoic acid methyl ester (A131)

3-((6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-benzoic acid methyl ester was synthesized (63% yield) according to Method BB using 3-((6-amino-5-chloro-pyrimidin-4-ylamino)-methyl)-benzoic acid methyl ester. MS: m/z = 427 [M+H] ⁺ . ^1H -NMR (DMSO- _d6 ) δ 7.92 (s, 1H), 7.85 (s, 1H), 7.79 (d, 1H), 7.53 (d, 1H), 7.45-7.40 (m, 3H), 7.29 (d, 2H), 7.19-7.11 (m, 5H), 6.17 (t, 1H), 5.52 (bs, 2H), 4.54 (d, 2H), 3.84 (s, 3H).

trans-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester (A132)

trans-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester was synthesized (63% yield) according to Method BB using trans-3-(6-amino-5-chloro-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester. MS: m/z = 419 [M+H] ⁺ . ^1H -NMR (DMSO-d ₆ ) δ 7.97 (s, 1H), 7.45 (dd, 2H), 7.28 (d, 2H), 7.26 (m, 5H), 5.54 (bs, 1H), 4.60 (d, 1H), 4.11 (bd, 1H), 3.60 (s, 3H), 1.77-1.39 (bm, 9H).

(1R,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester (A133)

(1R,3S)-3-(6-Amino-5-chloro-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester was synthesized according to Method BB (85% yield). MS: m/z = 419 [M+H] ⁺ .

3-((6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-benzoic acid (134)

3-((6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-benzoic acid was synthesized (104% yield) according to Method BB using 3-((6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-benzoic acid methyl ester. MS: m/z = 413 [M+H] ⁺ . ^1H -NMR (DMSO- _d6 ) δ 12.35 (bs, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.77 (d, 1H), 7.49 (d, 1H), 7.44 (dd, 3H), 7.29 (d, 2H), 7.18 (m, 5H), 6.15 (t, 3H), 5.51 (bs, 2H), 4.53 (d, 2H).

(1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid (A135)

(1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid was synthesized (83% yield) according to Method CC using (1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester. MS: m/z = 405 [M+H] ⁺ . ^1H -NMR (DMSO-d ₆ ) δ 12.06 (bs, 1H), 7.97 (s, 1H), 7.44 (t, 2H), 7.28 (d, 2H), 7.19 (m, 5H), 5.54 (bs, 2H), 4.57 (d, 1H), 4.12 (bs, 1H), 2.40 (bs, 1H), 1.77-1.30 (bm, 8H).

(1R,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid (A136)

(1R,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid was synthesized (71% yield) according to Method CC using (1R,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester. MS: m/z = 405 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ )δ11.99(bs, 1H), 8.24(s, 1H), 7.47(t, 2H), 7.26-7.13(bm, 6H), 6.48(bs, 2H), 6.10(bs , 1H), 4.07-4.01(bm, 1H), 2.32-2.26(bm, 1H), 1.84-1.71(bm, 3H), 1.40-1.10(bm, 5H).

(4-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-N-methoxy-N-methyl- acetamide (A137)

(4-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-N-methoxy-N-methyl-acetamide was synthesized according to Method DD (51% yield) using (4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-acetic acid. MS: m/z = 456 [M+H] ⁺ . ^1H -NMR (DMSO- _d6 ) δ 8.05 (s, 1H), 7.45 (t, 4H), 7.34 (d, 2H), 7.19 (s, 1H), 7.16 (d, 5H), 7.09 (d, 2H), 5.76 (bs, 2H), 3.66 (s, 3H), 3.64 (s, 2H), 3.10 (s, 3H).

3-((6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-N-methoxy-N-methyl- benzamide (A138)

3-((6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-N-methoxy-N-methyl-benzamide was synthesized according to Method DD (50% yield) using 3-((6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-benzoic acid. MS: m/z = 456 [M+H] ⁺ . ^1H -NMR (DMSO- _d6 ) δ 7.96 (s, 1H), 7.44 (m, 4H), 7.36 (d, 2H), 7.26 (d, 2H), 7.14 (m, 5H), 6.11 (t, 1H), 5.50 (bs, 1H), 4.52 (d, 2H), 3.50 (s, 3H), 3.23 (s, 3H).

(1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methoxy- methyl -amide (A139)

(1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methoxy-methyl-amide was synthesized according to Method DD (43% yield) using (1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid. MS: m/z = 448 [M+H] ⁺ . ^1H -NMR (DMSO-d ₆ ) δ 7.98 (s, 1H), 7.45 (t, 2H), 7.31 (d, 2H), 7.20 (t, 3H), 7.11 (d, 2H), 5.76 (s, 1H), 5.61 (bs, 2H), 3.50 (s, 3H), 3.04 (s, 3H), 1.74-1.19 (bm, 10H).

(1R,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methoxy- methyl -amide (A140)

(1R,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methoxy-methyl-amide was synthesized according to Method DD (84% yield) using (1R,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid. MS: m/z = 448 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ )δ7.96(s, 4H), 7.45(t, 2H), 7.22-7.09(m, 5H), 5.46(bs, 2H), 3.99(bs, 2H), 3. 68(s, 3H), 3.31(s, 3H), 1.80-1.64(bm, 3H), 1.61(bd, 1H), 1.38-1.09(bm, 4H).

1-(3-((6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-but-2-yn-1- one (A141)

1-(3-((6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-but-2-yn-1-one (13% yield) was synthesized according to Method FF using 3-((6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-N-methoxy-N-methyl-benzamide. MS: m/z = 435 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ )δ8.34(s, 1H), 7.97(t, 2H), 7.60(d, 2H), 7.55(t, 1H), 7.47(t, 2H), 7.34( d, 2H), 7.22 (t, 3H), 7.14 (d, 2H), 7.00 (bs, 2H), 4.46 (d, 2H), 2.20 (s, 3H).

1-(3-((6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-but-2-en-1-one ( A142)

1-(3-((6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-but-2-en-1-one was synthesized according to Procedure EE (20% yield) using 3-((6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-N-methoxy-N-methyl-benzamide. MS: m/z = 437 [M+H] ⁺ . ^1H -NMR (DMSO- _d6 ) δ 8.33 (s, 1H), 7.86 (bt, 2H), 7.56-7.43 (m, 5H), 7.34 (d, 2H), 7.22-7.08 (m, 6H), 7.01 (m, 3H), 4.65 (d, 2H), 1.98 (d, 3H).

1-((1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-propenone (A143)

1-((1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-propenone was synthesized (24% yield) using (1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methoxy-methyl-amide according to Method GG. MS: m/z = 415 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ )δ8.35(s, 1H), 7.47(t, 2H), 7.32(d, 2H), 7.21-7.13(m, 5H), 6.91(bs, 2H), 6.56( dd, 1H), 6.21 (d, 1H), 5.83 (d, 1H), 4.28 (bs, 1H), 3.00 (t, 1H), 1.85-1.38 (bm, 9H).

1-((1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-en- 1-one (A144)

1-((1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-en-1-one was synthesized (35% yield) according to Procedure EE using (1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methoxy-methyl-amide. MS: m/z = 429 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ )δ8.35(s, 1H), 7.47(t, 2H), 7.32(d, 2H), 7.23-7.13(m, 5H), 6.94(bs, 2H), 6.84(m, 1H), 6. 28/6.32(s, 1H), 6.24(bs, 1H), 4.29(bs, 1H), 2.90(t, 1H), 1.87(d, 3H), 1.49-1.35(m, 8H).

1-((1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-yn- 1-one (A145)

1-((1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-yn-1-one was synthesized (44% yield) according to Method FF using (1S,3S)-3-(6-A=amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methoxy-methyl-amide. MS: m/z = 427 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ )δ8.35 (s, 1H), 7.48 (t, 2H), 7.30 (d, 2H), 7.23-7.13 (bm, 5H), 6.91 (bs, 2H), 6.36 (bs, 1H), 4.16 (bs, 1H), 2.75 (t, 1H), 2.08-1.25 (bm, 12H).

1-((1S,3R)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-en- 1-one (A146)

1-((1S,3R)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-en-1-one was synthesized (23% yield) according to Procedure EE using (1S,3R)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methoxy-methyl-amide. MS: m/z = 429 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ )δ8.35(s, 1H), 7.47(t, 2H), 7.47-7.13(m, 6H), 6.90-6.85(bm, 3H), 6, 68(bd, 1H), 6.2 2(ss, 1H), 4.11(bs, 1H), 2.79(bm, 1H), 1.88(d, 3H), 1.74(bs, 4H), 1.46-1.00(bm, 5H).

1-((1S,3R)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-yn- 1-one (A147)

1-((1S,3R)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-yn-1-one was synthesized (31% yield) using (1S,3R)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methoxy-methyl-amide according to Method FF. MS: m/z = 427 [M+H] ⁺ . ¹ H-NMR (DMSO-d ₆ )δ8.35(s, 1H), 7.47(t, 2H), 7.27(d, 2H), 7.22(t, 3H), 7.17(m, 4H), 6.92(bs, 2H), 6.67(d, 1H), 4.0 9(bs, 2H), 2.07(s, 3H), 1.95(bm, 2H), 1.79-1.70(bm, 2H), 1.44-1.25(bm, 3H), 1.08-1.14(bm, 1H).

(S)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en- 1-one (A148)

(S)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC: 100%. MS: m/z = 402 [M+H] ⁺ .

N-(3-((2-amino-3-(4-(benzyloxy)phenyl)pyridin-4-yl)oxy)phenyl)acrylamide (A149)

N-(3-((2-amino-3-(4-(benzyloxy)phenyl)pyridin-4-yl)oxy)phenyl)acrylamide was synthesized using 4-chloro-3-iodopyridin-2-amine, 3-aminophenol, (4-(benzyloxy)phenyl)boronic acid, and acryloyl chloride according to Methods A, C, and F. HPLC: 100%. MS: m/z = 438 [M+H] ⁺ . ¹ H-NMR (DMSO-D6) δ10.36 (s, 1H), 7.92 (d, 1H), 7.64 (s, 1H), 7.47-7.32 (m, 11H), 7.16 (d , 2H), 6.86 (m, 1H), 6.40 (dd, 1H), 6.33 (d, 1H), 6.24 (d, 1H), 5.77 (d, 1H), 5.13 (s, 2H).

1-(3-((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (A150)

1-(3-((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one was synthesized using 5-bromo-4-chloropyrimidin-2-amine, tert-butyl 3-aminopiperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC: 97%. MS: m/z = 416 [M+H] ⁺ .

(E)-N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)-4-(dimethylamino) but-2-enamide (A151)

(E)-N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide was synthesized according to Methods A, C, and E using 4-chloro-3-iodopyridin-2-amine, 3-aminophenol, (4-phenoxyphenyl)boronic acid, and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride. HPLC: 100%. MS: m/z = 481 [M+H] ⁺ . ¹ H-NMR (DMSO-D6) δ10.51 (s, 1H), 9.88 (broad s, 1H), 7.95 (d, 1H), 7.61 (s, 1H), 7.43-7.32 (m, 8H), 7.17 (t, 1H), 7.12-7.08 (m, 4 H), 6.89 (s, 1H), 6.72 (m, 1H), 6.42 (d, 1H), 6.32 (d, 1H), 3.93 (d, 2H), 2.79 (s, 6H).

(E)-N-(3-((2-amino-3-(4-(benzyloxy)phenyl)pyridin-4-yl)oxy)phenyl)-4-(dimethylamino )but-2-enamide (A152)

(E)-N-(3-((2-amino-3-(4-(benzyloxy)phenyl)pyridin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide was synthesized according to Methods A, C, and E using 4-chloro-3-iodopyridin-2-amine, 3-aminophenol, (4-(benzyloxy)phenyl)boronic acid, and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride. HPLC: 100%. MS: m/z = 495 [M+H] ⁺ . ¹ H-NMR (DMSO-D6) δ10.51 (s, 1H), 9.90 (broad s, 1H), 7.92 (d, 1H), 7.59 (s, 1H), 7.47-7.27 (m, 11H), 7.16 (d, 2H), 6.88 (s, 1H) , 6.72(m, 1H), 6.42(d, 1H), 6.30(d, 1H), 5.13(s, 2H), 3.93(d, 2H), 2.79(s, 6H).

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4- (dimethylamino)but-2-en-1-one (A153)

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one was synthesized according to Methods B, C, D, and E using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride. HPLC: 100%. MS: m/z = 487 [M+H] ⁺ .

N-cis-4-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide (A154)

N-cis-4-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl (cis-4-aminocyclohexyl)carbamate, (4-(benzyloxy)phenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC: 99%. MS: m/z = 444 [M+H] ⁺ . ¹ H-NMR (DMSO-D6) δ8.33 (s, 1H), 7.78 (d, 1H), 7.51 (d, 2H), 7.43 (t, 2H), 7.37 (t, 1H), 7.25 (s, 4H), 6.81 (broad s, 2H), 6.27 (dd, 1H), 6.06 (d, 1H), 5.79 (broad s, 1H), 5.55 (d, 1H), 5.16 (s, 2H), 4.00 (s, 1H), 3.81 (s, 1H), 1.56 (s, 8H).

4-(4-(((1-Acryloylpyrrolidin-3-yl)methyl)amino)-6-aminopyrimidin-5-yl)-N- phenylbenzamide (A155)

4-(4-(((1-Acryloylpyrrolidin-3-yl)methyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamide was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate, N-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, and acryloyl chloride according to Methods B, C, D, and F. HPLC: 100%. MS: m/z = 443 [M+H] ⁺ .

1-(3-(((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1 -yl)prop-2-en-1-one (A156)

1-(3-(((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate, (4-(benzyloxy)phenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC: 97%. MS: m/z = 430 [M+H] ⁺ .

4-(4-(((1-Acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamide ( A157)

4-(4-(((1-Acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamide was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, N-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, and acryloyl chloride according to Methods B, C, D, and F. HPLC: 99%. MS: m/z = 457 [M+H] ⁺ .

N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)-4-fluorophenyl)acrylamide (A158)

N-(3-((2-Amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)-4-fluorophenyl)acrylamide was synthesized using 4-chloro-3-iodopyridin-2-amine, 5-amino-2-fluorophenol, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods A, C, and F. HPLC: 100%. MS: m/z = 442 [M+H] ⁺ . ¹ H-NMR (DMSO-D6) δ 10.35 (s, 1H), 7.96 (d, 1H), 7.79 (d, 1H), 7.45-7.38 (m, 6H), 7.21-7.10 (m, 6H), 6.41-6.36 (m, 2H), 6.26 (d, 1H), 5.79 (d, 1H).

4-(4-((cis-4-Acrylamidocyclohexyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamide (A159)

4-(4-((cis-4-Acrylamidocyclohexyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamide was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl (cis-4-aminocyclohexyl)carbamate, N-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, and acryloyl chloride according to Methods B, C, D, and E. HPLC: 100%. MS: m/z = 457 [M+H] ⁺ .

(E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino )but-2-en-1-one (A160)

(E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one was synthesized according to Methods B, C, D, and E using 5,6-dichloropyrimidin-4-amine, tert-butyl 3-aminopiperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride. HPLC: 100%. MS: m/z = 473 [M+H] ⁺ .

N-(3-((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamide (A161)

N-(3-((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 5-amino-2-fluorophenol, 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, and acryloyl chloride according to Methods A, C, and F. HPLC: 100%. MS: m/z = 444 [M+H] ⁺ . ¹ H-NMR (DMSO-D6) δ10.16 (s, 1H), 8.09 (s, 1H), 7.99 (s, 1H), 7.80 (d, 1H), 7.59 (d, 1H), 7.38-7.32 (m, 3H), 7.21-6.91 (m, 5H), 6.70 (broad s, 2H), 6.31 (dd, 1H), 6.18 (d, 1H), 5.69 (d, 1H).

N-(3-((6-amino-5-(4-(pyridin-2-yloxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A162)

N-(3-((6-amino-5-(4-(pyridin-2-yloxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine, and acryloyl chloride according to Methods A, C, and F. HPLC: 100%. MS: m/z = 426 [M+H] ⁺ . ¹ H-NMR (DMSO-D6) δ10.22 (s, 1H), 8.20 (d, 1H), 8.08 (s, 1H), 7.87 (t, 1H), 7.50 (s, 1H), 7.46 (d, 2H), 7.39 (d, 1H), 7.30 (t , 1H), 7.23(d, 2H), 7.16(m, 1H), 7.07(d, 1H), 6.80(d, 1H), 6.58(broads, 2H), 6.41(dd, 1H), 6.25(d, 1H), 5.76(d, 1H).

N-(3-((6-amino-5-(3-sulfamoylphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A163)

N-(3-((6-amino-5-(3-sulfamoylphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide, and acryloyl chloride according to Methods A, C, and F. HPLC: 98%. MS: m/z = 412 [M+H] ⁺ . ¹ H-NMR (DMSO-D6) δ10.17 (s, 1H), 8.04 (s, 1H), 7.79-7.75 (m, 2H), 7.61-7.58 (m, 2H), 7.43 (s, 1H) ), 7.32-7.30(m, 3H), 7.23(t, 1H), 6.77-6.52(m, 3H), 6.34(dd, 1H), 6.18(d, 1H), 5.70(d, 1H).

N-(3-((6-amino-5-(3-(trifluoromethoxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A164)

N-(3-((6-amino-5-(3-(trifluoromethoxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, (3-(trifluoromethoxy)phenyl)boronic acid, and acryloyl chloride according to Methods A, C, and F. HPLC: 100%. MS: m/z = 417 [M+H] ⁺ . ¹ H-NMR (DMSO-D6) δ10.22 (s, 1H), 8.09 (s, 1H), 7.59 (t, 1H), 7.48-7.44 (m, 2H), 7.39-7 .36(m, 3H), 7.28(t, 1H), 6.95-6.55(m, 3H), 6.39(dd, 1H), 6.23(d, 1H), 5.75(d, 1H).

N-(3-((6-amino-5-(6-(2-fluorophenoxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A165)

N-(3-((6-amino-5-(6-(2-fluorophenoxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, 2-(2-fluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, and acryloyl chloride according to Methods A, C, and F. HPLC: 99%. MS: m/z = 444 [M+H] ⁺ . ¹ H-NMR (DMSO-D6) δ10.16 (s, 1H), 8.07 (s, 1H), 8.02 (s, 1H), 7.84 (d, 1H), 7.42 (s, 1 H), 7.32-7.15(m, 7H), 6.86-6.60(m, 3H), 6.34(dd, 1H), 6.18(d, 1H), 5.69(d, 1H).

N-(3-((6-amino-5-(6-(4-fluorophenoxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A166)

N-(3-((6-amino-5-(6-(4-fluorophenoxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, 2-(4-fluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, and acryloyl chloride according to Methods A, C, and F. HPLC: 99%. MS: m/z = 444 [M+H] ⁺ . ¹ H-NMR (DMSO-D6) δ10.17 (s, 1H), 8.09 (d, 1H), 8.03 (s, 1H), 7.82 (d, 1H), 7.43 (s, 1H), 7.30 (d, 1 H), 7.25-7.15(m, 6H), 7.07(d, 1H), 6.92-6.58(m, 3H), 6.34(dd, 1H), 6.18(d, 1H), 5.70(d, 1H).

N-(6-((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyridin-2-yl)acrylamide

MSC2375022(A167)

N-(6-((5-(4-Phenoxyphenyl)pyrimidin-4-yl)amino)pyridin-2-yl)acrylamide was synthesized using 5-bromo-4-chloropyrimidine, pyridine-2,6-diamine, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods H, C, and F. HPLC: 97%. MS: m/z = 410 [M+H] ⁺ . ¹ H-NMR (DMSO-D6) δ10.43 (s, 1H), 8.75 (s, 1H), 8.33 (s, 1H), 8.04 (broads, 1H), 7.85-7.73 (m, 3H), 7.48 (d, 2H), 7.39 (t, 2H), 7.15 (t, 1H), 7.07 (d, 2H), 7.03 (d, 2H), 6.47 (dd, 1H), 6.22 (d, 1H), 5.70 (d, 1H).

1-(4-(((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl) prop-2-en-1 -one (A168)

1-(4-(((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, and acryloyl chloride according to Methods B, C, D, and F. HPLC: 100%. MS: m/z = 431 [M+H] ⁺ .

1-(4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)-4- hydroxypiperidin-1-yl)prop-2-en-1-one (A169)

1-(4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate, (4-(3-(trifluoromethyl)phenoxy)phenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC: 99%. MS: m/z = 514 [M+H] ⁺ . ¹ H NMR (500MHz, dmso) δ7.88 (s, 1H), 7.57 (t, J=7.9Hz, 1H), 7.44 (d, J=7.8Hz, 1H), 7.38 (s, 1H), 7.32 (dd, J=8.2, 2.3Hz, 1H), 7.22 (dd, J=6.5, 4.6Hz, 2H), 7.14 (t, 2H), 6.71(dd, 10.5Hz, 1H), 5.99(dd, 1H), 5.63–5.52(m, 3H), 5.15(t, 1H), 5.09 (s, 1H), 3.94 (d, 1H), 3.66 (d, 1H), 2.96 (t, 1H), 1.40–1.20 (m, 5H), 0.79 (t, 1H).

1-((3S,4S)-4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino) methyl)-3-hydroxypiperidin-1-yl)prop-2-en-1-one (A170)

1-((3S,4S)-4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (3S,4S)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate, (4-(3-trifluoromethyl)phenoxy)phenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC: 100%. MS: m/z = 514 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO) δ7.95 (d, J=5.4Hz, 1H), 7.64 (t, J=8.0Hz, 1H), 7.51 (d, J=7.8Hz, 1H), 7.45 ( s, 1H), 7.38 (dd, 1H), 7.31–7.24 (m, 2H), 7.19 (d, 2H), 6.79–6.69 (m, 1H), 6.06 (d, 1H), 5.69–5. 57(m, 2H), 5.54(s, 2H), 5.39(bs, 1H), 4.41(d, 1H), 4.22(d, 1H), 3.93(t, 1H), 3.49–3.35(m, 2H ), 3.16–2.99(m, 1H), 2.86(dt, 1H), 2.61(t, 1H), 2.34(t, 1H), 1.60(bs, 2H), 1.13–0.96(m, 1H).

1-(4-(((6-amino-2'-phenoxy-[5,5'-bipyrimidinyl]-4-yl)amino)methyl)piperidin-1-yl)prop-2- en-1-one (A171)

1-(4-(((6-amino-2'-phenoxy-[5,5'-bipyrimidinyl]-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine, and acryloyl chloride according to Methods B, C, D, and F. MS: m/z = 432 [M+H] ⁺ . ^1H NMR (400MHz, DMSO) δ8.37 (s, 2H), 7.96 (s, 1H), 7.47 (t, 2H), 7.30–7.20 (m, 3H), 6.76 (dd, 1H), 6.10–5.97 (m, 2H), 5.80 (s, 2H), 5. 62 (dd, 1H), 4.35 (d, 1H), 3.99 (d, 1H), 3.10 (t, 2H), 3.02–2.89 (m, 1H), 2.56 (m, 1H), 1.81 (m, 1H), 1.63 (d, 2H), 1.02–0.83 (m, 2H).

N-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A172)

N-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and acryloyl chloride according to Methods A, C, and F. HPLC: 100%. MS: m/z = 413 [M+H] ⁺ . ¹ H-NMR (DMSO-D6) δ10.18 (s, 1H), 8.08 (s, 1H), 7.98 (s, 1H), 7.66 (s, 1H), 7.45 (s, 1H), 7.33 (t, 1 H), 7.29-7.20(m, 6H), 6.99-6.64(m, 3H), 6.34(dd, 1H), 6.18(d, 1H), 5.70(d, 1H), 5.30(s, 2H).

N-((1S,3R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide (A173)

N-((1S,3R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl (cis-3-aminocyclohexyl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F using chiral separation. HPLC: 95%. MS: m/z = 430 [M+H] ⁺ .

N-((1R,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide (A174)

N-((1R,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl (cis-3-aminocyclohexyl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F using chiral separation. HPLC: 98%. MS: m/z = 430 [M+H] ⁺ .

N-((1R,3R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide (A175)

N-((1R,3R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl (trans-3-aminocyclohexyl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F using chiral separation. HPLC: 98%. MS: m/z = 430 [M+H] ⁺ .

N-((1S,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide (A176)

N-((1S,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide was synthesized from 5,6-dichloropyrimidin-4-amine, (trans-3-aminocyclohexyl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride using Methods B, C, D, and F and chiral separation. HPLC: 97%. MS: m/z = 430 [M+H] ⁺ .

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.1.1]hexan-1-yl)acrylamide ( A177)

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.1.1]hex-1-yl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, benzyl (4-aminobicyclo[2.1.1]hex-1-yl)carbamate hydrochloride, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, hydrogenation, and F. HPLC: 100%. MS: m/z = 428 [M+H] ⁺ . ¹ H-NMR (DMSO-d6) δ8.46 (s, 1H), 8.32 (s, 1H), 7.44 (t, 2H), 7.27-7.12 (m, 8H), 6.85 (broad s, 2H), 6.18 (dd, 1H), 6.04 (d, 1H), 5.54 (d, 1H), 1.99-1.94 (m, 4H), 1.85-1.81 (m, 4H).

(R)-N4-(1-((perfluorophenyl)sulfonyl)pyrrolidin-3-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6- diamine (A178)

(R)-N4-(1-((perfluorophenyl)sulfonyl)pyrrolidin-3-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine was synthesized using 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and 2,3,4,5,6-pentafluorobenzene-1-sulfonyl chloride according to Methods B, C, and D, using pyridine addition in the final step. HPLC: 99%. MS: m/z = 578 [M+H] ⁺ .

(R)-N4-(1-((perfluorophenyl)sulfonyl)piperidin-3-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine (A179)

(R)-N4-(1-((perfluorophenyl)sulfonyl)piperidin-3-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine was synthesized from 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl 3-aminopiperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and 2,3,4,5,6-pentafluorobenzene-1-sulfonyl chloride according to Methods B, C, and D, using pyridine addition in the final step. HPLC: 96%. MS: m/z = 592 [M+H] ⁺ .

(R)-1-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)piperidin-1-yl)prop- 2-en-1-one (A180)

(R)-1-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl 3-aminopiperidine-1-carboxylate, 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and acryloyl chloride according to Methods B, C, D, and F. HPLC: 100%. MS: m/z = 404 [M+H] ⁺ .

N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclopentyl)acrylamide (A181)

N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclopentyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl (cis-3-aminocyclopentyl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC: 98%. MS: m/z = 416 [M+H] ⁺ . ¹ H-NMR (DMSO-d6) δ8.36 (s, 1H), 8.11 (d, 1H), 7.45 (t, 2H), 7.28-7.12 (m, 7H), 7.07-6.82 (m, 3H), 6.15 (dd, 1H), 6.04 (d, 1H), 5.56 (d, 1H), 4.43 (broad s, 1H), 3.96 (sextet, 1H), 2.22 (m, 1H), 1.90-1.80 (m, 2H), 1.68-1.43 (m, 3H).

N-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)cyclobutyl)acrylamide (A182)

N-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)cyclobutyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl (3-(aminomethyl)cyclobutyl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC: 100%. MS: m/z = 416 [M+H] ⁺ .

N-(3-((6-amino-5-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl) acrylamide (A183)

N-(3-((6-amino-5-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, 1-(3,5-difluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and acryloyl chloride according to Methods A, C, and F. HPLC: 100%. MS: m/z = 449 [M+H] ⁺ . ¹ H-NMR (DMSO-d6) δ10.23 (s, 1H), 8.19 (s, 1H), 8.09 (s, 1H), 7.77 (s, 1H), 7.54 (s, 1H), 7.41 (d, 1H), 7.32 (t, 1H), 7.16 (t, 1H), 7.14-6.78 (m, 5H), 6.42 (dd, 1H), 6.25 (d, 1H), 5.76 (d, 1H), 5.42 (s, 2H).

N-(3-((6-amino-5-(1-(2-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl) acrylamide (A184)

N-(3-((6-amino-5-(1-(2-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, 1-(2-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and acryloyl chloride according to Methods A, C, and F. HPLC: 100%. MS: m/z = 431 [M+H] ⁺ . ¹ H-NMR (DMSO-d6) δ10.21 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.73 (s, 1H), 7.50 (s, 1H), 7.4 0-7.17(m, 6H), 6.82-6.65(m, 3H), 6.42(dd, 1H), 6.25(d, 1H), 5.77(d, 1H), 5.43(s, 2H).

1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)azetidin-1-yl)prop-2-en-1- one (A185)

1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)azetidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 3-aminoazetidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, D, and F. HPLC: 100%. MS: m/z = 388 [M+H] ⁺ . ¹ H-NMR (DMSO-d6) δ8.33 (s, 1H), 7.45 (t, 2H), 7.30-7.13 (m, 8H), 6.83 (broad s, 1.5H), 6.28 (dd, 1H), 6.08 (d, 1H), 5.66 (d, 1H), 4.90 (m, 1H), 4.44 (t, 1H), 1.12 (q, 2H), 3.87 (m, 1H).

N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)acrylamide (A186)

N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, pyridine-3,5-diamine, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods J, C, and F. HPLC: 100%. MS: m/z = 425 [M+H] ⁺ .

N-(3-((6-amino-5-(1-(4-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl) acrylamide (A187)

N-(3-((6-amino-5-(1-(4-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, 1-(4-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and acryloyl chloride according to Methods A, C, and F. HPLC: 99%. MS: m/z = 431 [M+H] ⁺ . ¹ H-NMR (DMSO-d6) δ10.22 (s, 1H), 8.14 (s, 1H), 8.04 (s, 1H), 7.73 (s, 1H), 7.52 (s, 1H), 7.39-7.32 (m, 4H), 7.17 (t, 2H), 6.95-6.68 (m, 2.5H), 6.42 (dd, 1H), 6.25 (d, 1H), 5.77 (d, 1H), 5.36 (s, 2H).

N-((1R,3S,5R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-hydroxycyclohexyl )acrylamide (racemate) (A188)

N-((1R,3S,5R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-hydroxycyclohexyl)acrylamide (racemate) was synthesized using 5,6-dichloropyrimidin-4-amine, (1R,3S,5r)-5-((tert-butyldimethylsilyl)oxy)cyclohexane-1,3-diamine dihydrochloride (racemate), (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, deprotection with TBAF, and F. HPLC: 97%. MS: m/z = 446 [M+H] ⁺ .

N-(5-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-3-yl) acrylamide (A189)

N-(5-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-3-yl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 5-aminopyridin-3-ol dihydrochloride, 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and acryloyl chloride according to Methods A, C, and F. HPLC: 77%. MS: m/z = 414 [M+H] ⁺ .

N-(3-((6-amino-5-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide ( A190)

N-(3-((6-amino-5-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, 1-(3-methylbenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and acryloyl chloride according to Methods A, C, and F. HPLC: 100%. MS: m/z = 427 [M+H] ⁺ . ¹ H-NMR (DMSO-d6) δ10.21 (s, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.72 (s, 1H), 7.51 (s, 1H), 7.40 (d, 1H), 7.31 (t, 1H), 7 .22(t, 1H), 7.11(m, 3H), 6.82-6.63(m, 2.7H), 6.42(dd, 1H), 6.25(d, 1H), 5.76(d, 1H), 5.32(s, 2H), 2.27(s, 3H).

N-(3-((6-amino-5-(1-(3-chlorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl) acrylamide (A191)

N-(3-((6-amino-5-(1-(3-chlorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, 1-(3-chlorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and acryloyl chloride according to Methods A, C, and F. HPLC: 99%. MS: m/z = 447 [M+H] ⁺ . ¹ H-NMR (DMSO-d6) δ10.21 (s, 1H), 8.18 (s, 1H), 8.03 (s, 1H), 7.75 (s, 1H), 7.52 (s, 1H), 7.42 -7.26(m, 6H), 6.96-6.65(m, 2.6H), 6.42(dd, 1H), 6.25(d, 1H), 5.76(d, 1H), 5.39(s, 2H).

(R)-1-(2-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)morpholino) prop-2-en-1-one (A192)

(R)-1-(2-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate, 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and acryloyl chloride according to Methods A, C, D, and F. HPLC: 99%. MS: m/z = 421 [M+H] ⁺ .

(S)-1-(2-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)morpholino) prop-2-en-1-one (A193)

(S)-1-(2-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate, 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and acryloyl chloride according to Methods A, C, D, and F. HPLC: 100%. MS: m/z = 421 [M+H] ⁺ .

N-(3-((6-amino-5-(1-(2-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide ( A194)

N-(3-((6-amino-5-(1-(2-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)benzonitrile, and acryloyl chloride according to Methods A, C, and F. HPLC: 96%. MS: m/z = 438 [M+H] ⁺ . ¹ H-NMR (DMSO-d6) δ10.21 (s, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.88 (d, 1H), 7.75 (s, 1H), 7.69 (t, 1H), 7.54-7.29 (m, 5H), 6.81 (d, 1H), 6.66 (broad s, 2H), 6.42 (dd, 1H), 6.25 (d, 1H), 5.77 (d, 1H), 5.59 (s, 2H).

N-(3-((6-amino-5-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy) phenyl )acrylamide (A195)

N-(3-((6-amino-5-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3-(trifluoromethyl)benzyl)-1H-pyrazole, and acryloyl chloride according to Methods A, C, and F. HPLC: 98%. MS: m/z = 481 [M+H] ⁺ . ¹ H-NMR (DMSO-d6) δ10.20 (s, 1H), 8.20 (s, 1H), 8.00 (s, 1H), 7.75-7.29 (m, 8H ), 6.93-6.58(m, 3H), 6.42(dd, 1H), 6.25(d, 1H), 5.77(d, 1H), 5.49(s, 2H).

(R)-1-(3-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)pyrrolidin- 1-yl)prop-2-en-1-one (A196)

(R)-1-(3-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one was synthesized using 5-bromo-6-chloropyrimidin-4-amine, (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate, 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and acryloyl chloride according to Methods A, C, D, and F. HPLC: 99%. MS: m/z = 405 [M+H] ⁺ .

N-(5-((6-amino-5-(4-(4-cyanophenoxy)phenyl)pyrimidin-4-yl)oxy)pyridin-3-yl) acrylamide (A197)

N-(5-((6-amino-5-(4-(4-cyanophenoxy)phenyl)pyrimidin-4-yl)oxy)pyridin-3-yl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 5-aminopyridin-3-ol dihydrochloride, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile, and acryloyl chloride according to Methods A, C, and F. HPLC: 98%. MS: m/z = 452 [M+H] ⁺ . ¹ H-NMR (DMSO-d6) δ10.48 (s, 1H), 8.57 (s, 1H), 8.12-8.09 (m, 2H), 7.97 (t, 1H), 7 .86(d,2H), 7.52(d,2H), 7.23(t,4H), 6.43(dd,1H), 6.29(d,1H), 5.83(d,1H).

N-(3-((6-amino-5-(1-(3-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl) acrylamide (A198)

N-(3-((6-amino-5-(1-(3-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, 1-(3-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and acryloyl chloride according to Methods A, C, and F. HPLC: 99%. MS: m/z = 443 [M+H] ⁺ . ¹ H-NMR (DMSO-d6) δ10.20 (s, 1H), 8.13 (s, 1H), 7.99 (s, 1H), 7.72 (s, 1H), 7.49 (s, 1H), 7.41 (d, 1H), 7.33-7.23 (m, 2H), 6.87-6.79 (m, 4H), 6.63 (broad s, 2H), 6.42 (dd, 1H), 6.25 (d, 1H), 5.76 (d, 1H), 5.33 (s, 2H), 3.70 (s, 3H).

4-(4-(4-((((3S,4S)-1-acryloyl-3-hydroxypiperidin-4-yl)methyl)amino)-6-aminopyrimidin- 5-yl)phenoxy)benzonitrile (A199)

4-(4-(4-((((3S,4S)-1-acryloyl-3-hydroxypiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile (racemate) was synthesized using 5,6-dichloropyrimidin-4-amine, (3S,4S)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (racemate), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile, and acryloyl chloride according to Methods B, C, D, and F. HPLC: 100%. MS: m/z = 471 [M+H] ⁺ .

(R)-4-(4-(4-((4-acryloylmorpholin-2-yl)methoxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile ( A200)

(R)-4-(4-(4-((4-acryloylmorpholin-2-yl)methoxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile was synthesized using 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile, and acryloyl chloride according to Methods A, C, D, and F. HPLC: 99%. MS: m/z = 458 [M+H] ⁺ .

(R)-4-(4-(4-((1-acryloylpyrrolidin-3-yl)methoxy)-6-aminopyrimidin-5-yl)phenoxy) benzonitrile (A201)

(R)-4-(4-(4-((1-acryloylpyrrolidin-3-yl)methoxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile was synthesized using 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile, and acryloyl chloride according to Methods A, C, D, and F. HPLC: 99%. MS: m/z = 442 [M+H] ⁺ .

4-(4-(4-((2-acryloyl-2-azaspiro[3.3]hept-6-yl)oxy)-6-aminopyrimidin-5-yl)phenoxy )benzonitrile (A202)

4-(4-(4-((2-Acryloyl-2-azaspiro[3.3]hept-6-yl)oxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile, and acryloyl chloride according to Methods A, C, D, and F. HPLC: 100%. MS: m/z = 454 [M+H] ⁺ .

N-(3-((6-amino-5-(1-(3-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide ( A203)

N-(3-((6-amino-5-(1-(3-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, 3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)benzonitrile, and acryloyl chloride according to Methods A, C, and F. HPLC: 100%. MS: m/z = 438 [M+H] ⁺ . ¹ H-NMR (DMSO-d6) δ10.20 (s, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 7.79-7.74 (m, 3H), 7.65-7.50 (m, 3H), 7.41 (d, 1H), 7.31 (t, 1H), 6.81 (d, 1H), 6.69 (broad s, 2H), 6.42 (dd, 1H), 6.25 (d, 1H), 5.77 (d, 1H), 5.44 (s, 2H).

1-((3S,5S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-fluoropiperidin-1-yl) prop-2-en-1-one (A204)

1-((3S,5S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-fluoropiperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (3S,5S)-5-fluoro-1-(4-methoxybenzyl)piperidin-3-amine, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, hydrogenation, and F. HPLC: 97%. MS: m/z = 434 [M+H] ⁺ .

1-((3R,5R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-fluoropiperidin-1-yl) prop-2-en-1-one (A205)

1-((3R,5R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-fluoropiperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (3R,5R)-5-fluoro-1-(4-methoxybenzyl)piperidin-3-amine, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, hydrogenation, and F. HPLC: 99%. MS: m/z = 434 [M+H] ⁺ .

Methyl 3-((4-(4-(3-acrylamidophenoxy)-6-aminopyrimidin-5-yl)-1H-pyrazol-1-yl)methyl) benzoate (A206)

Methyl 3-((4-(4-(3-acrylamidophenoxy)-6-aminopyrimidin-5-yl)-1H-pyrazol-1-yl)methyl)benzoate was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, methyl 3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)benzoate, and acryloyl chloride according to Methods A, C, and F. HPLC: 94%. MS: m/z = 471 [M+H] ⁺ . ¹ H-NMR (DMSO-d6) δ10.20 (s, 1H), 8.18 (s, 1H), 7.99 (s, 1H), 7.94 (s, 1H), 7.89 (d, 1H), 7.74 ( s, 1H), 7.59 (d, 1H), 7.53-7.49 (m, 2H), 7.41 (d, 1H), 7.31 (t, 1H), 6.81 (d, 1H), 6.65 (broad s, 2H), 6.42 (dd, 1H), 6.25 (d, 1H), 5.77 (d, 1H), 5.46 (s, 2H), 3.83 (s, 3H).

4-(4-(4-((2-Acryloyl-2-azaspiro[3.3]hept-6-yl)amino)-6-aminopyrimidin-5-yl)phenoxy )benzonitrile (A207)

4-(4-(4-((2-Acryloyl-2-azaspiro[3.3]hept-6-yl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile, and acryloyl chloride according to Methods B, C, D, and E. HPLC: 98%. MS: m/z = 453 [M+H] ⁺ . ¹ H-NMR (DMSO-d6) δ7.96 (s, 1H), 7.87 (d, 2H), 7.29-7.23 (m, 6H), 6.31-6.22 (m, 1H), 6.07 (d, 1H), 5.67-5.46 (m , 4H), 4.40(q, 1H), 4.25(s, 1H), 4.08(s, 1H), 3.96(s, 1H), 3.79(s, 1H), 2.47-2.40(m, 2H), 2.14-2.09(m, 2H).

4-(4-(4-(((8-Acryloyl-8-azabicyclo[3.2.1]oct-3-yl)methyl)amino)-6-aminopyrimidin- 5-yl)phenoxy)benzonitrile (A208)

4-(4-(4-(((8-Acryloyl-8-azabicyclo[3.2.1]oct-3-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile was synthesized using 5-bromo-6-chloropyrimidin-4-amine, tert-butyl 3-(aminomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile, and acryloyl chloride according to Methods B, C, D, and F. HPLC: 98%. MS: m/z = 481 [M+H] ⁺ .

1-(3-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo [3.2.1]oct-8-yl)prop-2-en-1-one (A209)

1-(3-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one was synthesized using 5-bromo-6-chloropyrimidin-4-amine, tert-butyl 3-(aminomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate, 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and acryloyl chloride according to Methods B, C, D, and F. HPLC: 99%. MS: m/z = 444 [M+H] ⁺ .

1-((3R,4R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-4-hydroxypiperidin-1- yl)prop-2-en-1-one (racemate) (A210)

1-((3R,4R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-4-hydroxypiperidin-1-yl)prop-2-en-1-one (racemate) was synthesized using 5,6-dichloropyrimidin-4-amine, (3R,4R)-benzyl 3-amino-4-hydroxypiperidine-1-carboxylate (racemate), (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Methods B, C, hydrogenation, and F. HPLC: 100%. MS: m/z = 432 [M+H] ⁺ .

N-(3-((6-amino-5-(1-(3-(methylsulfonyl)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy) phenyl)acrylamide (A211)

N-(3-((6-amino-5-(1-(3-(methylsulfonyl)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, 1-(3-(methylsulfonyl)benzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and acryloyl chloride according to Methods A, C, and F. HPLC: 83%. MS: m/z = 456 [M+H] ⁺ .

N-(3-((6-amino-5-(1-(3-(dimethylamino)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy) phenyl)acrylamide (A212)

N-(3-((6-amino-5-(1-(3-(dimethylamino)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, N,N-dimethyl-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)aniline, and acryloyl chloride according to Methods A, C, and F. HPLC: 100%. MS: m/z = 456 [M+H] ⁺ . ¹ H-NMR (DMSO-d6) δ10.20 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.71 (s, 1H), 7.49 (s, 1H), 7.41 (d, 1H), 7.31 (t, 1H), 7.12 (t, 1H), 6.80 (d, 1H), 6.64-6.56 (m, 5H), 6.42 (dd, 1H), 6.25 (d, 1H), 5.76 (d, 1H), 5.28 (s, 2H), 2.83 (s, 6H).

N-(3-((6-amino-5-(4-(3-cyanophenoxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A213)

N-(3-((6-amino-5-(4-(3-cyanophenoxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, 3-aminophenol, 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile, and acryloyl chloride according to Methods A, C, and F. HPLC: 98%. MS: m/z = 450 [M+H] ⁺ . ¹ H-NMR (DMSO-d6) δ10.21 (s, 1H), 8.07 (s, 0.5H), 7.61-7.57 (m, 3.5H), 7.49-7 .43(m, 4H), 7.38(d, 1H), 7.30(t, 1H), 7.19(d, 2H), 6.79(d, 1H), 6.57(broad s, 1.5H), 6.41 (dd, 1H), 6.25 (d, 1H), 5.76 (d, 1H).

3-(4-(4-(((1-acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile ( A214)

3-(4-(4-(((1-acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile, and acryloyl chloride according to Methods B, C, D, and F. HPLC: 100%. MS: m/z = 455 [M+H] ⁺ . ¹ H-NMR (DMSO-d6) δ7.96 (s, 1H), 7.63-7.56 (m, 3H), 7.50-7.45 (m, 1H), 7.29-7.19 (m, 4H), 6.78 (dd, 1H), 6.06 (d, 1H), 5.63 (d, 1H), 5.58- 5.42 (m, 3H), 4.36 (d, 1H), 4.00 (d, 1H), 3.15 (t, 2H), 2.96 (t, 1H), 2.58 (t, 1H), 1.90-1.78 (m, 1H), 1.69-1.55 (m, 2H), 1.04-0.87 (m, 2H).

1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin -1-yl)but-2-yn-1-one (A215)

1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)but-2-yn-1-one was synthesized in 41.3% yield using 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, (3S,4S)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate, and but-2-ynoic acid according to Methods S1, S2, S3, and S4A. ¹ HNMR (CD ₃ OD) δ8.26 (s, 1H), 7.14-7.40 (m, 9H), 4.28-4.48 (m, 2H), 3.66 (m, 1H), 3.5 2(m,1H), 3.01(m,1H), 2.60(m,1H), 2.0(m,3H), 1.75(m,2H), 1.20(m,1H). HPLC purity: 99%, MS: m/z=458[M+H]+.

1-Acryloyl-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidine-4- carboxylic acid (A216)

1-Acryloyl-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidine-4-carboxylic acid was synthesized in 35.9% yield using 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, 4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylate, and acrylic acid according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD) δ8.26 (s, 1H), 7.14-7.40 (m, 9H), 6.73 (m, 1H), 6.21 (d, 1H), 5.73 (d, 1H), 4 .25(d,1H), 3.89(d,1H), 3.73(s,2H), 3.02(t,1H), 2.08(t,2H), 1.45(m,2H). HPLC purity: 94%, MS: m/z=474[M+H]+.

(E)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-1-(4-( dimethylamino )but-2-enoyl)piperidine-4-carboxylic acid (A217)

(E)-4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-1-(4-(dimethylamino)but-2-enoyl)piperidine-4-carboxylic acid was synthesized using 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, 4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylate, and (E)-4-(dimethylamino)but-2-enoyl hydrochloride in 15.6% yield according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD) δ8.26 (s, 1H), 7.14-7.40 (m, 9H), 6.94 (d, 1H), 6.66 (m, 1H), 4.25 (d, 1H), 3 .97(m, 3H), 3.73(s, 2H), 3.31(m, 1H), 3.08(t, 1H), 2.08(t, 2H), 1.49(m, 2H). HPLC purity: 94%, MS: m/z=531[M+H]+.

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4- (3-fluoroazetidin-1-yl)but-2-en-1-one (A218)

(E)-1-(4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(3-fluoroazetidin-1-yl)but-2-ene-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, and (E)-4-(3-fluoroazetidin-1-yl)but-2-enoic acid in 6.0% yield according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD)δ8.04(s,1H),7.19-7.47(m,9H),6.57(m,2H),5.22(m,1H),4.50(d,1H),4.10(d,1H),3 .79 (m, 2H), 3.50 (m, 3H), 3.13 (m, 1H), 2.63 (t, 1H), 1.87 (m, 1H), 1.76 (t, 2H), 1.15 (m, 2H). HPLC purity: 99%, MS: m/z=517[M+H]+.

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4- (3,3-difluoroazetidin-1-yl)but-2-en-1-one (A219)

(E)-1-(4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(3,3-difluoroazetidin-1-yl)but-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, and (E)-4-(3,3-difluoroazetidin-1-yl)but-2-enoic acid in 19.3% yield according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD) δ8.26 (s, 1H), 7.19-7.47 (m, 9H), 6.78 (d, 1H), 6.14 (m, 1H), 4.50 (d, 1H), 4.41 (t, 3H), 4.09 (d , 1H), 3.89(d, 1H), 3.38(m, 2H), 3.13(m, 1H), 2.72(t, 1H), 1.91(m, 1H), 1.76(t, 2H), 1.28(m, 2H). HPLC purity: 99%, MS: m/z=535[M+H]+.

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4- (pyrrolidin-1-yl)but-2-en-1-one (A220)

(E)-1-(4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(pyrrolidin-1-yl)but-2-ene-1-one was synthesized in 9.1% yield using 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, and (E)-4-(pyrrolidin-1-yl)but-2-ene according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD)δ8.31(m,2H),7.19-7.47(m,9H),6.92(d,1H),6.63(m,1H),4.54(d,1H),4.07(d,1H),4.01(d , 2H), 3.64(s, 1H), 3.12(t, 2H), 2.75(t, 1H), 2.20(s, 1H), 2.03(s, 1H), 1.75(t, 2H), 1.11(t, 2H). HPLC purity: 91%, MS: m/z=513[M+H]+.

1-(6-((6-amino-5-(4-(pyridin-3-yloxy)phenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3] hept-2-yl)prop-2-en-1-one (A221)

1-(6-((6-amino-5-(4-(pyridin-3-yloxy)phenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, (4-(pyridin-3-yloxy)phenyl)boronic acid, tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate, and acrylic acid in 21.2% yield according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD)δ8.31(m,2H),8.13(s,1H),7.52(m,1H),6.97(m,1H),7.41(d,2H),7.19(m,2H),6.2 5(m,2H), 5.75(m,1H), 5.24(m,1H), 4.21(d,2H), 4.03(d,2H), 2.72(m,2H), 2.25(m,2H). HPLC purity: 99%, MS: m/z=430[M+H]+.

(E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]hept-2- yl)-4-(3-fluoroazetidin-1-yl)but-2-en-1-one (A222)

(E)-1-(6-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]hept-2-yl)-4-(3-fluoroazetidin-1-yl)but-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate, and (E)-4-(3-fluoroazetidin-1-yl)but-2-enoic acid in 1.7% yield according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD)δ8.28(s,1H),7.10-7.47(m,9H),6.62(m,1H),6.40(t,1H),5.41(m , 1H), 5.25(m, 1H), 4.27(d, 2H), 4.04(m, 4H), 2.74(m, 2H), 2.27(m, 2H). HPLC purity: 99%, MS: m/z=516[M+H]+.

(E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]hept-2- yl)-4-(3,3-difluoroazetidin-1-yl)but-2-en-1-one (A223)

(E)-1-(6-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]hept-2-yl)-4-(3,3-difluoroazetidin-1-yl)but-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate, and (E)-4-(3,3-difluoroazetidin-1-yl)but-2-enoic acid in 2.7% yield according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD) δ8.31 (s, 1H), 7.10-7.47 (m, 9H), 6.60 (m, 1H), 6.40 (t, 1H), 5.25 (m, 1H), 4 .54(qt, 4H), 4.27(d, 2H), 4.08(s, 1H), 4.00(m, 3H), 2.74(m, 2H), 2.27(m, 2H). HPLC purity: 95%, MS: m/z=534[M+H]+.

(E)-N-(1,3-cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-( dimethylamino)but-2-enamide (A224)

(E)-N-(1,3-cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamide was synthesized in 19.4% yield using 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, tert-butyl (1,3-cis-3-aminocyclobutyl)carbamate, and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD) δ8.31 (s, 1H), 7.10-7.47 (m, 9H), 6.60 (m, 1H), 6.40 (t, 1H), 5.25 (m, 1H), 4.54 (qt, 4H), 4.2 7 (d, 2H), 4.08 (s, 1H), 4.00 (m, 6H), 2.74 (m, 2H), 2.27 (m, 2H) HPLC. Purity: 99%, MS: m/z=459[M+H]+.

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop -2-en- 1-one (A225)

1-(4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate, and acrylic acid in 16.1% yield according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD) δ8.26 (s, 1H), 7.14-7.40 (m, 9H), 6.73 (m, 1H), 6.24 (d, 1H), 5.73 (d, 1H), 4.41 (d , 1H), 4.00(d, 1H), 3.74(d, 2H), 3.44(m, 1H), 3.02(t, 1H), 1.73(m, 2H), 1.61(m, 2H). HPLC purity: 94%, MS: m/z=448[M+H]+.

(E)-1-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]oct-6- yl)-4-(dimethylamino)but-2-en-1-one (A226)

(E)-1-(2-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]oct-6-yl)-4-(dimethylamino)but-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, tert-butyl 2-amino-6-azaspiro[3.4]octane-6-carboxylate, and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride in 5.4% yield according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD)δ8.31(s,1H),7.10-7.47(m,9H),6.75(m,2H),3.97(m,2H),3.65(m,1H),3.50(m , 1H), 2.92(m, 6H), 2.38(m, 2H), 2.12(m, 2H), 2.0(t, 1H), 1.80(m, 2H), 1.62(m, 2H). HPLC purity: 98%, MS: m/z=499[M+H]+.

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1- yl)-4-(dimethylamino)but-2-en-1-one (A227)

(E)-1-(4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)-4-(dimethylamino)but-2-ene-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate, and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride in 15.9% yield according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD) δ8.26 (s, 1H), 7.14-7.40 (m, 9H), 6.93 (d, 1H), 6.74 (m, 1H), 4.47 (d, 1H), 3.98 (m , 3H), 3.75(d, 2H), 3.41(t, 1H), 3.03(t, 1H), 2.97(m, 6H), 1.81(m, 2H), 1.62(m, 2H). HPLC purity: 99%, MS: m/z=505[M+H]+.

(E)-N-(1,3-trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-( dimethylamino)but-2-enamide (A228)

(E)-N-((1,3-trans)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamide was synthesized in 23.6% yield using 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, tert-butyl (1,3-trans-3-aminocyclobutyl)carbamate, and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD)δ8.25(s,1H),7.10-7.47(m,9H),6.73(m,1H),6.40(d,1H),4.26(m,1H),3.9 2(m, 2H), 2.96 (s, 6H), 1.79 (m, 2H), 1.67 (m, 2H) HPLC purity: 99%, MS: m/z=459[M+H]+.

N-(1,3-cis-3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide (A229)

N-(1,3-cis-3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide was synthesized in 8.2% yield using 5,6-dichloropyrimidin-4-amine, (1-benzyl-1H-pyrazol-4-yl)boronic acid, tert-butyl (1,3-cis-3-aminocyclobutyl)carbamate, and acrylic acid according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD)δ8.25(s,1H),7.80(s,1H),7.59(s,1H),7.38(m,5H),6.24(m,2H),5.6 1(d, 1H), 5.45(s, 2H), 4.37(m, 1H), 4.03(m, 1H), 2.74(m, 2H), 2.02(m, 2H). HPLC purity: 95%, MS: m/z=390[M+H]+.

(E)-N-(1,3-cis-3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino) cyclobutyl )-4-(dimethylamino)but-2-enamide (A230)

(E)-N-(1,3-cis-3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamide was synthesized in 31.2% yield using 6-dichloropyrimidin-4-amine, (1-benzyl-1H-pyrazol-4-yl)boronic acid, tert-butyl (1,3-cis-3-aminocyclobutyl)carbamate, and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD)δ7.95(s,1H),7.77(s,1H),7.38(m,5H),6.74(m,1H),6.01(d,1H),5.4 5(s, 2H), 4.25(m, 1H), 4.08(m, 1H), 3.09(d, 2H), 2.74(m, 2H), 2.27(m, 2H). HPLC purity: 91%, MS: m/z=447[M+H]+.

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-3 -phenylprop-2-en-1-one (A231)

(E)-1-(4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-3-phenylprop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, and cinnamic acid in 45.4% yield according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD)δ8.04(s,1H),7.19-7.47(m,14H),4.55(d,1H),4.25(d,1H),3.42(d , 2H), 3.14(t, 1H), 2.75(t, 1H), 2.00(m, 1H), 1.76(t, 2H), 1.15(m, 2H). HPLC purity: 98%, MS: m/z=506[M+H]+.

1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin -1-yl)-3-(dimethylamino)propan-1-one (A232)

1-((3S,4S)-4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-(dimethylamino)propan-1-one was synthesized in 17.3% yield using 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, (3S,4S)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate, and 3-(dimethylamino)propionic acid according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD) δ8.26 (s, 1H), 7.14-7.40 (m, 9H), 4.48 (dd, 1H), 3.89 (m, 1H), 3.66 (m, 1H), 3.28 (m , 1H), 3.01(m, 1H), 2.61(m, 4H), 2.44(t, 1H), 2.25(s, 6H), 1.75(m, 2H), 1.20(m, 1H). HPLC purity: 92%, MS: m/z=491[M+H]+.

1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin -1-yl)-3-(piperidin-1-yl)propan-1-one (A233)

1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-(piperidin-1-yl)propan-1-one was synthesized in 24.2% yield using 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, (3S,4S)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate, and 3-(piperidin-1-yl)propionic acid according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD) δ8.26 (s, 1H), 7.14-7.40 (m, 9H), 4.48 (dd, 1H), 3.89 (t, 1H), 3.67 (t, 1H), 3.2 8(m, 1H), 3.00(m, 1H), 2.31-2.61(m, 8H), 1.75(m, 5H), 1.49(s, 2H), 1.20(m, 1H). HPLC purity: 99%, MS: m/z=530[M+H]+.

1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin -1-yl)-3-morpholinopropan-1-one (A234)

1-((3S,4S)-4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-morpholinopropan-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, (3S,4S)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate, and 3-morpholinopropionic acid in 30.5% yield according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD) δ8.26 (s, 1H), 7.14-7.40 (m, 9H), 4.48 (dd, 1H), 3.88 (t, 1H), 3.66 (m, 5 H), 3.28 (m, 1H), 3.00 (m, 1H), 2.33-2.61 (m, 9H), 1.49 (s, 2H), 1.20 (m, 1H). HPLC purity: 99%, MS: m/z=533[M+H]+.

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)-3- (piperidin-1-yl)propan-1-one (A235)

1-(4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)-3-(piperidin-1-yl)propan-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate, and 3-(piperidin-1-yl)propanoic acid in 23.4% yield according to Methods S1, S2, S3, and S4A. ¹ H NMR (CD ₃ OD) δ8.26 (s, 1H), 7.14-7.40 (m, 9H), 4.29 (d, 1H), 3.80 (d, 1H), 3.62 (dd, 2 H), 3.00 (m, 1H), 2.60-2.77 (m, 7H), 1.78 (m, 2H), 1.69 (m, 5H), 1.52 (m, 2H). HPLC purity: 99%, MS: m/z=533[M+H]+.

(E)-N-(1,3-cis-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl) amino )cyclobutyl)-4-(dimethylamino)but-2-enamide (A236)

(E)-N-(1,3-cis-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamide was synthesized using 5,6-dichloropyrimidin-4-amine, (4-(3-(trifluoromethyl)phenoxy)phenyl)boronic acid, tert-butyl (1,3-cis-3-aminocyclobutyl)carbamate, and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride in 17.1% yield according to Methods S1, S2, S3, and S4A. ¹ H NMR (CDCl ₃ )δ8.26 (s, 1H), 7.18-7.53 (m, 8H), 6.74 (m, 1H), 6.49 (m, 1H), 4.58 (m, 2H), 4.26 (m, 1H), 4.13 (m, 1H), 3.58 (m, 2H), 2.69 (m, 6H), 1.74 (m, 2H). HPLC purity: 99%, MS: m/z=527[M+H]+.

N-(1,3-trans-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl )acrylamide (A237)

N-(1,3-trans-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide was synthesized in 22.8% yield using 5,6-dichloropyrimidin-4-amine, (4-(3-(trifluoromethyl)phenoxy)phenyl)boronic acid, tert-butyl (1,3-trans-3-aminocyclobutyl)carbamate, and acrylic acid according to Methods S1, S2, S3, and S4A. ¹ H NMR (CDCl ₃ ) δ 8.26 (s, 1H), 7.18-7.53 (m, 8H), 6.74 (d, 1H), 6.27 (m, 1H), 5.71 (d, 1H), 5.25 (m, 1H), 4.50 (m, 1H), 2.50 (m, 2H), 2.28 (m, 2H). HPLC purity: 99%, MS: m/z=470 [M+H] + .

N-(1,3-cis-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl )acrylamide (A238)

N-(1,3-cis-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide was synthesized using 5,6-dichloropyrimidin-4-amine, (4-(3-(trifluoromethyl)phenoxy)phenyl)boronic acid, tert-butyl (1,3-cis-3-aminocyclobutyl)carbamate, and propylene according to Methods S1, S2, S3, and S4A in 22.1% yield. ^1H NMR (CDCl ₃ ) δ 8.23 (s, 1H), 7.18-7.53 (m, 8H), 6.25 (d, 1H), 6.04 (m, 1H), 5.66 (d, 1H), 4.42 (m, 1H), 4.03 (m, 1H), 2.81 (m, 2H), 2.02 (m, 2H). HPLC purity: 98%, MS: m/z=470 [M+H]+.

1-Acryloyl-4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino) methyl)piperidine-4-carboxylic acid (A239)

1-Acryloyl-4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidine-4-carboxylic acid was synthesized in 11.2% yield using 5,6-dichloropyrimidin-4-amine, (4-(3-(trifluoromethyl)phenoxy)phenyl)boronic acid, 4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid, and acrylic acid according to Methods S1, S2, S3, and S4A. ¹ H NMR (DMSO-d ₆ )δ8.31(s, 1H), 7.25-7.75(m, 8H), 7.03(br., 2H), 6.77(m, 1H), 6.62(s, 1H), 6.04(d , 1H), 5.60 (d, 1H), 4.12 (m, 1H), 3.83 (m, 1H), 2.75 (m, 1H), 1.91 (m, 2H), 1.28 (m, 2H). HPLC purity: 98%, MS: m/z=542[M+H]+.

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-fluorophenyl)acrylamide (A240)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-fluorophenyl)acrylamide (82% yield) was synthesized according to Method F using 6-(3-amino-2-fluorophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine. HPLC: 99%, RT = 4.434 min. MS: m/z = 433 [M+H] ⁺ , RT = 2.36 min. ¹ H-NMR (DMSO-d ₆ ) δ 10.02 (s, 1H), 8.04 (s, 1H), 7.80 (t, 1H), 7.43-7.38 (m, 4H), 7.15 (q, 2H), 7.15 (q, 2H), 7.09 (d, 4H), 7.03 (t, 1H), 6.69 (broad s, 1.5H), 6.57 (dd, 1H), 6.26 (d, 1H), 5.77 (d, 1H).

N-(3-(4-amino-6-((4-phenoxyphenyl)amino)pyrimidin-5-yl)phenyl)acrylamide (A241)

N-(3-(4-amino-6-((4-phenoxyphenyl)amino)pyrimidin-5-yl)phenyl)acrylamide (21% yield) was synthesized using 5-(3-aminophenyl)-N-(4-phenoxyphenyl)pyrimidine-4,6-diamine according to Method E. HPLC: 98%, RT = 3.975 min. MS: m/z = 424 [M+H] ⁺ , RT = 2.51 min. ¹ H-NMR (DMSO-d ₆ )δ10.26(s, 1H), 8.42(s, 1H), 8.20(s, 1H), 7.77(d, 1H), 7.60)s, 1H), 7.45(t, 1H), 7.32(t, 2H), 7 .25 (d, 2H), 7.06 (t, 1H), 7.00 (d, 1H), 6.92-6.88 (m, 5H), 6.40 (dd, 1H), 6.21 (d, 1H), 5.71 (d, 1H).

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A242)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (20% yield) was synthesized using 6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine according to Method E. HPLC: 97%, RT = 4.264 min. MS: m/z = 425 [M+H] ⁺ , RT = 4.22 min. ¹ H-NMR (DMSO-d ₆ )δ10.14 (s, 1H), 8.00 (s, 1H), 7.41 (s, 1H), 7.36-7.30 (m, 5H), 7.22 (t, 1H), 7.09 (t, 1H), 7.03-7.01 (m, 4H), 6.71 (d, 1H), 6.53 (broad s, 2H), 6.34 (dd, 1H), 6.18 (d, 1H), 5.69 (d, 1H).

N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide (A243)

N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide (56% yield) was synthesized using 3-(3-aminophenyl)-4-(4-phenoxyphenoxy)pyridin-2-amine according to Method F. HPLC: 99%, RT = 4.196 min. MS: m/z = 424 [M+H] ⁺ , RT = 2.09 min. ¹ H-NMR (DMSO-d ₆ )δ10.24(s, 1H), 7.89(d, 1H), 7.75(s, 1H), 7.65(d, 1H), 7.43(t, 1H), 7.33(t, 2H), 7.15-7. 08(m, 6H), 7.02(d, 2H), 6.96(d, 2H), 6.40(dd, 1H), 6.30(d, 1H), 6.20(d, 1H), 5.71(d, 1H).

N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide (A244)

N-(3-((2-Amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide (52% yield) was synthesized using 4-(3-aminophenoxy)-3-(4-phenoxyphenyl)pyridin-2-amine according to Method F. HPLC: 99%, RT = 4.182 min. MS: m/z = 424 [M+H] ⁺ , RT = 2.08 min. ¹ H-NMR (DMSO-d ₆ )δ10.35(s, 1H), 7.93(d, 1H), 7.65(s, 1H), 7.43-7.37(m, 6H), 7.28(s, 2H), 7.18(t, 1H) , 7.12-7.08(m, 4H), 6.86(d, 1H), 6.40(dd, 1H), 6.33(d, 1H), 6.24(d, 1H), 5.77(d, 1H).

N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)acrylamide (A245)

N-(3-(4-Amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)acrylamide (24% yield) was synthesized according to Method E using 5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine. HPLC: 94%, RT = 4.298 min. MS: m/z = 425 [M+H] ⁺ , RT = 2.16 min. ^1H -NMR (DMSO-d ₆ ) δ 10.10 (s, 1H), 8.08 (s, 1H), 7.71 (s, 2H), 7.41 (t, 1H), 7.37 (t, 2H), 7.13-6.97 (m, 8H), 6.53 (broad s, 2H), 6.44 (dd, 1H), 6.25 (d, 1H), 5.75 (d, 1H).

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamide (A246)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamide (6% yield) was synthesized according to Method F using 6-(5-amino-2-fluorophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine. HPLC: 99%, RT = 4.470 min. MS: m/z = 443 [M+H] ⁺ , RT = 2.38 min. ¹ H-NMR (DMSO-d ₆ ) δ 10.18 (s, 1H), 7.96 (s, 1H), 7.58 (d, 1H), 7.36-7.32 (m, 5H), 7.20 (t, 1H), 7.10 (t, 1H), 7.05-7.03 (m, 4H), 6.51 (broad s, 2H), 6.32 (dd, 1H), 6.18 (d, 1H), 5.70 (d, 1H).

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1- one (A247)

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (42% yield) was synthesized according to Method F using (R)-5-(4-phenoxyphenyl)-N4-(piperidin-3-yl)pyrimidine-4,6-diamine. HPLC: 97%, RT = 3.713 min. MS: m/z = 416 [M+H] ⁺ , RT = 1.76 min.

(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-(dimethylamino)but- 2-enamide (A248)

(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-(dimethylamino)but-2-enamide (26% yield) was synthesized according to Procedure E using 5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride. HPLC: 97%, RT = 3.608 min. MS: m/z = 482 [M+H] ⁺ , RT = 3.57 min. ¹ H-NMR (DMSO-d ₆ ), δ10.33(s, 1H), 9.66(s, 1H), 8.01(s, 1H), 7.66-7.64(m, 2H), 7.38(t, 1H), 7.3 2(t, 2H), 7.11-6.92(m, 8H), 6.68(m, 1H), 6.41(m, 3H), 3.88(m, 2H), 2.73(s, 6H).

N-(3-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A249)

N-(3-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized (16% yield) using 6-(3-aminophenoxy)-5-(4-(benzyloxy)phenyl)pyrimidin-4-amine according to Method E. HPLC: 100%, RT = 4.251 min. MS: m/z = 439 [M+H] ⁺ , RT = 2.12 min. ¹ H-NMR (DMSO-d ₆ ), δ 10.18 (s, 1H), 8.04 (d, 1H), 7.47-7.25 (m, 10H), 7.10 (d, 2H), 6.74 (d, 1H), 6.49 (broad s, 2H), 6.39 (dd, 1H), 6.23 (d, 1H), 5.75 (d, 1H), 5.11 (s, 2H).

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en- 1-one (A250)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one was synthesized using 5,6-dichloropyrimidin-4-amine, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and acryloyl chloride according to Scheme 2 (using Methods B/I, C, D, and F). HPLC purity: 97%, RT = 3.665 min; MS: m/z = 430 [M+H] ⁺ , RT = 1.53 min. ¹ H-NMR (DMSO-d ₆ )δ7.93(s, 1H), 7.40(t, 2H), 7.21-7.08(m, 8H), 6.76(dd, 1H), 6.04(d, 1H), 5.61(d, 1H), 5.43(s, 2H), 4 .34 (d, 1H), 3.98 (d, 1H), 3.12 (t, 2H), 2.95 (t, 1H), 2.56 (t, 1H), 1.81 (m, 1H), 1.59 (m, 2H), 0.92 (m, 2H).

N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2,4-difluorophenyl)acrylamide (A251)

N-(5-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2,4-difluorophenyl)acrylamide (10% yield) was synthesized using 6-(5-amino-2,4-difluorophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine according to Method F. HPLC: 99%, RT = 4.569 min. MS: m/z = 461 [M+H] ⁺ , RT = 2.42 min. ¹ H-NMR (DMSO-d ₆ ), δ10.02 (s, 1H), 8.01 (s, 1H), 7.87 (t, 1H), 7.48 (t, 1H), 7.42-7.38 (m, 4H), 7.15 (t, 1H), 7.10-7.07 (m, 4H), 6.56 (dd, 1H), 6.55 (broad s, 2H), 6.24 (d, 1H), 5.77 (d, 1H).

(E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino) but-2-enamide (A252)

(E)-N-(3-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide (22% yield) was synthesized according to Method E using 6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride. HPLC: 98%, RT = 3.556 min. MS: m/z = 482 [M+H] ⁺ , RT = 3.53 min. ¹ H-NMR (DMSO-d ₆ )δ10.34(s, 1H), 9.73(s, 1H), 8.04(s, 1H), 7.45(s, 1H), 7.41-7.36(m, 5H), 7.29(t , 1H), 7.15(t, 1H), 7.09-7.06(m, 4H), 6.78(d, 1H), 6.74-6.68(m, 1H), 6.50(broad s, 2H), 6.41 (d, 1H), 3.93-3.92 (m, 2H), 2.78 (s, 6H).

1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (A253)

1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (27% yield) was synthesized using 5-(4-phenoxyphenyl)-N4-(piperidin-3-yl)pyrimidine-4,6-diamine according to Method F. HPLC: 99%, RT = 3.737 min. MS: m/z = 416 [M+H] ⁺ , RT = 1.88 min.

N-(3-((6-amino-5-(4-((2-methoxybenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide ( A254)

N-(3-((6-amino-5-(4-((2-methoxybenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized according to Method F (58% yield) using 6-(3-aminophenoxy)-5-(4-((2-methoxybenzyl)oxy)phenyl)pyrimidin-4-amine. HPLC: 99%, RT = 4.290 min. MS: m/z = 469 [M+H] ⁺ , RT = 2.32 min. ¹ H-NMR (DMSO-d ₆ )1H), 8.14(s, 1H), 7.50(s, 1H), 7.44-7.30(m, 6H), 7.13(d, 2H), 7.08(d, 1H), 6.99(t , 1H), 6.79 (m, 3H), 6.42 (dd, 1H), 6.27 (d, 1H), 5.78 (d, 1H), 5.10 (s, 2H), 3.84 (s, 3H).

N-(3-((5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A255)

N-(3-(5-(4-Phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized (86% yield) using 3-((5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)aniline according to Method F. HPLC: 97%, RT = 5.029 min. MS: m/z = 410 [M+H] ⁺ , RT = 2.57 min. ¹ H-NMR (DMSO-d ₆ )1H), 8.78(s, 1H), 8.69(s, 1H), 7.76(d, 2H), 7.66(s, 1H), 7.45-7.36(m, 4H), 7.1 8 (t, 1H), 7.13-7.08 (m, 4H), 6.96 (d, 1H), 6.41 (dd, 1H), 6.24 (d, 1H), 5.76 (d, 1H).

N-(3-((6-amino-5-(4-(benzyloxy)-3-methoxyphenyl)pyrimidin-4-yl)oxy)phenyl) acrylamide (A256)

N-(3-((6-amino-5-(4-(benzyloxy)-3-methoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized (53% yield) using 6-(3-aminophenoxy)-5-(4-(benzyloxy)-3-methoxyphenyl)pyrimidin-4-amine according to Method F. HPLC: 100%, RT = 4.133 min. MS: m/z = 469 [M+H] ⁺ , RT = 2.19 min. ¹ H-NMR (DMSO-d ₆ ) δ 10.13 (s, 1H), 7.99 (s, 1H), 7.41-7.20 (m, 8H), 7.07 (d, 1H), 6.93 (s, 1H), 6.85 (d, 1H), 6.71 (d, 1H), 6.50 (broad s, 2H), 6.34 (dd, 1H), 6.17 (d, 1H), 5.69 (d, 1H), 5.03 (s, 2H), 3.71 (s, 3H).

N-(3-((6-amino-5-(4-(benzyloxy)-2,3-difluorophenyl)pyrimidin-4-yl)oxy)phenyl) acrylamide (A257)

N-(3-((6-amino-5-(4-(benzyloxy)-2,3-difluorophenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (37% yield) was synthesized according to Method F using 6-(3-aminophenoxy)-5-(4-(benzyloxy)-2,3-difluorophenyl)pyrimidin-4-amine. HPLC: 100%, RT = 4.611 min. MS: m/z = 475 [M+H] ⁺ , RT = 2.39 min. ¹ H-NMR (DMSO-d ₆ 1H), δ10.14(s, 1H), 8.02(s, 1H), 7.43-7.28(m, 7H), 7.22(t, 1H), 7.12(quin tet, 2H), 6.68 (m, 3H), 6.34 (dd, 1H), 6.18 (d, 1H), 5.69 (d, 1H), 5.18 (s, 2H).

4-(4-(3-Acrylamidophenoxy)-6-aminopyrimidin-5-yl)-N-phenylbenzamide (A258)

4-(4-(3-Acrylamidophenoxy)-6-aminopyrimidin-5-yl)-N-phenylbenzamide was synthesized according to Method F (29% yield) using 4-(4-amino-6-(3-aminophenoxy)pyrimidin-5-yl)-N-phenylbenzamide. HPLC: 98%, RT = 3.775 min. MS: m/z = 452 [M+H] ⁺ , RT = 1.96 min. ¹ H-NMR (DMSO-d ₆ )δ10.22(s, 1H), 10.16(s, 1H), 8.04(s, 1H), 7.98(d, 2H), 7.72(d, 2H), 7.52( d, 2H), 7.44 (s, 1H), 7.30-7.22 (m, 4H), 7.04 (t, 1H), 6.73 (d, 1H), 6.63 (broad s, 2H), 6.34 (dd, 1H), 6.18 (d, 1H), 5.70 (d, 1H).

N-(3-((6-amino-5-(6-(benzyloxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A259)

N-(3-((6-amino-5-(6-(benzyloxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized (38% yield) according to Method F using 6-(3-aminophenoxy)-5-(6-(benzyloxy)pyridin-3-yl)pyrimidin-4-amine. HPLC: 99%, RT = 4.138 min. MS: m/z = 440 [M+H] ⁺ , RT = 2.20 min. ¹ H-NMR (DMSO-d ₆ ) δ 10.19 (s, 1H), 8.19 (s, 1H), 8.06 (s, 1H), 7.74 (d, 1H), 7.46-7.26 (m, 8H), 6.97 (d, 1H), 6.77 (d, 1H), 6.69 (broad s, 2H), 6.39 (dd, 1H), 6.23 (d, 1H), 5.74 (d, 1H), 5.36 (s, 2H).

N-(3-((6-amino-5-(4-((3-fluorobenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A260)

N-(3-((6-amino-5-(4-((3-fluorobenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized according to Method E (13% yield) using 6-(3-aminophenoxy)-5-(4-((3-fluorobenzyl)oxy)phenyl)pyrimidin-4-amine. HPLC: 99%, RT = 4.334 min. MS: m/z = 457 [M+H] ⁺ , RT = 2.17 min. ¹ H-NMR (DMSO-d ₆ ), δ 10.18 (s, 1H), 8.04 (s, 1H), 7.46-7.41 (m, 2H), 7.36-7.25 (m, 6H), 7.15 (t, 1H), 7.10 (d, 2H), 6.75 (d, 1H), 6.50 (broad s, 2H), 6.39 (dd, 1H), 6.23 (d, 1H), 5.74 (d, 1H), 5.14 (s, 2H).

N-(3-((6-amino-2'-(benzyloxy)-[5,5'-bipyrimidinyl]-4-yl)oxy)phenyl)acrylamide (A261)

N-(3-((6-Amino-2'-(benzyloxy)-[5,5'-bipyrimidinyl]-4-yl)oxy)phenyl)acrylamide (46% yield) was synthesized using 6-(3-aminophenoxy)-2'-(benzyloxy)-[5,5'-bipyrimidinyl]-4-amine according to Method F. HPLC: 99%, RT = 3.953 min. MS: m/z = 441 [M+H] ⁺ , RT = 2.04 min. ¹ H-NMR (DMSO-d ₆ )1H), 8.64 (s, 2H), 8.08 (s, 1H), 7.48-7.26 (m, 8H), 6.88 (broad s, 2H), 6.79 (d, 1H), 6.39 (dd, 1H), 6.23 (d, 1H), 5.74 (d, 1H), 5.42 (s, 2H).

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2- en-1 -one (A262)

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one (26% yield) was synthesized according to Method F using 5-(4-phenoxyphenyl)-N4-(pyrrolidin-3-ylmethyl)pyrimidine-4,6-diamine. HPLC: 97%, RT = 3.570 min. MS: m/z = 416 [M+H] ⁺ , RT = 1.77 min.

1-(4-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en -1 -one (A263)

1-(4-(4-Amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one (41% yield) was synthesized using 6-(4-phenoxyphenoxy)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-amine according to Method F. HPLC: 91%, RT = 3.997 min. MS: m/z = 415 [M+H] ⁺ , RT = 2.00 min. ¹ H-NMR (DMSO-d ₆ )δ7.94(s, 1H), 7.33(t, 2H), 7.08-6.93(m, 7H), 6.82-6.68(m, 3H), 6.07(dd, 1H) , 5.73(d, 1H), 5.63(t, 1H), 4.15(s, 1H), 4.07(s, 1H), 3.71(m, 2H), 2.25(m, 2H).

N-(3-((6-amino-5-(4-((4-methoxybenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide ( A264)

N-(3-((6-amino-5-(4-((4-methoxybenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized according to Method F (35% yield) using 6-(3-aminophenoxy)-5-(4-((4-methoxybenzyl)oxy)phenyl)pyrimidin-4-amine. HPLC: 98%, RT = 4.188 min. MS: m/z = 469 [M+H] ⁺ , RT = 2.25 min. ¹ H-NMR (DMSO-d ₆ ), δ 10.21 (s, 1H), 8.07 (s, 1H), 7.47 (s, 1H), 7.42-7.28 (m, 6H), 7.12 (d, 2H), 6.97 (d, 2H), 6.78 (d, 1H), 6.50 (broad s, 2H), 6.42 (dd, 1H), 6.26 (d, 1H), 5.77 (d, 1H), 5.05 (s, 2H), 3.77 (s, , 3H).

(E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-morpholinobut-2- enamide (A265)

(E)-N-(3-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-morpholinobut-2-enamide (19% yield) was synthesized according to Method E using 6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and (E)-4-morpholinobut-2-enoic acid. HPLC: 100%, RT = 3.605 min. MS: m/z = 524 [M+H] ⁺ , RT = 3.59 min.

N-((1s,4s)-4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide (A266)

N-((1s,4s)-4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide (20% yield) was synthesized according to Method F using N-((1s,4s)-4-aminocyclohexyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine. HPLC: 100%, RT = 3.712 min. MS: m/z = 430 [M+H] ⁺ , RT = 1.80 min.

N-(3-(4-((4-phenoxyphenyl)amino)pyridin-3-yl)phenyl)acrylamide (A267)

N-(3-(4-((4-Phenoxyphenyl)amino)pyridin-3-yl)phenyl)acrylamide (13% yield) was synthesized according to Method E using 3-(3-aminophenyl)-N-(4-phenoxyphenyl)pyridin-4-amine. HPLC: 97%, RT = 4.075 min. MS: m/z = 408 [M+H] ⁺ , RT = 2.04 min. ¹ H-NMR (DMSO-d ₆ )δ10.32(s, 1H), 9.31(s, 1H), 8.27(s, 1H), 8.23(d, 1H), 7.89(s, 1H), 7.77(d, 1H), 7.50(t, 1H), 7.41(t, 2H) , 7.30 (d, 2H), 7.24 (d, 1H), 7.16 (t, 1H), 7.05 (dd, 4H), 6.98 (d, 1H), 6.45 (dd, 1H), 6.27 (d, 1H), 5.77 (d, 1H).

N-(3-((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A268)

N-(3-((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide (70% yield) was synthesized according to Method F using 6-(3-aminophenoxy)-5-(6-phenoxypyridin-3-yl)pyrimidin-4-amine. HPLC: 97%, RT = 3.880 min. MS: m/z = 426 [M+H] ⁺ , RT = 2.03 min. ¹ H-NMR (DMSO-d ₆ )δ10.22(s, 1H), 8.15(s, 1H), 8.10(s, 1H), 7.87(d, 1H), 7.48(s, 1H), 7.40(t, 2H ), 7.36(d, 1H), 7.28(t, 1H), 7.21(t, 1H), 7.16(d, 2H), 7.11(d, 1H), 6.85(broad s, 1H), 6.78 (d, 1H), 6.39 (dd, 1H), 6.23 (d, 1H), 5.75 (d, 1H).

1-(3-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1- one (A269)

1-(3-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (26% yield) was synthesized according to Method F using 5-(4-(benzyloxy)phenyl)-N4-(piperidin-3-yl)pyrimidine-4,6-diamine. HPLC: 100%, RT = 3.701 min. MS: m/z = 430 [M+H] ⁺ , RT = 1.63 min.

N-(3-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide (A270)

N-(3-(3-(4-Phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide was synthesized (36% yield) using 3-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)aniline according to Method E. HPLC: 96%, RT = 4.161 min. MS: m/z = 409 [M+H] ⁺ , RT = 4.15 min. ¹ H-NMR (DMSO-d ₆ )δ10.37(s, 1H), 8.78(s, 1H), 8.55(d, 1H), 7.72-7.70(m, 3H), 7.46-7.40(m, 4H), 7.18( t, 1H), 7.10 (dd, 4H), 7.03 (d, 1H), 6.97 (m, 1H), 6.41 (dd, 1H), 6.24 (d, 1H), 5.77 (d, 1H).

N-(3-((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A271)

N-(3-((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (11% yield) was synthesized using 4-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-2-amine according to Method E. HPLC: 99%, RT = 4.256 min. MS: m/z = 425 [M+H] ⁺ , RT = 2.16 min. ¹ H-NMR (DMSO-d ₆ ) δ 10.27 (s, 1H), 8.28 (s, 1H), 7.62-7.60 (m, 3H), 7.45-7.35 (m, 4H), 7.20 (broad s, 2H), 7.15 (t, 1H), 7.05 (t, 4H), 6.96 (d, 1H), 6.41 (dd, 1H), 6.25 (d, 1H), 5.76 (d, 1H).

3-(3-Acrylamidophenyl)-4-(4-phenoxyphenoxy)picolinamide (A272)

3-(3-Acrylamidophenyl)-4-(4-phenoxyphenoxy)picolinamide (29% yield) was synthesized according to Method E using 3-(3-aminophenyl)-4-(4-phenoxyphenoxy)picolinamide. HPLC: 98%, RT = 4.218 min. MS: m/z = 452 [M+H] ⁺ , RT = 2.15 min.

1-(3-(4-amino-6-((4-phenoxyphenyl)amino)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl) prop-2-en-1-one (A273)

1-(3-(4-amino-6-((4-phenoxyphenyl)amino)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one (20% yield) was synthesized according to Method E using (4-phenoxyphenyl)-5-(1,2,5,6-tetrahydropyridin-3-yl)pyrimidine-4,6-diamine. HPLC: 97%, RT = 3.813 min. MS: m/z = 414 [M+H] ⁺ , RT = 1.94 min.

(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-morpholinobut-2- enamide (A274)

(E)-N-(3-(4-Amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-morpholinobut-2-enamide (15% yield) was synthesized according to Method E using 5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine and (E)-4-morpholinobut-2-enoic acid. HPLC: 100%, RT = 3.662 min. MS: m/z = 524 [M+H] ⁺ , RT = 3.66 min.

(S)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1- one (A275)

(S)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (42% yield) was synthesized according to Method F using (S)-5-(4-phenoxyphenyl)-N4-(piperidin-3-yl)pyrimidine-4,6-diamine. HPLC: 99%, RT = 3.701 min. MS: m/z = 416 [M+H] ⁺ , RT = 1.75 min.

N-((1r,4r)-4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide (A276)

N-((1r,4r)-4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide (13% yield) was synthesized according to Method F using N-((1r,4r)-4-aminocyclohexyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine. HPLC: 100%, RT = 3.690 min. MS: m/z = 430 [M+H] ⁺ , RT = 1.58 min.

N-(3-((6-amino-5-(4-fluoro-3-methoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A277)

N-(3-((6-amino-5-(4-fluoro-3-methoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (13% yield) was synthesized according to Method E using 6-(3-aminophenoxy)-5-(4-fluoro-3-methoxyphenyl)pyrimidin-4-amine. HPLC: 97%, RT = 3.519 min. MS: m/z = 381 [M+H] ⁺ , RT = 1.77 min. ¹ H-NMR (DMSO-d ₆ ) δ 10.19 (s, 1H), 8.06 (s, 1H), 7.47 (s, 1H), 7.35 (d, 1H), 7.29-7.25 (m, 2H), 7.17 (d, 1H), 6.94 (m, 1H), 6.77 (d, 1H), 6.61 (broad s, 2H), 6.39 (dd, 1H), 6.23 (d, 1H), 5.74 (d, 1H), 3.83 (s, 3H).

N-(3-((6-amino-5-(4-(2-hydroxypropan-2-yl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A278)

N-(3-((6-amino-5-(4-(2-hydroxypropan-2-yl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized (22% yield) according to Method E using 2-(4-(4-amino-6-(3-aminophenoxy)pyrimidin-5-yl)phenyl)propan-2-ol. HPLC: 97%, RT = 3.038 min. MS: m/z = 391 [M+H] ⁺ , RT = 1.53 min. ¹ H-NMR (DMSO-d ₆ ) δ 10.19 (s, 1H), 8.06 (s, 1H), 7.55 (d, 2H), 7.45 (s, 1H), 7.36-7.33 (m, 3H), 7.27 (t, 1H), 6.75 (d, 1H), 6.50 (broad s, 2H), 6.39 (dd, 1H), 6.23 (d, 1H), 5.74 (d, 1H), 1.44 (s, 6H).

1-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en -1 -one (A279)

1-(3-(4-Amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one (17% yield) was synthesized using 6-(4-phenoxyphenoxy)-5-(1,2,5,6-tetrahydropyridin-3-yl)pyrimidin-4-amine according to Method E. HPLC: 100%, RT = 4.065 min. MS: m/z = 415 [M+H] ⁺ , RT = 2.07 min. ¹ H-NMR (DMSO-D ₆ )δ8.00(s, 1H), 7.38(t, 2H), 7.14-7.08(m, 3H), 7.00(d, 4H), 6.88-6.70(m, 3H), 6.09(dd, 1H), 5.90 (m, 1H), 5.68 (d, 0.5H), 5.58 (d, 0.5H), 8.16 (d, 2H), 3.73 (dt, 2H), 2.25 (d, 2H).

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A280)

N-(4-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (23% yield) was synthesized using 6-(4-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine according to Method E. HPLC: 97%, RT = 4.191 min. MS: m/z = 425 [M+H] ⁺ , RT = 4.12 min. ¹ H-NMR (DMSO-d ₆ ) δ 10.14 (s, 1H), 8.04 (s, 1H), 7.62 (d, 2H), 7.42-7.38 (m, 4H), 7.15 (t, 1H), 7.08 (t, 4H), 7.02 (d, 2H), 6.54 (broad s, 2H), 6.41 (dd, 1H), 6.24 (d, 1H), 5.74 (d, 1H).

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide (A281)

N-(4-(4-Phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide (17% yield) was synthesized using 4-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline according to Method G. HPLC: 100%, RT = 4.216 min. MS: m/z = 409 [M+H] ⁺ , RT = 3.29 min. ¹ H-NMR (DMSO-d ₆ )δ9.89(s, 1H), 9.01(s, 1H), 8.85(d, 1H), 8.30(d, 2H), 8.10(d, 2H), 7.84(t, 2H), 7.64(d, 2H) , 7.58(t, 1H), 7.55(d, 2H), 7.48(d, 2H), 7.25(d, 1H), 6.92(dd, 1H), 6.82(d, 1H), 6.17(d, 1H).

(E)-4-(Dimethylamino)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide (A282)

(E)-4-(Dimethylamino)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide (35% yield) was synthesized according to Procedure E using 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and (E)-4-(dimethylamino)but-2-enoic acid. HPLC: 99%, RT = 3.399 min. MS: m/z = 466 [M+H] ⁺ , RT = 3.37 min. ¹ H-NMR (DMSO-d ₆ )δ10.52(s,1H),8.70(s,1H),8.56(d,1H),8.04(s,1H),7.74(d,1H),7.48(t,1H),7.43-7.38(m,3H),7.2 9-7.26 (d, 2H), 7.17-7.12 (m, 3H), 7.05-6.99 (m, 3H), 6.74 (m, 1H), 6.48 (d, 1H), 3.94 (d, 2H), 2.79 (s, 6H).

N-(3-(4-((4-phenoxyphenyl)amino)pyrimidin-5-yl)phenyl)acrylamide (A283)

N-(3-(4-((4-phenoxyphenyl)amino)pyrimidin-5-yl)phenyl)acrylamide was synthesized according to Procedure E from 3-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)aniline (19% yield). HPLC: 98%, RT=3.938min. MS: m/z=409[M+H] ⁺ , RT=1.93min. ¹ H-NMR (DMSO-d ₆ )δ10.31(s, 1H), 9.45(s, 1H), 8.73(s, 1H), 8.29(s, 1H), 7.87(s, 1H), 7.80(d, 1H), 7.51-7.49(m, 3H) , 7.38(t, 2H), 7.25(d, 1H), 7.13(t, 1H), 7.01-6.99(m, 4H), 6.45(dd, 1H), 6.27(d, 1H), 5.77(d, 1H).

1-(3-((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (A284)

1-(3-((5-(4-Phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (19% yield) was synthesized according to Method F using 5-(4-phenoxyphenyl)-N-(piperidin-3-yl)pyrimidin-4-amine. HPLC: 98%, RT = 3.632 min. MS: m/z = 401 [M+H] ⁺ , RT = 1.52 min.

N-(3-((6-amino-5-(4-(pyrrolidine-1-carbonyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A285)

N-(3-((6-amino-5-(4-(pyrrolidine-1-carbonyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized according to Method F (86% yield) using (4-(4-amino-6-(3-aminophenoxy)pyrimidin-5-yl)phenyl)(pyrrolidin-1-yl)methanone. HPLC: 99%, RT = 3.121 min. MS: m/z = 430 [M+H] ⁺ , RT = 1.62 min. ¹ H-NMR (DMSO-d ₆ ) δ 10.15 (s, 1H), 8.04 (s, 1H), 7.53 (d, 2H), 7.43-7.39 (m, 3H), 7.30 (d, 1H), 7.22 (t, 1H), 6.72 (d, 1H), 6.60 (broad s, 2H), 6.34 (dd, 1H), 6.18 (d, 1H), 5.69 (d, 1H), 3.42-3.37 (m, 4H), 1.77 (doublet of quintet, 4H).

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en- 1-one (A286)

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one (40% yield) was synthesized according to Method F using 5-(4-phenoxyphenyl)-N4-(piperidin-3-ylmethyl)pyrimidine-4,6-diamine. HPLC: 99%, RT = 3.733 min. MS: m/z = 430 [M+H] ⁺ , RT = 1.72 min.

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide (A287)

N-(4-(4-Phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide (23% yield) was synthesized according to Method G using (4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine, triethylamine instead of N,N-diethylethylamine, THF instead of methylpyrrolidin-2-one, and dichloromethane. HPLC: 93%, RT = 4.014 min. MS: m/z = 423 [M+H] ⁺ , RT = 3.16 min. ¹ H-NMR (DMSO-d ₆ )δ8.99(s, 1H), 8.36(d, 1H), 8.18(s, 1H), 8.08(d, 2H), 7.89-7.83(m, 4H), 7.65- 7.48 (m, 7H), 7.25 (d, 1H), 6.80 (dd, 1H), 6.69 (d, 1H), 6.05 (d, 1H), 4.98 (d, 2H).

1-(4'-(4-phenoxyphenoxy)-5,6-dihydro-[3,3'-bipyridyl]-1(2H)-yl)prop-2-en-1-one (A288)

1-(4'-(4-Phenoxyphenoxy)-5,6-dihydro-[3,3'-bipyridyl]-1(2H)-yl)prop-2-en-1-one (24% yield) was synthesized using 4'-(4-phenoxyphenoxy)-1,2,5,6-tetrahydro-3,3'-bipyridine according to Method E. HPLC: 98%, RT = 3.872 min. MS: m/z = 399 [M+H] ⁺ , RT = 1.97 min.

N-(3-((6-amino-5-(4-isopropoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A289)

N-(3-((6-amino-5-(4-isopropoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (79% yield) was synthesized using 6-(3-aminophenoxy)-5-(4-isopropoxyphenyl)pyrimidin-4-amine according to Method F. HPLC: 100%, RT = 3.826 min. MS: m/z = 391 [M+H] ⁺ , RT = 2.03 min. ¹ H-NMR (DMSO-d ₆ )δ10.22(s, 1H), 8.11(s, 1H), 7.48(s, 1H), 7.36-7.26(m, 4H), 6.76(m, 3H) , 6.39 (dd, 1H), 6.23 (d, 1H), 5.75 (d, 1H), 4.63 (septet, 1H), 1.28 (d, 6H).

(E)-N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino) but-2-enamide (A290)

(E)-N-(4-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide (29% yield) was synthesized according to Method E using 6-(4-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and (E)-4-(dimethylamino)but-2-enoic acid. HPLC: 99%, RT = 3.448 min. MS: m/z = 482 [M+H] ⁺ , RT = 3.40 min. ¹ H-NMR (DMSO-d ₆ ) δ 10.30 (s, 1H), 8.02 (s, 1H), 7.62 (d, 2H), 7.43-7.38 (m, 4H), 7.15 (tt, 1H), 7.10-7.01 (m, 6H), 6.73 (m, 1H), 6.49 (broad) s, 2H), 6.44 (d, 1H), 3.93 (m, 2H), 2.80 (s, 6H).

N-(3-((6-amino-5-(5-methoxypyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A291)

N-(3-((6-Amino-5-(5-methoxypyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized (13% yield) using 6-(3-aminophenoxy)-5-(5-methoxypyridin-3-yl)pyrimidin-4-amine according to Method E. HPLC: 99%, RT = 2.429 min. MS: m/z = 364 [M+H] ⁺ , RT = 1.17 min. ¹ H-NMR (DMSO-d ₆ )δ10.15(s, 1H), 8.32(s, 1H), 8.26(s, 1H), 8.04(s, 1H), 7.60(s, 1H), 7.45(s, 1H), 7.39 (d, 1H), 7.23 (t, 1H), 6.74 (m, 3H), 6.34 (dd, 1H), 6.18 (d, 1H), 5.69 (d, 1H), 3.83 (s, 3H).

1-(4-(((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl) prop-2-en-1 -one (A292)

1-(4-(((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one (36% yield) was synthesized according to Method F using 5-(4-(benzyloxy)phenyl)-N4-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine. HPLC: 100%, RT = 3.678 min. MS: m/z = 444 [M+H] ⁺ , RT = 1.65 min.

(E)-4-Morpholino-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide (A293)

(E)-4-Morpholino-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide (34% yield) was synthesized according to Procedure E using 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and (E)-4-morpholinobut-2-enoic acid. HPLC: 100%, RT = 3.493 min. MS: m/z = 508 [M+H] ⁺ , RT = 2.27 min.

N-(3-((6-amino-5-(4-(benzyloxy)-2,6-difluorophenyl)pyrimidin-4-yl)oxy)phenyl) acrylamide (A294)

N-(3-((6-amino-5-(4-(benzyloxy)-2,6-difluorophenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (14% yield) was synthesized according to Method F using 6-(3-aminophenoxy)-5-(4-(benzyloxy)-2,6-difluorophenyl)pyrimidin-4-amine. HPLC: 99%, RT = 4.662 min. MS: m/z = 475 [M+H] ⁺ , RT = 2.40 min. ¹ H-NMR (DMSO-D ₆ )δ10.19(s, 1H), 8.08(s, 1H), 7.47-7.33(m, 7H), 7.28(t, 1H), 6.92(d, 2H), 6.81 (broads, 2H), 6.70 (d, 1H), 6.39 (dd, 1H), 6.23 (d, 1H), 5.74 (d, 1H), 5.14 (s, 2H).

(E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(4-(5-((4S) -2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)piperazin-1-yl)but-2-enamide (A295)

((E)-N-(3-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(4-(5-((4S)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)piperazin-1-yl)but-2-enamide was synthesized according to Procedure F using (E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(piperazin-1-yl)but-2-enamide and perfluorophenyl 5-((4S)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate (45% yield). HPLC: 100%, RT = 3.635 min. MS: m/z = 750 [M+H] ⁺ , RT = 1.84 min.

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-ynamide (A296)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-ynamide (63% yield) was synthesized using 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and but-2-ynoic acid according to Method E. HPLC: 100%, RT = 4.097 min. MS: m/z = 421 [M+H] ⁺ , RT = 4.22 min. ¹ H-NMR (DMSO-d ₆ )δ10.75(s, 1H), 8.71(s, 1H), 8.56(d, 1H), 7.97(s, 1H), 7.66(d, 1H), 7.46(t, 1H), 7.42-7.39 (m, 3H), 7.28 (d, 2H), 7.17-7.13 (m, 3H), 7.05-7.02 (m, 3H), 2.04 (s, 3H).

N-(4-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide (A297)

N-(4-((3-(4-Phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide (41% yield) was synthesized using 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and but-2-ynoic acid according to Method E. HPLC: 87%, RT = 4.063 min. MS: m/z = 409 [M+H] ⁺ , RT = 4.05 min. ¹ H-NMR (DMSO-d ₆ )δ10.16(s, 1H), 8.48(s, 1H), 8.33(d, 1H), 7.68(d, 2H), 7.60(d, 2H), 7.35(t, 2H), 7.12 -7.08 (m, 3H), 7.03-7.00 (m, 4H), 6.67 (d, 1H), 6.37 (dd, 1H), 6.20 (d, 1H), 5.70 (d, 1H).

N-(1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-3-yl)acrylamide (A298)

N-(1-(6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-3-yl)acrylamide (14% yield) was synthesized using 6-(3-aminopiperidin-1-yl)-5-(4-phenoxyphenyl)pyrimidin-4-amine according to Method F. HPLC: 99%, RT = 3.670 min. MS: m/z = 416 [M+H] ⁺ , RT = 1.55 min.

1-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (A299)

1-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (52% yield) was synthesized using 5-(4-phenoxyphenyl)-N4-(piperidin-4-yl)pyrimidine-4,6-diamine according to Method F. HPLC: 98%, RT = 3.574 min. MS: m/z = 416 [M+H] ⁺ , RT = 1.74 min.

3-(3-Aminophenyl)-4-(4-phenoxyphenoxy)pyridin-2-amine (A300)

3-(4-(4-Phenoxyphenoxy)pyridin-3-yl)aniline (37% yield) was synthesized according to Method C using 3-iodo-4-(4-phenoxyphenoxy)pyridin-2-amine. HPLC: 98%, RT = 3.369 min. MS: m/z = 370 [M+H] ⁺ , RT = 3.37 min. ^1H -NMR (DMSO-d ₆ ) δ 7.88 (d, 1H), 7.34 (t, 2H), 7.28 (s, 2H), 7.19 (t, 1H), 7.13-7.08 (m, 3H), 7.03 (d, 2H), 6.97 (d, 2H), 6.73 (d, 1H), 6.67-6.65 (m, 2H), 6.29 (d, 1H).

(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-(3,3-difluoropiperidin-1- yl)but-2-enamide (A301)

(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-(3,3-difluoropiperidin-1-yl)but-2-enamide was synthesized according to Method E (48% yield) using 5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine and (E)-4-(3,3-difluoropiperidin-1-yl)but-2-enoic acid. HPLC: 97%, RT = 3.809 min. MS: m/z = 558 [M+H] ⁺ , RT = 1.92 min.

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide (A302)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide (6% yield) was synthesized according to Method G using (3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine, triethylamine, and tetrahydrofuran. HPLC: 96%, RT = 4.127 min. MS: m/z = 423 [M+H] ⁺ , RT = 3.22 min. ¹ H-NMR (DMSO-d ₆ )δ9.14(s, 1H), 9.02(d, 1H), 8.23(s, 1H), 8.16(s, 1H), 8.09(d, 1H), 7.93(t, 1H), 7.87-7.84(m, 3H), 7. 73 (d, 2H), 7.62-7.58 (m, 3H), 7.51-7.50 (m, 3H), 6.77 (dd, 1H), 6.67 (d, 1H), 6.03 (d, 1H), 5.02 (d, 2H).

6-(4-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine (A303)

6-(4-Aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine (78% yield) was synthesized using 6-(4-aminophenoxy)-5-bromopyrimidin-4-amine according to Method C. HPLC: 98%, RT = 3.259 min. MS: m/z = 371 [M+H] ⁺ , RT = 3.24 min. ¹ H-NMR (DMSO-d ₆ ) δ 8.05 (s, 1H), 7.43-7.38 (m, 5H), 7.21 (d, 2H), 7.17-7.06 (m, 8H), 6.64 (broad s, 2H).

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2-ynamide (A304)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2-ynamide (64% yield) was synthesized using (3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine and but-2-ynoic acid according to Method E. HPLC: 98%, RT = 4.069 min. MS: m/z = 435 [M+H] ⁺ , RT = 4.07 min. ¹ H-NMR (DMSO-d ₆ )δ9.01(t, 1H), 8.51(s, 1H), 8.42(d, 1H), 7.54-7.50(m, 2H), 7.43-7.37(m, 3H), 7.27(d, 1H), 7.22-7. 18(m, 2H), 7.13(tt, 1H), 7.10-7.07(m, 2H), 7.04-7.01(m, 2H), 6.79(d, 1H), 4.33(d, 2H), 1.93(s, 3H).

6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine (A305)

6-(3-Aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine (74% yield) was synthesized using 6-(3-aminophenoxy)-5-bromopyrimidin-4-amine according to Method C. HPLC: 99%, RT = 3.417 min. MS: m/z = 371 [M+H] ⁺ , RT = 3.42 min. ^1H -NMR (DMSO-d ₆₎ δ 8.09 (s, 1H), 7.42-7.38 (m, 4H), 7.20 (t, 1H), 7.15 (t, 1H), 7.09-7.06 (m, 4H), 6.75 (d, 1H), 6.64-6.63 (m, 2H).

N-(3-(2-amino-4-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)acrylamide (A306)

N-(3-(2-Amino-4-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)acrylamide (27% yield) was synthesized according to Method E using 5-(3-aminophenyl)-4-(4-phenoxyphenoxy)pyrimidin-2-amine. HPLC: 96%, RT = 4.208 min. MS: m/z = 425 [M+H] ⁺ , RT = 2.13 min. ^1H -NMR (DMSO-d ₆ ) δ 10.22 (s, 1H), 8.27 (s, 1H), 7.93 (s, 1H), 7.66 (d, 1H), 7.42-7.02 (m, 13H), 6.44 (dd, 1H), 6.25 (d, 1H), 5.75 (d, 1H).

(E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide (A307)

(E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide (56% yield) was synthesized according to Procedure E using 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and (E)-but-2-enoic acid. HPLC: 98%, RT = 4.292 min. MS: m/z = 423 [M+H] ⁺ , RT = 4.28 min. ¹ H-NMR (DMSO-d ₆ )δ9.91(s, 1H), 8.52(s, 1H), 8.43(d, 1H), 7.92(s, 1H), 7.68(d, 1H), 7.40-7.37(m, 3H), 7.30(d, 1H), 7.18-7.12(m, 3H), 7.08(d, 2H), 7.02(d, 2H), 6.83-6.76(m, 2H), 6.14(d, 1H), 1.86(d, 3H).

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)propionamide (A308)

N-(4-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized (51% yield) according to Method E using 6-(4-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine. HPLC: 96%, RT = 4.165 min. MS: m/z = 427 [M+H] ⁺ , RT = 4.11 min. ^1H -NMR (DMSO-d ₆ ) δ 9.78 (s, 1H), 7.94 (s, 1H), 7.48 (d, 2H), 7.36-7.32 (m, 4H), 7.09 (t, 1H), 7.02 (t, 4H), 6.91 (d, 2H), 6.39 (broad s, 2H), 2.24 (q, 2H), 1.01 (t, 3H).

N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-3-yl)methyl)acrylamide (A309)

N-((1-(6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-3-yl)methyl)acrylamide (43% yield) was synthesized according to Method F using 6-(3-(aminomethyl)piperidin-1-yl)-5-(4-phenoxyphenyl)pyrimidin-4-amine. HPLC: 100%, RT = 3.716 min. MS: m/z = 430 [M+H] ⁺ , RT = 1.53 min.

N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide (A310)

N-(3-(2-Amino-4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propanamide (49% yield) was synthesized according to Method C using 3-iodo-4-(4-phenoxyphenoxy)pyridin-2-amine and N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamide. HPLC: 98%, RT = 4.186 min. MS: m/z = 426 [M+H] ⁺ , RT = 4.18 min. ¹ H-NMR (DMSO-d ₆ )δ10.01(s, 1H), 7.94(d, 1H), 7.73(s, 1H), 7.63(d, 1H), 7.44(t, 1H), 7.39(t , 2H), 7.24(s, 2H), 7.16-7.01(m, 8H), 6.35(d, 1H), 2.32(q, 2H), 1.07(t, 3H).

(R)-N-(3-(4-amino-6-((1-phenylethyl)amino)pyrimidin-5-yl)phenyl)acrylamide (A311)

(R)-N-(3-(4-amino-6-((1-phenylethyl)amino)pyrimidin-5-yl)phenyl)acrylamide (16% yield) was synthesized according to Method F using (R)-5-(3-aminophenyl)-N4-(1-phenylethyl)pyrimidine-4,6-diamine. HPLC: 100%, RT = 3.515 min. MS: m/z = 360 [M+H] ⁺ , RT = 1.73 min. ¹ H-NMR (DMSO-d ₆ ), δ10.33(s, 1H), 8.28(s, 1H), 7.82(s, 1H), 7.64(d, 1H), 7.52(t, 1H), 7.29-6 .85 (m, 9H), 6.47 (dd, 1H), 6.27 (d, 1H), 5.77 (d, 1H), 5.40 (s, 1H), 1.39 (d, 3H).

3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline (A312)

3-(4-(4-Phenoxyphenoxy)pyridin-3-yl)aniline (55% yield) was synthesized using 3-bromo-4-(4-phenoxyphenoxy)pyridine according to Method C. HPLC: 100%, RT = 3.396 min. MS: m/z = 355 [M+H] ⁺ , RT = 2.88 min.

4-(3-Aminophenoxy)-3-(4-phenoxyphenyl)pyridin-2-amine (A313)

4-(3-Aminophenoxy)-3-(4-phenoxyphenyl)pyridin-2-amine (84% yield) was synthesized using 4-(3-aminophenoxy)-3-iodopyridin-2-amine according to Method C. HPLC: 98%, RT = 3.490 min. MS: m/z = 370 [M+H] ⁺ , RT = 3.44 min. ¹ H-NMR (DMSO-d ₆ ) δ 8.00 (d, 1H), 7.45-7.41 (m, 6H), 7.18 (t, 1H), 7.13-7.07 (m, 5H), 6.51 (d, 1H), 6.32-6.26 (m, 3H).

4-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline (A314)

4-(4-(4-Phenoxyphenoxy)pyridin-3-yl)aniline (74% yield) was synthesized using 3-bromo-4-(4-phenoxyphenoxy)pyridine according to Method C. HPLC: 100%, RT = 3.456 min. MS: m/z = 355 [M+H] ⁺ , RT = 2.75 min.

(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine (A315)

(4-(4-(4-Phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine (62% yield) was synthesized according to Method C using 3-bromo-4-(4-phenoxyphenoxy)pyridine. HPLC: 95%, RT = 3.286 min. MS: m/z = 369 [M+H] ⁺ , RT = 2.19 min.

(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine (A316)

3-(4-(4-Phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine (71% yield) was synthesized using 3-bromo-4-(4-phenoxyphenoxy)pyridine according to Method C. HPLC: 95%, RT = 3.376 min. MS: m/z = 369 [M+H] ⁺ , RT = 2.29 min.

5-(3-Aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine (A317)

5-(3-Aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine (76% yield) was synthesized according to Method C using 5-bromo-6-(4-phenoxyphenoxy)pyrimidin-4-amine. HPLC: 97%, RT = 3.433 min. MS: m/z = 371 [M+H] ⁺ , RT = 3.48 min. ¹ H-NMR (DMSO-d ₆ ) δ 8.01 (s, 1H), 7.34-7.26 (m, 3H), 7.06 (t, 1H), 7.01-6.87 (m, 9H), 6.41 (broad s, 2H).

N-(3-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)propionamide (A318)

N-(3-(3-(4-Phenoxyphenyl)pyridin-4-yl)oxy)phenyl)propanamide was synthesized (100% yield) according to Method E using 3-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)aniline. HPLC: 96%, RT = 4.161 min. MS: m/z = 409 [M+H] ⁺ , RT = 4.15 min. ¹ H-NMR (DMSO-d ₆ )δ10.37(s, 1H), 8.78(s, 1H), 8.55(d, 1H), 7.72-7.70(m, 3H), 7.45-7.40(m, 4H), 7.18(t, 1H), 7.13-7.07(m, 4H), 7.03(d, 1H), 6.97(s, 1H), 6.41(dd, 1H), 6.24(d, 1H), 5.77(d, 1H).

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide (A319)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propanamide (65% yield) was synthesized according to Method G using 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and pyridine instead of N,N-diethylethylamine, 1-methylpyrrolidin-2-one, and dichloromethane. HPLC: 92%, RT = 4.234 min. MS: m/z = 411 [M+H] ⁺ , RT = 3.35 min.

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide (A320)

N-(4-(4-Phenoxyphenoxy)pyridin-3-yl)phenyl)propanamide (77% yield) was synthesized according to Method G using 4-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and pyridine instead of N,N-diethylethylamine, 1-methylpyrrolidin-2-one, and dichloromethane. HPLC: 98%, RT = 4.157 min. MS: m/z = 411 [M+H] ⁺ , RT = 3.39 min.

N-(4-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)propionamide (A321)

N-(4-((3-(4-Phenoxyphenyl)pyridin-4-yl)oxy)phenyl)propanamide was synthesized according to Method E (98% yield) using 4-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)aniline. HPLC: 96%, RT = 4.061 min. MS: m/z = 411 [M+H] ⁺ , RT = 4.01 min. ^1H -NMR (DMSO-d ₆ ) δ 9.93 (s, 1H), 8.53 (s, 1H), 8.37 (d, 1H), 7.67-7.65 (m, 4H), 7.41 (t, 2H), 7.16 (t, 1H), 7.12-7.06 (m, 6H), 6.69 (d, 1H), 2.31 (q, 2H), 1.08 (t, 3H).

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methacrylamide (A322)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methacrylamide (56% yield) was synthesized using 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and methacrylic acid according to Method E. HPLC: 98%, RT = 4.345 min. MS: m/z = 423 [M+H] ⁺ , RT = 4.33 min. ¹ H-NMR (DMSO-d ₆ ), 1H), 8.51 (s, 1H), 8.42 (d, 1H), 7.96 (s, 1H), 7.73 (d, 1H), 7.42-7.33 (m, 4H), 7.19 (d, 2H), 7.13 (t, 1H), 7.09 (d, 2H), 7.02 (d, 2H), 6.79 (d, 1H), 5.80 (s, 1H), 5.51 (s, 1H), 1.94 (s, 3H).

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide (A323)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propanamide (58% yield) was synthesized according to Method G using (3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine and pyridine instead of N,N-diethylethylamine, 1-methylpyrrolidin-2-one, and dichloromethane. HPLC: 97%, RT = 4.034 min. MS: m/z = 425 [M+H] ⁺ , RT = 3.34 min.

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide (A324)

N-(4-(4-Phenoxyphenoxy)pyridin-3-yl)benzyl)propanamide (43% yield) was synthesized according to Method G using (4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine and pyridine instead of N,N-diethylethylamine, 1-methylpyrrolidin-2-one, and dichloromethane. HPLC: 99%, RT = 4.032 min. MS: m/z = 425 [M+H] ⁺ , RT = 3.22 min.

N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)propionamide (A325)

N-(3-(4-Amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)propanamide (82% yield) was synthesized according to Method C using 5-bromo-6-(4-phenoxyphenoxy)pyrimidin-4-amine and N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamide. HPLC: 99%, RT = 4.286 min. MS: m/z = 427 [M+H] ⁺ , RT = 4.25 min. ¹ H-NMR (DMSO-d ₆ ) δ9.93 (s, 1H), 8.10 (s, 1H), 7.64-7.63 (m, 2H), 7.38 (t, 3H), 7.12 (t, 1H), 7.08-7.05 (m, 3H), 6.99 (d, 4H), 6.60 (broad s, 2H), 2.32 (q, 2H), 1.07 (t, 3H).

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)propionamide (A326)

N-(3-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)propanamide (61% yield) was synthesized according to Method E using 6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine. HPLC: 94%, RT = 4.262 min. MS: m/z = 427 [M+H] ⁺ , RT = 4.22 min. ¹ H-NMR (DMSO-d ₆ ) δ9.90 (s, 1H), 8.03 (s, 1H), 7.41-7.38 (m, 5H), 7.29 (d, 1H), 7.23 (t, 1H), 7.15 (t, 1H), 7.07 (t, 4H), 6.70 (d, 1H), 6.49 (broad s, 2H), 2.28 (q, 2H), 1.04 (t, 3H).

(E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2-enamide (A327)

(E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2-enamide was synthesized (72% yield) using (3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine and (E)-but-2-enoic acid according to Procedure E. HPLC: 95%, RT = 4.079 min. MS: m/z = 437 [M+H] ⁺ , RT = 4.07 min. ¹ H-NMR (DMSO-d ₆ )δ8.51(s, 1H), 8.42-8.39(m, 2H), 7.53-7.52(m, 2H), 7.43-7.37(m, 3H), 7.28(d, 1H), 7.19(d, 2H), 7.1 4(t, 1H), 7.08(d, 2H), 7.02(d, 2H), 6.78(d, 1H), 6.63(qd, 1H), 5.94(d, 1H), 4.38(d, 2H), 1.76(d, 3H).

3-(4-Phenoxyphenyl)-4-(3-propionylaminophenoxy)picolinamide (A328)

3-(4-Phenoxyphenyl)-4-(3-propionamidophenoxy)picolinamide (24% yield) was synthesized according to Method F using 4-(3-aminophenoxy)-3-(4-phenoxyphenyl)picolinamide. HPLC: 100%, RT = 4.113 min. MS: m/z = 452 [M+H] ⁺ , RT = 2.05 min. ¹ H-NMR (DMSO-d ₆ )δ10.23(s, 1H), 8.37(d, 1H), 7.78(s, 1H), 7.48(s, 1H), 7.36-7.29(m, 7H), 7.09(t, 1H), 6. 97 (d, 2H), 6.92 (d, 2H), 6.84 (d, 1H), 6.74 (d, 1H), 6.33 (dd, 1H), 6.18 (d, 1H), 5.70 (d, 1H).

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-1-cyanocyclopropanecarboxamide (A329)

N-(3-((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-1-cyanocyclopropanecarboxamide (42% yield) was synthesized according to Method E using 6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and 1-cyanocyclopropanecarboxylic acid. HPLC: 96%, RT = 4.467 min. MS: m/z = 464 [M+H] ⁺ , RT = 2.24 min. ¹ H-NMR (DMSO-d ₆ ) δ 10.85 (s, 1H), 8.91 (s, 1H), 8.22-8.08 (m, 7H), 7.96 (t, 1H), 7.90-7.87 (m, 4H), 7.63 (d, 1H), 7.54 (broad s, 2H), 3.30 (s, 4H).

N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-1-cyanocyclopropanecarboxamide (A330)

N-(3-(4-Amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-1-cyanocyclopropanecarboxamide (66% yield) was synthesized according to Method E using 5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine and 1-cyanocyclopropanecarboxylic acid. HPLC: 100%, RT = 4.485 min. MS: m/z = 465 [M+H] ⁺ , RT = 2.26 min. ¹ H-NMR (DMSO-d ₆ )δ10.07 (s, 1H), 8.10 (s, 1H), 7.64-7.61 (m, 2H), 7.43-7.36 (m, 3H), 7.18 (d, 1H), 7.11 (t, 1H), 7.06 (d, 2H), 7.00-6.97 (m, 4H), 6.58 (broad s, 2H), 1.65 (s, 4H).

(E)-3-(7-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)naphthalen-2-yl)-N,N-dimethylacrylamide ( A331)

(E)-3-(7-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)naphthalen-2-yl)-N,N-dimethylacrylamide was synthesized according to Method C (16% yield) using (E)-3-(7-((6-amino-5-chloropyrimidin-4-yl)oxy)naphthalen-2-yl)-N,N-dimethylacrylamide. HPLC: 93%, RT = 4.680 min. MS: m/z = 503 [M+H] ⁺ , RT = 2.54 min. ¹ H-NMR (DMSO-d ₆ )δ8.09(d,2H),7.94(d,2H),7.66-7.58(m,2H),7.50(d,2H),7.42(t,2H),7.36-7.31(m,2H),7.18(t,1H),7.12-7.10(m,5H),6.70(broad s, 2H), 3.21 (s, 3H), 2.96 (s, 3H).

1-(4-(1-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)piperidin-1-yl)prop-2- en-1 -one (A332)

1-(4-(1-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)piperidin-1-yl)prop-2-en-1-one (30% yield) was synthesized according to Method F using 5-(4-phenoxyphenyl)-N4-(1-(piperidin-4-yl)ethyl)pyrimidine-4,6-diamine. HPLC: 100%, RT = 4.388 min. MS: m/z = 444 [M+H] ⁺ , RT = 1.66 min. ¹ H-NMR (DMSO-d ₆ ) (s, 1H), 7.38 (t, 2H), 7.19-7.06 (m, 7H), 6.85 (broad s, 2H), 6.70 (m, 1H), 6.52 (d, 1H), 5.99 (d, 1H), 5.56 (t, 1H), 4.33 (t, 1H), 3. 96 (t, 2H), 2.86 (m, 1H), 1.62-1.54 (m, 3H), 1.00 (d, 3H), 0.95-0.84 (m, 2H).

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)propan-1-one (A333)

1-(4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)propan-1-one (43% yield) was synthesized according to Method E using 5-(4-phenoxyphenyl)-N4-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine. HPLC: 99%, RT: 4.412 min. MS: m/z = 432 [M+H] ⁺ , RT = 1.49 min. ¹ H-NMR (DMSO-d ₆ )(s, 1H), 7.38(t, 2H), 7.20(d, 2H), 7.15-6.94(m, 8H), 4.27(d, 1H), 3.74(d, 1H), 3.16(s, 2H), 2.83(t, 1H), 2.39(t, 1H), 2.21(q, 2H), 1.72(m, 1H), 1.51(t, 2H), 0.96-0.79(m, 5H).

1-(4-(((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one (A334)

1-(4-(((5-(4-Phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one (6% yield) was synthesized according to Method F using 5-(4-phenoxyphenyl)-N-(piperidin-4-ylmethyl)pyrimidin-4-amine. HPLC: 99%, RT = 4.533 min. MS: m/z = 415 [M+H] ⁺ , RT = 1.67 min.

1-(4-(((6-amino-5-(4-(pyridin-2-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1 -yl)prop-2-en-1-one (A335)

1-(4-(((6-amino-5-(4-(pyridin-2-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one (28% yield) was synthesized according to Method F using N4-(piperidin-4-ylmethyl)-5-(4-(pyridin-2-yloxy)phenyl)pyrimidine-4,6-diamine. HPLC: 100%, RT: 4.401 min. MS: m/z = 431 [M+H] ⁺ , RT = 1.32 min. ¹ H-NMR (DMSO-d ₆ ). (s, 1H), 8.18 (d, 1H), 7.84 (t, 1H), 7.23 (s, 4H), 7.14 (t, 1H), 7.03-7.01 (m, 2H), 6.82 (broad s, 2H), 6.71 (dd, 1H), 5.99 (d, 1H), 5.57 (d, 1H), 4.30 (d, 1H), 3.95 (d, 1H), 3. 17 (m, 2H), 2.91 (t, 1H), 2.51 (t, 1H), 1.76 (m, 1H), 1.54 (m, 2H), 0.90 (m, 2H).

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2-yn- 1-one (A336)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2-yn-1-one (48% yield) was synthesized according to Method E using 5-(4-phenoxyphenyl)-N4-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine. HPLC: 99%, RT: 4.553 min. MS: m/z = 442 [M+H] ⁺ , RT = 1.62 min. ¹ H-NMR (DMSO-d ₆ ). (s, 1H), 7.38 (t, 2H), 7.20 (d, 2H), 7.13 (t, 1H), 7.10-7.05 (dd, 4H), 7.00 (m, 1H), 6.85 (broads, 2H), 4.15 (t, 2H), 3.16 (m, 2H)m 2.97 (t, 1H), 2.53 (t, 1H), 1.93 (s, 3H), 1.75 (m, 1H), 1.60-1.51 (dd, 2H), 0.98-0.80 (m, 2H).

N4-((1-(6-chloropyridin-2-yl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine (A337)

N-((1-(6-chloropyridin-2-yl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine (25% yield) was synthesized using 5-(4-phenoxyphenyl)-N-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine and 2,6-dichloropyridine according to Method B. HPLC: 99%, RT: 5.214 min. MS: m/z = 487 [M+H] ⁺ , RT = 2.11 min. ¹ H-NMR (DMSO-d ₆ ).(s, 1H), 7.44-7.36(m, 3H), 7.20(d, 2H), 7.15-6.95(m, 8H), 6.69(d, 1H), 6.52(d, 1H), 4.14(d, 2H), 3.18(m, 2H), 2.71(t, 2H), 1.77(m, 1H), 1.56(d, 2H), 0.98(m, 2H).

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en- 1-one (A338)

1-(4-(((6-Amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-one (10% yield) was synthesized according to Method F using 5-(4-phenoxyphenyl)-6-(piperidin-4-ylmethoxy)pyrimidin-4-amine. HPLC: 100%, RT: 4.366 min. MS: m/z = 431 [M+H] ⁺ , RT = 2.04 min. ¹ H-NMR (DMSO-d ₆ )(s, 1H), 7.35(t, 2H), 7.21(d, 2H), 7.10(t, 1H), 7.02-6.97(dd, 4H), 6.69(dd, 1H), 6.40(broads, 2H), 6.98(d, 1H), 5 .55 (d, 1H), 4.30 (d, 1H), 4.04 (d, 2H), 3.93 (d, 1H), 2.92 (t, 1H), 2.51 (t, 1H), 1.83 (m, 1H), 1.53 (m, 2H), 0.97 (m, 2H).

N-(3-((6-amino-5-(4-(benzyloxy)-2,5-difluorophenyl)pyrimidin-4-yl)oxy)phenyl) acrylamide (A339)

N-(3-((6-Amino-5-(4-(benzyloxy)-2,5-difluorophenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide was synthesized (69% yield) according to Method F using 6-(3-aminophenoxy)-5-(4-(benzyloxy)-2,5-difluorophenyl)pyrimidin-4-amine. HPLC: 89%, RT: 5.442 min. MS: m/z = 475 [M+H] ⁺ , RT = 2.38 min. ^1H -NMR (DMSO- _d6 ). (s, 1H), 8.00 (s, 1H), 7.42-7.20 (m, 11H), 6.67 (m, 3H), 6.34 (dd, 1H), 6.18 (d, 1H), 5.69 (d, 1H), 5.15 (d, 2H).

N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)but-2-ynamide (A340)

N-(3-((2-Amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)but-2-ynamide was synthesized according to Method E (13% yield) using 4-(3-aminophenoxy)-3-(4-phenoxyphenyl)pyridin-2-amine. HPLC: 98%, RT: 4.676 min. MS: m/z = 436 [M+H] ⁺ , RT = 1.95 min. ^1H -NMR (DMSO- _d6 ). (s, 1H), 7.92 (d, 1H), 7.48 (s, 1H), 7.43-7.34 (m, 6H), 7.28 (broad s, 2H), 7.17 (t, 1H), 7.09 (t, 4H), 6.86 (d, 1H), 6.30 (d, 1H), 2.03 (s, 3H).

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)but-2-yn- 1-one (A341)

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)but-2-yn-1-one (32% yield) was synthesized according to Method E using (R)-5-(4-phenoxyphenyl)-N4-(pyrrolidin-3-yl)pyrimidine-4,6-diamine. HPLC: 99%, RT: 4.106 min. MS: m/z = 414 [M+H] ⁺ , RT = 1.56 min.

N-{3-[6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloroacetamide (A342)

N-{3-[6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloroacetamide was synthesized according to Method E (41.5% yield). HPLC: 97%, RT: 4.26 min. MS: m/z = 447 [M+H] ⁺ , RT = 4.24 min. ¹ H-NMR: 400 MHz, DMSO-d ₆ : δ 10.45 (s, 1H), 8.05 (s, 1H), 7.40-7.36 (m, 5H), 7.36-7.26 (m, 2H), 7.17-7.12 (m, 1H), 7.09-7.05 (m, 4H), 6.79-6.76 (m, 1H), 6.50 (brs, 2H), 4.23 (s, 2H).

N-(3-{6-amino-5-[4-(2-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-acrylamide (A343)

N-(3-{6-Amino-5-[4-(2-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-acrylamide was synthesized (56.5% yield) according to Method E. HPLC: 94%, RT: 4.22 min. MS: m/z = 457 [M+H] ⁺ , RT = 4.22 min. ¹ H-NMR: 400MHz, DMSO-d ₆ : δ8.19 (s, 1H), 7.71 (s, 1H), 7.52 (t, J=8.00Hz, 1H), 7.41-7.33 (m, 6H), 7.21-7.10 (m, 6H), 6.84 (d, J=8.0 0Hz, 1H), 6.44 (d, J=16.00Hz, 1H), 6.22 (dd, J=18.00, 12.00Hz, 1H), 5.81 (d, J=12.00Hz, 1H), 5.19 (s, 2H).

N-(3-{6-amino-5-[4-(4-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-acrylamide (A344)

N-(3-{6-Amino-5-[4-(4-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-acrylamide was synthesized (5.1% yield) according to Method E. HPLC: 92%, RT: 4.22 min. MS: m/z = 457 [M+H] ⁺ , RT = 4.22 min. ¹ H-NMR: 400MHz, DMSO-d ₆ : δ10.20 (s, 1H), 8.06 (s, 1H), 7.53-7.49 (m, 2H), 7.46-7.45 (m, 1H), 7.37-7.20 (m, 6H), 7.10 (d, J=8.00Hz, 2H), 6.76- 6.74 (m, 1H), 6.60 (brs, 2H), 6.39 (dd, J=18.00, 12.00Hz, 1H), 6.25-6.21 (m, 1H), 5.75 (d, J=8.00Hz, 1H), 5.15 (s, 2H).

N-(3-{6-amino-5-[4-(3-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-2-chloro-acetamide ( A345)

N-(3-{6-amino-5-[4-(3-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-2-chloro-acetamide was synthesized according to Method E (14.3% yield). HPLC: 98%, RT: 4.35 min. MS: m/z = 479 [M+H] ⁺ , RT = 4.41 min. ¹ H-NMR: 400MHz, DMSO-d ₆ : δ10.35 (s, 1H), 8.02 (s, 1H), 7.47-7.42 (m, 1H), 7.35-7.26 (m, 7H), 7.18-7.16 (m, 1H) , 7.10 (d, J=8.00Hz, 2H), 6.78-6.75 (m, 1H), 6.43 (brs, 2H), 5.15 (s, 2H), 4.23 (s, 2H).

N-{3-[6-Amino-5-(4-benzyloxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-propionamide (A346)

N-{3-[6-Amino-5-(4-benzyloxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-propionamide (6.8% yield) was synthesized according to Method E. HPLC: 91%, RT: 4.18 min. MS: m/z = 441 [M+H] ⁺ , RT = 4.23 min. ¹ H-NMR: 400MHz, DMSO-d ₆ : δ9.90 (s, 1H), 8.01 (s, 1H), 7.46 (d, J=8.00Hz, 2H), 7.41-7.27 (m, 7H), 7.22 (t, J=8.00Hz, 1H), 7.10 (d, J=8 .00Hz, 2H), 6.70-6.67 (m, 1H), 6.45 (brs, 2H), 5.11 (s, 2H), 2.28 (q, J=8.00Hz, 2H), 1.05 (t, J=4.00Hz, 3H).

N-{3-[6-Amino-5-(4-benzyloxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloro-acetamide (A347)

N-{3-[6-Amino-5-(4-benzyloxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloro-acetamide (27.6% yield) was synthesized according to Method E. HPLC: 95%, RT: 4.31 min. MS: m/z = 461 [M+H] ⁺ , RT = 4.29 min. ¹ H-NMR: 400MHz, DMSO-d ₆ : δ10.35 (s, 1H), 8.02 (s, 1H), 7.46 (d, J = 8.00Hz, 2H), 7.39 (t, J = 4.00Hz, 2H), 7.35-7.26 (m , 6H), 7.10 (d, J=8.00Hz, 2H), 6.78-6.75 (m, 1H), 6.48 (brs, 2H), 5.11 (s, 2H), 4.22 (s, 2H).

N-{3-[6-Amino-5-(4-benzyloxy-3-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-acrylamide (A348)

N-{3-[6-Amino-5-(4-benzyloxy-3-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-acrylamide was synthesized (23.2% yield) according to Method E. HPLC: 98%, RT: 4.30 min. MS: m/z = 457 [M+H] ⁺ , RT = 4.35 min. 1H-NMR: 400MHz, DMSO-d ₆ : δ10.20 (s, 1H), 8.03 (s, 1H), 7.48-7.45 (m, 3H), 7.41 (t, J=8.00Hz, 2H), 7.38-7.25 (m, 5H), 7.15 (d, J=8.00Hz, 1H), 6.7 7-6.75 (m, 1H), 6.56 (brs, 2H), 6.40 (dd, J=16.00, 12.00Hz, 1H), 6.26-6.21 (m, 1H), 5.75 (d, J=8.00Hz, 1H), 5.19 (s, 2H).

N-{3-[6-Amino-5-(4-benzyloxy-2-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-acrylamide (A349)

N-{3-[6-Amino-5-(4-benzyloxy-2-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-acrylamide (11.8% yield) was synthesized according to Method E. HPLC: 97%, RT: 4.35 min. MS: m/z = 457 [M+H] ⁺ , RT = 4.39 min. 1H-NMR: 400MHz, DMSO-d ₆ : δ10.20 (s, 1H), 8.05 (s, 1H), 7.47-7.25 (m, 9H), 7.02 (d, J=12.00Hz, 1H), 6.95 (d, J=8.00Hz, 1H), 6.73- 6.70 (m, 1H), 6.60 (brs, 2H), 6.38-6.36 (m, 1H), 6.26-6.21 (m, 1H), 5.75 (d, J=8.00Hz, 1H), 5.13 (s, 2H).

N-{3-(6-amino-5-(4-benzyloxy-2-fluoro-phenyl)-pyrimidin-4-yloxy}-phenyl)-2-chloro- acetamide (A350)

N-{3-(6-Amino-5-(4-benzyloxy-2-fluoro-phenyl)-pyrimidin-4-yloxy}-phenyl)-2-chloro-acetamide was synthesized according to Method E. HPLC: 95%, RT: 4.52 min. MS: m/z = 479 [M+H] ⁺ , RT = 4.41 min. 1H-NMR: 400 MHz, DMSO- _d6 : δ 10.37 (s, 1H), 8.06 (s, 1H), 7.48-7.27 (m, 9H), 7.03 (d, J = 12.00 Hz, 1H), 6.95 (d, J = 8.00 Hz, 1H), 6.75 (d, J = 4.00 Hz, 1H), 6.59 (brs, 2H), 5.14 (s, 2H), 4.23 (s, 2H).

N-{3-[6-Amino-5-(4-benzyloxy-3-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloro- acetamide (A351)

N-{3-[6-Amino-5-(4-benzyloxy-3-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloro-acetamide (27.6% yield) was synthesized according to Method E. HPLC: 98%, RT: 4.39 min. MS: m/z = 479 [M+H] ⁺ , RT = 4.37 min. 1H-NMR: 400MHz, DMSO-d ₆ : δ10.35 (s, 1H), 8.02 (s, 1H), 7.48-7.47 (m, 2H), 7.41 (t, J=8.00Hz, 2H), 7.36-7.25 (m, 6 H), 7.15 (d, J=8.00Hz, 1H), 6.80-6.77 (m, 1H), 6.51 (brs, 2H), 5.19 (s, 2H), 4.23 (s, 2H).

N-{4-[4-(3-Acryloylamino-phenoxy)-6-amino-pyrimidin-5-yl]-phenyl}-benzamide (A352)

N-{4-[4-(3-Acryloylamino-phenoxy)-6-amino-pyrimidin-5-yl]-phenyl}-benzamide (8.8% yield) was synthesized according to Method E. HPLC: 92%, RT: 3.48 min. MS: m/z = 452 [M+H] ⁺ , RT = 3.53 min. 1H-NMR: 400 MHz, DMSO-d ₆ : δ10.36 (s, 1H), 10.20 (s, 1H), 8.04 (s, 1H), 7.95 (d, J=8.00Hz, 2H), 7.8 9(d, J=8.00Hz, 2H), 7.60-7.52(m, 3H), 7.46(s, 1H), 7.39-7.37(m, 3H), 7 .28 (t, J=8.00Hz, 1H), 6.77 (d, J=8.00Hz, 1H), 6.50 (brs, 2H), 6.40 (dd, J=16.00, 12.00Hz, 1H), 6.24 (d, J=16.00Hz, 1H), 6.75 (d, J=8.00Hz, 1H).

Biological activity

Overview of in vitro testing

BTK IC50 enzyme assay

The following describes a microfluidic off-chip mobility shift kinase assay for determining the intrinsic potency of compounds in inhibiting the BTK enzyme. Compounds described in the Examples were tested using this protocol, and the experimental data are reported in Table 2, under the column labeled "Time-Dependent BTK Enzyme Assay _IC50 ." These _IC50 values ranged from A <100 nM, B <1 μM, and C >1 μM.

A 2.5X stock solution of full-length human BTK (08-080) (from CarnaBio USA, Inc., Natick, MA), 1.6X ATP, and the appropriate kinKDR peptide substrate ₍ FITC-AHA-EEPLYWSFPAKKK-NH2) was prepared in kinase reaction buffer containing 25 mM MgCl2, 0.015% Brij-35 (30%), 100 mM Hepes, pH 7.5, and 10 mM DTT.

A mixture of 5 μL of enzyme buffer and 7.5 μL of ATP/kinKDR peptide substrate was added to a Matrix (#115304) 384-well sterile polypropylene plate (Thermo Fisher Scientific, Hudson, NH) containing 125 nL of serially diluted compounds in 100% DMSO and incubated for 90 minutes at 27° C. Following the incubation period, the reaction was terminated by adding 60 μL of stop buffer containing 100 mM Hepes, pH 7.5, 0.015% Brij-35 (30%), 0.277% coating reagent #3 (Caliper Life Sciences, Mountain View, CA), and 5% DMSO. The termination reaction was monitored on a LabChip 3000 microplate reader (set to -2 PSI, -3000 V/-700 V) purchased from Caliper Life Sciences, a PerkinElmer Company (Hopkinton, MA), and activity was determined by an off-chip mobility shift assay that measures the charge/mass difference between the substrate and the peptide phosphorylation product. IC50 and potency were determined by plotting the log inhibitor [inhibitor] versus the percentage of activity on a GeneData Screener (Basel, Switzerland). Compounds described in the Examples of the present invention were tested using this protocol, and the experimental data are recorded in Table 2, labeled "Time-dependent PBMC BTK enzyme assay _IC50 ". The range of these _IC50 values is: A <100 nM, B <1 μM, and C >1 μM.

I<1μM, II>1μM.

Time-dependent human whole blood IC50 test

The compounds described in the examples of this invention were tested using a human whole blood assay. The experimental data are reported in Table 2 in the column labeled "Time-dependent human whole blood BTK enzyme assay _IC50 ." The _IC50 values ranged from I < 1 μM to II > 1 μM.

Time-dependent PMBC IC50 assay

The compounds described in the examples of this invention were tested using a time-dependent PMBC assay. The experimental data are reported in Table 2 in the column labeled "Time-dependent PMBC enzyme assay _IC50 ." The _IC50 values ranged from I < 1 μM to II > 1 μM.

Table 2 lists the _IC50 values of selected compounds described in the Examples of the present invention, which were derived from the above-mentioned in vitro assays.

Table 2

Overview of in vitro data

Systemic lupus erythematosus (SLE) mouse model

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one, designated "CPD.B," was evaluated in an interferon-α-accelerated systemic lupus erythematosus mouse model. NZB/WF1 mice received intravenous injections of ¹⁰ infectious units of adenovirus (ADV-IFN-α) on days 0 and 1 to achieve transient overexpression of interferon-α. Oral dosing of the different groups was initiated on day 14 and continued every 24 hours until the end of the study. The different treatment groups included 20% Kleptose HPB in sodium citrate buffer (vehicle), or 0.1, 0.3, 1, or 3 mg/kg Cpd.B. Figure 1A shows the disease activity of each animal, which was calculated by the following formula: Disease activity = (0.5*(number of days with proteinuria for each animal/average number of days with proteinuria for control animals) + 0.5*(AUC for each animal/average AUC for control animals))*100. As shown in Figure 1B, CPD.B reduced disease activity in a dose-dependent manner, and the percentage of disease activity reduction was recorded for each experimental condition. Figure 2 shows another interferon-α-accelerated systemic lupus erythematosus experiment conducted on mice. NZB/W F1 mice received intravenous injections of 10 ⁸ infectious units of adenovirus (ADV-IFN-α) on days 0 and 1 to achieve transient overexpression of interferon-α. Different groups (n=10) started oral treatment on day 14 and continued dosing every 24 hours until the end of the study. The different treatment groups included 20% Kleptose HPB in sodium citrate buffer (vehicle), or 0.1, 0.3, 1 or 3 mg/kg Cpd.B or Cell Figure 2 shows the ratio of mean creatinine in urine at the indicated time points (standard error mean), which is an indicator of renal damage. Statistical analysis of all groups of animals was performed by two-way analysis of variance with Bonferroni post hoc test to compare with the group treated with vehicle (* = p < 0.05, ** = p < 0.01, *** = p < 0.001).

Rat collagen-induced arthritis model

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one, designated "CPD.A," was evaluated in a collagen-induced rat arthritis model. Female Lewis rats were anesthetized and received subcutaneous/intradermal injections of 300 μl of Freund's incomplete adjuvant containing bovine type II collagen at two sites, at the base of the tail and on the back, on days 0 and 6. The data shown in Figure 3 are from different treatment groups, with oral dosing initiated on day 6 and continued every 24 hours for 11 days until day 16. Treatment groups included 20% hydroxy-propyl-α-cyclodextrin in water (vehicle), or 0.3, 1, 3, or 10 mg/kg CPD.A, or 0.1 mg/kg methotrexate (MTX). Ankle size was measured daily with a caliper starting on day 9 (or day 0 of arthritis). Animals were sacrificed on day 17.

Mouse collagen-induced arthritis model

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one, designated "CPD.A," was evaluated in a collagen-induced mouse arthritis model. Male DBA/101aHsd mice received intradermal injections of 150 μl of Freund's complete adjuvant containing bovine type II collagen at the base of the tail on days 0 and 21. The data shown in Figure 4 are from this experiment. On day 18, mice were randomly divided into treatment groups based on body weight. Oral treatment was initiated after group assignment on day 18 and continued every 24 hours until day 33. Mice were treated with 20% hydroxypropyl-α-cyclodextrin in water (vehicle), 1, 3, 10, or 30 mg/kg CPD.A, or 0.5 mg/kg methotrexate (MTX). Arthritis developed between study days 22 and 34. Mice were sacrificed on day 34. Clinical scoring was performed on each paw (anterior right, anterior left, posterior right, posterior left) on days 18-34 of arthritis.

Passive cutaneous anaphylaxis (PCA) in mice

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one, designated "CPD.B," was evaluated in a PCA mouse model. In vivo, anaphylaxis mediated by the FceRI receptor is a mast cell-dependent allergic response to local or systemic exposure to an allergen. The allergen cross-links or activates antigen-specific IgE, which binds to FceRI on the surface of mast cells, leading to mast cell activation and degranulation. The mouse PCA model mimics these events in vivo and can be used to test the efficacy of newly developed compounds targeting tyrosine kinases downstream of FceRI-like BTK. The data shown in Figure 5 are from experiments in which 10-week-old BALB/c female mice received intradermal injections of immunoglobulin E (IgE) directed against the hapten 2,4-dinitrophenyl (DNP). Twenty-four hours after sensitization, mice were challenged systemically with DNP conjugated to human serum albumin (HSA) and Evans blue dye. Mice were orally administered CpdB three times daily. Thirty minutes after challenge, Evans blue extravasation was measured on the animals' backs.

Anti-IgD-induced CD69 upregulation in mouse whole blood

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one, designated "CPD.B," was evaluated in an anti-IgD-induced CD69 upregulation model in mouse whole blood. The data are shown in Figure 6 . BCR activation induces expression of cluster of differentiation antigen 69 (CD69), the earliest inducible cell surface glycoprotein during lymphoid activation and currently used as a marker for B cell activation in vivo and in vitro. One hour before blood collection, C57Bl/6 female mice were orally administered cyclodextrin or 1.19, 3.96, or 11.9 mg/kg of Cpd.B. Half an hour after intraperitoneal injection of heparin, blood was collected in heparinized tubes, and B cells were stimulated for 4 hours with 10 μl of PBS or polyclonal goat anti-mouse IgD antiserum. Individual cells were analyzed by flow cytometry and assayed for CD69 upregulation using rat anti-mouse B220-PerCP-Cy5.5 and hamster anti-mouse CD69-PE monoclonal antibodies for immunostaining.

Technical Field

Background of the Invention

Summary of the Invention

Where:

X represents CH or N,

R ¹ represents NH ₂ , CONH ₂ or H,

R ² represents Hal, Ar ¹ or Het ¹ ,

R ⁴ represents H, CH ₃ or NH ₂ ,

R ⁵ represents H or an alkyl group containing 1, 2, 3 or 4 C atoms,

Hal represents F, Cl, Br or I,

n represents 0, 1, 2, 3 or 4,

p means 1, 2, 3, 4, 5 or 6,

X represents CH or N,

R ¹ represents NH ₂ , CONH ₂ or H,

R ² represents Hal, Ar ¹ or Het ¹ ,

^R4 represents H,

R ⁵ represents H or an alkyl group containing 1, 2, 3 or 4 C atoms,

Hal represents F, Cl, Br or I,

n represents 0, 1, 2, 3 or 4,

p represents 1, 2, 3, 4, 5 or 6.

X is H or CH ₃ or NH ₂ ,

Y is H, Hal or does not exist,

B is N or CH,

E is _NH2 or H,

W is NR, O or cyclic amine,

Hal is F, Cl, Br or I,

r is 1-4,

n is 0-4, and

Table 1

X is O or NH,

Y is N or CH,

W is H, NH ₂ or CONH ₂ ,

Q is H or NH ₂ ,

^R1 is ^L1 ^–R4 –L2 ^–R5 ^,

^R2 is ^M1 - ^S4 - ^M2 - ^S5

^M1 is a single bond,

M ² O, NH, CH ₂ or not present,

Hal is F, Cl, Br or I.

Z is N or CH,

X is O or NH, and

^R3 is selected from the group consisting of the following structures:

Wherein, "R" represents the binding point with Z in the general formula IV.

in:

X represents CH or N,

R ¹ represents NR ⁵ [C(R ⁵ ) ₂ ] _n Het ² ,

R ² represents Hal, Ar ¹ or Het ¹ ,

R ³ represents NH ₂ ,

R ⁴ represents H, CH ₃ or NH ₂ ,

R ⁵ represents H or an alkyl group containing 1, 2, 3 or 4 C atoms,

Hal represents F, Cl, Br or I,

n represents 0, 1, 2, 3 or 4,

p means 1, 2, 3, 4, 5 or 6,

BRIEF DESCRIPTION OF THE DRAWINGS

DETAILED DESCRIPTION

b) an effective amount of another pharmaceutically active ingredient.

Experimental part

Certain abbreviations that may appear in this application are as follows:

abbreviation

Synthesis method

Process 1

Process 2

Methods related to the reaction steps in Schemes 1 and 2

Method A: Nucleophilic Aromatic Substitution Using Oxygen Nucleophiles

6-(3-aminophenoxy)-5-chloropyrimidin-4-amine

Method B: Nucleophilic Aromatic Substitution Using a Nitrogen Nucleophile

Method C: Suzuki coupling

6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine

Method D: Deprotection of tert-butyloxycarbonyl (BOC)-protected amines

5-(4-Phenoxyphenyl)-N-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine

Method E: Amide formation from carboxylic acid

N-(3-{[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]oxy}phenyl)acrylamide

N-[(1-Acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide

Method H: Nucleophilic Aromatic Substitution Using Aromatic Amines

N4-(3-Aminophenyl)-5-chloropyrimidine-4,6-diamine

Method I: Nucleophilic Aromatic Substitution Using Nitrogen Nucleophiles

4-(((6-amino-5-chloropyrimidin-4-yl)amino)methyl)piperidin-2-one

Process 3

Methods related to the reaction steps in Scheme 3

Method S1: Nucleophilic Aromatic Substitution

Method S2: Suzuki coupling

Method S3: Deprotection of tert-butyloxycarbonyl-protected amines

5-(4-Phenoxyphenyl)-N ⁴ -(2-azaspiro[3.3]hept-6-yl)pyrimidine-4,6-diamine

Method S3A: Deprotection of tert-butyloxycarbonyl-protected amines

5-(4-Phenoxyphenyl)-N ⁴ -(2-azaspiro[3.3]hept-6-yl)pyrimidine-4,6-diamine

Method S4A: Amide Generation Using T3P

Method S4B: Amide Formation Using Acid Chloride in Pyridine

Method S4C: Amide formation using acid chloride in THF

Method S4D: Amide Formation Using BOP-Cl

Process 4

Methods related to the reaction steps in Scheme 4

Method AA: Nucleophilic Aromatic Substitution

(4-(6-Amino-5-chloro-pyrimidin-4-ylamino)-phenyl)-acetic acid ethyl ester

Method BB: Suzuki coupling

Method CC: Ester Hydrolysis

(4-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-acetic acid

Method DD: Weinreb Amide Synthesis

Method EE: Synthesis of Weinreb's Ketone Using 1-Propylenmagnesium Bromide

1-(4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-pent-3-en-2-one

Method FF: Synthesis of Weinreb's Ketone Using 1-Propylenmagnesium Bromide

1-(4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-pent-3-yn-2-one

Method GG: Synthesis of Weinreb's ketone using vinylmagnesium bromide

1-(3-((Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-propenone

Analytical methods

Analytical LC/MS was performed using the following three methods:

HPLC purity determination

General Methods for Preparative HPLC

Example

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (A3)

N-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)acrylamide (A18)

N-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)ethyl)acrylamide (A27)

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)butyl)acrylamide (A50)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)propyl)acrylamide (A59)

N-(3-((2-amino-3-(4-(benzyloxy)phenyl)pyridin-4-yl)oxy)phenyl)acrylamide (A149)

N-(3-((6-amino-5-(3-sulfamoylphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A163)

N-(6-((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyridin-2-yl)acrylamide

MSC2375022(A167)

N-(3-(4-amino-6-((4-phenoxyphenyl)amino)pyrimidin-5-yl)phenyl)acrylamide (A241)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A242)

N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide (A243)

N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide (A244)

N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)acrylamide (A245)

N-(3-((5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A255)

4-(4-(3-Acrylamidophenoxy)-6-aminopyrimidin-5-yl)-N-phenylbenzamide (A258)

N-(3-(4-((4-phenoxyphenyl)amino)pyridin-3-yl)phenyl)acrylamide (A267)

N-(3-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide (A270)

N-(3-((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A271)

3-(3-Acrylamidophenyl)-4-(4-phenoxyphenoxy)picolinamide (A272)

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A280)

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide (A281)

N-(3-(4-((4-phenoxyphenyl)amino)pyrimidin-5-yl)phenyl)acrylamide (A283)

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide (A287)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-ynamide (A296)

N-(4-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide (A297)

3-(3-Aminophenyl)-4-(4-phenoxyphenoxy)pyridin-2-amine (A300)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide (A302)

6-(4-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine (A303)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2-ynamide (A304)

6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine (A305)

N-(3-(2-amino-4-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)acrylamide (A306)

(E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide (A307)

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)propionamide (A308)

N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide (A310)

3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline (A312)

4-(3-Aminophenoxy)-3-(4-phenoxyphenyl)pyridin-2-amine (A313)

4-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline (A314)

(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine (A315)

(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine (A316)

5-(3-Aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine (A317)

N-(3-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)propionamide (A318)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide (A319)

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide (A320)

N-(4-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)propionamide (A321)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methacrylamide (A322)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide (A323)

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide (A324)

N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)propionamide (A325)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)propionamide (A326)

(E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2-enamide (A327)

3-(4-Phenoxyphenyl)-4-(3-propionylaminophenoxy)picolinamide (A328)

N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)but-2-ynamide (A340)

Biological activity

Overview of in vitro testing

BTK IC50 enzyme assay

I<1μM, II>1μM.

Time-dependent human whole blood IC50 test

Time-dependent PMBC IC50 assay

Table 2

Overview of in vitro data

Systemic lupus erythematosus (SLE) mouse model

Rat collagen-induced arthritis model

Mouse collagen-induced arthritis model

Passive cutaneous anaphylaxis (PCA) in mice

Anti-IgD-induced CD69 upregulation in mouse whole blood

Technical Field

Background of the Invention

Summary of the Invention

Where:

X represents CH or N,

R ¹ represents NH ₂ , CONH ₂ or H,

R ² represents Hal, Ar ¹ or Het ¹ ,

R ⁴ represents H, CH ₃ or NH ₂ ,

R ⁵ represents H or an alkyl group containing 1, 2, 3 or 4 C atoms,

Hal represents F, Cl, Br or I,

n represents 0, 1, 2, 3 or 4,

p means 1, 2, 3, 4, 5 or 6,

X represents CH or N,

R ¹ represents NH ₂ , CONH ₂ or H,

R ² represents Hal, Ar ¹ or Het ¹ ,

^R4 represents H,

R ⁵ represents H or an alkyl group containing 1, 2, 3 or 4 C atoms,

Hal represents F, Cl, Br or I,

n represents 0, 1, 2, 3 or 4,

p represents 1, 2, 3, 4, 5 or 6.

X is H or CH ₃ or NH ₂ ,

Y is H, Hal or does not exist,

B is N or CH,

E is _NH2 or H,

W is NR, O or cyclic amine,

Hal is F, Cl, Br or I,

r is 1-4,

n is 0-4, and

Table 1

X is O or NH,

Y is N or CH,

W is H, NH ₂ or CONH ₂ ,

Q is H or NH ₂ ,

^R1 is ^L1 ^–R4 –L2 ^–R5 ^,

^R2 is ^M1 - ^S4 - ^M2 - ^S5

^M1 is a single bond,

M ² O, NH, CH ₂ or not present,

Hal is F, Cl, Br or I.

Z is N or CH,

X is O or NH, and

^R3 is selected from the group consisting of the following structures:

Wherein, "R" represents the binding point with Z in the general formula IV.

in:

X represents CH or N,

R ¹ represents NR ⁵ [C(R ⁵ ) ₂ ] _n Het ² ,

R ² represents Hal, Ar ¹ or Het ¹ ,

R ³ represents NH ₂ ,

R ⁴ represents H, CH ₃ or NH ₂ ,

R ⁵ represents H or an alkyl group containing 1, 2, 3 or 4 C atoms,

Hal represents F, Cl, Br or I,

n represents 0, 1, 2, 3 or 4,

p means 1, 2, 3, 4, 5 or 6,

BRIEF DESCRIPTION OF THE DRAWINGS

DETAILED DESCRIPTION

b) an effective amount of another pharmaceutically active ingredient.

Experimental part

Certain abbreviations that may appear in this application are as follows:

abbreviation

Synthesis method

Process 1

Process 2

Methods related to the reaction steps in Schemes 1 and 2

Method A: Nucleophilic Aromatic Substitution Using Oxygen Nucleophiles

6-(3-aminophenoxy)-5-chloropyrimidin-4-amine

Method B: Nucleophilic Aromatic Substitution Using a Nitrogen Nucleophile

Method C: Suzuki coupling

6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine

Method D: Deprotection of tert-butyloxycarbonyl (BOC)-protected amines

5-(4-Phenoxyphenyl)-N-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine

Method E: Amide formation from carboxylic acid

N-(3-{[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]oxy}phenyl)acrylamide

N-[(1-Acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide

Method H: Nucleophilic Aromatic Substitution Using Aromatic Amines

N4-(3-Aminophenyl)-5-chloropyrimidine-4,6-diamine

Method I: Nucleophilic Aromatic Substitution Using Nitrogen Nucleophiles

4-(((6-amino-5-chloropyrimidin-4-yl)amino)methyl)piperidin-2-one

Process 3

Methods related to the reaction steps in Scheme 3

Method S1: Nucleophilic Aromatic Substitution

Method S2: Suzuki coupling

Method S3: Deprotection of tert-butyloxycarbonyl-protected amines

5-(4-Phenoxyphenyl)-N ⁴ -(2-azaspiro[3.3]hept-6-yl)pyrimidine-4,6-diamine

Method S3A: Deprotection of tert-butyloxycarbonyl-protected amines

5-(4-Phenoxyphenyl)-N ⁴ -(2-azaspiro[3.3]hept-6-yl)pyrimidine-4,6-diamine

Method S4A: Amide Generation Using T3P

Method S4B: Amide Formation Using Acid Chloride in Pyridine

Method S4C: Amide formation using acid chloride in THF

Method S4D: Amide Formation Using BOP-Cl

Process 4

Methods related to the reaction steps in Scheme 4

Method AA: Nucleophilic Aromatic Substitution

(4-(6-Amino-5-chloro-pyrimidin-4-ylamino)-phenyl)-acetic acid ethyl ester

Method BB: Suzuki coupling

Method CC: Ester Hydrolysis

(4-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-acetic acid

Method DD: Weinreb Amide Synthesis

Method EE: Synthesis of Weinreb's Ketone Using 1-Propylenmagnesium Bromide

1-(4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-pent-3-en-2-one

Method FF: Synthesis of Weinreb's Ketone Using 1-Propylenmagnesium Bromide

1-(4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-pent-3-yn-2-one

Method GG: Synthesis of Weinreb's ketone using vinylmagnesium bromide

1-(3-((Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-propenone

Analytical methods

Analytical LC/MS was performed using the following three methods:

HPLC purity determination

General Methods for Preparative HPLC

Example

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (A3)

N-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)acrylamide (A18)

N-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)ethyl)acrylamide (A27)

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)butyl)acrylamide (A50)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)propyl)acrylamide (A59)

N-(3-((2-amino-3-(4-(benzyloxy)phenyl)pyridin-4-yl)oxy)phenyl)acrylamide (A149)

N-(3-((6-amino-5-(3-sulfamoylphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A163)

N-(6-((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyridin-2-yl)acrylamide

MSC2375022(A167)

N-(3-(4-amino-6-((4-phenoxyphenyl)amino)pyrimidin-5-yl)phenyl)acrylamide (A241)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A242)

N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide (A243)

N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide (A244)

N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)acrylamide (A245)

N-(3-((5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A255)

4-(4-(3-Acrylamidophenoxy)-6-aminopyrimidin-5-yl)-N-phenylbenzamide (A258)

N-(3-(4-((4-phenoxyphenyl)amino)pyridin-3-yl)phenyl)acrylamide (A267)

N-(3-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide (A270)

N-(3-((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A271)

3-(3-Acrylamidophenyl)-4-(4-phenoxyphenoxy)picolinamide (A272)

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A280)

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide (A281)

N-(3-(4-((4-phenoxyphenyl)amino)pyrimidin-5-yl)phenyl)acrylamide (A283)

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide (A287)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-ynamide (A296)

N-(4-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide (A297)

3-(3-Aminophenyl)-4-(4-phenoxyphenoxy)pyridin-2-amine (A300)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide (A302)

6-(4-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine (A303)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2-ynamide (A304)

6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine (A305)

N-(3-(2-amino-4-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)acrylamide (A306)

(E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide (A307)

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)propionamide (A308)

N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide (A310)

3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline (A312)

4-(3-Aminophenoxy)-3-(4-phenoxyphenyl)pyridin-2-amine (A313)

4-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline (A314)

(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine (A315)

(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine (A316)

5-(3-Aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine (A317)

N-(3-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)propionamide (A318)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide (A319)

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide (A320)

N-(4-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)propionamide (A321)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methacrylamide (A322)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide (A323)

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide (A324)

N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)propionamide (A325)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)propionamide (A326)

(E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2-enamide (A327)

3-(4-Phenoxyphenyl)-4-(3-propionylaminophenoxy)picolinamide (A328)

N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)but-2-ynamide (A340)

Biological activity

Overview of in vitro testing

BTK IC50 enzyme assay

I<1μM, II>1μM.

Time-dependent human whole blood IC50 test

Time-dependent PMBC IC50 assay

Table 2

Overview of in vitro data

Systemic lupus erythematosus (SLE) mouse model

Rat collagen-induced arthritis model

Mouse collagen-induced arthritis model

Passive cutaneous anaphylaxis (PCA) in mice

Anti-IgD-induced CD69 upregulation in mouse whole blood

Claims

1. A compound selected from the group consisting of,

And its pharmaceutically available salts and tautomers, including mixtures of them in all proportions.

2. The compound represented by general formula II,

In the formula,

X is H, _CH3 , or _NH2 .

Y does not exist.

B is CH.

E is _NH₂ or H.

W is NR, O, or a cyclic amine.

Z can be _CH₂ , _CH₂ - _CH₂ , CH- _CH₂ , NH, or it may not exist.

The "connector" is ( _CH₂ ) _ₙ , where n is 1, 2, or 3, or optionally substituted groups selected from benzene rings, branched or straight-chain alkyl groups, 5-6 membered monocyclic heteroaromatic rings containing 1-4 heteroatoms independently selected from nitrogen or oxygen, 4-7 membered saturated or partially unsaturated heterocycles containing 1-3 heteroatoms independently selected from nitrogen or oxygen, or 7-10 membered bicyclic saturated or partially unsaturated heterocycles containing 1-5 heteroatoms independently selected from nitrogen or oxygen, or 7-10 membered bicyclic saturated or partially unsaturated heterocycles containing 1-5 heteroatoms attached to a saturated heterocycle; the connector can also be a cycloalkanes optionally substituted with heteroatoms independently selected from nitrogen or oxygen, cycloalkanes optionally substituted with -NH or OH, cycloalkanes containing fused or bridged rings, or cycloalkanes containing optionally substituted spiro rings, wherein the spiro ring optionally contains heteroatoms.

A is a monocyclic or bicyclic aromatic carbocyclic ring or heterocyclic ring containing 0, 1, 2, 3, or 4 N and/or O oxygen atoms and 5, 6, 7, 8, 9, or 10 skeletal C atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or independently monosubstituted, disubstituted, or trisubstituted by Hal, OH, or OR.

Hal can be F, Cl, Br, or I.

R is independently hydrogen, oxygen, or a optionally substituted group, wherein the optionally substituted group is selected from _C1-6 straight-chain or cyclic aliphatic groups, benzyl, phenyl, phenyl optionally substituted with 1, 2, or 3 oxygen atoms, 4-7 membered heterocycles containing 1-2 heteroatoms independently selected from nitrogen or oxygen, or 5-6 membered monocyclic heteroaromatic rings containing 1-4 heteroatoms independently selected from nitrogen or oxygen, or monocyclic or bicyclic aromatic carbocyclic or heterocyclic rings containing 0, 1, 2, 3, or 4 nitrogen or oxygen atoms and 5, 6, 7, or 8 skeletal carbon atoms, wherein the carbocyclic or heterocyclic ring may be unsubstituted or independently monosubstituted, disubstituted, or trisubstituted with Hal, A, OH, _NH2 , nitrile, and/or CH(Hal) ₃ , or straight-chain or branched linear alkyl groups containing 1, 2, 3, 4, 5, 6, 7, or 8 C atoms, with one or two CH... _{The two} groups can be replaced by an O atom and/or by –NH-, -CO-, -NHCOO-, -NHCONH-, -CONH-, -NHCO- or –CH＝CH-, and 1-3 of the hydrogen atoms can be replaced by Hal.

R ^q is selected from -R, -A, halogen, -OR, -O( _CH₂ ) _rOR , -R(NH), _-NO₂ , -C(O)R, _-CO₂R , -C(O)N(R) _₂ , -NRC(O)R, -NRC(O) _NR₂ , _-NRSO₂R , or -N(R) _₂ .

r is 1-4,

n is 0-4, and

Q is an electrophilic group, which is selected from...