OA19500A - Amine-substituted Aryl or Heteroaryl compounds as Ehmt1 and Ehmt2 inhibitors. - Google Patents

Abstract

The present disclosure relates to aminesubstituted aryl or heteroaryl compounds. The present disclosure also relates to pharmaceutical compositions containing these compounds and methods of treating a disorder (e.g., sickle cell anemia) via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2, by administering an amine-substituted aryl or heteroaryl compound disclosed herein or a pharmaceutical composition thereof to subjects in need thereof. The present disclosure also relates to the use of such compounds for research or other non-therapeutic purposes. <img file="OA19500A_A0001.tif"/>

Description

AMINE-SUBSTITUTED ARYL OR HETEROARYL COMPOUNDS

Related Applications

This application daims priority to, and the benefit of, U.S. Provisional Application Nos.

62/323,602 filed April 15, 2016; 62/348,837 filed June 10, 2016 and 62/402,997 filed

September 30, 2016; the entire contents of each of which are incorporated herein by reference.

Background

Méthylation of protein lysine residues is an important signaling mechanism in eukaryotic 10 cells, and the méthylation state of histone lysines encodes signais that are recognized by a multitude of proteins and protein complexes in the context of epigenetic gene régulation. Histone méthylation is catalyzed by histone methyltransferases (HMTs), and HMTs hâve been implicated in various human diseases. HMTs can play a rôle in either activating or repressing gene expression, and certain HMTs (e.g., euchromatic histone-lysine N15 methyltransferase 2 or EHMT2, also called G9a) may methylate many nonhistone proteins, such as tumor suppressor proteins (see, e.g., Liu et al., Journal of Médicinal Chemistry 56:8931-8942, 2013 and Krivega et al., Blood 126(5):665-672, 2015).

Two related HMTs, EHMT1 and EHMT2, are overexpressed or play a rôle in diseases and disorders such as sickle cell anémia (see, e.g., Renneville et al., Blood 126(16): 1930-1939, 20 2015) and proliférative disorders (e.g., cancers), and other blood disorders.

SUMMARY

In one aspect, the présent disclosure features an amine-substituted aryl or heteroaryl compound of Formula (I) below:

or a tautomer thereof, or a pharmaceutically acceptable sait of the compound or the tautomer.

In Formula (I) above, ring Ά is phenyl or a 5- or 6-membered heteroaryl;

X¹ is N, CR², or NR²’ as valency permits;

X² is N, CR³, or NR³’ as valency permits;

X³ is N, CR⁴, or NR⁴’ as valency permits;

X⁴ is N or CR⁵, or X⁴ is absent such that ring A is a 5-membered heteroaryl containing at least one N atom;

X⁵ is C or N as valency permits;

B is absent or a ring structure selected from the group consisting of Cô-Cio aryl, C₃Cio cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S;

T is a bond or Ci-C₆ alkylene, C₂-C₆ alkenylene, or C₂-C₆ alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo; or Ci-Cô alkoxy when 10 B is présent; or T is H and n is 0 when B is absent; or T is Ci-C₆ alkyl optionally substituted with (R⁷)n when B is absent; or when B is absent, T and R¹ together with the atoms to which they are attached optionally form a 4-7 membered heterocycloalkyl or 5-6 membered η heteroaryl, each of which is optionally substituted with (R )n;

R¹ is H or C1-C4 alkyl;

each of R², R³, and R⁴, independently is selected from the group consisting of H, halo, cyano, Ci-C₆ alkoxyl, C₆-Ci₀ aryl, NR^aR^b, C(O)NR^aR^b, NR^aC(0)R^b, C₃-C₈ cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, and Ci-Cô alkyl, wherein Ci-Cô alkoxyl and Ci-Cô alkyl are optionally substituted with one or more of halo, OR^a, or NR^aR^b, in which each of R^a and R^b independently is H or Ci-Cô alkyl, or R³ is -Q'-T¹, in which Q¹ is a bond or Ci-C₆ alkylene, C₂-C₆ alkenylene, or C₂-C₆ alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or Ci-Cô alkoxyl, and T¹ is H, halo, cyano, NR⁸R⁹, C(O)NR⁸R⁹, OR⁸, OR⁹, or R^S1, in which R^S1 is C₃-C₈ cycloalkyl, phenyl, 4- to 12membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R^SI is optionally substituted with one or more of halo, Ci-Cô alkyl, hydroxyl, oxo, -C(O)R⁹, -SO2R⁸, -SO2N(R⁸)₂, -NR⁸C(O)R⁹, amino, mono- or dialkylamino, or Ci-Cô alkoxyl;; or when ring A is a 5-membered heteroaryl containing at least one N atom, R⁴ is a spiro-fused 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S;

each of R²’, R³’ and R⁴’ independently is H or Ci-C₃ alkyl;

R⁵ is selected from the group consisting of H, F, Br, cyano, Ci-Cô alkoxyl, Cô-Cio aryl, NR^aR^b, C(O)NR^aR^b, NR^aC(0)R^b, C3-C8 cycloalkyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, Cj-Cô alkyl optionally substituted with one or more of halo, OR^a or NR^aR^b, and C2-Cô alkynyl optionally substituted with 4- to 12membered heterocycloalkyl; wherein said C₃-C₈ cycloalkyl or 4- to 12-membered heterocycloalkyl are optionally substituted with one or more of halo, C(O)R^a, OR^a, NR^aR^b, 4to 7-membered heterocycloalkyl, -Ci-Cô alkylene-4- to 7-membered heterocycloalkyl, or CiC4 alkyl optionally substituted with one or more of halo, OR^a or NR^aR^b, in which each of R^a and R^b independently is H or Ci-Cô alkyl; or

R⁵ and one of R³ or R⁴ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R⁵ and one of R³’or R⁴’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl;

jo R⁶ is absent when X⁵ is N and ring A is a 6-membered heteroaryl; or R⁶ is -Q’-T¹, in which Q¹ is a bond or Ci-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or Ci-Cô alkoxyl, and T¹ is H, halo, cyano, NR⁸R⁹, C(O)NR⁸R⁹, C(O)R⁹, OR⁸, OR⁹, or R^S1, in which R^S1 is C3-C₈ cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R^S1 is optionally substituted with one or more of halo, Ci-Cô alkyl, hydroxyl, oxo, -C(O)R⁹, -SO2R⁸, -SO2N(R⁸)₂, -NR⁸C(O)R⁹, NR⁸R⁹, or Ci-Cô alkoxyl; and R⁶ is not NR⁸C(O)NR¹²R¹³; or

R⁶ and one of R² or R³ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R⁶ and one of R²’or R³’ together with the atoms 20 to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl, oxo (=0), C1-C3 alkoxyl, or -Q^T¹;

each R⁷ is independently oxo (=0) or -Q²-T², in which each Q² independently is a bond or Ci-Cô alkylene, C₂-C₆ alkenylene, or C₂-C₆ alkynylene linker optionally substituted 25 with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or Cj-Cô alkoxyl, and each T² independently is H, halo, cyano, OR¹⁰, OR¹¹, C(O)Rⁿ, NR¹⁰R^H, C(O)NR¹⁰Rⁿ, NR¹⁰C(O)R¹¹, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl, or 4- to 12membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the 5- to 10-membered heteroaryl, C3-C8 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, Ci-Cô alkyl optionally substituted with NR^xR^y, hydroxyl, oxo, N(R⁸)2, cyano, Ci-Cô haloalkyl, -SO2R⁸, or Ci-Cô alkoxyl, each of R^x and R^y independently being H or Ci-Cô alkyl; and R7 is not H or C(O)OR^g; or optionally, when B is présent, one R⁷ and R⁵ together form a C3-C10 alkylene, C2-Cio heteroalkylene, C4-C10 alkenylene, C₂-Cio heteroalkenylene, C4-C10 alkynylene or C₂

Cio heteroalkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxyl;

each R⁸ independently is H or Ci-Cô alkyl;

each R⁹ is independently -Q³-T³, in which Q³ is a bond or Ci-Cô alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxyl, and T³ is H, halo, OR¹², OR¹³, NR¹²R¹³, NR¹²C(O)R¹³, C(O)NR¹²R¹³, C(O)R¹³, S(O)2R¹³, S(O)2NR¹²R¹³, or R^S2, in which R^S2 is C3-C₈ cycloalkyl, C₆-Cio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and R^S2 is optionally substituted with one or more -Q⁴-T⁴, wherein each Q⁴ independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-C6 alkoxy, and each T⁴ independently is selected from the group consisting of H, halo, cyano, CrC₆ alkyl, C₃-C₈ cycloalkyl, C₆-Ci₀ aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^C, C(O)R^C, S(O)₂R^C, NR^cR^d, C(O)NR^cR^d, and NR^cC(O)R^d, each of R^c and R^d independently being H or Cj-Cô alkyl; or -Q⁴-T⁴ is oxo; or

R⁸ and R⁹ taken together with the nitrogen atom to which they are attached form a 4to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, which is optionally substituted with one or more of-Q⁵-T⁵, wherein each Q⁵ independently is a bond or Ci-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁵ independently is selected from the group consisting of H, halo, cyano, Ci-C6 alkyl, C₃-C₈ cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^e, C(O)R^e, S(O)2R^e, S(O)2NR^eR^f, NR^eR^f, C(O)NR^eR^f, and NR^eC(0)R^f, each of R^e and R^f independently being H or Ci-C₆ alkyl; or -Q⁵-T⁵ is oxo;

R¹⁰ is selected from the group consisting of H and Ci-Cô alkyl;

R¹¹ is -Q⁶-T⁶, in which Q⁶ is a bond or C]-C6 alkylene, C2-Cô alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or Ci-C6 alkoxyl, and T⁶ is H, halo, OR^g, NR^gR^h, NR^gC(O)R^h, C(O)NR^gR^h, C(O)R^g, S(O)2R^g, or R^S3, in which each of R^g and R^h independently is H, phenyl, C3-C8 cycloalkyl, or Cj-Cô alkyl optionally substituted with C3-C8 cycloalkyl, or R^g and R^h together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and R^S3 is C3-C₈ cycloalkyl, Cô-Cio aryl, 4- to 12 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, or a 5- to 10-membered heteroaryl, and R is optionally substituted with one or more -Q -T , wherein each Q⁷ independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁷ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C3-Cs cycloalkyl, C6-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^J, C(O)R^j, NR^jR^k, C(O)NR^jR^k, S(O)2R^j, and NR^jC(O)R^k, each of R^j and R^k independently being H or Ci-C₆ alkyl optionally substituted with one or more halo; or -Q -T is oxo; or

R¹⁰ and R¹¹ taken together with the nitrogen atom to which they are attached form a 4to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, which is optionally substituted with one or more of halo, Ci-Cô alkyl, hydroxyl, or Ci-Cô alkoxyl;

R¹² is H or Ci-Cô alkyl;

R¹³ is Ci-C6 alkyl, C3-C8 cycloalkyl, C6-Cio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more -Q⁸-T⁸, wherein each Q⁸ independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁸ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C3-C8 cycloalkyl, Cô-Ci0 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl; or -Q⁸-T⁸ is oxo; and n is 0, 1, 2, 3, or 4.

In certain embodiments, the compound of Formula (I) is not 4-(((2-(( 1 -acetylindolin-6yl)amino)-6-(trifluoromethyl)pyrimidin-4-yl)amino)methyl)benzenesulfonamide, 5-bromo-N⁴-(4-fluorophenyl)-N²-(4-methoxy-3-(2-(pyrrolidin-lyl)ethoxy)phenyl)pyrimidine-2,4-diamine,

N²-(4-methoxy-3-(2-(pyrrolidin-l-yl)ethoxy)phenyl)-N⁴-(5-(tert-pentyl)-lH-pyrazol3-yl)pyrimidine-2,4-diamine,

4-((2,4-dichloro-5-methoxyphenyl)amino)-2-((3-(2-(pyrrolidin-lyl)ethoxy)phenyl)amino)pyrimidine-5-carbonitrile,

N-(naphthalen-2-yl)-2-(piperidin-l-ylmethoxy)pyrimidin-4-amine, N-(3,5-difluorobenzyl)-2-(3-(pyrrolidin-l-yl)propyl)pyrimidin-4-amine, N-(((4-(3-(piperidin-l-yl)propyl)pyrimidin-2-yl)amino)methyl)benzamide,

N-(2-((2-(3-(dimethylamino)propyl)pyrimidin-4-yl)amino)ethyl)benzamide, 2-(hexahydro-4-m ethyl-1 H-1,4-diazepin-1 -yl)-6,7-dimethoxy-N-[ 1 -(phenylmethyl)-4piperidinyl]-4-quinazolinamine,

2-cyclohexyl-6-methoxy-N-[ 1 -(1 -methylethyl)-4-piperidinyl]-7-[3-(lpyrrolidinyl)propoxy]-4-quinazolinamine,

3-(l-cyano-l-methylethyl)-7V-[3-[(3,4-dihydro-3-methyl-4-oxo-6quinazolinyl)amino]-4-methylphenyl]benzamide,

6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-l-ylpyridin-2-yl)amino]pyrido[2,3d] pyrimidin-7-one,

N-[2-[[4-(Diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3c/]pyrimidin-7-yl]-N’-(l, 1 -dimethylethyl)urea, or

6-[[2-[[4-(2,4-dichlorophenyl)-5-(5-methyl-lH-imidazol-2-yl)-2pyrimidinyl]amino]ethyl]amino]-3-pyridinecarbonitrile.

In certain embodiments, when T is a bond, B is substituted phenyl, and R is NR R , in which R⁹ is -Q³-R^S2, and R^S2 is optionally substituted 4- to 7-membered heterocycloalkyl or a 5- to 6-membered heteroaryl, then B is substituted with at least one substituent selected from (i) Q²-OR^h in which R¹¹ is -Q⁶-R^S3 and Q⁶ is optionally substituted C₂-Ce alkylene, C₂-C₆ alkenylene, or C₂-Ce alkynylene linker and (ii) -Q²-NR¹⁰R^H in which R¹¹ is -Q⁶-R^S3.

In certain embodiments, when T is a bond and B is optionally substituted phenyl, then R⁶ is not OR⁹ or NR⁸R⁹ in which R⁹ is optionally substituted naphthyl.

In certain embodiments, when T is a bond and B is optionally substituted phenyl, naphthyl, indanyl or 1,2,3,4-tetrahydronaphthyl, then R⁶ is not NR⁸R⁹ in which R⁹ is optionally substituted phenyl, naphthyl, indanyl or 1,2,3,4-tetrahydronaphthyl.

In certain embodiments, when T is a bond and B is optionally substituted phenyl or thiazolyl, then R is not optionally substituted imidazolyl, pyrazolyl, pyridyl, pyrimidyl, or NR R in which R⁹ is optionally substituted imidazolyl, pyrazolyl, or 6- to 10-membered heteroaryl. In certain embodiments, when T is a Ci-Cô alkylene linker and B is absent or optionally substituted Ce-Cio aryl or 4- to 12-membered heterocycloalkyl; or when T is a bond and B is optionally substituted C3-C10 cycloalkyl or 4- to 12-membered heterocycloalkyl, then R⁶ is not NR⁸C(O)R¹³.

In certain embodiments, when X¹ and X³ are N, X² is CR³, X⁴ is CR⁵, X⁵ is C, R⁵ is 4- to 12membered heterocycloalkyl substituted with one or more Ci-Ce alkyl, and R and R together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted C1-C3 alkoxyl, then B is absent, Cô-Ci₀ aryl, C3-C10 cycloalkyl, or 5to 10-membered heteroaryl.

In certain embodiments, when X² and X³ are N, X¹ is CR², X⁴ is CR⁵, X⁵ is C, R⁵ is C3-C8 cycloalkyl or 4- to 12-membered heterocycloalkyl, each optionally substituted with one or 5 more Ci-Cô alkyl, and R⁶ and R² together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted C1-C3 alkoxyl, then B is absent, C₆-Ci₀ aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl.

In certain embodiments, when T is a bond and B is hydroxyl-substituted phenyl, then ring A is not pyrazinyl.

In certain embodiments, when ring A is phenyl and B is a 5-membered heteroaryl or phenyl, then T is not C(O),

In certain embodiments, when ring A is phenyl, B is absent, and T and R¹ together with the atoms to which they are attached form a 4-7 membered heterocycloalkyl, the heterocycloalkyl contains at most one N ring atom or the heterocycloalkyl is not substituted 15 by oxo,

In certain embodiments, when one of ring A or B is pyridyl and T is a bond, then the pyridinyl is not substituted at the para-position of N-^R1 with -Q^l-T^l or -Q²-T², in which T¹ or T² is phenyl or heteroaryl, or

In certain embodiments, when T is a bond or C1-C3 alkylene, ring A is a 6-membered heteroaryl and B is optionally substituted phenyl, pyridyl, or piperidinyl, then R⁶ is not H and at least one of R², R³, R⁴ and R⁵ is not H.

A subset of compounds of Formula (I) includes those of Formula (II):

R¹ (II), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein ring B is phenyl or pyridyl, one or both of X¹ and X² are N while X³ is CR⁴ and X⁴ is CR⁵ or one or both of X¹ and X³ are N while X² is CR³ and X⁴ is CR⁵; and n is 1, 2, or 3.

Subsets of the compounds of Formula (II) include those of Formula (liai), (IIa2), (IIa3), (IIa4) and (IIa5):

(IIa5) and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers.

Other subsets of the compounds of Formula (II) include those of Formula (Ilbl), (IIb2), (IIb3), (IIb4) or (IIb5):

acceptable salts of the compounds or the tautomers.

Further subsets of the compounds of Formula (II) include those of Formula (Ile 1 ), (IIc2), (IIc3), (IIc4) or (IIc5):

(IIc5), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers.

Yet further subsets of the compounds of Formula (II) include those of Formula (Ildl), (IId2), (IId3), (IId4) or (IId5):

(IId2),

(IId5), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers.

In another embodiment, the compounds of Formula (I) include those of Formula (III):

(III), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein ring B is phenyl or pyridyl, at least one of X² and X³ is N; and n is 1 or 2.

N subset of the compounds of Formula (III) includes compounds of Formula (Ilia):

(Ilia), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers.

Another subset of the compounds of Formula (I) includes those of Formula (IV):

(IV), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein ring B is C3-C6 cycloalkyl;

each of R²⁰, R²¹, R²² and R²³ independently is H, halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl; and n is 1 or 2.

Another subset of the compounds of Formula (I) includes those of Formula (IVa):

(IVa), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein ring B is C₃-Cô cycloalkyl;

each of R²⁰, R²¹, R²² and R²³ independently is H, halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl; and n is 1 or 2.

Yet another subset of the compounds of Formula (I) includes those of Formula (V):

R⁵

R¹ (V), jo and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers, wherein ring B is absent or C3-C6 cycloalkyl;

X³ is N or CR⁴ in which R⁴ is H or C1-C4 alkyl;

R¹ is H or C1-C4 alkyl;

or when B is absent, T and R¹ together with the atoms to which they are attached optionally form a 4-7 membered heterocycloalkyl or 5-6 membered heteroaryl, each of which is optionally substituted with (R⁷)_n; or when B is absent, T is H and n is 0;

each R⁷ is independently oxo (=O) or -Q²-T², in which each Q² independently is a bond or Ci-C₆ alkylene, C₂-Cô alkenylene, or C₂-C₆ alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or Ci-Cô alkoxyl, and each T² independently is H, halo, OR¹⁰, OR¹¹, C(O)Rⁿ, NR¹⁰R^h, C(O)NR¹⁰R, NR^l0C(O)R, C3-C8 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C3-C8 cycloalkyl or 4- to 12membered heterocycloalkyl is optionally substituted with one or more of halo, Ci-Cô alkyl optionally substituted with NR^xR^y, hydroxyl, oxo, N(R⁸)₂, cyano, Ci-Cô haloalkyl, -SO₂R⁸, or

Ci-Cô alkoxyl, each of R^x and R^y independently being H or Ci-Cô alkyl; and R7 is not H or C(O)OR^g;

R⁵ is selected from the group consisting of Ci-Cô alkyl, C3-C8 cycloalkyl and 4- to 12membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, wherein the C3-C8 cycloalkyl and 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of 4- to 7-membered heterocycloalkyl, -Cj-Cô alkylene-4- to 7-membered heterocycloalkyl, -C(O)Ci-C₆ alkyl or Ci-C₆ alkyl optionally substituted with one or more of halo or OR^a;

R⁹ is -Q³-T³, in which Q³ is a bond or Ci-C₆ alkylene, C₂-C₆ alkenylene, or C₂-C₆ alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxyl, and T³ is 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more -Q⁴-T⁴, wherein each Q⁴ independently is a bond or C1-C3 alkylene, C₂-C₂ alkenylene, or C₂-C₂ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C]-Cô alkoxy, and each T⁴ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C3-C8 cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^C, C(O)R^c, S(O)₂R^C, NR^cR^d, C(O)NR^cR^d, and NR^cC(0)R^d, each of R^c and R^d independently being H or Ci-Cô alkyl; or Q⁴-T⁴ is oxo; and n is 0, 1 or 2.

Yet another subset of the compounds of Formula (I) includes those of Formula (Va) or (Vb): R⁵R

R⁹-O'^k^^x7YN7z\Nx-T U(R⁷)n ΡΛθ'χ/^χ·ίγ\Ν·'Τ· ~b q^-(R⁷)n

I I

R¹ (Va), R¹(Vb), and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers, wherein R¹, R⁵, R⁷, R⁹, B, T, and n are as defined herein.

Yet another subset of the compounds of Formula (I) includes those of Formula (VI):

R⁵

R³ 1 । | || ^CH3

R⁶

H \ / (VI), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein R⁵ and R⁶ are independently selected from the group consisting of Ci-Cô alkyl and NR⁸R⁹, or R⁶ and R³ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl.

Yet another subset of the compounds of Formula (I) includes those of Formula (VII):

pharmaceutically acceptable salts of the compounds or the tautomers, wherein m is l or 2 and n is 0, 1, or 2.

A further subset of the compounds of Formula (I) includes those of Formula (Villa):

ρ9 I .

^K R (Villa), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein ίο X¹ is N or CR²;

X² is N or CR³;

X³ is N or CR⁴;

X⁴ is N or CR⁵;

R² is selected from the group consisting of H, C3-C8 cycloalkyl, and Ci-Cô alkyl optionally substituted with one or more of halo, OR^a, or NR^aR^b;

each of R³ and R⁴ is H; and

R⁵ are independently selected from the group consisting of H, C₃-Cs cycloalkyl, and Ci-Cô alkyl optionally substituted with one or more of halo or OR^a; or

R⁵ and one of R³ or R⁴ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R⁵ and one of R³’or R⁴’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl; and wherein at least one of R? or R5 are not H.

A further subset of the compounds of Formula (I) includes those of Formula (VlIIb):

wherein

X¹ is N or CR²;

X² is N or CR³;

X³ is N or CR⁴;

X⁴ is N or CR⁵;

R² is selected from the group consisting of H, C₃-C₈ cycloalkyl, and C\-C^ alkyl each of R³ and R⁴ is H; and

R⁵ is selected from the group consisting of H, C₃-C₈ cycloalkyl, and Ci-Cô alkyl; or

R⁵ and one of R³ or R⁴ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R⁵ and one of R³’or R⁴’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl; and wherein at least one of R₂ or R₅ are not H.

A further subset of the compounds of Formula (I) includes those of Formula (Ville):

X² ^X³ {\\ ^R1°

R⁸ JL 'N X¹ N O < |_|

R⁹ (Ville), wherein

X¹ is N or CR²;

X² is N or CR³;

X³ is N or CR⁴;

X⁴ is N or CR⁵;

R² is selected from the group consisting of H, C3-C8 cycloalkyl, and Ci-Cô alkyl each of R³ and R⁴ is H; and

R⁵ is selected from the group consisting of H, C₃-C₈ cycloalkyl, and Ci-Cô alkyl; or R⁵ and one of R³ or R⁴ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R⁵ and one of R³’or R⁴’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or

6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl; and wherein at least one of R₂ or R5 are not H.

In another aspect, the présent disclosure features a substituted aryl or heteroaryl compound of Formula (IX-1) below:

or a tautomer thereof, or a pharmaceutically acceptable sait of the compound or the tautomer, wherein,

X⁶ is N or CH;

X⁷ is N or CH;

X³ is N or CR⁴;

R⁴ is selected from the group consisting of H, halo, cyano, Ci-Cô alkoxyl, Cô-Cio aryl, NR^aR^b, C(O)NR^aR^b, NR^aC(O)R^b, C3-C8 cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, and Ci-Cô alkyl, wherein C]-Cô alkoxyl and Ci-Cô alkyl are optionally substituted with one or more of halo, OR^a, or NR^aR^b, in which each of R^a and R^b independently is H or Ci-Cô alkyl;

each Q¹ is independently a bond or Ci-Cô alkylene, C₂-Cô alkenylene, or C₂-Cô alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or Ci-Cô alkoxyl;

each T¹ is independently H, halo, cyano, NR⁸R⁹, C(O)NR⁸R⁹, C(O)R⁹, OR⁸, OR⁹, or R^S1, in which R^S1 is C3-C8 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R^S1 is optionally substituted with one or more of halo, Ci-Cô alkyl, hydroxyl, oxo, -C(O)R⁹, SO2R⁸, -SO2N(R⁸)2, -NR⁸C(O)R⁹, NR⁸R⁹, or Ci-C6 alkoxyl; and -Q'-T¹ is not NR⁸C(O)NR¹²R¹³;

each R⁸ independently is H or Ci-Cô alkyl;

each R⁹ is independently -Q³-T³, in which Q³ is a bond or Ci-Cô alkylene, C2-Cô alkenylene, or C2-Cô alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-C6 alkoxyl, and T³ is H, halo, OR¹², OR¹³, NR¹²R¹³, NR¹²C(O)R¹³, C(O)NR¹²R¹³, C(O)R¹³, S(O)2R¹³, S(O)2NR¹²R¹³, or R^S2, in which R^S2 is C3-C₈ cycloalkyl, Cô-Cio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and R is optionally substituted with one or more -Q⁴-T⁴, wherein each Q⁴ independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Cj-Cô alkoxy, and each T⁴ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C₃-C₈ cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing l-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^C, C(O)R^c, S(O)₂R^C, NR^cR^d, C(0)NR^cR^d, and NR^cC(O)R^d, each of R^c and R^d independently being H or Ci-Cô alkyl; or -Q⁴-T⁴ is oxo; or

R¹² is H or Cj-Cô alkyl;

R¹³ is Ci-Cô alkyl, C3-C8 cycloalkyl, C6-Cio aryl, 4- to 12-membered heterocycloalkyl 10 containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more -Q -T , wherein each Q independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁸ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C8-C₈ 15 cycloalkyl, Cô-Ci₀ aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl; or -Q -T is oxo;

R^l5a is CN, C(O)H, C(O)R¹⁸, OH, OR¹⁸, Ci-C6 alkyl, NHR¹⁷, C3-C₈ cycloalkyl, CôCio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or 5- to 10-membered heteroaryl, wherein each of said Ci-Cô alkyl, C3-C₈ cycloalkyl, 20 Cô-Cio aryl, 4- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl is optionally substituted with one or more -Q⁹-T⁹, wherein each Q⁹ independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁹ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C3-C8 cycloalkyl, Cô-Cio aryl, 4- to 25 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5to 6-membered heteroaryl; or-Q⁹-T⁹ is oxo;

R^16a is -Qⁿ-R¹⁶ in which Q¹¹ is a bond, O, NR^a, C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy; and R¹⁶ is H, Ci-Cô alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C8-C₈ 30 cycloalkyl, Cô-Cio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more -Q¹⁰-T¹⁰, wherein each Q¹⁰ independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T¹⁰ independently is selected from the group consisting of H, halo, cyano, C(O)H, C(O)R¹⁸, S(O)PR¹⁸, OH, OR¹⁸, Ci-Cô alkyl, C3-C8 cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl; or -Q¹⁰-T¹⁰ is oxo;

R¹⁷ is H or Ci-Cô alkyl;

each R¹⁸ is independently Ci-Cô alkyl, C₂-Cô alkenyl or C₂-Cô alkynyl;

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

For example, one subset of compounds of Formula (IX-1) is of Formula (IX) below:

or a tautomer thereof, or a pharmaceutically acceptable sait of the compound or the tautomer, wherein

X⁶ is N or CH;

X⁷ is N or CH;

X³ is N or CR⁴;

R⁴ is selected from the group consisting of H, halo, cyano, Ci-Cô alkoxyl, Cô-Cio aryl, NR^aR^b, C(O)NR^aR^b, NR^aC(O)R^b, C3-C8 cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, and Ci-Cô alkyl, wherein Ci-Cô alkoxyl and Ci-Cô alkyl are optionally substituted with one or more of halo, OR^a, or NR^aR^b, in which each of R^a and R^b independently is H or Ci-Cô alkyl;

each R⁹ is independently -Q³-T³, in which Q³ is a bond or Ci-Cô alkylene, C2-Cô alkenylene, or C2-Cô alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C,-C6 alkoxyl, and T³ is H, halo, OR¹², OR¹³, NR¹²R¹³, NR¹²C(O)R¹³, C(O)NR¹²R¹³, C(O)R¹³, S(O)2R¹³, S(O)2NR¹²R¹³, or R^S2, in which R^S2 is C3-C₈ cycloalkyl, Cô-Cio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and R is optionally substituted with one or more -Q⁴-T⁴, wherein each Q⁴ independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁴ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C3-C8 cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^C, C(O)R^c, S(O)₂R^C, NR^cR^d, C(0)NR^cR^d, and NR^cC(O)R^d, each of R^c and R^d independently being H or Ci-Cô alkyl; or -Q⁴-T⁴ is oxo; or

R¹² is H or Ci-C₆ alkyl;

R¹³ is C]-C6 alkyl, C3-C8 cycloalkyl, C6-Ci0 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more -Q⁸-T⁸, wherein each Q⁸ independently is a bond or Ci-C3 alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-C₆ alkoxy, and each T⁸ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C₃-C₈ cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl; or -Q⁸-T⁸ is oxo;

R¹⁵ is Ci-C6 alkyl, NHR¹⁷, C3-C₈ cycloalkyl, C₆-Ci₀ aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or 5- to 10membered heteroaryl, wherein each of said Ci-Cô alkyl, C₃-C₈ cycloalkyl, Cô-Cio aryl, 4- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl is optionally substituted with one or more -Q⁹-T⁹, wherein each Q⁹ independently is a bond or C]-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁹ independently is selected from the group consisting of H, halo, cyano, Ci-C6 alkyl, C₃-C₈ cycloalkyl, C₆-Ci₀ aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6membered heteroaryl; or -Q⁹-T⁹ is oxo;

R¹⁶ is Ci-Cô alkyl, C2-C6 alkenyl, C2-Cô alkynyl, C3-C8 cycloalkyl, Cô-Cio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5to 10-membered heteroaryl, each of which is optionally substituted with one or more -Q¹⁰T¹⁰, wherein each Q¹⁰ independently is a bond or Ci-C3 alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T¹⁰ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C₃-C₈ cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl; or Q -T is oxo;

R¹⁷ is H or Ci-Cô alkyl; and v is 0, 1, or 2.

A subset of the compounds of Formula (IX) includes those of Formula (X):

(X), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein X³ is N or CR⁴, wherein R⁴ is selected from the group consisting of H, halo, and cyano.

Subsets of the compounds of Formula (X) include those of Formula (Xa), (Xb), (Xc), (Xd), (Xe), (Xf), or (Xg):

R¹⁵ (Xg), wherein R⁹, R¹⁵ and R¹⁶ are as defined herein.

In certain embodiments, the compounds of any of Formulae (I)-(Xg) inhibit a kinase with an enzyme inhibition IC50 value of about 100 nM or greater, 1 μΜ or greater, ΙΟμΜ or greater, 100 μΜ or greater, or 1000 μΜ or greater.

In certain embodiments, the compounds of any of Formulae (I)-(Xg) inhibit a kinase with an enzyme inhibition IC50 value of about 1 mM or greater.

In certain embodiments, the compounds of any of Formulae (I)-(Xg) inhibit a kinase with an enzyme inhibition IC₅₀ value of 1 μΜ or greater, 2 μΜ or greater, 5 pM or greater, or 10 pM or greater, wherein the kinase is one or more of the following: Abl, AurA, CHK1, MAP4K, IRAK4, JAK3, EphA2, FGFR3, KDR, Lck, MARK1, MNK2, PKCb2, SIK, and Src.

Also provided herein are pharmaceutical compositions comprising one or more pharmaceutically acceptable carriers and one or more compounds of any of the Formulae (I)(Xg) described herein.

Another aspect of this disclosure is a method of preventing or treating an EHMT-mediated disorder. The method includes administering to a subject in need thereof a therapeutically effective amount of a compound of any of Formulae (I)-(Xg), or a tautomer thereof, or a pharmaceutically acceptable sait of the compound or the tautomer. The EHMT-mediated disorder is a disease, disorder, or condition that is mediated at least in part by the activity of EHMT1 or EHMT2 or both. In one embodiment, the EHMT-mediated disorder is a blood disease or disorder. In certain embodiments, the EHMT-mediated disorder is selected from proliférative disorders (e.g. Cancers such as leukemia, hepatocellular carcinoma, prostate carcinoma, and lung cancer), addiction (e.g., cocaine addiction), and mental retardation. Unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to préparé a médicament to treat or prevent such condition. The treatment includes treatment of human or non-human animais including rodents and other disease models. Methods described herein may be used to identify suitable candidates for treating or preventing EHMT-mediated disorders. For example, the disclosure also provides methods of identifying an inhibitor of EHMT1 or EHMT2 or both.

For example, the EHMT-mediated disease or disorder comprises a disorder that is associated with gene silencing by EHMT1 or EHMT2, e.g., blood diseases or disorders associated with gene silencing by EHMT2.

For example, the method comprises the step of administering to a subject having a disease or disorder associated with gene silencing by EHMT1 or EHMT2 a therapeutically effective amount of one or more compounds of the Formulae described herein, wherein the compound(s) inhibits histone methyltransferase activity of EHMT1 or EHMT2, thereby treating the disease or disorder.

For example, the blood disease or disorder is selected from the group consisting of sickle cell anémia and beta-thalassemia.

For example, the blood disease or disorder is hematological cancer.

For example, the hematological cancer is acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL).

For example, the method further comprises the steps of performing an assay to detect the degree of histone méthylation by EHMT1 or EHMT2 in a sample comprising blood cells from a subject in need thereof.

In one embodiment, performing the assay to detect méthylation of H3-K9 in the histone substrate comprises measuring incorporation of labeled methyl groups.

In one embodiment, the labeled methyl groups are isotopically labeled methyl groups.

In one embodiment, performing the assay to detect méthylation of H3-K9 in the histone substrate comprises contacting the histone substrate with an antibody that binds specifically to dimethylated H3-K9.

Still another aspect of the disclosure is a method of inhibiting conversion of H3-K9 to dimethylated H3-K9. The method comprises the step of contacting a mutant EHMT, the wild-type EHMT, or both, with a histone substrate comprising H3-K9 and an effective amount of a compound of the présent disclosure, wherein the compound inhibits histone methyltransferase activity of EHMT, thereby inhibiting conversion of H3-K9 to dimethylated

H3-K9.

Further, the compounds or methods described herein can be used for research (e.g., studying epigenetic enzymes) and other non-therapeutic purposes.

Unless otherwise defined, ail technical and scientific terms used herein hâve the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the spécification, the singular forms also include the plural unless the context clearly dictâtes otherwise. Although methods and materials similar or équivalent to those described herein can be used in the practice or testing of the présent disclosure, suitable methods and materials are described below. Ail publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the présent spécification, including définitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the Chemical structures and names of the compounds disclosed herein, the Chemical structures will control.

Other features and advantages of the disclosure will be apparent from the following figures, detailed description and daims.

Brief Descriptions of the Drawings

Figure l A is a graph indicating the effect of Compound 205 on histone H3K9 dimethylation (data illustrated by triangles) and on fêtai hemoglobin-containing cells (HbF+; data illustrated by squares).

Figure IB is a graph indicating the effect of Compound 418 on histone H3K9 dimethylation (data illustrated by triangles) and on fêtai hemoglobin-containing cells (HbF+; data illustrated by squares).

Figure IC is a graph indicating the effect of Compound 642 on histone H3K9 dimethylation (data illustrated by triangles) and on fêtai hemoglobin-containing cells (HbF+; data illustrated by squares).

Figure ID is a graph indicating the effect of Compound 332 on histone H3K9 dimethylation (data illustrated by triangles) and on fêtai hemoglobin-containing cells (HbF+; data illustrated by squares).

Figure 2 is a sériés of graphs indicating the effect of Compound 205, Compound 642, Compound 332, or Compound 418 on the ratio of Hbb-γ to total β globins.

Figure 3 is a sériés of graphs indicating the effect of Compound 205, Compound 642, Compound 332, or Compound 418 on the ratio of Hbb-γ to total β globins as measured by mass spectrometry and PCR.

Figure 4 is a graph indicating the effect of Compound 205 on the rate of growth of MV4-11 cells over 14 days. 0.2% DMSO was used as négative control (containing no compound of the disclosure).

Figure 5 is a graph indicating the effect of Compound 205 on the inhibition of growth of MV4-11 cells over 14 days.

Detailed Description

The présent disclosure provides novel amine-substituted aryl or heteroaryl compounds, synthetic methods for making the compounds, pharmaceutical compositions containing them and various uses of the compounds.

In one aspect, the compounds disclosed herein may be used to treat a blood disorder, e.g., sickle-cell anémia (i.e., sickle-cell disease). Non-limiting examples of sickle-cell anémia forms that may be treated using the contemplated compounds include hemoglobin SS disease, hemoglobin SC disease, hemoglobin 8β° thalassemia disease, hemoglobin 8β⁺ thalassemia disease, hemoglobin SD disease, and hemoglobin SE disease.

Without wishing to be bound by any theory, it is believed that sickle-cell anémia describes a group of inherited red blood cell disorders in which at least some of the red blood cells of a subject having sickle-cell anémia contain hemoglobin S (“HbS”). Hemoglobin S is a mutated, abnormal form of adult hemoglobin. Without wishing to be bound by any theory, it is believed that the contemplated compounds may treat sickle cell anémia by inducing fêtai hemoglobin (“HbF”) expression. See, e.g., Renneville et al., Blood 126(16): 1930-1939, 2015, the content of which is incorporated herein by reference in its entirety.

In some embodiments, one or more complications of sickle-cell anémia may be treated or prevented using the contemplated compounds disclosed herein. Non-limiting examples of complications that may be treated or prevented using the contemplated compounds include anémia (e.g., severe anémia), hand-foot syndrome, splenic séquestration, delayed developmental growth, eye disorders (e.g., vision loss caused by, e.g., blockages in blood vessels supplying the eyes), skin ulcers (e.g., leg ulcers), heart disease, chest syndrome (e.g., acute chest syndrome), priapism, and pain.

The présent disciosure provides compounds of Formula (I):

R¹ (D, and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers, wherein ring A is phenyl or a 5- or 6-membered heteroaryl;

X¹ is N, CR², or NR²’ as valency permits;

X² is N, CR³, or NR³’ as valency permits;

X³ is N, CR⁴, or NR⁴’ as valency permits;

X⁴ is N or CR⁵, or X⁴ is absent such that ring A is a 5-membered heteroaryl containing at least one N atom;

X⁵ is C or N as valency permits;

B is absent or a ring structure selected from the group consisting of Cô-Cio aryl, C3C10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S;

T is a bond or Ci-C₆ alkylene, C₂-C₆ alkenylene, or C₂-C₆ alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo; or Ci-Cô alkoxy when B is présent; or T is H and n is 0 when B is absent; or T is Ci-C₆ alkyl optionally substituted with (R⁷)n when B is absent; or when B is absent, T and R¹ together with the atoms to which 5 they are attached optionally form a 4-7 membered heterocycloalkyl or 5-6 membered heteroaryl, each of which is optionally substituted with (R⁷)n;

R¹ is H or C1-C4 alkyl;

each of R², R³, and R⁴, independently is selected from the group consisting of H, halo, cyano, Ci-C6 alkoxyl, C6-Ci0 aryl, NR^aR^b, C(0)NR^aR^b, NR^aC(0)R^b, C3-C₈ cycloalkyl, 4- to jo 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, and Ci-Cô alkyl, wherein Cj-Cô alkoxyl and Ci-C₆ alkyl are optionally substituted with one or more of halo, OR^a, or NR^aR^b, in which each of R^a and R^b independently is H or Ci-Cô alkyl, or R³ is —Q'-T¹, in which Q¹ is a bond or Ci-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or Ci-Cô alkoxyl, and T¹ is H, halo, cyano, 15 NR⁸R⁹, C(O)NR⁸R⁹, OR⁸, OR⁹, or R^S1, in which R^SI is C3-C₈ cycloalkyl, phenyl, 4- to 12membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R^S1 is optionally substituted with one or more of halo, Ci-C₆ alkyl, hydroxyl, oxo, -C(O)R⁹, -SO2R⁸, -SO2N(R⁸)₂, -NR⁸C(O)R⁹, amino, mono- or dialkylamino, or Ci-C₆ alkoxyl;; or when ring A is a 5-membered heteroaryl containing at least one N atom, R⁴ is a spiro-fùsed 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S;

each of R²’, R³’ and R⁴’ independently is H or Ci-C₃ alkyl;

R⁵ is selected from the group consisting of H, F, Br, cyano, Ci-Cô alkoxyl, Cô-Cio aryl, NR^aR^b, C(O)NR^aR^b, NR^aC(O)R^b, C3-C8 cycloalkyl, 4- to 12-membered heterocycloalkyl 25 containing 1-4 heteroatoms selected from N, O, and S, Ci-Cô alkyl optionally substituted with one or more of halo, OR^a or NR^aR^b, and C2-Cô alkynyl optionally substituted with 4- to 12membered heterocycloalkyl; wherein said C₃-C₈ cycloalkyl or 4- to 12-membered heterocycloalkyl are optionally substituted with one or more of halo, C(O)R^a, OR^a, NR^aR^b, 4to 7-membered heterocycloalkyl, -Ci-Cô alkylene-4- to 7-membered heterocycloalkyl, or Ci30 C4 alkyl optionally substituted with one or more of halo, OR^a or NR^aR^b, in which each of R^a and R^b independently is H or Ci-Cô alkyl; or

R⁵ and one of R³ or R⁴ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R⁵ and one of R³’or R⁴’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or

6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl;

R⁶ is absent when X⁵ is N and ring A is a 6-membered heteroaryl; or R⁶ is -Q'-T¹, in which Q¹ is a bond or Cj-C₆ alkylene, C₂-C₆ alkenylene, or C₂-C₆ alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or Ci-Cô alkoxyl, and T¹ is H, halo, cyano, NR⁸R⁹, C(O)NR⁸R⁹, C(O)R⁹, OR⁸, OR⁹, or R^S1, in which R^S1 is C₃-C₈ cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R^S1 is optionally substituted with one or more of halo, Cj-Cô alkyl, hydroxyl, oxo, -C(O)R⁹, -SO2R⁸, -SO2N(R⁸)₂, -NR⁸C(O)R⁹,

NR⁸R⁹, or Cj-Cô alkoxyl; and R⁶ is not NR⁸C(O)NR¹²R¹³; or

R⁶ and one of R² or R³ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R⁶ and one of R²’or R³’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl, oxo (=O), C1-C3 alkoxyl, or -Q^T¹;

each R⁷ is independently oxo (=O) or -Q²-T², in which each Q² independently is a bond or Ci-C₆ alkylene, C₂-C₆ alkenylene, or C₂-C₆ alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or Cj-Cô alkoxyl, and each T² independently is H, halo, cyano, OR¹⁰, OR¹¹, C(O)Rⁿ, NR¹⁰Rⁿ,

CfOjNR^R¹ ', NRⁱ⁰C(O)R‘', 5- to 10-membered heteroaryl, C3-C8 cycloalkyl, or 4- to 12membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the 5- to 10-membered heteroaryl, C3-C8 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, Cj-Cô alkyl optionally substituted with NR^xR^y, hydroxyl, oxo, N(R⁸)2, cyano, Cj-Cô haloalkyl, -SO₂R⁸, or Cj-Cô alkoxyl, each of R^x and R^y independently being H or Cj-Cô alkyl; and R7 is not H or C(O)OR^g; or optionally, when B is présent, one R⁷ and R⁵ together form a C₃-Cjo alkylene, C₂-Cjo heteroalkylene, C4-C10 alkenylene, C₂-Cjo heteroalkenylene, C4-C10 alkynylene or C₂Cjo heteroalkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or Cj-Cô alkoxyl;

each R⁸ independently is H or Cj-Cô alkyl;

each R⁹ is independently -Q³-T³, in which Q³ is a bond or Cj-Cô alkylene, C2-Cô alkenylene, or C2-Cô alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or Cj-C6 alkoxyl, and T³ is H, halo, OR¹², OR¹³, NR¹²R¹³, NR¹²C(O)R¹³, C(O)NR¹²R¹³, C(O)R¹³, S(O)2R¹³, S(O)2NRⁱ²R¹³, or R^S2, in which R^S2 is C3-C₈ cycloalkyl,

Cô-C|o aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and R^S2 is optionally substituted with one or more -Q⁴-T⁴, wherein each Q⁴ independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, 5 hydroxyl, or Ci-Cô alkoxy, and each T⁴ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C3-C8 cycloalkyl, Cô-Ciq aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^C, C(O)R^c, S(O)₂R^C, NR^cR^d, C(O)NR^cR^d, and NR^cC(O)R^d, each of R^c and R^d independently being H or Ci-Cô alkyl; or -Q⁴-T⁴ is oxo; or

R⁸ and R⁹ taken together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, which is optionally substituted with one or more of-Q⁵-T⁵, wherein each Q⁵ independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁵ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C₃-C₈ cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^e, C(0)R^e, S(O)2R^e, S(O)2NR^eR^f, NR^eR^f, C(O)NR^eR^f, and NR^eC(O)R^f, each of R^e and R^f independently being H or Ci-C6 alkyl; or -Q⁵-T⁵ is oxo;

R¹⁰ is selected from the group consisting of H and Ci-Cô alkyl;

R¹¹ is -Q⁶-T⁶, in which Q⁶ is a bond or Ci-Cô alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or Ci-C6 alkoxyl, and T⁶ is H, halo, OR^g, NR^gR^h, NR^ëC(0)R^h, C(O)NR^gR^h, C(O)R^g, S(O)2R^g, or R^S3, in which each of R^g and R¹¹ independently is H, phenyl, C3-C8 cycloalkyl, or Ci-Cô alkyl 25 optionally substituted with C₃-C₈ cycloalkyl, or R^g and R^h together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and R^S3 is C3-C8 cycloalkyl, Cô-Cio aryl, 4- to 12membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, or a 5- to 10-membered heteroaryl, and R^S3 is optionally substituted with one or more -Q⁷-T⁷, wherein 30 each Q⁷ independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁷ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C3-C8 cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR\ C(O)R^J, NR'R^k,

C(O)NR^jR^k, S(O)2R^j, and NR^jC(O)R^k, each of R^J and R^k independently being H or Ci-Cô alkyl optionally substituted with one or more halo; or -Q -T is oxo; or

R¹⁰ and R¹¹ taken together with the nitrogen atom to which they are attached form a 4to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5 which is optionally substituted with one or more of halo, Ci-Cô alkyl, hydroxyl, or Ci-Cô alkoxyl;

R¹² is H or Cj-Cô alkyl;

R¹³ is Ci-Cô alkyl, C₃-Cs cycloalkyl, C₆-Cio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, io each of which is optionally substituted with one or more -Q -T , wherein each Q independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁸ independently is selected from the group consisting of H, halo, cyano, Cj-Cô alkyl, C3-C8 cycloalkyl, C₆-Ci₀ aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl; or -Q -T is oxo; and n is 0, 1, 2, 3, or 4.

The compounds of Formula (I) can hâve one or more of the following features when applicable:

In certain embodiments, the compound of Formula (I) is not 4-(((2-(( l-acetylindolin-620 yl)amino)-6-(trifluoromethyl)pyrimidin-4-yl)amino)methyl)benzenesulfonamide, 5-bromo-N⁴-(4-fluorophenyl)-N²-(4-methoxy-3-(2-(pyrrolidin-lyl)ethoxy)phenyl)pyrimidine-2,4-diamine,

N²-(4-methoxy-3-(2-(pynOlidin-1-yl)ethoxy)phenyl)-N⁴-(5-(tert-pentyl)-1 Hpyrazol-3-yl)pyrimidine-2,4-diamine,

4-((2,4-dichloro-5-methoxyphenyl)amino)-2-((3-(2-(pynOlidin-lyl)ethoxy)phenyl)amino)pyrimidine-5-carbonitrile, N-(naphthalen-2-yl)-2-(piperidin-l-ylmethoxy)pyrimidin-4-amine, N-(3,5-difluorobenzyl)-2-(3-(pyrrolidin-l-yl)propyl)pyrimidin-4-amine, N-(((4-(3-(piperidin-l-yl)propyl)pyrimidin-2-yl)amino)methyl)benzamide,

N-(2-((2-(3-(dimethylamino)propyl)pyrimidin-4-yl)amino)ethyl)benzamide,

2-(hexahydro-4-m ethyl-1 H-1,4-diazepin-1 -yl)-6,7-dimethoxy-N-[ 1 (phenylmethyl)-4-piperidinyl]-4-quinazolinamine, 2-cyclohexyl-6-methoxy-N-[ 1 -( 1 -methylethyl)-4-piperidinyl]-7-[3-( 1 pynOlidinyl)propoxy]-4-quinazolinamine,

3-(1 -cyano-1 -methylethyl)-A-[3-[(3,4-dihydro-3-methyl-4-oxo-6quinazolinyl)amino]-4-methylphenyl]benzamide, 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-l-ylpyridin-2yl)amino]pyrido[2,3-d]pyrimidin-7-one,

N- [2- [ [4-(Diethylamino)butyl] amino] -6-(3,5 -dimethoxyphenyl)pyrido [2,3 J]pyrimidin-7-yl]-/V-( 1,1 -dimethylethyl)urea, or 6-[[2-[[4-(2,4-dichlorophenyl)-5-(5-methyl-lH-imidazol-2-yl)-2pyrimidinyl]amino]ethyl]amino]-3-pyridinecarbonitrile.

g Q

In certain embodiments, when T is a bond, B is substituted phenyl, and R is NR R , in which R⁹ is -Q³-R^S2, and R^S2 is optionally substituted 4- to 7-membered heterocycloalkyl or a 5- to 6-membered heteroaryl, then B is substituted with at least one substituent selected from (i) -Q²-ORⁿ in which R¹¹ is -Q⁶-R^S3 and Q⁶ is optionally substituted C₂-C₆ alkylene, C₂-Cô alkenylene, or C₂-C6 alkynylene linker and (ii) -Q²-NR¹⁰R¹¹ in which R¹¹ is -Q⁶-R^S3.

In certain embodiments, when T is a bond and B is optionally substituted phenyl, then R⁶ is not OR⁹ or NR⁸R⁹ in which R⁹ is optionally substituted naphthyl.

In certain embodiments, when T is a bond and B is optionally substituted phenyl, naphthyl, indanyl or 1,2,3,4-tetrahydronaphthyl, then R⁶ is not NR⁸R⁹ in which R⁹ is optionally substituted phenyl, naphthyl, indanyl or 1,2,3,4-tetrahydronaphthyl.

In certain embodiments, when T is a bond and B is optionally substituted phenyl or thiazolyl, then R⁶ is not optionally substituted imidazolyl, pyrazolyl, pyridyl, pyrimidyl, or NR⁸R⁹ in which R⁹ is optionally substituted imidazolyl, pyrazolyl, or 6- to 10membered heteroaryl.

In certain embodiments, when T is a Ci-Cô alkylene linker and B is absent or optionally substituted C₆-Cio aryl or 4- to 12-membered heterocycloalkyl; or when T is a bond and B is optionally substituted C3-C10 cycloalkyl or 4- to 12-membered heterocycloalkyl, then R⁶ is not NR⁸C(O)R¹³.

In certain embodiments, when X¹ and X³ are N, X² is CR³, X⁴ is CR⁵, X⁵ is C, R⁵ is 4- to 12-membered heterocycloalkyl substituted with one or more Cj-Cô alkyl, and R and R together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted C1-C3 alkoxyl, then B is absent, C₆-Cio aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl.

In certain embodiments, when X² and X³ are N, X¹ is CR², X⁴ is CR⁵, X⁵ is C, R⁵ is C3-C8 cycloalkyl or 4- to 12-membered heterocycloalkyl, each optionally substituted with one or more Ci-C₆ alkyl, and R⁶ and R² together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted C1-C3 alkoxyl, then B is absent, C₆-Cio aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl.

In certain embodiments, when T is a bond and B is hydroxyl-substituted phenyl, then ring A is not pyrazinyl.

In certain embodiments, when ring A is phenyl and B is a 5-membered heteroaryl or phenyl, then T is not C(O),

In certain embodiments, when ring A is phenyl, B is absent, and T and R¹ together with the atoms to which they are attached form a 4-7 membered heterocycloalkyl, the heterocycloalkyl contains at most one N ring atom or the heterocycloalkyl is not substituted by oxo,

In certain embodiments, when one of ring A or B is pyridyl and T is a bond, then the pyridinyl is not substituted at the para-position of N- with -Q -T or -Q -T , in which T¹ or T² is phenyl or heteroaryl, or

In certain embodiments, when T is a bond or C1-C3 alkylene, ring A is a 6-membered heteroaryl and B is optionally substituted phenyl, pyridyl, or piperidinyl, then R⁶ is not H and at least one of R², R³, R⁴ and R⁵ is not H.

For example, ring A is a 6-membered heteroaryl, wherein at least one of X , X , X and X⁴ is N and X⁵ is C (e.g., pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl). For example, ring A is a 6-membered heteroaryl, wherein two of X¹, X², X³ and X⁴ is N and X⁵ are C (e.g., pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl).

For example, R⁶ and one of R² or R³ together with the ring A to which they are attached form an optionally substituted 6,5- fused bicyclic heteroaryl; or R and one of R ’ or R ’ together the ring A to which they are attached form an optionally substituted 6,5-fused bicyclic heteroaryl. For example, the optionally substituted 6,5- fused bicyclic heteroaryl contains 1-4 N atoms. For example, the 6,5- fused bicyclic heteroaryl is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl, or C1-C3 alkoxyl.

For example, T is a bond and ring B is phenyl.

For example, T is a bond and ring B is pyridyl.

For example, T is a bond or Ci-Cô alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl or Ci-Cô alkoxy when B is présent.

For example, T is a bond or Ci-Cô alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker when B is présent.

For example, n is 1.

For example, n is 2.

For example, n is 3.

For example, at least one of R⁶, R², R³, and R⁴ is not H.

For example, when one or more of R², R³, and R⁴ are présent, at least one of R⁶, R², R³, and R⁴ is not H.

For example, the compounds of Formula (I) include those of Formula (II):

(Π), wherein ring B is phenyl or pyridyl, one or both of X¹ and X² are N while X³ is CR⁴ and X⁴ is CR⁵ or one or both of X¹ and X³ are N while X² is CR³ and X⁴ is CR⁵; and n is 1, 2, or 3.

For example, the compounds of Formula (II) include those of Formula (liai), (IIa2), (IIa3), (IIa4) or (IIa5):

R⁵ R⁵

R⁵ R⁵

¹ R^a । ,

R¹ (IIa3), R¹ (IIa4), or

R⁵

Γ' 1

R (IIa5), or tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers.

5

For example, at most one of R and R is not H.

For example, neither of R³ and R⁵ is H.

For example, each of R and R is H.

For example, the compounds of Formula (II) include those of Formula (Ilb 1 ), (IIb2), (IIb3), 5 (IIb4) or (IIb5):

R⁵ R⁵

R⁵

or ^r1 (IIb5), or tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers.

For example, at most one of R³, R⁴ and R⁵ is not H.

For example, at most two of R³, R⁴ and R⁵ are not H.

For example, none of R³, R⁴ and R⁵ is H.

For example, each of R³, R⁴ and R⁵ is H.

For example, the compounds of Formula (II) include those of Formula (IIcl), (IIc2), (IIc3), (IIc4) or (IIc5):

(IIc5), or tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers.

For example, at most one of R⁴ and R⁵ is not H.

For example, neither of R⁴ and R⁵ is H.

For example, each of R⁴ and R⁵ is H.

For example, the compounds of Formula (II) include those of Formula (lid 1 ), (IId2), (IId3), (IId4) or (IId5):

(IId3),

(IId5), or tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers. For example, at most one of R², R⁴ and R⁵ is not H. For example, at most two of R², R⁴ and R⁵ are not H.

For example, none of R², R⁴ and R⁵ is H.

For example, each of R², R⁴ and R⁵ is H.

For example, one R⁷ and R⁵ together form a C3-C10 alkylene, C2-C10 heteroalkylene, C4-C10 alkenylene, C₂-Ci₀ heteroalkenylene, C4-C10 alkynylene or C₂-Ci₀ heteroalkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Ce alkoxyl.

For example, one R⁷ and R⁵ together form an optionally substituted C₂-Ci₀ heteroalkylene linker, e.g., -NH(CH2)₂O(CH2)₂O-.

For example, ring A is a 5-membered heteroaryl (e.g., pyrrolyl, imidazolyl, triazolyl, tetrazolyl, or pyrazolyl).

For example, the compounds of Formula (I) include those of Formula (III):

X²—X³

R⁶ N

R² ।

R¹ (III), or tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein ring B is phenyl or pyridyl, at least one of X² and X³ is N; and n is 1 or 2.

For example, the compounds of Formula (III) include those of Formula (Ilia):

(Ilia), or tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers.

For example, at most one of R⁴’ and R² is not H.

For example, neither of R⁴’ and R² is H.

For example, each of R⁴’ and R² is H.

For example, the compounds of Formula (I) include those of Formula (IV):

R²⁰ R⁵

(IV), or tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein ring B is C3-C6 cycloalkyl;

each of R²⁰, R²¹, R²² and R²³ independently is H, halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl; and n is 1 or 2.

For example, ring B is cyclohexyl.

For example, B is absent and T is unsubstituted Ci-Cô alkyl or T is Ci-Cô alkyl substituted η with at least one R .

For example, B is 4 to 12-membered heterocycloalkyl (e.g., azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,6tetrahydropyridinyl, piperazinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl,

2,6-diazaspiro[3.3]heptanyl, morpholinyl, 3-azabicyclo[3.1.0]hexan-3-yl, benzo[d][l,3]dioxol-5-yl, isoindolinyl, indolinyl, 2,3-dihydrobenzo[d]oxazolyl, and the like) and T is unsubstituted Ci-Cô alkyl.

For example, the compounds of Formula (I) include those of Formula (IVa):

(IVa), or tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein ring B is C3-C6 cycloalkyl;

each of R²⁰, R²¹, R²² and R²³ independently is H, halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl; and n is 1 or 2.

For example, ring B is cyclohexyl.

For example, B is absent and T is unsubstituted Ci-Cô alkyl or T is Ci-Cô alkyl substituted with at least one R⁷.

For example, B is 4 to 12-membered heterocycloalkyl (e.g., azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,65 tetrahydropyridinyl, piperazinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5azabicyclo[2.2.1 ]heptanyl, 2,5-diazabicyclo[2.2.1 ]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl,

2,6-diazaspiro[3.3]heptanyl, morpholinyl, 3-azabicyclo[3.1,0]hexan-3-yl, benzo[d][l,3]dioxol-5-yl, isoindolinyl, indolinyl, 2,3-dihydrobenzo[d]oxazolyl, and the like) and T is unsubstituted Ci-Cô alkyl.

For example, the compounds of Formula (I) include those of Formula (V):

R⁵

R¹ (V), wherein ring B is absent or C₃-Cô cycloalkyl;

X³ is N or CR⁴ in which R⁴ is H or C1-C4 alkyl;

R¹ is H or C1-C4 alkyl;

or when B is absent, T and R¹ together with the atoms to which they are attached optionally form a 4-7 membered heterocycloalkyl or 5-6 membered heteroaryl, each of which is optionally substituted with (R⁷)_n; or when B is absent, T is H and n is 0;

each R⁷ is independently oxo (=O) or -Q²-T², in which each Q² independently is a bond or Ci-Cô alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or Ci-Cô alkoxyl, and each T² independently is H, halo, OR¹⁰, OR¹¹, C(O)R^U, NR¹⁰R^h, C(O)NR¹⁰R^h, NR¹⁰C(O)Rⁿ, C₃-C₈ cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C₃-C₈ cycloalkyl or 4- to 1225 membered heterocycloalkyl is optionally substituted with one or more of halo, Ci-Cô alkyl optionally substituted with NR^xR^y, hydroxyl, oxo, N(R⁸)2, cyano, Ci-Cô haloalkyl, -SO2R⁸, or Ci-Cô alkoxyl, each of R^x and R^y independently being H or Ci-Cô alkyl; and R7 is not H or C(O)OR^g;

R⁵ is selected from the group consisting of Ci-Cô alkyl, C₃-C₈ cycloalkyl and 4- to 1230 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, wherein the C3-C8 cycloalkyl and 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of 4- to 7-membered heterocycloalkyl, -Ci-Cô alkylene-4- to 7-membered heterocycloalkyl, -C(O)Ci-C6 alkyl or Ci-C₆ alkyl optionally substituted with one or more of halo or OR^a;

R⁹ is -Q³-T³, in which Q³ is a bond or Ci-Cô alkylene, C₂-C₆ alkenylene, or C₂-C₆ alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or Cj-Cô alkoxyl, and T³ is 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more -Q⁴-T⁴, wherein each Q⁴ independently is a bond or C1-C3 alkylene, C₂-C₃ alkenylene, or C₂-C₂ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁴ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C3-C8 cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^C, C(O)R^c, S(O)2R^C, NR^cR^d, C(O)NR^cR^d, and NR^cC(O)R^d, each of R^c and R^d independently being H or C]-C6 alkyl; or 15 Q⁴-T⁴ is oxo; and n is 0, 1 or 2.

For example, the compounds of Formula (V) include those of Formula (Va):

R⁵ .Οχ /¼ y-B -7—(R⁷)_n

R¹ (Va), and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers.

For example, in Formula (Va), ring B is absent or C3-C6 cycloalkyl;

R¹ is H or C1-C4 alkyl;

or when B is absent, T and R¹ together with the atoms to which they are attached optionally form a 4-7 membered heterocycloalkyl or 5-6 membered heteroaryl, each of which is optionally substituted with (R⁷)_n;

each R is independently oxo (=0) or -Q -T, in which each Q independently is a bond or Ci-Cô alkylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or Ci-Cô alkoxyl, and each T independently is H, halo, OR¹⁰, OR¹¹, C(O)Rⁿ, NR¹⁰R^h, C(O)NR¹⁰Rⁿ, NR¹⁰C(O)R^u, C₃-C₈ cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C3-C8 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, Ci-Cô alkyl optionally substituted with NR^xR^y, hydroxyl, oxo, N(R⁸)₂, cyano, Ci-Cô haloalkyl, -SO2R⁸, or Ci-Cô alkoxyl, and R7 is not H or C(O)OR^g; each of R^x and R^y independently being H or Cj-Cô alkyl; or R⁵ is selected from the group consisting of C3-C8 cycloalkyl and 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, optionally substituted with one or more of-C(O)Ci-C₆ alkyl or Ci-Cô alkyl optionally substituted with one or more of halo or OR^a;

R⁹ is -Q³-T³, in which Q³ is a bond or Ci-Cô alkylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cg alkoxyl, and T³ is 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, optionally substituted 10 with one or more -Q⁴-T⁴, wherein each Q⁴ independently is a bond or C1-C3 alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁴ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C₃-C₈ cycloalkyl, Cô-Ci₀ aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^C, C(O)R^c, S(O)2R^C, NR^cR^d, 15 C(O)NR^cR^d, and NR^cC(O)R^d, each of R^c and R^d independently being H or Ci-Cô alkyl; or Q⁴-T⁴ is oxo; and n is 1 or 2.

For example, the compounds of Formula (V) include those of Formula (Vb):

R⁵

R¹ (Vb), and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers, wherein ring B is absent or C3-C6 cycloalkyl;

R¹ is H or C1-C4 alkyl;

or when B is absent, T and R¹ together with the atoms to which they are attached optionally form a 4-7 membered heterocycloalkyl or 5-6 membered heteroaryl, each of which 25 is optionally substituted with (R⁷)_n; or when B is absent, T is H and n is 0;

each R⁷ is independently oxo (=O) or -Q²-T², in which each Q² independently is a bond or Ci-Cô alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or Ci-Cô alkoxyl, and each T² independently is H, halo, OR¹⁰, OR¹¹, C(O)R^U, NR¹⁰Rⁿ, C(O)NR¹⁰Rⁿ, 30 NR¹⁰C(O)Rⁿ, C3-C8 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C3-C8 cycloalkyl or 4- to 12membered heterocycloalkyl is optionally substituted with one or more of halo, Ci-Cô alkyl optionally substituted with NR^xR^y, hydroxyl, oxo, N(R⁸)2, cyano, Ci-Cô haloalkyl, -SO2R⁸, or Ci-Cô alkoxyl, each of R^x and R^y independently being H or Ci-Cô alkyl; and R7 is not H or

C(O)OR^g;

R⁵ is selected from the group consisting of Ci-Cô alkyl, C3-C8 cycloalkyl and 4- to 12membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, wherein the C3-C8 cycloalkyl and 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of 4- to 7-membered heterocycloalkyl, -Ci-Cô alkylene-4- to 7-membered heterocycloalkyl, -C(O)Ci-C₆ alkyl or Ci-C₆ alkyl optionally substituted with one or more of halo or OR^a;

R⁹ is -Q³-T³, in which Q³ is a bond or Ci-Cô alkylene, C₂-Cô alkenylene, or C₂-Cô alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or Cj-Cô alkoxyl, and T³ is 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more -Q⁴-T⁴, wherein each Q⁴ independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁴ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C3-C8 cycloalkyl, C6-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^C, C(O)R^c, S(O)₂R^C, NR^cR^d, C(O)NR^cR^d, and NR^cC(O)R^d, each of R^c and R^d independently being H or Ci-Cô alkyl; or Q⁴-T⁴ is oxo; and n is 0, 1 or 2.

For example, the compounds of Formula (I) include those of Formula (VI):

(VI), tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein

R⁵ and R⁶ are independently selected from the group consisting of Ci-Cô alkyl and NR⁸R⁹, or

R⁶ and R³ together with the atoms to which they are attached form phenyl or a 5- or 6membered heteroaryl.

For example, the compounds of Formula (I) include those of Formula (VII):

wherein m is 1 or 2 and n is 0, 1, or 2.

For example, the compounds of Formula (I) include those of Formula (Villa):

^K R (Villa), tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein

X¹ is N or CR²;

X² is N or CR³;

X³ is N or CR⁴;

ίο X⁴ is N or CR⁵;

R² is selected from the group consisting of H, C3-C8 cycloalkyl, and Cj-Cô alkyl optionally substituted with one or more of halo, OR^a, or NR^aR^b;

each of R³ and R⁴ is H; and

R⁵ are independently selected from the group consisting of H, C3-C8 cycloalkyl, and 15 Cj-Cô alkyl optionally substituted with one or more of halo or OR^a; or

R⁵ and one of R³ or R⁴ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R⁵ and one of R³’or R⁴’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl; and wherein at least one of R₂ or R₅ are not H.

For example, the compounds of Formula (I) include those of Formula (VlIIb):

pharmaceutically acceptable salts of the compounds or the tautomers, wherein X¹ is N or CR²;

X² is N or CR³;

X³ is N or CR⁴;

X⁴ is N or CR⁵;

R² is selected from the group consisting of H, C3-C8 cycloalkyl, and Ci-Ce alkyl each of R³ and R⁴ is H; and

R⁵ is selected from the group consisting of H, C3-C8 cycloalkyl, and Ci-Ce alkyl; or

R⁵ and one of R³ or R⁴ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R⁵ and one of R³’or R⁴’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or

6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl; and wherein at least one of R2 or R₅ are not H.

For example, the compounds of Formula (I) includes those of Formula (Ville):

¹ H

R⁹ (Ville), wherein

X¹ is N or CR²;

X² is N or CR³;

X³ is N or CR⁴;

X⁴ is N or CR⁵;

R² is selected from the group consisting of H, C3-C8 cycloalkyl, and Ci-Cô alkyl each of R³ and R⁴ is H; and

R⁵ is selected from the group consisting of H, C3-C8 cycloalkyl, and Ci-C₆ alkyl; or

R⁵ and one of R³ or R⁴ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R⁵ and one of R³’or R⁴’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl; and wherein at least one of R₂ or R₅ are not H.

For example, at least one of X¹, X², X³ and X⁴ is N.

For example, X² and X³ is CH, and X¹ and X⁴ is N.

For example, X² and X³ is N, X¹ is CR², and X⁴ is CR⁵.

For example, R⁶ is NR⁸R⁹ and R⁵ is Ci-6 alkyl or R⁵ and R³ together with the atoms to which they are attached form phenyl or a 5- to 6-membered heteroaryl ring.

For example, both of X¹ and X³ are N while X² is CR³ and X⁴ is CR⁵.

Further, the compounds of any of Formulae (I)-(VIIIc) above can hâve one or more of the following features when applicable:

For example, R¹ is H.

For example, R¹ is CH₃.

For example, R² is selected from the group consisting of H, halo, cyano, C1-C4 alkoxyl, phenyl, NR^aR^b, C(O)NR^aR^b, NR^aC(O)R^b, and Ci-C₆ alkyl optionally substituted with one or more of halo, OR^a or NR^aR^b.

For example, R³ is selected from the group consisting of H, halo, cyano, C1-C4 alkoxyl, phenyl, NR^aR^b, C(O)NR^aR^b, NR^aC(O)R^b, and Ci-C₆ alkyl optionally substituted with one or more of halo, OR^a or NR^aR^b.

For example, R⁴ is selected from the group consisting of H, halo, cyano, C1-C4 alkoxyl, phenyl, NR^aR^b, C(O)NR^aR^b, NR^aC(O)R^b, and Ci-C₆ alkyl optionally substituted with one or more of halo, OR^a or NR^aR^b.

For example, R⁵ is selected from the group consisting of H, cyano, C1-C4 alkoxyl, phenyl, NR^aR^b, C(O)NR^aR^b, NR^aC(O)R^b, and Ci-C₆ alkyl optionally substituted with one or more of halo, OR^a or NR^aR^b.

For example, R⁵ is 4 to 12-membered heterocycloalkyl (e.g., azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,620 tetrahydropyridinyl, piperazinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, morpholinyl, 3-azabicyclo[3.1,0]hexan-3-yl, benzo[d][l,3]dioxol-5-yl, isoindolinyl, indolinyl, 2,3-dihydrobenzo[d]oxazolyl, and the like). For example, each of R^a and R^b independently is H or C1-C4 alkyl.

For example, R⁶ is -T¹, in which T¹ is H, halo, cyano, NR⁸R⁹, C(O)NR⁸R⁹, OR⁸, OR⁹, or R^S1. For example, R⁶ is -Q¹-?¹, in which Q¹ is a Ci-Cô alkylene, C2-C6 alkenylene, or C2-C₆ alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo and T¹ is H, halo, cyano, NR⁸R⁹, C(O)NR⁸R⁹, OR⁸, OR⁹, or R^S1.

For example, R^S1 is C₃-C₈ cycloalkyl, phenyl, 4 to 12-membered heterocycloalkyl (e.g., azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, 1,4-diazepanyl, 1,4oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, morpholinyl, 3-azabicyclo[3.1.0]hexan-3yl, benzo[d][l,3]dioxol-5-yl, isoindolinyl, indolinyl, 2,3-dihydrobenzo[d]oxazolyl, 1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7tetrahydro-lH-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, and the like) or a 5- or 6-membered heteroaryl (e.g., pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like), each of which is optionally substituted with one or more of halo, Cj-Cô alkyl, hydroxyl, oxo, -C(O)R⁹,-SO₂R⁸, -SO2N(R⁸)2, -NR⁸C(O)R⁹, amino, mono- or dialkylamino, or Ci-Ce alkoxyl.

For example, R⁶ is NR⁸R⁹.

For example, R⁶ and one of R² or R³ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl (e.g., pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like), in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl, C1-C3 alkoxyl or -Q¹T¹.

For example, R⁶ and one of R²’or R^3, together with the atoms to which they are attached form a 5- or 6-membered heteroaryl (e.g., pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like), in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl, C1-C3 alkoxyl or -Q¹T*.

For example, n is 1 or 2, and at least one of R⁷ is -Q²-OR^h in which R¹¹ is -Q⁶-R^S3 and Q⁶ is optionally substituted C₂-C₆ alkylene, C2-C₆ alkenylene, or C₂-C₆ alkynylene linker.

For example, n is 1 or 2, and at least one of R⁷ is -Q²-NR¹⁰R^H in which R¹¹ is -Q⁶-R^S3.

For example, R¹¹ is -Q⁶-R^S3, in which Q⁶ is a bond or a Ci-Cé alkylene, C₂-Cô alkenylene, or C₂-C₆ alkynylene linker (e.g., C₂-Cô alkylene linker) optionally substituted with a hydroxyl and R^S3 is 4 to 12-membered heterocycloalkyl (e.g., a 4 to 7-membered monocyclic heterocycloalkyl or 7 to 12-membered bicyclic heterocycloalkyl such as azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, morpholinyl, 3-azabicyclo[3.1.0]hexan3-yl, 3-azabicyclo[3.1.0]hexanyl, l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridinyl, 5,6,7,842 tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxaazaspiro[3.4]octan-6-yl, and the like), which is optionally substituted with one or more -Q⁷5 T⁷.

For example, Q⁶ is Ci-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with a hydroxyl and R^S3 is C3-C₆ cycloalkyl optionally substituted with one or more -Q⁷-T⁷.

For example, each Q⁷ is independently a bond or a C1-C3 alkylene, C₂-C3 alkenylene, or C₂10 C3 alkynylene linker and each T⁷ is independently H, halo, Ci-Cô alkyl, or phenyl.

For example, -Q⁷-T⁷ is oxo.

For example, Q² is a bond or a C1-C4 alkylene, C₂-C4 alkenylene, or C₂-C4 alkynylene linker.

Çi^_^4 alkyl

A For example, at least one of R7 is C-] -C4 alkyl A. 0 γ^ γ^ \ u OH '---/ CrC4 alkyl A /N A 0 \ ' C Ef /5 A , H 3- < .n. _ A ? 0 Y An. C1-C4 alkyl V Ao/^^N-c3-8 cycloalkyl A H , or For example, at least one of R7 is Α°/^^^θΝΗ ^0^ 20 A_/

’ 'T \ 0 I N—Crc4 alkyl 7 D ) N-CrC4 alkyl ' [4-0^04 alkyl OH AA , Ay H ^N-C-i-4 alkyl alkyl 5 5 5 AA-8 cycloalkyl N-C3_8 cycloalkyl 5’ 5 0^^^n-c3-8 cycloalkyl I C1.4 alkyl H y 0 \ 5 5 ^2-^4 θΙ^γΙ 5 5 C2-C4 alkyl '''A Aa OH AA 5 5

For example, n is 2 and the compound further comprises another R⁷ selected from halo and methoxy.

For example, ring B is selected from phenyl, pyridyl and cyclohexyl, and the halo or methoxy is at the para-position to NR¹.

For example, R⁶ is NR⁸R⁹, in which R⁸ is H or C1-C4 alkyl and R⁹ is —Q³-T³; or R⁸ and R⁹ taken together with the nitrogen atom to which they are attached form a 4 to 12-membered heterocycloalkyl (e.g., azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, 1,4diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,510 diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, morpholinyl, 3-azabicyclo[3.1.0]hexan-3-yl, benzo[d][l,3]dioxol-5-yl, isoindolinyl, indolinyl, 2,3-dihydrobenzo[d]oxazolyl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-lH-pyrazolo[3,4c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, and the like) which is optionally substituted with one or more of-Q⁵T⁵.

For example, R⁹ is -Q³-T³, in which T³ is OR¹², NR¹²C(O)R¹³, C(O)R¹³, C(O)NR¹²R¹³, S(O)₂NR¹²R¹³, or R^S2.

For example, Q³ is Ci-C₆ alkylene, C₂-C₆ alkenylene, or C₂-C₆ alkynylene linker optionally substituted with a hydroxyl.

For example, R^S2 is C3-C6 cycloalkyl, phenyl, 4 to 12-membered heterocycloalkyl (azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, morpholinyl, 3-azabicyclo[3.1.0]hexan-3-yl, benzo[d][l,3]dioxol-5-yl, isoindolinyl, indolinyl, 2,3-dihydrobenzo[d]oxazolyl, 1,4,5,6tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7tetrahydro-lH-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, and the like), or a 5 to 10-membered heteroaryl (e.g., triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl), and R^S2 is optionally substituted with one or more -Q⁴-T⁴.

For example, each Q⁴ is independently a bond or C1-C3 alkylene, C₂-C3 alkenylene, or C₂-Cs alkynylene linker optionally substituted with one or more of hydroxyl and halo, and each T⁴ is independently H, halo, Ci-Cô alkyl, or phenyl; or -Q⁴-T⁴ is oxo.

For example, R⁶ or NR⁸R⁹ is selected from the group consisting of:

For example, R is H.

For example, R¹² is Ci-Cô alkyl.

For example, R is Ci-Cô alkyl optionally substituted with one or more -Q -T .

For example, R is C3-C8 cycloalkyl optionally substituted with one or more -Q -T . For example, R¹³ is C₆-Cio aryl (e.g., phenyl) optionally substituted with one or more -Q⁸-T⁸.

For example, R¹³ is 4 to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S (e.g., azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, morpholinyl, 3-azabicyclo[3.1.0]hexan-3-yl, benzo[d][l,3]dioxol-5-yl, isoindolinyl, indolinyl, 2,3-dihydrobenzo[d]oxazolyl, and the like) optionally substituted with one or zx8 τ’8 more-Q -T .

For example, R¹³ is 5 to 10-membered heteroaryl (e.g., triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl) optionally substituted with one or more -Q -T .

For example, Q⁸ is a bond.

For example, Q⁸ is a C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker.

For example, T⁸ is halo, cyano, Cj-Cô alkyl, C3-C8 cycloalkyl, phenyl, or 4 to 7-membered heterocycloalkyl (e.g., e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl,

1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5azabicyclo[2.2.1 ]heptanyl, 2,5-diazabicyclo[2.2.1 ]heptanyl, 2-oxa-6azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 3-azabicyclo[3.1.0]hexan-3-yl, and morpholinyl, and the like).

For example, -Q -T is oxo.

The présent disclosure also provides compounds of Formula (IX-1) below:

or a tautomer thereof, or a pharmaceutically acceptable sait of the compound or the 10 tautomer, wherein,

X⁶ is N or CH;

X⁷ is N or CH;

X³ is N or CR⁴;

R⁴ is selected from the group consisting of H, halo, cyano, Ci-Cô alkoxyl, Cô-Cio aryl, 15 NR^aR^b, C(O)NR^aR^b, NR^aC(O)R^b, C₃-C₈ cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, and Ci-Cô alkyl, wherein Ci-Cô alkoxyl and Ci-Cô alkyl are optionally substituted with one or more of halo, OR^a, or NR^aR^b, in which each of R^a and R^b independently is H or Ci-Cô alkyl;

each Q¹ is independently a bond or Cj-Cô alkylene, C2-C6 alkenylene, or C2-C6 20 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or Ci-Cô alkoxyl;

each T¹ is independently H, halo, cyano, NR⁸R⁹, C(O)NR⁸R⁹, C(O)R⁹, OR⁸, OR⁹, or R^S1, in which R^S1 is C3-C8 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and 25 R is optionally substituted with one or more of halo, Ci-Cô alkyl, hydroxyl, oxo, -C(O)R , SO2R⁸, -SO2N(R⁸)2, -NR⁸C(O)R⁹, NR⁸R⁹, or Ci-C6 alkoxyl; and -Q'-T¹ is not NR⁸C(O)NR¹²R¹³;

each R⁸ independently is H or Ci-Cô alkyl;

each R⁹ is independently -Q³-T³, in which Q³ is a bond or Cj-Cô alkylene, C2-C6 30 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or Cj-C₆ alkoxyl, and T³ is H, halo, OR¹², OR¹³, NR¹²R¹³, NR¹²C(O)R¹³,

C(O)NR¹²R¹³, C(O)R¹³, S(O)2R¹³, S(O)2NR¹²R¹³, or R^S2, in which R^s2 is C3-C8 cycloalkyl, Cô-Cio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and R^S2 is optionally substituted with one or more —Q⁴-T⁴, wherein each Q⁴ independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-C₆ alkoxy, and each T⁴ independently is selected from the group consisting of H, halo, cyano, Ci-C6 alkyl, C3-C8 cycloalkyl, C6-Ci0 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^C, C(O)R^c, S(O)2R^C, NR^cR^d, C(O)NR^cR^d, and NR^cC(O)R^d, each of R^c and R^d independently being H or Ci-Cô alkyl; or -Q⁴-T⁴ is oxo; or

R¹² is H or C|-C₆ alkyl;

R¹³ is Ci-C6 alkyl, C3-C8 cycloalkyl, C6-Ci0 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more -Q -T , wherein each Q independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁸ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C3-C8 cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl; or -Q -T is oxo;

R^l5a is CN, C(O)H, C(O)R¹⁸, OH, OR¹⁸, Ci-C6 alkyl, NHR¹⁷, C3-C₈ cycloalkyl, CôCio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or 5- to 10-membered heteroaryl, wherein each of said Ci-Cg alkyl, C3-C₈ cycloalkyl, Cô-Cio aryl, 4- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl is optionally substituted with one or more -Q⁹-T⁹, wherein each Q⁹ independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-C6 alkoxy, and each T⁹ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C3-C8 cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5to 6-membered heteroaryl; or-Q⁹-T⁹ is oxo;

R^16a is -Qⁿ-R¹⁶ in which Q¹¹ is a bond, O, NR^a, C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy; and R¹⁶ is H, Ci-Cô alkyl, C2-Cô alkenyl, C₂-Cô alkynyl, C3-C₈ cycloalkyl, Cô-Cio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more -Q¹⁰-T¹⁰, wherein each Q¹⁰ independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T¹⁰ independently is selected from the group consisting of H, halo, cyano, C(O)H, C(O)R¹⁸, S(O)_pR¹⁸, OH, OR¹⁸, Ci-Cô alkyl, C₃-C₈ cycloalkyl, C₆-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl; or -Q¹⁰-T¹⁰ is oxo;

R¹⁷ is H or Ci-C₆ alkyl;

each R¹⁸ is independently Ci-Cô alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

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

For example, R^15a is CN or C(O)R¹⁸.

For example, R^16a is -Qⁿ-R¹⁶ in which Q¹¹ is a bond, NR^a, or C1-C3 alkylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy.

For example, each Q¹ is independently a bond or Ci-Cô alkylene or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy.

For example, each T¹ is independently NR⁸R⁹, OR⁹, or R^SI, in which R^S1 is optionally substituted C₃-C₈ cycloalkyl or optionally substituted 4- to 12-membered heterocycloalkyl. For example, one subset of compounds of Formula (IX-1) is of Formula (IX):

(r⁹o

or a tautomer thereof, or a pharmaceutically acceptable sait of the compound or the tautomer, wherein

X⁶ is N or CH;

X⁷ is N or CH;

X³ is N or CR⁴;

R⁴ is selected from the group consisting of H, halo, cyano, Ci-Cô alkoxyl, Cô-Cio aryl,

NR^aR^b, C(O)NR^aR^b, NR^aC(O)R^b, C3-C₈ cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, and Ci-Cô alkyl, wherein Ci-Cô alkoxyl and Ci-Cô alkyl are optionally substituted with one or more of halo, OR^a, or NR^aR^b, in which each of R^a and R^b independently is H or Ci-Cô alkyl;

each R⁹ is independently -Q³-T³, in which Q³ is a bond or Ci-Cô alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxyl, and T³ is H, halo, OR¹², OR¹³, NR¹²R¹³, NR¹²C(O)R¹³, C(O)NR¹²R¹³, C(O)R¹³, S(O)₂R¹³, S(O)2NR¹²R¹³, or R^S2, in which R^S2 is C3-C₈ cycloalkyl, Cô-Cio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and R^S2 is optionally substituted with one or 5 more -Q⁴-T⁴, wherein each Q⁴ independently is a bond or Ci-C₃ alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-C₆ alkoxy, and each T⁴ independently is selected from the group consisting of H, halo, cyano, Ci-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-Ci₀ aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^C, C(O)R^c, S(O)₂R^C, NR^cR^d, C(O)NR^cR^d, and NR^cC(O)R^d, each of R^c and R^d independently being H or Ci-Cô alkyl; or -Q⁴-T⁴ is oxo; or

R¹² is H or Ci-Cô alkyl;

R¹³ is Ci-Cô alkyl, C₃-C₈ cycloalkyl, C₆-Ci₀ aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, 15 each of which is optionally substituted with one or more -Q -T , wherein each Q independently is a bond or Ci-C₃ alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁸ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C₃-C₈ cycloalkyl, C₆-Ci₀ aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl; or -Q -T is oxo;

R¹⁵ is Ci-Cô alkyl, NHR¹⁷, C3-C8 cycloalkyl, C6-Ci0 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or 5- to 10membered heteroaryl, wherein each of said Ci-Cg alkyl, C3-C8 cycloalkyl, Cô-Cio aryl, 4- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl is optionally substituted 25 with one or more -Q⁹-T⁹, wherein each Q⁹ independently is a bond or Ci-C3 alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁹ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C₃-C₈ cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6- membered heteroaryl; or -Q⁹-T⁹ is oxo;

R¹⁶ is Ci-Cô alkyl, C2-Cô alkenyl, C2-Cô alkynyl, C3-C8 cycloalkyl, Cô-Cio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5to 10-membered heteroaryl, each of which is optionally substituted with one or more -Q¹⁰T¹⁰, wherein each Q¹⁰ independently is a bond or Ci-C3 alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-C₆ alkoxy, and each T¹⁰ independently is selected from the group consisting of H, halo, cyano, Ci-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-Ci₀ aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl; or R¹⁷ is H or Ci-Cô alkyl; and v is 0, 1, or 2.

The compounds of Formula (IX) can hâve one or more of the following features when applicable:

For example, each T³ independently is OR¹² or OR¹³.

For example, each Q³ independently is a bond or Ci-Cô alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with a hydroxyl.

For example, R¹⁵ is Ci-C₆ alkyl, NHR¹⁷, or 4- to 12-membered heterocycloalkyl.

For example, R¹⁶ is Ci-C₆ alkyl or 4- to 12-membered heterocycloalkyl, each optionally substituted with one or more -Q¹⁰-T¹⁰.

For example, each T¹⁰ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, and 4- to 7-membered heterocycloalkyl.

For example, each Q¹⁰ independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker optionally substituted with a hydroxyl.

For example, the compounds of Formula (IX) include those of Formula (X):

R¹⁶

R¹⁵ (X), and tautomers thereof, or pharmaceutically acceptable salts of the compounds or the tautomers, wherein X³ is N or CR⁴, wherein R⁴ is selected from the group consisting of H, halo, and cyano.

For example, the compounds of Formula (X) include those of Formula (Xa), (Xb), (Xc), (Xd), (Xe), (Xf), or (Xg):

R¹⁶

For example, X² and X³ are CH, and X¹ and X⁴ is N.

For example, X² and X³ are N, X¹ is CR², and X⁴ is CR⁵.

For example, R⁶ is NR⁸R⁹ and R⁵ is Ci-6 alkyl or R⁵ and R³ together with the atoms to which they are attached form phenyl or a 5- to 6-membered heteroaryl ring.

For example, the compound is selected from those in Tables 1-5, tautomers thereof, and pharmaceutically acceptable salts of the compounds and tautomers.

The présent disclosure provides compounds which inhibit a kinase with an enzyme inhibition IC₅o value of about 100 nM or greater, 1 μΜ or greater, 10 μΜ or greater, 100 μΜ or greater, or 1000 μΜ or greater.

The présent disclosure provides compounds which inhibit a kinase with an enzyme inhibition IC50 value of about 1 mM or greater.

The présent disclosure provides compounds which inhibit a kinase with an enzyme inhibition IC50 value of 1 μΜ or greater, 2 μΜ or greater, 5 μΜ or greater, or 10 μΜ or greater, wherein the kinase is one or more of the following: Abl, AurA, CHK1, MAP4K, IRAK4, JAK3, EphA2, FGFR3, KDR, Lck, MARK1, MNK2, PKCb2, SIK, and Src. The présent disclosure provides a pharmaceutical composition comprising a compound of any one of the Formulae described herein or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier.

The présent disclosure provides a method of preventing or treating a blood disorder via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I):

R¹ (i), or a tautomer thereof, or a pharmaceutically acceptable sait of the compound or the tautomer, wherein ring A is phenyl or a 5- or 6-membered heteroaryl;

X¹ is N, CR², or NR²’ as valency permits;

X² is N, CR³, or NR³’ as valency permits;

X³ is N, CR⁴, or NR⁴’ as valency permits;

X⁴ is N or CR⁵, or X⁴ is absent such that ring A is a 5-membered heteroaryl containing at least one N atom;

X⁵ is C or N as valency permits;

B is absent or a ring structure selected from the group consisting of C₆-Ci₀ aryl, C3C10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S;

T is a bond or Ci-Cô alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo; or Ci-Cô alkoxy when B is présent; or T is H and n is 0 when B is absent; or T is Ci-Cô alkyl optionally substituted with (R⁷)nwhen B is absent; or when B is absent, T and R¹ together with the atoms to which they are attached optionally form a 4-7 membered heterocycloalkyl or 5-6 membered y heteroaryl, each of which is optionally substituted with (R )n;

R¹ is H or C1-C4 alkyl;

each of R²’, R³’ and R⁴’ independently is H or C1-C3 alkyl;

each of R², R³, and R⁴, independently is selected from the group consisting of H, halo, cyano, Ci-C6 alkoxyl, C6-Ci0 aryl, NR^aR^b, C(O)NR^aR^b, NR^aC(O)R^b, C3-C₈ cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and Ci-Cô alkyl, wherein C]-Cô alkoxyl and Ci-Cô alkyl are optionally substituted with one or more of halo, OR^a, or NR^aR^b, 5 in which each of R^a and R^b independently is H or Ci-Cô alkyl, or R³ is —Q'-T¹, in which Q is a bond or CrC6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or Ci-C6 alkoxyl, and T¹ is H, halo, cyano, NR⁸R⁹, C(O)NR⁸R⁹, OR⁸, OR⁹, or R^S1, in which R^S1 is C3-C₈ cycloalkyl, phenyl, 4- to 12membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or jo 6-membered heteroaryl and R^S1 is optionally substituted with one or more of halo, Ci-C₆ alkyl, hydroxyl, oxo, -C(O)R⁹, -SO2R⁸, -SO2N(R⁸)₂, -NR⁸C(O)R⁹, amino, mono- or dialkylamino, or Ci-C₆ alkoxyl; or when ring A is a 5-membered heteroaryl containing at least one N atom, R⁴ is a spiro-fused 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S;

/5 R⁵ is selected from the group consisting of H, halo, cyano, Ci-Cô alkoxyl, Cô-Cio aryl,

NR^aR^b, C(O)NR^aR^b, NR^aC(O)R^b, C3-C8 cycloalkyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more of-C(O)Ci-C6 alkyl or Ci-C6 alkyl optionally substituted with one or more of halo or OR^a, Ci-Cô alkyl optionally substituted with one or more of halo, OR^a, or NR^aR^b, and C2-Cô 20 alkynyl optionally substituted with 4- to 12-membered heterocycloalkyl; wherein said C₃-C₈ cycloalkyl and 4- to 12-membered heterocycloalkyl are optionally substituted with one or more of halo, C(O)R^a, OR^a, NR^aR^b, 4- to 7-membered heterocycloalkyl, -Ci-Cô alkylene-4- to 7-membered heterocycloalkyl, or C1-C4 alkyl optionally substituted with one or more of halo, OR^a or NR^aR^b, in which each of R^a and R^b independently is H or Ci-C₆ alkyl; or

R⁵ and one of R³ or R⁴ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R⁵ and one of R³’or R⁴’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, Cj-C₃ alkyl, hydroxyl or Ci-C₃ alkoxyl;

R⁶ is absent when X⁵ is N and ring A is a 6-membered heteroaryl; or R⁶ is -Q'-T¹, in which Q¹ is a bond or Ci-Cô alkylene, C2-Cô alkenylene, or C2-Cô alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or Ci-Cô alkoxyl, and T¹ is H, halo, cyano, NR⁸R⁹, C(O)NR⁸R⁹, C(O)R⁹, OR⁸, OR⁹, or R^S1, in which R^S1 is C3-C₈ cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R^sl is optionally substituted with one or more of halo, Ci-Cô alkyl, hydroxyl, oxo, -C(O)R⁹, -SO2R⁸, -SO2N(R⁸)₂, -NR⁸C(O)R⁹, NR⁸R⁹, or Cj-Cô alkoxyl; and R⁶ is not NR⁸C(O)NR¹²R¹³; or

R⁶ and one of R² or R³ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R⁶ and one of R²’or R³’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl, oxo (=O), C1-C3 alkoxyl or -Q^T¹;

each R⁷ is independently oxo (=0) or -Q²-T², in which each Q² independently is a bond or Ci-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or Cj-Cô alkoxyl, and each T² independently is H, halo, cyano, OR¹⁰, OR¹¹, C(O)Rⁿ, NR^R¹¹, C(O)NR^l0Rⁿ, NR¹⁰C(O)R^h, 5- to 10-membered heteroaryl, C3-C₈ cycloalkyl, or 4- to 12membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the 5- to 10-membered heteroaryl, C3-C₈ cycloalkyl, or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, Cj-Cô alkyl optionally substituted with NR^xR^y, hydroxyl, oxo, N(R⁸)2, cyano, Cj-C6 haloalkyl, -SO2R⁸, or Cj-C6 alkoxyl, each of R^x and R^y independently being H or Cj-Cô alkyl; and R7 is not H or C(O)OR^g; or optionally, when B is présent, one R⁷ and R⁵ together form a C3-C10 alkylene, C2-C₁₀ heteroalkylene, C4-C10 alkenylene, C₂-C₁₀ heteroalkenylene, C₄-Cj₀ alkynylene or C₂Cjo heteroalkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or Cj-Cô alkoxyl;

each R⁸ independently is H or Cj-Cô alkyl;

each R⁹ is independently -Q³-T³, in which Q³ is a bond or Cj-Cô alkylene, C2-Cô alkenylene, or C2-Cô alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl or Cj-Cô alkoxyl, and T³ is H, halo, OR¹², OR¹³, NR¹²R¹³, NR¹²C(O)R¹³, C(O)NR¹²R¹³, C(O)R¹³, S(O)2R¹³, S(O)2NR¹²R¹³, or R^S2, in which R^S2 is C3-C₈ cycloalkyl, Cô-Cio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and R^S2 is optionally substituted with one or more -Q⁴-T⁴, wherein each Q⁴ independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Cj-Cô alkoxy, and each T⁴ independently is selected from the group consisting of H, halo, cyano, Cj-Cô alkyl, C3-C8 cycloalkyl, Cô-Cjo aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^C, C(O)R^c, S(O)2R^C, S(0)2NR^cR^d, NR^cR^d, C(0)NR^cR^d, and NR^cC(0)R^d, each of R^c and R^d independently being H or Ci-Cô alkyl; or -Q⁴-T⁴ is oxo; or

R⁸ and R⁹ taken together with the nitrogen atom to which they are attached form a 4to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, which is optionally substituted with one or more of-Q⁵-T⁵, wherein each Q⁵ independently is a bond or Ct-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-C6 alkoxy, and each T⁵ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C3-C₈ cycloalkyl, C₆-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms io selected from N, O, and S, 5- to 6-membered heteroaryl, OR^e, C(O)R^e, S(O)2R^e, S(O)2NR^eR^f, NR^eR^f, C(O)NR^eR^f, and NR^eC(O)R^f, each of R^e and R^f independently being H or Ci-C₆ alkyl; or - Q⁵-T⁵ is oxo;

R¹⁰ is selected from the group consisting of H and Ci-Cô alkyl;

R¹¹ is -Q⁶-T⁶, in which Q⁶ is a bond or Ci-Cô alkylene, C₂-Cô alkenylene, or C₂-Cô 15 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or

Ci-C₆ alkoxyl, and T⁶ is H, halo, OR^g, NR^gR^h, NR^gC(O)R^h, C(O)NR^gR^h, C(O)R^g, S(O)2R^g, or R^S3, in which each of R^ë and R^h independently is H, phenyl, C3-C₈ cycloalkyl, or Ci-Cô alkyl optionally substituted with C₃-C₈ cycloalkyl, or R^g and R^h together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and R^S3 is C3-C8 cycloalkyl, Cô-Cio aryl, 4- to 12membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, or a 5- to 10-membered heteroaryl, and R^s3 is optionally substituted with one or more -Q⁷-T⁷, wherein each Q⁷ independently is a bond or Ci-C3 alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁷ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C3-C8 cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^j, C(O)R^j, NR^JR^k, C(O)NR^JR^k, S(O)2Rj and NR^jC(O)R^k, each of R^J and R^k independently being H or Ci-Cô alkyl optionally substituted with one or more halo; or -Q -T is oxo; or

R¹⁰ and R¹¹ taken together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, which is optionally substituted with one or more of halo, Ci-Cô alkyl, hydroxyl, or Ci-Cô alkoxyl;

R¹² is H or Ci-C₆ alkyl;

R¹³ is Ci-Cô alkyl, C3-C8 cycloalkyl, C6-Cl0 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more -Q -T , wherein each Q independently is a bond or Ci-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁸ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C3-C₈ cycloalkyl, C₆-Ci₀ aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, and 5- to 6-membered heteroaryl; or -Q⁸-T⁸ is oxo; and n is 0, 1,2, 3, or 4, provided that (1) the compound of Formula (I) is not 2-(hexahydro-4-methyl-lH-l,4-diazepin-l-yl)6,7-dimethoxy-N-[ 1 -(phenylmethyl)-4-piperidinyl]-4-quinazolinamine, or

2-cyclohexyl-6-methoxy-N-[l-(l-methylethyl)-4-piperidinyl]-7-[3-(lpyrrolidinyl)propoxy]-4-quinazolinamine;

(2) when X¹ and X³ are N, X² is CR³, X⁴ is CR⁵, X⁵ is C, R⁵ is 4- to 12-membered heterocycloalkyl substituted with one or more Ci-Cô alkyl, and R⁶ and R³ together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted Ci-C₃ alkoxyl, then B is absent, C₆-Cio aryl, C₃-Cio cycloalkyl, or 5 to 10-membered heteroaryl; or (3) when X² and X³ are N, X¹ is CR², X⁴ is CR⁵, X⁵ is C, R⁵ is C3-C8 cycloalkyl or 4to 12-membered heterocycloalkyl, each optionally substituted with one or more Ci-Cô alkyl, and R⁶ and R² together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted Ci-C3 alkoxyl, then B is absent, Cô-Cio aryl, C₃-Cio cycloalkyl, or 5- to 10-membered heteroaryl.

The présent disclosure also provides a method of preventing or treating a blood disorder via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, e.g., any compound of any of Formulae (I)-(Xg).

For example, the blood disorder is sickle cell anémia or β-thalassemia.

For example, the blood disorder is a hematological cancer.

For example, the hematological cancer is acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL).

The présent disclosure also provides compounds of Formula (I) which are sélective inhibitors ofEHMT2.

Représentative compounds of the présent disclosure include compounds listed in Tables 1-5 or tautomers and salts thereof.

6l

Compound No.	Structure
36	JJ £1 \ J H H 1 J
37	CY £1IX
38	? H H n ΓΛ ---
39	yVox0
40	°ΧΧτΥ^Ό
41	/--. O Cx^-Jy î: j x£J LJ
42	HO. HH 1 \ Xx_/N N ΝγγγγΟγγ-χ^,Ν^/ YX
43	/I H H o VNxV\/O\Y%A^ χΧΤ U C f
44	a Xa xx°x^ 1 H H L /

Compound No.	Structure
72	rj N N N H H
73	Γχ h H L_7
74	χΊ H H l /
75	O XL Yx X N N NH2 H
76	—z T.Z P IZ
77	/x /x XI /x /x N NH2 H H
78	Ί^Ί | H H
79	χΊ H H
80	O H II \ /N. /N. Y* >< nh2 Νχ^

Compound No.	Structure
				F
285		Y r Ύ		Z F F
			x0^
286	H	H T i		—OH
	H	H
287		Y T ï
		Z YZ	^o^
	Z—N	Z ||	'Z NX'Z
288		II	H	N^ H
		Z^N II	/X/°\
289	H	1 II 1 Z^^Z H	/Ν'
290	H	H	II
		Y	II
291	H /N^	H /N^/Nx 1 II ZZ	0 Il H Zz
	Z
292		F /0
	Z'N	x	\/ 'N^ H	N^ H
	H	H
293	Y		Y
			II

100

101

102

103

104

105

106

107

108

109

1I0

111

112

113

114

115

116

117

118

119

120

12I

122

123

124

125

126

127

128

129

130

131

132

133

Table 3

Compound No.

Structure

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

I7l

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

Compound No.	Structure
718	Q 1^0 ch3 JL J nX 1 if H3CKN'N nA ch3
719	XX ΗΝ-γΚ^ ΝγΝ NH Γ ¥ ch3 °'p^ ô

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

Table 5

Compound No.

1043

1045

1046

1047

1048

244

245

246

247

248

249

250

251

252

253

254

255

256

include Ci, C₂, C₃, C₄, C₅ or Cô straight chain (linear) saturated aliphatic hydrocarbon groups and C₃, C₄, C₅ or Cô branched saturated aliphatic hydrocarbon groups. For example, Ci-Cg alkyl is intended to include Cl, C2, C3, C4, C5 and C6 alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl or n-hexyl.

In certain embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., Ci-Cô for straight chain, C₃-Cô for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

/0 As used herein, the term “cycloalkyl” refers to a saturated or unsaturated nonaromatic hydrocarbon mono- or multi-ring (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C₃-Ci₂, C₃-Cio, or C₃-Cs). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl.

/5 The term heterocycloalkyl refers to a saturated or unsaturated nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as

257

O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, 5 indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, l,4-dioxa-8-azaspiro[4.5]decanyl, 1,410 dioxaspiro[4.5]decanyl, l-oxaspiro[4.5]decanyl, l-azaspiro[4.5]decanyl, 3Ήspiro[cyclohexane-l,l'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-l,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-l,r-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3azabicyclo[3.1.0]hexan-3-yl, l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridinyl, 5,6,7,815 tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxaazaspiro[3.4]octan-6-yl, and the like. In the case of multicyclic non-aromatic rings, only one of the rings needs to be non-aromatic (e.g., 1,2,3,4-tetrahydronaphthalenyl or 2,320 dihydroindole).

The term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, 30 thiocarboxylate, sulfates, alkylsulfmyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

As used herein, “alkyl linker” or “alkylene linker” is intended to include Ci, C₂, C₃, C4, C5 or Cô straight chain (linear) saturated divalent aliphatic hydrocarbon groups and C₃, C4, C5 or CJ

258 branched saturated aliphatic hydrocarbon groups. For example, Cj-C₆ alkylene linker is intended to include C_b C₂, C₃, C₄, C₅ and C₆ alkylene linker groups. Examples of alkylene linker include, moieties having from one to six carbon atoms, such as, but not limited to, methyl (-CH₂-), ethyl (-CH₂CH₂-), n-propyl (-CH₂CH₂CH₂-), i-propyl (-CHCH₃CH₂-), n-butyl (-CH₂CH₂CH₂CH₂-), s-butyl (-CHCH₃CH₂CH₂-), i-butyl (-C(CH₃)₂CH₂-), n-pentyl (CH₂CH₂CH₂CH₂CH₂-), s-pentyl (-CHCH₃CH₂CH₂CH₂-) or n-hexyl (CH₂CH₂CH₂CH₂CH₂CH₂-).

“Alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups.

In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C₂-C₆ for straight chain, C₃-C₆ for branched chain). The term “C₂-C₆” includes alkenyl groups containing two to six carbon atoms. The term “C₃-Cô” includes alkenyl groups containing three to six carbon atoms.

The term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. “Alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C₂-Cô for straight chain, C₃-Cô for branched chain). The term “C₂-C6” includes alkynyl groups containing two to six carbon atoms. The term “C₃-Cô” includes

259 alkynyl groups containing three to six carbon atoms. As used herein, “C₂-Cô alkenylene linker” or “C₂-C6 alkynylene linker” is intended to include C₂, C₃, C4, C5 or Cô chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C₂-C₆ alkenylene linker is intended to include C₂, C₃, C4, C5 and Cô alkenylene linker groups.

As used herein, the terms “heteroalkyl”, “heteroalkylene linker”, “heteroalkenyl”, “heteroalkenylene linker”, “heteroalkynyl”, and “heteroalkynylene linker”, are intended to refer to aliphatic hydrocarbon groups that include, e.g., Ci to Cio carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. These aliphatic hydrocarbon groups can either be linear or branched, saturated or unsaturated.

The term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

Other optionally substituted moieties (such as optionally substituted heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethylpiperidinyl and 2,2,6,6-tetramethyl-l ,2,3,6-tetrahydropyridinyl.

“Aryl” includes groups with aromaticity, including “conjugated,” or multicyclic Systems with one or more aromatic rings and do not contain any heteroatom in the ring structure.

Examples include phenyl, naphthalenyl, etc.

“Heteroaryl” groups are aryl groups, as defined above, except having from one to four heteroatoms in the ring structure, and may also be referred to as “aryl heterocycles” or “heteroaromatics.” As used herein, the term “heteroaryl” is intended to include a stable 5-, 6260 , or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be 5 substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined).

The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N—>O and S(O)_P, where p = 1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, io imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.

Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, 15 indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, 20 alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, 25 alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic System (e.g., tetralin, methyl enedioxyphenyl such as benzo[d][l,3]dioxole-5-yl).

As used herein, “carbocycle” or “carbocyclic ring” is intended to include any stable monocyclic, bicyclic or tricyclic ring having the specified number of carbons, any of which may be saturated, unsaturated, or aromatic. Carbocycle includes cycloalkyl and aryl. For example, a C3-C14 carbocycle is intended to include a monocyclic, bicyclic or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms. Examples of carbocycles include,

261 but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl, adamantyl and tetrahydronaphthyl. Bridged rings are also included in the définition of carbocycle, including, for example, 5 [3.3.0]bicyclooctane, [4.3.0]bicyclononane, and [4.4.0] bicyclodecane and [2.2.2] bicyclooctane. A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. In one embodiment, bridge rings are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be présent on the bridge. Fused (e.g., naphthyl, 10 tetrahydronaphthyl) and spiro rings are also included.

As used herein, “heterocycle” or “heterocyclic group” includes any ring structure (saturated, unsaturated, or aromatic) which contains at least one ring heteroatom (e.g., 1-4 heteroatoms selected from N, O and S). Heterocycle includes heterocycloalkyl and heteroaryl. Examples of heterocycles include, but are not limited to, morpholine, pyrrolidine, tetrahydrothiophene, 15 piperidine, piperazine, oxetane, pyran, tetrahydropyran, azetidine, and tetrahydrofuran.

Examples of heterocyclic groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-\,5,2-dithiazinyl, dihydrofuro[2,3-è]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 17f-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl (e.g., benzo[d][l,3]dioxole-5-yl), morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, l,2,4-oxadiazol5(4H)-one, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, 30 pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4/7-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,

262 thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

The term “substituted,” as used herein, means that any one or more hydrogen atoms on the designated atom is replaced with a sélection from the indicated groups, provided that the 5 designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not présent on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound 10 that is suffi ci ently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a 15 given formula, then such substituent may be bonded via any atom in such formula.

Combinations of substituents and/or variables are permissible, but only if such combinations resuit in stable compounds.

When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its définition at each occurrence is independent of its définition at every other 20 occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the définition of R. Also, combinations of substituents and/or variables are permissible, but only if such combinations resuit in stable compounds.

The term “hydroxy” or “hydroxyl” includes groups with an -OH or -O'.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo and iodo. The term “perhalogenated” generally refers to a moiety wherein ail hydrogen atoms are replaced by halogen atoms. The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

The term “carbonyl” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom. Examples of moieties containing a carbonyl include, but are not limited to, aldéhydes, ketones, carboxylic acids, amides, esters, anhydrides, etc. The term “carboxyl” refers to -COOH or its Ci-Cô alkyl ester.

263 “Acyl” includes moieties that contain the acyl radical (R-C(O)-) or a carbonyl group. “Substituted acyl” includes acyl groups where one or more of the hydrogen atoms are replaced by, for example, alkyl groups, alkynyl groups, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

“Aroyl” includes moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.

“Alkoxyalkyl,” “alkylaminoalkyl,” and “thioalkoxyalkyl” include alkyl groups, as described above, wherein oxygen, nitrogen, or sulfur atoms replace one or more hydrocarbon backbone carbon atoms.

The term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not Iimited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not Iimited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

The term “ether” or “alkoxy” includes compounds or moieties which contain an oxygen bonded to two carbon atoms or heteroatoms. For example, the term includes “alkoxyalkyl,”

264 which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to an alkyl group.

The term “ester” includes compounds or moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group. The term 5 “ester” includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.

The term “thioalkyl” includes compounds or moieties which contain an alkyl group connected with a sulfur atom. The thioalkyl groups can be substituted with groups such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, 10 alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, 15 thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties.

The tenu “thiocarbonyl” or “thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.

The tenu “thioether” includes moieties which contain a sulfur atom bonded to two carbon atoms or heteroatoms. Examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls. The term “alkthioalkyls” include moieties with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group. Similarly, the term “alkthioalkenyls” refers to moieties wherein an alkyl, alkenyl or alkynyl 25 group is bonded to a sulfur atom which is covalently bonded to an alkenyl group; and alkthioalkynyls” refers to moieties wherein an alkyl, alkenyl or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.

As used herein, “amine” or “amino” refers to -NH₂. “Alkylamino” includes groups of compounds wherein the nitrogen of -NH₂ is bound to at least one alkyl group. Examples of 30 alkylamino groups include benzylamino, methylamino, ethylamino, phenethylamino, etc.

“Dialkylamino” includes groups wherein the nitrogen of -NH₂ is bound to two alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino and diethylamino. “Arylamino” and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively. “Aminoaryl” and “aminoaryloxy” refer to

265 aryl and aryloxy substituted with amino. “Alkylarylamino,” “alkylaminoaryl” or “arylaminoalkyl” refers to an amino group which is bound to at least one alkyl group and at least one aryl group. “Alkaminoalkyl” refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group. “Acylamino” includes groups wherein nitrogen is bound to an acyl group. Examples of acylamino include, but are not limited to, alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.

The tenu “amide” or “aminocarboxy” includes compounds or moieties that contain a nitrogen atom that is bound to the carbon of a carbonyl or a thiocarbonyl group. The tenu includes “alkaminocarboxy” groups that include alkyl, alkenyl or alkynyl groups bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group. It also includes “arylaminocarboxy” groups that include aryl or heteroaryl moieties bound to an amino group that is bound to the carbon of a carbonyl or thiocarbonyl group. The terms “alkylaminocarboxy”, “alkenylaminocarboxy”, “alkynylaminocarboxy” and “arylaminocarboxy” include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties, respectively, are bound to a nitrogen atom which is in tum bound to the carbon of a carbonyl group. Amides can be substituted with substituents such as straight chain alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl or heterocycle. Substituents on amide groups may be further substituted.

Compounds of the présent disclosure that contain nitrogens can be converted to N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid (mCPBA) and/or hydrogen peroxides) to afford other compounds of the présent disclosure. Thus, ail shown and claimed nitrogen-containing compounds are considered, when allowed by valency and structure, to include both the compound as shown and its N-oxide dérivative (which can be designated as N—>O or N⁺-0‘). Furthermore, in other instances, the nitrogens in the compounds of the présent disclosure can be converted to N-hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds can be prepared by oxidation of the parent amine by an oxidizing agent such as m-CPBA. Ail shown and claimed nitrogen-containing compounds are also considered, when allowed by valency and structure, to cover both the compound as shown and its N-hydroxy (i.e., N-OH) and N-alkoxy (i.e., N-OR, wherein R is substituted or unsubstituted Ci-Cô alkyl, Ci-Cô alkenyl, Ci-Cô alkynyl, 3-14-membered carbocycle or 3-14membered heterocycle) dérivatives.

In the présent spécification, the structural formula of the compound represents a certain isomer for convenience in some cases, but the présent disclosure includes ail isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers,

266 tautomers, and the like, it being understood that not ail isomers may hâve the same level of activity. In addition, a crystal polymorphism may be présent for the compounds represented by the formula. It is noted that any crystal form, crystal form mixture, or anhydride or hydrate thereof is included in the scope of the présent disclosure.

“Isomerism” means compounds that hâve identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.” A carbon atom bonded to four nonidentical substituents is termed a “chiral center.” “Chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is présent, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under considération are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem.

Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem: 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

“Géométrie isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cylcobutyl). These configurations are differentiated in their names by the préfixés cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molécule according to the Cahn-Ingold-Prelog raies.

It is to be understood that the compounds of the présent disclosure may be depicted as different chiral isomers or géométrie isomers. It should also be understood that when compounds hâve chiral isomeric or géométrie isomeric forms, ail isomeric forms are intended to be included in the scope of the présent disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not ail isomers may hâve the same level of activity.

267

Furthermore, the structures and other compounds discussed in this disciosure include ail atropic isomers thereof, it being understood that not ail atropic isomers may hâve the same level of activity. “Atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted 5 rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a resuit of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

“Tautomer” is one of two or more structural isomers that exist in equilibrium and is readily 10 converted from one isomeric form to another. This conversion results in the formai migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds.

Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a Chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers dépends on several factors, including température, solvent and 15 pH. The concept of tautomers that are interconvertible by tautomerizations is called tautomerism.

Of the varions types of tautomerism that are possible, two are commonly observed. In ketoenol tautomerism a simultaneous shift of électrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a resuit of the aldéhyde group (-CHO) in a sugar chain moiecule reacting with one of the hydroxy groups (-OH) in the same moiecule to give it a cyclic (ringshaped) form as exhibited by glucose.

Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), imine-enamine and enamine-enamine. Examples of lactam-lactim tautomerism are 25 as shown below.

268

It is to be understood that the compounds of the présent disclosure may be depicted as different tautomers. It should also be understood that when compounds hâve tautomeric forms, ail tautomeric forms are intended to be included in the scope of the présent disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood 5 that certain tautomers may hâve a higher level of activity than others.

The term “crystal polymorphs”, “polymorphs” or “crystal forms” means crystal structures in which a compound (or a sait or solvaté thereof) can crystallize in different crystal packing arrangements, ail of which hâve the same elemental composition. Different crystal forms usually hâve different X-ray diffraction patterns, infrared spectral, melting points, density 10 hardness, crystal shape, optical and electrical properties, stability and solubility.

Recrystallization solvent, rate of crystallization, storage température, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions.

The compounds of any Formula described herein include the compounds themselves, as well 15 as their salts, and their solvatés, if applicable. A sait, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted benzene compound.

Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate). The term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable sait. Likewise, a sait can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted benzene compound. Suitable cations include sodium ion, potassium ion, magnésium ion, calcium ion, and an ammonium cation such as tétraméthylammonium ion. The substituted benzene compounds also include those salts containing quatemary nitrogen atoms.

Additionally, the compounds of the présent disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvatés with other solvent molécules. Nonlimiting examples of hydrates include monohydrates, 30 dihydrates, etc. Nonlimiting examples of solvatés include éthanol solvatés, acetone solvatés, etc.

“Solvaté” means solvent addition forms that contain either stoichiometric or nonstoichiometric amounts of solvent. Some compounds hâve a tendency to trap a fixed molar ratio of solvent molécules in the crystalline solid State, thus forming a solvaté. If the solvent

269 is water the solvaté formed is a hydrate; and if the solvent is alcohol, the solvaté formed is an alcoholate. Hydrates are formed by the combination of one or more molécules of water with one molécule of the substance in which the water retains its molecular state as H2O.

As used herein, the term “analog” refers to a Chemical compound that is structurally similar 5 to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.

As defined herein, the term “dérivative” refers to compounds that hâve a common core structure, and are substituted with various groups as described herein. For example, ail of the compounds represented by Formula (I) are amine-substituted aryl or heteroaryl compounds, and hâve Formula (I) as a common core.

The term “bioisostere” refers to a compound resulting from the exchange of an atom or of a 15 group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonimides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem.

Rev. 96, 3147-3176, 1996.

The présent disclosure is intended to include ail isotopes of atoms occurring in the présent compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-14.

The présent disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein. The présent disclosure also provides detailed methods for the synthesis of various disclosed compounds of the présent disclosure according to the following schemes as shown in the Examples.

In the descriptions and claims, articles such as “a,” “an,” and “the” may mean one or more 30 than one unless indicated to the contrary or otherwise évident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or ail of the group members are présent in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise évident from the context. The disclosure includes embodiments in which exactly one

270 member of the group is présent in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or ail, of the group members are présent in, employed in, or otherwise relevant to a given product or process. As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C”, “selected from A, B, and C,” “selected from the group consisting of A, B, and C,” and the like are used interchangeably and ail refer to a sélection from a group consisting of A, B, and /or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless otherwise specified.

It is also noted that the term “comprising” is intended to be open and permits but does not require the inclusion of additional éléments or steps. When the term “comprising” is used herein, the tenus “consisting essentially of ’ and “consisting of ’ are thus also encompassed and disclosed. Throughout the description, where compositions are described as having, including, or comprising spécifie components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising spécifie process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains opérable. Moreover, two or more steps or actions can be conducted simultaneously.

The synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be désirable in certain instances to further couvert the compound to a pharmaceutically acceptable sait thereof.

Compounds of the présent disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the préparation of organic molécules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, Μ. B., March, J., March ’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5^th édition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3^rd

271 édition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the préparation of compounds of the présent disclosure.

Compounds of the présent disclosure can be conveniently prepared by a variety of methods familiar to those skilled in the art. The compounds of this disclosure having any of the Formulae described herein may be prepared according to the procedures illustrated in Schemes 1-9 below, from commercially available starting materials or starting materials which can be prepared using literature procedures. The variables (such as n, R³, R⁷, R⁸, and R⁹, etc.) in Schemes 1-9 are as defined in any Formula described herein, unless otherwise specified.

One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups.

One of ordinary skill in the art will recognize that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molécules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3^rd édition, John Wiley & Sons: New York, 1999.

Preferred protecting groups include, but are not limited to:

For a hydroxyl moiety: TBS, benzyl, THP, Ac

For carboxylic acids: benzyl ester, methyl ester, ethyl ester, allyl ester

For amines: Cbz, BOC, DMB

For diols: Ac (x2) TBS (x2), or when taken together acetonides For thiols: Ac

For benzimidazoles: SEM, benzyl, PMB, DMB

For aldéhydes: di-alkyl acetals such as dimethoxy acetal or diethyl acetyl.

In the reaction schemes described herein, multiple stereoisomers may be produced. When no particular stereoisomer is indicated, it is understood to mean ail possible stereoisomers that could be produced from the reaction. A person of ordinary skill in the art will recognize that

272 the reactions can be optimized to give one isomer preferentially, or new schemes may be devised to produce a single isomer. If mixtures are produced, techniques such as préparative thin layer chromatography, préparative HPLC, préparative chiral HPLC, or préparative SFC may be used to separate the isomers.

The following abbreviations are used throughout the spécification and are defined below:

ACN acetonitrile

Ac acetyl

AcOH acetic acid

AICI3 aluminum chloride

BINAP (2,2'-bis(diphenylphosphino)-l,l'-binaphthyl) t-BuOK potassium t-butoxide tBuONa or t-BuONa sodium t-butoxide

	br broad
	BOC tert-butoxy carbonyl
15	Cbz benzyloxy carbonyl CDCI3CHCI3 chloroform CH2CI2 dichloromethane CH3CN acetonitrile CSCO3 césium carbonate
20	CH3NO3 nitromethane d doublet dd doublet of doublets dq doublet of quartets DCE 1,2 dichloroethane
25	DCM dichloromethane A heat δ Chemical shift DIEA Ν,Ν-diisopropylethylamine (Hunig's base) DMB 2,4 dimethoxy benzyl
30	DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DMSO-ώί deuterated dimethyl sulfoxide EA or EtOAc Ethyl acetate ES electrospray

273

Et3N	triethylamine
equiv	équivalents
g	grams
h	hours
5 H2O	water
HCl	hydrogen chloride or hydrochloric acid
HPLC	High performance liquid chromatography
Hz	Hertz
IPA	isopropyl alcohol
10 i-PrOH	isopropyl alcohol
J	NMR coupling constant
K2CO3	potassium carbonate
HI	potassium iodide
KCN	potassium cyanide
75 LCMS or LC-MS Liquid chromatography mass spectrum
M	molar
m	multiplet
mg	milligram
MHz	mégahertz
20 mL	milliliter
mm	millimeter
mmol	millimole
mol	mole
[M+l]	molecular ion plus one mass unit
25 m/z	mass/charge ratio
m-CPBA	meta-chloroperbenzoic acid
MeCN	Acetonitrile
MeOH	methanol
Mel	Methyl iodide
30 min	minutes
pm	micron
MsCl	Mesyl chloride
MW	microwave irradiation
N	normal

274

Na2SO4 sodium sulfate

NH3 ammonia

NaBH(AcO)3 sodium triacetoxyborohydride

Nal sodium iodide

Na2SÛ4 sodium sulfate

NH4CI ammonium chloride

NH4HCO3 ammonium bicarbonate nm nanometer

NMP N-methylpyrrolidinone

NMR Nuclear Magnetic Résonance

Pd(OAc)2 palladium (II) acetate

Pd/C Palladium on carbon

Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0)

PMB para methoxybenzyl ppm parts per million

POCI3 phosphoryl chloride prep-HPLC préparative High Performance Liquid Chromatography

PTSA para-toluenesulfonic acid p-TsOH para-toluenesulfonic acid

RT rétention time

rt	room température
s	singlet
t	triplet

t-BuXPhos 2-Di-ter/-butylphosphino-2', 4', 6'-triisopropylbiphenyl

25 TEA	Triethylamine
TFA	trifluoroacetic acid
TfO	triflate
THP	tetrahydropyran
TsOH	tosic acid

UV ultraviolet

Scheme 1

275

Scheme 1 shows the synthesis of A²-phenylpyrimidine-2,4-diamine compounds DI following a general route. 2,4-Dichloropyrimidine is combined in an organic solvent (e.g., DMSO) with a dialkylamine Al and a base (e.g. DIEA). The resulting 2-chloro- pyrimidine-4-amine B1 is heated with a substituted aniline Cl and an acid (e.g., PTS A) in an organic solvent (e.g., i-PrOH) and heated to afford the N²-phenylpyrimidine-2,4-diamine Dl.

Scheme 2

Scheme 2 shows the synthesis of phenylpyrimidine-2- amine compounds D2 following a general route. 2,4-Dichloropyrimidine is combined in an organic solvent (e.g., DMSO) with an alcohol A2 and a base (e.g. DIEA). The resulting 2-chloropyrimidine B2 is heated with a substituted aniline C2 and an acid (e.g., PTS A) in an organic solvent (e.g., i-PrOH) and heated to afford the phenylpyrimidine-2- amine D2.

Scheme 3

A3

PTSA, i-PrOH

C3

2. R⁸R⁹NH, NMP,

R⁸ i

l.mCPBA _O^N ____________R⁹

D3

Scheme 3 shows the synthesis of7V⁴-phenylpyrimidine-2,4-diamine compounds D3 following a general route. 2-Chloro-4-(methylthio)pyrimidine A3 is heated in an organic solvent (e.g., i-PrOH) with a substituted aniline B3 and an acid (e.g., PTSA). The resulting substituted 2(methylthio)-A-phenylpyrimidin-4-amine C3 is treated with an oxidizing agent (e.g.,

276 mCPBA), and then heated with an amine (e.g., NHR⁸R⁹) in an organic solvent (e.g., NMP) to afford the A⁴-phenylpyrimidine-2,4-diamine D3.

Scheme 4 ?^H l| ^H H ^Π H H ,_R. Va _R9--v^°h 125. _κ=-^Νγ^Νγ^α A__EL RS'-W, _Λ ^HzN DMSO, DIEA N^J PTSA, i-PrOH nJJ UtH

A4 B4 C4 △

Scheme 4 shows the synthesis of A^-phenylpyrimidine-2,4-diamine compounds E4 following a general route. 2-Chloropyrimidin-4-ol is combined with a primary amine A4 and a base (e.g., DIEA) in an organic solvent (e.g., DMSO) to afford 2-aminopyrimidin-4-ol B4, which is then treated with a chlorinating agent (e.g., phosphoryl chloride). The resulting 410 chloropyrimidin-2-amine C4 is heated with a substituted aniline D4 and an acid (e.g., PTSA) in an organic solvent (e.g., i-PrOH) to afford the 7V⁴-phenylpyrimidine-2,4-diamine E4.

Scheme 5 shows the synthesis of A²-phenylpyridine-2,4-diamine compounds D5 following a general route. 2-Bromo-4-chloropyridine is combined with a primary amine A5 and a base (e.g., DIEA) in an organic solvent (e.g., DMSO). The resulting 2-bromo-pyridin-4-amine B5 is coupled with a substituted aniline C5 in an organic solvent (e.g., toluene) via a Buchwald20 Hartwig amination employing a catalyst (e.g., Pd₂(dba)3), a ligand (e.g., BINAP), and a base (e.g., tBuONa) to afford the A²-phenylpyridine-2,4-diamine D5.

Scheme 6

277

toluene, tBuONa

D6

Scheme 6 shows the synthesis of N⁴-phenylpyridine-2,4-diamine compounds D6 foilowing a general route. 4-Chloro-2-fluoropyridine is combined with a primary amine A6 and a base (e.g., DIEA) in an organic solvent (e.g., DMSO). The resulting 4-chloro-pyridin-2-amine B6 is coupled with a substituted aniline C6 in an organic solvent (e.g., toluene) via a BuchwaldHartwig amination employing a catalyst (e.g., Pd2(dba)₃), a ligand (e.g., BINAP), and a base (e.g., tBuONa) to afford the A/⁴-phenylpyridine-2,4-diamine D6.

Scheme 7

H

A7

toluene, tBuONa

B7

D7

Scheme 7 shows the synthesis of A/²-phenylpyridine-2,6-diamine compounds D7 foilowing a general route. 2,6-Dichloropyridine is combined with an amine A7 and a base (e.g., DIEA) 15 in an organic solvent (e.g., DMSO). The resulting 6-chloro-pyridin-2-amine B7 is coupled with a substituted aniline C7 in an organic solvent (e.g., toluene) via a Buchwald-Hartwig amination employing a catalyst (e.g., Pd₂(dba)₃), a ligand (e.g., BINAP), and a base (e.g., tBuONa) to afford the jV²-phenylpyridine-2,6-diamine D7.

278

Scheme 8 shows the synthesis of/V-phenylpyrimidin-2-amine compounds C8 following a general route. 2-Chloro-pyrimidine A8 is heated with a substituted aniline B8 and an acid (e.g., PTSA) in an organic solvent (e.g., i-PrOH) to afford the A-phenylpyrimidin-2-amine C8.

Scheme 9

Scheme 9 shows the synthesis of 2-(alkylaminomethyl)-A-phenylpyrimidin-4-amine compounds F9 following a general route. 4-Chloropyrimidine-2-carbonitrile A9 is heated with a substituted aniline B9 and an acid (e.g., PTSA) in an organic solvent (e.g., i-PrOH). The resulting 4-(phenylamino)pyrimidine-2-carbonitrile C9 is treated with a reducing agent (e.g., Raney-Ni) to give the 2-(aminomethyl)-W-phenylpyrimidin-4-amine D9. Reductive amination with a carbonyl compound E9 affords the 2-(alkylamino)methyl)-Aphenylpyrimidin-4-amine F9.

A person of ordinary skill in the art will recognize that in the above schemes the order of many of the steps are interchangeable.

Compounds of the présent disclosure inhibit the histone methyltransferase activity of G9a, also known as KMTIC (lysine methyltransferase IC) or EHMT2 (euchromatic histone methyltransferase 2), or a mutant thereof and, accordingly, in one aspect of the disclosure, certain compounds disclosed herein are candidates for treating, or preventing certain conditions, diseases, and disorders in which EHMT2 plays a rôle. The présent disclosure provides methods for treating conditions and diseases the course of which can be influenced by modulating the méthylation status of histones or other proteins, wherein said méthylation status is mediated at least in part by the activity of EHMT2. Modulation of the méthylation status of histones can in tum influence the level of expression of target genes activated by méthylation, and/or target genes suppressed by méthylation. The method includes

279 administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the présent disclosure, or a pharmaceutically acceptable sait, polymorph, solvaté, or stereoisomer thereof.

Unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to préparé a médicament to treat or prevent such condition. The treatment includes treatment of human or non-human animais including rodents and other disease models.

In still another aspect, this disclosure relates to a method of modulating the activity of EHMT2, which catalyzes the dimethylation of lysine 9 on histone H3 (H3K9) in a subject in need thereof. For example, the method comprises the step of administering to a subject having a cancer expressing a mutant EHMT2 a therapeutically effective amount of a compound described herein, wherein the compound(s) inhibits histone methyltransferase activity of EHMT2, thereby treating the cancer.

For example, the EHMT2-mediated cancer is selected from the group consisting of leukemia, prostate carcinoma, hepatocellular carcinoma, and lung cancer.

For example, the compounds disclosed herein can be used for treating cancer. For example, the cancer is a hematological cancer.

For example, the cancer is selected from the group consisting of brain and central nervous System (CNS) cancer, head and neck cancer, kidney cancer, ovarian cancer, pancreatic cancer, leukemia, lung cancer, lymphoma, myeloma, sarcoma, breast cancer, and prostate cancer. Preferably, a subject in need thereof is one who had, is having or is predisposed to developing brain and CNS cancer, kidney cancer, ovarian cancer, pancreatic cancer, leukemia, lymphoma, myeloma, and/or sarcoma. Exemplary brain and central CNS cancer includes medulloblastoma, oligodendroglioma, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, ependymoma, glioblastoma, meningioma, neuroglial tumor, oligoastrocytoma, oligodendroglioma, and pineoblastoma. Exemplary ovarian cancer includes ovarian clear cell adenocarcinoma, ovarian endomethrioid adenocarcinoma, and ovarian serous adenocarcinoma. Exemplary pancreatic cancer includes pancreatic ductal adenocarcinoma and pancreatic endocrine tumor. Exemplary sarcoma includes chondrosarcoma, clear cell sarcoma of soft tissue, ewing sarcoma, gastrointestinal stromal tumor, osteosarcoma, rhabdomyosarcoma, and not otherwise specified (NOS) sarcoma. Altematively, cancers to be treated by the compounds of the présent invention are non NHL cancers.

280

For example, the cancer is selected from the group consisting of acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL), medulloblastoma, oligodendroglioma, ovarian clear cell adenocarcinoma, ovarian endomethrioid adenocarcinoma, ovarian serons adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic endocrine tumor, malignant rhabdoid tumor, astrocytoma, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, ependymoma, glioblastoma, meningioma, neuroglial tumor, oligoastrocytoma, oligodendroglioma, pineoblastoma, carcinosarcoma, chordoma, extragonadal germ cell tumor, extrarenal rhabdoid tumor, schwannoma, skin squamous cell carcinoma, chondrosarcoma, clear cell sarcoma of soft tissue, ewing sarcoma, gastrointestinal stromal tumor, osteosarcoma, rhabdomyosarcoma, and not otherwise specified (NOS) sarcoma. Preferably, the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), medulloblastoma, ovarian clear cell adenocarcinoma, ovarian endomethrioid adenocarcinoma, pancreatic ductal adenocarcinoma, malignant rhabdoid tumor, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, glioblastoma, meningioma, pineoblastoma, carcinosarcoma, extrarenal rhabdoid tumor, schwannoma, skin squamous cell carcinoma, chondrosarcoma, ewing sarcoma, epithelioid sarcoma, rénal medullary carcinoma, diffuse large B-cell lymphoma, follicular lymphoma and/or NOS sarcoma.

For example, the EHMT2-mediated disorder is a hematological disorder.

The compound(s) of the présent disclosure inhibit the histone methyltransferase activity of EHMT2 or a mutant thereof and, accordingly, the présent disclosure also provides methods for treating conditions and diseases the course of which can be influenced by modulating the méthylation status of histones or other proteins, wherein said méthylation status is mediated at least in part by the activity of EHMT2. In one aspect of the disclosure, certain compounds disclosed herein are candidates for treating, or preventing certain conditions, diseases, and disorders. Modulation of the méthylation status of histones can in tum influence the level of expression of target genes activated by méthylation, and/or target genes suppressed by méthylation. The method includes administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the présent disclosure.

As used herein, a “subject” is interchangeable with a “subject in need thereof’, both of which refer to a subject having a disorder in which EHMT2-mediated protein méthylation plays a part, or a subject having an increased risk of developing such disorder relative to the population at large. A “subject” includes a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat,

281 camel, sheep or a pig. The subject can also be a bird or fowl. In one embodiment, the mammal is a human. A subject in need thereof can be one who has been previously diagnosed or identified as having cancer or a precancerous condition. A subject in need thereof can also be one who has (e.g., is suffering from) cancer or a precancerous condition.

Altematively, a subject in need thereof can be one who has an increased risk of developing such disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can hâve a precancerous condition. A subject in need thereof can hâve refractory or résistant cancer (i.e., cancer that doesn't respond or hasn’t yet responded to treatment). The subject may be résistant at start of treatment or may become résistant during treatment. In some embodiments, the subject in need thereof has cancer récurrence following remission on most recent therapy. In some embodiments, the subject in need thereof received and failed ail known effective thérapies for cancer treatment. In some embodiments, the subject in need thereof received at least one prior therapy. In a preferred embodiment, the subject has cancer 15 or a cancerous condition. For example, the cancer is leukemia, prostate carcinoma, hepatocellular carcinoma, and lung cancer.

As used herein, “candidate compound” refers to a compound of the présent disclosure, or a pharmaceutically acceptable sait, polymorph or solvaté thereof, that has been or will be tested in one or more in vitro or in vivo biological assays, in order to détermine if that compound is 20 likely to elicit a desired biological or medical response in a cell, tissue, system, animal or human that is being sought by a researcher or clinician. A candidate compound is a compound of the présent disclosure, or a pharmaceutically acceptable sait, polymorph or solvaté thereof. The biological or medical response can be the treatment of cancer. The biological or medical response can be treatment or prévention of a cell proliférative disorder.

The biological response or effect can also include a change in cell prolifération or growth that occurs in vitro or in an animal model, as well as other biological changes that are observable in vitro. In vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

For example, an in vitro biological assay that can be used includes the steps of (1) mixing a histone substrate (e.g., an isolated histone sample or an isolated histone peptide représentative of human histone H3 residues 1-15) with recombinant EHMT2 enzymes; (2) adding a compound of the disclosure to this mixture; (3) adding non-radioactive and ³H-labeled SAdenosyl méthionine (SAM) to start the reaction; (4) adding excessive amount of non

282 radioactive SAM to stop the reaction; (4) washing off the free non-incorporated ³H-SAM; and (5) detecting the quantity of ³H-labeled histone substrate by any methods known in the art (e.g., by a PerkinElmer TopCount plate reader).

For example, an in vitro study that can be used includes the steps of (1) treating cancer cells (e.g., breast cancer cells) with a compound of this disclosure; (2) incubating the cells for a set period of time; (3) fixing the cells; (4) treating the cells with primary antibodies that bind to dimethylated histone substrates; (5) treating the cells with a secondary antibody (e.g. an antibody conjugated to an infrared dye); (6) detecting the quantity of bound antibody by any methods known in the art (e.g., by a Licor Odyssey Infrared Scanner).

jo As used herein, “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the présent disclosure, or a pharmaceutically acceptable sait, polymorph or solvaté thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include 15 treatment of a cell in vitro or an animal model.

A compound of the présent disclosure, or a pharmaceutically acceptable sait, polymorph or solvaté thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes. As used herein, “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

One skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or équivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3^rd édition), Cold Spring Harbor Press, Cold

Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18^th édition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure.

As used herein, “combination therapy” or “co-therapy” includes the administration of a compound of the présent disclosure, or a pharmaceutically acceptable sait, polymorph or solvaté thereof, and at least a second agent as part of a spécifie treatment regimen intended to provide the bénéficiai effect from the co-action of these therapeutic agents. The bénéficiai

283 effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamie co-action resulting from the combination of therapeutic agents. The présent disciosure also provides pharmaceutical compositions comprising a compound of any of the Formulae described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

A “pharmaceutical composition” is a formulation containing the compounds of the présent disciosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aérosol inhaler or a vial. The quantity of active ingrédient (e.g., a formulation of the disclosed compound or sait, hydrate, solvaté or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the âge and condition of the patient. The dosage will also dépend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parentéral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disciosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under stérile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animais without excessive toxicity, irritation, allergie response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

“Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the spécification and claims includes both one and more than one such excipient.

A pharmaceutical composition of the disciosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parentéral,

284

e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parentéral, intradermal, or subcutaneous application can include the following components: a stérile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycérine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acétates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parentéral préparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

A compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, for treatment of cancers, a compound of the disclosure may be injected directly into tumors, injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The State of the disease condition (e.g., cancer, precancer, and the like) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.

The term “therapeutically effective amount”, as used herein, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a détectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The précisé effective amount for a subject will dépend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine expérimentation that is within the skill and judgment of the clinician. In a preferred aspect, the disease or condition to be treated is cancer. In another aspect, the disease or condition to be treated is a cell proliférative disorder.

For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to déterminé the appropriate concentration range and route of administration. Such information can then be used to déterminé useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and

285 toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animais, e.g·, ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose léthal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50.

Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of 10 the disease State, general health of the subject, âge, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

The pharmaceutical compositions containing active compounds of the présent disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or 20 auxiliaries that facilitate processing of the active compounds into préparations that can be used pharmaceutically. Of course, the appropriate formulation is dépendent upon the route of administration chosen.

Pharmaceutical compositions suitable for injectable use include stérile aqueous solutions (where water soluble) or dispersions and stérile powders for the extemporaneous préparation 25 of stérile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In ail cases, the composition must be stérile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, éthanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of

286 surfactants. Prévention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phénol, ascorbic acid, thimerosal, and the like. In many cases, it will be préférable to include isotonie agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the 5 composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Stérile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingrédients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a stérile vehicle that contains a basic dispersion medium and the required other ingrédients from those enumerated above. In the case of stérile powders for the préparation of stérile injectable solutions, methods of préparation are vacuum drying and fireeze-drying that yields a powder of the active ingrédient 15 plus any additional desired ingrédient from a previously sterile-fdtered solution thereof.

Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared 20 using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingrédients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or 25 gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid,

Primogel, or corn starch; a lubricant such as magnésium stéarate or Sterotes; a glidant such as colloïdal Silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in the form of an aérosol spray 30 from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, pénétrants appropriate to the barrier to be permeated are used in the formulation. Such pénétrants are generally known in the art, and

287 include, for example, for transmucosal administration, détergents, bile salts, and fusidic acid dérivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid élimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery Systems. Biodégradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for préparation of 10 such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in 15 U.S. Pat. No. 4,522,811.

It is especially advantageous to formulate oral or parentéral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrète units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired 20 therapeutic effect in association with the required pharmaceutical carrier. The spécification for the dosage unit forms of the disclosure are dictated by and directly dépendent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

In therapeutic applications, the dosages of the pharmaceutical compositions used in 25 accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the récipient patient, and the expérience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to resuit in slowing, and preferably regressing, the growth of the tumors and also preferably causing complété régression of the cancer. Dosages 30 can range from about 0.01 mg/kg per day to about 5000 mg/kg per day. In preferred aspects, dosages can range from about 1 mg/kg per day to about 1000 mg/kg per day. In an aspect, the dose will be in the range of about 0.1 mg/day to about 50 g/day; about 0.1 mg/day to about 25 g/day; about 0.1 mg/day to about 10 g/day; about 0.1 mg to about 3 g/day; or about 0.1 mg to about 1 g/day, in single, divided, or continuous doses (which dose may be adjusted

288 for the patient’s weight in kg, body surface area in m², and age in years). An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. For example, régression of a tumor in a patient may be measured with reference to the diameter of a tumor. Decrease in the diameter of a tumor indicates régression. Régression is also indicated by failure of tumors to reoccur after treatment has stopped. As used herein, the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

The compounds of the présent disclosure are capable of further forming salts. Ail of these forms are also contemplated within the scope of the claimed disclosure.

As used herein, “pharmaceutically acceptable salts” refer to dérivatives of the compounds of the présent disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, minerai or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quatemary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l-carboxylic acid, 3phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the

289 like. The présent disclosure also encompasses salts formed when an acidic proton présent in the parent compound either is replaced by a métal ion, e.g., an alkali métal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the sait 5 form, it is understood that the ratio of the compound to the cation or anion of the sait can be

1:1, or any ration other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

It should be understood that ail references to pharmaceutically acceptable salts include solvent addition forms (solvatés) or crystal forms (polymorphs) as defined herein, of the same sait.

The compounds of the présent disclosure can also be prepared as esters, for example, pharmaceutically acceptable esters. For example, a carboxylic acid function group in a compound can be converted to its corresponding ester, e.g., a methyl, ethyl or other ester. Also, an alcohol group in a compound can be converted to its corresponding ester, e.g., acetate, propionate or other ester.

The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognize the advantages of certain routes of administration.

The dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, âge, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the rénal and hepatic function of the patient; and the particular compound or sait thereof employed. An ordinarily skilled physician or veterinarian can readily détermine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19^th édition, Mack

Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical préparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fdlers or diluents and stérile aqueous or organic solutions. The compounds will be présent in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.

290

Ail percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the présent disciosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the présent disciosure. The examples do not limit the claimed disciosure. Based on the 5 présent disciosure the skilled artisan can identify and employ other components and methodology useful for practicing the présent disciosure.

In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disciosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor 10 does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may hâve a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer. Compounds designed, selected and/or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to 15 détermine whether the compounds hâve biological activity. For example, the molécules can be characterized by conventional assays, including but not limited to those assays described below, to déterminé whether they hâve a predicted activity, binding activity and/or binding specificity.

Furthermore, high-throughput screening can be used to speed up analysis using such assays. 20 As a resuit, it can be possible to rapidly screen the molécules described herein for activity, using techniques known in the art. General méthodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

Ail publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of 30 written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.

Example 1: Synthesis of Compound 1

291

Synthesis of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴methylpyrimidine-2,4-diamine:

Cl

Z^H2 HCl

K₂CO₃, DMF

Step 1: Synthesis of 2-chloro-N-methylpyrimidin-4-amine:

Into a 50-mL round-bottom flask, was placed 2,4-dichloropyrimidine (1.1 g, 7.38 mmol, 1.00 equiv.), methanamine hydrochloride (498 mg, 7.38 mmol, 1.00 equiv.), potassium carbonate (3.07 g, 22.21 mmol, 3.00 equiv.), N,N-dimethylformamide (10 mL). The resulting solution was stirred for 18 h at 20 °C. The resulting solution was diluted with 60 mL of H₂O. The resulting solution was extracted with 3x80 mL of ethyl acetate and the organic layers io combined. The resulting mixture was washed with 3x100 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/2). This resulted in 0.67 g (63%) of 2-chloro-N-methylpyrimidin4-amine as a white solid.

Step 2: Synthesis of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴15 methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-chloro-N-methylpyrimidin-4-amine (200 mg, 1.39 mmol, 1.00 equiv.), 4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]aniline (350 mg, 1.40 mmol, 1.00 equiv.), 4-methylbenzene-l-sulfonic acid (476 mg, 2.76 mmol, 2.00 equiv.), isopropanol (10 mL). The resulting solution was stirred for 3 h at 85 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ACN/H₂O (1/5). This resulted in 66.3 mg (13%) of 2-N-[4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]phenyl]-4-N-methylpyrimidine-2,4-diamine as a pink solid.

Example 2: Synthesis of Compound 2

Synthesis of N⁴-((l-(2,2-difluoroethyl)piperidin-4-yl)methyI)-N²-(4-methoxy-3-(3(pyrrolidin-l-yl)propoxy)phenyl)pyrimidine-2,4-diamine:

292

90°C, 2h

Step 1: Synthesis of 2-chloro-N-(piperidin-4-ylmethyl)pyrimidin-4-amine:

Into a 50-mL 3-necked round-bottom flask, was placed tert-butyl 4-[[(2-chloropyrimidin-4yl)amino]methyl]piperidine-1-carboxylate (1.1 g, 3.37 mmol, 1.00 equiv.), trifluoroacetic acid (3 mL), dichloromethane (10 mL). The resulting solution was stirred for 2 h at room température. The resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography with H₂O/MeCN/NH₄HCO₃. This resulted in 1.5 g (crude) of 2chloro-N-(piperidin-4-ylmethyl)pyrimidin-4-amine as an off-white solid.

Step 2: Synthesis of 2-chloro-N-((l-(2,2-difluoroethyl)piperidin-4-yl)methyl)pyrimidin-4amine:

Into a 100-mL 3-necked round-bottom flask, was placed 2-chloro-N-(piperidin-4ylmethyl)pyrimidin-4-amine (1.5 g, 6.62 mmol, 1.00 equiv.), 2,2-difluoroethyl trifluoromethanesulfonate (1.56 g, 7.29 mmol, 1.10 equiv.), DIEA (1.7 g, 2.00 equiv.), MeCN (20 mL). The resulting solution was stirred for 2 h at room température. The resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography. This resulted in 1.1 g (57%) of 2-chloro-N-[[l-(2,2-difluoroethyl)piperidin-4yl]methyl]pyrimidin-4-amine as a yellow solid.

Step 3: Synthesis of N⁴-((l-(2,2-difluoroethyl)piperidin-4-yl)methyl)-N²-(4-methoxy-3-(3(pyrrolidin-1 -yl)propoxy)phenyl)pyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-chloro-N-[[l-(2,2-difluoroethyl)piperidin-4yl]methyl]pyrimidin-4-amine (291 mg, 1.00 mmol, 1.00 equiv.), 4-methoxy-3-[3-(pyrrolidin1-yl)propoxy]aniline (250 g, 998.66 mmol, 1.00 equiv.), TsOHH₂O (380 mg, 2.00 mmol, 2.00 equiv.), isopropanol (5 mL). The resulting solution was stirred for 5 h at 90°C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC. This resulted in 144.1 mg (29%) of 4-N-[[l-(2,2-difluoroethyl)piperidin-4yl]methyl]-2-N-[4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]phenyl]pyrimidine-2,4-diamine as a white solid.

293

Example 3: Synthesis of Compound 3

Synthesis N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴-((tetrahydro-2Hpyran-4-yl)methyl)pyrimidine-2,4-diamine:

Step 1: Synthesis of 1 -(3-(2-methoxy-5-nitrophenoxy)propyl)pyrrolidine:

Into a 250-mL round-bottom flask, was placed 2-methoxy-5-nitrophenol (10 g, 59.12 mmol, 1.00 equiv.), l-(3-chloropropyl)pyrrolidine hydrochloride (10.8 g, 58.66 mmol, 1.00 equiv.), Cs₂CO₃ (58 g, 178.01 mmol, 3.00 equiv.), Nal (8.9 g, 1.00 equiv.), N,Ndimethylformamide (100 mL). The resulting solution was stirred for 2 h at 110 °C. The io resulting solution was diluted with 300 mL of H₂O. The resulting solution was extracted with 3x400 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 5x400 mL of brine. The resulting mixture was concentrated under vacuum. This resulted in 14 g (84%) of l-[3-(2-methoxy-5-nitrophenoxy)propyl] pyrrolidine as a yellow solid.

Step 2: Synthesis of 4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)aniline: Into a 250-mL round-bottom flask, was placed l-[3-(2-methoxy-5nitrophenoxy)propyl]pyrrolidine (14 g, 49.94 mmol, 1.00 equiv.), methanol (100 mL), Palladium carbon (2 g). The mixture underwent three hydrogen/air exchange cycles. The resulting solution was stirred for 15 h at 20 °C. The solids were filtered out. The resulting 20 mixture was concentrated under vacuum. This resulted in 12.1 g (97%) of4-methoxy-3[3-(pyrrolidin-l-yl)propoxy]aniline as brown oil.

Step 3: Synthesis of 2-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidin-4-amine: Into a 25-mL round-bottom flask, was placed 2,4-dichloropyrimidine (500 mg, 3.36 mmol, 1.00 equiv.), oxan-4-ylmethanamine (389 mg, 3.38 mmol, 1.00 equiv.), potassium 25 carbonate (932 mg, 6.74 mmol, 2.00 equiv.), N,N-dimethylformamide (3 mL). The resulting solution was stirred for 1 h at 20 °C. The solids were filtered out. The residue

294 was applied onto a silica gel column with ACN/H2O (1/5). This resulted in 0.44 g (58%) of 2-chloro-N-(oxan-4-ylmethyl)pyrimidin-4-amine as a white solid.

Step 4: Synthesis of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N4((tetrahydro-2H-pyran-4-yl)methyl)pyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-chloro-N-(oxan-4-ylmethyl)pyrimidin-4amine (150 mg, 0.66 mmol, 1.00 equiv.), l-methanesulfonyl-4-methylbenzene (181 mg, 1.06 mmol, 1.10 equiv.), 4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]aniline (566 mg, 2.26 mmol, 5.00 equiv.), isopropanol (5 mL). The resulting solution was stirred for 12 h at 85 °C in an oil bath. The resulting solution was extracted with 3x30 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, Cl8 silica gel; mobile phase, CH3CN/H₂0(0.05%NH₃.H₂0)=17% increasing to CH₃CN/H₂0(0.05%NH₃.H₂0)=30% within 10 min; Detector, UV 254 nm. This resulted in 116 mg (40%) of 2-N-[4-methoxy3-[3-(pyrrolidin-l-yl)propoxy]phenyl]-4-N-(oxan-4-ylmethyl)pyrimidine-2,4-diamine as a white solid.

Example 4: Synthesis of Compound 4

Synthesis of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴-((l-(2,2,2trifluoroethyl)piperidin-4-yl)methyl)pyrimidine-2,4-diamine:

Into a 8-mL vial, was placed 2-N-[4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]phenyl]-4N-(piperidin-4-ylmethyl)pyrimidine-2,4-diamine (250 mg, 0.57 mmol, 1.00 equiv.), 2,2,2-trifluoroethyl trifluoromethanesulfonate (197 mg, 0.85 mmol, 1.50 equiv.), N,Ndimethylformamide (3 mL). The resulting solution was stirred for overnight at room température. After concentration, the residue was purified by flash chromatography with H2O/MeCN/NH4HCO₃. This resulted in 77.6 mg (26%) of 2-N-[4-methoxy-3-[3(pyrrolidin-1 -yl)propoxy]phenyl]-4-N-[[ 1-(2,2,2-trifluoroethyl)piperidin-4— yl]methyl]pyrimidine-2,4-diamine as a white solid.

Example 5: Synthesis of Compound 5

295

Synthesis of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴-(tetrahydro-2Hpyran-4-yl)pyrimidine-2,4-diamine:

Step 1: Synthesis of 2-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine:

Into a 50-mL round-bottom flask, was placed 2,4-dichloropyrimidine (500 mg, 3.36 mmol, 1.00 equiv.), oxan-4-amine (341.2 mg, 3.37 mmol, 1.00 equiv.), potassium carbonate (932.4 mg, 6.75 mmol, 2.00 equiv.), N,N-dimethylformamide (3 mL). The resulting solution was stirred for 1 h at 20 °C. The solids were filtered out. The residue was applied onto a silica gel column with dichloromethane/methanol (4:1). This resulted in 250 mg (35%) of 2-chloro-Nio (oxan-4-yl)pyrimidin-4-amine as a white solid.

Step 2: Synthesis of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N4-(tetrahydro2H-pyran-4-yl)pyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-chloro-N-(oxan-4-yl)pyrimidin-4-amine (150 mg, 0.70 mmol, 1.00 equiv.), 4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]aniline (192 mg, 0.77 15 mmol, 1.10 equiv.), 4-methylbenzene-l-sulfonic acid (603 mg, 3.50 mmol, 5.00 equiv.), iprOH (5 mL). The resulting solution was stirred for 12 h at 85 °C in an oil bath. The resulting solution was extracted with 3x30 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions : Column: X Bridge RP, 19*150 mm, 5 um; Mobile Phase A:Water/10mmol NH4HCO3 , Mobile Phase B: ACN; Flow rate:

mL/min; Gradient: 16%B to 45%B in 10 min; 254nm.This resulted in 51.8 mg (17%) of 2N-[4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]phenyl]-4-N-(oxan-4-yl)pyrimidine-2,4diamine as a white solid.

Example 6: Synthesis of Compound 6

Synthesis of N⁴-(tert-butyI)-N²-(4-methoxy-3-(3-(pyrrolidin-lyl)propoxy)phenyl)pyrimidine-2,4-diamine:

296 h₂n

Step 1: Synthesis of N-(tert-butyl)-2-chloropyrimidin-4-amine:

Into a 25-mL round-bottom flask, was placed 2,4-dichloropyrimidine (1 g, 6.71 mmol, 1.00 equiv.), 2-methylpropan-2-amine (496 mg, 6.78 mmol, 1.01 equiv.), potassium carbonate (2.8 g, 20.26 mmol, 3.02 equiv.), N,N-dimethylformamide (5 mL). The resulting solution was stirred for 3 h at room température. The solids were fïltered out. The residue was applied onto a silica gel column with ACN:water (45:100). This resulted in 600 mg (48%) of N-tert-butyl2-chloropyrimidin-4-amine as a white solid.

Step 2: Synthesis of N⁴-(tert-butyl)-N²-(4-methoxy-3-(3-(pyrrolidin-lyl)propoxy)phenyl)pyrimidine-2,4-diamine:

Into a 25-mL round-bottom flask, was placed N-tert-butyl-2-chloropyrimidin-4-amine (200 mg, 1.08 mmol, 1.00 equiv.), 4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]aniline (325 mg, 1.30 mmol, 1.21 equiv.), TsOH (185.7 mg, 1.08 mol, 1 equiv.), isopropanol (2 mL). The resulting solution was stirred for 3 h at 85 °C in an oil bath. The crude product was purified by PrepHPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU (HPLC-10)): Column, XSelect CSH Prep C18 OBD Column, 5um, 19*150mm; mobile phase, Waters (0.05%HCl) and ACN (5.0% ACN up to 15.0% in 6 min); Detector, UV 220nm. This resulted in 82.6 mg (18%) of 4-N-tert-butyl-2-N-[4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]phenyl]pyrimidine2,4-diamine hydrochloride as a brown solid.

Example 7: Synthesis of Compound 7

Synthesis of tert-butyl 4-(((4-((4-methoxy-3-(3-(pyrrolidin-lyl)propoxy)phenyl)amino)pyrimidin-2-yl)amino)methyl)piperidine-l-carboxylate:

297

Step 1: Synthesis of N-(4-methoxy-3-(3-(pyrrolidm-l-yl)propoxy)phenyl)-2(methylthio)pyrimidin-4-amine:

Into a 50-mL 3-necked round-bottom flask, was placed 4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]aniline (1 g, 3.99 mmol, 1.00 equiv.), 4-chloro-2-(methylsulfanyl)pyrimidine (640 mg, 3.98 mmol, 1.00 equiv.), TsOH-H₂O (1.52 g, 2.00 equiv.), isopropanol (10 mL). The resulting solution was stirred for 3 h at 70 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was purifïed by flash chromatography with H₂O/MeCN. This resulted in 950 mg (64%) of N-[4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]phenyl]-2-(methylsulfanyl)pyrimidin-4-amine as a black solid.

Step 2: Synthesis of N-(4-methoxy-3-(3-(pynOlidin-l-yl)propoxy)phenyl)-2(methylsulfonyl)pyrimidin-4-amine:

Into a 50-mL 3-necked round-bottom flask, was placed N-[4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]phenyl]-2-(methylsulfanyl)pyrimidin-4-amine (800 mg, 2.14 mmol, 1.00 equiv.), mCPBA (736 mg, 4.27 mmol, 2.00 equiv.), dichloromethane (10 mL). The resulting solution was stirred for 2 h at room température. The resulting mixture was concentrated under vacuum. The residue was purifïed by flash chromatography with MeCN/H₂O. This resulted in 500 mg (58%) of 2-methanesulfonyl-N-[4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]phenyl]pyrimidin-4-amine as a dark red solid.

Step 3: Synthesis of tert-butyl 4-(((4-((4-methoxy-3-(3-(pyrrolidin-lyl)propoxy)phenyl)amino)pyrimidin-2-yl)amino)methyl)piperidine-l-carboxylate:

Into a 10-mL sealed tube, was placed 2-methanesulfonyl-N-[4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]phenyl]pyrimidin-4-amine (200 mg, 0.49 mmol, 1.00 equiv.), tert-butyl 4(aminomethyl)piperidine-l-carboxylate (115.7 mg, 0.54 mmol, 1.10 equiv.), NMP (2 mL). The resulting solution was stirred for ovemight at 150°C in an oil bath. The residue was purifïed by flash chromatography with H₂O/MeCN. This resulted in 130 mg (49%) of tertbutyl 4-([[4-([4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]phenyl]amino)pyrimidin-2yl]amino]methyl)piperidine-l-carboxylate as yellow oil.

298

Step 4: Synthesis of tert-butyl 4-(((4-((4-methoxy-3-(3-(pyrrolidin-lyl)propoxy)phenyl)amino)pyrimidin-2-yl)amino)methyl)piperidine-l-carboxylate:

Into a 10-mL sealed tube, was placed tert-butyl 4-([[4-([4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]phenyl] amino )pyrimidin-2-yl]amino]methyl)piperidine-l-carboxylate (130 mg,

0.24 mmol, 1.00 equiv.), hydrogen chloride (6N, 0.5 mL), methanol (0.5 mL). The resulting solution was stirred for 30 min at room température. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-HPLC with the foilowing conditions (2#AnalyseHPLC-SHIMADZU (HPLC-10)): Column, XSelect CSH Prep Cl 8 OBD Column, 5um, 19*150mm; mobile phase, Waters (0.05%HCl) and ACN (3.0% ACN up to 15.0% in 6 min); Detector, UV 220nm. This resulted in 9.9 mg (9%) of 4-N-[4-methoxy-3-[3(pyrrolidin-l-yl)propoxy]phenyl]-2-N-(piperidin-4-ylmethyl)pyrimidine-2,4-diamine hydrochloride as an off-white solid.

Example 8: Synthesis of Compound 8

Synthesis of l-(4-(((2-((4-chloro-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)amino)pyrimidin4-yl)amino)methyl)piperidin-l-yl)ethan-l-one:

i-PrOH, PTSA

O

Step 1: Synthesis of l-(3-(2-chloro-5-nitrophenoxy)propyl)pyrrolidine:

Into a 50-mL round-bottom flask, was placed 2-chloro-5-nitrophenol (1 g, 5.76 mmol, 1.00 equiv.), N,N-dimethylformamide (10 mL), CS2CO3 (5.6 g, 17.13 mmol, 3.00 equiv.), Nal (867 mg, 5.78 mmol, 1.00 equiv.), l-(3-chloropropyl) pyrrolidine (1.1 g, 7.45 mmol, 1.00 equiv.). The resulting solution was stirred for 2 h at 110 °C in an oil bath. The reaction was quenched by the addition of water/ice. The resulting solution was extracted with 3x10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2x10 mL of Brine, drying with Na₂SO4.The resulting mixture was concentrated under vacuum.

This resulted in 1.3 g (79%) of l-[3-(2-chloro-5-nitrophenoxy)propyl] pyrrolidine as a yellow solid.

299

Step 2: Synthesis of 4-chloro-3-(3-(pyrrolidin-l-yl)propoxy)aniline:

Into a 100-mL round-bottom flask, was placed l-[3-(2-chloro-5-nitrophenoxy)propyl] pyrrolidine (900 mg, 3.16 mmol, 1.00 equiv.), methanol (20 mL), Fe (530.5 mg, 9.47 mmol, 3.00 equiv.), NH₄C1 (502 mg, 9.38 mmol, 3.00 equiv.), water(l mL). The resulting solution 5 was stirred for 12 h at 100 °C in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with CH3CN/H2O (1:19). The collected fractions were combined and concentrated under vacuum. This resulted in 420 mg (52%) of 4-chloro-3-[3-(pyrrolidin-l-yl)propoxy]aniline as yellow oil.

Step 3: Synthesis of l-(4-(((2-((4-chloro-3-(3-(pyrrolidin-1yl)propoxy)phenyl)amino)pyrimidin-4-yl)amino)methyl)piperidin-1 -yl)ethan-1 -one: Into a 10-mL sealed tube, was placed 4-chloro-3-[3-(pyrrolidin-l-yl)propoxy]aniline (400 mg, 1.57 mmol,1.00 equiv.), PTSA (541.7 mg, 3.15 mmol, 2.00 equiv.), l-(4-[(2chloropyrimidin-4-yl)amino]methylpiperidin-l-yl)ethan-l-one (422 mg, 1.57 mmol, 1.00 equiv.), isopropanol (5 mL). The resulting solution was stirred for 10 h at 85°C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (150 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, Cl 8 silica gel; mobile phase, CH₃CN/H20(0.05%NH3.H₂0)=15% increasing to CH₃CN/H₂0(0.05%NH₃.H20)=85% within 7 min; Detector, UV 254 nm. 78.3 mg product was obtained. This resulted in 78.3 mg (10%) of l-[4-([[2-([4-chloro-3-[3-(pyrrolidin-lyl)propoxy]phenyl] amino)pyrimidin-4-yl] amino]methyl)piperidin-1 -yl] ethan-1 -one as a white solid.

Example 9: Synthesis of Compound 9

Synthesis of 2-((4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)amino)-NmethyIpyrimidine-5-carboxamide :

300

Step 1: Synthesis of 2-chloropyrimidine-5-carbonyl chloride:

Into a 100-mL round-bottom flask, was placed 2-chloropyrimidine-5-carboxylic acid (1 g,

6.31 mmol, 1.00 equiv.), dichloromethane (20 mL), N,N-dimethylformamide (0.2 mL). This 5 was followed by the addition of oxalic dichloride (1.2 g, 9.45 mmol, 1.50 equiv.) dropwise with stirring at 0 °C. The resulting solution was stirred for 2 h at 20 °C. The resulting mixture was concentrated under vacuum. This resulted in 1.11 g (99%) of 2-chloropyrimidine-5carbonyl chloride as a yellow solid.

Step 2: Synthesis of 2-chloro-N-methylpyrimidine-5-carboxamide:

JO Into a 100-mL round-bottom flask, was placed methanamine hydrochloride (509 mg, 7.54 mmol, 1.20 equiv.), dichloromethane (20 mL), TEA (1.92 g, 18.97 mmol, 3.00 equiv.). This was followed by the addition of 2-chloropyrimidine-5-carbonyl chloride (1.11 g, 6.27 mmol, 1.00 equiv.) dropwise with stirring at 0 °C. The resulting solution was stirred for 2 h at 20 °C. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3).

/5 This resulted in 760 mg (71 %) of 2-chloro-N-methylpyrimidine-5-carboxamide as a light yellow solid.

Step 3: Synthesis of 2-((4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)amino)-Nmethylpyrimidine-5-carboxamide:

Into a 50-mL round-bottom flask, was placed 2-chloro-N-methylpyrimidine-5-carboxamide 20 (750 mg, 4.37 mmol, 1.00 equiv.), 4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]aniline (1.09 g,

4.35 mmol, 1.00 equiv.), TsOH (2.24 g, 13.18 mmol, 3.00 equiv.), isopropanol (10 mL). The resulting solution was stirred for 3 h at 85 °C in an oil bath. The crude product was purified by Prep-HPLC with the foilowing conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge Prep Cl8 OBD Column, 19x150mm 5um; mobile phase,

Waters(0.05%NH₃H20) and ACN (10.0% ACN up to 35.0% in 9 min); Detector, UV

220254nm. This resulted in 24.4 mg (1%) of 2-([4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]phenyl]amino)-N-methylpyrimidine-5-carboxamide as an off-white solid.

301

Example 10: Synthesis of Compound 10

Synthesis of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴-(piperidin-4ylmethyl)pyridine-2,4-dianiine:

Pd(dba)₃, BINAP, B°^c t-BuONa,toulene nh₂

Boc~N )—'

TEA, DMSO, microwave

Step 1: Synthesis of tert-butyl 4-(((2-bromopyridin-4-yl)amino)methyl)piperidine-lcarboxylate:

Into a 20-mL sealed tube, was placed 2-bromo-4-chloropyridine (1 g, 5.20 mmol, 1.00 equiv.), tert-butyl 4-(aminomethyl)cyclohexane-1-carboxylate (1.4 g, 6.56 mmol, 1.20 equiv.), TEA (1.1g, 10.87 mmol, 2.00 equiv.), DMSO (10 mL). The final reaction mixture was irradiated with microwave radiation for 1 h at 120 °C. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 510 mg (27%) of tert-butyl 4-[[(2-bromopyridin-4yl)amino]methyl]cyclohexane-l-carboxylate as a light yellow solid.

Step 2: Synthesis of tert-butyl 4-(((2-((4-methoxy-3-(3-(pyrrolidin-lyl)propoxy)phenyl)amino)pyridin-4-yl)amino)methyl)piperidine-l-carboxylate: Into a 50-mL 3-necked round-bottom flask, was placed tert-butyl 4-[[(2-bromopyridin-4yl)amino]methyl]piperidine-l-carboxylate (510 mg, 1.38 mmol, 1.00 equiv.), 4-methoxy-3[3-(pyrrolidin-l-yl)propoxy]aniline (346 mg, 1.38 mmol, 1.00 equiv.), PdzidbajsCHCB (127 mg, 0.14 mmol, 0.10 equiv.), BINAP (172 mg, 0.28 mmol, 0.20 equiv.), t-BuONa (265 mg, 2.76 mmol, 2.00 equiv.), toluene (10 mL). The resulting solution was stirred for 3 h at 85 °C in an oil bath. The resulting solution was extracted with 3x50 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The residue was purified by flash chromatography with HiO/MeCN. This resulted in 410 mg (55%) of tert-butyl 4-([[2-([425 methoxy-3-[3-(pyrrolidin-l-yl)propoxy]phenyl]amino)pyridin-4-yl]amino]methyl)piperidine1-carboxylate as a light yellow solid.

Step 3: Synthesis of N -(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N -(piperidin-4ylmethyl)pyridine-2,4-diamine:

302

Into a 50-mL round-bottom flask, was placed tert-butyl 4-([[2-([4-methoxy-3-[3-(pyrrolidin1 -yl)propoxy]phenyl]amino)pyridin-4-yl]amino]methyl)piperidine-l -carboxylate (390 mg, 0.72 mmol, 1.00 equiv.), dioxane (4 mL), hydrogen chloride (2 mL). The resulting solution was stirred for 2 h at room température. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 9 with potassium carbonate (1 mol/L). The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column: X Bridge RP, 19*150 mm, 5 um; Mobile Phase A:Water/10mmol NH4HCO3 , Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 10%B to 40%B in 10 min; 254nm.This resulted in 28.6 mg (9%) of 2-N-[4-methoxy-3-[3-(pyrrolidin-l10 yl)propoxy]phenyl]-4-N-(piperidin-4-ylmethyl)pyridine-2,4-diamine as a brown solid.

Example 11: Synthesis of Compound 11

Synthesis of N⁴-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N²-(piperidin-4ylmethyl)pyridine-2,4-diamine :

Et₃N, DMSO, 120 °C, MW, 1h

Pd₂(dba)₃, BINAP, t-BuONa, toluene

Step 1: Synthesis of tert-butyl 4-(((4-bromopyridin-2-yl)amino)methyl)piperidine-lcarboxylate:

Into a 25-mL sealed tube, was placed tert-butyl 4-(aminomethyl)piperidine-l-carboxylate (500 mg, 2.33 mmol, 1.00 equiv.), 4-bromo-2-fluoropyridine (727 mg, 4.13 mmol, 1.00 equiv.), DMSO (8 mL), triethylamine (687 mg, 6.79 mmol, 2.0 equiv.). The final reaction mixture was irradiated with microwave radiation for 1 h at 120 °C. The reaction mixture was cooled to 20 degree C. The resulting solution was diluted with 30 mL of H₂O. The resulting solution was extracted with 3x30 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with

H2O/MeCN (1-0). This resulted in 400 mg (47%) of 2-chloro-N-[4-methoxy-3-[3-(pyrrolidinl-yl)propoxy]phenyl]pyridin-4-amine as a solid.

303

Step 2: Synthesis of tert-butyl 4-(((4-((4-methoxy-3-(3-(pyrrolidin-lyl)propoxy)phenyl)amino)pyridin-2-yl)amino)methyl)piperidine-l-carboxylate: Into a 50-mL round-bottom flask, was placed 4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]aniline (270 mg, 1.08 mmol, 1.00 equiv.), tert-butyl 4-[[(4-bromopyridin-25 yl)amino]methyl]piperidine-l-carboxylate (400 mg, 1.08 mmol, 1.00 equiv.), BINAP (135 mg, 0.22 mmol, 0.20 equiv.), t-BuONa (201 mg, 2.09 mmol, 2.00 equiv.), Pd₂(dba)₃CHC13 (112 mg, 0.11 mmol, 0.10 equiv.), toluene. The resulting solution was stirred for 2.5 h at 85 °C in an oil bath. The reaction mixture was cooled to 20 degree C. The resulting solution was diluted with 20 mL of H₂O. The resulting solution was extracted with 3x15 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with H₂O/MeCN (3/1). This resulted in 320 mg (55%) of tert-butyl 4-([[4-([4-methoxy-3-[3(pyrrolidin-l-yl)propoxy]phenyl]amino)pyridin-2-yl]amino]methyl)piperidine-l-carboxylate as a solid.

Step 3: Synthesis of N⁴-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N²-(piperidin-4ylmethyl)pyridine-2,4-diamine:

Into a 100-mL round-bottom flask, was placed tert-butyl 4-([[4-([4-methoxy-3-[3-(pyrrolidin1 -yl)propoxy]phenyl]ammo)pyridin-2-yl]amino]methyl)piperidine-l-carboxylate (300 mg, 0.56 mmol, 1.00 equiv.), dioxane (15 mL), hydrogen chloride/dioxane (15 mL). The resulting 20 solution was stirred for 16 h at 20 °C. The resulting mixture was concentrated under vacuum.

The pH value of the solution was adjusted to 8-9 with potassium carbonate. The residue was applied onto a silica gel column with H₂O/MeCN (1-0). The crude product (200 mg) was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLCSHIMADZU(HPLC-IO)): Column, XBridge Shield RP 18 OBD Column,, 5um, 19* 150mm;

mobile phase, Waters(0.05%NH3H₂0) and ACN (3.0% ACN up to 70.0% in 6 min);

Detector, UV 254/220nm. 23.5 . This resulted in 23.5 mg (10%) of 4-N-[4-methoxy-3-[3(pynOlidin-l-yl)propoxy]phenyl]-2-N-(piperidin-4-ylmethyl)pyridine-2,4-diamine as a light yellow solid.

Example 12: Synthesis of Compound 12

Synthesis of 5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)-N-(2-(((tetrahydro-2H-pyran-4yl)amino)methyl)pyridin-4-yl)pyridin-2-amine:

304

Step 1: Synthesis of 4-((diphenylmethylene)amino)picolinonitrile:

Into a 100-mL round-bottom flask, was placed 4-chloropyridine-2-carbonitrile (1 g, 7.22 mmol, 1.00 equiv.), diphenylmethanimine (1.9 g, 10.48 mmol, 1.50 equiv.), CS2CO3 (7 g,

21.48 mmol, 3.00 equiv.), Xantphos (0.832 g, 0.20 equiv.), Pd(OAc)₂ (346 mg, 1.54 mmol,

0.10 equiv.), dioxane (30 mL). The resulting solution was stirred for 2 h at 80 °C in an oil bath. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1x100 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were fïltered out. The resulting mixture was concentrated under vacuum. The crude product (1.9 g) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, Cl8 silica gel; mobile phase, MeCN:Water=0:5 increasing to MeCN:Water=3:l within 120 min; Detector, UV 254 nm. This resulted in 1.3 g (33% yield) of 4-(diphenylamino)pyridine-2-carbonitrile as a yellow solid.

Step 2: Synthesis of 4-aminopicolinonitrile:

Into a 50-mL round-bottom flask, was placed 4-[(diphenylmethylidene)amino] pyridine-2carbonitrile (1.23 g, 2.17 mmol, 1.00 equiv., 50%), hydrogen chloride(2M) (8 mL, 2.00 equiv.), methanol (24 mL). The resulting solution was stirred for 120 min at room température. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with 2x10 mL of dichloromethane and the water phase combined. The pH value of the water phase was adjusted to 8 with sodium bicarbonate (sat. solution). The resulting solution was extracted with 3x10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1x20 mL of brine, dried over Na2SO4, the solids were fïltered out. The residue was evaporated and the resuit solid was dried in an oven under reduced pressure. This resulted in 0.28 g (81%) of 4-aminopyridine-2-carbonitrile as a yellow solid.

305

Step 3: Synthesis of 4-((5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2yl)amino)picolinonitrile:

Into a 30-mL sealed tube, was placed 2-bromo-5-methoxy-4-[3-(pyrrolidin-lyl)propoxy]pyridine (314 mg, 1.00 mmol, 1.00 equiv.), 4-aminopyridine-2-carbonitrile (240 mg, 2.01 mmol, 2.00 equiv.), Pd₂(dba)₃-chloroform (0.1 g, 0.10 equiv.), t-BuXPhos (0.085 g, 0.20 equiv.), Cs₂CO₃ (970 mg, 2.97 mmol, 3.00 equiv.), dioxane (10 mL). The resulting solution was stirred for 16 h at 110 °C in an oil bath. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x30 mL of ethyl acetate and the organic layers combined. The organic layer was washed with 1x50 mL of brine, dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product (3 mL) was purified by FlashPrep-HPLC with the following conditions (CombiFlash-1): Column, Cl 8 silica gel; mobile phase, MeCN:Water=l :5 increasing to MeCN :Water= 10:1 within 120 min; Detector, UV 254 nm. 70 mg product was obtained. This resulted in 70 mg (20%) of 4-([5-methoxy-4-[3(pyrrolidin-l-yl)propoxy]pyridin-2-yl]amino)pyridine-2-carbonitrile as an off-white solid. Step 4: Synthesis of N-(2-(aminomethyl)pyridin-4-yl)-5-methoxy-4-(3-(pyrrolidin-lyl)propoxy)pyridin-2-amine:

Into a 25-mL round-bottom flask, was placed 4-([5-methoxy-4-[3-(pyrrolidin-lyl)propoxy]pyridin-2-yl]amino)pyridine-2-carbonitrile (70 mg, 0.20 mmol, 1.00 equiv.), Raney-Ni (0.2 g), methanol (5 mL). The mixture underwent three hydrogen/air exchange cycles. The resulting solution was stirred for 120 min at room température. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 65 mg (92%) ofN-[2-(aminomethyl)pyridin-4-yl]-5-methoxy-4-[3-(pyrrolidin-lyl)propoxy]pyridin-2-amine as an off-white solid

Step 5: Synthesis of 5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)-N-(2-(((tetrahydro-2Hpyran-4-yl)amino)methyl)pyridin-4-yl)pyridin-2-amine:

Into a 25-mL round-bottom flask, was placed N-[2-(aminomethyl)pyridin-4-yl]-5-methoxy4-[3-(pyrrolidin-l-yl)propoxy]pyridin-2-amine (66 mg, 0.18 mmol, 1.00 equiv.), 1(sodioboranyl)ethan-l-one acetyl acetate dihydrate (84 mg, 0.39 mmol, 3.50 equiv.), oxan-4one (18 mg, 0.18 mmol, 1.00 equiv.), dichloromethane (3 mL). The resulting solution was stirred for 120 min at room température. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product (1 mL) was purified by Prep-HPLC with the following conditions: Column, XBride Prep Cl8 OBD Columnl9X150 mm 5umC-0013; mobile phase, Phase A:Waters(HCl) Phase B: ACN =1:1; Detector, 254/220nm. 30.1 mg

306 product was obtained. This resulted in 30.1 mg (34%) of 5-methoxy-N-(2-[[(oxan-4yl)amino]methyl]pyridin-4-yl)-4-[3-(pyrrolidin-l-yl)propoxy]pyridin-2-amine hydrochloride as a white solid.

Example 13: Synthesis of Compound 13

Synthesis of l-(4-(((4-((4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)amino)pyridin2-yl)(methyl)amino)methyl)piperidin-l-yl)ethan-l-one:

Step 1 : Synthesis of 1 -(4-(((4-bromopyridin-2-yl)amino)methyl)piperidin-1 -yl)ethan-1 -one: Into a 50-mL round-bottom flask, was placed l-[4-(aminomethyl)piperidin-l-yl]ethan-l-one hydrochloride (500 mg, 2.59 mmol, 1.00 equiv.), 4-bromo-2-fluoropyridine (500 mg, 2.84 mmol, 1.10 equiv.), DIEA (0.546 g, 2.00 equiv.), DMSO (10 mL). The resulting solution was stirred for 180 min at 120 °C in an oil bath. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x50 mL of BRINE. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product (3 mL) was purified by Flash-Prep-HPLC with the foilowing conditions (IntelFlash-1): Column, Cl 8 silica gel; mobile phase, MeCN:Water=l :10 increasingto MeCN:Water=10:l within 60 min; Detector, UV 254 nm. 0.34 g product was obtained. This resulted in 0.34 g (40%) of l-(4-[[(4bromopyridin-2-yl)amino]methyl]piperidin-l-yl)ethan-l-one as off-white oil.

Step 2: Synthesis of l-(4-(((4-bromopyridin-2-yl)(methyl)arnino)methyl)piperidin-lyl)ethan-l-one:

Into a 25-mL round-bottom flask, was placed l-(4-[[(4-bromopyridin-2yl)amino]methyl]piperidin-l-yl)ethan-l-one (340 mg, 1.09 mmol, 1.00 equiv.), N,Ndimethylformamide (3 mL). The mixture was cooled to 0 °C, then sodium hydride (28 mg, 1.20 mol, 1.10 equiv.) was added in one portion and stirred at 0 °C for 30 min, iodomethane

307 (250 mg, 1.76 mmol, 1.50 equiv.) was added drop wise. The resulting solution was stirred for 120 min at 0 °C in a water/ice bath. The reaction was then quenched by the addition of 25 mL of water. The resulting solution was extracted with of dichloromethane and the organic layers combined and concentrated under vacuum. The crude product (3 mL) was purified by Flash5 Prep-HPLC with the following conditions (IntelFlash-1): Column, Cl8 silica gel; mobile phase, MeCN:Water=l:10 increasing to MeCN:Water=10:l within 120 min; Detector, UV 254 nm. 0.31 g product was obtained. This resulted in 0.31 g (87%) of l-(4-[[(4bromopyridin-2-yl)(methyl)amino]methyl] piperidin-l-yl)ethan-l-one as a white solid. Step 3: Synthesis of l-(4-(((4-((4-methoxy-3-(3-(pyrrolidin-lio yl)propoxy)phenyl)amino)pyridin-2-yl)(methyl)amino)methyl)piperidin-l-yl)ethan-l-one:

Into a 100-mL round-bottom flask, was placed l-(4-[[(4-bromopyridin-2yl)(methyl)amino]methyl]piperidin-l-yl)ethan-l-one (290 mg, 0.89 mmol, 1.00 equiv.), 4methoxy-3-[3-(pyrrolidin-l-yl)propoxy]aniline (440 mg, 1.76 mmol, 2.00 equiv.), Pd₂(dba)₃ chloroform (0.092 g, 0.10 equiv.), BINAP (116 mg, 0.19 mmol, 0.20 equiv.), tBuONa (256 mg, 2.67 mmol, 3.00 equiv.), toluene (15 mL). The resulting solution was stirred for 16 h at 100 °C in an oil bath. The reaction was then quenched by the addition of 100 of water. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1x100 mL of BRINE. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product (1.5 mL) was purified by Prep-HPLC with the following conditions: Column, Xbridge Prep Cl 8 OBD Column 19* 150mm 5umC-OO13; mobile phase, Phase A:Waters(0.05%NH₃H₂0) Phase B:ACN Gradient; Detector, 254/220. 60.5 mg product was obtained. This resulted in 60.5 mg (14%) of l-[4-([[4-([4-methoxy-3-[3(pyrrolidin-l-yl)propoxy]phenyl] amino )pyridin-2-yl] (methyl)amino]methyl)piperidin-l25 yl]ethan-l-one as a white solid.

Example 14: Synthesis of Compound 14

Synthesis of l-(4-(((2-((4-methoxy-3-(3-(pyrrolidin-lyl)propoxy)phenyl)amino)pyrimidin-4-yl)oxy)methyl)piperidin-l-yl)ethan-l-one:

308

Step 1: Synthesis of tert-butyl 4-(((2-chloropyrimidin-4-yl)oxy)methyl)piperidine-lcarboxylate:

Into a 100-mL round-bottom flask, was placed 2,4-dichloropyrimidine (1 g, 6.71 mmol, 1.00 equiv.), tert-butyl 4-(hydroxymethyl)piperidine-l-carboxylate (1.45 g, 6.74 mmol, 1.00 equiv.), tetrahydrofuran (20 mL), t-BuOK (1.51 g, 13.46 mmol, 2.00 equiv.). The resulting solution was stirred for 12 h at 20 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 1.5 g (68%) of tert-butyl 4-[[(2-chloropyrimidin-4-yl)oxy]methyl]piperidine10 1-carboxylate as an off-white solid.

Step 2: Synthesis of 2-chloro-4-(piperidin-4-ylmethoxy)pyrimidine:

Into a 100-mL round-bottom flask, was placed tert-butyl 4-[[(2-chloropyrimidin-4yl)oxy]methyl]piperidine-l-carboxylate (1.5 g, 4.58 mmol, 1.00 equiv.), dichloromethane (15 mL), trifluoroacetic acid (5 mL). The resulting solution was stirred for 12 h at 20 °C. The resulting mixture was concentrated under vacuum. The crude product was purified by FlashPrep-HPLC with the foilowing conditions (IntelFlash-1): Column, silica gel; mobile phase, ; Detector, UV 254 nm. This resulted in 1.8 mg (crude) of 2-chloro-4-(piperidin-4ylmethoxy)pyrimidine as yellow crude oil.

Step 3 : Synthesis of 1 -(4-(((2-chloropyrimidin-4-yl)oxy)methyl)piperidin-1 -yl)ethan-1 -one: 20 Into a 100-mL 3-necked round-bottom flask, was placed 2-chloro-4-(piperidin-4ylmethoxy)pyrimidine (1.5 g, 6.59 mmol, 1.00 equiv.), dichloromethane (10 mL), TEA (2 g, 19.76 mmol, 3.00 equiv.). This was followed by the addition of acetyl chloride (780 mg, 9.94 mmol, 1.50 equiv.) dropwise with stirring at 0 °C. The resulting solution was stirred for 2 h at 20 °C. The resulting mixture was concentrated under vacuum. This resulted in 1 g (56%) of 25 l-(4-[[(2-chloropyrimidin-4-yl)oxy]methyl]piperidin-l-yl)ethan-l-one as yellow oil.

Step 4: Synthesis of l-(4-(((2-((4-methoxy-3-(3-(pyrrolidin-lyl)propoxy)phenyl)amino)pyrimidin-4-yl)oxy)methyl)piperidin-1 -yl)ethan-1 -one:

Into a 50-mL round-bottom flask, was placed 4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]aniline (278.8 mg, 1.11 mmol, 1.00 equiv.), l-(4-[[(2-chloropyrimidin-4309 yl)oxy]methyl]piperidin-l-yl)ethan-l-one (300 mg, 1.11 mmol, 1.00 equiv.), TosOH (568.8 mg, 3.35 mmol, 3.00 equiv.), isopropanol (5 mL). The resulting solution was stirred for 2 h at 85 °C in an oil bath. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, ; Detector, UV 254 nm. This resulted in 71.6 mg (13%) of l-[4-([[2-([4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]phenyl]amino)pyrimidin-4-yl]oxy]methyl)piperidin-l-yl]ethan-l-one as a pink solid.

Example 15: Synthesis of Compound 15

Synthesis of l-(2-methoxy-5-((4-((piperidin-4-ylmethyl)amino)pyrimidin-2yl)amino)phenoxy)-3-(pyrrolidin-l-yl)propan-2-ol:

Step 1: Synthesis of 2-((2-methoxy-5-nitrophenoxy)methyl)oxirane:

Into a 100-mL 3-necked round-bottom flask, was placed a solution of 2-methoxy-5nitrophenol (2 g, 11.82 mmol, 1.00 equiv.) in N,N-dimethylformamide (20 mL), 2(bromomethyl)oxirane (2.43 g, 17.74 mmol, 1.50 equiv.), potassium carbonate (3.27 g, 23.66 mmol, 2.00 equiv.). The resulting solution was stirred for ovemight at room température. The resulting solution was diluted with 50 mL of EA, washed with 3x50 mL of brine, concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:1). The collected fractions were combined and concentrated under vacuum. This resulted in 1.71 g (64%) of 2-(2-methoxy-5-nitrophenoxymethyl)oxirane as an off-white solid.

Step 2: Synthesis of l-(2-methoxy-5-nitrophenoxy)-3-(pyrrolidin-l-yl)propan-2-ol: Into a 50-mL 3-necked round-bottom flask, was placed a solution of 2-(2-methoxy-5nitrophenoxymethyl)oxirane (1.4 g, 6.22 mmol, 1.00 equiv.) in éthanol (8 mL), pyrrolidine (1.1 g, 15.47 mmol, 2.50 equiv.), chloroform (8 mL). The resulting solution was stirred for 2 h at 40 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (100:-10:1). The

310 collected fractions were combined and concentrated under vacuum. This resulted in 1.7 g (92%) of l-(2-methoxy-5-nitrophenoxy)-3-(pyrrolidin-l-yl)propan-2-ol as yellow oil.

Step 3: Synthesis of l-(5-amino-2-methoxyphenoxy)-3-(pyrrolidin-l-yl)propan-2-ol: Into a 100-mL round-bottom flask, was placed l-(2-methoxy-5-nitrophenoxy)-3-(pyrrolidinl-yl)propan-2-ol (1.7 g, 5.74 mmol, 1.00 equiv.), Palladium carbon(10%) (200 mg) and Methanol (20 mL). The mixture underwent three hydrogen/air ex change cycles. The resulting solution was stirred for 4 h at room température. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 1.6 g (105%) of l-(5-amino-2methoxyphenoxy)-3-(pyrrolidin-l-yl)propan-2-ol as dark red oil.

Step 4: Synthesis of l-(2-methoxy-5-((4-((piperidin-4-ylmethyl)amino)pyrimidin-2yl)amino)phenoxy)-3-(pyrrolidin-l-yl)propan-2-ol:

Into a 50 mL 3-necked round-bottom flask, was placed l-(5-amino-2-methoxyphenoxy)-3(pyrrolidin-l-yl)propan-2-ol (310 mg, 1.16 mmol, 1.00 equiv.), isopropanol (10 mL), tertbutyl 4-[[(2-chloropyrimidin-4-yl)amino]methyl]piperidine-l-carboxylate (381 mg, 1.17 mmol, 1.00 equiv.), TsOH (1H₂O) (1.107 g, 5.83 mmol, 5.00 equiv.). The resulting solution was stirred for 4 h at 85 °C in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was dissolved in 20 mL of H₂O. Sodium carbonate was employed to adjust the pH to 9. The resulting solution was extracted with 3x20 mL of chloroform/ isopropanol (1/1) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Flash chromatography with MeCN/H₂O(40%). The collected fractions were combined and concentrated under vacuum. This resulted in 77.9 mg (15%) of l-[2-methoxy-5-([4((piperidin-4-ylmethyl)amino]pyrimidin-2-yl)amino)phenoxy]-3-(pyrrolidin-l-yl)propan-2-ol as a white solid.

Example 16: Synthesis of Compound 16

Synthesis of N2-(4-methoxy-3-(3-morpholinopropoxy)phenyl)-N4-(piperidin-4ylmethyl)pyrimidine-2,4-diamine:

311

Cs₂CO₃, Nal, DMF

Fe,NH₄CI

EtOH, H2O

PTSA, i-PrOH

Step 1: Synthesis of 4-(3-(2-methoxy-5-nitrophenoxy)propyl)morpholine:

Into a 50-mL round-bottom flask, was placed 2-methoxy-5-nitrophenol (1.1g, 6.50 mmol, 1.00 equiv.), 4-(3-chloropropyl)morpholine hydrochloride (1.3 g, 6.50 mmol, 1.00 equiv.), Cs₂CO₃ (6.39 g, 19.61 mmol, 3.00 equiv.), Nal (980 mg, 1.00 equiv.), N,Ndimethylformamide (10 mL). The resulting solution was stirred for 16 h at 110 °C. The resulting solution was diluted with 50 mL of H₂O. The resulting solution was extracted with 100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 5x100 mL of brine. The resulting mixture was concentrated under vacuum. This resulted in 1.17 g (61%) of 4-[3-(2-methoxy-5-nitrophenoxy)propyl]morpholine as a yellow solid Step 2: Synthesis of 4-methoxy-3-(3-morpholinopropoxy)aniline:

Into a 50-mL round-bottom flask, was placed 4-[3-(2-methoxy-5nitrophenoxy)propyl]morpholine (450 mg, 1.52 mmol, 1.00 equiv.), NH4CI (242 mg, 4.52 mmol, 3.00 equiv.), éthanol (12 mL), water(3 mL), Fe (256 mg, 4.57 mmol, 3.00 equiv.). The resulting solution was stirred for 12 h at 85 °C in an oil bath. The solids were fïltered out. The resulting mixture was concentrated under vacuum. The crade product was purified by Cl8 Flash: ACN/H₂O(l/4).This resulted in 200 mg (49%) of 4-methoxy-3-[3-(morpholin-4yl)propoxy]aniline as a yellow oil.

Step 3: Synthesis of N²-(4-methoxy-3-(3-morpholinopropoxy)phenyl)-N⁴-(piperidin-4ylmethyl)pyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 4-methoxy-3-[3-(morpholin-4yl)propoxy]aniline (200 mg, 0.75 mmol, 1.00 equiv.), tert-butyl 4-[(2-chloropyrimidin-4yl)amino]methylpiperidine-l-carboxylate (184 mg, 0.56 mmol, 1.00 equiv.), PTSA (485 mg, 2.82 mmol, 5.00 equiv.), isopropanol (8 mL). The resulting solution was stirred for 2 h at 85 °C in an oil bath. The resulting solution was extracted with 3x30 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The crade product was purified by Prep-HPLC with the following conditions : Column: X Bridge RP, 19*150 mm, 5 um;

312

Mobile Phase A:Water/10mmol NH4HCO3 , Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 15%B to 43%B in 10 min; 254nm.This resulted in 31.1 mg (9%) of 2-N-[4methoxy-3-[3-(morpholin-4-yl)propoxy]phenyl]-4-N-(piperidin-4-ylmethyl)pyrimidine-2,4diamine as a white solid.

Example 17: Synthesis of Compound 17

Synthesis of N²-(3-(2-((cyclopentylmethyl)amino)ethyl)-4-methoxyphenyl)-N⁴(piperidin-4-ylmethyl)pyrimidine-2,4-diamine:

O

AICI3, CH₃NO₃

Boc

KCN, DMSO °C,3h

Pd(OAc)₂, Xantphos, K₂CO₃, toulene, 110 °C, 36h

Step 1: Synthesis of 2-(chloromethyl)-l-methoxy-4-nitrobenzene:

Into a 250-mL 3-necked round-bottom flask, was placed 1-methoxy-4-nitrobenzene (12 g, 78.36 mmol, 1.00 equiv.), CH₃NO₃ (100 mL), A1C1₃ (25.9 g, 2.50 equiv.). This was followed by the addition of 2-methoxyacetyl chloride (9.32 g, 85.88 mmol, 1.10 equiv.) dropwise with stirring at 0 °C. The resulting solution was stirred for 5 h at 20 °C. The reaction was then quenched by the addition of 100 mL of water/ice. The resulting solution was extracted with 2x120 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/petroleum ether (1/4). The collected fractions were combined and concentrated under vacuum. This resulted in 6.9 g (44%) of 2-(chloromethyl)-l-methoxy-4-nitrobenzene as an off-white solid.

Step 2: Synthesis of 2-(2-methoxy-5-nitrophenyl)acetonitrile:

Into a 250-mL round-bottom flask, was placed 2-(chloromethyl)-l-methoxy-4-nitrobenzene (6.9 g, 34.23 mmol, 1.00 equiv.), DMSO (100 mL), KCN (13.4 g, 205.77 mmol, 6.00 equiv.). The resulting solution was stirred for 2 h at 50 °C. The resulting solution was diluted with 200 mL of H₂O. The resulting solution was extracted with 2x200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 4x300 mL of brine. The

313 resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/petroleum ether (1/1). This resulted in 4.58 g (70%) of 2-(2methoxy-5-nitrophenyl)acetonitrile as an off-white solid.

Step 3: Synthesis of 2-(5-amino-2-methoxyphenyl)acetonitrile:

Into a 250-mL round-bottom flask, was placed 2-(2-methoxy-5-nitrophenyl)acetonitrile (4.58 g, 23.83 mmol, 1.00 equiv.), Fe (4 g, 3.00 equiv.), NH4C1 (3.79 g, 70.85 mmol, 3.00 equiv.), éthanol (100 mL), water (20 mL). The resulting solution was stirred for 2 h at 85 °C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 3.6 g (93%) of 2-(5-amino-2-methoxyphenyl)acetonitrile as a brown solid.

Step 4: Synthesis of tert-butyl 4-(((2-((3-(cyanomethyl)-4-methoxyphenyl)amino)pyrimidin4-yl)amino)methyl)piperidine-l-carboxylate:

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed 2-(5-amino-2-methoxyphenyl)acetonitrile (1.8 g, 11.10 mmol, 1.00 equiv.), tert-butyl 4-[[(2-chloropyrimidin-4-yl)amino]methyl]piperidine-l-carboxylate (3.62 g, 11.08 mmol, 1.00 equiv.), Pd(OAc)2 (249 mg, 1.11 mmol, 0.10 equiv.), Xantphos (642 mg, 1.11 mmol, 0.20 equiv.), potassium carbonate (4.6 g, 33.28 mmol, 3.00 equiv.), Toluene (100 mL). The resulting solution was stirred for 16 h at 115 °C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ACN/H2O (3/2). This resulted in 2.52 g (50%) of tert-butyl 4-[[(2-[[320 (cyanomethyl)-4-methoxyphenyl]amino]pyrimidin-4-yl)amino]methyl]piperidine-lcarboxylate as a yellow solid.

Step 5: Synthesis of tert-butyl 4-(((2-((3-(2-aminoethyl)-4-methoxyphenyl)amino)pyrimidin4-yl)amino)methyl)piperidine-1 -carboxylate:

Into a 250-mL round-bottom flask, was placed tert-butyl 4-[[(2-[[3-(cyanomethyl)-425 methoxyphenyl]amino]pyrimidin-4-yl)amino]methyl]piperidine-l-carboxylate (2.52 g, 5.57 mmol, 1.00 equiv.), NH3/MeOH (20 mL), ethyl acetate (10 mL), Raney Ni (1 g). The mixture underwent three hydrogen/air exchange cycles. The resulting solution was stirred for 18 h at 20 °C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 2.4 g (94%) of tert-butyl 4-[[(2-[[3-(2-aminoethyl)-430 methoxyphenyl]amino]pyrimidin-4-yl)amino]methyl] piperidine-1-carboxylate as brown oil. Step 6: Synthesis of tert-butyl 4-(((2-((3-(2-((cyclopentylmethyl)amino)ethyl)-4methoxyphenyl)amino)pyrimidin-4-yl)amino)methyl)piperidine-l-carboxylate:

Into a 50-mL round-bottom flask, was placed tert-butyl 4-[[(2-[[3-(2-aminoethyl)-4methoxyphenyl]amino]pyrimidin-4-yl)amino]methyl]piperidine-l-carboxylate (400 mg, 0.88

314 mmol, 1.00 equiv.), cyclopentanecarbaldehyde (69 mg, 0.70 mmol, 0.80 equiv.), dichloromethane (20 mL)and was stirred for 0.5h at 20 °C. This was followed by the addition of acetyl ethaneperoxoate sodioboranyl acetate (1.1 g, 5.19 mmol, 6.00 equiv.), in portions at 0 °C. The resulting solution was stirred for 1 h at 20 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ACN/H₂O (2/3). This resulted in 130 mg (28%) of tert-butyl 4-[([2-[(3-[2[(cyclopentylmethyl)amino]ethyl]-4-methoxyphenyl)amino]pyrimidin-4yl]amino)methyl]piperidine-l-carboxylate as yellow oil.

Step 7: Synthesis of N²-(3-(2-((cyclopentylmethyl)amino)ethyl)-4-methoxyphenyl)-N⁴10 (piperidin-4-ylmethyl)pyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed tert-butyl 4-[([2-[(3-[2[(cyclopentylmethyl)amino]ethyl]-4-methoxyphenyl)amino]pyrimidin-4yl]amino)methyl]piperidine-l-carboxylate (130 mg, 0.24 mmol, 1.00 equiv.), dichloromethane (10 mL), trifluoroacetic acid (1.5 mL). The resulting solution was stirred for

1 h at 20 °C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of H₂O. The pH value of the solution was adjusted to 8 with sodium bicarbonate. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ACN/H₂O (1/6). This resulted in 48.2 mg (46%) of 2-N-(3-[2[(cyclopentylmethyl)amino]ethyl]-4-methoxyphenyl)-4-N-(piperidin-4-ylmethyl)pyrimidine20 2,4-diamine as a white solid.

Example 18: Synthesis of Compound 18

Synthesis of l-(4-(((2-((4-methoxy-3-((l-methyIpyrrolidin-3yl)methoxy)phenyl)amino)pyrimidin-4-yl)amino)methyl)piperidin-l-yl)ethan-l-one:

Step 1: Synthesis of (l-methylpyrrolidin-3-yl)m ethyl methanesulfonate:

315

Into a 100-mL round-bottom flask, was placed (l-methylpyrrolidin-3-yl)methanol (500 mg, 4.34 mmol, 1.00 equiv.), TEA (1.3 g, 12.85 mmol, 3.00 equiv.), dichloromethane (20 mL). MsCl (743 mg, 1.50 equiv.) was added drop wise at 0 °C. The resulting solution was stirred for 2 h at 25 °C. The resulting solution was quenched with 20 mL of water, extracted with 3x100 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3x50 mL of Brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 700 mg (83%) of (l-methylpyrrolidin-3yl)methyl methanesulfonate as yellow oil.

Step 2: Synthesis of 3-((2-methoxy-5-nitrophenoxy)methyl)-l-methylpyrrolidine: Into a 50-mL round-bottom flask, was placed (l-methylpyrrolidin-3-yl)methyl methanesulfonate (150 mg, 0.78 mmol, 1.00 equiv.), CS2CO3 (760 mg, 2.33 mmol, 3.00 equiv.), N,N-dimethylformamide (10 mL), 2-methoxy-5-nitrophenol (132 mg, 0.78 mmol, 1.00 equiv.). The resulting solution was stirred for 2 h at 80 °C in an oil bath. The solids were filtered out. The residue was washed with 10 mL of water, extracted with 3x20 mL of ethyl acetate, the organic phase was combined and washed with 3x50 mL of brine, dried over Na2SÛ4, the solid was filtered out, the residue was evaporated, The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, ACN/H₂O=6/1; Detector, UV 254 nm. This resulted in 180 mg (87%) of 3-(2-methoxy-5-nitrophenoxymethyl)-l-methylpynOhdine as yellow oil.

Step 3: Synthesis of 4-methoxy-3-((l-methylpynOlidin-3-yl)methoxy)aniline: Into a 100-mL round-bottom flask, was placed 3-(2-methoxy-5-nitrophenoxymethyl)-lmethylpyrrolidine (250 mg, 0.94 mmol, 1.00 equiv.), Palladium carbon, methanol (30 mL), The mixture underwent three hydrogen/air ex change cycles. The resulting solution was stirred for 4 h at 25 °C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 200 mg (90%) of 4-methoxy-3-[(l-methylpyrrolidin-3yl)methoxy]aniline as a white solid.

Step 4: Synthesis of l-(4-(((2-((4-methoxy-3-((l-methylpyrrolidin-3yl)methoxy)phenyl)amino)pyrimidin-4-yl)amino)methyl)piperidin-1 -yl)ethan-1 -one: Into a 50-mL round-bottom flask, was placed 4-methoxy-3-[(l-methylpyrrolidin-3yl)methoxy]aniline (150 mg, 0.63 mmol, 1.00 equiv.), isopropanol (20 mL), p-TsOH (327 mg, 3.00 equiv.), l-(4-[(2-chloropyrimidin-4-yl)amino]methylpiperidin-l-yl)ethan-l-one (170 mg, 0.63 mmol, 1.00 equiv.). The resulting solution was stirred for 4 h at 85 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: X Select C18, 19*150 mm, 5 um):

316

Column; mobile phase, Mobile Phase A:Water/0.05% NH4HCO3, Mobile Phase B: ACN;

Detector. This resulted in 156.6 mg (53%) of l-[4-([[2-([4-methoxy-3-[(l-methylpyrrolidin2-yl)methoxy]phenyl]amino)pyrimidin-4-yl]amino]methyl)piperidin-l-yl]ethan-l-one as a white solid.

Example 19: Synthesis of Compound 19

Synthesis of l-(4-(((2-((4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)amino)-6methylpyrimidin-4-yl)amino)methyl)piperidin-l-yl)ethan-l-one:

Step 1: Synthesis of 1 -(4-(((2-chloro-6-methylpyrimidin-4-yl)amino)methyl)piperidin-1yl)ethan-l-one:

Into a 25-mL round-bottom flask, was placed l-[4-(aminomethyl)piperidin-l-yl]ethan-l-one (300 mg, 1.92 mmol, 1.00 equiv.), N,N-dimethylformamide (5 mL), potassium carbonate (651 mg, 4.71 mmol, 3.00 equiv.), 2,4-dichloro-6-methylpyrimidine (251 mg, 1.54 mmol, 15 1.00 equiv.). The resulting solution was stirred for 7 h at 60 °C in an oil bath. The solids were fïltered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with H₂O/MeCN (1-0). This resulted in 0.21 g (48%) of l-(4-[[(2chloro-6-methylpyrimidin-4-yl)amino]methyl] piperidin-l-yl)ethan-l-one as a white solid.

Step 2: Synthesis of l-(4-(((2-((4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)amino)-620 methylpyrimidin-4-yl)amino)methyl)piperidin-1 -yl)ethan-1 -one:

Into a 25-mL round-bottom flask, was placed l-(4-[[(2-chloro-6-methylpyrimidin-4yl)amino]methyl]piperidin-l-yl)ethan-l-one (200 mg, 0.71 mmol, 1.00 equiv.), 4-methoxy-3[3-(pyrrolidin-l-yl)propoxy]aniline (195 mg, 0.78 mmol, 1.10 equiv.), TsOH (269 mg, 1.42 mmol, 2.00 equiv.), isopropanol (5 mL). The resulting solution was stirred for 7 h at 85 °C in 25 an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with H₂O/MeCN (1-0). This resulted in 61.2 mg (17%) of l-[4-([[2317 ([4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]phenyl]amino)-6-methylpyrimidin-4yl]amino]methyl)piperidin-l-yl]ethan-l-one as a pink solid.

Example 20: Synthesis of Compound 47

Compound 47: Synthesis of l-(4-(((2-((4-methoxy-3-(3-(pyrro!idin-lyl)propoxy)phenyl)amino)pyrimidin-4-yl)amino)methyl)piperidin-l-yl)ethan-l-one

Step 1: Synthesis of tert-butyl 4-[[(2-chloropyrimidin-4-yl)amino]methyl]piperidine-lcarboxylate:

Into a 250-mL 3-necked round-bottom flask, was placed a solution of 2,4-dichloropyrimidine (5.0 g, 33.56 mmol, 1 equiv) in N,N-dimethylformamide (50 mL), tert-butyl 4(aminomethyl)piperidine-l-carboxylate (7.18 g, 33.50 mmol, 1 equiv), potassium carbonate (9.26 g, 2.00 equiv). The resulting solution was stirred for 2 h at RT. The resulting solution was diluted with 50 mL of EA, washed with 3x50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:2). The collected fractions were combined and concentrated under vacuum. This resulted in 8.1 g (74%) of the title compound as colorless oil.

Analytical Data: (ES, m/z): RT = 1.449 min, LCMS 28: m/z = 327 [M+l], H-NMR: (400

MHz, Methanol-iZ₄) δ 8.83 - 8.68 (m, 1H), 7.26 (d, J = 5.8 Hz, 1H), 5.01 - 4.56 (m, 2H), 4.06 - 3.80 (m, 2H), 3.49 (s, 2H), 2.58 - 2.37 (m, 3H), 2.20 (s, 9H), 1.95 - 1.69 (m, 2H).

Step 2: Synthesis of 2-N-[4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]phenyl]-4-N-(piperidin4-ylmethyl)pyrimidine-2,4-diamine:

Into a 50-mL 3-necked round-bottom flask, was placed 4-methoxy-3-[3-(pyrrolidin-l25 yl)propoxy]aniline (764 mg, 3.05 mmol, 1 equiv), tert-butyl 4-[[(2-chloropyrimidin-4yl)amino]methyl]piperidine-l-carboxylate (1 g, 3.06 mmol, 1 equiv), TsOH (2.9 g, 15.26 mmol, 5.00 equiv), IPA (10 mL). The resulting solution was stirred for 4 h at 85 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was purified by

318 flash chromatography with ACN/H2O(l/10). This resulted in 800 mg (59%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.900 min, LCMS 07: m/z = 441 [M+l].

Step 3: Synthesis of l-[4-([[2-([4-methoxy-3-[3-(pyrrolidin-l5 yl)propoxy]phenyl]amino)pyrimidin-4-yl]amino]methyl)piperidin-l-yl]ethan-l-one:

Into a 10-mL sealed tube, was placed 2-N-[4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]phenyl]-4-N-(piperidin-4-ylmethyl)pyrimidine-2,4-diamine (250 mg, 0.57 mmol, 1 equiv), acetyl acetate (63.6 mg, 0.62 mmol, 1.10 equiv), TEA (114.5 mg, 2.00 equiv), ACN (3 mL). The resulting solution was stirred for 4 h at RT. The resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography with ACN/H₂O (1/10). This resulted in 61.2 mg (22%) of l-(4-(((2-((4-methoxy-3-(3-(pyrrolidin1 -yl)propoxy)phenyl)amino)pyrimidin-4-yl)amino)methyl)piperidin-1 -yl)ethan-1 -one as a white solid.

Example 21: Synthesis of Compound 205

Compound 205: Synthesis of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴,6dimethylpyrimidine-2,4-diamine

TFA,i-PrOH

q 4

Step 1: Synthesis of N -(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N ,620 dimethylpyrimidine-2,4-diamine:

Into a 250-mL round-bottom flask, was placed 2-chloro-N,6-dimethylpyrimidin-4-amine (1.5 g, 9.52 mmol, 1 equiv), 4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]aniline (864 mg, 3.45 mmol, 1 equiv), trifluoroacetic acid (684 mg, 6.05 mmol, 1 equiv), isopropanol (50 mL). The resulting solution was stirred ovemight at 85 °C. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC G. This resulted in 1.295 g (32%) of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴,6-dimethylpyrimidine2,4-diamine as a solid.

Example 22: Synthesis of Compound 207

319

Compound 207: Synthesis of N⁴-methyl-N²-(3-(3-(pyrrolidin-lyl)propoxy)phenyl)pyrimidine-2,4-diamine

Step 1: Synthesis of l-[3-(3-nitrophenoxy)propyl]pyrrolidine:

Into a 50-mL round-bottom flask, was placed 3-nitrophenol (600 mg, 4.31 mmol, 1 equiv), 1(3-chloropropyl)pyrrolidine hydrochloride (790 mg, 4.29 mmol, 1 equiv), Cs2CO3 (4.22 g, 12.95 mmol, 3.00 equiv), Nal (647 mg, 4.31 mmol, 1 equiv), N,N-dimethylformamide (10 mL). The resulting solution was stirred for 4 h at 110 °C. The resulting solution was diluted with 30 mL of H₂O. The resulting solution was extracted with 3x60 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 4x60 mL of brine. The resulting mixture was concentrated under vacuum. This resulted in 1 g (93%) of the title compound as brown oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.975 min, LCMS 53: m/z = 251 [M+l].

Step 2: Synthesis of 3-[3-(pyrrolidin-l-yl)propoxy]aniline:

Into a 100-mL round-bottom flask, was placed l-[3-(3-nitrophenoxy)propyl]pyrrolidine (1 g, 4.00 mmol, 1 equiv), methanol (20 mL), Pd/C (0.5 g). The resulting solution was stirred for 1 h at 20 °C. The solids were fïltered out. The resulting mixture was concentrated under vacuum. This resulted in 0.7 g (80%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.586 min, LCMS 07: m/z = 221 [M+l],

Step 3: Synthesis of N⁴-methyl-N²-(3-(3-(pyrrolidin-l-yl)propoxy)phenyl)pyrimidine-2,4di amine:

Into a 50-mL round-bottom flask, was placed 3-[3-(pyrrolidin-l-yl)propoxy]aniline (400 mg, 1.82 mmol, 1 equiv), 2-chloro-N-methylpyrimidin-4-amine (259 mg, 1.80 mmol, 1 equiv), 4methylbenzene-l-sulfonic acid (464 mg, 2.69 mmol, 1.50 equiv), isopropanol (10 mL). The resulting solution was stirred for 2 h at 85 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ACN/H2O (1/5). This resulted in 104.7 mg (18%) of N⁴-methyl-N²-(3-(3-(pyrrolidin-lyl)propoxy)phenyl)pyrimidine-2,4-diamine as a white solid.

320

Example 23: Synthesis of Compound 209 Ί 4

Compound 209: Synthesis of N -(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N methylpyridine-2,4-diamine

Br

NH₂CH₃/THF

BINAP, t-BuONa, Toi

Step 1: Synthesis of 2-bromo-N-methylpyridin-4-amine:

Into a 60-mL sealed tube, was placed 2-bromo-4-fluoropyridine (500 mg, 2.84 mmol, 1 equiv), NH₂CH₃-THF (20 mL). The resulting solution was stirred for 16 h at 80 °C in an oil bath. The resulting mixture was concentrated under vacuum. This resulted in 480 mg (90%) of the title compound as colorless oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.758 min, LCMS 27: m/z = 187 [M+l], Step 2: Synthesis of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴methylpyridine-2,4-diamine:

Into a 16-mL sealed tube purged and maintained with an inert atmosphère of nitrogen, was placed 2-bromo-N-methylpyridin-4-amine (400 mg, 2.14 mmol, 1 equiv), 4-methoxy-3-[3(pyrrolidin-1-yl)propoxy]aniline (640 mg, 2.56 mmol, 1.20 equiv), t-BuONa (616 mg, 6.41 mmol, 3.00 equiv), BINAP (133 mg, 0.21 mmol, 0.10 equiv), Pd₂(dba)₃CHCl₃ (220 mg, 0.10 equiv), toluene (8 mL). The resulting solution was stirred for 3 h at 100 °C in an oil bath. The solids were filtered out. The crude product was purified by Flash-Prep-HPLC with the foilowing conditions (CombiFlash-1): Column, Cl 8 silica gel; mobile phase, methanol/H2O increasing to methanol/H2O=9/l within min; Detector, UV 254 nm product was obtained. The crude product was purified by Prep-HPLC H. This resulted in 57.5 mg (7%) of N²-(4methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴-methylpyridine-2,4-diamine as a solid.

Example 24: Synthesis of Compound 256 î 4

Compound 256: Synthesis ofN -(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N (oxetan-3-ylmethyl)pyrimidine-2,4-diamine

321

Step 1: Synthesis of 2-chloro-N-(oxetan-3-ylmethyl)pyrimidin-4-amine:

Into a 20-mL vial, was placed N,N-dimethylformamide (3 mL), 2,4-dichloropyrimidine (595 mg, 3.99 mmol, 1 equiv), oxetan-3-ylmethanamine (350 mg, 4.02 mmol, LOI equiv), potassium carbonate (555 mg, 4.02 mmol, 1.01 equiv). The resulting solution was stirred for 5 2 h at 20 °C. The residue was applied onto a silica gel column with ACN/H₂O (1:9). The collected fractions were combined and concentrated under vacuum. This resulted in 570 mg (71%) of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.84min, LCMS33: m/z = 200 [M+l].

Step 2: Synthesis of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴io methylpyrimidine-2,4-diamine:

Into a 20-mL round-bottom flask, was placed 2-chloro-N-(oxetan-3-ylmethyl)pyrimidin-4amine (200 mg, 1 mmol, 1 equiv), 4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]aniline (251 mg, 1 mmol, 1 equiv), trifluoroacetic acid (195 mg, 1.73 mmol, 2.00 equiv), propan-2-ol (2 mL).

The resulting solution was stirred for 2 h at 85 °C in an oil bath. The resulting mixture was 15 concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC C. This resulted in 20.1 mg (4%) of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴(oxetan-3-ylmethyl)pyrimidine-2,4-diamine as a yellow solid.

Example 25: Synthesis of Compound 257

Compound 257: Synthesis of N-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-lmethyl-lH-pyrazolo[3,4-b]pyridin-6-amine

Step 1: Synthesis of 6-chloro-l-methyl-lH-pyrazolo[3,4-b]pyridine:

Into a 100-mL round-bottom flask, was placed N,N-dimethylformamide (10 mL), sodium hydride (235 mg, 9.79 mmol, 1.50 equiv).This was followed by addition of 6-chloro-lHpyrazolo[3,4-b]pyridine (1 g, 6.51 mmol, 1 equiv) at 0 °C. The resulting solution was stirred for 30 min at 0 °C. To this above, iodomethane (1.02g, 7.19 mmol, 1.10 equiv) was added. The reaction was allowed to react for 2h at 0 °C. The reaction was then quenched by the addition of 5 mL of water. The residue was applied onto a Cl8 column with Water/ACN (7:3). This resulted in 500 mg (46%) of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.729min, LCMS 27: m/z = 168 [M+l],

322

Step 2: Synthesis of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴-(oxetan-3ylmethyl)pyrimidine-2,4-diamine:

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed dioxane (10 mL), 6-chloro-l-methyl-lH-pyrazolo[3,4-b]pyridine (200 5 mg, 1.19 mmol, 1 equiv), 4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]aniline (300 mg, 1.20 mmol, 1 equiv), Pd₂(dba)₃CHC13 (186 mg, 0.18 mmol, 0.15 equiv), xantphos (210 mg, 0.36 mmol, 0.30 equiv), Cs2CO3 (780 mg, 2.39 mmol, 2.01 equiv). The resulting solution was stirred for 14 h at 80 °C. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purifïed by Prep-HPLC D. This resulted in 97.0 mg (19%) of N-(410 methoxy-3 -(3 -(pyrrolidin-1 -yl)propoxy)phenyl)-1 -methyl-1 H-pyrazolo [3,4-b]pyridin-6amine as a solid.

Example 26: Synthesis of Compound 258

Compound 258: Synthesis of N-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-l15 methyl- IH-imidazo [4,5-c] pyridin-6-amine

MeNH₂

Fe, NH₄CI

O.

Cs₂CO₃, Pd₂(dba)₃

Step-4

Step 1: Synthesis of 2-chloro-N-methyl-5-nitropyridin-4-amine:

Into a 30-mL sealed tube, was placed 2,4-dichloro-5-nitropyridine (2 g, 10.36 mmol, 1 equiv), DIEA (2.69 g, 20.81 mmol, 2.00 equiv), tetrahydrofuran (20 mL), NH₂CH₃-HC1 (1.06 20 g, 2.00 equiv). The resulting solution was stirred for 12 h at 25 °C. The crude product was purifïed by Flash-Prep-HPLC A. This resulted in 1.2 g (62%) of as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): 188 [M+l], R: 1.12 min.

Step 2: Synthesis of 6-chloro-4-N-methylpyridine-3,4-diamine:

Into a 100-mL round-bottom flask, was placed 2-chloro-N-methyl-5-nitropyridin-4-amine (2 25 g, 10.66 mmol, 1 equiv), Fe (2.99 g, 5.00 equiv), NH4CI (5.7 g, 106.56 mmol, 10.00 equiv), methanol (20 mL), water (20 mL). The resulting solution was stirred for 12 h at 80 °C in an

323 oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 600 mg (36%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): 158 [M+l], R: 0.982 min.

Step 3: Synthesis of 6-chloro-l-methyl-lH-imidazo[4,5-c]pyridine:

Into a 100-mL round-bottom flask, was placed 6-chloro-4-N-methylpyridine-3,4-diamine (500 mg, 3.17 mmol, 1 equiv), trimethoxymethane (20 mL). The resulting solution was stirred for 4 h at 100 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC A. This resulted in 200 mg (38%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): 168 [M+l], R: 0.841 min.

Step 4: Synthesis of N-[4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]phenyl]-l-methyl-lHimidazo[4,5-c]pyridin-6-amine:

Into a 30-mL sealed tube, was placed 6-chloro-l-methyl-lH-imidazo[4,5-c]pyridine (300 mg, 1.79 mmol, 1 equiv), Cs2CO3 (1.76 g, 5.40 mmol, 3.00 equiv), Pd₂(dba)₃-CHC1₃ (100 mg), 15 X-phos (100 mg), 1,4-dioxane (15 mL), 4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]aniline (540 mg, 2.16 mmol, 1.20 equiv). The resulting solution was stirred for 4 h at 100 °C in an oil bath. The solids were filtered out. The crude product was purified by Prep-HPLC E. This resulted in 54.2 mg (7%) of N-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-l-methyllH-imidazo[4,5-c]pyridin-6-amine as a yellow solid.

I. Example 27: Synthesis of Compound 259

Compound 259: Synthesis of N²-(4-methoxy-3-((2-methyl-2-azaspiro[4.5]decan-8yl)oxy)phenyl)-N⁴-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidine-2,4-diamine

324

Step 1: Synthesis of ethyl 2-[l,4-dioxaspiro[4.5]decan-8-ylidene]acetate:

Into a 250-mL round-bottom flask, was placed ethyl 2-(diethoxyphosphoryl)acetate (14.4 g,

64.23 mmol, 1 equiv), tetrahydrofuran (150 mL), sodium hydride (5.12 g, 213.33 mmol, 3.33 equiv), l,4-dioxaspiro[4.5]decan-8-one (10 g, 64.03 mmol, 1 equiv). The resulting solution was stirred ovemight at 0 °C. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x50 mL of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 12 g (83%) of as a yellow liquid.

Analytical Data: ’H NMR (300 MHz, Chloroform-ίΖ) δ 5.67 (p, J = 1.1 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.98 (s, 4H), 3.00 (ddd, J = 7.8, 5.1, 1.2 Hz, 2H), 2.44 - 2.32 (m, 2H), 1.841.70 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H).

Step 2: Synthesis of ethyl 2-[8-(nitromethyl)-l,4-dioxaspiro[4.5]decan-8-yl]acetate:

Into a 500-mL round-bottom flask, was placed ethyl 2-[l,4-dioxaspiro[4.5]decan-8ylidene]acetate (12 g, 53.03 mmol, 1 equiv), tetrahydrofuran (150 mL), nitromethane (13 g, 212.98 mmol, 4.02 equiv), TBAF tetrahydrofuran (80 mL). The resulting solution was stirred ovemight at 70 °C. The resulting solution was extracted with 3x30 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3x30 mL of H2O.

325

The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 11 g (72%) of the title compound as a yellow liquid.

Analytical Data: *H NMR (300 MHz, Chloroform-t/) δ 4.73 (s, 2H), 4.17 (q, J= 7.1 Hz, 2H),

3.95 (s, 4H), 2.57 (s, 2H), 1.85 - 1.63 (m, 6H), 1.35-1.18 (m, 3H).

Step 3: Synthesis of l,4-dioxa-10-azadispiro[4.2.4⁸.2⁵]tetradecan-l 1-one:

Into a 500-mL round-bottom flask, was placed ethyl 2-[8-(nitromethyl)-l,4dioxaspiro[4.5]decan-8-yl]acetate (5 g, 17.40 mmol, 1 equiv), methanol (200 mL), Raney-Ni (1 g), TEA (5 g, 49.41 mmol, 2.84 equiv), hydrogen (500 mL). The resulting solution was stirred ovemight at RT. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 4 g (100%) of the title compound as a white solid.

Analytical Data: ^lH NMR (300 MHz, Chloroform-7) δ 6.35 (s, 1H), 3.96 (s, 4H), 3.21 (s, 2H), 2.23 (s, 2H), 1.79- 1.60 (m, 8H).

Step 4: Synthesis of l,4-dioxa-10-azadispiro[4.2.4⁸.2⁵]tetradecane:

Into a 1-L round-bottom flask, was placed l,4-dioxa-10-azadispiro[4.2.4⁸.2⁵]tetradecan-l 1one (5.28 g, 24.99 mmol, 1 equiv), tetrahydrofuran (500 mL), LAH (2.85 g, 75.10 mmol, 3.00 equiv) at 0 °C. After 1 h, the resulting solution was stirred ovemight at 50 °C. The reaction was then quenched by the addition of 2.85 g of water, 2.85 g of 15% NaOH, 8.55 g of water The solids were filtered out. The resulting mixture was concentrated under vacuum.

This resulted in 3.6 g (73%) of the title compound as a colorless oil.

Analytical Data: ^lH NMR (300 MHz, Chloroform-J) δ 5.14 (s, 1H), 3.96 (s, 4H), 3.06 (t, J = 7.2 Hz, 2H), 2.81 (s, 2H), 1.65 (d, 7=6.2 Hz, 10H).

Step 5: Synthesis of benzyl l,4-dioxa-10-azadispiro[4.2.4⁸.2⁵]tetradecane-10-carboxylate: Into a 250-mL round-bottom flask, was placed l,4-dioxa-10-azadispiro[4.2.4⁸.2⁵]tetradecane 25 (3.6 g, 18.25 mmol, 1 equiv), sodium carbonate (7.3 g, 68.87 mmol, 3.77 equiv), water(20 mL), tetrahydrofuran (20 mL), benzyl chloroformate (3.7 g, 21.69 mmol, 1.19 equiv). The resulting solution was stirred ovemight at RT. The resulting solution was extracted with 3x50 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3x50 mL of H2O. The solid was dried in an oven under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1). This resulted in 3.5 g (58%) of the title compound as a colorless liquid.

'H NMR (300 MHz, Chloroform-7) δ 7.47 - 7.30 (m, 5H), 3.96 (s, 4H), 3.49 (t, J= 7.2 Hz, 2H), 3.28 (s, 2H), 1.86-1.51 (m, 10H).

Step 6: Synthesis of benzyl 8-oxo-2-azaspiro[4.5]decane-2-carboxylate:

326

Into a 250-mL round-bottom flask, was placed benzyl l,4-dioxa-10azadispiro[4.2.4^A[8].2^A[5]]tetradecane-10-carboxylate (2.5 g, 7.54 mmol, 1 equiv), methanol (50 mL). This was followed by the addition of HCl (10 mL). 2N The resulting solution was stirred ovemight at RT. The resulting solution was extracted with 3x30 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3x30 mL of H₂O. The solid was dried in an oven under reduced pressure. This resulted in 2.0 g (83%) of the title compound as a colorless liquid.

Analytical Data: LC-MS: (ES, m/z): RT=0.877min, LCMS 45, m/z =288 [M+l].

Step 7: Synthesis of benzyl 8-hydroxy-2-azaspiro[4.5]decane-2-carboxylate:

jo Into a 100-mL round-bottom flask, was placed benzyl 8-oxo-2-azaspiro[4.5]decane-2carboxylate (1.77 g, 6.16 mmol, 1 equiv), methanol (30 mL), NaBH₄ (350 mg, 9.25 mmol, 1.50 equiv). The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3x20 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with

3x20 mL of H₂O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.6 g (81%) of the title compound as a colorless liquid. LC-MS: (ES, m/z): RT=0.876 min, LCMS 45, m/z =290 [M+l],

Step 8: Synthesis of benzyl 8-(methanesulfonyloxy)-2-azaspiro[4.5]decane-2-carboxylate: Into a 250-mL round-bottom flask, was placed benzyl 8-hydroxy-2-azaspiro[4.5]decane-220 carboxylate (1.87 g, 6.46 mmol, 1 equiv), dichloromethane (50 mL), TEA (1.96 g, 19.37 mmol, 3.00 equiv), MsCl (885 mg). The resulting solution was stirred for 1 h at 0 °C. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3x30 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3x30 mL of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2.0 g (76%) of the title compound as a colorless liquid.

Analytical Data: LC-MS: (ES, m/z): RT=1.301 min, LCMS 53, m/z =368 [M+l], Step 9: Synthesis of benzyl 8-(2-methoxy-5-nitrophenoxy)-2-azaspiro[4.5]decane-2carboxylate:

Into a 100-mL round-bottom flask, was placed benzyl 8-(methanesulfonyloxy)-2azaspiro[4.5]decane-2-carboxylate (2.5 g, 6.80 mmol, 1 equiv), 2-methoxy-5-nitrophenol (1.27 g, 7.51 mmol, 1.10 equiv), Cs₂CO₃ (4.5 g, 13.81 mmol, 2.03 equiv), N,Ndimethylformamide (25 mL). The resulting solution was stirred for 5 h at 80 °C. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted

327 with 3x50 mL of ether and the organic layers combined. The resulting mixture was washed with 3x50 mL of H₂O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1). This resulted in 970 mg (31%) of the title compound as a solid. Analytical Data: LC-MS: (ES, m/z): RT=1.486 min, LCMS 53, m/z =441 [M+l], Step 10: Synthesis of 8-(2-methoxy-5-nitrophenoxy)-2-azaspiro[4.5]decane:

Into a 100-mL round-bottom flask, was placed benzyl 8-(2-methoxy-5-nitrophenoxy)-2azaspiro[4.5]decane-2-carboxylate (900 mg, 2.04 mmol, 1 equiv), trifluoroacetic acid (5 mL). The resulting solution was stirred for 2 h at 60 °C. The resulting mixture was concentrated under vacuum. This resulted in 900 mg (129%) of the title compound as a yellow liquid.

Analytical Data: LC-MS: (ES, m/z): RT=0.968 min, LCMS 34, m/z =307 [M+l], Step 11: Synthesis of 8-(2-methoxy-5-nitrophenoxy)-2-methyl-2-azaspiro[4.5]decane: Into a 100-mL round-bottom flask, was placed 8-(2-methoxy-5-nitrophenoxy)-2azaspiro[4.5]decane (800 mg, 2.61 mmol, 1 equiv), methanol (20 mL), NaBH₃CN (832 mg, 13.24 mmol, 5.07 equiv), HCHO (780 mg). The resulting solution was stirred ovemight at RT. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3x50 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3x50 mL of H₂O. The mixture was dried over anhydrous sodium sulfate. The crude product was purified by Flash-Prep-HPLC A MeOH. This resulted in 300 mg (32%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.777 min, LCMS 45, m/z =321 [M+l], Step 12: Synthesis of 4-methoxy-3-([2-methyl-2-azaspiro[4.5]decan-8-yl]oxy)aniline: Into a 100-mL round-bottom flask, was placed 8-(2-methoxy-5-nitrophenoxy)-2-methyl-2azaspiro[4.5]decane (300 mg, 0.94 mmol, 1 equiv), methanol (20 mL), Pd/Cl (50 mg), hydrogen (100 mL). The resulting solution was stirred for 2 h at RT. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 220 mg (73%) of the title compound as a light red liquid.

Analytical Data: LC-MS: (ES, m/z): RT=0.773 min, LCMS 28, m/z =291 [M+l].

Step 13: Synthesis of N2-(4-methoxy-3-((2-methyl-2-azaspiro[4.5]decan-8-yl)oxy)phenyl)N4-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidine-2,4-diamine:

Into a 10-mL round-bottom flask, was placed 4-methoxy-3-([2-methyl-2-azaspiro[4.5]decan8-yl]oxy)aniline (120 mg, 0.41 mmol, 1 equiv), 2-chloro-N-(oxan-4-ylmethyl)pyrimidin-4amine (94 mg, 0.41 mmol, 1 equiv), trifluoroacetic acid (50 mg, 0.44 mmol, 1.07 equiv), isopropanol (5 mL). The resulting solution was stirred for 2 h at 85 °C. The resulting mixture

328 was concentrated under vacuum. The crude product was purified by Prep-HPLC C-HCl. This resulted in 14.0 mg (6%) of N²-(4-methoxy-3-((2-methyl-2-azaspiro[4.5]decan-8yl)oxy)phenyl)-N⁴-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidine-2,4-diamine as a white solid.

Example 28: Synthesis of Compound 260

Compound 260: Synthesis of N²-(4-methoxy-3-((2-methyl-2-azaspiro[3.5]nonan-7yl)oxy)phenyl)-N⁴-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidine-2,4-diamine

Step 1: Synthesis of tert-butyl 7-(methanesulfonyloxy)-2-azaspiro[3.5]nonane-2-carboxylate: Into a 100-mL round-bottom flask, was placed tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2carboxylate (300 mg, 1.24 mmol, 1 equiv), dichloromethane (10 mL), triethylamine (377 mg, 3.73 mmol, 3.00 equiv), methanesulfonyl chloride (286 mg, 2.50 mmol, 2.01 equiv). The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3x50 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 350 mg (88%) of the title compound as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.279min, LCMS 31: m/z= 320.45[M+l].

Step 2: Synthesis of tert-butyl 7-(2-methoxy-5-nitrophenoxy)-2-azaspiro[3.5]nonane-2carboxylate:

Into a 50-mL round-bottom flask, was placed tert-butyl 7-(methanesulfonyloxy)-2azaspiro[3.5]nonane-2-carboxylate (450 mg, 1.41 mmol, 1 equiv), Cs2CO3 (1.38 g, 4.24 mmol, 3.01 equiv), N,N-dimethylformamide (5 mL), 2-methoxy-5-nitrophenol (358 mg, 2.12

329 mmol, l .50 equiv). The resulting solution was stirred for 2 h at 80 °C. The solids were filtered out. The crude product was purified by Flash-Prep-HPLC A Grad. This resulted in 220 mg (40%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): RT = 2.215min, LCMS 45: m/z= 378.20[M+l]. *H NMR 5 (300 MHz, Chloroform-d) δ 7.90 (dd, J= 9.0, 2.6 Hz, 1H), 7.74 (d, J= 2.7 Hz, 1H), 6.92 (d,

J=9.0 Hz, 1H), 4.40-4.28 (m, 1H), 3.95 (s, 3H), 3.64 (d, J=7.1 Hz, 4H), 2.05- 1.92 (m, 4H), 1.77 - 1.58 (m, 4H), 1.45 (s, 9H).

Step 3: Synthesis of 7-(2-methoxy-5-nitrophenoxy)-2-azaspiro[3.5]nonane:

Into a 50-mL round-bottom flask, was placed tert-butyl 7-(2-methoxy-5-nitrophenoxy)-210 azaspiro[3.5]nonane-2-carboxylate (220 mg, 0.56 mmol, 1 equiv), trifluoroacetic acid (5 mL), dichloromethane (10 mL). The resulting solution was stirred for 30 min at RT. The resulting mixture was concentrated under vacuum. This resulted in 150 mg (92%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.864 min, LCMS 45: m/z= 293.10 [M+l]. *H

NMR (300 MHz, Chloroform-d) δ 10.24 (s, 1H), 7.91 (dd, J = 9.0, 1.9 Hz, 1H), 7.75 - 7.71 (m, 1H), 6.93 (d, J = 9.0 Hz, 1H), 4.40 - 4.28 (m, 1H), 3.94 (s, 3H), 3.90 - 3.80 (m, 4H), 2.22 -2.10 (m, 2H), 1.99- 1.82 (m, 2H), 1.81-1.49 (m, 4H).

Step 4: Synthesis of 7-(2-methoxy-5-nitrophenoxy)-2-methyl-2-azaspiro[3.5]nonane:

Into a 50-mL round-bottom flask, was placed 7-(2-methoxy-5-nitrophenoxy)-220 azaspiro[3.5]nonane (150 mg, 0.51 mmol, 1 equiv), HCHO (23 mg), methanol (5 mL), NaBH₃CN (162 mg, 2.58 mmol, 5.02 equiv). The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3x50 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 100 mg (64%) of the title compound as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.817min, LCMS 45: m/z= 307.15 [M+l], *H NMR (300 MHz, Chloroform-d) δ 8.00 - 7.88 (m, 1H), 7.76 (d, J= 2.7 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 4.40 - 4.31 (m, 1H), 3.96 (s, 3H), 3.44 (d, J= 5.7 Hz, 4H), 2.62 (s, 3H), 2.20 30 2.04 (m,2H), 2.02- 1.88 (m, 2H), 1.80-1.61 (m, 4H).

Step 5: Synthesis of 4-methoxy-3-([2-methyl-2-azaspiro[3.5]nonan-7-yl]oxy)aniline:

Into a 50-mL round-bottom flask purged and maintained with H₂, was placed 7-(2-methoxy5-nitrophenoxy)-2-methyl-2-azaspiro[3.5]nonane (100 mg, 0.33 mmol, 1 equiv), Pd/C(20 mg), methanol (10 mL). The resulting solution was stirred for 1 h at RT. The solids were

330 filtered out. The resulting mixture was concentrated under vacuum. This resulted in 80 mg (89%) of the title compound as a light yellow liquid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.734min, LCMS 15: m/z= 277.10 [M+l]. ^[Η NMR (300 MHz, Chloroform-d) δ 6.72 (d, J = 8.4 Hz, 1H), 6.38 - 6.22 (m, 2H), 4.19 - 4.08 5 (m, 1H), 3.77 (s, 3H), 3.31 (d, J= 11.4 Hz, 4H), 2.53 (s, 3H), 2.16 - 2.01 (m, 2H), 1.961.81 (m, 2H), 1.73 - 1.52 (m, 4H).

Step 6: Synthesis of N2-(4-methoxy-3-((2-methyl-2-azaspiro[3.5]nonan-7-yl)oxy)phenyl)N4-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 4-methoxy-3-([2-methyl-2-azaspiro[3.5]nonan10 7-yl]oxy)aniline (75 mg, 0.27 mmol, 1 equiv), isopropanol (5 mL), trifluoroacetic acid (62 mg, 0.54 mmol, 2.00 equiv), 2-chloro-N-(oxan-4-ylmethyl)pyrimidin-4-amine (62 mg, 0.27 mmol, 1 equiv). The resulting solution was stirred for 2 h at 80 °C. The crude product was purified by Prep-HPLC F. This resulted in 86.1 mg (63%) of N²-(4-methoxy-3-((2-methyl-2azaspiro[3.5]nonan-7-yl)oxy)phenyl)-N⁴-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidine-2,415 diamine as a solid.

Example 29: Synthesis of Compound 261

[0517] Compound 261: Synthesis of 6-methoxy-N²-(4-methoxy-3-(3-(pyrrolidin-lyl)propoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine

Step 1: Synthesis of 4-chloro-6-methoxy-N-[4-methoxy-3-[3-(pyrrolidin-lyl)propoxy] phenyl] pyrimidin-2 -amine :

Into a 50-mL round-bottom flask, was placed 4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]aniline (800 mg, 3.20 mmol, 1 equiv), 2,4-dichloro-6-methoxypyrimidine (573 mg, 3.20 mmol, 1 equiv), TsOH (608 mg, 3.20 mmol, 1 equiv), isopropanol (10 mL). The resulting solution was stirred for 3d at 50 °C in an oil bath. The resulting mixture was

331 concentrated under vacuum. The residue was purified by flash chromatography with H2O/ACN/NH4HCO3. This resulted in 120 mg (10%) as an oil.

Analytical Data: LC-MS: (ES, m/z): RT = 1.113 min, LCMS 28: m/z =393 [M+l].

Step 2: Synthesis of 6-methoxy-N -(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N 5 methylpyrimidine-2,4-diamine:

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed 4-chloro-6-methoxy-N-[4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]phenyl]pyrimidin-2-amine (350 mg, 0.89 mmol, 1 equiv), Methylamine 2M in tetrahydrofuran (0.9 mg, 2.00 equiv), Pd2(dba)3CHC13 (93 mg, 0.10 equiv), BINAP (111 mg, 10 0.18 mmol, 0.20 equiv), t-BuONa (256 mg, 2.66 mmol, 3.00 equiv), Toluene (10 mL). The resulting solution was stirred for ovemight at 80 °C in an oil bath under N₂ (g) atmosphère. The resulting mixture was concentrated under vacuum. The solids were filtered out. The residue was purified by flash chromatography with ACN/H2O(l/10). This resulted in 40.3 mg (12%) of 6-methoxy-N²-(4-methoxy-3-(3-(pyrrolidin-l -yl)propoxy)phenyl)-N⁴15 methylpyrimidine-2,4-diamine as an off-white solid.

Example 30: Synthesis of Compounds 262a and 262b

Compound 262a and 262b: Synthesis of N⁴-methyl-N²-((lR,3S)-3-(3-(pyrrolidin-lyl)propoxy)cyclohexyI)pyrimidine-2,4-diamine and N‘ ⁴-methyl-N²-((lS,3R)-3-(320 (pyrrolidin-l-yl)propoxy)cyclohexyl)pyrimidine-2,4-diamine

PTSA,IPA,110 °C

Rh/AI₂O₃,HOAc

60atm, 100 °C

Step 1: Synthesis of 3-[3-(pyrrolidin-l-yl)propoxy]cyclohexan-l-amine:

Into a 30-mL pressure tank reactor (60 atm), was placed 3-[3-(pyrrolidm-lyl)propoxy]aniline (500 mg, 2.27 mmol, 1 equiv), acetic acid (15 mL), RI1/AI2O3 (0.3 g), hydrogen (1 g). The resulting solution was stirred for 5 h at 100 °C in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 1.9 g (crude) of as an oil.

Analytical Data: LC-MS: (ES, m/z): MS = 227 [M+l],

332

Step 2: Synthesis of N⁴-methyl-N²-((lR,3S)-3-(3-(pyrrolidin-lyl)propoxy)cyclohexyl)pyrimidine-2,4-diamine and N⁴-methyl-N²-((lS,3R)-3-(3-(pyrrolidinl-yl)propoxy)cyclohexyl)pyrimidine-2,4-diamine:

Into a 30-mL pressure tank reactor, was placed 2-chloro-N-methylpyrimidin-4-amine (550 mg, 3.83 mmol, 1.20 equiv), 3-[3-(pyrrolidin-l-yl)propoxy]cyclohexan-l-amine (720 mg,

3.18 mmol, 1 equiv), PTSA (1 g, 5.81 mmol, 2.00 equiv), IPA (10 mL). The resulting solution was stirred for 12 h at 110 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purifïed by Flash-Prep-HPLC A MeOH. The crude product 120mg was purifïed by Chiral-Prep-HPLC This resulted in 42.6 mg (3%) of enantiomer 1 (randomly assigned) as yellow oil and 32.0 mg (2%) enantiomer 2 (randomly assigned) as an oil.

Example 31: Synthesis of Compound 263

Compound 263: Synthesis of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴15 methylquinazoline-2,4-diamine

Step 3: Synthesis of 2-chloro-N-methylquinazolin-4-amine:

Into a 50-mL round-bottom flask, was placed 2,4-dichloroquinazoline (1 g, 5.02 mmol, 1 equiv), tetrahydrofuran (10 mL), TEA (772 mg, 7.63 mmol, 1.50 equiv), CH3NH2.THF (7.5 20 mL, 3.00 equiv). The resulting solution was stirred for 1 h at 0 °C in a water/ice bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with CH₃CN/H₂O (1:7). This resulted in 900 mg (93%) of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.33min, LCMS33: m/z = 194 [M+l], 'H NMR 25 (400 MHz, Methanol-d4) δ 8.08 - 8.00 (m, 1H), 7.78 (m, 1H), 7.63-7.61 (m, 1H), 7.54-7.49 (m, 1 H), 3.13 (s, 3H).

Step 4: Synthesis of N -(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N methylquinazoline-2,4-diamine:

Into a 25-mL round-bottom flask, was placed 2-chloro-N-methylquinazolin-4-amine (300 30 mg, 1.55 mmol, 1 equiv), trifluoroacetic acid (354.4 mg, 3.14 mmol, 2.00 equiv), 4-methoxy3-[3-(pyrrolidin-l-yl)propoxy]aniline (388.6 mg, 1.55 mmol, 1 equiv), propan-2-ol (5 mL).

The resulting solution was stirred for 2 h at 85 °C in an oil bath. The resulting mixture was

333 concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC D. This resulted in 64.7 mg (10%) of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴methylquinazoline-2,4-di amine as an off-white solid.

Example 32: Synthesis of Compound 264

Compound 264: Synthesis of 7-((4-(methyIamino)pyrinüdin-2-yl)amino)-2-(2(pyrrolidin-l-yl)ethyl)-3,4-dihydroisoquinolin-l(2H)-one

Step 1: Synthesis of 7-amino-2-[2-(pyrrolidin-l-yl)ethyl]-l,2,3,4-tetrahydroisoquinolin-lone:

Into a 100-mL round-bottom flask, was placed 7-nitro-2-[2-(pyrrolidin-l-yl)ethyl]-l,2dihydroisoquinolin-l-one (100 mg, 0.35 mmol, 1 equiv), methanol (20 mL), Pd(OH₂), hydrogen. The resulting solution was stirred for 16 h at 25 °C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 60 mg (66%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z): RT=0.302min, LCMS 31, m/z =260 [M+l],

Step 2: Synthesis of 7-((4-(methylamino)pyrimidin-2-yl)amino)-2-(2-(pyrrolidin-l-yl)ethyl)3,4-dihydroisoquinolin-l(2H)-one:

Into a 25-mL round-bottom flask, was placed 7-amino-2-[2-(pyrrolidin-l-yl)ethyl]-l,2,3,4tetrahydroisoquinolin-l-one (60 mg, 0.23 mmol, 1 equiv), 2-chloro-N-methylpyrimidin-4amine (34 mg, 0.24 mmol, 1 equiv), isopropanol (6 mL), trifluoroacetic acid (52 mg, 0.46 mmol, 2.00 equiv). The resulting solution was stirred for 4 h at 85 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by PrepHPLC C TFA. This resulted in 45.3 mg (41%) of the title compound as a solid.

Example 33: Synthesis of Compound 265

Compound 265: Synthesis of N-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyI)-lHindol-4-amine

3rd-Brettphos

K₂CO₃,DMSO

334

Step 1: Synthesis of N-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-lH-indol-4amine:

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed 4-bromo-lH-indole (200 mg, 1.02 mmol, 1 equiv), 3rd-BrettPhos (46 mg, 0.05 mmol, 0.05 equiv), potassium methaneperoxoate (283 mg, 2.03 mmol, 2.00 equiv), 4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]aniline (256.4 mg, 1.02 mmol, 1 equiv), DMSO (5 mL). The resulting solution was stirred for 6 h at 85 °C in an oil bath. The resulting solution was diluted with 10 mL of H₂O. The pH value of the solution was adjusted to 8 with sodium carbonate. The resulting solution was extracted with 3x10 mL of dichloromethane and the organic layers combined. HCl (aq) was employed to adjust the pH to 4. The resulting mixture was washed with 3x10 mL of H₂O. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC C TFA. This resulted in 91.9 mg (19%) of N-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-lH-indol-4-amine as a white solid.

Example 34: Synthesis of Compound 266

Compound 266: Synthesis of N-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-lHpyrrolo [3,2-c] pyridin-4-amine

Step 1: Synthesis of N-[4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]phenyl]-lH-pyrrolo[3,2c]pyridin-4-amine:

Into a 20-mL vial, was placed dioxane (2 mL), 4-chloro-lH-pyrrolo[3,2-c]pyridine (200 mg, 1.31 mmol, 1 equiv), 4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]aniline (329 mg, 1.31 mmol, 1 equiv), Brettphos (230 mg), Cs₂CO₃ (781 mg, 2.40 mmol, 1.83 equiv). The vial was purged and maintained with N₂.The resulting solution was stirred for 12 h at 100°C. The resulting mixture was concentrated under vacuum. The crude product was purified by Chiral-PrepHPLC D TFA. This resulted in 74.1 mg (12%) of N-(4-methoxy-3-(3-(pyrrolidin-lyl)propoxy)phenyl)-lH-pyrrolo[3,2-c]pyridin-4-amine as a an solid.

Example 35: Synthesis of Compound 267

335

Compound 267: Synthesis of N⁴-methyl-N²-(6-((2-(pyrrolidin-lyl)ethoxy)methyl)pyridin-2-yl)pyridine-2,4-diamine

NaH, DMF

Step 1 : Synthesis of 2-bromo-6-[[2-(pyrrolidin-1 -yl)ethoxy]methyl]pyridine:

Into a 250-mL round-bottom flask, was placed 2-bromo-6-(bromomethyl)pyridine (2 g, 7.97 mmol, 1 equiv), sodium hydride (956 mg, 39.83 mmol, 5.00 equiv), N,N-dimethylformamide (80 mL), 2-(pyrrolidin-l-yl)ethan-l-ol (1.1 g, 9.55 mmol, 1.20 equiv). The resulting solution was stirred for 1 h at 0 °C in a water/ice bath. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x100 mL of brine. The mixture was dried over anhydrous sodium sulfate. The crude product was purified by Flash-Prep-HPLC A 1:1. This resulted in 910 mg (40%) of the title compound as colorless oil.

Analytical Data: LC-MS: (ES, m/zy. RT= 0.85 min, LCMS 34: m/z = 285 [M+l],

Step 2: Synthesis of N-(6-[[2-(pyrrolidin-l-yl)ethoxy]methyl]pyridin-2-yl)acetamide:

Into a 250-mL round-bottom flask, was placed 2-bromo-6-[[2-(pyrrolidin-lyl)ethoxy]methyl]pyridine (910 mg, 3.19 mmol, 1 equiv), X-phos (100 mg), CS2CO3 (3.134 g, 9.62 mmol, 3.00 equiv), dioxane (10 mL), Pd2(dba)3.CHCl₃ (100 mg), acetamide (567 mg, 9.60 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at 80 °C in an oil bath. The crude product was purified by Flash-Prep-HPLC ALL This resulted in 460 mg (55%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/zy. RT= 0.72 min, LCMS 28: m/z = 264 [M+l],

Step 3: Synthesis of 6-[[2-(pyrrolidin-l-yl)ethoxy]methyl]pyridin-2-amine:

Into a 100-mL round-bottom flask, was placed N-(6-[[2-(pyrrolidin-lyl)ethoxy]methyl]pyridin-2-yl)acetamide (460 mg, 1.75 mmol, 1 equiv), sodiumol (350 mg, 25 8.75 mmol, 5.00 equiv), methanol (20 mL), water(20 mL). The resulting solution was stirred for 12 h at 70 °C. The crude product was purified by Flash-Prep-HPLC A 1:1. This resulted in 230 mg (59%) of the title compound as colorless oil.

Analytical Data: LC-MS: (ES, m/z): RT= 0.62 min, LCMS 53: m/z = 222 [M+l],

336

Step 4: Synthesis of N⁴-methyl-N²-(6-((2-(pyrrolidin-l-yl)ethoxy)methyl)pyridin-2yl)pyridine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-bromo-N-methylpyridin-4-amine (180 mg, 0.96 mmol, 1 equiv), 6-[[2-(pyrrolidin-l-yl)ethoxy]methyl]pyridin-2-amine (255.3 mg, 1.15 mmol, 1.20 equiv), Cs₂CO₃ (939 mg, 2.88 mmol, 3.00 equiv), Pd₂dba₃-CHC1₃ (10 mg), Xphos (10 mg), 1,4-dioxane (10 mL). The resulting solution was stirred for 10 h at 100 °C. The crude product was purified by Flash-Prep-HPLC A 1 :l.This resulted in 39.3 mg (11%) of N⁴methyl-N²-(6-((2-(pyrrolidin-l-yl)ethoxy)methyl)pyridin-2-yl)pyridine-2,4-diamine as a light yellow solid.

Example 36: Synthesis of Compound 268

Compound 268: Synthesis of N²-methyl-N⁴-(6-((2-(pyrrolidin-lyl)ethoxy)methyl)pyridin-2-yl)pyridine-2,4-diamine

Step 1: Synthesis of N²-methyl-N⁴-(6-((2-(pyrrolidin-l-yl)ethoxy)methyl)pyridin-2yl)pyridine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 6-[[2-(pyrrolidin-l-yl)ethoxy]methyl]pyridin-2amine (220 mg, 0.99 mmol, 1 equiv), 4-bromo-N-methylpyridin-2-amine (224 mg, 1.20 mmol, 1.20 equiv), Cs₂CO₃ (978 mg, 3.00 mmol, 3.00 equiv), Pd₂dba₃-CHC1₃ (50 mg), Xantphos (50 mg), 1,4-dioxane (10 mL). The resulting solution was stirred for 4 h at 100 °C. The crude product was purified by Flash-Prep-HPLC with the foilowing conditions (IntelFlash-1): Column, silica gel; mobile phase, ACN/H2O=1/1; Detector, UV 254 nm. This resulted in 56.5 mg (17%) of N²-methyl-N⁴-(6-((2-(pyrrolidin-l-yl)ethoxy)methyl)pyridin-2yl)pyridine-2,4-diamine as a solid.

Example 37: Synthesis of Compound 272

Compound 272: Compound Synthesis of 5-fluoro-N²-(4-methoxy-3-(3-(pyrrolidin-lyl)propoxy)phenyl)-N⁴-methylpyridine-2,4-diamine ci

337

Step 1: Synthesis of 2-chloro-5-fluoro-N-methylpyridin-4-amine:

Into a 20-mL vial, was placed tetrahydrofuran (8 mL), 2,4-dichloro-5-fluoropyridine (300 mg, 1.81 mmol, 1 equiv), a solution of methanamine (113 mg, 3.64 mmol, 2.01 equiv) in tetrahydrofùran (1.82 mL). The resulting solution was stirred for 18 h at 80 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 200 mg (69%) of as a white solid. Analytical Data: LC-MS: (ES, m/z): RT = 0.469 min, LCMS 32: m/z = 161 [M+l], Step 2: Synthesis of 5-fluoro-N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴methylpyridine-2,4-diamine:

Into a 40-mL vial purged and maintained with an inert atmosphère of nitrogen, was placed toluene (10 mL), 2-chloro-5-fluoro-N-methylpyridin-4-amine (190 mg, 1.18 mmol, 1 equiv), 4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]aniline (327 mg, 1.31 mmol, 1.10 equiv), Pd₂(dba)₃-CHC1₃ (184 mg, 0.18 mmol, 0.15 equiv), BINAP (222 mg, 0.36 mmol, 0.30 equiv), t-BuONa (342 mg, 3.56 mmol, 3.01 equiv). The resulting solution was stirred for 13 h at 100 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with Water (0.05% HC1)/ACN (5:1). This resulted in 89.1 mg (18%) of 5fluoro-N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴-methylpyridine-2,4-diamine as a light yellow solid.

Example 38: Synthesis of Compound 276

Compound 276: Synthesis of N²-(3-(2-fIuoro-3-(pyrrolidin-l-yI)propoxy)phenyl)-N⁴methylpyrimidine-2,4-diamine

TsOH

Step 1: Synthesis of l-[2-fluoro-3-(3-nitrophenoxy)propyl]pyrrolidine:

Into a 50-mL 3-necked round-bottom flask, was placed l-(3-nitrophenoxy)-3-(pyrrolidin-lyl)propan-2-ol (500 mg, 1.88 mmol, 1 equiv), dichloromethane (15 mL). This was followed by the addition of a solution of DAST (363 mg, 2.25 mmol, 1.20 equiv) in dichloromethane (3 mL) dropwise with stirring at -78 °C in 1 min. The resulting solution was stirred ovemight at RT. The reaction was then quenched by the addition of 5M/M mL of water. The resulting

338 solution was extracted with 3xl0 mL of dichloromethane and the aqueous layers combined and concentrated under vacuum. This resulted in 400 mg (71%) of the title compound as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.950 min, LCMS 31, m/z =269.0 [M+l].

Step 2: Synthesis of 3-[2-fluoro-3-(pyrrolidin-l-yl)propoxy]aniline:

Into a 100-mL round-bottom flask, was placed l-[2-fluoro-3-(3nitrophenoxy)propyl]pyrrolidine (400 mg, 1.49 mmol, 1 equiv), methanol (5 mL), hydrogen (100 mL), Pd/C (100 mg). The resulting solution was stirred for 2 h at RT. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 370 mg 10 (104%) of the title compound as a yellow liquid.

LC-MS: (ES, m/z): RT=1.040 min, LCMS 34, m/z =239.0 [M+l]. ^]H NMR: (300 MHz, Chloroform-t/) δ 7.08 (t, J= 8.0 Hz, 1H), 6.43 - 6.25 (m, 3H), 4.83 (d, J = 4.4 Hz, 1H), 4.75 -4.63 (m, 1H), 4.28 - 4.07 (m, 2H), 3.69 (s, 2H), 3.18 - 2.69 (m, 5H), 2.01 - 1.77 (m, 4H). Step 3: Synthesis of N²-(3-(2-fluoro-3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴15 methylpyrimidine-2,4-diamine:

Into a 8-mL round-bottom flask, was placed 2-chloro-N-methylpyrimidin-4-amine (120 mg, 0.84 mmol, 1 equiv), 3-[2-fluoro-3-(pyrrolidin-l-yl)propoxy] aniline (80 mg, 0.34 mmol, 0.40 equiv), trifluoroacetic acid (0.2 mL), isopropanol (3 mL). The resulting solution was stirred ovemight at 85 °C. The crude product was purified by Prep-HPLC C TFA. This resulted in 20 37.4 mg (11%) of N²-(3-(2-fluoro-3-(pynOlidin-l-yl)propoxy)phenyl)-N⁴-methylpyrimidine2,4-diamine as a white solid.

Example 39: Synthesis of Compound 277

Compound 277: Synthesis of N²-(3-(2,2-difluoro-3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴25 methylpyrimidine-2,4-diamine

339

Step 1: Synthesis of 2,2-difluoro-3-[[(4-methylbenzene)sulfonyl]oxy]propan-l-ol: Into a 100-mL round-bottom flask, was placed 2,2-difluoropropane-l,3-diol (600 mg, 5.35 mmol, 1 equiv), TEA (1.4 g, 13.84 mmol, 3.00 equiv), dichloromethane (50 mL), 4methylbenzene-l-sulfonyl chloride (1.02 g, 5.35 mmol, 1 equiv). The resulting solution was stirred for 12 h at 25 °C. The resulting solution was extracted with 3x100 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3x100 mL of Brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC A 1:1. This resulted in 500 mg (35%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z); R: 1.19 min, 267 [M+l],

Step 2: Synthesis of 2,2-difluoro-3-(3-nitrophenoxy)propan-l-ol: Into a 100-mL round-bottom flask, was placed 2,2-difluoro-3-[[(4methylbenzene)sulfonyl]oxy]propan-l-ol (550 mg, 2.07 mmol, 1 equiv), Cs2CO3 (2 g, 6.14 mmol, 3.00 equiv), N,N-dimethylformamide (50 mL), 3-nitrophenol (431 mg, 3.10 mmol, 1.50 equiv). The resulting solution was stirred for 12 h at 100 °C in an oil bath. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC A 1:1. This resulted in 60 mg (12%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z); R: 1.086 min, 234 [M+l], 'H-NMR: (Chloroform-d, ppm); δ 7.91-7.92 (m, 1 H), 7.80 (t, J = 2.4 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.31-7.33 (m, 1H), 4.38 (t, J= 11.6 Hz, 2H), 4.03 (t, J= 12.5 Hz, 2H).

Step 3: Synthesis of 2,2-difluoro-3-(3-nitrophenoxy)propyl methanesulfonate:

Into a 100-mL round-bottom flask, was placed 2,2-difluoro-3-(3-nitrophenoxy)propan-l-ol (50 mg, 0.21 mmol, 1 equiv), MsCl (37 mg, 1.50 equiv), TEA (65 mg, 0.64 mmol, 3.00 equiv), dichloromethane (50 mL). The resulting solution was stirred for 2 h at 25 °C. The resulting solution was extracted with 3x100 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3x50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 60 mg (90%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z); R: 1.266 min, 312 [M+l], 'H-NMR: (DMSO-4 ppm): δ 7.96 - 7.85 (m, 2H), 7.71 - 7.49 (m, 2H), 4.82 - 4.57 (m, 4H), 3.33 (s, 3H).

Step 4: Synthesis of l-[2,2-difluoro-3-(3-nitrophenoxy)propyl]pyrrolidine:

340

Into a 20-mL sealed tube, was placed 2,2-difluoro-3-(3-nitrophenoxy)propyl methanesulfonate (60 mg, 0.19 mmol, 1 equiv), pyrrolidine (10 mL). The resulting solution was stirred for 12 h at 80 °C in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic 5 layers combined. The resulting mixture was washed with 3x50 mL of brine. The mixture was dried over anhydrous sodium sulfate. This resulted in 50 mg (91%) of as yellow oil.

Analytical Data: LC-MS: (ES, m/z): 287 [M+l], R: 0.962 min.

Step 5: Synthesis of 3-[2,2-difluoro-3-(pyrrolidin-l-yl)propoxy]aniline:

Into a 100-mL round-bottom flask, was placed l-[2,2-difluoro-3-(310 nitrophenoxy)propyl]pyrrolidine (50 mg, 0.17 mmol, 1 equiv), Raney-Ni, hydrogen, methanol (10 mL). The resulting solution was stirred for 4 h at 25 °C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 40 mg (89%) of as yellow oil.

Analytical Data: LC-MS: (ES, m/z): 257 [M+l], R: 0.734 min.

Step 6: Synthesis of N²-(3-(2,2-difluoro-3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 3-[2,2-difluoro-3-(pyrrolidin-lyl)propoxy]aniline (40 mg, 0.16 mmol, 1 equiv), trifluoroacetic acid (35 mg, 0.31 mmol, 2.00 equiv), isopropanol (10 mL), 2-chloro-N-methylpyrimidin-4-amine (27 mg, 0.19 mmol, 1.20 20 equiv). The resulting solution was stirred for 4 h at 80 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC F TFA. This resulted in 39.2 mg (53%) of N²-(3-(2,2-difluoro-3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴methylpyrimidine-2,4-diamine as a white solid.

Example 40: Synthesis of Compound 279

Compound 279: Synthesis of N⁴-methyl-N²-(3-(l-(2-(pyrroIidin-lyl)ethoxy)ethyl)phenyl) pyrimidine-2,4-diamine

Step 1: Synthesis of l-(3-nitrophenyl)ethyl methanesulfonate:

341

Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed l-(3-nitrophenyl)ethan-l-ol (1 g, 5.98 mmol, 1 equiv), dichloromethane (15 mL, 1.50 equiv), TEA (1.8 g, 17.79 mmol, 3.00 equiv). This was followed by the addition of MsCl (1.1 g) dropwise with stirring at 0 °C. The resulting solution 5 was stirred for 3 h at 0 °C in a water/ice bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2x100 mL of water and 2x50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum.

This resulted in 1.4 g (95%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT=0.801 min. 'H NMR (300 MHz, DMSO-d6) δ 8.36 - 8.15 (m, 2H), 8.02 - 7.87 (m, 1H), 7.79 - 7.65 (m, 1H), 5.97 (q, J = 6.5 Hz, 1H), 3.20 (s, 3H), 1.67 (d, J =6.5 Hz, 3H).

Step 2: Synthesis of l-[2-[l-(3-nitrophenyl)ethoxy]ethyl]pyrrolidine:

Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphère 15 of nitrogen, was placed sodium hydride (1.14 g, 28.50 mmol, 7.00 equiv, 60%), N,Ndim ethyl formamide (5 mL). This was followed by the addition of a solution of 2-(pyrrolidinl-yl)ethan-l-ol (2.82 g, 24.48 mmol, 6.00 equiv) in N,N-dimethylformamide (8 mL) dropwise with stirring at -20 °C. The resulting solution was stirred for 0.5 h at -20 °C in an ice/salt bath. To this was added a solution of l-(3-nitrophenyl)ethyl methanesulfonate (1 g, 20 4.08 mmol, 1 equiv) in N ,N-dimethyl formamide (7 mL) dropwise with stirring at -20 °C. The resulting solution was stirred for 1 h at -20 °C in an ice/salt bath. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x50 mL of water and 2x50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC A Grad. This resulted in 400 mg (37%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT=0.740min, LCMS 40, m/z =265 [M+l], 'H NMR (300 MHz, DMSO-î/₆) δ 8.23 - 8.07 (m, 2H), 7.85 - 7.74 (m, 1H), 7.76 - 7.60 (m, 1H), 4.64 (q, 7=6.4 Hz, 1H), 3.55 -3.39 (m, 1H), 3.41 - 3.25 (m, 1H), 2.68 - 2.30 (m, 6H), 1.7330 1.54 (m,4H), 1.37 (d, J =6.5 Hz, 3H).

Step 3: Synthesis of 3-[l-[2-(pyrrolidin-l-yl)ethoxy]ethyl]aniline:

Into a 100-mL round-bottom flask, was placed 1 -[2-[l-(3nitrophenyl)ethoxy]ethyl]pynOlidine (430 mg, 1.63 mmol, 1 equiv), methanol (30 mL), Pd/Cl, hydrogen. The resulting solution was stirred for 4 h at 25 °C. The solids were filtered

342 out. The resulting mixture was concentrated under vacuum. This resulted in 370 mg (97%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT=0.742min, LCMS 45, m/z =235 [M+l],

Step 4: Synthesis of N⁴-methyl-N²-(3-(l-(2-(pyrrolidin-l-yl)ethoxy)ethyl)phenyl) pyrimidine-2,4-diamine:

Into a 100-mL round-bottom flask, was placed 3-[l-[2-(pyrrolidin-l-yl)ethoxy]ethyl]aniline (350 mg, 1.49 mmol, 1 equiv), 2-chloro-N-methylpyrimidin-4-amine (214 mg, 1.49 mmol, 1 equiv), isopropanol (20 mL), trifluoroacetic acid (341 mg, 3.02 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 90 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC C TFA. This resulted in 171.5 mg (25%) of N⁴-methyl-N²-(3-(l-(2-(pyrrolidin-l-yl)ethoxy)ethyl)phenyl) pyrimidine-2,4-diamine as a semisolid.

Example 41: Synthesis of Compound 280

Compound 280: Synthesis of N -(3-(3-(diethylamino)propoxy)-4-methoxyphenyl)-N methylpyrimidine-2,4-diamine

*7 4

Step 1: Synthesis of N -(3-(3-(diethylamino)propoxy)-4-methoxyphenyl)-N methylpyrimidine-2,4-di amine :

Into a 16-mL sealed tube, was placed 2-N-[3-(3-chloropropoxy)-4-methoxyphenyl]-4-Nmethylpyrimidine-2,4-diamine (200 mg, 0.62 mmol, 1 equiv), Nal (100 mg, 1 equiv), potassium carbonate (180 mg, 1.30 mmol, 2.00 equiv), ACN (8 mL), diethylamine (100 mg, 1.37 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 85 °C in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC D HCl. This resulted in 73.7 mg (30%) of N²-(3-(3(diethylamino)propoxy)-4-methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine as a light yellow solid.

Example 42: Synthesis of Compound 283

343

Compound 283: Synthesis of N²-(4-methoxy-3-(3-(3-methoxypyrrolidin-lyl)propoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine

Step 1: Synthesis of N²-(4-methoxy-3-(3-(3-methoxypyrrolidin-l-yl)propoxy)phenyl)-N⁴5 methylpyrimidine-2,4-diamine:

Into a 8-mL round-bottom flask, was placed 2-N-[3-(3-chloropropoxy)-4-methoxyphenyl]-4N-methylpyrimidine-2,4-diamine (300 mg, 0.93 mmol, 1 equiv), 3-methoxypyrrolidine (303 mg, 3.00 mmol, 3.22 equiv), Nal (150 mg), potassium carbonate (414 mg, 3.00 mmol, 3.22 equiv), CH₃CN (5 mL). The resulting solution was stirred ovemight at 70 °C. The crude product was purified by Prep-HPLC C NH3. This resulted in 59.7 mg (17%) of N²-(4methoxy-3-(3-(3-methoxypyrrolidin-l-yl)propoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine as a white solid.

Example 43: Synthesis of Compound 285

Compound 285: Synthesis of N²-(4-methoxy-3-(3-(3-(trifhioromethyl)pyrrolidin-lyl)propoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine

Step 1: Synthesis of N²-(4-methoxy-3-(3-(3-(trifluoromethyl)pyrrolidin-lyl)propoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-N-[3-(3-chloropropoxy)-4-methoxyphenyl]4-N-methylpyrimidine-2,4-diamine (300 mg, 0.93 mmol, 1 equiv), Cs2CO₃ (911 mg, 2.80 mmol, 3.00 equiv), Nal (13.98 mg, 0.10 equiv), 3-(trifluoromethyl)pyrrolidine (388.5 mg, 2.79 mmol, 3.00 equiv), CH₃CN (6 mL). The resulting solution was stirred for 16 h at 85 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC C TFA. This resulted in 88 mg (18%) of t N²-(4-methoxy-3(3-(3-(trifluoromethyl)pyrrolidin-l-yl)propoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine as a white solid.

344

Example 44: Synthesis of Compound 286

Compound 286: Synthesis of l-(3-(2-methoxy-5-((4-(methylamino)pyrimidin-2yl)amino)phenoxy)propyl)pyrrolidin-3-ol

OH

OH

Step 1: Synthesis ofl-(3-(2-methoxy-5-((4-(methylamino)pyrimidin-2yl)amino)phenoxy)propyl)pyrrolidin-3-ol:

Into a 20-mL vial, was placed N,N-dimethylformamide (5 mL), 2-N-[3-(3-chloropropoxy)-4methoxyphenyl]-4-N-methylpyrimidine-2,4-diamine (250 mg, 0.77 mmol, 1 equiv), pyrrolidin-3-ol (135 mg, 1.55 mmol, 2.00 equiv), CS2CO3 (506 mg, 1.55 mmol, 2.01 equiv), 10 Nal (117 mg). The resulting solution was stirred for 2 h at 80 °C. The solids were fïltered out.

The crude product was purified by Prep-HPLC C NH3. This resulted in 64.7mg (22%) of 1(3-(2-methoxy-5-((4-(methylamino)pyrimidin-2-yl)amino)phenoxy)propyl)pyrrolidin-3-ol as a white solid.

Example 45: Synthesis of Compound 287

Compound 287: Synthesis of l-(3-(2-methoxy-5-((4-(methylamino)pyrimidin-2yl)amino)phenoxy)propyl)pyrrolidine-3-carbonitrile

CN

Step 1: Synthesis of l-(3-(2-methoxy-5-((4-(methylamino)pyrimidin-220 yl)amino)phenoxy)propyl)pyrrolidine-3-carbonitrile:

Into a 20-mL vial, was placed ACN (3 mL), 2-N-[3-(3-chloropropoxy)-4-methoxyphenyl]-4N-methylpyrimidine-2,4-diamine (300 mg, 0.93 mmol, 1 equiv), pyrrolidine-3-carbonitrile (98 mg, 1.02 mmol, 1.10 equiv), Nal (140 mg), potassium carbonate (257 mg, 1.86 mmol, 2.00 equiv), TB AI (34 mg, 0.09 mmol, 0.10 equiv). The resulting solution was stirred for 14 25 h at 80 °C. The residue was applied onto a silica gel column with H2O/ACN (4:1). The collected fractions were combined and concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC D HCl. This resulted in 43 mg (11%) of l-(3-(2-methoxy-5((4-(methylamino)pyrimidin-2-yl)amino)phenoxy)propyl)pynOlidine-3-carbonitrile as a white solid.

345

Example 46: Synthesis of Compound 288

Compound 288: Synthesis of N²-(4-methoxy-3-(2-(l-methylpyrrolidin-2yl)ethoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine

Step 1: Synthesis of 2-[2-(2-methoxy-5-nitrophenoxy)ethyl]-l-methylpyrrolidine:

Into a 50-mL round-bottom flask, was placed N,N-dimethylformamide (10 mL), 2-methoxy5-nitrophenol (500 mg, 2.96 mmol, 1 equiv), Cs₂CO₃ (1.93 g, 5.92 mmol, 2.00 equiv), Nal (444 mg, 2.96 mmol, 1 equiv), 2-(2-chloroethyl)-l-methylpyrrolidine (870 mg, 5.89 mmol, 1.99 equiv). The resulting solution was stirred for 2 h at 80 °C. The resulting solution was diluted with 10 mL of H₂O. The resulting solution was extracted with 3x10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x10 mL of water and 3x10 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were collected by filtration. The resulting mixture was concentrated under vacuum. This resulted in 540 mg (65%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.836 min, LCMS 27: m/z = 281 [M+l], Step 2: Synthesis of 4-methoxy-3-[2-(l-methylpyrrolidin-2-yl)ethoxy]aniline: Into a 100-mL round-bottom flask, was placed methanol (30 mL), 2-[2-(2-methoxy-5nitrophenoxy)ethyl]-l-methylpyrrolidine (520 mg, 1.86 mmol, 1 equiv), Rany-Ni (100 mg).The flask was purged and maintained with H₂.The resulting solution was stirred for 3 h at 20 °C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 460 mg (99%) of the title compound as a light red oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.398 min, LCMS 32: m/z = 251 [M+l]. Step 3: Synthesis of N²-(4-methoxy-3-(2-( 1-methylpyrrolidin-2-yl)ethoxy)phenyl)-N⁴methylpyrimidine-2,4-diamine:

Into a 100-mL round-bottom flask, was placed isopropanol (10 mL), 2-chloro-Nmethylpyrimidin-4-amine (252 mg, 1.76 mmol, 1 equiv), 4-methoxy-3-[2-(lmethylpyrrolidin-2-yl)ethoxy]aniline (440 mg, 1.76 mmol, 1 equiv), PTSA (303 mg, 1.76 mmol, 1 equiv). The resulting solution was stirred for 2 h at 85 °C. The crude product (600 mg) was purified by Prep-HPLC D HCl. 310 mg product was obtained. This resulted in 310

346 mg (45%) ofN²-(4-methoxy-3-(2-( l-methylpyrrolidin-2-yl)ethoxy)phenyl)-N⁴methylpyrimidine-2,4-diamine as light yellow oil.

Example 47: Synthesis of Compound 289

Compound 289: Synthesis of N²-(4-methoxy-3-((l-methylpyrrolidin-2yl)methoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine

Step 1: Synthesis of (l-methylpyrrolidin-2-yl)methyl methanesulfonate:

Into a 50-mL round-bottom flask, was placed (l-methylpyrrolidin-2-yl)methanol (1 g, 8.68 10 mmol, 1 equiv), TEA (2.66 g, 26.29 mmol, 3.00 equiv), dichloromethane (10 mL), methanesulfonyl chloride (1.29 g, 11.26 mmol, 1.30 equiv). The resulting solution was stirred for 1 h at 20 °C. This resulted in 2 g (119%) of the title compound as yellow oil.

Step 2: Synthesis of 2-(2-methoxy-5-nitrophenoxymethyl)-1 -methylpyrrolidine

Into a 50-mL sealed tube, was placed (l-methylpyrrolidin-2-yl)methyl methanesulfonate (1 g, 15 5.17 mmol, 1 equiv), Cs₂CO₃ (3.75 g, 11.51 mmol, 2.00 equiv), 2-methoxy-5-nitrophenol (876 mg, 5.18 mmol, 1 equiv), N,N-dimethylformamide (10 mL). The resulting solution was stirred for 16 h at 90 °C in an oil bath. The residue was applied onto a silica gel column with H₂O:CH3CN (1:5). This resulted in 500 mg (36%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.73min, LCMS40: m/z = 267.25 [M+l], 20 Step 3: Synthesis of 4-methoxy-3-[(l-methylpyrrolidin-2-yl)methoxy]aniline:

Into a 50-mL round-bottom flask, was placed 2-(2-methoxy-5-nitrophenoxymethyl)-lmethylpyrrolidine (500 mg, 1.88 mmol, 1 equiv), methanol (20 mL), Pd/C (1 g, 1 equiv), hydrogen. The resulting solution was stirred for 1 h at 20 °C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 350 mg (79%) of the title 25 compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.39min, LCMS07: m/z = 237.25 [M+l],

Step 4: Synthesis of N²-(4-methoxy-3-((l-methylpyrrolidin-2-yl)methoxy)phenyl)-N⁴methylpyrimidine-2,4-di amine :

347

Into a 50-mL round-bottom flask, was placed 4-methoxy-3-[(l-methylpyrrolidin-2yl)methoxy]aniline (350 mg, 1.48 mmol, 1 equiv), trifluoroacetic acid (338 mg, 2.99 mmol, 2.00 equiv), 2-chloro-N-methylpyrimidin-4-amine (212 mg, 1.48 mmol, 1 equiv), propan-2ol (10 mL). The resulting solution was stirred for 6 h at 85 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by PrepHPLC C NH3. This resulted in 64.7 mg (13%) of 4-methoxy-3-[(l-methylpyrrolidin-2yl)methoxy] aniline as an off-white solid.

Example 48: Synthesis of Compound 290

Compound 290: Synthesis of N²-(4-methoxy-3-(3-(2-methylpyrrolidin-lyI)propoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine

Step 1: Synthesis of N²-(4-methoxy-3-(3-(2-methylpyrrolidin-l-yl)propoxy)phenyl)-N⁴methylpyrimidine-2,4-diamine:

Into a 25-mL round-bottom flask, was placed N,N-dimethylformamide (5 mL), 2-N-[3-(3chloropropoxy)-4-methoxyphenyl]-4-N-methylpyrimidine-2,4-diamine (200 mg, 0.62 mmol, 1 equiv), 2-methylpyrrolidine (53 mg, 0.62 mmol, 1 equiv), CS2CO3 (405 mg, 1.24 mmol, 2.01 equiv), Nal (93 mg, 0.62 mmol, 1 equiv). The resulting solution was stirred for 4 h at 80 °C. The solids were filtered out. The crude product (200 mg) was purified by Prep-HPLC D HCl. 39.7 mg light yellow solid N²-(4-methoxy-3-(3-(2-methylpyrrolidin-1yl)propoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine was obtained.

Example 49: Synthesis of Compound 291

Compound 291: Synthesis of N-ethyl-4-((4-(methylamino)pyrimidin-2yl)amino)picolinamide

348

Step 1: Synthesis of N-ethyl-4-nitropyridine-2-carboxamide:

Into a 50-mL round-bottom flask, was placed 4-nitropyridine-2-carboxylic acid (400 mg, 2.38 mmol, 1 equiv), CDI (582 mg, 3.59 mmol, 1.50 equiv), N,N-dimethylformamide (10 mL), 5 ethanamine (1.2 mL). The resulting solution was stirred for 6 h at 25 °C. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. This resulted in 464mg (99%) of the title compound as a yellow solid.

JO Analytical Data: LC-MS: (ES, m/z): RT = 0.871 min, LCMS 34: m/z = 195 [M+l].

Step 2: Synthesis of 4-amino-N-ethylpyridine-2-carboxamide:

Into a 50-mL round-bottom flask, was placed N-ethyl-4-nitropyridine-2-carboxamide (464 mg, 2.38 mmol, 1 equiv), Pd/C (156.3 mg), hydrogen. The resulting solution was stirred for 4 h at 25 °C. The solids were collected by filtration. This resulted in 370 mg (94%) of the title 15 compound as a yellow liquid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.684 min, LCMS 34: m/z = 166 [M+l], Step 3: Synthesis of N-ethyl-4-((4-(methylamino)pyrimidin-2-yl)amino)picolinamide: Into a 50-mL round-bottom flask, was placed 4-amino-N-ethylpyridine-2-carboxamide (200 mg, 1.21 mmol, 1 equiv), 2-chloro-N-methylpyrimidin-4-amine (174 mg, 1.21 mmol, 1 equiv), Xantphos (140.3 mg, 0.24 mmol, 0.20 equiv), DBU (368.5 mg, 2.42 mmol, 2.00 equiv), dioxane (10 mL), Pd(OAc)₂ (27.1 mg, 0.12 mmol, 0.10 equiv). The resulting solution was stirred for 24 h at 100 °C in an oil bath. The resulting solution was extracted with 3x10 mL of water and the organic layers combined. The crude product was purified by (ACN/H₂O=l/20). This resulted in 30.2 mg (8%) of N-ethyl-4-((4-(methylamino)pyrimidin25 2-yl)amino)picolinamide as a white solid.

Example 50: Synthesis of Compound 293

349

Compound 293: Synthesis of N²-(4-methoxy-3-(3-(3-methylpyrrolidin-lyl)propoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine

H

Step 1: Synthesis of N²-(4-methoxy-3-(3-(3-methylpyrrolidin-l-yl)propoxy)phenyl)-N⁴5 methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-N-[3-(3-chloropropoxy)-4-methoxyphenyl]4-N-methylpyrimidine-2,4-diamine (300 mg, 0.93 mmol, 1 equiv), 3-methylpyrrolidine hydrochloride (112.7 mg, 0.93 mmol, 1 equiv), CS2CO3 (939 mg, 2.88 mmol, 3.00 equiv), Nal (279.5 mg, 2.00 equiv), CH3CN (10 mL). The mixture solution was stirred for 20 h at 85 10 °C. The resulting solution was diluted with 20 mL of water and extracted with 3x30 mL of ethyl acetate and the organic layers combined. The crude product was purified by Prep-HPLC C NH4HCO3. The resulting solution was stirred for 24 h at 85 °C in an oil bath. This resulted in 39.3mg (11%) of N²-(4-methoxy-3-(3-(3-methylpyrrolidin-1-yl)propoxy)phenyl)-N⁴methylpyrimidine-2,4-diamine as a white solid.

Example 51: Synthesis of Compound 298

Compound 298: Synthesis of N²-(3-(3-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)-4methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine

Step 1: Synthesis of N²-(3-(3-(3-azabicyclo[3.1.0]hexan-3-yl)propoxy)-4-methoxyphenyl)N⁴-methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-N-[3-(3-chloropropoxy)-4-methoxyphenyl]4-N-methylpyrimidine-2,4-diamine (300 mg, 0.93 mmol, 1 equiv), 3-azabicyclo[3.1.0]hexane hydrochloride (166.3 mg, 1.39 mmol, 1.50 equiv), CS2CO3 (609 mg, 1.87 mmol, 2.00 equiv), 25 Nal (279 mg, 1.86 mmol, 2.00 equiv), N,N-dimethylformamide (5 mL). The resulting solution was stirred for 12 h at 80 °C in an oil bath. The solids were filtered out. The crude product was purified by Prep-HPLC D NH3. This resulted in 33.5 mg (10%) of N²-(3-(3-(3

350 azabicyclo[3.1.0]hexan-3-yl)propoxy)-4-methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine as a white solid.

Example 52: Synthesis of Compound 299

Compound 299: Synthesis of (R)-l-(2-methoxy-5-((4-(methylamino)pyrimidin-2yl)amino)phenoxy)-3-(pyrrolidin-l-yl)propan-2-ol

N Y cCn n'

H

IPA, TFA

Step 1: Synthesis of 2-(2-methoxy-5-nitrophenoxymethyl)oxirane:

Into a 250-mL round-bottom flask, was placed 2-methoxy-5-nitrophenol (3.5 g, 20.69 mmol, 1 equiv), 2-(bromomethyl)oxirane (2.84 g, 20.73 mmol, 1 equiv), potassium carbonate (5.7 g, 41.24 mmol, 2.00 equiv), N,N-dimethylformamide (80 mL). The resulting solution was stirred for 16 h at 25 °C. The resulting solution was allowed to react, with stirring, for an additional 3 h while the température was maintained at 50 °C in an oil bath. The resulting mixture was washed with 1x100 mL of H2O. The resulting solution was extracted with 3x300 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x200 mL of water and 2x100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 4.2 g (crude) of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT=1.02 min. *H NMR (300 MHz, DMSO-d6) δ 7.93 (dd, J= 9.0, 2.7 Hz, 1H), 7.78 (d, J = 2.7 Hz, 1H), 7.20 (d, J= 9.0 Hz, 1H), 4.49 (dd, J = 11.4, 2.4 Hz, 1H), 3.99-3.86 (m, 4H), 3.43 -3.28 (m, 1H), 2.91 -2.81 (m, 1H), 2.78 - 2.68 (m, 1H).

Step 2: Synthesis of l-(2-methoxy-5-nitrophenoxy)-3-(pyrrolidin-l-yl)propan-2-ol:

Into a 50-mL round-bottom flask, was placed 2-(2-methoxy-5-nitrophenoxymethyl)oxirane (500 mg, 2.22 mmol, 1 equiv), éthanol (10 mL), chloroform (10 mL), pyrrolidine (394 mg, 5.54 mmol, 2.50 equiv). The resulting solution was stirred for 3 h at 60 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash

351

Prep-HPLC A DCM/MeOH. This resulted in 600 mg (91%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT=0.927min, LCMS 31, m/z =297[M+1], *H NMR (400 MHz, DMSO-d6) δ 7.90 (dd, J= 9.0, 2.7 Hz, 1H), 7.79 (d, J = 2.7 Hz, 1H), 7.18 (d, J =

9.0 Hz, 1H), 4.99 (s, 1H), 4.19 - 4.05 (m, 1H), 4.04 - 3.87 (m, 5H), 2.71 - 2.41 (m, 6H), 1.76

- 1.61 (m, 4H).

Step 3: Synthesis of l-(5-amino-2-methoxyphenoxy)-3-(pyrrolidin-l-yl)propan-2-ol:

Into a 100-mL round-bottom flask, was placed l-(2-methoxy-5-nitrophenoxy)-3-(pyrrolidinl-yl)propan-2-ol (700 mg, 2.36 mmol, 1 equiv), methanol (40 mL), Pd/Cl, hydrogen. The resulting solution was stirred for 16 h at 25 °C. The solids were fdtered out. The resulting mixture was concentrated under vacuum. This resulted in 600 mg (95%) of the title compound as yellow oil.

LC-MS: (ES, m/z): RT=0.671min, LCMS 31, m/z =267 [M+l],

Step 4: Synthesis of (R)-l-(2-methoxy-5-((4-(methylamino)pyrimidin-2-yl)amino)phenoxy)15 3 -(pyrrolidin-1 -yl)propan-2-ol :

Into a 50-mL round-bottom flask, was placed l-(5-amino-2-methoxyphenoxy)-3-(pyrrolidin1-yl)propan-2-ol (600 mg, 1 equiv), 2-chloro-N-methylpyrimidin-4-amine (324 mg, 2.26 mmol, 1 equiv), isopropanol (10 mL), trifluoroacetic acid (514 mg, 4.55 mmol, 2.00 equiv).

The resulting solution was stirred for 3 h at 90°C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by Chiral-Prep-HPLC ID. This resulted in 42 mg (5%) of l-(5-amino-2-methoxyphenoxy)-3-(pyrrolidin-l-yl)propan-2-ol (600 mg, 1 equiv), 2-chloro-N-methylpyrimidin-4-amine as a light yellow solid.

Example 53: Synthesis of Compound 300

Compound 300: Synthesis of (S)-l-(2-methoxy-5-((4-(methylamino)pyrimidin-2yl)amino)phenoxy)-3-(pyrrolidin-l-yl)propan-2-ol

Step 1: Synthesis of (S)-l-(2-methoxy-5-((4-(methylamino)pyrimidin-2-yl)amino)phenoxy)3 -(pyrrolidin-1 -yl)propan-2-ol :

Into a 50-mL round-bottom flask, was placed l-(5-amino-2-methoxyphenoxy)-3-(pyrrolidinl-yl)propan-2-ol (600 mg, 2.25 mmol, 1 equiv), 2-chloro-N-methylpyrimidin-4-amine (324

352 mg, 2.26 mmol, 1 equiv), isopropanol (10 mL), trifluoroacetic acid (514 mg, 4.55 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at 90 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by Chiral-Prep-HPLC IB4.

This resulted in 41.1 mg (5%) of (S)-l-(2-methoxy-5-((4-(methylamino)pyrimidin-2- yl)amino)phenoxy)-3-(pyrrolidin-l-yl)propan-2-ol as a light yellow solid.

Example 54: Synthesis of Compound 301

Compound 301: Synthesis of N2-(3-fluoro-4-methoxy-5-(3-(pyrrolidin-lyI)propoxy)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine

Pd/C,MeOH

Step 1: Synthesis of l-[3-(3-fhioro-2-methoxy-5-nitrophenoxy)propyl]pyrrolidine:

Into a 250-mL round-bottom flask, was placed l,3-difluoro-2-methoxy-5-nitrobenzene (1 g,

5.29 mmol, 1 equiv), 3-(pyrrolidin-l-yl)propan-l-ol (683 mg, 5.29 mmol, 1 equiv), t-BuOK (10.6 mL, 2.00 equiv), tetrahydrofuran (f 5 mL). The resulting solution was stirred for 1 h at 0 °C in a water/ice bath. The resulting mixture was concentrated under vacuum. The crude product (5 mL) was purified by ACN/H₂O(l/l).This resulted in 550mg (35%) of as a yellow solid.

[0517] Analytical Data: LC-MS: (ES, m/z): RT = 0.986min, LCMS 53: m/z = 299 [M+l], 'H NMR (400 MHz, Methanol-d4) δ 7.75 (s, 1H), 7.73 (s, 1H), 4.28 - 4.25 (m, 2H), 4.03 20 3.99 (m, 6H), 2.78 - 2.66 (m, 2H), 2.65 - 2.62 (m, 2H), 2.03 - 1.99 (s, 3H), 1.88 - 1.85 (m,

2H).

Step 2: Synthesis of 3-fluoro-4-methoxy-5-[3-(pyrrolidin-l-yl)propoxy]aniline:

Into a 250-mL round-bottom flask, was placed l-[3-(3-fluoro-2-methoxy-5nitrophenoxy)propyl]pyrrolidine (450 mg, 1.51 mmol, 1 equiv), methanol (10 mL), Pd/C 25 (150 mg), hydrogen. The resulting solution was stirred for 2 h at 25 °C. The solids were

353 filtered out. The resulting mixture was concentrated under vacuum. This resulted in 350 mg (86%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.803min, LCMS 34: m/z = 269 [M+l].

Step 3: Synthesis of N -(3-fluoro-4-methoxy-5-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N ,65 dimethylpyrimidine-2,4-diamine:

Into a 100-mL round-bottom flask, was placed 3-fluoro-4-methoxy-5-[3-(pyrrolidin-lyl)propoxy]aniline (300 mg, 1.12 mmol, 1 equiv), 2-chloro-N,6-dimethylpyrimidin-4-amine (176 mg, 1.12 mmol, 1 equiv), trifluoroacetic acid (255.2 mg, 2.26 mmol, 2.00 equiv), isopropanol (15 mL). The resulting solution was stirred for 24 h at 85 °C in an oil bath. The io resulting mixture was concentrated under vacuum. The crude product was purified by PrepHPLC C NH3. This resulted in 9.7 mg (2%) of N²-(3-fluoro-4-methoxy-5-(3-(pyrrolidin-lyl)propoxy)phenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine as a yellow solid.

Example 55: Synthesis of Compound 302

Compound 302: Synthesis of N²-(2-fluoro-4-methoxy-5-(3-(pyrrolidin-lyl)propoxy)phenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine

Step 1: Synthesis l-(3-chloropropoxy)-4-fluoro-2-methoxybenzene:

Into a 50-mL round-bottom flask, was placed 4-fluoro-2-methoxyphenol (1 g, 7.04 mmol, 1 equiv), l-chloro-3-iodopropane (2.87 g, 14.04 mmol, 2.00 equiv), potassium carbonate (2.92 g, 21.13 mmol, 3.00 equiv), ACN (15 mL). The resulting solution was stirred for 14 h at 85 °C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 1.5 g (98%) of as yellow oil.

Step 2: Synthesis of l-(3-chloropropoxy)-4-fluoro-2-methoxy-5-nitrobenzene:

Into a 100-mL round-bottom flask, was placed l-(3-chloropropoxy)-4-fluoro-2methoxybenzene (1.53 g, 7.00 mmol, 1 equiv), acetyl acetate (25 mL). This was followed by the addition of HNO₃ (2.56 g, 4.00 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 16 h at 20 °C. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with 2x80 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2x100 mL of sodium bicarbonate

354 and 2x100 mL of brine. The resulting mixture was washed and the filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/5). This resulted in 1.62 g (88%) of the title compound as a yellow solid.

Analytical Data: ⁴H NMR (400 MHz, Methanol-d4) δ 7.70 (s, 1H), 7.06 (s, 1H), 4.20 (t, J= 5.9 Hz, 2H), 3.79 (t, J= 6.4 Hz, 2H), 2.26 (q, J= 6.1 Hz, 2H), 2.03 (s, 3H).

Step 3: Synthesis of 5-(3-chloropropoxy)-2-fluoro-4-methoxyaniline:

Into a 100-mL round-bottom flask, was placed l-(3-chloropropoxy)-4-fluoro-2-methoxy-5nitrobenzene (200 mg, 0.76 mmol, 1 equiv), RaneyNi (0.1 g), methanol (20 mL). The resulting solution was stirred for 16 h at 50 °C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 170 mg (96%) of the title compound as a brown oil.

Analytical Data: LC-MS: (ES, m/z): RT = 1.032 min; LCMS34: m/z = 234 [M+l].

Step 4: Synthesis of 2-N-[5-(3-chloropropoxy)-2-fluoro-4-methoxyphenyl]-4-N,6dimethylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 5-(3-chloropropoxy)-2-fluoro-4-methoxyaniline (150 mg, 0.64 mmol, 1 equiv), 2-chloro-N,6-dimethylpyrimidin-4-amine (101 mg, 0.64 mmol, 1 equiv), trifluoroacetic acid (125 mg, 1.11 mmol, 2.00 equiv), isopropanol (10 mL). The resulting solution was stirred for 16 h at 85 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ACN/H2O (1/1). This resulted in 180 mg (79%) of the title compound as brown oil.

Analytical Data: LC-MS: (ES, m/z): RT = 1.153 min; LCMS34: m/z = 255 [M+l], Step 5: Synthesis N -(2-fluoro-4-methoxy-5-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N ,6dimethylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-N-[5-(3-chloropropoxy)-2-fluoro-4methoxyphenyl]-4-N,6-dimethylpyrimidine-2,4-diamine (162 mg, 0.46 mmol, 1 equiv), pyrrolidine (64 mg, 0.90 mmol, 2.00 equiv), Nal (69 mg, 0.46 mmol, 1 equiv), CS2CO3 (298 mg, 0.91 mmol, 2.00 equiv), CH3CN (10 mL). The resulting solution was stirred for 16 h at 85 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ACN/H₂O (1/1). This resulted in 46 mg (26%) of N²-(2-fluoro-4methoxy-5-(3-(pyrrolidin-1 -yl)propoxy)phenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine as a solid.

Example 56: Synthesis of Compound 303

355

Compound 303: Synthesis ofN -(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2yl)-N⁴,6-dimethylpyrimidine-2,4-diamine

4

Step 1: Synthesis of N -(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)-N ,65 dimethylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed 5-methoxy-4-[3-(pyrrolidin-l-yl)propoxy]pyridin-2-amine (200 mg, 0.80 mmol, 1 equiv), 2-chloro-N,6-dimethylpyrimidin-4-amine (125.1 mg, 0.79 mmol, 1 equiv), CS2CO3 (779.3 mg, 2.39 mmol, 3.00 equiv), 3rd-BrettPhos (72.2 mg, 0.08 mmol, 0.20 10 equiv), Pd₂(dba)3-CHC13 (41.2 mg, 0.04 mmol, 0.10 equiv), DMSO (5 mL). The resulting solution was stirred for 2 h at 100 °C in an oil bath. The solids were filtered out. The crude product was purified by Prep-HPLC C TFA. This resulted in 133.8 mg (35%) of N²-(5methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)-N⁴,6-dimethylpyrimidine-2,4-diamine as a white solid.

Example 57: Synthesis of Compound 305

Compound 305: Synthesis of N²-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2yl)-N⁴-methylpyridine-2,4-diamine

4

Step 1: Synthesis of N -(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)-N methylpyridine-2,4-diamine:

Into a 100-mL round-bottom flask, was placed 5-methoxy-4-[3-(pyrrolidin-lyl)propoxy]pyridin-2-amine (135 mg, 0.54 mmol, 1 equiv), 2-bromo-N-methylpyridin-4amine (100 mg, 0.53 mmol, 1 equiv), Xphos (51.2 mg, 0.20 equiv), CS2CO3 (350.5 mg, 1.08 25 mmol, 2.00 equiv), DMSO (5 mL), Pd₂(dba)3-CHC13 (55.6 mg, 0.10 equiv). The resulting solution was stirred for 24 h at 100 °C in an oil bath. The resulting mixture was concentrated

356 under vacuum. The crude product (120 mg) was purified by Flash-Prep-HPLC A Grad. This resulted in 18.6 mg (7%) of N²-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)-N⁴methylpyridine-2,4-di amine as a yellow solid.

Example 58: Synthesis of Compound 306

Compound 306: Synthesis of N⁴-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2yl)-N²,6-dimethylpyrimidine-2,4-diamine

Step 1: Synthesis of N⁴-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)-N⁹,610 dimethylpyrimidine-2,4-diamine:

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed 5-methoxy-4-[3-(pyrrolidin-l-yl)propoxy]pyridin-2-amine (200 mg, 0.80 mmol, 1 equiv), 3rd Brettphos (130 mg, 0.14 mmol, 0.10 equiv), CS2CO3 (650 mg, 1.99 mmol, 2.00 equiv), 4-chloro-N,6-dimethylpyrimidin-2-amine (140 mg, 0.89 mmol, 1 equiv), 15 DMSO (10 mL). The resulting solution was stirred for 3 h at 100 °C in an oil bath. The solids were filtered out. The crude product was applied onto a silica gel column with TFA/H2O:ACN (10:1),Detector, UV 254 nm. This resulted in 88.6 mg (22%) of N⁴-(5methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)-N²,6-dimethylpyrimidine-2,4-diamine as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.83 min, LCMS 53: m/z = 373.0 [M+l], ’H NMR (400 MHz, Methanol-i/4) δ 8.04 (s, 1H), 7.37 (s, 1H), 6.46 (s, 1H), 4.33 (s, 2H), 3.96 (d, J = 1.3 Hz, 3H), 3.91 - 3.73 (m, 2H), 3.48 (t, J= 7.3 Hz, 2H), 3.24-3.12 (m, 2H), 3.09 (d, J = 1.8 Hz, 3H), 2.38 - 2.35 (m, 5H), 2.29 - 2.17 (m, 2H), 2.10 - 2.09 (m, 2H).

Example 59: Synthesis of Compound 307

Compound 307: Synthesis ofN -(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2yl)-N⁴,6-dimethylpyridine-2,4-diamine

3rd-Brettphos,DMSO,Cs₂CO₃

357

Step 1: Synthesis of N²-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)-N⁴,6dimethylpyridine-2,4-diamine:

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed 5-methoxy-4-[3-(pyrrolidin-l-yl)propoxy]pyridin-2-amine (200 mg,

0.80 mmol, 1 equiv), CS2CO3 (75 mg, 0.23 mmol, 3 equiv), 3rd-Brettphos (140 mg, 0.20 equiv), 2-chloro-N,6-dimethylpyridin-4-amine (130 mg, 0.83 mmol, 1 equiv), DMSO (15 mL). The resulting solution was stirred for 3 h at 100 °C in an oil bath. The solids were filtered out. The crude product (200 mg) was applied onto a silica gel column with TFA/H₂O:ACN (8:1). This resulted in 64.6 mg (21%) of N²-(5-methoxy-4-(3-(pyrrolidin-l10 yl)propoxy)pyridin-2-yl)-N⁴,6-dimethylpyridine-2,4-diamine as a white solid.

Example 60: Synthesis of Compound 308

Compound 308: Synthesis of N⁴-(5-methoxy-4-(3-(pyrrolidin-l-yI)propoxy)pyridin-22 yl)-N ,6-dimethylpyridine-2,4-diamine

Step 1: Synthesis of N⁴-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridine-2-yl)-N²,6dimethylpyridine-2,4-diamine.·

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed 5-methoxy-4-[3-(pyrrolidin-l-yl)propoxy]pyridin-2-amine (200 mg,

0.80 mmol, 1 equiv), 3rd Brettphos (140 mg, 0.15 mmol, 0.20 equiv), Cs₂CO₃ (750 mg, 2.30 mmol, 3.00 equiv), 4-chloro-N,6-dimethylpyridin-2-amine (130 mg, 0.83 mmol, 1 equiv), DMSO (15 mL). The resulting solution was stirred for 3 h at 100 °C in an oil bath. The solids were filtered out. The crude product (300 mg) was applied onto a silica gel column with TFA/H₂O:ACN (10:1),Detector, UV 254 nm. This resulted in 121.9 mg (30%) ofN⁴-(525 methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridine-2-yl)-N²,6-dimethylpyridine-2,4-diamine as a white solid.

Example 61: Synthesis of Compound 309

Compound 309: Synthesis of 5-fluoro-N -(5-methoxy-4-(3-(pyrrolidin-l30 yl)propoxy)pyridin-2-yl)-N⁴,6-dimethylpyridine-2,4-diamine

358

Step 1: Synthesis 6-bromo-3-fluoro-2-methylpyridine 1-oxide:

Into a 50-mL round-bottom flask, was placed 6-bromo-3-fluoro-2-methylpyridine (1 g, 5.26 mmol, 1 equiv), H2O2 (4 mL), trifluoroacetic acid (10 mL). The resulting solution was stirred 5 for 20 h at 70 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (100/0). This resulted in 1.09 g (101%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.714 min; LCMS40: m/z = 206 [M+l], *H NMR (400 MHz, Chloroform-<7) 67.61 (d, J = 9.1 Hz, 1H), 7.13 (d, J = 9.2 Hz, 1H), 2.61 (s, 3H).

Step 2: Synthesis of 6-bromo-3-fluoro-2-methyl-4-nitropyridine 1-oxide:

Into a 50-mL round-bottom flask, was placed 6-bromo-3-fluoro-2-methylpyridine 1-oxide (1 g, 4.85 mmol, 1 equiv), sulfuric acid (10 mL), potassium nitrate (1.97 g, 4.00 equiv). The resulting solution was stirred for 6 h at 120 °C. The reaction mixture was cooled with a water/ice bath. The resulting solution was extracted with 2x50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2x50 mL of sodium bicarbonate. The resulting mixture was washed with 100 mL of brine. The resulting mixture was concentrated under vacuum. This resulted in 650 mg (53%) of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.068 min; LCMS33: m/z = 251 [M+l],

Step 3: Synthesis of 6-bromo-3-fluoro-2-methylpyridin-4-amine:

Into a 50-mL round-bottom flask, was placed 6-bromo-3-fluoro-2-methyl-4-nitropyridine 1oxide (600 mg, 2.39 mmol, 1 equiv), acetic acid (10 mL), Fe (672 mg, 5.00 equiv). The resulting solution was stirred for 1 h at 100 °C. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with 100 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ACN/H2O (1/10). This resulted in 260 mg (53%) of the title compound as an off-white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.774 min; LCMS33: m/z = 205 [M+l], *H NMR (400 MHz, DMSO-J6) 6 6.67 (d, J= 5.9 Hz, 1H), 6.46 (s, 2H), 2.24 (s, 3H).

Step 4: Synthesis of tert-butyl N-(6-bromo-3-fluoro-2-methylpyridin-4-yl)carbamate:

359

Into a 50-mL round-bottom flask, was placed a solution of 6-bromo-3-fluoro-2methylpyridin-4-amine (250 mg, 1.22 mmol, 1 equiv) in dichloromethane (10 mL), 4dimethylaminopyridine (299 g, 2.45 mol, 2.00 equiv), (Boc)2O (536 mg, 2.46 mmol, 2.00 equiv), TEA (0.34 mL). The resulting solution was stirred for 16 h at 20 °C. The reaction was 5 then quenched by the addition of 10 mL of 10% NaOH. The resulting solution was extracted with 20 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/petroleum ether (1/1). This resulted in 0.3 g (81%) of as an off-white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.458 min; LCMS53: m/z = 305 [M+l], *H NMR 10 (400 MHz, Methanol-c/4) δ 8.19 (s, 1H), 2.52 (s, 1H), 2.42 (s, 3H), 1.56 (d, J= 2.2 Hz, 9H).

Step 5: Synthesis of tert-butyl N-(6-bromo-3-fluoro-2-methylpyridin-4-yl)-Nmethylcarbamate :

Into a 50-mL round-bottom flask, was placed a solution of tert-butyl N-(6-bromo-3-fluoro-2methylpyridin-4-yl)carbamate (278 mg, 0.91 mmol, 1 equiv) in tetrahydrofuran (10 mL).

This was followed by the addition of sodium hydride (110 mg, 3.00 equiv), in portions at 0 °C in 1 hr. To this was added CH3I (388 mg, 2.73 mmol, 3.00 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 18 h at 20 °C. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 2x50 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/petroleum ether (1/1). This resulted in 150 mg (52%) of as a yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 1.449 min; LCMS53: m/z = 319 [M+l], Step 6: Synthesis of tert-butyl N-[3-fluoro-6-([5-methoxy-4-[3-(pyrrolidin-lyl)propoxy]pyridin-2-yl]amino)-2-methylpyridin-4-yl]-N-methylcarbamate:

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed 5-methoxy-4-[3-(pyrrolidin-l-yl)propoxy]pyridin-2-amine (112 mg, 0.45 mmol, 1 equiv), tert-butyl N-(6-bromo-3-fluoro-2-methylpyridin-4-yl)-Nmethylcarbamate (140 mg, 0.44 mmol, 1 equiv), 3^ld Brettphos (40 mg, 0.10 equiv), CS2CO3 (287 mg, 0.88 mmol, 2.00 equiv), DMSO (4 mL). The resulting solution was stirred for 4 h at 30 100 °C. The resulting solution was diluted with 15 mL of H2O. The resulting solution was extracted with 2x50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x50 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ACN/H2O (1/5). This resulted in 80 mg (37%) of as colorless crude oil.

360

Analytical Data: LC-MS: (ES, m/z): RT =1.015 min; LCMS53: m/z = 490 [M+l].

Step 7: Synthesis of 5-fluoro-N²-(5-methoxy-4-(3-(pynOlidin-l-yl)propoxy)pyridin-2-yl)N⁴,6-dimethylpyridine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed tert-butyl N-[3-fluoro-6-([5-methoxy-4-[35 (pyrrolidin-l-yl)propoxy]pyridin-2-yl]amino)-2-methylpyridin-4-yl]-N-methylcarbamate (80 mg, 0.16 mmol, 1 equiv), dichloromethane (6 mL), trifluoroacetic acid (1.5 mL). The resulting solution was stirred for 16 h at 20 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ACN/H₂O (1/5). This resulted in 33.1 mg (40%) of 5-fluoro-N²-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)10 N⁴,6-dimethylpyridine-2,4-diamine as a brown solid.

Example 62: Synthesis of Compound 311

Compound 311: Synthesis of N²-(4-methoxy-3-(2-methoxyethoxy)phenyl)-N⁴,6dimethylpyrimidine-2,4-diamine

Cs₂CO₃,Nal

Step 1: Synthesis of l-methoxy-2-(2-methoxyethoxy)-4-nitrobenzene:

Into a 100-mL round-bottom flask, was placed 2-methoxy-5-nitrophenol (1 g, 5.91 mmol, 1 equiv), Cs₂CO3 (3.8 g, 11.66 mmol, 2.00 equiv), Nal (1.8 g, 12.00 mmol, 2.00 equiv), N,Ndimethylformamide (40 mL), l-chloro-2-methoxyethane (850 mg, 8.99 mmol, 1.5 equiv).

The resulting solution was stirred for 2 h at 100 °C in an oil bath. The reaction was then quenched by the addition of 50 mL of NaHSO₃. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers were washed with 3x20 mL of sodium chloride. The resulting mixture was concentrated under vacuum. This resulted in 1.18 g (86%) of the title compound as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.21 min, LCMS 33: m/z = 228.0 [M+l], 'HNMR (300 MHz, DMSO-ck) δ 7.91 (q, J= 9.0 Hz, 1H), 7.76 (d, J = 2.7 Hz, 1H), 7.19 (d, J= 9.0 Hz, 1H), 4.27 - 4.17 (m, 2H), 3.92 (s, 3H), 3.76 - 3.65 (m, 2H), 3.34 - 3.32 (s, 3H).

Step 2: Synthesis of 4-methoxy-3-(2-methoxyethoxy)aniline:

361

Into a 100-mL round-bottom flask, was placed l-methoxy-2-(2-methoxyethoxy)-4nitrobenzene (580 mg, 2.55 mmol, 1 equiv), Pd/C (200 mg), methanol (25 mL). The resulting solution was stirred for 1 h at 25 °C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 430 mg (85%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.72 min, LCMS 33: m/z = 198.0 [M+l], Step 3: Synthesis of N²-(4-methoxy-3-(2-methoxyethoxy)phenyl)-N⁴,6-dimethylpyrimidine2,4-diamine:

Into a 100-mL round-bottom flask, was placed 4-methoxy-3-(2-methoxyethoxy)aniline (430 mg, 2.18 mmol, 1 equiv), TsOH (825 mg, 4.79 mmol, 2.00 equiv), 2-chloro-N,610 dimethylpyrimidin-4-amine (340 mg, 2.16 mmol, 1 equiv), isopropanol (23 mL). The resulting solution was stirred for 3 h at 90 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (300 mg) was applied onto a silica gel column with NH₄HCO₃:ACN (1:1), Detector, UV 254 nm. 75 mg product was obtained. This resulted in 75 mg (11%) of N -(4-methoxy-3-(2-methoxyethoxy)phenyl)-N ,615 dimethylpyrimidine-2,4-diamine as a solid.

Example 63: Synthesis of Compound 312

Compound 312: Synthesis of N²-(4-methoxy-3-(3-methoxypropoxy)phenyl)-N⁴,6dimethylpyrimidine-2,4-diamine

H

Step 1: Synthesis of l-methoxy-2-(3-methoxypropoxy)-4-nitrobenzene:

Into a 100-mL round-bottom flask, was placed 2-methoxy-5-nitrophenol (1 g, 5.91 mmol, 1 equiv), l-chloro-3-methoxypropane (645 mg, 5.94 mmol, 1 equiv), Cs2CO₃ (3.8 g, 11.66 mmol, 2.00 equiv), Nal (1.3 g, 1.50 equiv), N,N-dimethylformamide (20 mL). The resulting solution was stirred for 2 h at 100 °C in an oil bath. The resulting solution was diluted with 50 mL of EA. The resulting mixture was washed with 3x50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.4 g (98%) of as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.317 min, LCMS 33: m/z = 242 [M+l],

362

Step 2: Synthesis of 4-methoxy-3-(3-methoxypropoxy)aniline:

Into a 50-mL round-bottom flask, was placed l-methoxy-2-(3-methoxypropoxy)-4nitrobenzene (500 mg, 2.07 mmol, 1 equiv), Pd/C (10%) (100 mg), methanol (10 mL). The resulting solution was stirred for 1 h at RT under H₂ (g) atmosphère. The solids were fïltered out. The resulting mixture was concentrated under vacuum. This resulted in 410 mg (94%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.792 min, LCMS 33: m/z = 212 [M+l].

Step 3: Synthesis of N²-(4-methoxy-3-(3-methoxypropoxy)phenyl)-N⁴,6dimethylpyrimidine-2,4-diamine:

jo Into a 50-mL round-bottom flask, was placed 4-methoxy-3-(3-methoxypropoxy)aniline (350 mg, 1.66 mmol, 1 equiv), 2-chloro-N,6-dimethylpyrimidin-4-amine (262 mg, 1.66 mmol, 1 equiv), CF3COOH (378 mg, 3.32 mmol, 2.00 equiv), isopropanol (5 mL). The resulting solution was stirred for ovemight at 80 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography with

H₂O/NH₄HCO₃/ACN (41%). This resulted in 315.0 mg (57%) of N²-(4-methoxy-3-(3methoxypropoxy)phenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine as a white solid.

Example 64: Synthesis of Compound 313

Compound 313: Synthesis of N²-(4-cyclopropyl-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)20 N⁴,6-dimethylpyrimidine-2,4-diamine

Step 1: Synthesis of l-[3-(2-bromo-5-nitrophenoxy)propyl]pyrrolidine:

Into a 100-mL round-bottom flask, was placed 2-bromo-5-nitrophenol (2 g, 9.17 mmol, 1 equiv), l-(3-chloropropyl)pyrrolidine hydrochloride (1.69 g, 9.18 mmol, 1 equiv), Nal (1.65 g, 1.20 equiv), Cs₂CO₃ (5.96 g, 18.29 mmol, 2.00 equiv), CH3CN (30 mL). The resulting solution was stirred for 5 h at 80 °C in an oil bath. The solids were fïltered out. The resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography with ACN/H₂O(28%). This resulted in 2.4 g (79%) of as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.964 min, LCMS33: m/z = 329 [M+l],

363

Step 2: Synthesis of l-[3-(2-cyclopropyl-5-nitrophenoxy)propyl]pyrrolidine: Into a 250-mL 3-necked round-bottom flask, was placed l-[3-(2-bromo-5nitrophenoxy)propyl]pyrrolidine (1.9 g, 5.77 mmol, 1 equiv), cyclopropylboronic acid (745 mg, 8.67 mmol, 1.50 equiv), Pd(dppf)Cl₂ (845 mg, 1.15 mmol, 0.20 equiv), potassium carbonate (1.59 g, 11.50 mmol, 2.00 equiv), water(2 mL), 1,4-dioxane (20 mL). The resulting solution was stirred for 16 h at 80 °C in an oil bath under N₂ (g) atmosphère. The resulting mixture was concentrated under vacuum. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography with H₂O/ACN (32%). This resulted in 440 mg (26%) of as an oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.956 min, LCMS39 : m/z = 291 [M+l].

Step 3: Synthesis of 4-cyclopropyl-3-[3-(pyrrolidin-l-yl)propoxy]aniline:

Into a 100-mL round-bottom flask, was placed l-[3-(2-cyclopropyl-5nitrophenoxy)propyl]pyrrolidine (400 mg, 1.38 mmol, 1 equiv), Fe (385 mg, 6.88 mmol, 5.00 equiv), NH₄C1 (368 mg, 6.88 mmol, 5.00 equiv), water (6 mL), éthanol (12 mL). The resulting solution was stirred for 3 h at 80 °C in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 1.1 g of the title compound as a yellow crude solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.794 min, LCMS33 : m/z = 261 [M+l], Step 4: Synthesis of N²-(4-cyclopropyl-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴,6dimethylpyrimidine-2,4-diamine:

Into a 5-mL round-bottom flask, was placed 4-cyclopropyl-3-[3-(pyrrolidin-lyl)propoxy]aniline (300 mg, 1.15 mmol, 1 equiv), 2-chloro-N,6-dimethylpyrimidin-4-amine (181.2 mg, 1.15 mmol, 1 equiv), CF3COOH (263.1 mg, 2.31 mmol, 2.00 equiv), isopropanol (5 mL). The resulting solution was stirred for overnight at 80 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-PrepHPLC C NH3. This resulted in 40.6 mg of N²-(4-cyclopropyl-3-(3-(pyrrolidin-lyl)propoxy)phenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine as a white solid.

Example 65: Synthesis of Compound 314

Compound 314: Synthesis of N²-(4-cyclopropyl-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)N⁴-methylpyrimidine-2,4-diamine

364

Step 1: Synthesis of N²-(4-cyclopropyl-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴methylpyrimidine-2,4-di amine :

Into a 50-mL round-bottom flask, was placed 4-cyclopropyl-3-[3-(pyrrolidin-l5 yl)propoxy]aniline (300 mg, 1.15 mmol, 1 equiv), 2-chloro-N-methylpyrimidin-4-amine (166 mg, 1.16 mmol, 1 equiv), CF₃COOH (263 mg, 2.31 mmol, 2.00 equiv), isopropanol (5 mL). The resulting solution was stirred for ovemight at 80 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC C TFA. This resulted in 21.9 mg of N²-(4-cyclopropyl-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴10 methylpyrimidine-2,4-diamine as a white solid.

Example 66: Synthesis of Compound 315

Compound 315: Synthesis of N⁴-methyI-N²-(3-(3-(pyrrolidin-l-yl)propoxy)-4(trifluoromethoxy)phenyl)pyrimidine-2,4-diamine

Step 1: Synthesis of 5-bromo-2-(trifluoromethoxy)phenol:

Into a 250-mL 3-necked round-bottom flask, was placed 5-bromo-2-(trifluoromethoxy) aniline (2 g, 7.81 mmol, 1 equiv), éthanol (20 mL), HCl (2 mL). This was followed by the addition of NaNO₂ (595 mg, 8.62 mmol, 1.10 equiv) dropwise with stirring at 0 °C. To this was added water (110 mL), sulfuric acid (5.5 mL). The resulting solution was stirred for 1.5 h at 0 °C in a water/ice bath. The resulting solution was allowed to react, with stirring, for an additional 12 h while the température was maintained at 100 °C in an oil bath. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x50 mL of sodium bicarbonate. The mixture was dried over anhydrous sodium sulfate. This resulted in 1 g (50%) of the title compound as an oil.

365

Analytical Data: LC-MS: (ES, m/z): RT =1.715min, LCMS 53: m/z = 257 [M+l]. *H NMR (400 MHz, DMSO-î/₆) δ 13.29 (s, 1H), 7.96 (s, 1H), 7.77 - 7.51 (m, 1H), 7.44 (d, J= 8.5 Hz, 1H).

Step 2: Synthesis of l-[3-[5-bromo-2-(trifluoromethoxy)phenoxy]propyl]pyrrolidine: Into a 100-mL round-bottom flask, was placed 5-bromo-2-(trifluoromethoxy)phenol (1000 mg, 3.89 mmol, 1 equiv), l-(3-chloropropyl)pyrrolidine hydrochloride (720 mg, 3.91 mmol, 1 equiv), Cs₂CO₃ (2550 mg, 7.83 mmol, 2.00 equiv), Nal (589 mg, 1 equiv), N,Ndimethylformamide (10 mL). The resulting solution was stirred for 2 h at 90 °C in an oil bath. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.4 g (98%) of the title compound as red oil.

Analytical Data: LC-MS: (ES, m/z): RT =1.346min, LCMS 53: m/z =368 [M+l], Step 3: Synthesis of N-[3-[3-(pyrrolidin-l-yl)propoxy]-4-(trifluoromethoxy)phenyl] acetamide:

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed l-[3-[5-bromo-2-(trifluoromethoxy)phenoxy] propyl]pyrrolidine (700 mg, 1.90 mmol, 1 equiv), acetamide (228.9 mg, 3.88 mmol, 2.00 equiv), Cs₂CO₃ (1.24 g, 3.81 mmol, 2.00 equiv), XantPhos (220.5 mg, 0.38 mmol, 0.20 equiv), Pd₂(dba)₃-CHC1₃ (197.4 mg, 0.10 equiv), dioxane (20 mL). The resulting solution was stirred for 12 h at 80 °C in an oil bath. The solids were collected by filtration. The crude product was purified by ACN/H₂O=2/5. This resulted in 450 mg (68%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT =0.940min, LCMS 33: m/z =347[M+1]. ’H NMR (300 MHz, Methanol-J₄) δ 7.63 (d, J = 2.4 Hz, 1H), 7.21 (d, J= 8.4 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 4.14 (t, J= 5.9 Hz, 2H), 3.63 (q, J = 7.0 Hz, 1H), 2.97 - 2.83 (m, 5H), 2.19 - 2.09 (m, 4H), 1.94- 1.83 (m, 4H), 1.21 (t, J=1A Hz, 1H).

Step 4: Synthesis of 3-[3-(pyrrolidin-l-yl)propoxy]-4-(trifluoromethoxy)aniline:

Into a 50-mL round-bottom flask, was placed N-[3-[3-(pyrrolidin-l-yl)propoxy]-4(trifluoromethoxy)phenyl]acetamide (450 mg, 1.30 mmol, 1 equiv), éthanol (6 mL), water(2 mL), sodium hydroxide (208 mg, 5.20 mmol, 4.00 equiv). The resulting solution was stirred for 12 h at 80 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by ACN/H₂O = 1/20. This resulted in 350 mg (89%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT =0.930min, LCMS 31: m/z =305 [M+l].

366

Step 5: Synthesis of N⁴-methyl-N²-(3-(3-(pyrrolidin-l-yl)propoxy)-4(trifluoromethoxy)phenyl)pyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 3-[3-(pyrrolidin-l-yl)propoxy]-4(trifluoromethoxy)aniline (350 mg, 1.15 mmol, 1 equiv), 2-chloro-N-methylpyrimidin-45 amine (164.7 mg, 1.15 mmol, 1 equiv), trifluoroacetic acid (262.5 mg, 2.32 mmol, 2.00 equiv), isopropanol (6 mL). The resulting solution was stirred for 4 h at 80 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (450 mg) was purified by Prep-HPLC C NH3. This resulted in 104 mg (17%) of N⁴-methyl-N²-(3-(3(pyrrolidin-l-yl)propoxy)-4-(trifluoromethoxy)phenyl)pyrimidine-2,4-diamine as a white 10 solid.

Example 67: Synthesis of Compounds 329 and 317

Compound 329 and 317: Synthesis of Diastereomer 1: N²-(3-((lr,3r)-3(dimethyIamino)cyclobutoxy)-4-methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine and Diastereomer 2: N²-(3-((ls,3s)-3-(dimethylamino)cyclobutoxy)-4-methoxyphenyl)N⁴,6-dimethylpyrimidine-2,4-diamine

DEAD,PPh₃THF

Boc

I

Boc p-ÇJ-NO₂

HO

TFA

DCM

HCHO

NaBH₃CN,MeOH

Step 1: Synthesis of tert-butyl N-[3-(2-methoxy-5-nitrophenoxy)cyclobutyl]carbamate:

Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed tert-butyl N-(3-hydroxycyclobutyl)carbamate (500 mg, 2.67 mmol, 1 equiv), 2-methoxy-5-nitrophenol (452 mg, 2.67 mmol, 1 equiv), PPI13 (1.541 g, 5.88 mmol, 2.20 equiv), tetrahydrofuran (20 mL). This was followed by the addition of a solution of DEAD (1.188 g, 5.88 mmol, 2.20 equiv) in tetrahydrofuran (5 mL) dropwise with stirring at 0 °C. The resulting solution was stirred for 10 min at 0 °C. The resulting solution was stirred for 16 h at 25 °C. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC A EA/PE. This resulted in 900 mg (100%) of as yellow oil.

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Analytical Data: LC-MS: (ES, m/z): RT=0.707min, LCMS 40, m/z =239 [M+l]. ‘H NMR (300 MHz, DMSO-Jô) δ 8.98 (s, 1H), 8.00 - 7.69 (m, 1H), 7.62 - 7.47 (m, 1H), 7.28 - 7.13 (m, 1H), 5.01 - 4.46 (m, 1H), 3.91 (d, J= 3.0 Hz, 3H), 2.89 - 2.68 (m, 1H), 2.45 - 2.28 (m, 2H), 2.10-1.93 (m, 2H), 1.39 (d, J =3.3 Hz, 9H).

Step 2: Synthesis of 3-(2-methoxy-5-nitrophenoxy)cyclobutan-l-amine:

Into a 50-mL round-bottom flask, was placed tert-butyl N-[3-(2-methoxy-5nitrophenoxy)cyclobutyl]carbamate (900 mg, 2.66 mmol, 1 equiv), dichloromethane (10 mL), trifluoroacetic acid (5 mL). The resulting solution was stirred for 30 min at 25 °C. This resulted in 1.2 g (crude) of as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT=0.557min, LCMS 30, m/z =239[M+1], ‘H NMR (300 MHz, DMSO-rié) δ 8.17 (s, 2H), 8.00 - 7.86 (m, 1H), 7.64 - 7.42 (m, 2H), 5.20 - 4.62 (m, 1H), 3.93 (s, 3H), 3.89 - 3.34 (m, 1H), 2.97 - 2.57 (m, 2H), 2.38 - 2.15 (m, 2H).

Step 3: Synthesis of 3-(2-methoxy-5-nitrophenoxy)-N,N-dimethylcyclobutan-1 -amine: Into a 50-mL round-bottom flask, was placed 3-(2-methoxy-5-nitrophenoxy)cyclobutan-l15 amine; trifluoroacetic acid (942 mg, 2.67 mmol, 1 equiv), methanol (20 mL), formaldéhyde (241 mg, 8.03 mmol, 3.00 equiv), NaBH₃CN (843 mg, 13.42 mmol, 5.00 equiv). The resulting solution was stirred for 6 h at 25 °C. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC A MeOHÆUO. This resulted in 330 mg (46%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT=0.901min, LCMS 15, m/z =267 [M+l]. *H NMR (300 MHz, DMSCMO δ 7.92 (dd, J= 9.0, 2.7 Hz, 1H), 7.63 - 7.42 (m, 1H), 7.20 (dd, J= 9.1, 2.5 Hz, 1H), 4.94 - 4.51 (m, 1H), 3.92 (s, 3H), 2.92 - 2.56 (m, 2H), 2.46 - 2.12 (m, 2H), 2.07 (d, J =6.8 Hz, 6H), 1.94- 1.77 (m, 1H).

Step 4: Synthesis of 3-[3-(dimethylamino)cyclobutoxy]-4-methoxyaniline:

Into a 50-mL round-bottom flask, was placed 3-(2-methoxy-5-nitrophenoxy)-N,Ndimethylcyclobutan-1-amine (330 mg, 1.24 mmol, 1 equiv), methanol (20 mL), Pd/C, hydrogen. The resulting solution was stirred for 1 h at 25 °C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 285 mg (97%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT=0.261min, LCMS 31, m/z =237 [M+l], *H NMR (300 MHz, DMSO-ri₆) δ 6.64 (dd, J = 8.3, 1.8 Hz, 1H), 6.25 - 6.00 (m, 2H), 4.72-4.51 (m, 2H), 4.36 - 4.14 (m, 1H), 3.61 (d, J= 2.7 Hz, 3H), 2.85 - 2.54 (m, 2H), 2.38 - 1.98 (m, 8H), 1.87- 1.72 (m, 1H).

368

Step 5: Synthesis of Diastereomer 1: N²-(3-((lr,3r)-3-(dimethylamino)cyclobutoxy)-4methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine and Diastereomer 2: N²-(3-((ls,3s)3-(dimethylamino)cyclobutoxy)-4-methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom flask, was placed 3-[3-(dimethylamino)cyclobutoxy]-4methoxyaniline (250 mg, 1.06 mmol, 1 equiv), 2-chloro-N,6-dimethylpyrimidin-4-amine (167 mg, 1.06 mmol, 1 equiv), IPA (10 mL), trifluoroacetic acid (242 mg, 2.14 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at 90 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by Chiral-Prep-HPLC IF. The crude product was purified by Prep-HPLC C HCl. This resulted in 49.6 mg (12%) ofN²(3-((lr,3r)-3-(dimethylamino)cyclobutoxy)-4-methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4diamine diastereomer 1 (randomly assigned) as an off-white solid. And 69.4 mg (17%) of N (3-((ls,3s)-3-(dimethylammo)cyclobutoxy)-4-methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4diamine diastereomer 2 (randomly assigned) as an off-white solid.

Example 68: Synthesis of Compound 318

Compound 318: Synthesis of N²-(3-((ls,3s)-3-((dimethylamino)methyl) cyclobutoxy)-4methoxyphenyl)-N⁴,6-dimethyIpyrimidine-2,4-diamine

Step 1: Synthesis of N²-(3-((ls,3s)-3-((dimethylamino)methyl)cyclobutoxy)-4methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 3-(2-methoxy-5-[[4-methyl-6(methylamino)pyrimidin-2-yl] amino]phenoxy)-N, N-dimethyl cyclobutane-1-carboxamide (200 mg, 0.52 mmol, 1 equiv), LAH (78.96 mg, 2.08 mmol, 4.00 equiv), oxolane (10 mL). The resulting solution was stirred for 2 h at 0 °C in a water/ice bath. The reaction was then quenched by the addition of 200 mg of water/ice. The pH value of the solution was adjusted to 8 with sodium hydroxide (aq) (10 %). The resulting solution was diluted with 2 mL of H₂O. The resulting solution was extracted with 20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The crude product was purified by Prep-HPLC A. This resulted in 61.8 mg (32%) of N²-(3-((ls,3s)-3((dimethylamino)methyl)cyclobutoxy)-4-methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4diamine as a white solid.

369

Example 69: Synthesis of Compound 319

Compound 319: Synthesis of 6-ethyl-5-fluoro-N²-(4-methoxy-3-(3-(pyrrolidin-lyl)propoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine

Cl

Cl

k₂co₃,dmf

NH₂

MgBr

Et₃N, l₂, THF

Step 1: Synthesis of 2,4-dichloro-6-ethyl-5-fluoropyrimidine:

Into a 100-mL 3-necked round-bottom flask, was placed 2,4-dichloro-5-fluoropyrimidine (1 g, 5.99 mmol, 1 equiv), GDE (3 mL), 12 (1.5 g, 1 equiv), tetrahydrofuran (8 mL), TEA (605 mg, 5.98 mmol, 1 equiv), bromo(ethyl)magnesium (1.2 g, 9.00 mmol, 1.50 equiv). The resulting solution was stirred for 1 h at 0 °C in a water/ice bath. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x50 mL of NaHSO3. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 600 mg (51%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): 195 [M+l], RT: 1.38 min.

Step 2: Synthesis of 2-chloro-6-ethyl-5-fluoro-N-methylpyrimidin-4-amine:

Into a 50-mL round-bottom flask, was placed 2,4-dichloro-6-ethyl-5-fluoropyrimidine (300 mg, 1.54 mmol, 1 equiv), CH3NH2-HCI (206 mg, 2.00 equiv), CS2CO3 (1 g, 3.07 mmol, 2.00 equiv), N,N-dimethylformamide (10 mL). The resulting solution was stirred for 12 h at 80 °C. The crude product was purified by Flash-Prep-HPLC ALI. This resulted in 150 mg (51 %) of the title compound as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z): 190 [M+l], R: 0.79 min.

Step 3: Synthesis of 6-ethyl-5-fIuoro-N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)25 N⁴-methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-chloro-6-ethyl-5-fluoro-N-methylpyrimidin4-amine (100 mg, 0.53 mmol, 1 equiv), 4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]aniline

370 (198 mg, 0.79 mmol, 1.50 equiv), CS2CO3 (508 mg, 1.56 mmol, 3.00 equiv), Pd₂(dba)3.CHC13 (50 mg), X-phos (50 mg), 1,4-dioxane (10 mL). The resulting solution was stirred for 4 h at 100 °C. The crude product was purified by Flash-Prep-HPLC with the foilowing conditions (IntelFlash-1): Column, silica gel; mobile phase, ACN/H2O=1/1; Detector, UV 254 nm product was obtained. This resulted in 44.1 mg (21%) of 6-ethyl-5fluoro-N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴-methylpyrimidine-2,4diamine as a light yellow solid.

Example 70: Synthesis of Compound 320

Compound 320: Synthesis of 6-cyclopropyl-N²-(4-methoxy-3-(3-(pyrrolidin-lyl)propoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine

Step 1: Synthesis of 2,4-dichloro-6-cyclopropylpyrimidine:

Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed 2,4,6-trichloropyrimidine (1 g, 5.45 mmol, 1 equiv), tetrahydrofuran (20 mL), Cul (110 mg, 0.58 mmol, 0.10 equiv). This was followed by the addition of bromo(cyclopropyl)magnesium (5.5 mL, 1 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 2 h at 0 °C in a water/ice bath. The resulting solution was allowed to react, with stirring, for an additional 2 h at 25 °C. The reaction was then quenched by the addition of NH4CI. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2x100 mL of water and 2x100 mL of Brine. The mixture was dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC A EA/PE. This resulted in 300 mg (29%) of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT=1.355min, LCMS 53, m/z =189 [M+l], *H NMR (300 MHz, DMSO-d6) δ 7.77 (s, 1H), 2.27 - 2.13 (m, 1H), 1.29- 1.03 (m, 4H).

Step 2: Synthesis of 2-chloro-6-cyclopropyl-N-methylpyrimidin-4-amine:

371

Into a 8-mL sealed tube, was placed 2,4-dichloro-6-cyclopropylpyrimidine (200 mg, 1.06 mmol, 1 equiv), N,N-dimethylformamide (4 mL), potassium carbonate (365 mg, 2.64 mmol, 2.50 equiv), methanamine hydrochloride (72 mg, 1.07 mmol, 1 equiv). The resulting solution was stirred for 2 h at 0 °C in a water/ice bath. The resulting solution was allowed to react, 5 with stirring, for an additional 2 h at 25 °C. The solids were filtered out. The crude product (4 mL) was purified by Flash-Prep-HPLC A Grad. This resulted in 80 mg (41 %) of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.682min, LCMS 30, m/z =184[M+1]. 'H NMR (300 MHz, DMSO-d6) δ 7.61 (s, 1H), 6.33 (s, 1H), 2.76 (d, 7=4.8 Hz, 3H), 1.91 - 1.85 (m, ίο 1H), 0.95 — 0.85 (m, 4H).

Step 3: Synthesis of 6-cyclopropyl-N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)N⁴-methylpyrimidine-2,4-diamine :

Into a 8-mL sealed tube, was placed 2-chloro-6-cyclopropyl-N-methylpyrimidin-4-amine (80 mg, 0.44 mmol, 1 equiv), 4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]aniline (109 mg, 0.44 mmol, 1 equiv), isopropanol (5 mL), trifluoroacetic acid (100 mg, 0.88 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 90 °C in an oil bath. The resulting solution was extracted with of ethyl acetate and the organic layers combined. The crude product (5mL) was purified by Prep-HPLC C HCl. This resulted in 91.9 mg (49%) of 6-cyclopropyl-N²-(4methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine as a solid.

Example 71: Synthesis of Compound 321

Compound 321: Synthesis of N-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2yl)imidazo [ 1,2-a] pyridin-3-amine

Step 1: Synthesis of N-(diphenylmethylidene)imidazo[l,2-a]pyridin-3-amine:

372

Into a 100-mL 3-necked round-bottom flask, was placed toluene (20 mL), 3-iodoimidazo[l,2a]pyridine (2 g, 8.20 mmol, 1 equiv), diphenylmethanimine (1.5 g, 8.28 mmol, 1.01 equiv), Pd₂(dba)₃CHCl₃ (1.3 g), BINAP (1.5 g, 2.41 mmol, 0.29 equiv), t-BuONa (2.4 g, 24.97 mmol, 3.05 equiv). The resulting solution was stirred for 5 h at 80 °C. The resulting solution was diluted with 10 mL of H₂O. The 3-necked round-bottom flask was purged and maintained with N₂. The resulting solution was extracted with 3x20 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.5 g (62%) of as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.769 min, LCMS 32: m/z = 297 [M+l],

Step 2: Synthesis of imidazo[l,2-a]pyridin-3-amine:

Into a 250-mL round-bottom flask, was placed HC1(2M) (30 mL), N(diphenylmethylidene)imidazo[l,2-a]pyridin-3-amine (1.5 g, 5.04 mmol, 1 equiv). The resulting solution was stirred for 12 h at 20 °C. The resulting solution was extracted with 3x10 mL of dichloromethane and the organic layers combined. The pH value of the solution was adjusted to 10 with sodium hydroxide. The resulting mixture was washed with 3x20 mL of chloromethane2. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 370 mg (55%) of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.290 min, LCMS 40: m/z = 133 [M+l].

Step 3: Synthesis of N-[imidazo[l,2-a]pyridin-3-yl]-5-methoxy-4-[3-(pyrrolidin-lyl)propoxy]pyridin-2-amine:

Into a 40-mL vial, was placed dioxane (20 mL), imidazo[l,2-a]pyridin-3-amine (180 mg, 1.35 mmol, 1 equiv), 2-bromo-5-methoxy-4-[3-(pyrrolidin-l-yl)propoxy]pyridine (469 mg, 1.49 mmol, 1.10 equiv), Pd₂(dba)3-CHC13 (1035 mg), Xantphos (247 mg, 0.43 mmol, 0.32 equiv), Cs₂CO₃ (880 mg, 2.70 mmol, 2.00 equiv). The vial was purged and maintained with N2.The resulting solution was stirred for 12 h at 80 °C. The resulting mixture was concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC C TFA. This resulted in 262.2 mg (40%) of N-[imidazo[l,2-a]pyridin-3-yl]-5-methoxy-4-[3(pyrrolidin-l-yl)propoxy]pyridin-2-amine as a light brown solid.

Example 72: Synthesis of Compound 322

Compound 322: Synthesis of N³-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2yl)-N⁵-methylpyridazine-3,5-diamine

373

Step 1: Synthesis of 6-chloro-N-methylpyridazin-4-amine:

Into a 20-mL sealed tube, was placed 3,5-dichloropyridazine (1 g, 6.71 mmol, 1 equiv), CH₃NH₂-H₂O (2 mL), dioxane (2 mL). The resulting solution was stirred for 2 h at 50 °C in an oil bath. The resulting solution was diluted with 2 mL of methanol. The residue was applied onto a silica gel column with CH₃CN:H2O (1:10). This resulted in 620 mg (64%) of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.62min, LCMS07: m/z = 144.00 [M+l], Step 2: Synthesis of N³-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)-N⁵methylpyridazine-3,5-diamine:

Into a 50-mL round-bottom flask, was placed 6-chloro-N-methylpyridazin-4-amine (300 mg, 2.09 mmol, 1 equiv), trifluoroacetic acid (604 mg, 5.34 mmol, 3.00 equiv), 5-methoxy-4-[3(pyrrolidin-l-yl)propoxy]pyridin-2-amine (526.6 mg, 2.10 mmol, 1 equiv), isopropanol (5 mL). The resulting solution was stirred for 2 h at 85 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC G. This resulted in 83.1 mg (8%) of N³-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)N⁵-methylpyridazine-3,5-diamine as a white solid.

Example 73: Synthesis of Compound 323

Compound 323: Synthesis of N⁵-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2yl)-N³-methylpyridazine-3,5-diamine

3rd-brettphos

Step 1: Synthesis 6-chloropyridazin-4-amine:

Into a 25-mL round-bottom flask, was placed 3,5-dichloropyridazine (1 g, 6.71 mmol, 1 equiv), ammonia (8 mL), dioxane (2 mL). The resulting solution was stirred ovemight at 100

374 °C. The solids were collected by filtration. This resulted in 570 mg (62%) of the title compound as a brown solid.

Analytical Data: LC-MS: (ES, m/z): RT= 0.434 min, LCMS 53, m/z = 130 [M+l], Step 2: Synthesis of 3-N-methylpyridazine-3,5-diamine:

Into a 50-mL round-bottom flask, was placed 6-chloropyridazin-4-amine (570 mg, 4.40 mmol, 1 equiv), dioxane (20 mL), CH3NH2-H2O (4 mL). The resulting solution was stirred ovemight at 140 °C. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC A. This resulted in 320 mg (59%) of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT= 0.187 min, LCMS 45, m/z = 125 [M+l], Step 3: Synthesis of N⁵-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)-N³methylpyridazine-3,5-diamine:

Into a 100-mL round-bottom flask, was placed 3-N-methylpyridazine-3,5-diamine (250 mg, 2.01 mmol, 1 equiv), 2-bromo-5-methoxy-4-[3-(pyrrolidin-l-yl)propoxy]pyridine (628 mg, 15 1.99 mmol, 0.99 equiv), 3rd-Brettphos (181.2 mg), CS2CO3 (1.3 g, 3.99 mmol, 1.98 equiv),

DMSO (25 mL). The resulting solution was stirred for 1 h at 80 °C. The crude product was purified by Prep-HPLC C HCl. This resulted in 31.2 mg (4%) of N⁵-(5-methoxy-4-(3(pyrrolidin-l-yl)propoxy)pyridin-2-yl)-N³-methylpyridazine-3,5-diamine as a light yellow solid.

Example 74: Synthesis of Compound 324

Compound 324: Synthesis of N⁴-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2yl)-N⁶-methylpyrimidine-4,6-diamine

Step 1: Synthesis of 6-chloro-N-methylpyrimidin-4-amine:

Into a 100-mL round-bottom flask, was placed N,N-dimethylformamide (10 mL), 4,6dichloropyrimidine (1 g, 6.71 mmol, 1 equiv), CS2CO3 (4.4 g, 13.50 mmol, 2.01 equiv), methanamine hydrochloride (905 mg, 13.40 mmol, 2.00 equiv). The resulting solution was stirred for 14 h at 80 °C. The resulting solution was diluted with 10 mL of H₂O. The resulting 30 solution was extracted with 4x10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1x10 mL of H2O. The resulting mixture was concentrated

375 under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 750 mg (78%) of as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.476min, LCMS 32: m/z = 144 [M+l].

Step 2: Synthesis of N⁴-(5-methoxy-4-(3-(pynOlidin-l-yl)propoxy)pyridin-2-yl)-N⁶5 methylpyrimidine-4,6-diamine:

Into a 40-mL vial purged and maintained with an inert atmosphère of nitrogen, was placed dioxane (10 mL), 6-chloro-N-methylpyrimidin-4-amine (114 mg, 0.79 mmol, 1 equiv), 5methoxy-4-[3-(pyrrolidin-l-yl)propoxy]pyridin-2-amine (200 mg, 0.80 mmol, 1 equiv), Pd₂(dba)3-CHC13 (123 mg, 0.12 mmol, 0.15 equiv), xantphos (138 mg, 0.24 mmol, 0.30 jo equiv), Cs₂CO₃ (520 mg, 1.60 mmol, 2.01 equiv). The resulting solution was stirred for 14 h at 80 °C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 5 mL of H₂O. The resulting solution was extracted with 3x10 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC D TFA. This resulted in 40.6 mg (11%) of N⁴15 (5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)-N⁶-methylpyrimidine-4,6-diamine as a white solid.

Example 75: Synthesis of Compound 325

Compound 325: Synthesis of N⁴-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-220 yl)-N⁶,2-dimethylpyrimidine-4,6-diamine ci

^nh₂ ^hci

NaBH₃CN,MeOH

Pd₂(dba)3CHCl3,xantphos

Step 1: Synthesis of 6-chloro-N,2-dimethylpyrimidin-4-amine:

Into a 40-mL vial, was placed N,N-dimethylforrnamide (10 mL), 4,6-dichloro-2methylpyrimidine (500 mg, 3.07 mmol, 1 equiv), methanamine hydrochloride (411 mg, 6.09 mmol, 1.98 equiv), Cs₂CO₃ (1.9 g, 5.83 mmol, 1.90 equiv). The resulting solution was stirred for 12 h at 80 °C. The resulting solution was diluted with 10 mL of H2O. The resulting solution was extracted with 3x20 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3x10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 450 mg (93%) of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.763 min, LCMS 07: m/z = 157 [M+l],

376

Step 2: Synthesis of N⁴-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)-N⁶,2dimethylpyrimidine-4,6-diamine:

Into a 20-mL vial, was placed dioxane (10 mL), 6-chloro-N,2-dimethylpyrimidin-4-amine (114 mg, 0.72 mmol, 1 equiv), 5-methoxy-4-[3-(pyrrolidin-l-yl)propoxy]pyridin-2-amine (200 mg, 0.80 mmol, 1.10 equiv), Pd₂(dba)3-CHC13 (112 mg), Xantphos (133 mg, 0.23 mmol, 0.32 equiv), Cs₂CO₃ (472 mg, 1.45 mmol, 2.00 equiv).The vial was purged and maintained with N₂. The resulting solution was stirred for 12 h at 80 °C. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC D TFA. This resulted in 48.8 mg (14%) of N⁴-(5-methoxy-4-(3-(pyrrolidin-lio yl)propoxy)pyridin-2-yl)-N⁶,2-dimethylpyrimidine-4,6-diamine as a white solid.

Example 76: Synthesis of Compound 409

Compound 409: Synthesis of N²-(3-((l-isopropylpyrrolidin-3-yl)methoxy)-4methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine

Compound 409 was synthesized as illustrated above.

Example 77: Synthesis of Compound 326

Compound 326: Synthesis of N-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)20 2-methyI-7H-pyrrolo [2,3-d] pyrimidin-4-amine

Step 1: Synthesis of N-(5-methoxy-4-(3-(pynOlidin-l-yl)propoxy)pyridin-2-yl)-2-methyl7H-pyrrolo[2,3-d]pyrimidin-4-amine:

Into a 40-mL vial purged and maintained with an inert atmosphère of nitrogen, was placed 25 dioxane (10 mL), 5-methoxy-4-[3-(pyrrolidin-l-yl)propoxy]pyridin-2-amine (200 mg, 0.80 mmol, 1 equiv), 4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (133 mg, 0.79 mmol, 1 equiv), Pd₂(dba)3-CHC13 (124 mg, 0.12 mmol, 0.15 equiv), xantphos (138 mg, 0.24 mmol, 0.30 equiv), Cs₂CO₃ (519 mg, 1.59 mmol, 2.00 equiv). The resulting solution was stirred for

377 h at 80 °C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC D TFA. This resulted in 47.2 mg (12%) of N-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)-2-methyl-7Hpyrrolo[2,3-d]pyrimidin-4-amine as a white solid.

Example 78: Synthesis of Compound 328

Compound 328: Synthesis of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

Step 1: Synthesis of 2-chloro-N-methyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine:

Into a 50-mL round-bottom flask, was placed 2,4-dichloro-5H,6H,7Hcyclopenta[d]pyrimidine (850 mg, 4.50 mmol, 1 equiv), potassium carbonate (1.87 g, 13.53 mmol, 3.01 equiv), N,N-dimethylformamide (5 mL), methanamine hydrochloride (303 mg, 4.49 mmol, 1 equiv). The resulting solution was stirred for 1 h at 0 °C. The solids were filtered out. The crude product was purified by Flash-Prep-HPLC A Grad. This resulted in 500 mg (61%) of the title compound as an off white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.856 min, LCMS 45: m/z = 184.0 [M+1].’H NMR (300 MHz, DMSO-d6) δ 8.19 (s, 1H), 2.86 (s, 3H), 2.82 - 2.70 (m, 2H), 2.63 (t, J= 7.5 Hz, 2H), 2.12-1.95 (m, 2H).

Step 2: Synthesis of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴-methyl-6,7dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-chloro-N-methyl-5H,6H,7Hcyclopenta[d]pyrimidin-4-amine (200 mg, 1.09 mmol, 1 equiv), isopropanol (5 mL), trifluoroacetic acid (249 mg, 2.18 mmol, 2.01 equiv), 4-methoxy-3-[3-(pynOlidin-l25 yl)propoxy]aniline (273 mg, 1.09 mmol, 1 equiv). The resulting solution was stirred for 2 h at °C. The crude product was purified by Prep-HPLC A. This resulted in 93.2 mg (20%) of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴-methyl-6,7-dihydro-5Hcyclopenta[d]pyrimidine-2,4-diamine as an off white solid.

Example 79: Synthesis of Compound 331

Compound 331: Synthesis of N²-(3-((lr,3r)-3-((dimethylamino)methyl)cyclobutoxy)-4methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine

378

Step 1 : Synthesis of 3-hydroxy-N,N-dimethylcyclobutane-1 -carboxamide:

Into a 250-mL round-bottom flask, was placed 3-(benzyloxy)-N,N-dimethylcyclobutane-lcarboxamide (3 g, 12.86 mmol, 1 equiv), methanol (100 mL), Pd/C, hydrogen . The resulting 5 solution was stirred for 3 h at 50 °C in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 1.8 g (98%) of the title compound as a yellow oil.

Analytical Data: LC-MS: (ES, m/z)·. RT = 0.56min, LCMS07: m/z =144 [M+l],

Step 2: Synthesis of 3-(dimethylcarbamoyl)cyclobutyl methanesulfonate:

Into a 50-mL round-bottom flask, was placed 3-hydroxy-N,N-dimethylcyclobutane-lcarboxamide (900 mg, 6.29 mmol, 1 equiv), dichloromethane (10 mL), MsCl (2.1 g, 3.00 equiv), TEA (1.9 g, 18.78 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at 20 °C. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3x10 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3x10 mL of H₂O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.5 g (108%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.85min, LCMS07: m/z =222 [M+l],

Step 3: Synthesis of 3-(2-methoxy-5-nitrophenoxy)-N,N-dimethylcyclobutane-l20 carboxamide:

Into a 50-mL round-bottom flask, was placed 3-(dimethylcarbamoyl)cyclobutyl methanesulfonate (1.3 g, 5.88 mmol, 1 equiv), Cs₂CO3 (5.75 g, 17.59 mmol, 3.00 equiv), 2methoxy-5-nitrophenol (994 mg, 5.88 mmol, 1 equiv), N,N-dimethylformamide (10 mL). The resulting solution was stirred for 10 h at 80 °C in an oil bath. The resulting solution was diluted with 10 mL of H₂O. The resulting solution was extracted with 3x10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2x10 mL of H₂O. The resulting mixture was washed with 2x10 mL of sodium chloride(aq). The mixture

379 was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). This resulted in 1.2 g (69%) ofthe title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z)·. RT = 0.82min, LCMS32: m/z =295 [M+l], Step 4: Synthesis of 3-(5-amino-2-methoxyphenoxy)-N,N-dimethylcyclobutane-lcarboxamide:

Into a 250-mL round-bottom flask, was placed 3-(2-methoxy-5-nitrophenoxy)-N,Ndimethylcyclobutane-1-carboxamide (600 mg, 2.04 mmol, 1 equiv), methanol (150 mL), Raney-Ni, hydrogen. The resulting solution was stirred for 1 h at 20 °C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 480 mg (89%) of the title compound as blue green oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.79min, LCMS33: m/z =265 [M+l]. *H NMR (400 MHz, Methanol-d4) δ 6.76 (dd, J= 8.3, 3.8 Hz, 1H), 6.43 - 6.21 (m, 2H), 4.78 - 4.54 (m, 1H), 3.75 (d, J= 8.4 Hz, 3H), 3.55 - 3.47 (m, 1H), 3.06 - 2.92 (m, 6H), 2.77 - 2.64 (m, 2H), 2.50-2.31 (m, 2H).

Step 5: Synthesis of 3-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2yl]amino]phenoxy)-N,N-dimethylcyclobutane-1 -carboxamide:

Into a 50-mL round-bottom flask, was placed 3-(5-amino-2-methoxyphenoxy)-N,Ndimethylcyclobutane-1 -carboxamide (467 mg, 1.77 mmol, 1 equiv), 2-chloro-N,6dimethylpyrimidin-4-amine (277 mg, 1.76 mmol, 1 equiv), IPA (10 mL), trifluoroacetic acid (514.7 mg, 4.55 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at 85 °C in an oil bath. The resulting mixture was concentrated under vacuum. This resulted in 967 mg (>100% crude) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.89min, LCMS07: m/z =386 [M+l], Step 6: Synthesis of N²-(3-((lr,3r)-3-((dimethylamino)methyl)cyclobutoxy)-4methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 3-(2-methoxy-5-[[4-methyl-6(methylamino)pyrimidin-2-yl]amino]phenoxy)-N,N-dimethylcyclobutane-l-carboxamide (200 mg, 0.52 mmol, 1 equiv), oxolane (0 mg), LAH (78.96 mg, 2.08 mmol, 4.00 equiv). The resulting solution was stirred for 2 h at 0 °C in a water/ice bath. The reaction was then quenched by the addition of 200 mg of water/ice. The pH value of the solution was adjusted to 8 with sodium hydroxide(aq) (10 mol/L). The resulting solution was extracted with 20 mL of ethyl acetate and the organic layers combined and dried in an oven under reduced pressure. The solids were filtered out. The crude product (400 mg) was purified by Prep-HPLC C HCl.

380

The crude product (300 mg) was purified by Chiral-Prep-HPLC IC. This resulted in 66.4 mg (34%) ofN²-(3-((lr,3r)-3-((dimethylamino)methyl)cyclobutoxy)-4-methoxyphenyl)-N⁴,6dimethylpyrimidine-2,4-diamine as a white solid.

Example 80: Synthesis of Compound 332

Compound 332: Synthesis of N²-(6-methoxy-5-(3-(pyrrolidin-l-yl)propoxy)pyridin-3yl)-N⁴,6-dimethylpyrimidine-2,4-diamine

Step 1: Synthesis of 5-bromo-2-chloro-3-[3-(pyrrolidin-l-yl)propoxy]pyridine:

io Into a 100-mL round-bottom flask, was placed 5-bromo-2-chloropyridin-3-ol (1.1 g, 5.28 mmol, 1 equiv), Cs₂CO₃ (5.3 g, 16.27 mmol, 3.08 equiv), N,N-dimethylformamide (10 mL), l-(3-chloropropyl)pyrrolidine hydrochloride (1 g, 5.43 mmol, 1.03 equiv). The resulting solution was stirred for 2 h at 80 °C. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.05 g (62%) of as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z); RT = 0.827min, LCMS 45: m/z= 319.00 [M+l]. *HNMR: (300 MHz, Chloroform-d) δ 8.05 (d, J = 2.0 Hz, 1H), 7.41 (d, J= 2.0 Hz, 1H), 4.15 (t, 20 J = 6.3 Hz, 2H), 2.73 - 2.46 (m, 6H), 2.17 - 1.93 (m, 2H), 1.92 - 1.73 (m, 4H).

Step 2: Synthesis of 5-bromo-2-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]pyridine:

Into a 50-mL round-bottom flask, was placed 5-bromo-2-chloro-3-[3-(pyrrolidin-lyl)propoxy]pyridine (1 g, 3.13 mmol, 1 equiv), methanol (10 mL), methoxysodium (849 mg, 15.72 mmol, 5.02 equiv). The resulting solution was stirred for 48 h at 70 °C. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 100 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 910 mg (92%) of as a light yellow liquid.

381

Analytical data: LC-MS: (ES, m/z): RT = 13min, LCMS 31: m/z= 315.35 [M+l], ‘H-NMR: (300 MHz, Chloroform-d) δ 7.77 (d, J= 2.0 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H), 4.12 (t, J = 6.5 Hz, 2H), 3.98 (s, 3H), 2.62 - 2.51 (m, 6H), 2.15 - 2.02 (m, 2H), 1.85 - 1.78 (m, 4H).

Step3: Synthesis of N-[6-methoxy-5-[3-(pyrrolidin-l-yl)propoxy]pyridin-3-yl]acetamide:

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed 5-bromo-2-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]pyridine (870 mg, 2.76 mmol, 1 equiv), Cs₂CO₃ (2.7 g, 8.29 mmol, 3.00 equiv), 3rd-Brettphos (251 mg), dioxane (5 mL), acetamide (245 mg, 4.15 mmol, 1.50 equiv). The resulting solution was stirred for 16 h at 65 °C. The solids were filtered out. The crude product was purified by

Flash-Prep-HPLC A Grad. This resulted in 200 mg (25%) of as a light yellow solid. Analytical Data: LC-MS: (ES, m/z): RT = 0.541min, LCMS45: m/z= 294.10 [M+l], ^lHNMR-PH-EPISOK-350-4: (300 MHz, Deuterium Oxide) δ 7.57 (d, J = 2.1Hz, 1H), 7.33 (d, J= 2.1 Hz, 1H), 4.09 - 3.97 (m, 1H), 3.85 (s, 3H), 3.08 - 2.87 (m, 2H), 2.23 - 1.80 (m, 9H). Step 4: Synthesis of 6-methoxy-5-[3-(pyrrolidin-l-yl)propoxy]pyridin-3-amine:

Into a 100-mL round-bottom flask, was placed N-[6-methoxy-5-[3-(pyrrolidin-l yl)propoxy]pyridin-3-yl]acetamide (180 mg, 0.61 mmol, 1 equiv), potassium hydroxide (172 mg, 3.07 mmol, 5.00 equiv), water (5 mL), methanol (5 mL). The resulting solution was stirred for 16 h at 60 °C. The resulting solution was extracted with 4x50 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 110 mg (71%) of the title compound as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.414min, LCMS53: m/z= 252.20 [M+l], £NMR: (300 MHz, Methanol-d4) δ 7.19 (d, J = 2.4 Hz, 1H), 6.81 (d, J = 2.3 Hz, 1H), 4.15 3.92 (m, 2H), 3.86 (s, 3H), 2.78-2.51 (m, 4H), 2.04 (m, 2H), 1.95 - 1.70 (m, 9H).

Step 5: Synthesis of N²-(6-methoxy-5-(3-(pyrrolidin-l-yl)propoxy)pyridin-3-yl)-N⁴,6dimethylpyrimidine-2,4-diamine:

Into a 25-mL round-bottom flask, was placed 6-methoxy-5-[3-(pyrrolidin-lyl)propoxy]pyridin-3-amine (100 mg, 0.40 mmol, 1 equiv), isopropanol (5 mL), trifluoroacetic acid (91 mg, 0.80 mmol, 2.01 equiv), 2-chloro-N,6-dimethylpyrimidin-430 amine (63 mg, 0.40 mmol, 1 equiv). The resulting solution was stirred for 2 h at 80 °C. The crude product was purified by Prep-HPLC C HCl. This resulted in 71 mg (44%) of N²-(6methoxy-5-(3-(pyrrolidin-l-yl)propoxy)pyridin-3-yl)-N⁴,6-dimethylpyrimidine-2,4-diamine as an off-white solid.

382

Example 81: Synthesis of Compound 334

Compound 334: Synthesis of N²-(3-((l-ethylazetidin-3-yl)methoxy)-4-methoxyphenyl)N⁴,6-dimethylpyrimidine-2,4-diamine

Step 1: Synthesis ofN²-(3-((l-ethylazetidin-3-yl)methoxy)-4-methoxyphenyl)-N⁴,6dimethylpyrimidine-2,4-diamine:

Into a 100-mL round-bottom flask, was placed 2-N-[3-(azetidin-3-ylmethoxy)-4methoxyphenyl]-4-N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.91 mmol, 1 equiv), acetaldehyde (32.1 mg, 0.73 mmol, 0.80 equiv), methanol (15 mL), NaBH₃CN (344.68 mg, 10 5.49 mmol, 6.00 equiv), HOAC (0.002 mL). The resulting solution was stirred for 20 min at °C. The resulting solution was allowed to react, with stirring, for an additional 2 h at 25 °C. The resulting mixture was concentrated under vacuum. The crude product was purified by

Prep-HPLC D TFA. This resulted in 32.4 mg (8%) of N²-(3-((l-ethylazetidin-3-yl)methoxy)4-methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine as a white solid.

Example 82: Synthesis of Compound 335

Compound 335: Synthesis of N-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridine-2yl)-1 H-pyrrolo [2,3-b] pyridin-4-amine

Step 1: Synthesis of N-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)-lHpyrrolo[2,3-b]pyridin-4-amine:

Into a 50-mL round-bottom flask, was placed 5-methoxy-4-[3-(pyrrolidin-lyl)propoxy]pyridin-2-amine (128 mg, 0.51 mmol, 1 equiv), 4-bromo-lH-pyrrolo[2,3b]pyridine (100 mg, 0.51 mmol, 1 equiv), Cs₂CO₃ (496 mg, 1.52 mmol, 3.00 equiv), 25 Pd₂(dba)₃-CHC1₃ (50 mg), X-phos (50 mg), 1,4-dioxane (10 mL). The resulting solution was stirred for 4 h at 100 °C. The crude product was purified by Flash-Prep A 1:1. This resulted in 35.8 mg (15%) of N-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)-lH-pyrrolo[2,3b]pyridin-4-amine as a white solid.

383

Example 83: Synthesis of Compound 336

Compound 336: Synthesis of N-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)6-methyl-l H-pyrrolo [2,3-b] pyridin-4-amine

Step 1: Synthesis of N-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)-6-methyl1 H-pyrrolo[2,3 -b]pyridin-4-amine:

Into a 50-mL round-bottom flask, was placed 4-chloro-6-methyl-lH-pyrrolo[2,3-b]pyridine (150 mg, 0.90 mmol, 1 equiv), 5-methoxy-4-[3-(pynOlidin-l-yl)propoxy]pyridin-2-amine (228 mg, 0.91 mmol, 1 equiv), Cs₂CO₃ (884 mg, 2.71 mmol, 3.00 equiv), Pd₂(dba)₃-CHC1₃ (50 mg), X-phos (50 mg), 1,4-dioxane (10 mL). The resulting solution was stirred for 4 h at 100 °C. The crude product was purified by Flash-Prep-HPLC A 1:1. This resulted in 35.9 mg (9.5%) ofN-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)-6-methyl-lHpyrrolo[2,3-b]pyridin-4-amine as a light yellow solid.

Example 84: Synthesis of Compound 388

Compound 388: Synthesis of N²-(l-(3-(dimethylamino)propyl)-lH-indazol-6-yl)-N⁴-

Step 1: Synthesis of dimethyl[3-(6-nitro-2H-indazol-2-yl)propyl]amine:

Into a 40-mL vial, was placed N,N-dimethylformamide (20 mL), 6-nitro-lH-indazole (1 g, 6.13 mmol, 1 equiv), (3-chloropropyl)dimethylamine hydrochloride (963 mg, 6.09 mmol, 0.99 equiv), Cs₂CO₃ (4 g, 12.28 mmol, 2.00 equiv), ΚΙ (1 g). The resulting solution was stirred for 12 h at 60 °C. The resulting solution was diluted with 20 mL of H2O. The resulting

384 solution was extracted with 3x20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x20 mL of water and 3x20 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (50:l). This resulted in 200 mg (13%) of the title compound 5 as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT =0.861 min, LCMS 07: m/z = 249 [M+l].

Step 2: Synthesis of 2-[3-(dimethylamino)propyl]-2H-indazol-6-amine:

Into a 100-mL round-bottom flask, was placed methanol (30 mL), Raney-Ni (40 mg), dimethyl[3-(6-nitro-2H-indazol-2-yl)propyl]amine (200 mg, 0.81 mmol, 1 equiv), hydrogen. /0 The resulting solution was stirred for 2 h at 20 °C. The solids were filtered out. The flask was purged and maintained with H₂.The resulting mixture was concentrated under vacuum. This resulted in 190 mg (108%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT =0.322 min, LCMS 33: m/z = 219 [M+l],

Step 3 : Synthesis of N²-( 1 -(3 -(dimethylamino)propyl)-1 H-indazol-6-yl)-N⁴15 methylpyrimidine-2,4-diamine:

Into a 20-mL vial, was placed isopropanol (2 mL), 2-[3-(dimethylamino)propyl]-2H-indazol6-amine (150 mg, 0.69 mmol, 1 equiv), 2-chloro-N-methylpyrimidin-4-amine (109 mg, 0.76 mmol, 1.10 equiv), PTSA (118 mg, 0.69 mmol, 1 equiv). The resulting solution was stirred for 12 h at 80 °C. The resulting mixture was concentrated under vacuum. The crude product 20 (100 mg) was purified by Prep-HPLC G. This resulted in 35.1 mg (14%) of N²-(l-(3(dimethylamino)propyl)-lH-indazol-6-yl)-N⁴-methylpyrimidine-2,4-diamine as a yellow solid.

Example 85: Synthesis of Compound 404

Compound 404: Synthesis of N²-(2-(2-(dimethylamino)ethyl)-2H-indazoI-6-yI)-N⁴methylpyrimidine-2,4-diamine

HN'

CRN

TFA,i-PrOH

ci^^^HCI

Cs₂CO₃,DMF,Nal

Step 1: Synthesis of dimethyl[2-(6-nitro-2H-indazol-2-yl)ethyl]amine:

385

Into a 100-mL round-bottom flask, was placed 6-nitro-lH-indazole (1 g, 6.13 mmol, 1 equiv), N,N-dimethylformamide (10 mL), Cs₂CO₃ (8 g, 24.48 mmol, 3.99 equiv), iodosodium (920 mg, 6.14 mmol, 1 equiv). Reaction 30 min at RT. And then added (2chloroethyl)dimethylamine hydrochloride (1.75 g, 12.15 mmol, 1.98 equiv). The resulting solution was stirred for 16 h at 60 °C. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 480 mg (33%) of the title compound as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.629min, LCMS45: m/z= 235.10 [M+l].

Step 2: Synthesis of 2-[2-(dimethylamino)ethyl]-2H-indazol-6-amine:

Into a 100-mL round-bottom flask purged and maintained with H₂, was placed dimethyl[2-(6nitro-2H-indazol-2-yl)ethyl]amine (480 mg, 2.05 mmol, 1 equiv), Raney-Ni (50 mg), methanol (10 mL). The resulting solution was stirred for 2 h at RT. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 380 mg (91 %) of the title compound as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.373min, LCMS31: m/z= 205.48 [M+l]. Step 3: Synthesis of N²-(2-(2-(dimethylamino)ethyl)-2H-indazol-6-yl)-N⁴methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-[2-(dimethylamino)ethyl]-2H-indazol-6amine (370 mg, 1.81 mmol, 1 equiv), isopropanol (5 mL), trifluoroacetic acid (414 mg, 3.63 mmol, 2.00 equiv), 2-chloro-N-methylpyrimidin-4-amine (259 mg, 1.80 mmol, 1 equiv). The resulting solution was stirred for 2 h at 80 °C. The crude product was purified by Prep-HPLC F HCl. This resulted in 73 mg (12%) of N²-(2-(2-(dimethylamino)ethyl)-2H-indazol-6-yl)25 N⁴-methylpyrimidine-2,4-diamine as a light yellow solid.

Example 86: Synthesis of Compound 407

Compound 407: Synthesis of N²-(4-methoxy-3-(((l-methylpyrrolidin-3yl)oxy)methyl)phenyl)-N⁴-methylpyrimidine-2,4-diamine

386

Step 1: Synthesis of 3-[(2-methoxy-5-nitrophenyl)methoxy]-l-methylpyrrolidine:

Into a 250-mL round-bottom flask, was placed l-methylpyrrolidin-3-ol (900 mg, 8.90 mmol, 1.10 equiv), N,N-dimethylformamide (30 mL). This was followed by the addition of sodium hydride (1.96 g, 81.67 mmol, 6.00 equiv) in several batches at 0 °C. 60%.The resulting solution was stirred for 30 min at 0 °C in a water/ice bath. To this was added 2(bromomethyl)-l-methoxy-4-nitrobenzene (2 g, 8.13 mmol, 1 equiv). The resulting solution was allowed to react, with stirring, for an additional 2 h while the température was maintained at 20 °C in an oil bath. The reaction was then quenched by the addition of 60 mL of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined and dried in an oven under reduced pressure. This resulted in 740 mg (34%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.923 min, LCMS34: m/z = 267.2 [M+l], *H NMR (300 MHz, Methanol-^) δ 8.36 - 8.14 (m, 2H), 7.17 - 7.07 (m, 1H), 4.63 - 4.47 (m, 2H),

3.99 (d, J= 1.2 Hz, 3H), 2.85-2.70 (m, 2H), 2.58-2.36 (m, 5H), 2.31 -2.12 (m, 2H), 2.09

-1.90 (m, 1H).

Step 2: Synthesis of 4-methoxy-3-[[(l-methylpyrrolidin-3-yl)oxy]methyl]aniline:

Into a 50-mL round-bottom flask, was placed 3-[(2-methoxy-5-nitrophenyl)methoxy]-lmethylpyrrolidine (700 mg, 2.63 mmol, 1 equiv), Fe (735.0 mg, 13.12 mmol, 5.00 equiv),

NH4CI (714 mg, 13.35 mmol, 5.00 equiv), water(3 mL), éthanol (10 mL). The resulting solution was stirred for 2 h at 80 °C in an oil bath. The solids were fïltered out. The crude product was purified by Flash-Prep-HPLC A. This resulted in 1.5 g (crude) of the title compound as a crude solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.687 min, LCMS53: m/z = 237.2 [M+l],

Step 3: Synthesis of N -(4-methoxy-3-(((l-methylpyrrolidin-3-yl)oxy)methyl)phenyl)-N methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 4-methoxy-3-[[(l-methylpyrrolidin-3yl)oxy]methyl]aniline (200 mg, 0.85 mmol, 1 equiv), 2-chloro-N-methylpyrimidin-4-amine

387 (121.2 mg, 0.84 mmol, 1 equiv), isopropanol (5 mL), trifluoroacetic acid (193.2 mg, 1.71 mmol, 2.00 equiv). The resulting solution was stirred for 12 h at 85 °C in an oil bath. The crude product was purified by Prep-HPLC C HCl. This resulted in 49.0 mg (15%) of N²-(4methoxy-3-(((l-methylpyrrolidin-3-yl)oxy)methyl)phenyl)-N⁴-methylpyrimidine-2,4-diamine as an oil.

Example 87: Synthesis of Compound 408

Compound 408: Synthesis of N²-(3-((l-ethylpyrrolidin-3-yl)methoxy)-4methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine

4

Step 1: Synthesis of N -(3-(( l-ethylpyrrolidin-3-yl)methoxy)-4-methoxyphenyl)-N methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-N-[4-methoxy-3-(pyrrolidin-3ylmethoxy)phenyl]-4-N-methylpyrimidine-2,4-diamine (200 mg, 0.61 mmol, 1 equiv), methanol (10 mL), NaBH₃CN (114.9 mg, 1.83 mmol, 3.00 equiv), acetaldehyde (26.7 mg, 0.61 mmol, 1 equiv). The resulting solution was stirred for 2 h at 20 °C. The reaction was then quenched by the addition of water/ice. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC C TFA. This resulted in 29 mg (12%) of N²-(3-((l-ethylpyrrolidin-3-yl)methoxy)-4-methoxyphenyl)-N⁴methyIpyrimidine-2,4-diamine as a white solid.

Example 88: Synthesis of Compound 410

Compound 410: Synthesis ofN -(4-methoxy-3-((l-(2-methoxyethyl)pyrrolidin-3yl)methoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine

Step 1: Synthesis of N -(4-methoxy-3-((l-(2-methoxyethyl)pyrrolidin-3yl)methoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine:

Into a 30-mL sealed tube, was placed 2-N-[4-methoxy-3-(pyrrolidin-3-ylmethoxy)phenyl]-4N-methylpyrimidine-2,4-diamine (200 mg, 0.61 mmol, 1 equiv), N,N-dimethylformamide (10 mL), potassium carbonate (252 mg, 1.82 mmol, 3.00 equiv), 1 -bromo-2-methoxyethane

388 (101 mg, 0.73 mmol, 1.20 equiv). The resulting solution was stirred for 12 h at 50 °C in an oil bath. The crude product was purified by Prep-HPLC C TFA. This resulted in 60.9 mg (20%) of N²-(4-methoxy-3 -(( 1 -(2-methoxyethyl)pyrrolidin-3 -yl)methoxy)phenyl)-N⁴methylpyrimidine-2,4-diamine as a white solid.

Example 89: Synthesis of Compound 411

Compound 411: Synthesis of N²-(3-((l-cyclopropylpyrroIidin-3-yl)methoxy)-4methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine

Step 1: Synthesis of N²-(3-((l-cyclopropylpyrrolidin-3-yl)methoxy)-4-methoxyphenyl)-N⁴ methylpyrimidine-2,4-diamine:

Into a 25-mL round-bottom flask, was placed 2-N-[4-methoxy-3-(pyrrolidin-3ylmethoxy)phenyl]-4-N-methylpyrimidine-2,4-diamine (250 mg, 0.76 mmol, 1 equiv), methanol (10 mL), (l-ethoxycyclopropoxy)trimethylsilane (200 mg, 1.15 mmol, 1.50 equiv), NaBH₃CN (144 mg, 2.29 mmol, 3.00 equiv), AcOH (0.2 mL). The resulting solution was stirred for 16 h at 65 °C in an oil bath. The reaction was then quenched by the addition of water. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC C TFA. This resulted in 95.3 mg (26%) of N²-(3-((l-cyclopropylpyrrolidin-3yl)methoxy)-4-methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine as a white solid.

Example 90: Synthesis of Compound 412

Compound 412: Synthesis of N²-(4-methoxy-3-((l-methylpiperidin-3yl)methoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine

TsOH,i-PrOH

Step 1: Synthesis of (l-methylpiperidin-3-yl)methyl methanesulfonate:

389

Into a 100-mL round-bottom flask, was placed (l-methylpiperidin-3-yl)methanol (1 g, 7.74 mmol, 1 equiv), dichloromethane (20 mL), TEA (2.349 g, 23.21 mmol, 3.00 equiv), MsCl (1.326 g, 11.63 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 20 °C. The resulting mixture was concentrated under vacuum. This resulted in 1.6 g (100%) of the title 5 compound as a yellow solid.

Step 2: Synthesis of 3-(2-methoxy-5-nitrophenoxymethyl)-l-methylpiperidine:

Into a 50-mL round-bottom flask, was placed 2-methoxy-5-nitrophenol (1.09 g, 6.44 mmol, 1 equiv), (l-methylpiperidin-3-yl)methyl methanesulfonate (1.6 g, 7.72 mmol, 1.20 equiv), Cs₂CO₃ (4.21 g, 12.92 mmol, 2.00 equiv), N,N-dimethylformamide (10 mL). The resulting 10 solution was stirred for 24 h at 90 °C in an oil bath. The resulting solution was extracted with

3x50 mL of ethyl acetate and the organic layers combined. The crude product was purified by Flash-Prep-HPLC A Grad. This resulted in 900 mg (50%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.901 min, LCMS07: m/z = 281.15 [M+l]. H NMR (300 MHz, Methanol-i/4) δ 7.96 - 7.92 (m, 1H), 7.80 (d, J = 2.7 Hz, 1H), 7.13 (d, J= 15 9.0 Hz, 1H), 4.08-3.88 (m, 5H), 3.11 -3.07 (m, 1H), 2.89-2.85 (m, 1H), 2.33 (s, 3H), 2.26

- 1.49 (m, 6H), 1.29- 1.14 (m, 1H).

Step 3: Synthesis of 4-methoxy-3-[(l-methylpiperidin-3-yl)methoxy]aniline:

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphère of H₂, was placed 3-(2-methoxy-5-nitrophenoxymethyl)-l-methylpiperidine (900 mg, 3.21 mmol, 1 20 equiv), methanol (20 mL), Pd/C (300 mg). The resulting solution was stirred for 2 h at 20 °C.

The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 800 mg (100%) of as dark red oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.149 min, LCMS48: m/z = 281.2 [M+l].

Step 4: Synthesis of N²-(4-methoxy-3-((l-methylpiperidin-3-yl)methoxy)phenyl)-N⁴25 methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 4-methoxy-3-[(l-methylpiperidin-3yl)methoxy]aniline (300 mg, 1.20 mmol, 1 equiv), 2-chloro-N-methylpyrimidin-4-amine (170.9 mg, 1.19 mmol, 1 equiv), isopropanol (5 mL), trifluoroacetic acid (272.5 mg, 2.41 mmol, 2.00 equiv). The resulting solution was stirred for 12 h at 85 °C in an oil bath. The 30 crude product was purified by Prep-HPLC C HCl. This resulted in 93.5 mg (20%) of N²-(4methoxy-3-((l-methylpiperidin-3-yl)methoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine as an off-white solid.

Example 91: Synthesis of Compound 413

390

Compound 413: Synthesis of N²-(4-methoxy-3-((l-methylpiperidin-3yl)methoxy)phenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine

Step 1: Synthesis of N²-(4-methoxy-3-((l-methylpiperidin-3-yl)methoxy)phenyl)-N⁴,65 dimethylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 4-methoxy-3-[(l-methylpiperidin-3yl)methoxy]aniline (300 mg, 1.20 mmol, 1 equiv), 2-chloro-N,6-dimethylpyrimidin-4-amine (187.6 mg, 1.19 mmol, 1 equiv), isopropanol (5 mL), trifluoroacetic acid (272.5 mg, 2.41 mmol, 2.00 equiv). The resulting solution was stirred for 12 h at 85 °C in an oil bath. The crude product was purified by Prep-HPLC G NH4HCO3. This resulted in 43.1 mg (10%) of N²-(4-methoxy-3-((l-methylpiperidin-3-yl)methoxy)phenyl)-N⁴,6-dimethylpyrimidine-2,4diamine as an off-white solid.

Example 92: Synthesis of Compound 414

Compound 414: Synthesis of l-(3-(2-methoxy-5-((4-(methylamino)pyrimidin-2yl)amino)phenoxy)propyl)azetidin-3-ol

HlA HCl HlA

Step 1: Synthesis of l-(3-(2-methoxy-5-((4-(methylamino)pyrimidin-2yl)amino)phenoxy)propyl)azetidin-3-ol:

Into a 50-mL round-bottom flask, was placed 2-N-[3-(3-chloropropoxy)-4-methoxyphenyl]4-N-methylpyrimidine-2,4-diamine (200 mg, 0.62 mmol, 1 equiv), Nal (93 mg), potassium carbonate (514 mg, 3.72 mmol, 6.00 equiv), ACN (10 mL), azetidin-3-ol hydrochloride (203 mg, 1.85 mmol, 2.99 equiv). The resulting solution was stirred for 16 h at 80 °C. The solids were filtered out. The crude product was purified by Prep-HPLC C HCl. This resulted in 59.3 mg (24%) of l-(3-(2-methoxy-5-((4-(methylamino)pyrimidin-2yl)amino)phenoxy)propyl)azetidin-3-ol as a light yellow solid.

Example 93: Synthesis of Compounds 415 and 416

391

Compound 415 and 416: Synthesis of (S)-N²-(4-methoxy-3-((l-methylpyrrolidin-3yl)methoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine and (R)-N²-(4-methoxy-3-((lmethylpyrrolidin-3-yl)methoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine

Step 1: Synthesis of (l-methylpyrrolidin-3-yl)methyl methanesulfonate:

Into a 100-mL round-bottom flask, was placed (l-methylpyrrolidin-3-yl)methanol (1.5 g, 13.02 mmol, 1 equiv), TEA (4.0 g, 39.53 mmol, 3.00 equiv), dichloromethane (15 mL), methanesulfonyl chloride (2.23 mg, 0.02 mmol, 1.5 equiv). The resulting solution was stirred for 3 h at 25 °C. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 15 mL of dichloromethane and the organic layers combined and concentrated under vacuum. This resulted in 1.78 g (crude) of the title compound as a brown solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.34 min, LCMS 33: m/z = 194.0 [M+l].

Step 2: Synthesis of 3-(2-methoxy-5-nitrophenoxymethyl)-l-methylpyrrolidine:

Into a 100-mL round-bottom flask, was placed (l-methylpyrrolidin-3-yl)methyl methanesulfonate (1.78 g, 9.21 mmol, 1 equiv), CS2CO3 (9 g, 27.62 mmol, 3.00 equiv), 2methoxy-5-nitrophenol (2.3 g, 13.60 mmol, 1.5 equiv), N,N-dimethylformamide (40 mL). The resulting solution was stirred for 2 h at 80 °C in an oil bath. The resulting solution was extracted with 3x40 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2x30 mL of sodium chloride. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). This resulted in 1.46 g (58%) of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.89 min, LCMS 07: m/z = 267.0 [M+l]. ^[H NMR (300 MHz, Methanol-^) δ 7.93 (q, J= 2.7 Hz, 1H), 7.80 (d, J= 2.7 Hz, 1H), 7.12 (d, J= 9.0 25 Hz, 1H), 4.11 - 3.99 (m, 2H), 3.97 (s, 3H), 2.94 - 2.64 (m, 4H), 2.56 (q, J= 9.4 Hz, 1H), 2.43 (s, 3H), 2.23 -2.02 (m, 1 H), 1.72 - 1.69 (m, 1 H).

Step 3: Synthesis of 4-methoxy-3-[(l-methylpyrrolidin-3-yl)methoxy]aniline:

Into a 100-mL round-bottom flask, was placed 3-(2-methoxy-5-nitrophenoxymethyl)-lmethylpyrrolidine (1.46 g, 5.48 mmol, 1 equiv), Raney-Ni (300 mg), methanol (25 mL). The

392 resulting solution was stirred for 1 h at 25 °C. The solids were fdtered out. The resulting mixture was concentrated under vacuum. This resulted in 630 mg (42%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z)·. RT = 0.60 min, LCMS 07: m/z = 237.0 [M+l], 5 Step 4: Synthesis of (S)-N²-(4-methoxy-3-((l-methylpyrrolidin-3-yl)methoxy)phenyl)-N⁴methylpyrimidine-2,4-diamine (El) and (R)-N²-(4-methoxy-3-((l-methylpyrrolidin-3yl)methoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine (E2):

Into a 100-mL round-bottom flask, was placed 4-methoxy-3-[(l-methylpyrrolidin-3yl)methoxy]aniline (300 mg, 1.27 mmol, 1 equiv), trifluoroacetic acid (290 mg, 2.57 mmol, io 2.00 equiv, 98%), 2-chloro-N-methylpyrimidin-4-amine (182 mg, 1.27 mmol, 1 equiv), isopropanol (15 mL). The resulting solution was stirred for 3 h at 90 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was applied onto a silica gel column with NH₄HCO₃:ACN (1:1), Detector, UV 254 nm. This resulted in 23 mg (5%) of (S)-N²-(4-methoxy-3-((l -methylpyrrolidin-3-yl)methoxy)phenyl)-N⁴15 methylpyrimidine-2,4-diamine El (arbitrarily assigned, S) and 22.7 mg (5%) of (R)-N -(4methoxy-3-((l-methylpyrrolidin-3-yl)methoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine E2 (arbitrarily assigned, R) as a white solid.

Example 94: Synthesis of Compounds 417 and 418

Compound 417 and 418: Synthesis of (S)-N²-(4-methoxy-3-((l-methylpyrrolidin-3yl)methoxy)phenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine and (R)-N²-(4-methoxy-3-((lmethylpyrrolidin-3-yl)methoxy)phenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine

Step 1: Synthesis of (S)-N -(4-methoxy-3-((l-methylpyrrolidin-3-yl)methoxy)phenyl)-N ,625 dimethylpyrimidine-2,4-diamine (El) and (R)-N²-(4-methoxy-3-((l-methylpyrrolidin-3yl)methoxy)phenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine (E2):

Into a 100-mL round-bottom flask, was placed 4-methoxy-3-[(l-methylpyrrolidin-3yl)methoxy]aniline (300 mg, 1.27 mmol, 1 equiv), 2-chloro-N,6-dimethylpyrimidin-4-amine (200 mg, 1.27 mmol, 1 equiv), trifluoroacetic acid (290 mg, 2.57 mmol, 2.00 equiv, 98%), 30 isopropanol (15 mL). The resulting solution was stirred for 3 h at 90 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (300 mg) was applied onto a silica gel column with NH₄HCO₃:ACN (1:1),Detector, UV 254 nm. This resulted in

393

82.4 mg (18%) of (S)-N²-(4-methoxy-3-((l-methylpyrrolidiii-3-yl)mcthoxy)phenyl)-N⁴,6dimethylpyrimidine-2,4-diamine El (arbitrarily assigned, S) as a white solid. And 49.6 mg ( 11 %) of (R)-N²-(4-methoxy-3 -((1 -methylpyrrolidin-3 -yl)methoxy)phenyl)-N⁴,6dimethylpyrimidine-2,4-diamine El (arbitrarily assigned, R) as a white solid.

Example 95: Synthesis of Compound 419

Compound 419: Synthesis of N²-(3-(((l-ethylpyrrolidin-3-yl)oxy)methyl)-4methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine

io Step 1: Synthesis of tert-butyl 3-(5-amino-2-methoxyphenoxymethyl)pyrrolidine-lcarboxylate:

Into a 250-mL round-bottom flask, was placed tert-butyl 3-(2-methoxy-5nitrophenoxymethyl)pyrrolidine-l-carboxylate (600 mg, 1.70 mmol, 1 equiv), methanol (50 mL), Raney-Ni, hydrogen. The resulting solution was stirred for 1 h at 20 °C. The solids were 15 filtered out. The resulting mixture was concentrated under vacuum. This resulted in 496 mg (90%) of as a solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.76min, LCMS33: m/z = 322 [M+l]. *H NMR (300 MHz, Methanol-d4) δ 6.77 (d, J = 8.5 Hz, 1H), 6.47 (d, J= 2.6 Hz, 1H), 6.33 (dd, J= 8.5, 2.5 Hz, 1H), 4.02 - 3.85 (m, 2H), 3.76 (s, 3H), 3.63 - 3.48 (m, 2H), 3.26 (dd, J = 20.0, 20 11.5 Hz, 2H), 2.77-2.66 (m, 1H), 2.10 (d, J= 10.7 Hz, 1H), 1.85 (dd, J= 13.9, 6.7 Hz, 1H),

1.48 (s, 9H).

Step 2: Synthesis of tert-butyl 3-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2yl]amino]phenoxymethyl)pyrrolidine-l-carboxylate:

Into a 100-mL round-bottom flask, was placed tert-butyl 3-(5-amino-225 methoxyphenoxymethyl)pyrrolidine-1-carboxylate (496 mg, 1.54 mmol, 1 equiv), 2-chloroN,6-dimethylpyrimidin-4-amine (242 mg, 1.54 mmol, 1 equiv), trifluoroacetic acid (445 mg, 3.94 mmol, 3.00 equiv), isopropanol (10 mL). The resulting solution was stirred for 2 h at 85 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was

394 applied onto a silica gel column with CH₃CN/H₂O (1:5). This resulted in 560 mg (82%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.15min, LCMS28: m/z = 444 [M+l]. ‘H NMR (300 MHz, Methanol-d4) δ 7.29 (s, 1H), 7.13 - 6.99 (m, 2H), 5.99 (d, J = 1.2 Hz, 1H), 5.51 (s, 1H), 4.02 (q, J= 8.0, 6.8 Hz, 2H), 3.87 (s, 3H), 3.68 - 3.38 (m, 3H), 3.00 (s, 3H), 2.73 (s, 1H), 2.29 (s, 3H), 2.12 (s, 1H), 1.86 (s, 1H), 1.48 (s, 9H).

Step 3: Synthesis of 2-N-[4-methoxy-3-(pyrrolidin-3-ylmethoxy)phenyl]-4-N,6dimethylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed tert-butyl 3-(2-methoxy-5-[[4-methyl-6(methylamino)pyrimidin-2-yl]amino]phenoxymethyl)pyrrolidine-l-carboxylate (560 mg, 1.26 mmol, 1 equiv), trifluoroacetic acid (364 mg, 3.22 mmol, 3.00 equiv), dichloromethane (10 mL). The resulting solution was stirred for 3 h at 20 °C. The resulting mixture was concentrated under vacuum. TEA was employed to adjust the pH to 8. The resulting mixture was concentrated under vacuum. This resulted in 900 mg (>100%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.78min, LCMS07: m/z = 344 [M+l]. *H NMR (300 MHz, Methanol-d4) δ 7.28 (d, J= 2.5 Hz, 1H), 7.19 (dd, J= 8.7, 2.5 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 5.99 (d, J = 1.1 Hz, 1H), 4.19-4.04 (m, 2H), 3.88 (s, 3H), 3.71-3.47 (m, 3H), 3.01 (s, 5H), 2.37 - 2.22 (m, 4H), 2.12-1.94 (m, 1H).

Step 4: Synthesis of N²-(3-(((l-ethylpyrrolidin-3-yl)oxy)methyl)-4-methoxyphenyl)-N⁴,6dimethylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-N-[4-methoxy-3-(pyrrolidin-3ylmethoxy)phenyl]-4-N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.87 mmol, 1 equiv), NaBH₃CN (165.3 mg, 2.63 mmol, 3.00 equiv), acetaldehyde (38.5 mg, 0.87 mmol, 1 equiv), methanol (10 mL). The resulting solution was stirred for 2 h at 20 °C. The reaction was then quenched by the addition of water/ice. The resulting mixture was concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC C HCl. This resulted in 77.6 mg (22%) of N²-(3-(((l-ethylpyrrolidin-3-yl)oxy)methyl)-4-methoxyphenyl)-N⁴,6dimethylpyrimidine-2,4-diamine as a white solid.

Example 96: Synthesis of Compound 420

Compound 420: Synthesis of N²-(4-methoxy-3-((l-propylpyrrolidin-3yl)methoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine

395

Step 1: Synthesis of N²-(4-methoxy-3-((l-propylpyrrolidin-3-yl)methoxy)phenyl)-N⁴methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-N-[4-methoxy-3-(pyrrolidin-35 ylmethoxy)phenyl]-4-N-methylpyrimidine-2,4-diamine (300 mg, 0.91 mmol, 1 equiv), propanai (60 mg, 1.03 mmol, 1.10 equiv), methanol (15 mL), NaBH₃CN (172 mg, 2.74 mmol, 3.00 equiv), AcOH (0.2 mL). The resulting solution was stirred for 2 h at 25 °C. The reaction was then quenched by the addition of water. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC C TFA. This resulted in 144.6 io mg (33%) of N²-(4-methoxy-3-((l-propylpyrrolidin-3-yl)methoxy)phenyl)-N⁴methylpyrimidine-2,4-diamine as an off-white solid.

Example 97: Synthesis of Compound 421

Compound 421: Synthesis of N²-(4-methoxy-3-(((l-methylpyrrolidin-315 yl)oxy)methyl)phenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine

Step 1: Synthesis of N²-(4-methoxy-3-(((l-methylpyrrolidin-3-yl)oxy)methyl)phenyl)-N⁴,6dimethylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 4-methoxy-3-[[(l-methylpyrrolidin-320 yl)oxy]methyl]aniline (200 mg, 0.85 mmol, 1 equiv), 2-chloro-N,6-dimethylpyrimidin-4amine (133.0 mg, 0.84 mmol, 1 equiv), isopropanol (5 mL), trifluoroacetic acid (193.2 mg, 1.71 mmol, 2.00 equiv). The resulting solution was stirred for 12 h at 85 °C in an oil bath. The crude product was purified by Prep-HPLC G NH4HCO3. This resulted in 54.2 mg (18%)

Λ 4 of N -(4-methoxy-3-(((l-methylpyrrolidin-3-yl)oxy)methyl)phenyl)-N ,625 dimethylpyrimidine-2,4-diamine as an off-white solid.

Example 98: Synthesis of Compound 422

Compound 422: Synthesis of N²-(3-((l-(cyclopropylmethyl)pyrroIidin-3-yI)methoxy)-4methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine

396

Step 1: Synthesis of N²-(3-((l-(cyclopropylmethyl)pyrrolidin-3-yl)methoxy)-4methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-N-[4-methoxy-3-(pyrrolidin-35 ylmethoxy)phenyl]-4-N-methylpyrimidine-2,4-diamine (200 mg, 0.61 mmol, 1 equiv), cyclopropanecarbaldehyde (64 mg, 0.91 mmol, 1.50 equiv), methanol (10 mL). After 10 min, added NaBH₃CN (191 mg, 3.04 mmol, 5.01 equiv). The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of water. The crude product was purified by Prep-HPLC C HCl. This resulted in 66.4 mg (26%) of N²-(3-((l10 (cyclopropylmethyl)pyrrolidin-3-yl)methoxy)-4-methoxyphenyl)-N⁴-methylpyrimidine-2,4diamine as an off-white solid.

Example 99: Synthesis of Compound 423

Compound 423: Synthesis of N²-(4-methoxy-3-(3-(3-methylazetidin-l/5 yl)propoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine

4

Step 1: Synthesis of N -(4-methoxy-3-(3-(3-methylazetidin-l-yl)propoxy)phenyl)-N methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-N-[3-(3-chloropropoxy)-4-methoxyphenyl]20 4-N-methylpyrimidine-2,4-diamine (200 mg, 0.62 mmol, 1 equiv), potassium methaneperoxoate (257.1 mg, 1.85 mmol, 3.00 equiv), acetonitrile (10 mL), 3methylazetidine hydrochloride (132.9 mg, 1.24 mmol, 2.00 equiv), iodosodium (93.2 mg, 0.62 mmol, 1 equiv). The resulting solution was stirred for 12 h at 85 °C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC C TFA. This resulted in 75.3 mg (26%) of N²-(4-methoxy3-(3-(3-methylazetidin-l-yl)propoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine as a white solid.

Example 100: Synthesis of Compound 424

397

Compound 424: Synthesis of N²-(3-(3-((cyclopropylmethyl)(methyl)amino) propoxy)-4methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine

V HCl H

K₂CO₃,Nal

Step 1: Synthesis of N²-(3-(3-((cyclopropylmethyl)(methyl)amino)propoxy)-45 methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-N-[3-(3-chloropropoxy)-4-methoxyphenyl]4-N-methylpyrimidine-2,4-diamine (200 mg, 0.62 mmol, 1 equiv), potassium carbonate (257 mg, 1.86 mmol, 3.00 equiv), Nal (93 mg, 1 equiv), CH₃CN (10 mL), (cyclopropylmethyl)(methyl)amine (150 mg, 1.76 mmol, 2.00 equiv). The resulting solution was stirred for 12 h at 85 °C in an oil bath. The solids were fdtered out. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by Flash-PrepHPLC A. This resulted in 41.8 mg (14%) of N²-(3-(3((cyclopropylmethyl)(methyl)amino)propoxy)-4-methoxyphenyl)-N⁴-methylpyrimidine-2,4diamine as an off-white solid.

Example 101: Synthesis of Compound 425

Compound 425: Synthesis of N²-(4-methoxy-3-(3-(3-methoxyazetidin-lyl)propoxy)phenyl)-N⁴-methyIpyrimidine-2,4-diamine

Step 1: Synthesis of N -(4-methoxy-3-(3-(3-methoxyazetidin-l-yl)propoxy)phenyl)-N methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-N-[3-(3-chloropropoxy)-4-methoxyphenyl]4-N-methylpyrimidine-2,4-diamine (200 mg, 0.62 mmol, 1 equiv), 3-methoxyazetidine hydrochloride (228 mg, 1.84 mmol, 3.00 equiv), Nal (93 mg, 1 equiv), potassium carbonate (513 mg, 3.71 mmol, 6.00 equiv), ACN (10 mL). The resulting solution was stirred for 12 h at 80 °C. The crude product was purified by Flash-Prep-HPLC A 1:1. This resulted in 74.9 mg (25%) of N²-(4-methoxy-3-(3-(3-methoxyazetidin-l-yl)propoxy)phenyl)-N⁴methylpyrimidine-2,4-diamine as a white solid.

398

Example 102: Synthesis of Compound 426

Compound 426: Synthesis of N²-(3-((5-cyclopropylisoxazol-3-yl)methoxy)-4methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine

H

Cs₂CO₃, DMF

Step 1: Synthesis of (5-cyclopropyl-l,2-oxazol-3-yl)methanol:

Into a 100-mL 3-necked round-bottom flask, was placed tetrahydrofuran (20 mL), LAH (1.99 g, 52.44 mmol, 4.00 equiv). This was followed by the addition of a solution of 5-cyclopropyll,2-oxazole-3-carboxylic acid (2 g, 13.06 mmol, 1 equiv) in tetrahydrofuran (5 mL) dropwise with stirring at 0 °C. The resulting solution was stirred for 3 h at 0 °C. The reaction was then quenched by the addition of 2 mL of water. The resulting solution was diluted with 100 mL of EA. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 1.8 g (99%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z): RT =0.572 min, LCMS 32: m/z = 140 [M+l], Step 2: Synthesis of (5-cyclopropyl-l,2-oxazol-3-yl)methyl methanesulfonate: Into a 100-mL round-bottom flask, was placed dichloromethane (50 mL), (5-cyclopropyl-l,2oxazol-3-yl)methanol (1.8 g, 12.94 mmol, 1 equiv), TEA (3.96 g, 39.13 mmol, 3.03 equiv). This was followed by the addition of MsCl (1.9 g, 16.67 mmol, 1.29 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 14 h at 20 °C. The resulting mixture was washed with 3x10 mL of H₂O. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 1.2 g (43%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z): RT =0.834 min, LCMS 07

Step 3: Synthesis of N²-(3-((5-cyclopropylisoxazol-3-yl)methoxy)-4-methoxyphenyl)-N⁴methylpyrimidine-2,4-diamine:

Into a 40-mL vial, was placed Ν,Ν-dimethylformamide (5ml), (5-cyclopropyl-l,2-oxazol-3yl)methyl methanesulfonate (200 mg, 0.92 mmol, 1 equiv), 2-methoxy-5-[[4399 (methylamino)pyrimidin-2-yl]amino]phenol (270 mg, 1.10 mmol, 1.19 equiv), Cs2CO3 (600 mg, 1.84 mmol, 2.00 equiv). The resulting solution was stirred for 4 h at 80 °C. The solids were filtered out. The crude product (200 mg) was purified by Prep-HPLC C HCl. This resulted in 72.6 mg (20%) of N²-(3-((5-cyclopropylisoxazol-3-yl)methoxy)-45 methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine as an off-white solid.

Example 103: Synthesis of Compound 428 7 4

Compound 428: Synthesis of N -(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N methyl-6-(2,2,2-trifluoroethyl)pyrimidine-2,4-diamine

MeONa/MeOH

O

-78°C-rt,THF

Step 1: Synthesis of 2,4,6-tribromopyrimidine:

Into a 1-L 3-necked round-bottom flask, was placed l,3-diazinane-2,4,6-trione (30 g, 234.22 mmol, 1 equiv), N,N-dimethylaniline (42.54 g, 351.05 mmol, 1.50 equiv), POBr (263 g, 4.00 equiv), toluene (300 mL). The resulting solution was stirred for 3 h at 110 °C. The resulted mixture was cooled into RT, the yellow organic layer decanted off. The red gum was rinse once with EA. The combined organic layer was washed with 3x500 mL of Saturated sodium bicarbonate, 3x500 mL of brine and 2x500 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 54 g of the title compound as a yellow crude solid.

Step 2: Synthesis of 4-bromo-2,6-dimethoxypyrimidine:

Into a 2-L 3-necked round-bottom flask, was placed 2,4,6-tribromopyrimidine (54 g, 170.47 mmol, 1 equiv), methanol (500 mL), diethyl ether (500 mL), and MeONa/MeOH (30%) (76.7 g, 2.50 equiv) was added dropwise. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 1 25 L of EA. The resulting mixture was washed with 3x500 mL of brine. The resulting mixture

400 was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100-1:10). The collected fractions were combined and concentrated under vacuum. This resulted in 23 g (62%) of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.287 min, LCMS 28: m/z = 219 [M+l].

Step 3: Synthesis of l-(2,6-dimethoxypyrimidin-4-yl)-2,2,2-trifluoroethane-l,l-diol:

Into a 1-L 3-necked round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed 4-bromo-2,6-dimethoxypyrimidine (23 g, 105.01 mmol, 1 equiv), tetrahydrofuran (250 mL), Diethyl ether (250 mL). And n-BuLi(2.5M) (46.2 mg, 0.72 mmol, 1.10 equiv) was added dropwise at -78 °C. After stirred for 5 min at -78 °C, ethyl 2,2,2trifluoroacetate (16.4 g, 115.43 mmol, 1.10 equiv) was added dropwise. After stirred for 30 min at -78 °C, the resulting solution was stirred for ovemight at RT. The reaction was then quenched by the addition of 200 mL of saturated NH₄C1. Sodium carbonate was employed to adjust the pH to 8. The resulting solution was diluted with 1 L of EA. The resulting mixture was washed with 3x500 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1001:10). The collected fractions were combined and concentrated under vacuum. This resulted in 15 g (56%) of the title compound as an off-white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.739 min, LCMS 32: m/z = 255 [M+l], Step 4: Synthesis of 1 -(2,6-dimethoxypyrimidin-4-yl)-2,2,2-trifluoroethan-1 -ol: Into a 500-mL 3-necked round-bottom flask, was placed l-(2,6-dimethoxypyrimidin-4-yl)2,2,2-trifluoroethane-l,l-diol (15 g, 59.02 mmol, 1 equiv), methanol (150 mL), and NaBH4 (8.98 g, 237.38 mmol, 4.00 equiv) was added portionwise at 0 °C. The resulting solution was stirred for Ih at RT. The reaction was then quenched by the addition of 50 mL of saturated NH₄C1. The resulting solution was diluted with 500 mL of EA. The resulting mixture was washed with 3x500 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100-1:10). The collected fractions were combined and concentrated under vacuum. This resulted in 14 g of the title compound as an off-white solid. Analytical Data: LC-MS: (ES, m/z): RT = 0.806 min, LCMS 32: m/z = 239 [M+l], ^!H NMR (300 MHz, DMSO-î/₆) δ 7.14 (d, J= 6.4 Hz, 1H), 6.72 (s, 1H), 5.01-4.95 (m, 1H), 3.92 (d, J = 5.4 Hz, 6H).

Step 5: Synthesis of [l-(2,6-dimethoxypyrimidin-4-yl)-2,2,2-trifluoroethoxy](phenoxy) methanethione:

401

Into a 500-mL 3-necked round-bottom flask, was placed l-(2,6-dimethoxypyrimidin-4-yl)2,2,2-trifluoroethan-l-ol (14 g, 58.78 mmol, 1 equiv), 4-dimethylaminopyridine (21.53 g, 176.23 mmol, 3.00 equiv), dichloromethane (200 mL). And phenyl chloromethanethioate (10.76 g, 62.33 mmol, 1.50 equiv) was added dropwise at 0 °C. The resulting solution was 5 stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 200 mL of EA. The resulting mixture was washed with 3x200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 37 g of the title compound as a yellow crude solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.806 min, LCMS 32: m/z = 375 [M+l].

io Step 6: Synthesis of 2,4-dimethoxy-6-(2,2,2-trifluoroethyl)pyrimidine:

Into a 1-L 3-necked round-bottom flask, was placed [l-(2,6-dimethoxypyrimidin-4-yl)-2,2,2trifluoroethoxy](phenoxy)methanethione (37 g, 98.84 mmol, 1 equiv), AIBN (3.2 g, 19.49 mmol, 0.20 equiv), (n-Bu)₃SnH (114.76 g, 4.00 equiv), Toluene (500 mL). The resulting solution was stirred for 2 h at 110 °C in an oil bath. The resulting solution was diluted with 1 15 L of EA. The resulting mixture was washed with 3x1 L of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100-1:10). The collected fractions were combined and concentrated under vacuum. This resulted in 13 g (59%) of the title compound as yellow crude oil.

Analytical Data: LC-MS: (ES, m/z): RT = 1.271 min, LCMS 28: m/z = 223 [M+l],

Step 7: Synthesis of 6-(2,2,2-trifluoroethyl)pyrimidine-2,4-diol:

Into a 500-mL 3-necked round-bottom flask, was placed 2,4-dimethoxy-6-(2,2,2trifluoroethyl)pyrimidine (11g, 49.51 mmol, 1 equiv), Conc. HCl (150 mL). The resulting solution was stirred for 6 h at 105 °C in an oil bath. The resulting mixture was concentrated 25 under vacuum. This resulted in 7.7 g (80%) of the title compound as an off-white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.773 min, LCMS 15: m/z = 195 [M+l].

Step 8: Synthesis of 2,4-dichloro-6-(2,2,2-trifluoroethyl)pyrimidine:

Into a 50-mL round-bottom flask, was placed 6-(2,2,2-trifluoroethyl)pyrimidine-2,4-diol (2.2 g, 11.33 mmol, 1 equiv), phosphoroyl trichloride (5 mL). The resulting solution was stirred 30 for 3 h at 120°C in an oil bath. The resulted mixture was poured into ice/water. The resulting solution was extracted with 2x50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2x50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 760 mg (29%) of the title compound as colorless oil.

402

Analytical Data: *H NMR (300 MHz, Chloro form-fr) δ 7.41 (s, 1H), 3.63 (q, J= 10.2 Hz, 2H).

Step 9: Synthesis of 2-chloro-N-methyl-6-(2,2,2-trifluoroethyl)pyrimidin-4-amine:

Into a 50-mL round-bottom flask, was placed 2,4-dichloro-6-(2,2,2-trifluoroethyl)pyrimidine 5 (720 mg, 3.12 mmol, 1 equiv), methanamine hydrochloride (318 mg, 4.71 mmol, 1.50 equiv), potassium carbonate (1.29 g, 9.33 mmol, 3.00 equiv), N,N-dimethylformamide (10 mL). The resulting solution was stirred for 4 h at RT. The resulting solution was diluted with 50 mL of EA. The resulting mixture was washed with 3x50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a 10 silica gel column with ethyl acetate/petroleum ether (1:100-1:10). The collected fractions were combined and concentrated under vacuum. This resulted in 300 mg (43%) of the title compound as an off-white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.799 min, LCMS 32: m/z = 226 [M+l], *H NMR (400 MHz, DMSO-r/₆) δ 8.06 (d, J= 5.5 Hz, 1H), 6.52 (m, 1H), 3.76 - 3.52 (m, 2H), 2.94 15 2.70 (m, 3H).

Step 10: Synthesis of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴-methyl-6(2,2,2-trifluoroethyl)pyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-chloro-N-methyl-6-(2,2,2trifluoroethyl)pyrimidin-4-amine (260 mg, 1.15 mmol, 1 equiv), 4-methoxy-3-[3-(pyrrolidin20 1-yl)propoxy]aniline (288 mg, 1.15 mmol, 1 equiv), CF3COOH (393 mg, 3.45 mmol, 3.00 equiv), isopropanol (5 mL). The resulting solution was stirred for ovemight at 80 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography with H2O/ACN/NH4HCO3. This resulted in 72.6 mg (14%) of N²-(4methoxy-3-(3-(pynOlidin-l-yl)propoxy)phenyl)-N⁴-methyl-6-(2,2,225 trifluoroethyl)pyrimidine-2,4-diamine as an off-white solid.

Example 104: Synthesis of Compound 429

Compound 429: Synthesis of N²-(4-methoxy-3-(3-(2-methylazetidin-l-yl)propoxy)phenyl)N⁴-methylpyrimidine-2,4-diamine

403

Step 1: Synthesis of N²-(4-methoxy-3-(3-(2-methylazetidin-l-yl)propoxy)phenyl)-N⁴methylpyrimidine-2,4-diamine:

Into a 16-mL sealed tube, was placed 2-N-[3-(3-chloropropoxy)-4-methoxyphenyl]-4-Nmethylpyrimidine-2,4-diamine (200 mg, 0.62 mmol, 1 equiv), ACN (8 mL), Nal (93 mg, 1 equiv), potassium carbonate (214 mg, 1.55 mmol, 2.50 equiv), 2-methylazetidine hydrochloride (100 mg, 0.93 mmol, 1.50 equiv). The resulting solution was stirred for 3 h at 80 °C in an oil bath. The solids were filtered out. The crude product was purified by PrepHPLC C TFA. This resulted in 36.7 mg (13%) of N²-(4-methoxy-3-(3-(2-methylazetidin-lyl)propoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine as a white solid.

Example 105: Synthesis of Compound 430

Compound 430: Synthesis of N²-(4-ethoxy-3-(3-(pyrrolidin-l-yI)propoxy)phenyl)-N⁴methylpyrimidine-2,4-diamine

J5 Step 1: Synthesis of N²-(4-ethoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 4-ethoxy-3-[3-(pyrrolidin-l-yl)propoxy]aniline (250 mg, 0.95 mmol, 1 equiv), 2-chloro-N-methylpyrimidin-4-amine (135.4 mg, 0.94 mmol, 1 equiv), propan-2-ol (5 mL), trifluoroacetic acid (275.6 mg, 2.44 mmol, 3.00 equiv). The 20 resulting solution was stirred for 2 h at 80v°C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (250 mg) was purified by Prep-HPLC C HCl.

This resulted in 87.6 mg (23%) of N²-(4-ethoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴methylpyrimidine-2,4-diamine as a white solid.

Example 106: Synthesis of Compound 432

404 î 4

Compound 432: Synthesis of N -(4-ethoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N ,6dimethylpyrimidine-2,4-diamine

HO'^'^NOs Cs₂CO₃,Nal

Raney-Ni

H₂,CH₃OH

Step 1: Synthesis of l-[3-(2-ethoxy-5-nitrophenoxy)propyl]pyrrolidine:

Into a 50-mL round-bottom flask, was placed 2-ethoxy-5-nitrophenol (1 g, 5.46 mmol, 1 equiv), N,N-dimethylformamide (5 mL), CS2CO3 (5.3 g, 16.22 mmol, 3.00 equiv), iodosodium (819.7 mg, 5.47 mmol, 1 equiv), l-(3-chloropropyl)pyrrolidine hydrochloride (1 g, 5.43 mmol, 1 equiv). The resulting solution was stirred for 2 h at 110 °C in an oil bath. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with 3x10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2x10 mL of sodium chloride (aq). The resulting mixture was washed with 2x10 mL of H₂O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.48 g (92%) of the title compound as an oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.96min, LCMS07: m/z = 295.05 [M+l], *H NMR (300 MHz, Methanol-d4) δ 7.36 (dd, J = 2.5, 0.9 Hz, 1H), 7.24 - 7.14 (m, 2H), 4.15 (q, J =

7.0 Hz, 2H), 4.05 (t, 7=6.1 Hz, 2H), 2.75 - 2.57 (m, 6H), 2.08- 1.98(m, 2H), 1.90- 1.79 (m, 4H), 1.41 (t,7=7.0 Hz, 3H).

Step 2: Synthesis of 4-ethoxy-3-[3-(pyrrolidin-l-yl)propoxy]aniline: Into a 250-mL round-bottom flask, was placed l-[3-(2-ethoxy-520 nitrophenoxy)propyl]pyrrolidine (800 mg, 2.72 mmol, 1 equiv), Raney-Ni, methanol (100 mL). The resulting solution was stirred for 2 h at 20 °C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 700 mg (97%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.77min, LCMS33: m/z = 265.19 [M+l], ‘H NMR: 25 (400 MHz, Methanol-d4) δ 6.72 (d, 7= 8.7 Hz, 1H), 6.40 (d, 7= 2.9 Hz, 1H), 6.23 (dd, 7 =

8.7, 2.9 Hz, 1H), 4.12 - 3.85 (m, 4H), 2.70 - 2.56 (m, 6H), 2.05 - 1.73 (m, 6H), 1.40 (t, 7 = 7.0 Hz, 3H).

Step 3: Synthesis of N -(4-ethoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N ,6dimethylpyrimidine-2,4-diamine:

405

Into a 50-mL round-bottom flask, was placed 4-ethoxy-3-[3-(pyrrolidin-l-yl)propoxy]aniline (250 mg, 0.95 mmol, 1 equiv), trifluoroacetic acid (275.6 mg, 2.44 mmol, 3.00 equiv), 2chloro-N,6-dimethylpyrimidin-4-amine (148.7 mg, 0.94 mmol, 1 equiv), propan-2-ol (5 mL). The resulting solution was stirred for 2 h at 80 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (250 mg) was purified by Prep-HPLC C HCl. This resulted in 111 mg (28%) of N -(4-ethoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N ,6dimethylpyrimidine-2,4-diamine as a white solid.

Example 107: Synthesis of Compound 433

Compound 433: Synthesis of N²-(3-((5-cyclopropyl-l,2,4-oxadiazoI-3-yl)methoxy)-4methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine h₂n /)—\ O-N Cl DMF l₂UU3, n₂U ΐίΖΛΛ,υοινι q

Cs₂CO₃, DMF 'q-N

Step 1: Synthesis of (E)-2-chloro-N’-hydroxyethenimidamide

Into a 100-mL round-bottom flask, was placed water (20 g), 2-chloroacetonitrile (5 g, 66.23 mmol, 1 equiv), hydroxylamine hydrochloride (4.6 g, 66.20 mmol, 1 equiv). This was followed by the addition of sodium carbonate (3.5 g, 33.02 mmol, 0.50 equiv), in portions. The resulting solution was stirred for 2 h at 20 °C. The resulting solution was extracted with 4x20 mL of ether and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 3.9 g (54%) of the title compound as a white solid. Analytical Data: LC-MS: (ES, m/z): RT =0.259 min, LCMS 33: m/z = 109 [M+l],

Step 2: Synthesis of (Z)-(l-amino-2-chloroethylidene)amino cyclopropanecarboxylate: Into a 250-mL round-bottom flask, was placed dichloromethane (100 mL), cyclopropanecarbonyl chloride (5.5 g, 52.61 mmol, 1.50 equiv), (E)-2-chloro-N’- hydroxyethenimidamide (3.8 g, 35.01 mmol, 1 equiv).The resulting solution was stirred for 30 min at 20 °C. This was followed by addition of TEA (3.9 g, 38.54 mmol, 1.10 equiv). The resulting solution was allowed to react, with stirring, for an additional 1 h at 20 °C. The resulting mixture was washed with 2x50 mL of water and 1x50 mL of brine. The mixture was

406 dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 5.2 g (84%) of the title compound as light red oil. Analytical Data: LC-MS: (ES, m/z): RT =0.504 min, LCMS 32: m/z =177 [M+l].

Step 3: Synthesis of 3-(chloromethyl)-5-cyclopropyl-l,2,4-oxadiazole:

Into a 20-mL sealed tube, was placed N,N-dimethylformamide (10 mL), (Z)-(l-amino-2chloroethylidene)amino cyclopropanecarboxylate (1.5 g, 8.49 mmol, 1 equiv). The resulting solution was stirred for 3 h at 135 °C. The resulting solution was diluted with 10 mL of H₂O. The resulting solution was extracted with 3x10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x10 mL of water and 2x10 mL of brine.

The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 550 mg (41%) of the title compound as an oil. Analytical Data: LC-MS: (ES, m/z): RT =0.775 min, LCMS 32: m/z = 159 [M+l].

Step 4: Synthesis of N²-(3-((5-cyclopropyl-l,2,4-oxadiazol-3-yl)methoxy)-415 methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed N,N-dimethylformamide (5 mL), 3(chloromethyl)-5-cyclopropyl-l,2,4-oxadiazole (550 mg, 3.47 mmol, 4.27 equiv), 2-methoxy5-[[4-(methylamino)pyrimidin-2-yl]amino]phenol (200 mg, 0.81 mmol, 1 equiv), Cs₂CO3 (530 mg, 1.63 mmol, 2.00 equiv), Nal (122 mg). The resulting solution was stirred for 8 h at 20 80 °C. The solids were filtered out. The crude product (300 mg) was purified by Prep-HPLC

C NH4HCO3. This resulted in 36.8 mg (12%) of N²-(3-((5-cyclopropyl-l,2,4-oxadiazol-3yl)methoxy)-4-methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine as a light yellow solid.

Example 108: Synthesis of Compound 434

Compound 434: Synthesis of N²-(3-((l-cyclopropyl-lH-l,2,3-triazol-4-yI)methoxy)-4methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine

Step 1: Synthesis of methyl 1-cyclopropyl-1 H-1,2,3-triazole-4-carboxylate:

407

Into a 250-mL round-bottom flask, was placed methyl lH-l,2,3-triazole-4-carboxylate (2 g, 15.74 mmol, 1 equiv), Cu(OAc)₂ (8.6 g, 47.35 mmol, 3.00 equiv), pyridine (12.4 g, 156.76 mmol, 10.00 equiv), tetrahydrofuran (100 mL), cyclopropylboronic acid (2.7 g, 31.43 mmol, 2.00 equiv). The resulting solution was stirred for 72 h at 55 °C in an oil bath. The resulting solution was extracted with 3x200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC ALI. This resulted in 150 mg (6%) of the title compound as a yellow solid. Analytical Data: LC-MS: (ES, m/z): 168 [M+l], R: 1.065 min. 'H-NMR: (DMSO-îZô, ppm): δ 8.84 (s, 1H), 4.06-4.08 (m, 1H), 3.83 (s, 3H), 1.31 - 1.06 (m, 4H).

Step 2: Synthesis of (l-cyclopropyl-lH-l,2,3-triazol-4-yl)methanol:

Into a 100-mL round-bottom flask, was placed methyl l-cyclopropyl-lH-l,2,3-triazole-4carboxylate (120 mg, 0.72 mmol, 1 equiv), LÎA1H4 (144 mg, 3.79 mmol, 5.00 equiv), tetrahydrofuran (20 mL). The resulting solution was stirred for 1 h at 0 °C in a water/ice bath. The reaction was then quenched by the addition of water. The solids were filtered out. The crude product was purified by Flash-Prep-HPLC A. This resulted in 30 mg (30%) ofthe title compound as a white solid. Analytical Data: LC-MS: (ES, m/z): 140 [M+l], R: 0.856 min. Step 3: Synthesis of 4-(chloromethyl)-l-cyclopropyl-lH-l,2,3-triazole:

Into a 100-mL round-bottom flask, was placed (l-cyclopropyl-lH-l,2,3-triazol-4-yl)methanol (20 mg, 0.14 mmol, 1 equiv), phosphoroyl trichloride (4 mL). The resulting solution was stirred for 3 h at 100 °C in an oil bath. The resulting mixture was concentrated under compound as a white solid. Analytical Data: LC-MS: (ES, m/z): 158 [M+l], R: 1.267 min. Step 4: Synthesis of N²-(3-((l-cyclopropyl-lH-l,2,3-triazol-4-yl)methoxy)-4methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 4-(chloromethyl)-l-cyclopropyl-lH-l,2,3triazole (100 mg, 0.63 mmol, 1 equiv), Cs₂CO₃ (619 mg, 1.90 mmol, 3.00 equiv), N,Ndimethylformamide (10 mL), 2-methoxy-5-[4-(methylamino)pyrimidin-2-yl]aminophenol (156 mg, 0.63 mmol, 1 equiv). The resulting solution was stirred for 2 h at 50 °C in an oil bath. The solids were filtered out. The crude product was purified by Prep-HPLC C TFA. This resulted in 21.3 mg (7%) of N²-(3-((l-cyclopropyl-lH-l,2,3-triazol-4-yl)methoxy)-4methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine as a white solid.

Example 109: Synthesis of Compound 435

408

Compound 435: Synthesis of N²-(4-methoxy-3-((l-methylpiperidin-4yl)methoxy)phenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine

Step 1: Synthesis of tert-butyl 4-[(methanesulfonyloxy)methyl]piperidine-l-carboxylate:

Into a 250-mL round-bottom flask, was placed tert-butyl 4-(hydroxymethyl)piperidine-lcarboxylate (500 mg, 2.32 mmol, 1 equiv), methanesulfonyl chloride (530 mg, 4.63 mmol, 2.00 equiv), TEA (704 mg, 6.96 mmol, 3.00 equiv), dichloromethane (15 mL). The resulting solution was stirred for 1 h at 25 °C. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The crude product was purified by Flash-Prep10 HPLC A 1:1. This resulted in 550 mg (81 %) of as light yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT= 1.26 min, LCMS 53: m/z = 294 [M+l], 'H-NMR: (DMSOZ^w): δ 4.07 (d, J = 6.4 Hz, 2H), 3.96 (d, J= 13.0 Hz, 2H), 3.18 (s, 3H), 2.72 (s, 2H), 1.92- 1.78 (m, 1H), 1.72- 1.57 (m, 2H), 1.40 (s, 9H), 1.18-0.99 (m, 4H).

Step 2: Synthesis of tert-butyl 4-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-215 yl]amino]phenoxymethyl)piperidine-1 -carboxylate:

Into a 250-mL round-bottom flask, was placed 2-methoxy-5-[[4-methyl-6(methylamino)pyrimidin-2-yl]amino]phenol; trifluoroacetic acid (730 mg, 1.95 mmol, 1 equiv), tert-butyl 4-[(methanesulfonyloxy)methyl]piperidine-l-carboxylate (720 mg, 2.45 mmol, 1.20 equiv), CS2CO3 (2 g, 6.14 mmol, 3.00 equiv), N,N-dimethylformamide (30 mL).

The resulting solution was stirred for 12 h at 80 °C. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with x mL of sodium chloride. The crude product was purified by Flash-Prep-HPLC A 1:1. This resulted in 600 mg (67%) of the title compound as light yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT= 1.14 min, LCMS 15: m/z = 458 [M+l], ‘H-NMR:

(OMSO-d₆, ppm):5 8.78-8.71 (m, 1H), 7.81 (s, 1H), 7.19 - 7.09 (m, 1H), 6.93 (s, 1H), 6.80 (d, J = 8.7 Hz, 1H), 5.75 (s, 1H), 3.98 (d, J= 12.7 Hz, 2H), 3.79 (d, J = 6.4 Hz, 2H), 3.69 (s, 3H), 2.83 (d, 7=4.5 Hz, 3H), 2.74 (s, 2H), 2.10 (s, 3H), 1.97- 1.87 (m, 1H), 1.76 (d,7 = 13.3 Hz, 2H), 1.40 (s, 9H), 1.25-1.03 (m, 2H).

409

Step 3: Synthesis of 2-N-[4-methoxy-3-(piperidin-4-ylmethoxy)phenyl]-4-N,6dimethylpyrimidine-2,4-diamine:

Into a 100-mL round-bottom flask, was placed tert-butyl 4-(2-methoxy-5-[[4-methyl-6(methylamino)pyrimidin-2-yl]amino]phenoxymethyl)piperidine-l-carboxylate (600 mg, 1.31 5 mmol, 1 equiv), trifluoroacetic acid (10 mL), dichloromethane (20 mL). The resulting solution was stirred for 1 h at 25 °C. The crude product was purified by Flash-Prep-HPLC A 1:1. This resulted in 420 mg (90%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): RT= 1.14 min, LCMS 15: m/z = 358 [M+l].

Step 4: Synthesis of N²-(4-methoxy-3-((l-methylpiperidin-4-yl)methoxy)phenyl)-N⁴,610 dimethylpyrimidine-2,4-diamine:

Into a 100-mL round-bottom flask, was placed 2-N-[4-methoxy-3-(piperidin-4ylmethoxy)phenyl]-4-N,6-dimethylpyrimidine-2,4-diamine (210 mg, 0.59 mmol, 1 equiv), HCHO (364 mg, 10.00 equiv), NaBH₃CN (280 mg, 4.46 mmol, 16.00 equiv), methanol (15 mL). The resulting solution was stirred for 4 h at 25 °C. The solids were filtered out. The crude product was purified by Flash-Prep-HPLC A. This resulted in 94.0 mg (39%) of N²-(4methoxy-3-((l-methylpiperidin-4-yl)methoxy)phenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine as a white solid.

Example 110: Synthesis of Compound 436

Compound 436: Synthesis of N²-(3-((l-(cyclopropylmethyl)piperidin-4-yl)methoxy)-4methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine

Step 1: Synthesis of N²-(3-((l-(cyclopropylmethyl)piperidin-4-yl)methoxy)-4methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine:

Into a 100-mL round-bottom flask, was placed 2-N-[4-methoxy-3-(piperidin-4ylmethoxy)phenyl]-4-N,6-dimethylpyrimidine-2,4-diamine (270 mg, 0.76 mmol, 1 equiv), cyclopropanecarbaldehyde (847 mg, 12.08 mmol, 16 equiv), NaBH₃CN (476 g, 7.57 mol, 10.00 equiv), methanol (15 mL), HOAC (0.5 mL). The resulting solution was stirred for 2 h at 25°C. The crude product was purified by Flash-Prep-HPLC A 1 : L This resulted in 111.1 mg (3.3%) of N²-(3-((l-(cyclopropylmethyl)piperidin-4-yl)methoxy)-4-methoxyphenyl)N⁴,6-dimethylpyrimidine-2,4-diamine as a white solid.

410

Example 111: Synthesis of Compound 437

Compound 437: Synthesis of N²-(3-(azetidin-3-ylmethoxy)-4-methoxyphenyl)-N⁴,6dimethyIpyrimidine-2,4-diamine

Step 1: Synthesis of tert-butyl 3-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2yl]amino]phenoxymethyl)azetidine-l-carboxylate:

Into a 100-mL round-bottom flask, was placed 2-methoxy-5-[[4-methyl-6(methylamino)pyrimidin-2-yl]amino]phenol (2 g, 7.68 mmol, 1 equiv), tert-butyl 310 [(methanesulfonyloxy)methyl]azetidine-l-carboxylate (2.4 g, 9.05 mmol, 1.20 equiv), Cs₂CO₃ (5.0 g, 15.35 mmol, 2.00 equiv), N,N-dimethylformamide (20 mL). The resulting solution was stirred for 12 h at 80 °C in an oil bath. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The crude product was purified by Flash-Prep-HPLC A. This resulted in 0.5 g (15%) of the title compound as a light brown solid.

Analytical Data: LC-MS: (ES, m/z)\ RT =1.130 min, LCMS53: m/z = 430.2 [M+l], Step 2: Synthesis of N²-(3-(azetidin-3-ylmethoxy)-4-methoxyphenyl)-N⁴,6dimethylpyrimidine-2,4-diamine:

Into a 100-mL round-bottom flask, was placed tert-butyl 3-(2-methoxy-5-[[4-methyl-620 (methylammo)pyrimidin-2-yl]amino]phenoxymethyl)azetidine-l-carboxylate (500 mg, 1.16 mmol, 1 equiv), dichloromethane (10 mL), trifluoroacetic acid (2 mL). The resulting solution was stirred for 3 h at 20 °C. The resulting mixture was concentrated under vacuum. The crude product was purifïed by Flash-Prep-HPLC A. This resulted in 39.4 mg (10%) of N²-(3(azetidin-3-ylmethoxy)-4-methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine as a light brown solid.

Example 112: Synthesis of Compounds 438 and 439

Compound 438 and 439: Synthesis of N2-(3-(((3S,4S)-l,4-dimethylpyrrolidin-3yl)methoxy)-4-methoxyphenyl)-N4-methylpyrimidine-2,4-diamine and N2-(3-(((3R,4R)30 l,4-dimethylpyrrolidin-3-yl)methoxy)-4-methoxyphenyl)-N4-methylpyrimidine-2,4diamine

411

Step 1: Synthesis of tert-butyl 3-[(methanesulfonyloxy)methyl]-4-methylpyrrolidine-lcarboxylate:

Into a 100-mL round-bottom flask, was placed dichloromethane (10 mg, 0.12 mmol, 0.05 equiv), tert-butyl 3-(hydroxymethyl)-4-methylpyrrolidine-l-carboxylate (500 mg, 2.32 mmol, 1 equiv), TEA (712 mg, 7.04 mmol, 3.03 equiv).This was followed by addition of MsCl (345 mg, 3.03 mmol, 1.30 equiv)at 0 °C. The resulting solution was stirred for 2 h at 20 °C. The resulting solution was diluted with 10 mL of DCM. The resulting mixture was washed with 2x10 mL of water and 1x10 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were fïltered out. The resulting mixture was concentrated under vacuum. This resulted in 800 mg (N/A) of the title compound as off-white oil.

Analytical Data: LC-MS: (ES, m/z): LCMS 32: m/z = 294 [M+l],

Step 2: Synthesis of tert-butyl 3-(2-methoxy-5-[[4-(methylamino)pyrimidin-2yl]amino]phenoxymethyl)-4-methylpyrrolidine-l-carboxylate:

Into a 100-mL round-bottom flask, was placed N,N-dimethylformamide (20 L), tert-butyl 3[(methanesulfonyloxy)methyl]-4-methylpyrrolidine-l-carboxylate (800 mg, 2.73 mmol, 1 equiv), 2-methoxy-5-[[4-(methylamino)pyrimidin-2-yl]amino]phenol (739 mg, 3.00 mmol, 1.10 equiv), Cs₂CO₃ (1.78 g, 5.46 mmol, 2.00 equiv). The resulting solution was stirred for 4 h at 80 °C. The resulting solution was diluted with 20 mL of H2O. The resulting solution was extracted with 3x20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x10 mL of water and 3x10 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were fïltered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (7:3). This resulted in 900 mg (74%) of the title compound as a solid. Analytical Data: LC-MS: (ES, m/z): RT =0.848 min, LCMS 32: m/z = 444 [M+l],

Step 3: Synthesis of 2-N-[3-[(l,4-dimethylpyrrolidin-3-yl)methoxy]-4-methoxyphenyl]-4-Nmethylpyrimidine-2,4-diamine:

412

Into a 100-mL round-bottom flask, was placed tetrahydrofuran (20 mL), LAH (386 mg, 10.17 mmol, 5.01 equiv).This was followed by addition of a solution of tert-butyl 3-(2-methoxy-5[[4-(methylamino)pyrimidin-2-yl]amino]phenoxymethyl)-4-methylpyrrolidine-l-carboxylate (900 mg, 2.03 mmol, 1 equiv) in tetrahydrofuran (2 mL) at 0 °C. The resulting solution was stirred for 5 h at 80 °C. The reaction was then quenched by the addition of 0.4 mL of water and 0.4 mL as a solution of NaOH in H2O (0.4ml). The resulting solution was diluted with 50 mL of EA. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 440 mg (61%) of the title compound as a solid.

Analytical Data: LC-MS: (ES, m/z): RT =0.589 min, LCMS 32: m/z = 358 [M+l], Step 4: Synthesis of N²-(3-(((3S,4S)-l,4-dimethylpyrrolidin-3-yl)methoxy)-4methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine and N²-(3-(((3R,4R)-l,4dimethylpyrrolidin-3-yl)methoxy)-4-methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine: Into a 100-mL round-bottom flask, was placed 2-N-[3-[(l,4-dimethylpyrrolidin-3yl)methoxy]-4-methoxyphenyl]-4-N-methylpyrimidine-2,4-diamine (450 mg, 1.26 mmol, 1 equiv). This resulted in 48.8 mg (11%) of N²-(3-(((3S,4S)-l,4-dimethylpyrrolidin-3yl)methoxy)-4-methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine El (randomly assigned) as a light yellow solid. And 75.0 mg (17%) of N²-(3-(((3R,4R)-l,4-dimethylpyrrolidin-3yl)methoxy)-4-methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine E2 (randomly assigned) as a light yellow solid.

Example 113: Synthesis of Compound 440 2 4

Compound 440: Synthesis ofN -(3-(2-(cycIopentyloxy)ethoxy)-4-methoxyphenyl)-N methylpyrimidine-2,4-diamine

4

Step 1: Synthesis of N -(3-(2-(cyclopentyloxy)ethoxy)-4-methoxyphenyl)-N methylpyrimidine-2,4-diamine:

Into a 20-mL vial, was placed isopropanol (2 mL), 3-[2-(cyclopentyloxy)ethoxy]-4methoxyaniline (150 mg, 0.60 mmol, 1 equiv), 2-chloro-N-methylpyrimidin-4-amine (103 mg, 0.72 mmol, 1.20 equiv), trifluoroacetic acid (136 mg, 1.20 mmol, 2.02 equiv). The

413 resulting solution was stirred for 2 h at 80 °C. The crude product was purified by PrepHPLC B TFA. This resulted in 124.7 mg (44%) of N²-(3-(2-(cyclopentyloxy)ethoxy)-4methoxyphenyl)-N⁴-methylpyrimidine-2,4-diamine as a white solid.

Example 114: Synthesis of Compound 441

Compound 441: Synthesis of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-6(methoxymethyl)-N⁴-methylpyrimidine-2,4-diamine

POCI₃

h₂n—

Step 1: Synthesis of 6-(methoxymethyl)-l,2,3,4-tetrahydropyrimidine-2,4-dione:

Into a 20-mL round-bottom flask, was placed 6-(chloromethyl)-1,2,3,4-tetrahydropyrimidine2,4-dione (2 g, 12.46 mmol, 1 equiv), methanol; methoxysodium (10 mL). The resulting solution was stirred for 3 h at 70 °C. The resulting mixture was concentrated under vacuum. The residue was dissolved in 30 mL of H2O. The pH value of the solution was adjusted to 7 with HCl (2 mmol). The resulting solution was extracted with 3x30 mL of ethyl acetate and the organic layers combined. This resulted in 350 mg (17%) of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT= 0.467 min, LCMS 07, m/z =157 [M+l]. 'H NMR (300 MHz, Deuterium Oxide) δ 5.70 (d, J= 1.2 Hz, 1H), 4.23 (d, J = 1.0 Hz, 2H), 3.33 (s, 3H).

Step 2: Synthesis of 2,4-dichloro-6-(methoxymethyl)pyrimidine:

Into a 100-mL round-bottom flask, was placed 6-(methoxymethyl)-l,2,3,4tetrahydropyrimidine-2,4-dione (350 mg, 2.24 mmol, 1 equiv), phosphoroyl trichloride (5 mL). The resulting solution was stirred for 5 h at 120 °C. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 30 mL of water. The pH value of the solution was adjusted to 7 with sodium bicarbonate-H2O (100 %). The resulting solution was extracted with 3x20 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3x20 mL of H2O. The mixture was dried

414 over anhydrous sodium sulfate. This resulted in 360 mg (75%) of the title compound as a light yellow liquid.

Analytical Data: LC-MS: (ES, m/z): RT= 0.914 min, LCMS07, m/z =193 [M+l], Step 3: Synthesis of 2-chloro-6-(methoxymethyl)-N-methylpyrimidin-4-amine:

Into a 50-mL round-bottom flask, was placed 2,4-dichloro-6-(methoxymethyl)pyrimidine (350 mg, 1.81 mmol, 1 equiv), TEA (545 mg, 5.39 mmol, 2.97 equiv), tetrahydrofuran (10 mL), MeNH₂-THF (2.7 mL). The resulting solution was stirred for 2 h at 0 °C. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-PrepHPLC A. This resulted in 160 mg (42%) of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT= 0.650 min, LCMS 45, m/z =188 [M+l], ’H NMR (300 MHz, Chloroform-r/) δ 6.44 (s, 1H), 4.41 (s, 2H), 3.51 (s, 3H), 3.06 - 2.97 (m, 3H). Step 4: Synthesis of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-6(methoxymethyl)-N⁴-methylpyrimidine-2,4-diamine:

Into a 25-mL round-bottom flask, was placed 2-chloro-6-(methoxymethyl)-N15 methylpyrimidin-4-amine (158 mg, 0.84 mmol, 1 equiv), 4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]aniline (210 mg, 0.84 mmol, 1 equiv), isopropanol (5 mL), trifluoroacetic acid (287 mg, 2.54 mmol, 3.02 equiv). The resulting solution was stirred for 2 h at 80 °C. The resulting mixture was concentrated under vacuum. The crude product was purified by PrepHPLC C HCl. This resulted in 61.2 mg (16%) of N²-(4-methoxy-3-(3-(pyrrolidin-l20 yl)propoxy)phenyl)-6-(methoxymethyl)-N⁴-methylpyrimidine-2,4-diamine as a light brown solid.

Example 115: Synthesis of Compound 442

Compound 442: Synthesis of N²-(4-methoxy-3-((l-methylazetidin-3-yl)methoxy)phenyl)25 N⁴,6-dimethylpyrimidine-2,4-diamine

4

Step 1: Synthesis of N -(4-methoxy-3-((l-methylazetidin-3-yl)methoxy)phenyl)-N ,6dimethylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-N-[3-(azetidin-3-ylmethoxy)-430 methoxyphenyl]-4-N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.91 mmol, 1 equiv),

415 methanol (ΙΟ mL), HCHO (90 mg, 3.00 mmol, 1 equiv), NaBH₃CN (360 mg, 5.73 mmol, 6.00 equiv). The resulting solution was stirred for 2 h at 20 °C. The crude product was purified by Prep-HPLC C HCl. This resulted in 30.4 mg (9%) of N²-(4-methoxy-3-((lmethylazetidin-3-yl)methoxy)phenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine as an off-white solid.

Example 116: Synthesis of Compound 445

Compound 445: Synthesis of N²-(3-((l-(cyclopropylmethyl)azetidin-3-yl)methoxy)-4methoxyphenyI)-N⁴,6-dimethylpyrimidine-2,4-diamine

NaBH₃CN,MeOH

Step 1: Synthesis of N²-(3-((l-(cyclopropylmethyl)azetidin-3-yl)methoxy)-4methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-N-[3-(azetidin-3-ylmethoxy)-4methoxyphenyl]-4-N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.91 mmol, 1 equiv), methanol (10 mL), cyclopropanecarbaldehyde (63.8 mg, 0.91 mmol, 1 equiv), NaBH₃CN (361 mg, 5.74 mmol, 6.00 equiv). The resulting solution was stirred for 2 h at 20 °C. The crude product was purified by Prep-HPLC C TFA. This resulted in 65.8 mg (15%) of N²-(3((l-(cyclopropylmethyl)azetidin-3-yl)methoxy)-4-methoxyphenyl)-N⁴,6-dimethylpyrimidine2,4-diamine as a white solid.

Example 117: Synthesis of Compound 446

Compound 446: Synthesis of N²-(3-((l-cyclobutylpyrrolidin-3-yl)methoxy)-4methoxyphenyl)-N⁴,6-dimethyIpyrimidine-2,4-diamine

NaBH₃CN,AcOH,MeOH

4

Step 1: Synthesis of N -(3-((1-cyclobutylpyrrolidin-3-yl)methoxy)-4-methoxyphenyl)-N ,6dimethylpyrimidine-2,4-diamine:

N²-(3-((l-cyclobutylpyrrolidin-3-yl)methoxy)-4-methoxyphenyl)-N⁴,6-dimethylpyrimidine2,4-diamine was prepared as for N²-(3-(((l-ethylpyrrolidin-3-yl)oxy)methyl)-4416 methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine using cyclobutanone in place of acetaldehyde in the final step.

Example 118: Synthesis of Compounds 447 and 448

Compound 447 and 448: Synthesis of 2-((4-methoxy-3-(3-(pyrrolidin-lyl)propoxy)phenyl)amino)-6-methylpyrimidin-4-ol and 4-((4-methoxy-3-(3-(pyrrolidinl-yl)propoxy)phenyl)amino)-6-methylpyrimidin-2-ol

OH

I

Step 1: Synthesis of 2-((4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)amino)-6io methylpyrimidin-4-ol and 4-((4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)amino)-6methylpyrimidin-2-ol:

Into a 100-mL round-bottom flask, was placed 2-chloro-6-methylpyrimidin-4-ol (360 mg,

2.49 mmol, 1 equiv), 4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]aniline (600 mg, 2.40 mmol, equiv), TsOH (900 mg, 5.23 mmol, 2.00 equiv, 96%), isopropanol (40 mL). The resulting 15 solution was stirred for 3 h at 85 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was applied onto a silica gel column with NH4HCO3:ACN (1:1),Detector, UV 254 nm. This resulted in 84.4 mg (9%) of 2-((4-methoxy-3-(3-(pyrrolidinI-yl)propoxy)phenyl)amino)-6-methylpyrimidin-4-ol, regioisomer 1 as a solid. And 30.6 mg (3%) of 4-((4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)amino)-6-methylpyrimidin-220 ol, regioisomer 2 as a solid.

Example 119: Synthesis of Compound 449

Compound 449: Synthesis of N²-(4-methoxy-3-((l-(oxetan-3-yl)pyrrolidin-3yl)methoxy)phenyl)-N⁴,6-dimethylpyrimidine-2,4-diamme

Step 1: Synthesis of N²-(4-methoxy-3-((l-(oxetan-3-yl)pyrrolidin-3-yl)methoxy)phenyl)N⁴,6-dimethylpyrimidine-2,4-diamine:

417

N²-(4-methoxy-3-((l-(oxetan-3-yl)pyrrolidin-3-yl)methoxy)phenyl)-N⁴,6dimethylpyrimidine-2,4-diamine was prepared as for N²-(3-(((l-ethylpyrrolidin-3yl)oxy)methyl)-4-methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine using oxetan-3-one in place of acetaldehyde in the final step.

Example 120: Synthesis of Compound 450

Compound 450: Synthesis of N -(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N methyl-6-(pyrrolidin-l-yl)pyrimidine-2,4-diamine

Step 1: Synthesis of N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴-methyl-6(pyrrolidin-l-yl)pyrimidine-2,4-diamine:

Into a 10-mL vial, was placed 6-chloro-2-N-[4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]phenyl]-4-N-methylpyrimidine-2,4-diamine (150 mg, 0.38 mmol, 1 equiv), pyrrolidine (2 mL). The resulting solution was stirred for 3 h at 100 °C in an oil bath. The 15 crude product (150 mg) was purified by Prep-HPLC C HCl. This resulted in 96.1 mg (54%) ofN²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N⁴-methyl-6-(pyrrolidin-lyl)pyrimidine-2,4-diamine as a solid.

Example 121: Synthesis of Compound 451

Compound 451: Synthesis of N²-(4-methoxy-3-((l-methylpyrrolidin-3yl)methoxy)phenyl)-6-methyl-N⁴-((tctrahydro-2H-pyran-4-yl)methyl)pyrimidine-2,4diamine

418

4

Step 1: Synthesis of N -(4-methoxy-3-(pyrrolidin-3-ylmethoxy)phenyl)-6-methyl-N ((tetrahydro-2H-pyran-4-yl)methyl)pyrimidine-2,4-diamine:

Into a 100-mL round-bottom flask, was placed 2-chloro-6-methyl-N-(oxan-4ylmethyl)pyrimidin-4-amine (870 mg, 3.60 mmol, 1 equiv), tert-butyl 3-(5-amino-2methoxyphenoxymethyl)pyrrolidine-l-carboxylate (1.163 g, 3.61 mmol, 1 equiv), TsOH (1.242 g, 7.21 mmol, 2.00 equiv), isopropanol (20 mL). The resulting solution was stirred for 24 h at 85 °C in an oil bath. The crude product was purified by (CH3OH/H2O=l/10). This resulted in 1.1 g (71%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT =0.885 min, LCMS28: m/z = 428 [M+l], Step 2: Synthesis of N²-(4-methoxy-3-((l-methylpyrrolidin-3-yl)methoxy)phenyl)-6-methylN⁴-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidine-2,4-diamine:

Into a 100-mL round-bottom flask, was placed N²-(4-methoxy-3-(pyrrolidin-3ylmethoxy)phenyl)-6-methyl-N⁴-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidine-2,4-diamine (300 mg, 0.70 mmol, 1 equiv). This was followed by the addition of HCHO (70.3 mg, 2.34 mmol, 1 equiv, 30% aq), methanol (20 mL)was stirred for 0.5h at 20 °C. Then NaBLLCN (265.6 mg, 4.23 mmol, 6.00 equiv), HOAC (0.2 mL) was added and stirred for 2h at 25 °C. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC D TFA. This resulted in 71.2 mg (18%) of N²-(4-methoxy-3-((lmethylpynOlidin-3-yl)methoxy)phenyl)-6-methyl-N⁴-((tetrahydro-2H-pyran-4yl)methyl)pyrimidine-2,4-diamine as a white solid.

Example 122: Synthesis of Compound 452

Compound 452: Synthesis of N²-(4-methoxy-3-((tetrahydrofuran-2-yl)methoxy)phenyl)N⁴,6-dimethylpyrimidine-2,4-diamine

Step 1: Synthesis of N²-(4-methoxy-3-((tetrahydrofuran-2-yl)methoxy)phenyl)-N⁴,6dimethylpyrimidine-2,4-diamine:

Into a 20-mL vial, was placed N,N-dimethylformamide (5 mL), 2-methoxy-5-[[4-methyl-6(methylamino)pyrimidin-2-yl]amino]benzene-l-peroxol (200 mg, 0.72 mmol, 1 equiv), 2(bromomethyl)oxolane (330 mg, 2.00 mmol, 2.76 equiv), CS2CO3 (330 mg, 1.01 mmol, 1.40 equiv). Adding 2-(bromomethyl)oxolane every two minutes. The resulting solution was

419 stirred for 12 h at 20 °C. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC C HCl. This resulted in 95.4 mg (35%) of N²-(4methoxy-3-((tetrahydrofuran-2-yl)methoxy)phenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine as a light brown solid.

Example 123: Synthesis of Compound 453

Compound 453: Synthesis of N -(3-(2-cyclopropoxyethoxy)-4-methoxyphenyl)-N methylpyrimidine-2,4-diamine

Th

Step 1: Synthesis of 3-(2-cyclopropoxyethoxy)-4-methoxyaniline

Into a 50-mL round-bottom flask, was placed 2-(2-cyclopropoxyethoxy)-l-methoxy-4nitrobenzene (300 mg, 1.18 mmol, 1 equiv), NH₄C1 (192 mg, 3.59 mmol, 3.00 equiv), iron (199 mg, 3.56 mmol, 3.00 equiv), methanol (5 mL), water (1 mL). The resulting solution was stirred for 12 h at 90 °C in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with methanol/H₂O (1:4). This resulted in 200 mg (76%) of the title compound as a light brown solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.82min, LCMS07: m/z = 224 [M+l],

Step 2: Synthesis of N -(3-(2-cyclopropoxyethoxy)-4-methoxyphenyl)-N methylpyrimidine-2,4-di amine :

Into a 50-mL round-bottom flask, was placed 3-(2-cyclopropoxyethoxy)-4-methoxyaniline (200 mg, 0.90 mmol, 1 equiv), trifluoroacetic acid (306.7 mg, 2.71 mmol, 3.00 equiv), IPA (10 mL), 2-chloro-N-methylpyrimidin-4-amine (129 mg, 0.90 mmol, 1 equiv). The resulting solution was stirred for 5 h at 85 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC D TFA. This resulted in 65 mg (16%) of N -(3-(2-cyclopropoxyethoxy)-4-methoxyphenyl)-N methylpyrimidine-2,4-diamine as a white solid.

Example 124: Synthesis of Compound 456

420

Compound 456: Synthesis of N²-(3-((l-cyclopentylpyrrolidin-3-yI)methoxy)-4methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine

Step 1 : Synthesis of N²-(3 -(( 1 -cyclopentylpyrrolidin-3 -yl)methoxy)-4-methoxyphenyl)-N⁴,6 dimethylpyrimidine-2,4-diamine:

N²-(3-((l-cyclopentylpyrrolidin-3 -yl)methoxy)-4-methoxyphenyl)-N⁴,6-dimethylpyrimi dine2,4-diamine was prepared as for N²-(3-(((l-ethylpyrrolidin-3-yl)oxy)methyl)-4methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine using cyclopentanone in place of acetaldehyde in the final step.

Example 125: Synthesis of Compound 458

Compound 458: Synthesis of 6-cyclopentyl-N²-(4-methoxy-3-(3-(pyrroiidin-lyl)propoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine

Pd(dppf)CI₂.Na₂CO₃, dioxane,H₂O

BPIN

Step 1: Synthesis of 6-(cyclopent-l-en-l-yl)-2-N-[4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]phenyl]-4-N-methylpyrimidine-2,4-diamine:

Into a 40-mL round-bottom flask, was placed 6-chloro-2-N-[4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]phenyl]-4-N-methylpyrimidine-2,4-diamine (300 mg, 0.77 mmol, 1 equiv), Pd(dppf)C12 (127 mg, 0.17 mmol, 0.23 equiv), sodium carbonate (245 mg, 2.31 mmol, 3.02 equiv), dioxane (9 mL), water(3 mL), LiCl (37 mg), [cyclopent-l-en-1yl(iodo)boranyl]phosphanimine (173 mg, 0.69 mmol, 0.90 equiv). The resulting solution was stirred overnight at 80 °C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of H2O. The resulting solution was extracted with 3x20 mL of dichloromethane and the organic layers combined and dried in an oven under

421 reduced pressure. The resulting mixture was washed with 3x50 mL of IN HCl/H₂O. The pH value of the solution was adjusted to 9 with sodium carbonate (100 %). The resulting solution was extracted with 3x50 mL of dichloromethane and the organic layers combined dried in an oven under reduced pressure. The resulting mixture was concentrated under vacuum. This resulted in 500 mg (crude) of as a brown solid.

Analytical Data: LC-MS: (ES, m/z): RT= 0.914 min, LCMS 07, m/z =424 [M+l],

Step 2: Synthesis of 6-cyclopentyl-N²-(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)N⁴-methylpyrimidine-2,4-diamine:

Into a 100-mL round-bottom flask, was placed 6-(cyclopent-l-en-l-yl)-2-N-[4-methoxy-3-[3(pyrrolidin-l-yl)propoxy]phenyl]-4-N-methylpyrimidine-2,4-diamine (500 mg, 1.18 mmol, 1 equiv), Pd/C (100 mg), hydrogen (100 mL), dichloromethane (20 mL). The resulting solution was stirred ovemight at RT. The solids were fdtered out. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC C HCl. This resulted in 50.9 mg (9%) of 6-cyclopentyl-N²-(4-methoxy-3-(3-(pyrrolidin-lyl)propoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine as a white solid.

Example 126: Synthesis of Compound 459 7 4

Compound 459: Synthesis of N -(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N methyl-6-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4-diamine

(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4-diamine:

N -(4-methoxy-3-(3-(pyrrolidin-l-yl)propoxy)phenyl)-N -methyl-6-(tetrahydro-2H-pyran-4yl)pyrimidine-2,4-diamine was prepared as for 6-cyclopentyl-N²-(4-methoxy-3-(3(pyrrolidin-l-yl)propoxy)phenyl)-N⁴-methylpyrimidine-2,4-diamine using 2-(3,6-dihydro2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane in place of2-(cyclopent-l-en-l-yl)4,4,5,5-tetramethyl-l,3,2-dioxaborolane in step L

422

Example 127: Synthesis of Compound 460

Compound 460: Synthesis ofN-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridine-2yl)-6-methyl-lH-pyrazolo[4,3-c]pyridine-4-amine

Step 1: Synthesis of N-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridine-2-yl)-6-methyllH-pyrazolo[4,3-c]pyridine-4-amine:

Into a 40-mL vial purged and maintained with an inert atmosphère of nitrogen, was placed DMSO (10 mL), 4-chloro-6-methyl-lH-pyrazolo[4,3-c]pyridine (100 mg, 0.60 mmol, 1 equiv), 5-methoxy-4-[3-(pyrrolidin-l-yl)propoxy]pyridin-2-amine (180 mg, 0.72 mmol, 1.20 equiv), 3rd-Brettphos (81 mg, 0.09 mmol, 0.15 equiv), CS2CO3 (390 mg, 1.20 mmol, 2.01 equiv). The resulting solution was stirred for 4 h at 80 °C. The resulting solution was diluted with 10 mL of H₂O. The resulting solution was extracted with 3x10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x10 mL of water and

3x10 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC D TFA. This resulted in 30.4 mg (10%) ofN-(5-methoxy-4(3-(pyrrolidin-l-yl)propoxy)pyridine-2-yl)-6-methyl-lH-pyrazolo[4,3-c]pyridine-4-amine as a white solid.

Example 128: Synthesis of Compound 461

Compound 461: Synthesis of 2-(3-((2-methoxy-5-((4-methyl-6-(methylamino)pyrimidin2-yl)amino)phenoxy)methyl)pyrrolidin-l-yl)ethan-l-ol

ΗΟ^^^Βγ

Cs₂CO₃,DMF

Step 1: Synthesis of 2-(3-((2-methoxy-5-((4-methyl-6-(methylamino)pyrimidin-2yl)amino)phenoxy)methyl)pyrrolidin-1 -yl)ethan-1 -ol :

Into a 100-mL round-bottom flask, was placed 2-N-[4-methoxy-3-(pyrrolidin-3ylmethoxy)phenyl]-4-N,6-dimethylpyrimidine-2,4-diamine (200 mg, 0.58 mmol, 1 equiv), 2

423 bromoethan-l-ol (70 mg, 0.56 mmol, 1 equiv), CS2CO3 (380 mg, 1.17 mmol, 2.00 equiv), Nal (170 mg, 2.00 equiv), ACN (15 mL). The resulting solution was stirred for 4 h at 80 °C in an oil bath. The solids were fïltered out. The residue was applied onto a silica gel column with TFA:ACN (5:1). This resulted in 44.2 mg (15%) of 2-(3-((2-methoxy-5-((4-methyl-65 (methylamino)pyrimidin-2-yl)amino)phenoxy)methyl)pyrrolidin-1 -yl)ethan-1 -ol as a solid.

Example 129: Synthesis of Compound 462

Compound 462: Synthesis of N²-(3-((l-cyclopropylpyrrolidin-3-yl)methoxy)-4methoxyphenyl)-6-methyl-N⁴-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidine-2,410 diamine

TsOH,i-PrOH,85°C

Step 1: Synthesis l-cyclopropyl-3-(2-methoxy-5-nitrophenoxymethyl)pyrrolidine: Into a 100-mL round-bottom flask, was placed 3-(2-methoxy-5nitrophenoxymethyl)pyrrolidine (340 mg, 1.35 mmol, 1 equiv), (115 ethoxycyclopropoxy)trimethylsilane (354 mg, 2.03 mmol, 1.50 equiv), methanol (20 mL), NaBH₃CN (512 mg, 8.15 mmol, 6.00 equiv), HOAc (0.02 mL). The resulting solution was stirred for 30 min at 25 °C. The resulting solution was allowed to react, with stirring, for an additional 24 h while the température was maintained at 65 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by (H₂O/ACN=1/1). This resulted in 300 mg (76%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT =0.930min, LCMS 27: m/z = 293 [M+l], Step 2: Synthesis of3-[(l-cyclopropylpyrrolidin-3-yl)methoxy]-4-methoxyaniline: Into a 100-mL round-bottom flask, was placed l-cyclopropyl-3-(2-methoxy-5nitrophenoxymethyl)pyrrolidine (280 mg, 0.96 mmol, 1 equiv), Pd/C (100 mg, 0.30 equiv), methanol (15 mL), hydrogen. The resulting solution was stirred for 1 h at 25 °C. The solids

424 were filtered out and concentrated under vacuum. This resulted in 243 mg (97%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z)\ RT =0.702min, LCMS 07: m/z = 263 [M+l],

Step 3: Synthesis of N²-(3-((l-cyclopropylpyrrolidin-3-yl)methoxy)-4-methoxyphenyl)-65 methyl-N⁴-((tetrahydro-2H-pyran-4-yl)methyl)pyrimidine-2,4-diamine:

Into a 100-mL round-bottom flask, was placed 3-[(l-cyclopropylpyrrolidin-3-yl)methoxy]-4methoxyaniline (200 mg, 0.76 mmol, 1 equiv), TsOH (257 mg, 1.49 mmol, 2.00 equiv), 2chloro-6-methyl-N-(oxan-4-ylmethyl)pyrimidin-4-amine (180 mg, 0.74 mmol, 1 equiv), isopropanol (15 mL). The resulting solution was stirred for 4 h at 85 °C in an oil bath. The crude product was purified by (H2O/ACN=1/1). This resulted in 107.4 mg (24%) of N²-(3((l-cyclopropylpyrrolidin-3-yl)methoxy)-4-methoxyphenyl)-6-methyl-N⁴-((tetrahydro-2Hpyran-4-yl)methyl)pyrimidine-2,4-diamine as a white solid.

Example 130: Synthesis of Compound 463

Compound 463: Synthesis of N²-(3-(3-(cyclopropyl(methyl)amino)propoxy)-4methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine

Step 1: Synthesis of N²-(3-(3-(cyclopropyl(methyl)amino)propoxy)-4-methoxyphenyl)-N⁴,6dimethylpyrimidine-2,4-diamine:

Into a 40-mL round-bottom flask, was placed 2-N-[3-(3-chloropropoxy)-4-methoxyphenyl]4-N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.89 mmol, 1 equiv), Nmethylcyclopropanamine (76 mg, 1.07 mmol, 1.20 equiv), potassium carbonate (368 mg, 2.66 mmol, 2.99 equiv), CH₃CN (20 mL), Nal (134 mg). The resulting solution was stirred ovemight at 80 °C. The solids were filtered out. The crude product was purified by Prep25 HPLC C HCl. This resulted in 38.5 mg (11%) of N²-(3-(3(cyclopropyl(methyl)amino)propoxy)-4-methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4diamine as a white solid.

Example 131: Synthesis of Compound 464

Compound 464: Synthesis of N²-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2yl)-6-methyl-N⁴-((tetrahydro-2H-pyran-4-yl)methyl)pyridine-2,4-diamine

425

Step 1: Synthesis of N²-(5-methoxy-4-(3-(pyrrolidin-l-yl)propoxy)pyridin-2-yl)-6-methylN⁴-((tetrahydro-2H-pyran-4-yl)methyl)pyridine-2,4-diamine:

Into a 20-mL vial, was placed DMSO (10 mg, 0.13 mmol, 0.15 equiv), 2-chloro-6-methyl-N(oxan-4-ylmethyl)pyridin-4-amine (200 mg, 0.83 mmol, 1 equiv), 5-methoxy-4-[3(pyrrolidin-l-yl)propoxy]pyridin-2-amine (250 mg, 0.99 mmol, 1.20 equiv), Pd2(dba)3-CHC13 (130 mg), Xantphos (150 mg, 0.26 mmol, 0.31 equiv), CS2CO3 (54 mg, 0.17 mmol, 0.20 equiv). The vial was purged and maintained with N₂. The resulting solution was stirred for 12 h at 80°C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with H₂O/ACN (9:1). The crude product was purified by PrepHPLC D HCl. This resulted in 30.2 mg (7%) of N²-(5-methoxy-4-(3-(pyrrolidin-lyl)propoxy)pyridin-2-yl)-6-methyl-N⁴-((tetrahydro-2H-pyran-4-yl)methyl)pyridine-2,4 diamine as a white solid.

Example 132: Synthesis of Compound 465

Compound 465: Synthesis of l-(3-(2-methoxy-5-((4-methyl-6-(methylamino)pyrimidin2-yl)amino)phenoxy)propyl)azetidin-3-ol

k₂co₃,ch₃cn

Step 1: Synthesis of l-(3-(2-methoxy-5-((4-methyl-6-(methylamino)pyrimidin-2yl)amino)phenoxy)propyl)azetidin-3-ol:

Into a 50-mL round-bottom flask, was placed 2-N-[3-(3-chloropropoxy)-4-methoxyphenyl]4-N,6-dimethylpyrimidine-2,4-diamine (200 mg, 0.59 mmol, 1 equiv), potassium methaneperoxoate (246.4 mg, 1.77 mmol, 3.00 equiv), azetidin-3-ol hydrochloride (129.8 mg, 1.18 mmol, 2.00 equiv), acetonitrile (10 mL). The resulting solution was stirred for 12 h at 85 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC D TFA. This resulted in 72.5 mg (25%) of 1426 (3-(2-methoxy-5-((4-methyl-6-(methylamino)pyrimidin-2yl)amino)phenoxy)propyl)azetidin-3-ol as a solid.

Example 133: Synthesis of Compound 466

Compound 466: Synthesis of N²-(3-((l-cyclopropylpiperidin-4-yl)oxy)-4methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine

?si^x O

NaBH₃CN

H

Step 1: Synthesis of N²-(3-((l-cyclopropylpiperidin-4-yl)oxy)-4-methoxyphenyl)-N⁴,6 dimethylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-N-[4-methoxy-3-(piperidin-4-yloxy)phenyl]4-N,6-dimethylpyrimidine-2,4-diamine (150 mg, 0.44 mmol, 1 equiv), NaBHsCN (86 mg, 1.37 mmol, 3.00 equiv), methanol (5 mL), (1-ethoxycyclopropoxy) trimethylsilane (118.9 mg, 0.68 mmol, 1.50 equiv), acetic acid (10 mg, 0.17 mmol, 0.38 equiv). The resulting solution was stirred for 6 h at 65 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (150 mg) was purified by Prep-HPLC D TFA. This resulted in 55.7 mg (26%) of N²-(3-((l-cyclopropylpiperidin-4-yl)oxy)-4-methoxyphenyl)N⁴,6-dimethylpyrimidine-2,4-diamine as a white solid.

Example 134: Synthesis of Compounds 481 and 482

Compound 481 and 482: Synthesis of (S)-N²-(3-((l-cyclopropylpyrrolidin-3yl)methoxy)-4-methoxyphenyI)-N⁴,6-dimethylpyrimidine-2,4-diamine and (R)-N²-(3-((lcyclopropylpyrroIidin-3-yl)methoxy)-4-methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4diamine

Chiral-separation

427

Step 1: Synthesis of (S)-N²-(3-((l-cycIopropylpyrrolidin-3-yl)methoxy)-4-methoxyphenyl)N⁴,6-dimethylpyrimidine-2,4-diamine and (R)-N²-(3-((l-cyclopropylpyrrolidin-3yl)methoxy)-4-methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine:

Into a 100-mL round-bottom flask, was placed 2-N-[4-methoxy-3-(pyrrolidin-35 ylmethoxy)phenyl]-4-N,6-dimethylpyrimidine-2,4-diamine (400 mg, 1.16 mmol, 1 equiv), (l-ethoxycyclopropoxy)trimethylsilane (300 mg, 1.72 mmol, 1.50 equiv), AcOH (0.4 mL), methanol (20 mL), NaBH₃CN (330 mg, 5.25 mmol, 3.00 equiv). The resulting solution was stirred for 24 h at 65 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with TFA:ACN (5:1). This resulted in 31.9 mg (3%) of the racemic mixture as a white solid.

The product was Prep-Chiral-HPLC: Column: Chiralpak ID-2, 2x25cm, 5um;Mobile Phase A:Hex 0.1%DEA) HPLC, Mobile Phase B: IPA-HPLC; Flow rate: 20 mL/min; Gradient: 20 B to 20 B in 30 min; 220/254 nm. This resulted in 27.7 mg (2%) of (S)-N²-(3-((lcyclopropylpyrrolidin-3-yl)methoxy)-4-methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,415 diamine El (randomly assigned S) and 25.5mg (2%) (R)-N²-(3-((l-cyclopropylpyrrolidin-3yl)methoxy)-4-methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine E2 (randomly assigned R).

Example 135: Synthesis of Compound 498

Compound 498: Synthesis of N²-(3-(3-(5-azaspiro[2.4]heptan-5-yl)propoxy)-4methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine

4

Step 1: Synthesis of N -(3-(3-(5-azaspiro[2.4]heptan-5-yl)propoxy)-4-methoxyphenyl)-N ,6dimethylpyrimidine-2,4-diamine:

Into a 20-mL round-bottom flask, was placed 2-N-[3-(3-chloropropoxy)-4-methoxyphenyl]4-N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.89 mmol, 1 equiv), potassium carbonate (300 mg, 2.17 mmol, 2.44 equiv), CH₃CN (5 mL), Nal (135 mg), 5-azaspiro[2.4]heptane (372 mg, 3.83 mmol, 4.30 equiv). The resulting solution was stirred for 48 h at 80 °C. The crude product was purified by Prep-HPLC D TFA. This resulted in 75.7 mg (16%) of N²-(3428 (3-(5-azaspiro[2.4]heptan-5-yl)propoxy)-4-methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4diamine as a white solid.

Example 136: Synthesis of Compound 504

Compound 504: Synthesis of N²-(4-methoxy-3-(3-(2-methylpyrrolidin-lyl)propoxy)phenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine

4

Step 1: Synthesis ofN -(4-methoxy-3-(3-(2-methylpyrrolidin-l-yl)propoxy)phenyl)-N ,6dimethylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-N-[3-(3-chloropropoxy)-4-methoxyphenyl]4-N,6-dimethylpyrimidine-2,4-diamine (200 mg, 0.59 mmol, 1 equiv), 2-methylpyrrolidine (101 mg, 1.19 mmol, 2.00 equiv), Nal (89 mg, 1 equiv), potassium carbonate (246 mg, 1.78 mmol, 3.00 equiv), ACN (10 mL). The resulting solution was stirred for 12 h at 85 °C in an oil bath. The solids were filtered out. The crude product was purified by Flash-Prep-HPLC A

1:1. This resulted in 78.7 mg (31%) of N²-(4-methoxy-3-(3-(2-methylpyrrolidin-lyl)propoxy)phenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine as a white solid.

Example 137: Synthesis of Compound 518

Compound 518: Synthesis of 4-cyclopentyl-6-methoxy-N-methyl-7-(3-(pyrrolidin-l20 yl)propoxy)quinazolin-2-amine

Step 1: Synthesis of 2-chloro-4-(cyclopent-l-en-l-yl)-6-methoxy-7-[3-(pyrrolidin-lyl)propoxy] quinazoline :

429

Into a 20-mL vial purged and maintained with an inert atmosphère of nitrogen, was placed 2,4-dichloro-6-methoxy-7-[3-(pynOlidin-l-yl)propoxy]quinazoline (500 mg, 1.40 mmol, 1 equiv), Pd(dppf)2 (115 mg, 0.10 equiv), 2-(cyclopent-l-en-l-yl)-4,4,5,5-tetramethyl-l,3,2dioxaborolane (273 mg, 1.41 mmol, 1 equiv), sodium methaneperoxoate (447.9 mg, 4.19 5 mmol, 3.00 equiv), dioxane (8 mL), water (2 mL). The resulting solution was stirred for 4 h at 60 °C in an oil bath. The resulting solution was diluted with 5 mL of H₂O. The resulting solution was extracted with 3x10 mL of dichloromethane and the organic layers combined.

The resulting mixture was washed with 3x10 mL of H₂O. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with 10 methanol/H₂O (10:1). This resulted in 300 mg (55%) of as a solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.03min, m/z = 388 [M+l],

Step 2: Synthesis of 2-chloro-4-cyclopentyl-6-methoxy-7-[3-(pyrrolidin-lyl)propoxy]quinazoline:

Into a 250-mL round-bottom flask, was placed 2-chloro-4-(cyclopent-l-en-l-yl)-6-methoxy15 7-[3-(pyrrolidin-l-yl)propoxy]quinazoline (300 mg, 0.77 mmol, 1 equiv), dichloromethane (100 mL), dioxoplatinum, hydrogen . The resulting solution was stirred for 12 h at 20 °C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with CH₃CN/H₂O (1:5). This resulted in 200 mg (66%) of the title compound as a brown solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.871min, m/z =390 [M+l],

Step 3: Synthesis of 4-cyclopentyl-6-methoxy-N-methyl-7-[3-(pyrrolidin-lyl)propoxy]quinazolin-2-amine:

Into a 10-mL sealed tube, was placed 2-chloro-4-cyclopentyl-6-methoxy-7-[3-(pyrrolidin-lyl)propoxy]quinazoline (130 mg, 0.33 mmol, 1 equiv), éthanol; methanamine (2 mL). The 25 resulting solution was stirred for 3 h at 80°C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (130 mg) was purified by Flash-Prep-HPLC A Grad. This resulted in 31.2 mg (19%) of 4-cyclopentyl-6-methoxy-N-methyl-7-[3(pyrrolidin-l-yl)propoxy]quinazolin-2-amine as a yellow solid.

Example 138: Synthesis of Compound 523

Compound 523: Synthesis of 4-cyclohexyl-6-methoxy-N-methyl-7-(3-(pyrrolidin-lyl)propoxy)quinazolin-2-amine

430

Step 1: Synthesis of 2-chloro-4-(cyclohex-l-en-l-yl)-6-methoxy-7-[3-(pyrrolidin-lyl)propoxy]quinazoline:

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed 2,4-dichloro-6-methoxy-7-[3-(pyrrolidin-l-yl)propoxy]quinazoline (300 mg, 0.84 mmol, 1 equiv), (cyclohex-l-en-l-yl)boronic acid (116 mg, 0.92 mmol, 1.1 equiv), Pd(dppf)C12 dichloromethane (69 mg, 0.10 equiv), sodium carbonate (179 mg, 1.69 mmol, 2.00 equiv), dioxane (16 mL), water(4 mL). The resulting solution was stirred for 7 h at 60 °C in an oil bath. The solids were fïltered out. The resulting mixture was concentrated under vacuum. The crude product (350 mg) was purified by Flash HPLC MeOH. This resulted in 220 mg (64%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 1.08 min, LCMS 53: m/z = 402.0 [M+l]. Ή NMR (400 MHz, Methanol-i/4) δ 7.47 (s, 1H), 7.25 (s, 1H), 6.25 - 6.22 (m, 1H), 4.29 (t, J = 6.1 Hz, 2H), 3.98 (s, 3H), 2.82 - 2.74 (m, 2H), 2.67 - 2.60 (m, 4H), 2.56 - 2.49 (m, 2H), 2.39 - 2.20 (m, 2H), 2.17 — 2.10 (m, 2H), 1.97 - 1.78 (m, 8H).

Step 2: Synthesis of 2-chloro-4-cyclohexyl-6-methoxy-7-[3-(pynOlidin-lyl)propoxy] quinazoline :

Into a 100-mL round-bottom flask, was placed 2-chloro-4-(cyclohex-l-en-l-yl)-6-methoxy-7[3-(pyrrolidin-l-yl)propoxy]quinazoline (220 mg, 0.55 mmol, 1 equiv), PtO2 (200 mg), methanol (15 mL). The resulting solution was stirred for 12 h at 25 °C under H₂(g). The solids were fïltered out. The resulting mixture was concentrated under vacuum. This resulted in 218 mg (87%) of as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT =1.15 min, LCMS 53: m/z = 404.0 [M+l], Step 3: Synthesis of 4-cyclohexyl-6-methoxy-N-methyl-7-[3-(pyrrolidin-l25 yl)propoxy]quinazolin-2-amine:

Into a 50-mL round-bottom flask, was placed 2-chloro-4-cyclohexyl-6-methoxy-7-[3(pyrrolidin-l-yl)propoxy] quinazoline (200 mg, 0.50 mmol, 1 equiv), Methylamine éthanol

431 solution(32%) (15 mL, 1 equiv). The resulting solution was stirred for 1 h at 80 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (210mg) was purified by Flash HPLC A Grad. This resulted in 71.8 mg (35%) of 4-cyclohexyl-6-methoxyN-methyl-7-[3-(pynOlidin-l-yl)propoxy]quinazolin-2-amine as a yellow solid.

Example 139: Synthesis of Compound 538

Compound 538: Synthesis of N⁴-methyI-N²-(4-(3-(pyrrolidin-l-yl)propoxy)-lH-indazol6-yl)pyrimidine-2,4-diamine

Step 1: Synthesis of 4-bromo-2-fluoro-6-[3-(pyrrolidin-l-yl)propoxy]benzonitrile: Into a 100-mL round-bottom flask, was placed 4-bromo-2,6-difluorobenzonitrile (1 g, 4.59 mmol, 1 equiv), LiHMDS (5.5 mL), tetrahydrofuran (30 mL), 3-(pyrrolidin-l-yl)propan-l-ol (710 mg, 5.50 mmol, 1.20 equiv). The resulting solution was stirred for 30 min at 25 °C. The resulting solution was allowed to react, with stirring, for an additional 2 h at 25 °C. The reaction was then quenched by the addition of water. The resulting solution was extracted with 2x100 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC A. This resulted in 0.18 g of the title compound as yellow oil.

Analytical Data: *H NMR (300 MHz, Chloroform-i/) δ 7.13 - 6.95 (m, 2H), 4.22 (t, J = 6.3 Hz, 2H), 2.65-2.35 (m, 4H),2.11 - 1.76 (m, 6H).

Step 2: Synthesis of 4-bromo-2-fluoro-6-[3-(pyrrolidin-l-yl)propoxy]benzaldehyde: Into a 250-mL round-bottom flask, was placed 4-bromo-2-fluoro-6-[3-(pyrrolidin-lyl)propoxy]benzonitrile (2.3 g, 7.03 mmol, 1 equiv), DIBAL-H (12 mL), dichloromethane (50 mL). The resulting solution was stirred for 1 h at 25 °C. The resulting solution was allowed to react, with stirring, for an additional 2 h while the température was maintained at 40 °C in an oil bath. The reaction was then quenched by the addition of HCl. The resulting

432 mixture was concentrated under vacuum. The crude product was purified by Flash-PrepHPLC and this resulted in 1 g (39%) of the title compound as a yellow solid.

Analytical Data: *H NMR (300 MHz, DMSO4) δ 10.29 (d, J= 1.4 Hz, 1H), 10.14 (s, 1H), 7.32 (d, J= 10.0 Hz, 2H), 4.28 (t, J= 5.8 Hz, 2H), 3.65 - 6.48 (m, 2H), 3.02 - 2.98 (m, 2H), 2.26- 1.82 (m, 6H).

Step 3: Synthesis of 6-bromo-4-[3-(pyrrolidin-l-yl)propoxy]-lH-indazole:

Into a 50-mL round-bottom flask, was placed 4-bromo-2-fluoro-6-[3-(pyrrolidin-lyl)propoxy]benzaldehyde (1 g, 3.03 mmol, 1 equiv), NH2NH2H2O (3 mL), ethylene glycol (5 mL). The resulting solution was stirred for 2 h at 120 °C in an oil bath. The resulting solution was extracted with 2x100 mL of dichloromethane and the organic layers combined. The crude product was purified by Flash-Prep-HPLC and this resulted in 0.45 g (41%) of the title compound as a light yellow solid.

Analytical Data: *H NMR (300 MHz, Chkirofbrm-J) δ 10.35 (s, 1H), 8.08 (d, J= 1.0 Hz, 1 H), 7.26 (t, J = 1.2 Hz, 1 H), 6.63 (d, J = 1.2 Hz, 1 H), 4.21 (t, J = 6.2 Hz, 2H), 2.79 (t, J = 7.5 Hz, 2H), 2.70 (s, 4H), 2.18 (p, J = 6.6 Hz, 2H), 1.89 (p, J= 3.3 Hz, 4H).

Step 4: Synthesis of 6-bromo-4-[3-(pyrrolidin-l-yl)propoxy]-l-[[2(trimethylsilyl)ethoxy]methyl]-1 H-indazole:

Into a 250-mL round-bottom flask, was placed 6-bromo-4-[3-(pyrrolidin-l-yl)propoxy]-lHindazole (400 mg, 1.23 mmol, 1 equiv), sodium hydride (300 mg, 12.50 mmol, 10.13 equiv), tetrahydrofuran (40 mL), SEMC1 (0.6 g). The resulting solution was stirred for 20 min at 0 °C in a water/ice bath. The resulting solution was allowed to react, with stirring, for an additional 3 h at 25 °C. The reaction was then quenched by the addition of water. The resulting solution was extracted with 2x100 mL of dichloromethane and the organic layers combined. The crude product was purified by Flash-Prep-HPLC and this resulted in 0.22 g (39%) of the title compound as yellow oil.

Analytical Data: 'H NMR (300 MHz, Chloroform-r/) δ 8.14 - 8.02(m, 1H), 7.49 - 7.35(m, 1H), 6.67 - 6.48 (m, 1H), 5.66 (d, J= 2.6 Hz, 2H), 4.25 - 4.15(m, 2H), 3.69 - 3.47 (m, 2H), 3.08-2.48 (m, 6H), 2.25 - 2.12 (m, 2H), 1.27 (d,J= 1.6 Hz, 1H), 1.03 -0.84 (m, 2H), 0.10 -0.01 (m, 12H).

Step 5: Synthesis of 4-N-methyl-2-N-[4-[3-(pyrrolidin-l-yl)propoxy]-l-[[2(trimethylsilyl)ethoxy]methyl]-lH-indazol-6-yl]pyrimidine-2,4-diamine:

Into a 10-mL round-bottom flask, was placed 4-N-methylpyrimidine-2,4-diamine (200 mg, 1.61 mmol, 4.07 equiv), 6-bromo-4-[3-(pyrrolidin-l-yl)propoxy]-l-[[2(trimethylsilyl)ethoxy]methyl]-l H-indazole (180 mg, 0.40 mmol, 1 equiv), 3rd-brettphos (50

433 mg), Cs₂CO₃ (300 mg, 0.92 mmol, 2.32 equiv), dioxane (5 mL). The resulting solution was stirred for 12 h at 110 °C in an oil bath. The resulting solution was extracted with 2x50 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1x100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.22 g of the title compound as an oil.

Step 6: Synthesis of N⁴-methyl-N²-(4-(3-(pyrrolidin-l-yl)propoxy)-lH-indazol-6yl)pyrimidine-2,4-diamine:

Into a 25-mL round-bottom flask, was placed 4-N-methyl-2-N-[4-[3-(pyrrolidin-lyl)propoxy]-l-[[2-(trimethylsilyl)ethoxy]methyl]-lH-indazol-6-yl]pyrimidine-2,4-diamine jo (40 mg, 0.08 mmol, 1 equiv), trifluoroacetic acid (3 mL). The resulting solution was stirred for 30 min at 50 °C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC B. This resulted in 10 mg (33%) of N⁴-methyl-N²(4-(3-(pynOlidin-l-yl)propoxy)-lH-indazol-6-yl)pyrimidine-2,4-diamine as yellow oil.

Example 140: Synthesis of Compound 541

Compound 541: Synthesis of N⁴-methyl-N²-(piperidin-3-yl)pyrimidine-2,4-diamine

Step 1: Synthesis of N⁴-methyl-N²-(piperidin-3-yl)pyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-chloro-N-methylpyrimidin-4-amine (150 mg, 20 1.04 mmol, 1 equiv), tert-butyl 3-aminopiperidine-1-carboxylate (220 mg, 1.10 mmol, 1.05 equiv), trifluoroacetic acid (380 mg, 3.36 mmol, 3.00 equiv), IPA (5 mL). The resulting solution was stirred for 16 h at 90 °C in an oil bath. The crude product was purified by PrepHPLC C NH4HCO3. This resulted in 132.4 mg (61%) of N⁴-methyl-N²-(piperidin-3yl)pyrimidine-2,4-diamine as a white powder.

Example 141: Synthesis of Compound 542

Compound 542: Synthesis of N⁴-methyl-N²-(piperidin-4-yl)pyrimidine-2,4-diamine

434

Step 1: Synthesis of N⁴-methyl-N²-(piperidin-4-yl)pyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-chloro-N-methylpyrimidin-4-amine (150 mg, 1.04 mmol, 1 equiv), trifluoroacetic acid (480 mg, 4.25 mmol, 4.00 equiv), IPA (5 mL), tertbutyl 4-aminopiperidine-1 -carboxylate (250 mg, 1.25 mmol, 1.19 equiv). The resulting solution was stirred for 16 h at 90 °C in an oil bath. The crude product was purified by PrepHPLC C NH4HCO3. This resulted in 42.2 mg (19%) of N⁴-methyl-N²-(piperidin-4yl)pyrimidine-2,4-diamine as light yellow oil.

Example 142: Synthesis of Compound 543

Compound 543: Synthesis of N²-butyl-N⁴-methylpyrimidine-2,4-diamine

Step 1: Synthesis of N²-butyl-N⁴-methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-chloro-N-methylpyrimidin-4-amine (150 mg, 1.04 mmol, 1 equiv), butan-1-amine (80 mg, 1.09 mmol, 1.05 equiv), trifluoroacetic acid (380 mg, 3.36 mmol, 3.00 equiv), IPA (5 mL). The resulting solution was stirred for 16 h at °C in an oil bath. The crude product was purified by Prep-HPLC C NH4HCO3. This resulted in 35.1 mg (19%) of N²-butyl-N⁴-methylpyrimidine-2,4-diamine as white oil.

Analytical Data: LC-MS: (ES, m/z): RT = 1.15 min, LCMS 07: m/z = 181.1 [M+l], ’H NMR (300 MHz, MethanolY₄) δ 7.61 (d, J= 6.0 Hz, 1H), 5.77 (d, J= 6.0 Hz, 1H), 3.34 (t, J= 4.5

Hz, 1H), 3.32 (t, J= 1.5 Hz, 1H), 2.87 (s, 3H), 1.63 - 1.53 (m, 2H), 1.48- 1.36 (m, 2H), 0.98 (t,7=7.2 Hz, 3H).

Example 143: Synthesis of Compound 546

Compound 546: Synthesis of N⁴-methyl-N²-(3-methylpiperidin-3-yl)pyrimidine-2,425 diamine

NH

Step 1: Synthesis of N⁴-methyl-N²-(3-methylpiperidin-3-yl)pyrimidine-2,4-diamine:

435

Into a 50-mL round-bottom flask, was placed 2-chloro-N-methylpyrimidin-4-amine (200 mg, 1.39 mmol, 1 equiv), tert-butyl 3-amino-3-methylpiperidine-l-carboxylate (357 mg, 1.67 mmol, 1.20 equiv), trifluoroacetic acid (791 mg, 7.00 mmol, 5.02 equiv), IPA (4 mL). The resulting solution was stirred for 16 h at 90 °C in an oil bath. The crude product was purified by Prep-HPLC C NH4HCO3. This resulted in 52.4 mg (17%) N⁴-methyl-N²-(3methylpiperidin-3-yl)pyrimidine-2,4-diamine as a light yellow solid.

Example 144: Synthesis of Compound 547

Compound 547: Synthesis of N⁴-methyl-N²-(4-methylpiperidin-4-yl)pyrimidine-2,4diamine \h

Step 1: Synthesis of N⁴-methyl-N²-(4-methylpiperidin-4-yl)pyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 2-chloro-N-methylpyrimidin-4-amine (400 mg, 2.79 mmol, 1 equiv), trifluoroacetic acid (1109 mg, 9.81 mmol, 4.00 equiv), IPA (10 mL), tert-butyl 4-amino-4-methylpiperidine-l-carboxylate (573 mg, 2.67 mmol, 1.10 equiv). The 15 resulting solution was stirred for 16 h at 90 °C in an oil bath. The crude product was purified by Prep-HPLC C NH4HCO3. This resulted in 34 mg (6%) of N⁴-methyl-N²-(4methylpiperidin-4-yl)pyrimidine-2,4-diamine as a white semisolid.

Example 145: Synthesis of Compound 548

Compound 548: Synthesis of N²-((lR,3S)-3-aminocyclopentyl)-N⁴-methylpyrimidine2,4-diamine ^NH

H

Step 1: Synthesis of N²-((lR,3S)-3-aminocyclopentyl)-N⁴-methylpyrimidine-2,4-diamine: Into a 100-mL round-bottom flask, was placed 2-chloro-N-methylpyrimidin-4-amine (300 mg, 2.09 mmol, 1 equiv), trifluoroacetic acid (2.375 g, 21.01 mmol, 10.06 equiv), IPA (5 mL), tert-butyl N-[(lS,3R)-3-aminocyclopentyl]carbamate (459 mg, 2.29 mmol, 1.10 equiv).

436

The resulting solution was stirred for 16 h at 90 °C in an oil bath. The crude product was purified by Prep-HPLC C TFA. This resulted in 33.2 mg (5%) of N²-((lR,3S)-3aminocyclopentyl)-N⁴-methylpyrimidine-2,4-diamine as light yellow oil.

Example 146: Synthesis of Compound 549

Compound 549: Synthesis of N²-(l-butyl-3-methylpiperidin-3-yl)-N⁴-methylpyrimidine2,4-diamine

Step 1: Synthesis of N²-(l-butyl-3-methylpiperidin-3-yl)-N⁴-methylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed 4-N-methyl-2-N-(3-methylpiperidin-3yl)pyrimidine-2,4-diamine (150 mg, 0.68 mmol, 1 equiv), CsCO3 (231 mg, 2.50 equiv), N,Ndimethylformamide (2 mL), 1-iodobutane (187 mg, 1.02 mmol, 1.50 equiv). The resulting solution was stirred for 3 days at 20 °C. The crude product was purified by Prep-HPLC C TFA. This resulted in 53.6 mg (20%) of N²-(l-butyl-3-methylpiperidin-3-yl)-N⁴15 methylpyrimidine-2,4-diamine as a light yellow oil.

Example 147: Synthesis of Compound 550

Compound 550: Synthesis of N²-(l-butyl-4-methylpiperidin-4-yl)-N⁴-methylpyrimidine2,4-diamine

4

Step 1: Synthesis of N -(l-butyl-4-methylpiperidin-4-yl)-N -methylpyrimidine-2,4-diamine: Into a 50-mL round-bottom flask, was placed 4-N-methyl-2-N-(4-methylpiperidin-4yl)pyrimidine-2,4-diamine (220 mg, 0.99 mmol, 1 equiv), CS2CO3 (338.5 mg), N,Ndimethylformamide (3 mL), 1-iodobutane (275 mg, 1.49 mmol, 1.50 equiv). The resulting solution was stirred for 2 days at 20 °C. The residue was applied onto a silica gel column with CH3CN/H2O (40%). This resulted in 62.1 mg (23%) of N²-(l-butyl-4-methylpiperidin-4-yl)N⁴-methylpyrimidine-2,4-diamine as light yellow oil.

437

Example 148: Synthesis of Compound 551

Compound 551: Synthesis of N²-(3-(3-(cyclobutyl(methyl)amino)propoxy)-4methoxyphenyl)-N⁴,6-dimethylpyrimidine-2,4-diamine

Step 1: Synthesis of N²-(3-(3-(cyclobutyl(methyl)amino)propoxy)-4-methoxyphenyl)-N⁴,6dimethylpyrimidine-2,4-diamine:

Into a 100-mL round-bottom flask, was placed 2-N-[3-(3-chloropropoxy)-4-methoxyphenyl]4-N,6-dimethylpyrimidine-2,4-diamine (200 mg, 0.59 mmol, 1 equiv), potassium carbonate (246 mg, 1.78 mmol, 3.00 equiv), Nal (89 mg, 1 equiv), N-methylcyclobutanamine (144 mg, 1.69 mmol, 2.00 equiv), CH3CN (20 mL). The resulting solution was stirred for 10 h at 85 °C in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC C HCl. This resulted in 82.3 mg (33%) of N²-(3-(3-(cyclobutyl(methyl)amino)propoxy)-4-methoxyphenyl)-N⁴,6dimethylpyrimidine-2,4-diamine as a white solid.

Example 149: Synthesis of Compound 642

Compound 642: Synthesis of 2-N-(6-methoxy-5-[[(3R)-l-methylpyrrolidin-3yl]methoxy]pyridin-3-yl)-4-N,6-dimethylpyrimidine-2,4-diamine

Step 1: Synthesis of tert-butyl (3R)-3-[(methanesulfonyloxy)methyl]pyrrolidine-lcarboxylate:

438

Into a 100-mL round-bottom flask, was placed tert-butyl (3R)-3(hydroxymethyl)pyrrolidine-1 -carboxylate (1 g, 4.97 mmol, 1.00 equiv), dichloromethane (10 mL), TEA (1.5 g, 14.82 mmol, 3.00 equiv), MsCl (850 mg, 7.46 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 25 °C. The resulting mixture was concentrated under vacuum. This resulted in 2 g (crude) of the title compound as yellow crude oil.

Step 2: Synthesis of tert-butyl (3R)-3-[[(5-bromo-2-chloropyridin-3yl)oxy]methyl]pyrrolidine-1 -carboxylate:

Into a 100-mL round-bottom flask, was placed 5-bromo-2-chloropyridin-3-ol (1.04 g, 4.99 mmol, 1.00 equiv), tert-butyl (3R)-3-[(methanesulfonyloxy)methyl]pyrrolidine-l-carboxylate (1.4 g, 5.01 mmol, l.OOequiv), potassium carbonate (2.06 g, 14.90 mmol, 3.00 equiv), N,Ndimethylformamide (10 mL). The resulting solution was stirred for 12 h at 80 °C in an oil bath. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x30 mL of brine. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 1.4 g (72%) of the title compound as a white solid.

Analytical Data: LCMS: (ES, m/z): RT = 1.469 min, LCMS15: m/z = 393 [M+l], *H NMR: (400 MHz, Methanol-t/₄) δ 8.07 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1 H), 4.19 - 4.09 (m, 2H), 3.69-2.69 (m, 8H), 2.24- 1.76 (m, 2H), 1.48 (s, 9H).

Step 3: Synthesis of : tert-butyl (3R)-3-[[(5-bromo-2-methoxypyridin-3yl)oxy]methyl]pyrrolidine-1 -carboxylate

Into a 25-mL round-bottom flask, was placed tert-butyl (3R)-3-[[(5-bromo-2-chloropyridin-3yl)oxy]methyl]pyrrolidine-l-carboxylate (1.4 g, 3.57 mmol, 1.00 equiv), methanol (4 mL), NaOCHs/MeOH (2 mL, 1.00 equiv). The resulting solution was stirred for 12 h at 70 °C in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with 3x30 mL of ethyl acetate and the organic layers combined. This resulted in the title compound 1.4 g (crude) of as colorless oil.

Analytical Data: LC-MS: (ES, m/z): RT = 1.491 min, LCMS28: m/z = 387 [M+l],

Step 4: Synthesis of tert-butyl (3R)-3-[[(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin2-yl]amino]pyridin-3-yl)oxy]methyl]pynOlidine-l-carboxylate:

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed tert-butyl (3R)-3-[[(5-bromo-2-methoxypyridin-3yl)oxy]methyl]pyrrolidine-l-carboxylate (500 mg, 1.29 mmol, 1.00 equiv), 4-N,6dimethylpyrimidine-2,4-diamine (196.6 mg, 1.42 mmol, 1.10 equiv), CS2CO3 (1.26 g, 3.87 mmol, 3.00 equiv), 3rd-Brettphos (117.4 mg, 0.13 mmol, 0.10 equiv), DMSO (5 mL). The

439 resulting solution was stirred for 12 h at 100 °C in an oil bath. The solids were filtered out. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, H₂O:ACN = 40% ; Detector, UV 254 nm. This resulted in 340 mg (59%) of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.077 min, LCMS53: m/z = 445 [M+l].

Step 5: Synthesis of 2-N-[6-methoxy-5-[(3R)-pyrrolidin-3-ylmethoxy]pyridin-3-yl]-4-N,6dimethylpyrimidine-2,4-diamine:

Into a 50-mL round-bottom flask, was placed tert-butyl (3R)-3-[[(2-methoxy-5-[[4-methyl-6(methylamino)pyrimidin-2-yl]amino]pyridin-3-yl)oxy]methyl]pyrrolidine-l-carboxylate (340 10 mg, 0.76 mmol, 1.00 equiv), dichloromethane (5 mL), trifluoroacetic acid (1 mL). The resulting solution was stirred for 2 h at 25 °C. The resulting mixture was concentrated under vacuum. This resulted in 1 g (crude) of the title compound as yellow crude oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.814 min, LCMS33: m/z = 345 [M+l],

Step 6: Synthesis of 2-N-(6-methoxy-5-[[(3R)-l-methylpyrrolidin-3-yl]methoxy]pyridin-315 yl)-4-N,6-dimethylpyrimidine-2,4-diamine

Into a 50-mL round-bottom flask, was placed 2-N-[6-methoxy-5-[(3R)-pyrrolidin-3ylmethoxy]pyridin-3-yl]-4-N,6-dimethylpyrimidine-2,4-diamine (100 mg, 0.29 mmol, 1.00 equiv), methanol (5 mL), HCHO (29 mg, 0.97 mmol, 1.00 equiv), NaBH₃CN (115 mg, 1.83 mmol, 6.00 equiv). The resulting solution was stirred for 2 h at 25 °C. The crude product was 20 purified by Prep-HPLC with Method C NH4HCO3. This resulted in 55.8 mg (54%) of the title compound as a white solid.

Example 150: Synthesis of Compound 644

Compound 644: Synthesis of :2-N-[4-methoxy-3-([[2-(pyrrolidin-l25 yl)ethyl] amino] methyl)phenyl]-4-N,6-dimethylpyrimidine-2,4-diamine

440

Step 1: Synthesis of [(2-methoxy-5-nitrophenyl)methyl][2-(pyrrolidin-l-yl)ethyl]amine: Into a 100-mL round-bottom flask, was placed methanol (50 mL), 2-methoxy-55 nitrobenzaldehyde (1 g, 5.52 mmol, 1.00 equiv), 2-(pyrrolidin-l-yl)ethan-l-amine (630 mg, 5.52 mmol, 1.00 equiv), NaBH₃CN (1 g, 15.91 mmol, 2.88 equiv). The resulting solution was stirred for 1 h at 20 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with H2O/ACN (10:1). This resulted in 240 mg (16%) of the title as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.861min, LCMS 69: m/z = 280 [M+l], Step 2: Synthesis of tert-butyl N-[(2-methoxy-5-nitrophenyl)methyl]-N-[2-(pyrrolidin-lyl)ethyl]carbamate:

Into a 50-mL round-bottom flask, was placed dichloromethane (10 mL), [(2-methoxy-5nitrophenyl)methyl][2-(pyrrolidin-l-yl)ethyl]amine (240 mg, 0.86 mmol, 1.00 equiv), Βοο₂Ο (281 mg, 1.29 mmol, 1.50 equiv), TEA (261 mg, 2.58 mmol, 3.00 equiv), 4dimethylaminopyridine (10 mg, 0.08 mmol, 0.10 equiv). The resulting solution was stirred for 12 h at 20 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with H2O/ACN (1:1). This resulted in 170 mg (52%) ofthe title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.76 min, LCMS 45: m/z = 380 [M+l], Step 3: Synthesis of tert-butyl N-[(5-amino-2-methoxyphenyl)methyl]-N-[2-(pyrrolidin-lyl) ethyl] carbamate:

Into a 100-mL round-bottom flask, was placed ethyl acetate (10 mL), tert-butyl N-[(2methoxy-5-nitrophenyl)methyl]-N-[2-(pyrrolidin-l-yl)ethyl]carbamate (170 mg, 0.45 mmol, 25 1.00 equiv), Raney-Ni (20 mg). The flask was purged and maintained with H2.The resulting

441 solution was stirred for 1 h at 20°C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 110 mg (70%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z)·. RT = 0.86 min, LCMS 28: m/z = 350 [M +1], *H NMR (300 MHz, Methanol-^) δ 6.78 (d, J= 8.5 Hz, 1H), 6.74 - 6.60 (m, 2H), 4.41 (s, 2H), 3.76 (s, 3H), 2.57 (d, J = 13.2 Hz, 7H), 1.85- 1.74 (m, 5H), 1.48 (d, J= 17.1 Hz, 9H).

Step 4: Synthesis of tert-butyl N-[(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2yl]amino]phenyl)methyl]-N-[2-(pyrrolidin-1 -yl)ethyl]carbamate:

Into a 100-mL round-bottom flask, was placed isopropanol (10 mL), tert-butyl N-[(5-amino10 2-methoxyphenyl)methyl]-N-[2-(pynOlidin-l-yl)ethyl]carbamate (110 mg, 0.31 mmol, 1.00 equiv), 2-chloro-N,6-dimethylpyrimidin-4-amine (49 mg, 0.31 mmol, 0.99 equiv), trifluoroacetic acid (61 mg, 0.54 mmol, 1.71 equiv). The resulting solution was stirred for 2 h at 20°C. The resulting mixture was concentrated under vacuum. This resulted in 248 mg (167%) of as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 1.45 min, LCMS 33: m/z = 471 [M+l], Step 5: Synthesis of 2-N-[4-methoxy-3-([[2-(pyrrolidin-l-yl)ethyl]amino]methyl)phenyl]-4N,6-dimethylpyrimidine-2,4-diamine:

Into a 100-mL round-bottom flask, was placed dichloromethane (2 mL), tert-butyl N-[(2methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)methyl]-N-[220 (pyrrolidin-l-yl)ethyl]carbamate (248 mg, 0.53 mmol, 1.00 equiv), trifluoroacetic acid (2 mL). The resulting solution was stirred for 1 h at 20 °C. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with Method C TFA. This resulted in 70.6 mg (28%) of the title compound as a trifluoroacetic acid as an off-white solid.

Example 151: Synthesis of Compound 524

Compound 524: Synthesis of 6-methoxy-N-methyl-4-(oxan-4-yl)-7-[3-(pyrrolidin-lyl)propoxy] quinolin-2-amine

442

Step 1: Synthesis of 2,2-dimethyl-5-[(oxan-4-yl)carbonyl]-l,3-dioxane-4,6-dione:

Into a 250-mL round-bottom flask, was placed oxane-4-carboxylic acid (6 g, 46.10 mmol, 1.00 equiv), 4-dimethylaminopyridine (8.4 g, 68.76 mmol, 1.49 equiv), DCC (9.6 g, 46.53 mmol, 1.01 equiv), dichloromethane (50 mL), 2,2-dimethyl-l,3-dioxane-4,6-dione (6.6 g, 45.79 mmol, 0.99 equiv). The resulting solution was stirred for 1 ovemight at 0 °C. The resulting solution was extracted with of dichloromethane and the organic layers combined and concentrated under vacuum. This resulted in 9.2 g (78%) of the title compound as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.422 min, LCMS34, m/z=255 [M+l].

Step 2: Synthesis of methyl 3-(oxan-4-yl)-3-oxopropanoate:

Into a 100-mL round-bottom flask, was placed 2,2-dimethyl-5-[(oxan-4-yl)carbonyl]-l,3dioxane-4,6-dione (5 g, 19.51 mmol, 1.00 equiv), methanol (20 mL). The resulting solution was stirred for 1 ovemight at 60 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (31/69). This resulted in 3.2 g (88%) of the title compound as an off-white liquid.

Analytical Data: LC-MS: (ES, m/z): RT=0.735 min, LCMS34, m/z=185 [M-l]. 'H NMR: (300 MHz, Chloroform-d) δ 4.08 - 3.96 (m, 2H), 3.75 (s, 3H), 3.52 (s, 2H), 3.49 - 3.38 (m, 2H), 2.79-2.65 (m,lH), 1.87- 1.62 (m, 4H).

Step 3: N-[4-methoxy-3-[3-(pyrrolidin-l-yl)propoxy]phenyl]-3-(oxan-4-yl)-3oxopropanamide:

Into a 10-mL vial, was placed methyl 3-(oxan-4-yl)-3-oxopropanoate (500 mg, 2.69 mmol, 1.00 equiv), AlMes (0.4 mL, 3.00 equiv), toluene (2 mL), 4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]aniline (672 mg, 2.68 mmol, 1.00 equiv). The resulting solution was stirred for 48 h at 80 °C. The resulting solution was extracted with of dichloromethane and the organic layers combined and concentrated under vacuum. This resulted in 880 mg (81%) of the title compound as a brown oil.

Analytical Data: LC-MS: (ES, m/z): RT=0.600 min, LCMS45, m/z=405 [M+l],

443

Step 4: Synthesis of 6-methoxy-4-(oxan-4-yl)-7-[3-(pyrrolidin-l-yl)propoxy]quinolin-2-ol Into a 100-mL round-bottom flask, was placed N-[4-methoxy-3-[3-(pyrrolidin-lyl)propoxy]phenyl]-3-(oxan-4-yl)-3-oxopropanamide (1 g, 2.47 mmol, 1.00 equiv), sulfuric acid (5 mL). The resulting solution was stirred for 0.5 h at 50 °C. The resulting solution was extracted with of dichloromethane and the organic layers combined and concentrated under vacuum. This resulted in 960 mg (98%) of the title compound as a gray solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.837 min, LCMS07, m/z=387 [M+l], Step 5: Synthesis of 2-chloro-6-methoxy-4-(oxan-4-yl)-7-[3-(pyrrolidin-lyl)propoxy]quinoline:

Into a 50-mL round-bottom flask, was placed 6-methoxy-4-(oxan-4-yl)-7-[3-(pyrrolidin-lyl)propoxy]quinolin-2-ol (50 mg, 0.13 mmol, 1.00 equiv), phosphoroyl trichloride (2 mL).

The resulting solution was stirred for 2 h at 110 °C. The resulting solution was extracted with of dichloromethane and the organic layers combined and concentrated under vacuum. This resulted in 38 mg (73%) of the title compound as a gray solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.758 min, LCMS45, m/z = 405 [M+l], 'H NMR: (300 MHz, Chloroform-d) δ 7.39 (s, 1H), 7.17 (d, J = 13.9 Hz, 2H), 4.30 - 4.12 (m, 4H), 4.02 (s, 3H), 3.82-3.61 (m, 2H), 3.49-3.34 (m, 1H), 2.83-2.51 (m, 6H), 2.32- 1.68 (m, 10H). Step 6: Synthesis of 6-methoxy-N-methyl-4-(oxan-4-yl)-7-[3-(pyrrolidin-lyl)propoxy]quinolin-2-amine:

Into a 10-mL vial, was placed 2-chloro-6-methoxy-4-(oxan-4-yl)-7-[3-(pyrrolidin-lyl)propoxy]quinoline (300 mg, 0.74 mmol, 1.00 equiv), MeNHa-HzO (5 g). The resulting solution was stirred for 48 h at 100 °C. The resulting mixture was concentrated under vacuum. The crude product (165.1 mg) was purified by Prep-HPLC with Method D TFA. This resulted in 165.1 mg (43%) of the title compound trifluoroacetic acid as a solid.

Example 152: Synthesis of Compound 906

Compound 906: Synthesis of (2S)-l-(2-methoxy-5-[[4-methyl-6(methylamino)pyrimidin-2-yl]amino]phenoxy)-3-(pyrrolidin-l-yl)propan-2-ol

Step 1: Synthesis of (2R)-l-(5-amino-2-methoxyphenoxy)-3-(pyrrolidin-l-yl)propan-2-ol:

444

Synthesis as for Compound 1038 starting with (2R)-2-(2-methoxy-5nitrophenoxymethyl)oxirane and using pyrrolidine in place of azetidine.

Step 2: Synthesis of (2S)-l-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2yl]amino]phenoxy)-3-(pyrrolidin-l-yl)propan-2-ol:

Into a 20-mL round-bottom flask, was placed (2R)-l-(5-amino-2-methoxyphenoxy)-3(pyrrolidin-l-yl)propan-2-ol (267 mg, 1.00 mmol, 1.00 equiv), 2-chloro-N,6dimethylpyrimidin-4-amine (157 mg, 1.00 mmol, 0.99 equiv), trifluoroacetic acid (342 mg, 3.03 mmol, 3.02 equiv), IPA (10 mL). The resulting solution was stirred for 1 h at 8 °C. The solids were collected by filtration. The crude product was purified by Prep-HPLC with Method B TFA. This resulted in 12.3 mg of the title compound as a white solid.

Example 153: Synthesis of Compound 1038

Compound 1038: Synthesis of (2R)-l-(azetidin-l-yl)-3-(2-methoxy-5-[[4-methyl-6(methylamino)pyrimidm-2-yI] amino] phenoxy)propan-2-ol

''NH

TFA, IPA

Step 1: Synthesis of (2R)-l-(azetidin-l-yl)-3-(2-methoxy-5-nitrophenoxy)propan-2-ol:

Into a 40-mL round-bottom flask, was placed (2R)-2-(2-methoxy-5nitrophenoxymethyl)oxirane (1 g, 4.44 mmol, 1.00 equiv), éthanol (10 mL), chloroform (10 mL), azetidine (507 mg, 8.88 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 75 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 650 mg (52%) of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.84 min, LCMS07:m/z= 283.15 [M+l],

Step 2: Synthesis of (2R)-l-(5-amino-2-methoxyphenoxy)-3-(azetidin-l-yl)propan-2-ol:

Into a 100-mL round-bottom flask, was placed (2R)-l-(azetidin-l-yl)-3-(2-methoxy-5nitrophenoxy)propan-2-ol (600 g, 2.13 mol, 1.00 equiv), ethyl acetate (50 mL), Palladium carbon, hydrogen. The resulting solution was stirred for 1 h at 20 °C. The solids were filtered out. This resulted in the title compound 400 mg (75%) of as yellow oil.

445

Analytical Data: LC-MS: (ES, m/z): RT=0.35min, LCMS15: m/z=253.15 [M+l], Step 3: Synthesis of (2R)-l-(azetidin-l-yl)-3-(2-methoxy-5-[[4-methyl-6(methylamino)pyrimidin-2-yl]amino]phenoxy)propan-2-ol:

Into a 20-mL round-bottom flask, was placed (2R)-l-(5-amino-2-methoxyphenoxy)-35 (azetidin-l-yl)propan-2-ol (400 mg, 1.59 mmol, 1.00 equiv), trifluoroacetic acid (538 mg, 4.76 mmol, 3.00 equiv), IPA (8 mL), 2-chloro-N,6-dimethylpyrimidin-4-amine (199 mg, 1.26 mmol, 0.80 equiv). The resulting solution was stirred for 2 h at 80 °C in an oil bath. The solids were fdtered out. The resulting mixture was concentrated under vacuum. This resulted in 294.3 mg (38%) of the title compound as a trifluoroacetic acid as a pink solid.

Example 154: Synthesis of Compound 965

Compound 965: Synthesis of 2-N-[3-([[2-(azetidin-l-yl)ethyl]amino]methyl)-4methoxyphenyl]-4-N-methylpyrimidine-2,4-diamine

Step 1: Synthesis of [2-(azetidin-l-yl)ethyl][(2-methoxy-5-nitrophenyl)methyl]amine:

Into a 250-mL round-bottom flask, was placed 2-(azetidin-l-yl)ethan-l-amine (500 mg, 4.99 mmol, 1.00 equiv), 2-methoxy-5-nitrobenzaldehyde (905 mg, 5.00 mmol, 1.00 equiv) in DCE (50 mL) and stirred for 15 min at 25 °C. Then NaBH(OAc)3 (6.36 g) was added and stirred for 2 h at 25 °C. The resulting solution was extracted with 3x30 mL of dichloromethane and the organic layers combined and concentrated under vacuum. This resulted in 500 mg (38%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.726min, LCMS07: m/z = 266 [M+l],

Step 2: Synthesis of 3-((2-(azetidin-l-yl)ethylamino)methyl)-4-methoxybenzenamine:

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed Raney-Ni (100 mg), [2-(azetidin-l-yl)ethyl][(2-methoxy-5nitrophenyl)methyl]amine (400 mg, 1.51 mmol, 1.00 equiv), methanol (50 mL). The resulting

446 solution was stirred for 2 h at 25 degrees. The resulting solution was filtered and concentrated under vacuum. This resulted in 200 mg (56%) of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 0.285min, LCMS15: m/z = 236 [M+l],

Step 3: Synthesis of 2-N-[3-([[2-(azetidin-l-yl)ethyl]amino]methyl)-4-methoxyphenyl]-4-Nmethylpyrimidine-2,4-diamine:

Into a 100-mL round-bottom flask, was placed 3-([[2-(azetidin-l-yl)ethyl]amino]methyl)-4methoxyaniline (100 mg, 0.42 mmol, 1.00 equiv), 2-chloro-N,6-dimethylpyrimidin-4-amine (67 mg, 0.43 mmol, 1.00 equiv), trifluoroacetic acid (97 mg, 0.86 mmol, 2.02 equiv), IPA (10 mL). The resulting solution was stirred for 3 h at 80 °C. The resulting solution was extracted with 3x10 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The crude product was purified by Prep-HPLC with Method C NH4HCO3. This resulted in 75.8 mg (52%) of the title compound as a light brown solid.

Example 155: HPLC Methods for Compound Purification

Method A. Column: IntelFlash-1, Cl8 silica gel; Detector, UV 254 nm

A. Mobile phase, H2O/ACN

A MeOH. Mobile phase, methanol

A Grad. (IntelFlash-1): Mobile phase, H20/ACN=100/0 increasing to H20/ACN=30/70 within 30 min

A 1:1. Mobile phase, ACN/H2O=1/1

A DCM/MeOH. Mobile phase, DCM/MeOH

A EA/PE. Mobile phase, EA/PE

Method B. Column, XBridge Prep Cl8 OBD Column, 30xl00mm,5um; Detector, UV 254 nm

B HCl. Mobile phase, Water (0.05% HCl) and ACN (Gradient)

B TFA. Mobile phase, Water (0.05% TFA) and ACN (Gradient)

Method C. Column, SunFire Prep Cl8 OBD Column, 19x150mm 5um lOnm; Detector, UV 254/220nm

C HCl. Mobile phase, Water (0.05% HCl) and ACN (Gradient)

C TFA. Mobile phase, Water (0.1% TFA) and CAN (Gradient)

C NH3. Mobile phase, Water (0.05% NH3-H2O) and ACN (Gradient)

C. NH4HCO3. Mobile Phase, Water with lOmmol NH4HCO3 and ACN (Gradient)

447

Method D. Column, XSelect CSH Prep Cl8 OBD Column, 19x250mm, 5um; Detector, uv 254nm

D HCl. Mobile phase, Water (0.05% HCl) and ACN (Gradient);

D TFA. Mobile phase, Water (0.06% TFA) and ACN (Gradient); Detector 254 mu.

D NH3. Mobile phase, Water (0.05% NH3-H=2O) and ACN (20.0% ACN up to 60.0% in 7 min); Detector, UV 220nm

D NH4HCO3. Mobile Phase, Water with lOmmol NH4HCO3 and CAN (Gradient) Method E. Column: X Select Cl8, 19x150 mm, 5 um; Mobile Phase A: Water/0.05% HCl, Mobile Phase B: ACN; Detector 254 nm.

Method F. Column: X Bridge RP, 19x150 mm, 5 um; Detector 254 nm.

F HCl. Mobile phase Water (0.05% HCl) and ACN (Gradient)

F TFA. Mobile phase Water (0.05% TFA) and ACN (Gradient)

Method G. Column: GeminisoNX Cl8 AXAI Packed, 21.2x150mm 5um; Detector, UV 254nm.

G HCl Mobile phase, Water (0.05% HCl) and ACN (3.0% ACN up to 10.0% in 10 min)

G NH4HCO3. Mobile Phase, Water with lOmmol NH4HCO3 and ACN (Gradient) Method H. Column: Sunfire Prep Cl8 OBD Column, lOum, 19x250mm; Mobile phase, Water (0.05% HCl) and methanol (3.0% methanol-up to 20.0% in 8 min); Detector, UV 254nm.

Method Chiral IC. Column: Chiralpak IC, 2x25cm, 5um; Mobile phase, Hex0.1%DEA- and IPA- (hold 25.0% IPA- in 21 min); Detector, UV 220/254nm.

Method Chiral ID. Column: Chiralpak ID-2, 2x25cm, 5um; Mobile phase, Hex(0.1%DEA)and éthanol- (hold 50.0% éthanol- in 14 min); Detector, UV 220/254nm

Method Chiral IB4. Column: Chiralpak IB4.6x250,5umHPLC Chiral-A(IB)001IB00CELA026; Mobile phase, Hex (0.1%DEA):EtOH=50:50; Detector, 254nm

Method Chiral IF. Column: CHIRALPAK IF, 2x25cm,5um; Mobile phase, Hex(0.2%DEA)and IPA- (hold 30.0% IPA- in 22 min); Detector, UV 220/254nm

Other compounds were synthesized in the similar manner and the characterization data are listed in Tables IA and IB below.

Table IA

Cpd No.	Data
1	LC-MS: (ES, m/z): RT = 1.224 min, LCMS: m/z = 358.20 [M+l], 1H NMR (400

448

	MHz, Methanol-d4) δ 7.71 (s, 1H), 7.48 (s, 1H), 7.09 (d, J = 8.8 Hz, IH), 6.89 (d, J = 8.8 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 4.08 (t, J = 5.6 Hz, 2H), 3.82 (s, 3H), 2.93 (s, 3H), 2.76 (t, J = 6.4 Hz, 2H), 2.67 - 2.69 (m, 4H), 2.07 - 2.02(m, 2H), 1.86 1.85 (m, 4H).
2	LC-MS: (ES, m/z): RT = 1.035 min, LCMS: m/z = 505 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.70 (s, 1H), 7.35 (s, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.12 - 5.84 (m, 2H), 4.10 (t, J = 6.0 Hz, 2H), 3.82 (s, 3H), 3.34 3.33 (m, 2H), 3.00 - 2.97 (m, 2H), 2.82 - 2.69 (m, 8H), 2.20 (t, J = 9.6 Hz, 2H), 2.09-2.05 (m, 2H), 1.89- 1.86 (m, 4H), 1.78- 1.75 (m, 2H), 1.70- 1.60 (m, 1H), 1.35 (q, J = 3.2 Hz, 2H).
3	LC-MS: (ES, m/z): RT = 1.124min; LCMS: m/z = 442 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.72 (s, 1H), 7.36 (s, 1H), 7.13 (d, J = 8.7Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.93 (d, J = 6.0 Hz, 1H), 4.10 (t, J = 6.3 Hz, 2H), 3.97 (d, J = 1.9 Hz, 2H), 3.83 (s, 3H), 3.49 - 3.34 (m, 4H), 2.77 - 2.72 (m, 2H), 2.72 - 2.64 (m, 4H), 2.14 1.98 (m, 2H), 2.00 - 1.78 (m, 5H), 1.77 - 1.65 (m, 2H), 1.44 - 1.23 (m, 2H).
4	LC-MS: (ES, m/z): RT = 1.367 min, LCMS: m/z = 523 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.68 (d, J = 6.1 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.19-7.15 (m, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.93 (d, J = 6.0 Hz, 1H), 4.14 (t, J = 6.3 Hz, 2H), 3.83 (s, 3H), 3.33 - 3.32 (m, 2H), 3.15 - 2.97 (m, 10H), 2.37 - 2.30 (m, 2H), 2.22 2.15 (m, 2H), 2.03 - 1.98 (m, 4H), 1.76- 1.66 (m, 2H), 1.63- 1.62 (m, 1H), 1.391.30 (m, 2H).
5	LC-MS: (ES, m/z): RT = 1.115 min, LCMS: m/z = 428 [M+l], 1HNMR (400 MHz, Methanol-d4) δ 7.71 (d, J = 6.0 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.10 - 4.07 (m, 3H), 3.99 - 3.82 (m, 2H), 3.83 (s, 3H), 3.57 - 3.50 (m, 2H), 2.81 - 2.71 (m, 2H), 2.66 2.65 (m, 4H), 2.12- 1.93 (m, 4H), 1.92- 1.80 (m, 4H), 1.57 (m, 2H).
6	LC-MS: (ES, m/z): RT = 1.321 min, LCMS: m/z = 400.3 [M-HC1+1]. 1HNMR (300 MHz, Methanol-d4) δ 7.53 (d, J = 7.3 Hz, 1H), 7.13 - 6.99 (m, 3H), 6.19 (d, J = 7.3 Hz, 1H), 4.21 (t, J = 5.5 Hz, 2H), 3.91 (s, 3H), 3.87 - 3.78 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.18 (dt, J = 12.2, 7.2 Hz, 2H), 2.40 - 2.29 (m, 2H), 2.28 - 2.16 (m, 2H), 2.15- 2.04 (m, 2H), 1.45 (s, 9H).
7	LC-MS: (ES, m/z): RT = 1.013 min, LCMS: m/z = 441 [M+l], 1H NMR (300 MHz, Deuterium Oxide) δ 7.52 (d, J = 7.2 Hz, 1H), 7.19 (s, 1H), 7.02 (d, J = 8.7 Hz, 2H), 6.13 (d, J = 6.9 Hz, 1H), 4.11 (t, J = 5.7 Hz, 2H), 3.79 (s, 3H), 3.63 - 3.62 (m, 2H), 3.35 - 3.20 (m, 6H), 3.06 - 2.97 (m, 2H), 2.81 - 2.80 (m, 2H), 2.19 - 2.04 (m, 4H), 2.01 - 1.84 (m, 5H), 1.36-1.18 (m, 2H).
8	LC-MS: (ES, m/z): RT = 1.43 min, LCMS: m/z = 487 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.77 (s, 1H), 7.51 (d, J = 2.2 Hz, 1H), 7.33 - 7.17 (m, 2H), 5.99 (d, J = 6.0 Hz, 1H), 4.53 (d, J = 13.3 Hz, 1H), 4.17 (t, J = 5.8 Hz, 2H), 3.94 (d, J = 13.7 Hz, 1H), 3.19-2.93 (m, 7H), 2.72 - 2.57 (m, 1H), 2.19 - 2.12 (m, 2H), 2.10 (s, 3H), 2.02 - 1.76 (m, 8H), 1.34 - 1.07 (m, 2H).
9	LC-MS: (ES, m/z): RT= 1.976 min, LCMS: m/z = 386 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.77 (s, 2H), 7.38 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 6.0 Hz, 1H), 6.92

449

	(d, J = 8.7 Hz, 1H), 4.07 (t, J = 6.3 Hz, 2H), 3.82 (s, 3H), 2.90 (s, 3H), 2.73 (d, J = 7.5 Hz, 2H), 2.63 - 2.60 (m, 4H), 2.07 - 2.02 (m, 2H), 1.86-1.81 (m, 4H).
10	LC-MS: (ES, m/z): RT =1.509 min, LCMS: m/z = 440 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.57 (d, J = 6.2 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.95 - 6.92 (m, 1H), 6.85-6.82 (m, 1H), 6.11 (d, J = 6.4 Hz, 1H), 5.92 (s, 1H), 4.08 (t, J = 6.0 Hz, 2H), 3.84 (s, 3H), 3.24 - 3.21 (m, 2H), 3.02 (d, J = 6.4 Hz, 2H), 2.86 - 2.74 (m, 8H), 2.11- 2.04 (m, 2H), 1.93 - 1.80 (m, 7H), 1.35 - 1.29 (m, 2H).
11	LC-MS: (ES, m/z): RT = 1.776 min, LCMS: m/z = 440 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.58 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 9.6 Hz, 1H), 6.85 - 6.83 (m, 2H), 6.38 (d, J = 5.2 Hz, 1H), 6.11 (d, J = 5.2 Hz, 1H), 4.07 (t, J = 5.6 Hz, 2H), 3.80 (s, 3H), 3.60 - 3.58 (m, 2H), 3.33 - 3.28 (m, 4H), 3.13 - 3.00 (m, 4H), 2.91 2.72 (m, 2H), 2.20 - 1.97 (m, 4H), 1.90 - 1.85 (m, 5H), 1.42 - 1.23 (m, 2H).
12	LC-MS: RT= 0.918 min, LCMS: m/z = 442.30 [M+l], 1H NMR (300 MHz, Deuterium Oxide, ppm) δ: 8.28 (d, J = 7.0 Hz, 1H), 7.98 (s, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.45 (dd, J = 7.0, 2.5 Hz, 1H), 7.00 (s, 1H), 4.46 (s, 2H), 4.28 (t, J = 5.6 Hz, 2H), 4.02 (dd, J = 11.8, 4.6 Hz, 2H), 3.90 (s, 3H), 3.72-3.51 (m, 3H), 3.50-3.30 (m, 4H), 3.10-2.97 (m, 2H), 2.24-2.22 (m, 2H), 2.10-2.05 (m, 4H), 1.95-1.91 (m, 2H), 1.72-1.67 (m, 2H).
13	LC-MS: RT= 1.19 min, LCMS: m/z = 496.30 [M+l], 1H-NMR (400 MHz, Chloroform-d, ppm) δ: 7.88 (d, J = 5.7 Hz, 1H), 6.90 - 6.79 (m, 2H), 6.75 (dd, J = 8.5,2.4 Hz, 1H), 6.11 (dd, J = 5.7, 1.9 Hz, 1H), 5.94 - 5.74 (m, 2H), 4.61 (d, J = 13.5 Hz, 1H), 4.07 (t, J = 6.7 Hz, 2H), 3.88 (s, 3H), 3.82 - 3.79 (m, 1H), 3.49 (dd, J = 14.2, 7.4 Hz, 1H), 3.35 (dd, J = 14.2, 7.0 Hz, 1H), 2.98 (s, 4H), 2.65 (t, J = 7.3 Hz, 2H), 2.60-2.39 (m, 5H), 2.09 (s, 5H), 2.03-2.01 (m, 1H), 1.84- 1.60 (m, 6H), 1.21 - 1.15 (m, 2H).
14	LC-MS: (ES, m/z): RT = 2.434 min, LCMS: m/z = 484 [M+l], 1H NMR (300 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.14 (d, J = 5.6 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.20 (d, J = 5.6 Hz, 1H), 4.434.38 (m, 1H), 4.20 (d, J = 6.6 Hz, 2H), 3.98 (t, J = 6.3 Hz, 2H), 3.86 - 3.73 (m, 1H), 3.71 (s, 3H), 3.07-2.99 (m, 1H), 2.56-2.52 (m, 2H), 2.50-2.42 (m, 5H), 1.98 (s, 4H), 1.88 - 1.83 (m, 2H), 1.79 - 1.66 (m, 6H), 1.29 - 1.06 (m, 2H).
15	LC-MS: (ES, m/z): RT = 0.957 min, LCMS: m/z = 457 [M+l]. 1H NMR (300 MHz, Chloroform-d) δ 7.90 (d, J = 5.7 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 7.03 6.99 (m, 1H), 6.81 (d, J = 8.7 Hz, 2H), 5.80 (d, J = 5.7 Hz, 1H), 4.92 (br s, 1H), 4.18-4.13 (m, 1H), 4.12-4.01 (t, J = 1.5 Hz, 2H), 3.83 (s, 3H), 3.22-3.21 (m, 2H), 3.14-3.10 (m, 2H), 2.82 - 2.54 (m, 10H), 1.79- 1.67 (m, 7H), 1.30-1.16 (m, 2H).
16	LC-MS: (ES, m/z): RT = 1.423 min, LCMS: m/z = 457 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.70 (s, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.10 (t, J = 6.0 Hz, 2H), 3.82 (s, 3H), 3.72 (d, J = 4.4 Hz, 4H), 3.32 - 3.35 (m, 2H), 3.16-3.09 (m, 2H), 2.68 2.49 (m, 8H), 2.02 - 1.99 (m, 2H), 1.85 - 1.77 (m, 3H), 1.24 - 1.12 (m, 2H).
17	LC-MS: (ES, m/z): RT = 2.234 min, LCMS: m/z = 439 [M+l], 1H NMR (400

450

	MHz, Methanol-d4) δ 7.70 (s, 1H), 7.44 (d, J = 1.2 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 3.84 (s, 3H), 3.30 -3.28 (m, 2H), 3.13 - 3.10 (m, 2H), 2.92 - 2.87 (m, 4H), 2.66 - 2.60 (m, 4H), 2.07 - 2.05 (m, 1H), 1.85 - 1.79 (m,5H), 1.79 - 1.57 (m, 4H), 1.26 - 1.15 (m, 4H).
18	LC-MS: (ES, m/z): RT = 1.13 min, LCMS: m/z = 469 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.70 (s, 1H), 7.27 (d, J = 2.5 Hz, 1H), 7.15 (dd, J = 8.7, 2.5 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 4.48 (d, J = 13.3 Hz, 1H), 4.02 3.85 (m, 3H), 3.81 (s, 3H), 3.16 - 2.99 (m, 1H), 2.85-2.46 (m, 7H), 2.40 (s, 3H), 2.21 - 1.58 (m, 9H), 1.32 - 1.00 (m, 2H).
19	LC-MS: (ES, m/z): RT = 2.264 min, LCMS: m/z = 497 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.34 (s, 1H), 7.05 (d, J = 2.1 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 6.67 (s, 1H), 5.69 (s, 1H), 4.76 (s, 1H), 4.67 - 4.62 (m, 1H), 4.11 (t, J = 6.6 Hz, 2H), 3.81- 3.97 (m, 4H), 3.24 (s, 2H), 3.06 - 2.97 (m, 1H), 2.69 (s, 2H), 2.69 - 2.45 (m, 4H), 2.24 (s, 3H), 2.13 - 2.03 (m, 5H), 1.81 - 1.63 (m, 7H), 1.20- 1.88 (m, 2H).
20	1H NMR (300 MHz, Methanol-d4) δ 7.74 - 7.65 (m, 1H), 7.44 (s, 1H), 7.09 (d, J = 8.6 Hz, 1H), 6.94 - 6.84 (m, 1H), 5.93 - 5.84 (m, 1H), 4.23 (d, J = 9.8 Hz, 1H), 4.08 (d, J = 6.8 Hz, 2H), 3.82 (s, 3H), 2.77 (t, J = 7.7 Hz, 2H), 2.66 - 2.64 (m, 4H), 2.14-1.94 (m, 2H), 1.91-1.81 (m, 4H), 1.39- 1.02 (m, 6H).
21	LC-MS: (ES, m/z): RT = 0.801 min, LCMS: m/z = 434 [M+H], 1H NMR (400 MHz, Methanol-d4) δ 7.62 (d, J = 7.2 Hz, 1H), 7.42 - 7.27 (m, 5H), 7.17 (s, 1H), 7.10 - 6.96 (m, 2H), 6.24 (d, J = 7.3 Hz, 1H), 4.69 (s, 2H), 4.03 (t, J = 5.5 Hz, 2H), 3.90 (s, 3H), 3.82 - 3.77 (m, 2H), 3.41 (t, J = 7.2 Hz, 2H), 3.17 - 3.10 (m, 2H), 2.24 - 2.17 (m, 4H), 2.10 - 2.05 (m, 2H).
22	LC-MS: (ES, m/z): RT =1.160 min, LCMS: m/z = 416 [M+H], 1H NMR (400 MHz, Methanol-d4) δ 7.72 (s, 1H), 7.40 (s, 1H), 7.11 (dd, J = 8.7, 2.5 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 5.90 (d, J = 6.0 Hz, 1H), 4.04 (t, J = 6.2 Hz, 2H), 3.80 (s, 3H), 3.46 (t, J = 6.1 Hz, 4H), 3.32 (s, 3H), 2.72 - 2.63 (m, 2H), 2.62 - 2.52 (m, 4H), 2.07 - 1.95 (m, 2H), 1.91-1.75 (m, 6H).
23	LC-MS: (ES, m/z): RT = 0.643 min, LCMS: m/z = 435 [M+l], 1H NMR (300 MHz, Chloroform-d) δ 8.59 (d, J = 1.5 Hz, 1H), 7.92 (d, J = 6.0 Hz, 1H), 7.70 7.64 (m, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.23 - 7.19 (m, 1H), 7.01 - 6.97 (m, 1H), 6.82 (d, J = 8.7 Hz, 1H), 6.75 (br s, 1H), 5.93 (d, J = 5.7 Hz, 2H), 4.70 (d, J = 4.8 Hz, 2H), 4.11 (t, J = 6.6 Hz, 2H), 3.84 (s, 3H), 2.69 - 2.66 (m, 2H), 2.58-2.54 (m, 4H), 2.16 - 2.02 (m, 2H), 1.80 - 1.76 (m, 4H).
24	LC-MS: (ES, m/z): RT = 1.016 min, LCMS: m/z = 435 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.52 - 8.43 (m, 2H), 7.78 (d, J = 6.0 Hz, 1H), 7.42 - 7.39 (m, 2H), 7.23 (d, J = 3.0 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 6.02 (d, J = 5.7 Hz, 1H), 4.68 (s, 2H), 3.95 (t, J = 6.0 Hz, 2H), 3.80 (s, 3H), 2.70 2.65 (m, 6H), 2.04- 1.94 (m, 2H), 1.91-1.88 (m, 4H).
25	LC-MS: (ES, m/z): RT = 0.528 min, LCMS: m/z = 435 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.55 (d, J = 2.1 Hz, 1H), 8.43 (d, J = 1.6 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 6.0 Hz, 1H), 7.42 - 7.39 (m, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 5.99 (d, J = 6.0 Hz, 1H), 4.67 (s, 2H), 3.99 (t, J = 6.1 Hz, 2H), 3.83 (s, 3H), 2.79 - 2.72 (m, 6H), 2.04 - 1.99 (m, 2H), 1.94- 1.82 (m, 4H).

451

26	LC-MS: (ES, m/z): RT = 1.301 min, LCMS: m/z = 464 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.75 (d, J = 6.0 Hz, 1H), 7.50 (s, 1H), 7.27-7.23 (t, J = 8.1 Hz, 1H), 6.95 - 6.93 (m, 3H), 6.86 - 6.81 (m, 2H), 5.97 (d, J = 4.0 Hz, 1H), 4.62 (s, 2H), 3.92 (s, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 2.61 (m, 6H), 1.95 (q, J = 7.2 Hz, 2H), 1.87- 1.80 (m, 4H).
27	LC-MS: (ES, m/z): RT = 1.674 min, LCMS: m/z = 402 [M+l], 1H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J = 5.6 Hz, 1H), 7.35 (d, J = 1.6 Hz, 1H), 7.03 7.01 (m, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.74 (s, 1H), 5.85 (d, J = 5.6 Hz, 1H), 5.06 (br s, 1H), 4.12 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 3.58 (s, 4H), 3.41 (s, 3H), 2.67 (t, J = 7.6 Hz, 2H), 2.55 (br s, 4H), 2.14 - 2.07 (m, 2H), 1.81 - 1.77 (m, 4H).
28	LC-MS: (ES, m/z): RT = 0.799 min, LCMS: m/z = 464 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.73 (d, J = 6.0 Hz, 1H), 7.56 (br s, 1H), 7.29 (d, J = 8.8 Hz, 2H), 6.96 - 6.85 (m, 4H), 5.95 (d, J = 6.0 Hz, 1H), 4.58 (s, 2H), 3.92 (d, J = 6.4 Hz, 2H), 3.80 (d, J = 6.4 Hz, 6H), 2.60 - 2.58 (m, 6H), 1.94 (q, J = 7.6 Hz, 2H), 1.85 1.82 (m, 4H).
29	LC-MS: (ES, m/z): RT = 0.991 min, LCMS: m/z = 483 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.61 (d, J = 5.2 Hz, 1H), 7.16 (d, J = 6.8 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.19 (d, J = 7.2 Hz, 1H), 4.19 (t, J = 5.6 Hz, 2H), 3.90 (s, 3H), 3.51 3.46 (m, 9H), 3.41 - 3.32 (m, 2H), 3.06 - 2.99 (m, 2H), 2.31 - 2.25 (m, 2H), 2.15 (s, 4H), 2.10-1.95 (m, 3H), 1.62 (q, J = 7.6 Hz, 2H), 1.36 (d, J = 6.6 Hz, 6H).
30	LC-MS: (ES, m/z): RT = 1.999 min, LCMS: m/z = 438 [M+l], 1H NMR (300 MHz, Chloroform-d) δ 7.93 (d, J = 1.5 Hz, 1H), 7.61 (s, 1H), 7.45 - 7.32 (m, 2H), 7.02 (d, J = 2.5 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.74 (br s, 1H), 5.83 (d, J = 5.7 Hz, 1H), 4.86 (br s, 1H), 4.42 (d, J = 5.1 Hz, 2H), 4.07 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 2.63 - 2.61 (m, 2H), 2.58 - 2.52 (m, 4H), 2.11 - 2.02 (m, 2H), 1.82- 1.73 (m, 4H).
31	LC-MS: (ES, m/z): RT = 1.492 min, LCMS: m/z = 474 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.82 (d, J = 6.0 Hz, 1H), 7.55 - 7.52 (m, 2H), 7.28 (s, 1H), 7.25 - 7.21 (m, 2H), 6.89 (d, J = 8.8 Hz, 1H), 6.68 (d, J = 8.4Hz, 1H), 6.07 (d, J = 6.0 Hz, 1H), 4.87 (s, 2H), 3.83 (d, J = 5.6 Hz, 2H), 3.75 (s, 3H), 2.60 - 2.56 (m, 6H), 1.87- 1.82 (m, 6H).
32	LC-MS: (ES, m/z): RT =1.175 min, LCMS: m/z = 455 [M+l], 1H NMR (300 MHz, Chloroform-d) δ 7.88 (d, J = 5.7 Hz, 1H), 7.31 (d, J = 2.1 Hz, 1H), 7.05 6.91 (m, 2H), 6.82 (d, J = 9.0 Hz, 1H), 5.83 (d, J = 6.0 Hz, 1H), 5.02 (br s, 1H), 4.11 (t, J = 3.0 Hz, 2H), 3.83 (s, 3H), 3.26 - 3.24 (m, 2H), 2.99 - 2.91 (m, 8H), 2.36 (s, 3H), 2.24 - 2.19 (m, 2H), 2.17 - 2.01 (m, 2H), 1.90 - 1.94 (m, 4H), 1.80 - 1.76 (m, 2H), 1.65- 1.49 (m, 1H), 1.49- 1.25 (m, 2H).
33	LC-MS: (ES, m/z): RT = 5.231 min, LCMS: m/z = 517 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.70 (s, 1H), 7.38 (s, 1H), 7.25 - 7.21 (m, 2H), 7.12 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 8.0 Hz, 2H), 6.90 - 6.82 (m, 2H), 5.94 (d, J = 6.0 Hz, 1H), 4.11 (t, J = 6.0 Hz, 2H), 3.82 (s, 3H), 3.71 - 3.68 (m, 2H), 3.43 - 3.35 (m, 2H), 2.85-2.81 (m, 2H), 2.73 - 2.66 (m, 6H),2.11 (q, J = 6.0 Hz, 2H), 1.91-1.87 (m, 6H), 1.81-1.80 (m, 1H), 1.48 - 1.41 (m, 2H).
34	LC-MS: (ES, m/z): RT =1.313 min, LCMS: m/z = 426.15 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.74 - 7.65 (m, 1H), 7.43 (s, 1H), 7.09 (dd, J = 8.7, 2.5 Hz,

452

	1H), 6.88 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.1 Hz, 1H), 4.08 (t, J = 6.1 Hz, 2H), 3.82 (s, 3H), 3.34-3.30 (m, 2H), 2.78-2.56 (m, 6H), 2.30-2.16 (m, 1H), 2.13 - 1.97 (m, 2H), 1.93 - 1.53 (m, 10H), 1.36- 1.22 (m, 2H).
35	LC-MS: (ES, m/z): RT = 1.203 min, LCMS: m/z = 398.1 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.71 (d, J = 5.8 Hz, 1H), 7.44 (s, 1H), 7.07 (dd, J = 8.6, 2.5 Hz, 1H), 6.95 - 6.84 (m, 1H), 5.95 - 5.80 (m, 1H), 4.50 (br s, 1H), 4.12 (t, J = 6.1 Hz, 2H), 3.82 (s, 3H), 2.75 - 2.64 (m, 6H), 2.42 - 2.34 (m, 2H), 2.10 - 1.94 (m, 5H), 1.90-1.81 (m, 5H).
36	LC-MS: (ES, m/z): RT = 0.843 min, LCMS: m/z = 464 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.72 (d, J = 6.0 Hz, 1H), 7.48 (s, 1H), 7.27 - 7.22 (m, 2H), 7.00 - 6.81 (m, 4H), 5.96 (d, J = 6.0 Hz, 1H), 4.60 (s, 2H), 3.96 (t, J = 5.7 Hz, 2H), 3.87 (s, 3H), 3.80 (s, 3H), 2.76 - 2.70 (m, 6H), 2.02 - 1.95 (m, 2H), 1.93 - 1.83 (m, 4H).
37	LC-MS: (ES, m/z): RT = 1.015 min, LCMS: m/z = 449 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.45 - 8.35 (m, 2H), 7.70 (t, J = 6.8 Hz, 2H), 7.41 - 7.30 (m, 2H), 7.11 (dd, J = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.89 (d, J = 6.0 Hz, 1H), 4.04 (t, J = 6.1 Hz, 2H), 3.83 (s, 3H), 3.66 (t, J = 7.2 Hz, 2H), 2.96 (t, J = 7.2 Hz, 2H), 2.79 - 2.66 (m, 6H), 2.16 - 1.78 (m, 6H).
38	LC-MS: (ES, m/z): RT = 1.008 min, LCMS: m/z = 429.10 [M-HCl+1]. 1H NMR (300 MHz, Methanol-d4) δ 7.84 - 7.70 (m, 1H), 7.20 (s, 1H), 7.16 - 7.02 (m, 2H), 6.24 (d, J = 7.2 Hz, 1H), 4.25 (t, J = 5.4 Hz, 2H), 3.94 (s, 3H), 3.90 - 3.83 (m, 2H), 3.64 (dd, J = 6.6, 5.0 Hz, 2H), 3.53 (t, J = 7.0 Hz, 2H), 3.45 (dd, J = 6.6, 5.0 Hz, 2H), 3.26 - 3.08 (m, 2H), 2.41-2.19 (m, 4H), 2.19 - 2.05 (m, 2H), 1.90 (s, 3H).
39	LC-MS: (ES, m/z): RT = 1.005 min, LCMS: m/z = 449 [M-HCl+1]. 1H NMR (400 MHz, Deuterium Oxide) δ 8.36 (d, J = 5.7 Hz, 2H), 7.61 (d, J = 5.9 Hz, 2H), 7.42 (d, J = 7.3 Hz, 1H), 7.11 - 6.87 (m, 3H), 6.04 (d, J = 7.3 Hz, 1H), 4.05 (t, J = 5.7 Hz, 2H), 3.82 (s, 3H), 3.74 - 3.58 (m, 4H), 3.31 (t, J = 7.5 Hz, 2H), 3.14 - 2.88 (m, 4H), 2.22-1.81 (m, 6H).
40	LC-MS: (ES, m/z): RT = 1.421 min, LCMS: m/z = 464.3 [M-HCl+1], 1H NMR (400 MHz, Methanol-d4) δ 7.65 - 7.60 (m, 1H), 7.29 (t, J = 7.7 Hz, 2H), 7.24 7.20 (m, 1H), 7.08 - 7.01 (m, 2H), 6.97 - 6.94 (m, 3H), 6.26 (d, J = 6.8 Hz, 1H), 4.19 - 4.16 (m, 4H), 3.89 - 3.80 (m, 5H), 3.80 (t, J = 8.9 Hz, 2H), 3.44 (d, J = 6.6 Hz, 2H), 3.17 - 3.07 (m, 2H), 2.22 - 2.01 (m, 4H), 2.07 (d, J = 5.9 Hz, 2H).
41	LC-MS: (ES, m/z): RT = 1.414 min, LCMS: m/z = 415 [M+l], 1H NMR (300 MHz, Chloroform-d) δ 7.93 (d, J = 5.7 Hz, 1H), 7.40 (s, 1H), 6.92 - 6.89 (m, 1H), 6.88 - 6.76 (m, 2H), 6.57 (br s, 1H), 5.91 (d, J = 6.0 Hz, 1H), 5.41 (br s, 1H), 4.15 (t, J = 6.4 Hz, 2H), 4.08 (d, J = 5.2 Hz, 2H), 3.84 (s, 3H), 2.80 - 2.67 (m, 9H), 2.19 (q, J = 6.9 Hz, 2H), 1.86 - 1.84 (m, 4H).
42	LC-MS: (ES, m/z): RT = 1.67 min, LCMS: m/z = 416.25 [M-HCl+1], 1H NMR (300 MHz, Deuterium Oxide) δ 7.64 - 7.40 (m, 1H), 7.09 - 6.93 (m, 3H), 6.14 (d, J = 7.3 Hz, 1H), 4.10 (t, J = 5.6 Hz, 2H), 3.82 (s, 3H), 3.73 - 3.57 (m, 2H), 3.46 3.26 (m, 4H), 3.13-2.95 (m, 2H), 2.24-2.02 (m, 4H), 2.02 - 1.82 (m, 2H), 1.17 (s, 6H).
43	LC-MS: (ES, m/z): RT = 1.105 min, LCMS: m/z = 479 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.76 (d, J = 6.0 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.19 (d, J = 6.4 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 5.95 (d, J = 5.6 Hz, 1H), 4.07 (t, J = 6.0 Hz,

453

	2H), 3.84 - 3.81 (m, 5H), 3.34 - 3.29 (m, 2H), 2.81 (s, 6H), 2.72 (t, J = 6.0 Hz, 2H), 2.61 (d, J = 6.4 Hz, 4H), 2.08 - 2.01 (m, 2H), 1.85 - 1.83 (m, 4H).
44	LC-MS: (ES, m/z): RT = 1.063 min, LCMS: m/z = 457.15 [M-HC1+1], 1H NMR (300 MHz, Methanol-d4) δ 7.62 (t, J = 6.8 Hz, 1H), 7.20 - 7.05 (m, 3H), 6.26 - 6.16 (m, 1H), 4.21 (q, J = 5.5 Hz, 2H), 3.94 - 3.81 (m, 5H), 3.51 - 3.42 (m, 6H), 3.22 - 3.12 (m, 2H), 3.05 (s, 2H), 2.89 (s, 1H), 2.34 - 2.20 (m, 4H), 2.15 2.01 (m, 5H), 1.95 - 1.84 (m, 2H).
45	LC-MS: (ES, m/z): RT = 2.140 min, LCMS: m/z = 456.3 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.72 (d, J = 6.0 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.08 - 7.01 (m, 1H), 6.91 (d, J = 8.7 Hz, 1H), 5.99 (d, J = 6.0 Hz, 1H), 4.11 (t, J = 6.1 Hz, 2H), 3.83 (s, 3H), 3.47 (br s, 2H), 2.76 (t, J = 7.8 Hz, 2H), 2.67 - 2.65 (m, 4H), 2.11 2.00 (m, 2H), 1.89- 1.79 (m, 4H), 1.68- 1.45 (m, 9H), 1.39-1.21 (m, 1H).
46	LC-MS: (ES, m/z): RT = 1.146 min, LCMS: m/z = 424.3 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.75 (d, J = 6.0 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.00 (d, J = 8.6, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.29 (d, J = 2.2 Hz, 1H), 5.98 (d, J = 6.0, 1H), 4.66 (s, 2H), 3.98 (t, J = 5.6 Hz, 2H), 3.81 (s, 3H), 2.78 - 2.59 (m, 6H), 2.01 - 1.86 (m, 6H).
47	LC-MS: (ES, m/z): RT = 1.135 min, LCMS: m/z = 483 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.90 (d, J = 5.7 Hz, 1H), 7.25 (d, J = 5.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.68 (s, 1H), 5.82 (d, J = 5.7 Hz, 1H), 4.85 (br s, 1H), 4.67-4.62 (m, 1H), 4.11 (t, J = 6.6 Hz, 2H), 3.83 - 3.80 (m, 4H), 3.263.25 (m, 2H), 3.07 - 2.98 (m, 1H), 2.72 - 2.50 (m, 7H), 2.17 - 2.02 (m, 5H), 1.83 1.76 (m, 7H), 1.24 - 1.12 (m, 2H).
48	LC-MS: (ES, m/z): RT = 1.203 min, LCMS: m/z = 483 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.69 (s, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.53 - 7.50 (m, 1H), 6.91 (d, J = 8.8 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 4.57 (s, 2H), 4.49 - 4.48 (m, 1H), 3.92 - 3.89 (m, 1H), 3.83 (s, 3H), 3.70 (t, J = 5.6 Hz, 2H), 3.45 - 3.30 (m, 2H), 3.12 - 3.06 (m, 1H), 2.88 - 2.85 (m, 2H), 2.79 - 2.72 (m, 4H), 2.64 - 2.62 (m, 1H), 2.09 (s, 3H), 1.89- 1.95 (m, 1H), 1.92- 1.77 (m, 6H), 1.25-1.12 (m, 2H).
49	LC-MS: (ES, m/z): RT = 1.815 min, LCMS: m/z = 458.2 [M-HCl+1], 1H NMR (300 MHz, Methanol-d4) δ 7.62 (d, J = 7.0 Hz, 1H), 7.18 - 7.06 (m, 3H), 6.30 (d, J = 6.9 Hz, 1H), 4.27 - 4.18 (m, 2H), 3.91 (s, 3H), 3.85 - 3.66 (m, 6H), 3.58 (s, 2H), 3.49 (d, J = 6.7 Hz, 2H), 3.19 (d, J = 8.9 Hz, 2H), 2.38 - 2.15(m, 4H), 2.13- 2.05 (m, 2H), 1.72 - 1.62 (m, 2H), 1.54 - 1.48 (m, 2H).
50	LC-MS: (ES, m/z): RT = 1.314 min, LCMS: m/z = 426.20 [M+l], 1HNMR (300 MHz, Methanol-d4) δ 7.66 (d, J = 6.1 Hz, 1H), 7.30 (d, J = 2.5 Hz, 1H), 7.14 (dd, J = 8.7, 2.5 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 5.87 (d, J = 6.1 Hz, 1H), 4.10 (t, J = 6.1 Hz, 2H), 3.91 - 3.82 (m, 4H), 2.81 (t, J = 7.7 Hz, 2H), 7.73 - 7.71 (m, 4H), 2.14 1.96 (m, 4H), 1.93 - 1.75 (m, 6H), 1.69 - 1.59 (m, 1 H), 1.51 - 1.16 (m, 5H).
51	LC-MS: (ES, m/z): RT = 1.020 min, LCMS: m/z = 471 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.77 (d, J = 5.6 Hz, 1H), 7.18 (s, 1H), 7.14-7.11 (m, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.04 (d, J = 6.0 Hz, 1H), 4.26 (s, 2H), 4.10 (t, J = 6.0 Hz, 2H), 3.85 (s, 3H), 3.84 - 3.67 (m, 4H), 3.59 - 3.53 (m, 4H), 2.95 - 2.91 (m, 2H), 2.86 - 2.76 (m, 4H), 2.14 - 2.07 (m, 2H), 1.96 - 1.93 (m, 4H).
52	LC-MS: (ES, m/z): RT = 1.220 min, LCMS: m/z = 491 [M+l], 1H NMR (400 MHz, Chloroform-d) δ 7.86 (d, J = 5.6 Hz, 1H), 7.51 - 7.42 (m, 3H), 7.26 - 7.24

454

	(m, 2H), 7.08 - 7.05 (m, 1H), 6.93 (br s, 1H), 6.69 - 6.65 (m, 2H), 5.84 (br s, 1H), 5.72 (t, J = 4.4 Hz, 1H), 4.02 (t, J = 6.8 Hz, 2H), 3.85 (s, 5H), 3.33 (s, 3H), 2.64 (t, J = 7.6 Hz, 2H), 2.52 - 2.50 (m, 4H), 2.09 - 2.02 (m, 2H), 1.81 - 1.77 (m, 4H).
53	LC-MS: (ES, m/z): RT = 1.189 min, LCMS: m/z = 436.3 [M-HC1+1]. 1H NMR (300 MHz, Deuterium Oxide) δ 7.66 (dd, J = 7.4, 2.8 Hz, 1H), 7.49 (d, J = 10.5 Hz, 1H), 7.26 - 6.87 (m, 3H), 6.23 (d, J = 7.5 Hz, 1H), 4.53 (d, J = 7.3 Hz, 4H), 4.09 3.98 (m, 2H), 3.78 - 3.58 (m, 5H), 3.38 - 3.28 (m, 2H), 3.12 - 2.96 (m, 2H), 2.21 1.89 (m, 6H).
54	LC-MS: (ES, m/z): RT = 1.12 min, LCMS: m/z = 469 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.71 (d, J = 6.0 Hz, 1H), 7.25 (d, J = 2.5 Hz, 1H), 7.15 (dd, J = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 4.51 - 4.42 (m, 1H), 4.10-4.06 (m, 3H), 3.98-3.84-3.82 (m, 1H), 3.81 (s, 3H), 3.29 - 3.20 (m, 1H), 2.97 - 2.84 (m, 1H), 2.81 - 2.54 (m, 6H), 2.19 - 1.97 (m, 7H), 1.88 - 1.72 (m, 4H), 1.54- 1.32 (m, 2H).
55	LC-MS: (ES, m/z): RT = 1.152 min, LCMS: m/z = 497 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.56 (s, 1H), 7.26 (d, J = 2.8 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 6.87 (d, J = 8.4Hz, 1H), 4.49 - 4.46 (m, 1H), 4.07 (t, J = 6.0 Hz, 2H), 3.90 3.88 (m, 1H), 3.81 (s, 3H), 3.46 - 3.35 (m, 2H), 3.06 (t, J = 5.6 Hz, 1H), 2.72 (t, J = 5.6 Hz, 2H), 2.65 - 2.62 (m, 5H), 2.09 (s, 3H), 2.07 - 2.00 (m, 3H), 1.97 (s, 3H), 1.84- 1.77 (m, 6H), 1.23-1.11 (m, 2H).
56	LC-MS: (ES, m/z): RT = 1.34 min, LCMS: m/z = 449 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.50 (d, J = 1.6 Hz, 2H), 7.94 (d, J = 6.1 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.26 (br s, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 6.18 (d, J = 6.1 Hz, 1H), 4.93 - 4.90 (m, 2H), 3.99 - 3.95 (m, 2H), 3.82 (s, 3H), 3.25 - 3.11 (m, 9H), 2.15-2.02 (m, 6H).
57	LC-MS: (ES, m/z): RT = 1.18 min, LCMS: m/z = 487.3 [M+l], 1H NMR (300 MHz, Chloroform-d) δ 7.90 (d, J = 5.9 Hz, 1H), 7.54 (dd, J = 8.8, 2.7 Hz, 1H), 7.45 (d, J = 2.7 Hz, 1H), 6.98 (br s, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.81 (d, J = 5.9 Hz, 1H), 5.21 - 4.91 (m , 2H), 4.68 - 4.61 (m, 1H), 4.55 (s, 2H), 3.90 - 3.62 (m, 6H), 3.55 (t, J = 5.5 Hz, 2H), 3.29 - 3.13 (m, 4H), 3.11 - 2.95 (m, 1H), 2.74 (t, J = 5.4 Hz, 2H), 2.54 - 2.41 (m, 1H), 2.09 (s, 3H), 1.85 - 1.75 (m, 3H), 1.19 - 1.15 (m, 2H).
102	LC-MS: (ES, m/z): RT = 1.88 min, LCMS 07: m/z = 414 [M+l], 1H NMR (300 MHz, Chloroform-d) δ 8.00 (d, J = 6.0 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 6.96 6.91 (m, 1H), 6.82 (d, J = 8.7 Hz, 1H), 6.75 (s, 1H), 5.96 (d, J = 6.0 Hz, 1H), 4.07 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 3.78 - 3.70 (m, 4H), 3.61 - 3.44 (m, 4H), 3.66 3.64 (m, 2H), 3.54 - 3.62 (m, 4H), 2.12 - 2.05 (m, 2H), 1.78 - 2.03 (m, 4H).
103	LC-MS: (ES, m/z): RT = 1.245 min, LCMS28: m/z = 510.35 [M+l]. 1H NMR (300 MHz, Chloroform-d) δ 7.57 (d, J = 2.4 Hz, 1H), 7.27 - 7.26 (m, 1H), 6.98 - 6.92 (m, 1H), 6.80 (d, J = 8.7 Hz, 1H), 6.63 (s, 1H), 4.84 (s, 1H), 4.54 (s, 1H), 4.12 (t, J = 6.6 Hz, 2H), 3.83 (s, 3H), 3.52 - 3.42 (m, 4H), 3.26 - 3.10 (m, 4H), 2.85 - 2.60 (m, 8H), 2.24 -2.17 (m, 2H), 2.01-1.93 (m, 4H), 1.94 - 1.57 (m, 7H), 1.39 - 1.27 (m, 2H).
104	LC-MS: (ES, m/z): RT=1.410 min; LCMS15: m/z = 441 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.32 (d, J = 5.1 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.29 - 7.16

455

	(m, 1H), 6.93 (d, J = 8.7 Hz, 1H), 6.78 (d, J = 5.1 Hz, 1H), 4.09 (t, J = 6.3 Hz, 2H), 3.87 (s, 3H), 3.82 (s, 2H), 3.24 - 3.20 (m, 2H), 2.90 - 2.71 (m, 9H), 2.14 - 2.02 (m, 4H), 1.97- 1.87 (m, 4H), 1.54- 1.38 (m, 2H).
105	LC-MS: (ES, m/z): RT = 0.645 min, LCMS48: m/z = 410.3 [M+l]. 1H NMR (400 MHz, Methanol-d4) δ 7.78 - 7.70 (m, 2H), 7.59 (d, J = 7.2 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.10 (d, J = 7.2 Hz, 1H), 3.72 - 3.69 (m, 2H), 3.64 (t, J = 5.8 Hz, 2H), 3.50 - 3.42 (m, 3H), 3.42 - 3.40 (m, 1H), 340 - 3.30 (m, 2H), 3.03 - 2.97 (m, 2H), 2.05 - 1.94 (m, 3H), 1.56 - 1.47 (m, 2H).
106	LC-MS: (ES, m/z): RT = 1.477 min; LCMS 15: m/z = 483 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H), 7.25 (s, 1H), 7.17 - 7.15 (m, 3H), 4.70 (s, 3H), 4.25 (t, J = 5.6 Hz, 2H), 4.13 - 4.12 (m, 1H), 3.93 (s, 3H), 3.85 - 3.80 (m, 2H), 3.65 (s, 1H), 3.49(t, J = 7.2 Hz, 2H), 3.34 - 3.14 (m, 4H), 2.80 - 2.65 (m, 1H), 2.34 2.26 (m, 3H), 2.24-2.18 (m, 2H), 2.07 (s, 3H), 2.12 - 2.07 (m, 2H), 1.76 (s, 1H), 1.60 (s, 1H).
107	LC-MS: (ES, m/z): RT = 1.712 min, LCMS 07: m/z = 442 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.31 (d, J = 5.2 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 5.2 Hz, 1H), 4.11 (t, J = 6.0 Hz, 2H), 3.98 - 3.95 (m, 2H), 3.83 (d, J = 9.8 Hz, 5H), 3.44 (t, J = 2.0 Hz, 2H), 2.93 2.84 (m, 2H), 2.80-2.75 (m, 5H), 2.17-2.05 (m, 2H), 1.98 - 1.85 (m, 6H), 1.51 1.42 (m, 2H).
108	LC-MS: (ES, m/z): RT = 1.45 min, LCMS 33: m/z = 441 [M+l]. 1H NMR (400 MHz, Methanol-d4) δ 8.22 (s, 1H), 7.09 (d, J = 8.6 Hz, 1H), 7.03 (s, 1H), 6.98 (s, 1H), 5.90 (s, 1H), 4.22 (t, J = 5.6 Hz, 2H), 3.91 (s, 3H), 3.82 (dd, J = 10.9, 5.1 Hz, 3H), 3.53 - 3.40 (m, 5H), 3.18 (dd, J = 12.4, 6.5 Hz, 2H), 3.02 (t, J = 12.7 Hz, 2H), 2.38 - 2.16 (m, 4H), 2.17 - 1.94 (m, 5H), 1.52 (t, J = 12.7 Hz, 2H).
109	LC-MS: (ES, m/z): RT = 5.062 min, LCMS33: m/z = 440 [M+l]. 1H NMR (300 MHz, Chloroform-d) δ 7.92 (d, J = 5.7 Hz, 1H), 7.32 - 7.20 (m, 1H), 7.05 - 7.02 (m, 1H), 6.82 (d, J = 8.7 Hz, 1H), 6.70 (s, 1H), 5.82 (d, J = 5.8 Hz, 1H), 4.77 (d, J = 6.3 Hz, 1H), 4.02 (t, J = 6.9 Hz, 2H), 3.85 (s, 3H), 3.24 - 3.17 (m, 2H), 3.17-3.13 (m, 2H), 2.66 - 2.58 (m, 2H), 2.00 - 1.37 (m, 15H), 1.39 - 1.05 (m, 4H).
110	LC-MS: (ES, m/z): RT = 2.24 min; m/z = 442.10 [M+l], 1H NMR (300 MHz, CD3OD) δ: 8.13 (d, J = 7.0 Hz, 1H), 7.77 (s, 1H), 7.45 (s, 1H), 7.34 (s, 1H), 6.90 (d, J = 6.0 Hz, 1H), 4.17 (t, J = 6.0 Hz, 2H), 4.01 - 3.92 (m, 2H), 3.86 (s, 3H), 3.79 (s, 2H), 3.47-3.35 (m, 2H), 2.78 - 2.60 (m, 7H), 2.18 - 2.02 (m, 2H), 1.92-1.81 (m, 6H), 1.51 - 1.38 (m, 2H).
111	LC-MS: (ES, m/z): RT = 1.401 min, LCMS 07: m/z = 455 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.30 (d, J = 5.2 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 5.2 Hz, 1H), 4.10 (t, J = 6.0 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 2H), 2.90 - 2.87 (m, 2H), 2.84 - 2.79 (m, 2H), 2.73 (s, 4H), 2.60-2.52 (m, 1H), 2.28 (s, 3H), 2.10-2.05 (m, 4H), 1.98- 1.92 (m, 2H), 1.88 (s, 4H), 1.53 - 1.40 (m, 2H).
112	LC-MS: (ES, m/z): RT = 1.401 min, LCMS 07: m/z = 455 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.31 (d, J = 5.2 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.95 - 6.85 (m, 2H), 4.10 (t, J = 6.0 Hz, 2H), 4.02 - 3.98 (m, 2H), 3.83 (s, 3H), 3.64 (s, 2H), 3.42 - 3.36 (m, 2H), 2.80 - 2.71 (m, 2H), 2.70 - 2.68 (m, 5H), 2.35 (s, 3H), 2.09-2.05 (m, 2H), 1.88 - 1.83 (m, 6H), 1.64- 1.60 (m, 2H).
113	LC-MS: (ES, m/z): RT = 1.70 min, LCMS 15: m/z = 440 [M+l], 1H NMR (300 MHz, MethanoLd4) δ 7.22 - 7.17 (m, 2H), 7.09 - 7.06 (m, 1H), 6.87 (d, J = 8.7 Hz, 1H), 5.96 (d, J = 7.8 Hz, 1H), 5.87 (d, J = 8.1 Hz, 1H), 4.09 (t, J = 6.0 Hz, 2H)„ 3.81 (s, 3H), 3.56- 3.08 (m, 4H), 2.85 - 2.74 (m, 8H), 2.11 - 2.02 (m, 2H), 2.07 -

456

	2.02 (m, 7H), 1.97- 1.89 (m, 2H).
114	LC-MS: (ES, m/z): RT = 0.944 min, LCMS27: m/z = 466.1 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.00 (s, 1H), 7.66 (s, 1H), 7.38 - 7.25 (m, 3H), 6.15 (d, J = 6.6 Hz, 1H), 4.87 - 4.42 (m, 1H), 3.91 - 3.86 (m, 1H), 3.65 - 3.38 (m, 7H), 3.14 2.82 (m, 4H), 2.70 - 2.56 (m, 1H), 2.13 - 2.08 (m, 7H), 2.03 - 1.84 (m, 1H), 1.88 1.71 (m, 2H), 1.25 - 1.11 (m, 2H).
115	LC-MS: (ES, m/z): RT = 1.23 min, LCMS 15: m/z = 500 [M+l], 1H NMR (300 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.95 (s, 1H), 8.91 (s, 1H), 8.26 (s, 1H), 7.847.78 (m, 2H), 7.78 - 7.76 (m, 1H), 7.41 (s, 1H), 7.20 - 7.13 (m, 3H), 6.91 (d, J = 8.7 Hz, 1H), 5.95 (d, J = 6.0 Ηζ,ΙΗ), 4.30 - 4.26 ( m, 1H), 3.72- 3.68 (m, 1H), 3.58 (s, 2H), 3.25 (s, 2H), 2.91-2.72 (m, 1H), 2.51-2.45 (m, 1H), 1.92 (s, 3H), 1.781.63 (m, 3H), 1.08 -0.99 (m, 2H).
116	LC-MS: (ES, m/z): RT = 1.238 min, LCMS 28: m/z = 531 [M+l], 1H-NMR: (400 MHz, Methanol-d4) δ 7.66 - 7.57 (m, 1H), 7.43 - 7.23 (m, 5H), 7.11 (s, 3H), 6.31 6.22 (m, 1H), 4.25-4.17 (m, 1H), 4.17-4.13 (m, 1H), 3.97 - 3.85 (m, 4H), 3.85 3.72 (m, 1H), 3.72-3.60 (m, 1H), 3.53 - 3.42 (m, 4H), 3.42 - 3.34 (m, 3H), 3.06 2.95 (m, 3H), 2.40 - 2.33 (m, 2H), 2.21 - 2.10 (m, 3H), 2.07 - 1.86 (m, 4H), 1.57 1.42 (m, 2H).
117	LC-MS: (ES, m/z): RT = 1.725 min, LCMS 15: m/z = 501 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.70 (s, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 5.30 - 5.20 (m, 1H), 4.51 4.48 (m, 1H), 4.08 (t, J = 6.0 Hz, 2H), 3.93 - 3.90 (m, 1H), 3.82 (s, 3H), 3.32 - 3.28 (m, 2H), 3.08 - 2.94 (m, 3H), 2.77 - 2.63 (m, 4H), 2.48 - 2.46 (m, 1H), 2.31 - 2.12 (m, 1H), 2.10 (s, 3H), 2.09 - 1.93 (m, 4H), 1.86 - 1.78 (m, 2H), 1.25 - 1.15 (m, 2H).
118	LC-MS: (ES, m/z): RT =1.111 min, LCMS 15: m/z = 501 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.69 (s, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 5.32 - 5.09 (m, 1H), 4.50 4.46 (m, 1H), 4.07 (t, J = 6.3 Hz, 2H), 3.92 - 3.88 (m, 1H), 3.81 (s, 3H), 3.32 - 3.22 (m, 2H), 3.07 - 2.92 (m, 3H), 2.76 - 2.62 (m, 4H), 2.47 - 2.44 (m, 1H), 2.32 - 2.13 (m, 1H), 2.08- 1.92 (m, 7H), 1.85- 1.76 (m, 2H), 1.19-1.14 (m, 2H).
119	LC-MS: (ES, m/z): RT = 1.357 min, LCMS31: m/z = 497.4 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.70 (s, 1 H), 7.31 (d, J = 2.4 Hz, 1H), 7.14-7.12 (m, 1H), 6.89 (d, J = 8.8 Hz, 1H), 5.93 (d, J = 6.0 Hz, 1H), 4.52-4.48 (m, 1H), 4.05 (t, J = 6.0 Hz, 2H), 3.94 - 3.91 (m, 1H), 3.83 (s, 3H), 3.56 - 3.50 (m, 4H), 3.36 - 3.33 (m, 2H), 3.15-3.03 (m, 1H), 2.67 - 2.61 (m, 1H), 2.38 (t, J = 8.0 Hz, 2H), 2.12 - 1.99 (m, 7H), 1.96- 1.94 (m, 1H), 1.90- 1.76 (m, 2H), 1.33 - 1.07 (m, 2H).
120	LC-MS: (ES, m/z): RT = 0.82 min, LCMS 15: m/z = 469 [M+l], 1H NMR (300 MHz, Chloroform-d) δ 7.90 (d, J = 5.8 Hz, 1H), 7.26 -7.05 (m, 1H), 6.91 - 6.74 (m, 2H), 5.80 (d, J = 6.0 Hz, 1H), 4.79 (s, 1H), 4.67 (d, J = 1.8 Hz, 1H), 4.06 - 4.04 (m, 1H), 3.99 - 3.78 (m, 5H), 3.28 (s, 2H), 3.19 - 2.96 (m, 2H), 2.85 - 2.65 (m, 1H), 2.63 - 2.50 (m,3H), 2.32 -2.30 (m, 2H), 2.14 - 2.08 (m, 5H), 1.81 - 1.76 (m, 5H), 1.12-1.13 (m, 2H).
121	LC-MS: (ES, m/z): RT = 1.22 min, LCMS 07: m/z = 496 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.47 (d, J = 2.6 Hz, 1H), 7.68 (s, 1H), 7.26 (dd, J = 8.8, 2.6 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 5.91 (d, J = 6.1 Hz, 1H), 4.44 (d, J = 13.3 Hz, 1H), 3.88 (s, 4H), 3.35 (s, 2H), 3.06 (td, J = 13.4, 13.0, 2.8 Hz, 1H), 2.88 (t, J = 6.6 Hz, 2H), 2.74 - 2.58 (m, 7H), 2.08 (s, 3H), 1.97 - 1.71 (m, 7H), 1.29 - 1.07 (m, 2H).

457

122	LC-MS: (ES, m/z): RT = 1.554 min, LCMS 28: m/z = 476.2 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.27 (s, 1H), 7.75 (s, 1H), 7.40 - 7.16 (m, 3H), 6.49 (s, 1H), 5.97 (d, J = 6.0 Hz, 1H), 4.46 (d, J = 12.9 Hz, 1H), 3.87 (d, J = 13.5 Hz, 1H), 3.34 3.33 (m, 2H), 3.11 - 2.96 (m, 1H), 2.68 - 2.55 (m, 1H), 2.22 (t, J = 8.4, 1H), 2.08 (s, 3H), 1.99 - 1.70 (m, 3H), 1.31 - 1.07 (m, 4H), 1.07 - 0.97 (m, 2H).
123	LC-MS: (ES, m/z): RT = 3.287 min, LCMS 27: m/z = 476.1 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.26 (s, 1H), 7.80 - 7.70 (m, 1H), 7.36 - 7.20 (m, 3H), 5.97 (d, J = 6.0 Hz, 1H), 4.42 (d, J = 13.2 Hz, 1H), 4.12 - 3.97 (m, 1H), 3.87 (d, J= 13.7 Hz, 1H), 3.50 - 3.36 (m, 2H), 3.14 - 2.97 (m, 1H), 2.60 (t, J = 12.1 Hz, 1H), 2.06 (s, 3H), 2.01 - 1.70 (m, 3H), 1.42 - 1.02 (m, 6H).
124	LC-MS: (ES, m/z): RT = 1.277 min, LCMS 33: m/z = 398.3 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.81 (d, J = 6.1 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.10 (dd, J = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.93 (d, J = 6.1 Hz, 1H), 4.09 (t, J = 6.2 Hz, 2H), 3.82 (s, 3H), 3.70 - 3.40 (m, 4H), 2.82 - 2.57 (m, 6H), 2.14 - 1.80 (m, 10H).
125	LC-MS: (ES, m/z): RT = 4.209 min,UFLC05, LCMS 48: m/z = 412.3 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.82 (d, J = 6.3 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.00 (dd, J = 8.7, 2.4 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 6.15 (d, J = 6.3 Hz, 1H), 4.07 (t, J = 6.1 Hz, 2H), 3.81 (s, 3H), 3.72 - 3.62 (m, 4H), 2.83 - 2.63 (m, 6H), 2.14 - 1.55 (m, 12H).
126	LC-MS: (ES, m/z): RT = 1.028 min, LCMS 28: m/z = 443 [M+l], 1H-NMR: (300 MHz, Deuterium Oxide) δ 6.97 - 6.88 (m, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.75-6.67 (m, 1H), 6.03 (s, 1H), 4.32 (s, 2H), 4.07 (t, J = 5.7 Hz, 2H), 3.73 (s, 3H), 3.70 - 3.44 (m, 8H), 3.32 (t, J = 7.5 Hz, 2H), 3.12 - 2.90 (m, 4H), 2.45 - 2.29 (m, 2H), 2.19 1.99 (m, 4H), 1.99 - 1.74 (m, 4H).
127	LC-MS: (ES, m/z): RT = 1.102 min, LCMS 28: m/z = 444 [M+l], 1H-NMR: (400 MHz, Methanol-d4) δ 6.94 (d, J = 2.4 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.75 - 6.70 (m, 1H), 5.88 (s, 1H), 4.08 (t, J = 6.0 Hz, 2H), 3.99 - 3.92 (m, 2H), 3.80 (d, J = 6.4 Hz, 5H), 3.74 (s, 3H), 3.48 - 3.38 (m, 2H), 2.88 (t, J = 7.6 Hz, 2H), 2.82 - 2.73 (m, 5H), 2.14- 2.04 (m, 2H), 1.95 - 2.82 (m, 6H), 1.52 - 1.39 (m, 2H).
128	LC-MS: (ES, m/z): RT = 1.08 min; LCMS 27: m/z = 450.30 [M+l]. 1H NMR (300 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.87 (s, 1H), 7.96 (d, J - 6.0 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 6.30 (d, J = 6.1 Hz, 1H), 4.65 (s, 2H), 4.13 - 3.88 (m, 4H), 3.72 (s, 3H), 2.76 (d, J = 5.9 Hz, 2H), 2.56 (d, J = 7.0 Hz, 2H), 2.49 - 2.38 (m, 6H), 1.92 (t, J = 6.8 Hz, 2H), 1.72 - 1.61 (m, 4H).
129	LC-MS: (ES, m/z): RT = 1.15 min; LCMS 33: m/z = 423.24 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 8.30 (d, J = 5.3 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 8.7, 2.5 Hz, 1H), 6.95 - 6.78 (m, 2H), 4.04 (t, J = 6.2 Hz, 2H), 3.81 (s, 3H), 2.74 2.51 (m, 6H), 2.45 (s, 6H), 2.09- 1.93 (m, 2H), 1.89- 1.73 (m, 4H).
130	LC-MS: (ES, m/z): RT = 8.151min; m/z = 424.24 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.41 (d, J = 5.2 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.19 (dd, J = 8.7, 2.5 Hz, 1H), 6.98 - 6.85 (m, 2H), 4.07 (t, J = 6.2 Hz, 2H), 3.83 (s, 3H), 2.78 - 2.57 (m, 9H), 2.46 (s, 3H), 2.15-1.96 (m, 2H), 1.93 - 1.76 (m, 4H).
131	LC-MS: (ES, m/z): RT = 1.14 min; LCMS 33: m/z = 409.20 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.26 (d, J = 5.3 Hz, 1H), 8.09 (s, 1H), 7.34 (d, J = 2.5 Hz, 1H), 7.18 (dd, J = 8.7, 2.5 Hz, 1H), 7.00 - 6.87 (m, 2H), 4.07 (t, J = 6.2 Hz, 2H), 3.82 (s, 3H), 2.78-2.56 (m, 9H), 2.10 - 1.90 (m, 2H), 1.91 - 1.75 (m, 4H).
132	LC-MS: (ES, m/z): RT = 1.725 min, LCMS07: m/z = 441.1 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.95 - 7.93 (m, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.07 - 7.05 (m,

458

	1H), 6.95 - 6.87 (m, 1H), 6.25 - 6.16 (m, 1H), 4.31 - 4.24 (m, 2H), 4.15 - 4.05 (m, 2H), 3.96 - 3.80 (m, 5H), 3.57 - 3.48 (m, 2H), 3.04 (s, 3H), 2.89 - 2.39 (m, 6H), 2.15 - 2.07 (m, 2H), 1.91 - 1.80 (m, 4H).
133	LC-MS: (ES, m/z): RT = 2.345 min, LCMS27: m/z = 441.1 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.91 (d, J = 6.3 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.12-7.08 (m, 1H), 6.90 (d, J = 8.6 Hz, 1H), 6.22 (d, J = 6.3 Hz, 1H), 4.33 (s, 2H), 4.08 (t, J = 6.3 Hz, 2H), 4.00 - 3.90 (m, 2H), 3.81 (s, 3H), 3.38-3.31 (m, 2H), 2.76 - 2.68 (m, 2H), 2.65 - 2.60 (m, 4H), 2.12 - 1.96 (m, 2H), 1.94 - 1.76 (m, 6H).
134	LC-MS: (ES, m/z): RT = 1.133 min, LCMS 28: m/z = 478.3 [M+l]. 1H NMR (300 MHz, Deuterium Oxide) δ8.24 - 8.16 (m, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.16 - 6.92 (m, 3H), 6.60 - 6.46 (m, 1H), 4.65 (s, 1H), 4.48 (s, 1H), 4.18 - 4.04 (m, 3H), 3.95 - 3.80 (m, 4H), 3.73 - 3.65 (m, 2H), 3.38 (t, J = 7.4 Hz, 2H), 3.73 - 3.65 (m, 2H), 3.73 - 3.65 (m, 3H), 2.27 - 1.84 (m, 6H).
135	LC-MS: (ES, m/z): RT = 0.992 min, LCMS 33: m/z = 449.6 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.53 - 8.43 (m, 2H), 7.92 (d, J = 6.1 Hz, 1H), 7.77 - 7.74 (m, 1H), 7.44 - 7.40 (m, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.00 (dd, J = 8.7, 2.5 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 6.16 (d, J = 6.2 Hz, 1H), 4.94 (s, 2H), 3.91 (t, J = 6.1 Hz, 2H), 3.79 (s, 3H), 3.10 (s, 3H), 2.69 - 2.57 (m, 6H), 2.00 - 1.78 (m, 6H).
136	LC-MS: (ES, m/z): RT = 1.07 min, LCMS 33: m/z = 449.6 [M+l], 1H NMR (300 MHz, Methanol-d4) Ô8.55 - 8.52 (m, 1H), 7.90 (d, J = 6.1 Hz, 1H), 7.82 - 7.76 (m, 1H), 7.39 - 7.21 (m, 3H), 7.02 - 6.91 (m, 1H), 6.80 (d, J = 8.7 Hz, 1H), 6.15 (d, J = 6.2 Hz, 1H), 4.97 (s, 2H), 3.91 (t, J = 6.0 Hz, 2H), 3.79 (s, 3H), 3.16 (s, 3H), 2.73 2.57 (m, 6H), 2.03 - 1.79 (m, 6H).
137	LC-MS: (ES, m/z): RT = 1.071 min, LCMS 33: m/z = 400 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.99 (d, J = 6.4 Hz, 1H), 7.25 (s, 1 H), 7.11 (q, J = 8.8 Hz, 2H), 6.54 - 6.23 (m, 1H), 4.64 (s, 2H), 4.43 (s, 1H), 4.25 - 4.16 (m, 2H), 3.89 3.58 (d, 7H), 3.47 (d, J = 6.6 Hz, 2H), 3.15 (d, J = 11.1 Hz, 2H), 2.33 - 2.05 (m, 6H).
138	LC-MS: (ES, m/z): RT = 0.676min, LCMS 30: m/z = 469.2 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.75 (d, J = 13.6 Hz, 1H), 7.13 - 6.98 (m, 3H), 6.56 (dd, J = 14.4, 7.6 Hz, 1H), 4.30-4.20 (m, 2H), 4.13-3.94 (m, 2H), 3.91 (s, 3H), 3.88 - 3.73 (m, 6H), 3.71 - 3.57 (m, 2H), 3.55-3.45 (m, 2H), 3.22 - 3.12 (m, 2H), 2.30 (s, 2H), 2.27-2.15 (m, 2H), 2.16-2.02 (m, 5H), 2.00-1.82 (m, 2H).
139	LC-MS: (ES, m/z): RT = 1.04min, LCMS07: m/z = 455.15 [M+l]. 1H NMR (400 MHz, Methanol-d4) δ 7.92 (d, J = 6.2 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.07 (dd, J = 8.7, 2.4 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 6.22 (d, J = 6.2 Hz, 1H), 4.09 (t, J = 6.1 Hz, 2H), 3.83 (s, 3H), 3.81 - 3.73 (m, 2H), 3.73 - 3.62 (m, 6H), 2.83 (t, J = 7.7 Hz, 2H), 2.75 (s, 4H), 2.17 (s, 3H), 2.10 (q, J = 6.9 Hz, 2H), 1.93 - 1.85 (m, 4H).
140	LC-MS: (ES, m/z): RT = 1.09 min, LCMS 33: m/z = 416 [M+l], 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 7.88 (d, J = 6.0 Hz, 1H), 7.50 (s, 1H), 7.25 (d, J = 8.6 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.06 (d, J = 6.1 Hz, 1H), 4.54 (s, 1H), 3.98 (t, J = 6.3 Hz, 2H), 3.71 (s, 3H), 3.45 (t, J = 6.2 Hz, 2H), 3.33 (s, 2H), 3.04 (s, 3H), 2.90-2.60 (m, 6H), 1.99 (q, J = 7.0 Hz, 2H), 1.78 (s, 4H), 1.76 - 1.64 (m, 2H).
141	LC-MS: (ES, m/z): RT = 1.15min, LCMS33: m/z = 442 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.69 (d, J = 7.6 Hz, 1H), 7.16 - 7.00 (m, 3H), 6.60 (d, J = 7.7 Hz, 1H), 4.63 (d, J = 13.3 Hz, 1H), 4.19 (t, J = 5.5 Hz, 2H), 3.92 - 3.81 (m, 6H), 3.59 (m, 1H), 3.49 (t, J = 7.0 Hz, 3H), 3.16 (s, 2H), 2.31-2.11 (m, 4H), 2.11-2.07 (m, 2H), 1.77 - 1.61 (m, 4H), 1.29 (s, 3H).
142	LC-MS: (ES, m/z): RT = 1.874 min, LCMS 07: m/z = 442.10 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.80 - 7.69 (m, 1H), 7.31 - 7.01 (m, 3H), 6.71 - 6.47

459

	(m, 1H), 5.20-4.99 (m, 1H), 4.28-4.14 (m, 2H), 4.06-3.98 (m, 2H), 3.91 (s, 3H), 3.85 - 3.71 (m, 2H), 3.62 - 3.51 (m, 1H), 3.55 - 3.36 (m, 3H), 3.21 - 3.09 (m, 5H), 2.34 - 1.85 (m, 8H), 1.81 - 1.68 (m, 2H).
143	LC-MS: (ES, m/z): RT = 1.255 min, LCMS 28: m/z = 430.3 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.84 (d, J = 6.2 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.15 (dd, J = 8.7, 2.5 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 6.10 (d, J = 6.3 Hz, 1H), 4.11 (t, J = 6.1 Hz, 2H), 3.84 (s, 3H), 3.66 (t, J = 7.1 Hz, 2H), 3.46 - 3.35 (m, 5H), 3.11 (s, 3H), 2.85 - 2.66 (m, 6H), 2.16 - 2.04 (m, 2H), 1.94 - 1.84 (m, 6H).
144	LC-MS: (ES, m/z): RT = 1.07 min, LCMS 53: m/z = 400 [M+l], 1H NMR (300 MHz, Chloroform-d) δ 8.31 (d, J = 5.1 Hz, 1H), 7.32 (d, J = 3.9 Hz, 1H), 7.04 7.01 (m, 1H), 6.95 - 6.91 (m, 1H), 6.85 (d, J = 8.7 Hz, 1H), 6.63 (d, J = 5.1 Hz, 2H), 4.41 (d, J = 4.8 Hz, 2H), 4.12 (t, J = 6.6 Hz, 2H), 3.88 (s, 3H), 2.72 - 2.54 (m, 6H), 2.18-2.13 (m, 2H), 2.11 (s, 3H), 2.01-1.82(m,4H).
145	LC-MS: (ES, m/z): RT = 2.06 min, LCMS 33: m/z = 467 [M+l]. 1H NMR (400 MHz, Methanol-d4) δ 7.60 (d, J = 7.3 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.03 (d, J = 7.1 Hz, 2H), 6.21 (d, J = 7.3 Hz, 1H), 4.47 (d, J = 13.3 Hz, 1H), 4.16 (t, J = 5.8 Hz, 2H), 3.91 (d, J = 13.8 Hz, 1H), 3.80-3.70 (m, 2H), 3.51-3.39 (m, 4H), 3.23 - 3.05 (m, 3H), 2.65 (t, J = 11.8 Hz, 1H), 2.31 (t, J = 7.6 Hz, 2H), 2.26 (s, 3H), 2.22-2.15 (m, 2H), 2.14-1.88 (m, 6H), 1.79-1.70 (m, 2H), 1.34 - 1.06 (m, 2H).
146	LC-MS: (ES, m/z): RT = 1.212 min, LCMS 33: m/z = 456 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.84 (d, J = 6.2 Hz, 1H), 7.29 (s, 1H), 7.16 (dd, J = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 6.08 (d, J = 6.2 Hz, 1H), 4.09 (t, J = 6.2 Hz, 2H), 4.00 - 3.89 (m, 2H), 3.82 (s, 3H), 3.58 - 3.35 (m, 4H), 3.11 (s, 3H), 2.80 - 2.60 (m, 6H), 2.14 - 1.98 (m, 3H), 1.92 - 1.78 (m, 4H), 1.62 - 1.52 (m, 2H), 1.42 - 1.26 (m, 2H).
147	LC-MS: (ES, m/z): RT = 1.271 min, LCMS 28: m/z = 470.3 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.84 (d, J = 6.2 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.01 (dd, J = 8.7, 2.4 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 6.19 (d, J = 6.3 Hz, 1H), 4.57 (d, J = 13.1 Hz, 2H), 4.09 (t, J = 6.1 Hz, 2H), 3.83 (s, 3H), 2.92 - 2.74 (m, 4H), 2.68 (d, J = 6.3 Hz, 4H), 2.08 (d, J = 15.5 Hz, 2H), 1.87 (p, J = 2.9 Hz, 6H), 1.62 (t, J = 12.1 Hz, 1H), 1.40- 1.25 (m, 2H), 1.18 (s, 6H).
148	LC-MS: (ES, m/z): RT = 1.11 min, LCMS 33: m/z = 428.3 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.71 (dd, J = 7.9, 3.1 Hz, 1H), 7.18 - 6.98 (m, 3H), 6.60 (d, J = 7.7 Hz, 1H), 4.40-4.33 (m, 1H), 4.19 (t, J = 5.5 Hz, 2H), 4.03 - 3.97 (m, 2H), 3.91 (s, 3H), 3.86 - 3.80 (m, 2H), 3.74 - 3.54 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.21 - 3.14 (m, 2H), 2.42 - 2.19 (m, 4H), 2.13 - 2.06 (m, 2H), 2.02- 1.93 (m, 2H), 1.63 -1.56(m, 2H).
149	LC-MS: (ES, m/z): RT = 1.180min, LCMS 07: m/z = 442.25 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.70 (d, J = 7.6 Hz, 1H), 7.15 - 6.98 (m, 3H), 6.59 (d, J = 7.7 Hz, 1H), 4.19 (t, J = 5.5 Hz, 3H), 3.91 (s, 7H), 3.69 - 3.51 (m, 2H), 3.48 (d, J = 7.1 Hz, 2H), 3.42 (s, 3H), 3.29 - 3.08 (m, 2H), 2.31 - 2.25 (m, 4H), 2.10-1.70 (m, 6H).
150	LC-MS: (ES, m/z): RT = 1.121 min, LCMS28: m/z = 402.2 [M+l], 1H NMR (300 MHz, Deuterium Oxide) δ 7.56 (dd, J = 15.3, 7.6 Hz, 1H), 7.14 - 6.93 (m, 3H), 6.42 - 6.28 (m, 1H), 4.10 (t, J = 5.7 Hz, 2H), 3.86 - 3.58 (m, 9H), 3.36 (t, J = 7.5 Hz, 2H), 3.18 - 2.98 (m, 5H), 2.25- 1.86 (m, 6H).
151	LC-MS: (ES, m/z): RT =1.199 min, LCMS 28: m/z = 428.3 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.75 (d, J = 7.6 Hz, 1H), 7.10 (dd, J = 9.7, 4.6 Hz, 3H), 6.57 (dd, J = 12.5, 7.6 Hz, 1H), 4.20 (t, J = 5.6 Hz, 2H), 4.14 - 4.00 (m, 2H), 3.97 - 3.74 (m, 11H), 3.50 (t, J = 7.1 Hz, 2H), 3.18 (s, 2H), 2.42 - 1.88 (m, 8H).

460

152	LC-MS: (ES, m/z): RT = 1.72 min, LCMS 33: m/z = 476.2 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.60-7.80 (m, 1H), 7.11-7.30 (m, 3H), 6.22 (d, J = 7.3 Hz, 1H), 4.15-4.25 (m, 3H), 3.92 (s, 3H), 3.87 - 3.77 (m, 2H), 3.52 - 3.47 (m, 2H), 3.27 -3.12(m, 6H), 2.46-2.04 (m, 10H).
153	LC-MS: (ES, m/z): RT = 1.04min, LCMS07: m/z = 455.20 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.71 (d, J = 7.6 Hz, 1H), 7.19 - 6.97 (m, 3H), 6.60 (d, J = 7.7 Hz, 1H), 4.30-4.14 (m, 3H), 3.91 (s, 5H), 3.49 (t, J = 7.1 Hz, 2H), 3.35 (s, 1H), 3.17 (q, J = 12.3 Hz, 3H), 2.37 - 2.15 (m, 4H), 2.16 - 1.88 (m, 4H), 1.74 (q, J = 12.3 Hz, 2H).
154	LC-MS: (ES, m/z): RT = 1.313 min, LCMS 28: m/z = 475.3 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.69 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 7.10 - 7.00 (m, 3H), 6.86 (dd, J = 14.2, 8.0 Hz, 2H), 6.67 (t, J = 7.2 Hz, 1H), 4.81 (d, J = 12.6 Hz, 2H), 4.20 (q, J = 5.9 Hz, 3H), 3.97 (s, 3H), 3.83 (s, 2H), 3.59 - 3.43 (m, 2H), 3.35 (s, 3H), 3.30 - 3.02 (m, 2H), 2.32 - 2.04 (m, 6H).
155	LC-MS: (ES, m/z): RT = 1.01 min, LCMS 33: m/z = 450.6 [M+l], 1H NMR (300 MHz, Deuterium Oxide) δ 8.50-8.60 (m, 1H), 7.64-7.84 (m, 1H), 7.11 - 6.91 (m, 3H), 6.51-6.70 (m, 1H), 4.91 (s, 1H), 4.74 (s, 1H), 4.15 - 4.06 (m, 3H), 3.96 (t, J = 5.7 Hz, 1H), 3.82 (s, 3H), 3.69 - 3.63 (m, 2H), 3.34 (t, J = 7.5 Hz, 2H), 3.07 - 2.98 (m, 2H), 2.94 - 2.79 (m, 2H), 2.24 - 1.99 (m, 4H), 2.00 - 1.86 (m, 2H).
156	LC-MS: (ES, m/z): RT = 0.541 min, LCMS 48: m/z = 462.3 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.96 (s, 1H), 8.66 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.35 (d, J = 2.5 Hz, 1H), 7.09 (dd, J = 8.7, 2.5 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.35 (d, J = 6.2 Hz, 1H), 4.89 (s, 2H), 4.08 - 4.12 (m, 4H), 3.84 (s, 3H), 3.08 (t, J = 5.9 Hz, 2H), 2.82-2.73 (m, 2H), 2.71 -2.62 (m, 4H), 2.14 - 2.02 (m, 2H), 1.92- 1.79 (m, 4H).
157	LC-MS: (ES, m/z): RT = 1.112 min, LCMS 15: m/z = 483.30 [M+l], 1HNMR (300 MHz, Chloroform-d) δ 7.83 (d, J = 5.8 Hz, 1H), 6.87 (d, J = 9.2 Hz, 1H),6.716.83 (m, 2H), 6.34 (dd, J = 5.8, 2.1 Hz, 1H), 6.08 (d, J = 2.0 Hz, 1H), 5.83 (s, 1H), 4.64 (d, J= 13.7 Hz, 1H), 4.15 - 4.03 (m, 4H), 3.75-3.88 (s, 4H), 2.97-3.14 (m, 1 H),2.80-2.47 (m, 7H), 2.18-1.96 (m, 6H), 1.93- 1.74 (m, 6H), 1.36- 1.19 (m, 2H).
158	LC-MS: (ES, m/z): RT = 1.143 min, LCMS07: m/z = 497.3 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.63 (d, J = 6.0 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.83 - 6.79 (m, 1H), 5.81 (d, J = 6.0 Hz, 1H), 4.42 - 4.32 (m, 1H), 4.04 (t, J = 6.2 Hz, 2H), 3.84 - 3.78 (m, 4H), 3.38 (s, 3H), 3.16 - 2.94 (m, 3H), 2.73 - 2.60 (m, 7H), 2.08 - 2.00 (m, 5H), 1.85 - 1.80 (m, 5H), 1.71 - 1.55 (m, 2H), 1.12 - 0.90 (m, 2H).
159	LC-MS: (ES, m/z): RT = 1.56 min, LCMS 27: m/z = 477.1 [M+l], 1H NMR (300 MHz, Methanol-d4) Ô7.69 (d, J = 6.1 Hz, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.21 - 7.05 (m, 3H), 6.90 (d, J = 8.7 Hz, 1H), 6.76 - 6.58 (m, 3H), 5.91 (d, J = 6.0 Hz, 1H), 4.17 (t, J = 5.9 Hz, 2H), 3.85 - 3.25 (m, 4H), 2.85 (d, J = 11.5 Hz, 2H), 2.24 (s, 3H), 2.16 - 2.06 (m, 2H), 2.05 - 1.90 (m, 2H), 1.75 (d, J = 13.3 Hz, 2H), 1.70 - 1.54 (m, 1H), 1.40-1.21 (m, 2H).
160	LC-MS: (ES, m/z): RT = 1.31 min; LCMS 33: m/z = 505.30 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.70 (d, J = 6.0 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1 H), 7.18 - 7.02 (m, 3H), 6.89 (dd, J = 8.8, 1.3 Hz, 1H), 6.73 - 6.56 (m, 3H), 5.92 (d, J = 6.0 Hz, 1H), 4.45 (d, J = 13.3 Hz, 1H), 4.17-4.14 (m, 2H), 3.89 - 3.84 (m, 4H), 3.38 3.20 (m, 4H), 3.09-2.93 (m, 1H), 2.71 -2.51 (m, 1H), 2.16 - 2.01 (m, 5H), 1.951.68 (m, 3H), 1.23 - 1.00 (m, 2H).
161	LC-MS: (ES, m/z): RT = 1.106 min, LCMS 33: m/z = 469 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.86 (d, J = 6.2 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.02 (dd, J

461

	= 8.7, 2.4 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 6.21 (d, J = 6.3 Hz, 1H), 4.42 (d, J = 13.6 Hz, 2H), 4.13 - 3.89 (m, 3H), 3.82 (s, 3H), 3.16 - 3.00 (m, 2H), 2.81 - 2.58 (m, 6H), 2.18-1.68 (m, 11 H), 1.52- 1.34 (m, 2H).
162	LC-MS: (ES, m/z): RT = 1.78min, LCMS07: m/z = 491.20 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.92 (d, J = 6.1 Hz, 1H), 7.35 (d, J = 2.5 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 6.25 (d, J = 6.2 Hz, 1H), 4.09 (t, J = 6.2 Hz, 2H), 3.85-3.81 (m, 7H), 3.50 - 3.29 (m, 4H), 2.87 (s, 3H), 2.84 - 2.76 (m, 2H), 2.71(d, J = 5.9 Hz, 4H), 2.14 - 2.02 (m, 2H), 1.92 - 1.84 (m, 4H).
163	LC-MS: (ES, m/z): RT = 1.18 min, LCMS 33: m/z = 496 [M+l], 1H NMR (400 MHz, DMSO-d6) δ 7.57 (d, J = 7.3 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.96 - 6.81 (m, 2H), 6.61 (s, 1H), 5.93 (s, 1H), 4.37 (d, J = 13.0 Hz, 1H), 4.05 (t, J = 6.0 Hz, 2H), 3.88-3.78 (m, 4H), 3.61 - 3.53 (m, 2H), 3.47 - 3.22 (m, 4H), 3.07 - 2.90 (m, 6H), 2.44 (t, J = 12.4 Hz, 1H), 2.18-2.08 (m, 2H), 2.01 (d, J = 6.8 Hz, 2H), 1.98 (s, 3H), 1.92-1.82 (m, 3H), 1.61 - 1.51 (m, 2H), 1.20 - 1.10 (m, 1H), 1.09-0.96 (m, 1H).
164	LC-MS: RT = 2.26min, LCMS07: m/z = 474 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 9.12 (s, 1H), 8.56 (d, J = 5.4 Hz, 1H), 7.73 - 7.64 (m, 2H), 7.51 (d, J = 5.4 Hz, 1H), 7.47 - 7.37 (m, 2H), 7.26 (dd, J = 8.7, 2.5 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 4.15 (t, J = 6.1 Hz, 2H), 3.89 - 3.85 (m, 5H), 2.84- 2.75 (m, 2H), 2.67 (t, J = 6.2 Hz, 4H), 2.15 -2.08 (m, 2H), 1.90 - 1.81 (m, 4H).
165	LC-MS: (ES, m/z): RT = 0.61 min, LCMS 32: m/z = 451.4 [M+l], 1HNMR (300 MHz, Methanol-d4) δ 7.75 (d, J = 6.0 Hz, 1H), 7.65 (dd, J = 9.4, 2.6 Hz, 1H), 7.44 - 7.33 (m, 2H), 7.06 (dd, J = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 6.53 (dd, J = 9.3, 0.8 Hz, 1H), 5.95 (d, J = 6.0 Hz, 1H), 4.41 (s, 2H), 4.05 (t, J = 6.0 Hz, 2H), 3.83 (s, 3H), 2.87 - 2.78 (m, 6H), 2.14 - 1.98 (m, 2H), 1.96 - 1.88 (m, 4H).
166	LC-MS: (ES, m/z): RT = 0.826 min, LCMS 30: m/z = 497 [M+l], 1H NMR (400 MHz, Chloroform-d) δ 7.70 (s, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 6.4 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 5.90 (d, J = 6.0 Hz, 1H), 4.45 - 4.40 (m, 1H), 4.30 (t, J = 6.0 Hz, 2H), 3.90 - 3.86 (m, 1H), 3.77 (s, 3H), 3.61 (t, J = 6.8 Hz, 2H), 3.42 (t, J = 6.8 Hz, 2H), 3.32 -3.30 (m, 2H), 3.06 (t, J = 1.2 Hz, 1H), 2.80 (t, J = 6.4 Hz, 2H), 2.60 (t, J = 2.8 Hz, 1H), 2.06 (s, 3H), 1.99 - 1.75 (m, 7H), 1.23 - 1.10 (m, 2H).
167	LC-MS: (ES, m/z): RT = 1.356 min, LCMS 15: m/z = 449.25 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.69 - 8.59 (m, 1H), 8.50 (t, J = 7.9 Hz, 1H), 7.97 (d, J = 7.9, 5.8 Hz, 2H), 7.63 (d, J = 7.2 Hz, 1H), 7.15 - 7.07 (m, 2H), 7.03 (d, J = 8.6, 2.4 Hz, 1H), 6.22 (d, J = 7.3 Hz, 1H), 4.23 (t, J = 5.6 Hz, 2H), 4.00 - 3.89 (m, 5H), 3.89 - 3.75 (m, 2H), 3.61 - 3.49 (m, 4H), 3.22 - 3.08 (m, 2H), 2.35 - 2.16 (m, 4H), 2.15-2.00 (m, 2H).
168	LC-MS: (ES, m/z): RT = 1.165 min, LCMS53: m/z = 490.30 [M+l], 1H NMR (300 MHz, Deuterium Oxide) δ 8.04 -7.96 (m, 1H),7.88 - 7.78 (m, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 9.3 Hz, 1H), 7.13- 6.98 (m, 3H), 6.97 - 6.89 (m, 1H), 6.40 (d, J = 7.6 Hz, 1H), 4.10 (t, J = 5.9 Hz, 4H), 3.89 (s, 4H), 3.82 (s, 5H), 3.72 - 3.59 (m, 2H), 3.36 (t, J = 7.5 Hz, 2H), 3.12 - 2.96 (m, 2H), 2.25 - 2.02 (m, 4H), 1.94 (m,2H).
169	LC-MS: (ES, m/z): RT = 1.081 min, LCMS 33: m/z = 462 [M+l], 1H-NMR: (400 MHz, Methanol-d4) δ 7.99 (d, J = 6.0 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.07 - 7.03 (m, 1H), 6.4 (d, J = 8.8 Hz, 1H), 6.35 (d, J = 6.4 Hz, 1H), 4.28 - 4.08 (m, 4H), 4.06 (t, J = 6.2 Hz, 2H), 3.83 (s, 3H), 3.20-3.11 (m, 4H), 2.78 - 2.69 (m, 2H), 2.62 (q, J = 4.4 Hz, 4H), 2.11 -1.99 (m, 2H), 1.90- 1.80 (m, 4H).
170	LC-MS: (ES, m/z): RT = 1.068 min, LCMS 07: m/z = 455 [M+l], 1H-NMR: (400 MHz, Methanol-d4) δ 7.86 (d, J = 6.0 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.08 - 7.03

462

	(m, 1H), 6.89 (d, J = 8.8 Hz, 1H), 5.83 (d, J = 6.0 Hz, 1H), 4.29 (t, J = 8.8 Hz, 2H), 4.25 - 4.20 (m, 2H), 4.09 (t, J = 6.0 Hz, 2H), 3.98 - 3.90 (m, 1H), 3.82 (s, 3H), 3.01 (d, J = 8.4 Hz, 6H), 2.81 - 2.75 (m, 2H), 2.72 - 2.62 (m, 4H), 2.11 - 2.02 (m, 2H), 1.92- 1.80 (m, 4H).
I7l	LC-MS: (ES, m/z): RT = 1.74 min, LCMS 53: m/z = 372 [M+l], 1H NMR (400 MHz, Chloroform-d) δ 7.93 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 6.98 - 6.95 (m, 1H), 6.82 - 6.80 (d, J = 8.8 Hz, 2H), 5.92 (d, J = 6.0 Hz, 1H), 4.09 (t, J = 6.8 Hz, 2H), 3.86 (s, 3H), 3.12 (s, 6H), 2.66 - 2.62 (t, J = 8.0 Hz, 2H), 2.54 (d, J = 6.1 Hz, 4H), 2.12 - 2.05 (m, 2H), 1.83 - 1.79 (m, 4H).
172	LC-MS: (ES, m/z): RT = 2.821 min, LCMS07: m/z = 497.25 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.83 (d, J = 6.3 Hz, 1 H), 7.24 (s, 1 H), 7.17 - 7.13 (m, 1H), 6.88 (d, J = 8.7 Hz, 1H), 6.07 (d, J = 6.3 Hz, 1H), 4.43 - 4.39 (m, 1H), 4.08 (t, J = 6.1 Hz, 2H), 3.87 - 3.81 (m, 4H), 3.60 - 3.50(m, 1H), 3.50 - 3.40 (m, 1H), 3.09 3.00 (m, 4H), 2.82 - 2.74 (m, 6H), 2.68 - 2.60 (m, 1H), 2.14 - 1.98 (m, 6H), 1.93 1.83 (m, 4H), 1.80 - 1.60 (m, 2H), 1.33 - 1.06 (m, 2H).
173	LC-MS: (ES, m/z): RT = 1.16 min, LCMS 33: m/z =483 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.74 (d, J = 7.3 Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 7.07 - 6.94 (m, 2H), 6.67 (dd, J = 7.3, 2.3 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 4.61 (d, J = 13.3 Hz, 1H), 4.22 (t, J = 5.5 Hz, 2H), 4.10 (d, J = 6.0 Hz, 3H), 3.92 (s, 3H), 3.93 - 3.71 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.31 - 3.09 (m, 3H), 2.84 (t, J = 12.8 Hz, 1H), 2.38-2.18 (m, 8H), 2.18-1.88 (m, 4H), 1.55-1.28 (m, 2H).
174	LC-MS: (ES, m/z): RT = 1.14 min, LCMS 15: m/z = 343 [M+l], 1H NMR (300 MHz, Chloroform-d) δ 8.24 (d, J = 4.8 Hz, 1H), 7.38 (d, J = 2.7 Hz, 1H), 7.04 7.00 (m, 1H), 6.93 (s, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 5.1 Hz, 1H), 4.12 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 2.72 (t, J = 7.2 Hz, 2H), 2.68 - 2.60 (m, 4H), 2.39 (s, 3H), 2.17 - 2.07 (m, 2H), 1.92 - 1.76 (m, 4H).
175	LC-MS: (ES, m/z): RT = 1.15 min, LCMS 15: m/z = 357 [M+l], 1H NMR (300 MHz, Chloroform-d) δ 7.54 (d, J = 2.4 Hz, 1H), 7.07 - 6.98 (m, 1H), 6.91 (s, 1H), 6.82 (d, J = 8.7 Hz, 1H), 6.48 (s, 1H), 4.12 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 2.69 (t, J = 7.5 Hz, 2H), 2.58 (q, J = 5.2 Hz, 4H), 2.34 (s, 6H), 2.15- 2.06 (m, 2H), 1.811.77 (m, 4H).
176	LC-MS: (ES, m/z): RT= 1.152, LCMS m/z = 357.30 [M+l], 1HNMR (300 MHz, Methanol-d4, ppm) δ 7.34 (d, J = 2.5 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.97 (dd, J = 8.6, 2.4 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 5.99 (d, J = 7.5 Hz, 1H), 5.85 (d, J = 8.0 Hz, 1H), 4.05 (t, J = 6.2 Hz, 2H), 3.80 (s, 3H), 2.87 (s, 3H), 2.72 - 2.65 (m, 2H), 2.61 - 2.57 (m, 4H), 2.07 - 1.97 (m, 2H), 1.87- 1.75 (m, 4H).
177	LC-MS: (ES, m/z): RT = 1.04 min, LCMS 33: m/z = 416 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.79 - 7.63 (m, 1H), 7.15 (d, J = 12.9 Hz, 1H), 7.10 - 7.03 (m, 2H), 6.60 - 6.45 (m, 1H), 4.20 (t, J = 5.5 Hz, 2H), 3.99 - 3.75 (m, 7H), 3.70 3.60 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.35 (d, J = 6.5 Hz, 3H), 3.28 (d, J = 9.7 Hz, 3H), 3.17-3.10 (m, 2H), 2.42 - 2.01 (m, 6H).
178	LC-MS: (ES, m/z): RT = 1.14 min, LCMS 07: m/z = 456 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.59 (d, J = 7.3 Hz, 1H), 7.14 - 7.01 (m, 3H), 6.18 (d, J = 7.3 Hz, 1H), 4.20 (t, J = 5.6 Hz, 2H), 3.96 - 3.75 (m, 7H), 3.57 - 3.34 (m, 6H), 3.203.10 (m, 2H), 2.37 - 2.15 (m, 4H), 2.18- 2.02 (m, 2H), 1.66 - 1.51 (m, 5H), 1.301.15 (m, 2H).
179	LC-MS: (ES, m/z): RT = 0.572 min, LCMS 32: m/z = 427 [M+l], 1H-NMR: (400 MHz, Methanol-d4) δ 7.86 (d, J = 5.6 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.07 - 7.03 (m, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.83 (d, J = 6.0 Hz, 1H), 4.26 (t, J = 8.6 Hz, 2H), 4.22 - 4.15 (m, 2H), 4.11 (t, J = 6.0 Hz, 2H), 3.82 (s, 3H), 3.65 - 3.55 (m, 1H), 2.92

463

	(t, J = 7.6 Hz, 2H), 2.85 (d, J = 6.2 Hz, 4H), 2.16 - 2.05 (m, 2H), 1.96- 1.86 (m, 4H).
180	LC-MS: (ES, m/z): RT = 1.462 min, LCMS33: m/z = 409 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.28 (d, J = 6.6 Hz, 1H), 7.83 (s, 1H), 7.54 7.44 (m, 1H), 7.22 (s, 1H), 7.20 - 7.10 (m, 2H), 4.23 (t, J = 5.4 Hz, 2H), 3.93 (s, 3H), 3.87 - 3.80 (m, 2H), 3.50 (t, J = 7.2 Hz, 2H), 3.25 - 3.10 (m, 2H), 2.35 - 2.23 (m, 3H), 2.21 - 2.20 (m, 4H), 2.18 - 2.05 (m, 2H).
181	LC-MS: (ES, m/z): RT = 1.070 min, LCMS07: m/z = 359.0 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 8.38 (s, 2H), 7.38 (d, J = 2.5 Hz, 1H), 7.16-7.12 (m, 1H), 6.91 (d, J = 8.7 Hz, 1H), 4.49 (s, 2H), 4.09 (t, J = 6.1 Hz, 2H), 3.82 (s, 3H), 2.84 2.76 (m, 2H), 2.76 - 2.66 (m, 4H), 2.15-1.99 (m, 2H), 1.95 - 1.79 (m, 4H).
182	LC-MS: (ES, m/z): RT = 2.06 min, LCMS 33: m/z = 483 [M+l]. 1H NMR (300 MHz, DMSO-d6) δ 7.90-7.70 (m, 2H), 6.70-6.45 (m, 2H), 6.09 (s, 1H), 4.39 (d, J = 12.8 Hz, 1H), 4.16 (t, J = 5.8 Hz, 2H), 3.83 (s, 4H), 3.65-3.50 (m, 3H), 3.29 (t, J = 7.6 Hz, 2H), 3.20-2.90 (m, 5H), 2.20 (t, J = 7.3 Hz, 2H), 2.10-1.95 (m, 5H), 1.941.83 (m, 3H),1.83- 1.73(m, 2H), 1.33 -0.85 (m, 2H).
183	LC-MS: (ES, m/z): RT = 0.714 min, LCMS 32: m/z = 497 [M+l]. 1H-NMR: (300 MHz, Chloroform-d) δ 7.92 (d, J = 6.0 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 7.12 7.06 (m, 1H), 6.93 - 6.75 (m, 2H), 5.80 (d, J = 6.0 Hz, 1H), 4.89 (s, 1H), 4.69 - 4.50 (m, 1H), 4.18 - 4.05 (m, 1H), 3.91 - 3.70 (m, 5H), 3.35 - 3.16 (m, 2H), 3.10 - 2.90 (m, 1H), 2.66 - 2.42 (m, 6H), 2.41 - 2.19 (m, 2H), 2.09 (s, 3H), 1.93 - 1.68 (m, 7H), 1.31-1.02 (m, 5H).
184	LC-MS: (ES, m/z): RT = 1.00 min, LCMS 15: m/z = 482.4 [M+l]. 1H NMR: (400 MHz, Methanol-d4) δ 7.48 - 7.41 (m, 2H), 7.08 - 7.01 (m, 2H), 6.93 - 6.83 (m, 2H), 4.57 (d, J = 13.4 Hz, 1H), 4.20 (t, J = 5.5 Hz, 2H), 4.02 (d, J = 13.6 Hz, 1H), 3.89 (s, 3H), 3.87 - 3.79 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.37 (s, 1H), 3.26 - 3.09 (m, 3H), 3.08 (d, J = 6.4 Hz, 2H), 2.70-2.80 (m, 1H), 2.35 - 2.02 (m, 9H), 2.02 1.84 (m, 3H), 1.39-1.14 (m, 2H).
185	LC-MS: (ES, m/z): RT = 0.962 min, LCMS 53: m/z = 483.35 [M+l], 1H NMR: (300 MHz, Methanol-d4) δ 8.04 (d, J = 2.4 Hz, 1H), 7.19 (t, J = 1.4 Hz, 1H), 6.93 (d, J = 1.3 Hz, 2H), 5.99 (d, J = 2.5 Hz, 1H), 4.62 - 4.49 (m, 1H), 4.08 (t, J = 6.1 Hz, 2H), 4.01 - 3.91 (m, 1H), 3.83 (s, 3H), 3.20 - 2.98 (m, 3H), 2.81 - 2.55 (m, 7H), 2.14 - 1.98 (m, 5H), 1.95 - 1.75 (m, 7H), 1.35 - 1.05 (m, 2H).
186	LC-MS: (ES, m/z): RT = 0.997 min, LCMS53: m/z = 390.30 [M+l], 1H NMR: (300 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.76 (s, 1H), 7.14 (dd, J = 8.7, 2.2 Hz, 1H), 6.91 (s, 1H), 6.79 (d, J = 8.7 Hz, 1H), 5.73 (s, 1H), 5.29 - 5.06 (m, 1H),3.96 (t, J = 6.5 Hz, 2H), 3.68 (s, 3H), 2.89 - 2.70 (m, 5H), 2.68 - 2.48 (m, 3H), 2.34 - 2.26 (m, 1H), 2.26 - 2.02 (m, 4H), 1.98 - 1.74 (m, 3H).
187	LC-MS: RT= 1.025, m/z = 376.30 [M+l]. 1H NMR: (300 MHz, Methanol-d4, ppm) δ: 7.54 (d, J = 4.0 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 6.97 (dd, J = 8.7, 2.5 Hz, 1H), 6.75 (d, J = 8.7 Hz, 1H), 3.93 (t, J = 6.2 Hz, 2H), 3.69 (s, 3H), 2.89 (s, 3H), 2.62 - 2.57 (m, 2H), 2.52 - 2.46 (m, 4H), 1.96- 1.87 (m, 2H), 1.77 - 1.72 (m, 4H).
188	LC-MS: (ES, m/z): RT = 0.955 min, LCMS 28: m/z = 358.2 [M+l]. 1H-NMR: 1H NMR (300 MHz, Methanol-d4) δ 8.03 (d, J = 2.5 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 7.00 - 6.89 (m, 2H), 6.37 (d, J = 2.5 Hz, 1H), 4.22 (t, J = 5.5 Hz, 2H), 3.90 (s, 3H), 3.86 - 3.75 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.17 (d, J = 10.8Hz, 2H), 2.96 (s, 3H), 2.35-2.01 (m, 6H).
190	LC-MS: (ES, m/z): RT = 0.871 min, LCMS 53: m/z = 442.3 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.24 (d, J = 6.3 Hz, 1H), 7.25 - 7.11 (m, 2H), 7.04 (d, J = 8.7 Hz, 1H), 6.76 - 6.67 (m, 1H), 4.40 - 4.32 (m, 2H), 4.20 (t, J = 5.5 Hz, 2H), 4.07-

464

	4.10 (m, 2H), 3.90 (s, 3H), 3.88 - 3.77 (m, 2H), 3.62 - 3.37 (m, 5H), 3.25 - 3.09 (m, 2H), 2.34 -2.17 (m, 4H), 2.15- 2.03 (m, 4H), 1.86 - 1.66 (m, 2H).
191	LC-MS: (ES, m/z): RT = 0.840 min, LCMS 07: m/z = 474.20 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.88 (d, J = 20.6 Hz, 1H), 8.29 - 8.16 (m, 1H), 8.09 (d, J = 1.9 Hz, 1H), 8.03 - 7.90 (m, 2H), 7.68 (d, J = 7.5 Hz, 1H), 7.14 - 6.96 (m, 3H), 6.37 - 6.29 (m, 1H), 4.82 (s, 2H), 4.28 - 4.12 (m, 2H), 3.90 (s, 3H), 3.86 - 3.73 (m, 2H), 3.48 (t, J = 7.1 Hz, 2H), 3.15 (t, J = 8.3, 2H), 2.37 - 1.99 (m, 6H).
192	LC-MS: (ES, m/z): RT = 1.253 min, LCMS07: m/z = 441.10 [M+l], 1H NMR (300 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.77 (s, 1H), 9.60 (t, J = 4.1 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.20 - 7.00 (m, 3H), 6.23 (d, J = 7.2 Hz, 1H), 4.60 - 4.48 (m, 1H), 4.39 (t, J = 8.3 Hz, 1H), 4.16 - 4.00 (m, 4H), 3.85 - 3.56 (m, 6H), 3.36 - 3.26 (m, 2H), 3.10 - 2.96 (m, 2H), 2.22 - 1.73 (m, 9H).
193	LC-MS: (ES, m/z): RT = 0.987 min, LCMS 33: m/z = 439 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.63 - 7.48 (m, 3H), 7.11 (d, J = 7.2 Hz, 3H), 6.30 (t, J = 2.1 Hz, 1H), 6.15 (d, J = 7.3 Hz, 1H), 4.40 (t, J = 6.0 Hz, 2H), 4.19 (t, J = 5.5 Hz, 2H), 3.95 - 3.77 (m, 7H), 3.48 (t, J = 7.1 Hz, 2H), 3.19 - 3.01 (m, 2H), 2.30-2.15 (m, 4H), 2.10-2.00 (m, 2H).
194	LC-MS: (ES, m/z): RT = 1.00 min, LCMS 15: m/z = 386 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.57 (s, 2H), 7.39 (s, 1H), 7.13 (d, J = 6.4 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.09 (t, J = 6.2 Hz, 2H), 3.82 (s, 3H), 2.76 - 2.72 (m, 2H), 2.69 2.64 (m, 4H), 2.14 (s, 3H), 2.12 - 2.00 (m, 2H), 1.88-1.81 (m, 4H).
195	LC-MS: (ES, m/z): RT = 1.007 min, LCMS 15: m/z = 497 [M+l]. 1H NMR (400 MHz, Methanol-d4) δ 7.70 (s, 1H), 7.32 (s, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.55 - 4.39 (m, 2H), 3.97 - 3.87 (m, 1H), 3.82 (s, 3H), 3.32-3.30 (m, 1H), 3.29-3.25 (m, 1H), 3.09 (t, J = 1.2 Hz, 1H), 2.80 - 2.75 (m, 1H), 2.70 - 2.56 (m, 6H), 2.09 (s, 3H), 2.05 - 1.76 (m, 9H), 1.32 (d, J = 6.0 Hz, 3H), 1.28- 1.15 (m, 2H).
196	LC-MS: (ES, m/z): RT = 0.902 min, LCMS 30: m/z = 483.36 [M+H], 1H NMR (300 MHz, Methanol-d4) δ 8.31 (d, J = 5.4 Hz, 1H), 7.33 - 7.15 (m, 2H), 7.02 (d, J = 8.7 Hz, 1H), 6.82 (d, J = 5.4 Hz, 1H), 4.20 (t, J = 5.5 Hz, 2H), 3.93 - 3.76 (m, 8H), 3.66 (t, J = 6.8 Hz, 2H), 3.51-3.40 (m, 6H), 3.29 - 3.11 (m, 5H), 2.36 - 2.01 (m, 9H).
197	LC-MS: (ES, m/z): RT = 1.207 min, LCMS15: m/z = 381.2 [M+l], 1HNMR (300 MHz, Methanol-d4) δ 8.14 (s, 1H), 7.15-7.10 (m, 1H), 7.03 -7.00 (m, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.79 - 6.78 (m, 1H), 6.62 - 6.59 (m, 1H), 4.18 (s, 3H), 4.05 (t, J = 6.0 Hz, 2H), 3.84 (s, 3H), 2.75 (t, J = 7.5Hz, 2H), 2.68 -2.63 (m, 4H), 2.13-1.97 (m, 2H), 1.93 - 1.77 (m, 4H).
199	LC-MS: (ES, m/z): RT = 1.06 min, LCMS 53: m/z = 519.3 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.61 (d, J = 7.3 Hz, 1H), 7.19 - 6.99 (m, 3H), 6.20 (d, J = 7.3 Hz, 1H), 4.21 (t, J = 5.5 Hz, 2H), 3.91 (s, 3H), 3.80 - 3.71 (m, 4H), 3.55 - 3.38 (m, 4H), 3.32 - 3.18 (m, 2H), 2.84 (s, 3H), 2.80 - 2.65 (m, 2H), 2.38 - 2.01 (m, 6H), 1.89 - 1.72 (m, 3H), 1.39 - 1.24 (m, 2H).
200	LC-MS: (ES, m/z): RT = 0.98 min, LCMS 33: m/z = 381 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 9.14 (s, 1H), 7.63 (dd, J = 8.9, 0.7 Hz, 1H), 7.32 - 7.20 (m, 2H), 7.07 - 6.97 (m, 1H), 6.96 - 6.85 (m, 2H), 4.19 (t, J = 5.6 Hz, 2H), 4.02 (s, 3H), 3.89 -3.79 (m, 5H), 3.50 (t, J = 7.0 Hz, 2H), 3.25 - 3.10 (m, 2H), 2.36 - 2.02 (m, 6H).
201	LC-MS: (ES, m/z): RT = 0.78 min, LCMS 48: m/z = 368.2 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.99 (s, 1H), 8.47 (dd, J = 6.5, 1.0 Hz, 1H), 7.49 - 7.31 (m, 2H), 7.12 - 6.89 (m, 3H), 4.20 (t, J = 5.6 Hz, 2H), 3.90 (s, 3H), 3.88 - 3.78 (m, 2H),

465

	3.50 (t, J = 7.1 Hz, 2H), 3.26 - 3.09 (m, 2H), 2.37 - 1.99 (m, 6H).
202	LC-MS: (ES, m/z): RT = 0.99 min ; LCMS 33: m/z = 383.21 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.76 (s, 1H), 7.24 - 7.07 (m, 3H), 6.54 (s, 1H), 4.24 (t, J = 5.5 Hz, 2H), 3.95 (s, 3H), 3.90 - 3.77 (m, 2H), 3.50 (t, J = 7.2 Hz, 2H), 3.25 - 3.10 (m, 2H), 2.60 (d, J = 0.5 Hz, 3H), 2.39 - 2.02 (m, 6H).
203	LC-MS: (ES, m/z): RT = 1.17 min; LCMS 33: m/z = 513.30 [M+l]. 1H NMR (300 MHz, MethanoLd4) δ 7.70 (d, J = 6.0 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.13 (dd, J = 8.7, 2.5 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.19 - 4.03 (m, 6H), 3.82 (s, 3H), 3.30 (s, 2H), 2.89-2.61 (m, 8H), 2.06 (m, 2H), 1.92 - 1.72 (m, 7H), 1.32- 1.06 (m, 5H).
204	LC-MS: (ES, m/z): RT = 1.285 min, LCMS 07: m/z = 444.1 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.70 (s, 1H), 7.35 (d, J = 2.5 Hz, 1H), 7.15 (d, J = 8.7, 2.5 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.93 (d, J = 6.0 Hz, 1H), 4.19 (t, J = 5.5 Hz, 2H), 4.02 - 3.92 (m, 2H), 3.82 (s, 3H), 3.76 - 3.69 (m, 4H), 3.48 - 3.37 (m, 2H), 3.32 (d, J = 1.6 Hz, 2H), 2.84 (t, J = 5.5 Hz, 2H), 2.71 - 2.57 (m, 4H), 1.99 - 1.79 (m, 1H), 1.74 - 1.64 (m, 2H), 1.43 - 1.24 (m, 2H).
205	LC-MS: (ES, m/z): RT= 0.970 min, LCMS 33, m/z =372 [M+l], 1H NMR (300 MHz, Deuterium Oxide) δ7.20 - 6.90 (m, 3H), 5.91 (s, 1H), 4.09 (t, J = 5.6 Hz, 2H), 3.80 (s, 3H), 3.72 - 3.60 (m, 2H), 3.40 - 3.28 (m, 2H), 3.10 - 2.95 (m, 2H), 2.84 (s, 3H), 2.29 - 1.85 (m, 9H).
206	LC-MS: (ES, m/z): RT = 0.96 min ; LCMS 33: m/z = 357.20 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.53 (d, J = 7.3 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.91 (m, 2H), 6.44 - 6.34 (m, 1H), 6.02 (d, J = 2.2 Hz, 1H), 4.20 (t, J = 5.5 Hz, 2H), 3.90 (s, 3H), 3.88 - 3.78 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.25 - 3.09 (m, 2H), 2.89 (s, 3H), 2.37- 1.99 (m, 6H).
207	LC-MS: (ES, m/z): RT =1.540 min, LCMS 15: m/z = 328 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.74 (d, J = 5.2 Hz, 1H), 7.49 (s, 1H), 7.17 7.11 (m, 2H), 6.55 - 6.52 (m, 1H), 5.95 (d, J = 6.0 Hz, 1H), 4.06 (t, J = 6.1 Hz, 2H), 2.95 (s, 3H), 2.74 (t, J = 8.0 Hz, 2H), 2.66 (d, J = 5.6 Hz, 4H), 2.07 - 2.00 (m, 2H), 1.91 - 1.88 (m, 4H).
208	LC-MS: (ES, m/z): RT = 1.07min, LCMS07: m/z = 372.10 [M+l], 1HNMR (400 MHz, Methanol-d4) δ 7.52 (s, 1H), 7.35 - 7.21 (m, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.10 (s, 1H), 4.21 (t, J = 5.5 Hz, 2H), 3.94 - 3.78 (m, 5H), 3.50 (t, J = 7.0 Hz, 2H), 3.17 (q, J = 8.1 Hz, 2H), 3.04 (s, 3H), 2.40 - 2.16 (m, 7H), 2.11 - 2.06 (m, 2H).
209	LC-MS: (ES, m/z): RT = 0.963 min, LCMS 53: m/z = 357.25 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.41 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.00 - 6.89 (m, 2H), 6.31 (s, 1H), 5.83 (s, 1H), 4.21 (t, J = 5.6 Hz, 2H) 3.91 (s, 3H), 3.88 - 3.77 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.25 - 3.09 (m, 2H), 2.86 (s, 3H), 2.37 - 2.02 (m, 6H).
210	LC-MS: (ES, m/z): RT = 0.918 min, LCMS33: m/z = 374 [M+l], 1H-NMR: (300 MHz, Methanol-d4) δ 7.70 (d, J = 6.0 Hz, 1H), 7.47 (s, 1H), 7.10 - 7.02 (m, 1H), 6.87 (d, J = 8.7 Hz, 1H), 5.90 (d, J = 6.0 Hz, 1H), 4.07 (t, J = 6.4 Hz, 2H), 3.80 (s, 3H), 3.75 - 3.64 (m, 4H), 2.92 (s, 3H), 2.64 - 2.41 (m, 6H), 2.08 - 1.91 (m, 2H).
211	LC-MS: (ES, m/z): RT= 0.997, m/z = 392.20 [M+l]. 1H NMR (300 MHz, Chloroform-d, ppm) δ: 7.87 (s, 1H), 7.40 (d, J = 2.5 Hz, 1H), 7.05 - 7.00 (m, 2H), 6.83 (d, J = 8.7 Hz, 1H), 5.32 (d, J = 5.0 Hz, 1H), 4.11 (t, J = 5.5 Hz, 2H), 3.94 3.76 (m, 4H), 3.58 - 3.40 (m, 1H), 3.34 - 3.29 (m, 2H), 3.22 - 2.95 (m, 5H), 2.49 2.40 (m, 2H), 2.15 (s, 4H).
212	LC-MS: (ES, m/z): RT =0.906 min, LCMS 33: m/z = 344 [M+l], 1H-NMR-PHEPI-K-244-0: (300 MHz, Methanol-d4) δ 7.74 (d, J = 6.0 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.20 - 7.06 (m, 2H), 6.63 - 6.52 (m, 1H), 5.94 (d, J = 6.0 Hz, 1H), 4.14 -

466

	4.07 (m, 1H), 4.06 - 3.86 (m, 2H), 2.94 (s, 3H), 2.83 - 2.77 (m, 1H), 2.74 - 2.56 (m, 5H), 1.92- 1.72 (m, 4H).
213	LC-MS: (ES, m/z): RT = 1.40 min, LCMS15: m/z = 344 [M+l]. 1H NMR (300 MHz, Chloroform-d) δ 8.03 (s, 2H), 7.24 (d, J = 2.4 Hz, 1H), 7.04 - 7.01 (m, 1H), 6.85 (d, J = 8.7 Hz, 1H), 6.76 (s, 1H), 4.12 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 3.29 (s, 2H), 2.72 - 2.67 (m, 6H), 2.16 - 2.07 (m, 2H), 1.94 - 1.78 (m, 4H).
214	LC-MS: (ES, m/z): RT = 1.25 min, LCMS53: m/z = 423.2 [M+l], 1HNMR (300 MHz, Chloroform-d) δ 8.38 (d, J = 5.7 Hz, 1H), 7.29 (d, J = 5.7 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.00 (d, J = 0.9 Hz, 1H), 4.12 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 2.68 - 2.49 (m, 9H), 2.30 (s, 3H), 2.12 2.04 (m, 2H), 1.79 (s, 4H).
215	LC-MS: (ES, m/z): RT = 0.864 min, LCMS07: m/z = 372.1 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.67 (s, 2H), 7.31 (d, J = 2.4 Hz, 1H), 7.19 - 7.17 (m, 1H), 7.07 (d, J = 8.8 Hz, 1H), 4.26 - 4.19 (m, 4H), 3.90 (s, 3H), 3.86 - 3.80 (m, 2H), 3.50 (t, J = 7.2 Hz, 2H), 3.21 - 3.14 (m, 2H), 2.79 (s, 3H), 2.31 - 2.27 (m, 2H), 2.25 - 2.21 (m, 2H), 2.17 - 2.02 (m, 2H).
216	LC-MS: (ES, m/z): RT = 1.465min, LCMS07: m/z = 483.15 [M+l], 1HNMR (400 MHz, Methanol-d4) δ 7.75 (d, J = 6.1 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.25 - 7.18 (m, 1H), 6.97 (d, J = 8.7 Hz, 1H), 6.01 (d, J = 6.1 Hz, 1H), 4.49 (d, J = 13.3 Hz, 1H), 4.19 (t, J = 5.5 Hz, 2H), 3.87 (s, 4H), 3.45 (t, J = 6.8 Hz, 6H), 3.30 (d, J = 6.4 Hz, 2H), 3.15 - 3.03 (m, 1H), 2.64 - 2.63 (m, 1H), 2.32 - 2.21 (m, 2H), 2.20 - 2.07 (m, 7H), 1.98 - 1.76 (m, 3H), 1.38 - 1.06 (m, 3H).
217	LC-MS: (ES, m/z): RT = 1.25min, LCMS07: m/z = 381.05 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.82 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.94 - 6.82 (m, 4H), 4.18 (t, J = 5.5 Hz, 2H), 3.93 - 3.78 (m, 8H), 3.49 (t, J = 6.9 Hz, 2H), 3.20 - 3.13 (m, 2H), 2.29 - 2.19 (m, 4H), 2.13 - 2.06 (m, 2H).
218	LC-MS: (ES, m/z): RT = 0.96 min; LCMS07: m/z = 382.05 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 9.15 (s, 1H), 7.95 (d, J = 9.1 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.36 (dd, J = 8.7, 2.5 Hz, 1H), 7.03 - 6.91 (m, 2H), 4.26 (t, J = 5.5 Hz, 2H), 4.06 (s, 3H), 3.89 - 3.60 (m, 5H), 3.52 (t, J = 7.0 Hz, 2H), 3.27 - 3.11 (m, 2H), 2.40 -2.03 (m, 6H).
219	LC-MS: (ES, m/z): RT = 0.663 min, LCMS 32: m/z = 383 [M+l], 1H-NMR: (300 MHz, Methanol-d4) δ 8.84 (s, 2H), 7.38 (d, J = 2.4 Hz, 1H), 7.31 - 2.25 (m, 1H), 7.06 (d, J = 8.7 Hz, 1H), 4.23 (t, J = 5.4 Hz, 2H), 3.90 (d, J = 0.9 Hz, 6H), 3.88 3.78 (m, 2H), 3.50 (t, J = 7.2 Hz, 2H), 3.20 - 2.13 (m, 2H), 2.36 - 2.27 (m, 2H), 2.27 - 2.16 (m, 2H), 2.15 - 2.00 (m, 2H).
220	LC-MS: (ES, m/z): RT = 1.016 min, LCMS 33: m/z = 368 [M+l], 1H-NMR: (300 MHz, Methanol-d4) δ 8.37 (s, 1H), 7.56 - 7.50 (m, 1H), 7.14 - 6.95 (m, 4H), 6.48 6.40 (m, 1H), 4.09 (t, J = 6.3 Hz, 2H), 3.88 (s, 3H), 2.79 - 2.70 (m, 2H), 2.70 - 2.58 (m, 4H), 2.12 - 2.00 (m, 2H), 1.90 - 1.78 (m, 4H).
221	LC-MS: (ES, m/z): RT = 1.81 min, LCMS 53: m/z = 381.25 [M+l], 1H NMR (300 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.09 (s, 1H), 7.61 - 7.44 (m, 1H), 7.21 (s, 1H), 7.04 (dd, J = 9.2, 2.1 Hz, 1H), 6.89 (d, J = 8.6 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 6.66 (dd, J = 8.6, 2.5 Hz, 1H), 4.11 (s, 3H), 4.01 (t, J = 6.0 Hz, 2H), 3.73 (s, 3H), 3.62 - 3.47 (m, 2H), 3.32 - 3.20 (m, 2H), 3.07 - 2.90 (m, 2H), 2.23 - 1.80 (m, 6H).
222	LC-MS: (ES, m/z): RT = 1.33 min; LCMS 33 :m/z = 381.20 [M+l], 1HNMR (300 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.98 - 6.73 (m, 5H), 4.11 (s, 3H), 4.01 (t, J = 5.8 Hz, 2H), 3.72 (s, 3H), 3.64 - 3.50 (m, 2H), 3.27 (t, J = 7.5

467

	Hz, 2H), 3.06 - 2.91 (m, 2H), 2.17-1.99 (m, 4H), 2.00 - 1.87 (m, 2H).
223	LC-MS: (ES, m/z): RT = 1.02 min ; LCMS 33: m/z = 382.22 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.01 (d, J = 9.8 Hz, 1H), 7.74 (d, J = 1.3 Hz, 1H), 7.59 (d, J = 2.5 Hz, 1H), 7.46 - 7.31 (m, 2H), 7.04 (d, J = 8.8 Hz, 1H), 4.26 (t, J = 5.5 Hz, 2H), 3.89 - 3.70(m, 5H), 3.52 (t, J = 7.0 Hz, 2H), 3.20 (s, 2H), 2.61 (m, 3H), 2.42 - 2.02 (m, 6H).
224	LC-MS: (ES, m/z): RT = 1.02 min, LCMS 33: m/z = 409 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H), 8.23 (s, 1H), 8.14 (d, J = 6.7 Hz, 1H), 7.31 (d, J = 6.7 Hz, 1H), 7.22 - 7.12 (m, 3H), 4.23 (t, J = 5.6 Hz, 2H), 4.02 (s, 3H), 3.93 (s, 3H), 3.88-3.80 (m, 2H), 3.50 (t, J = 7.1 Hz, 2H), 3.23 - 3.12 (m, 2H), 2.36 - 2.02 (m, 6H).
225	LC-MS: (ES, m/z): RT = 1.13min, LCMS33: m/z = 438 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.82 (s, 1H), 7.73 (s, 1H), 7.38 - 7.30 (m, 2H), 7.09 (d, J = 8.6 Hz, 3H), 6.93 (t, J = 8.1 Hz, 1H), 6.45 (d, J = 7.2 Hz, 1H), 4.13 (d, J = 5.9 Hz, 2H), 3.93 (s, 3H), 3.87 - 3.76 (m, 2H), 3.46 (t, J = 7.1 Hz, 2H), 3.19-3.12 (m, 2H), 2.31 -2.16 (m, 4H), 2.16 - 2.03 (m, 2H).
226	LC-MS: (ES, m/z): RT = 1.032 min, LCMS 53: m/z = 441.35 [M+l]. 1H NMR (300 MHz, Deuterium Oxide) δ 7.70 - 7.31 (m, 2H), 7.30 - 7.09 (m, 2H), 6.13 (d, J = 6.1 Hz, 1H), 4.01 - 3.81 (m, 5H), 3.72 - 3.52 (m, 2H), 3.52 - 3.16 (m, 8H), 3.12 2.91 (m, 2H), 2.24- 1.75 (m, 7H), 1.73 - 1.44 (m, 2H), 1.38- 1.02 (m, 2H).
227	LC-MS: (ES, m/z): RT = 1.00min, LCMS07: m/z = 442.27 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.22 (d, J = 3.0 Hz, 1H), 7.74 (d, J = 6.0 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.49 (dd, J = 8.8, 3.0 Hz, 1H), 5.98 (d, J = 6.0 Hz, 1H), 4.12 - 3.86 (m, 7H), 3.49-3.33 (m, 4H), 2.78-2.58 (m, 6H), 2.09 - 1.93 (m, 3H), 1.94- 1.74 (m, 6H), 1.46- 1.25 (m, 2H).
228	LC-MS: (ES, m/z): RT = 0.918 min, LCMS 53: m/z = 441.35 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.05 - 7.92 (m, 1H), 7.69 (d, J = 7.3 Hz, 1H), 7.53 7.23 (m, 2H), 6.39-6.60 (m, 1H), 4.09 - 3.89 (m, 5H), 3.79 - 3.68 (m, 2H),3.63 3.51 (m, 2H), 3.50 - 3.36 (m, 6H), 3.22 - 3.07 (m, 2H), 2.44 - 1.85 (m, 7H), 1.85 1.62 (m, 2H), 1.49- 1.25 (m, 2H).
229	LC-MS: (ES, m/z): RT = 0.96 min, LCMS 53: m/z = 376.2 [M+l], 1H NMR (300 MHz, Chloroform-d) δ 7.92 - 7.83 (m, 1H), 7.49 - 7.35 (m, 2H), 7.00 (d, J = 8.7 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 5.87 (d, J = 6.1 Hz, 1H), 5.13 (s, 2H), 4.16 (t, J = 6.5 Hz, 2H), 3.86 (s, 3H), 3.13 - 2.88 (m, 6H), 2.82 (t, J = 7.3 Hz, 2H), 2.72 - 2.62 (m, 1H), 2.36-2.00 (m, 4H).
230	LC-Ms: (ES, m/z): RT = 0.94 min, LCMS 53: m/z = 362.2 [M+l], 1H NMR (300 MHz, Chloroform-d) δ 7.91 (d, J = 6.0 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.10 — 6.95 (m, 2H), 6.84 (d, J = 8.7 Hz, 1H), 5.86 (d, J = 6.0 Hz, 1H), 5.10 - 4.92 (m, 2H), 4.10 (t, J = 6.6 Hz, 2H), 3.86 (s, 3H), 3.79 - 3.62 (m, 2H), 3.28 - 3.05 (m, 2H), 2.99 (d, J = 5.1 Hz, 3H), 2.71 (t, J = 7.2 Hz, 2H), 2.06- 1.89 (m, 2H).
231	LC-MS: (ES, m/z): RT = 1.35min, LCMS 07: m/z = 358 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.70 (d, J = 7.2 Hz, 1H), 7.54 (s, 1H), 7.37 - 7.29 (m, 1H), 7.13 - 6.89 (m, 1H), 6.30 (d, J = 7.2 Hz, 1H), 4.21 (t, J = 8.2, 2H), 3.93 - 3.78 (m, 5H), 3.50 (t, J = 7.0 Hz, 2H), 3.24 - 3.12 (m, 2H), 3.03 (s, 3H), 2.36 - 2.16 (m, 4H), 2.15-2.05 (m, 2H).
232	LC-MS: (ES, m/z): RT = 0.987 min, LCMS 33: m/z =360 [M+l]. 1H NMR (300 MHz, Methanol-d4) Ô7.51-7.69 (m, 1H),7.2O (t, J = 10.2 Hz, 1H), 6.78 - 6.92 (m, 1H), 6.08 (s, 1H), 4.14 (t, J = 5.8 Hz, 2H), 3.78-3.62 (m, 2H), 3.43-3.35 (m,2H), 3.16 - 3.02(m, 2H), 3.00 (s, 3H), 2.34 (s, 3H), 2.32 - 2.17 (m, 4H), 2.11 - 1.98 (m, 2H).

468

233	LC-MS: RT= 1.076, m/z= 383.25 [M+l], 1H NMR (300 MHz, Methanol-d4, ppm) δ: 8.37 (s, 1H), 7.21 - 7.10 (m, 3H), 4.21 (t, J = 5.5 Hz, 2H), 3.97 (s, 3H), 3.91 3.79 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.24 - 3.09 (m, 5H), 2.34 - 2.15 (m, 6H).
234	LC-MS: (ES, m/z): RT = 1.07 min, LCMS 33: m/z = 426 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.15 (s, 1H), 7.41 - 6.89 (m, 3H), 4.21 (t, J = 5.5 Hz, 2H), 3.91 (s, 3H), 3.90-3.80 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.23 - 3.08 (m, 5H), 2.36 2.17 (m, 4H), 2.15 - 2.05 (m, 2H).
235	LC-MS: (ES, m/z): RT = 1.01 min, LCMS 07: m/z = 426 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.51 - 7.92 (m, 1H), 7.21 - 7.03 (m, 3H), 4.19 (t, J = 5.5 Hz, 2H), 3.95 - 3.76 (m, 5H), 3.49 (t, J = 7.1 Hz, 2H), 3.20 - 3.10 (m, 2H), 2.93 (s, 3H), 2.37 - 2.14 (m, 4H), 2.10-1.98 (m, 2H).
236	LC-MS: RT= 1.035, m/z = 390.30 [M+l]. 1H NMR (300 MHz, Methanol-d4, ppm) δ: 7.54 (d, J = 2.5 Hz, 1H), 7.08 (dd, J = 8.7, 2.5 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 4.10 (t, J = 6.1 Hz, 2H), 3.82 (s, 3H), 3.00 (s, 3H), 2.89 - 2.70 (m, 6H), 2.21 (d, J = 2.9 Hz, 3H), 2.12-2.03 (m, 2H), 1.93 - 1.87 (m, 4H).
237	LC-MS: (ES, m/z): RT = 0.938 min, LCMS 28: m/z = 360.15 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.58 (d, J = 7.3 Hz, 1H), 7.32 - 7.19 (m, 2H), 7.11 (d, J = 8.8 Hz, 1H), 6.17 (d, J = 7.3 Hz, 1H), 4.50 - 4.36 (m, 2H), 4.22 - 3.98 (m, 2H), 3.92 - 3.72 (m, 5H), 3.72 - 3.62 (m, 4H), 3.43 - 3.30 (m, 2H), 3.03 (s, 3H).
238	LC-MS: (ES, m/z): RT = 1.356 min, LCMS 07: m/z = 426 [M+l], 1H-NMR: (400 MHz, Methanol-d4) δ 7.69 (s, 1H), 7.13 - 7.05 (m, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.23 (s, 1H), 4.10 (t, J = 6.2 Hz, 2H), 3.82 (s, 3H), 2.98 (s, 3H), 2.78 - 2.68 (m, 2H), 2.64 (q, J = 4.8 Hz, 4H), 2.8 - 2.00 (m, 2H), 1.91-1.78 (m, 4H).
239	LC-MS: (ES, m/z): RT = 0.911 min, LCMS33: m/z = 341 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.53 (s, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.20 - 7.16 (m, 1H), 6.19 (d, J = 7.2 Hz, 1H), 4.23 (t, J = 8.4 Hz, 2H), 3.52 (t, J = 6.3 Hz, 2H), 3.28 (t, J = 8.1 Hz, 2H), 3.13-2.99 (m, 5H), 2.97 (s, 6H).
240	LC-MS: (ES, m/z): RT = 1.044 min, LCMS07: m/z = 386.15 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.61 (s, 1H), 7.08 - 7.05 (m, 1H), 6.89 (d, J = 8.8 Hz, 1H), 5.81 (s, 1H), 4.10 (t, J = 6.0 Hz, 2H), 3.82 (s, 3H), 2.93 (s, 3H), 2.80 - 2.71 (m, 2H), 2.71 - 2.61 (m, 4H), 2.47 (q, J = 7.6 Hz, 2H), 2.12 - 2.00 (m, 2H), 1.92- 1.80 (m, 4H), 1.25 (t, J = 7.6 Hz, 3H).
241	LC-MS: (ES, m/z): RT = 1.17 min; LCMS 33: m/z = 464.3 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.43 (d, J = 5.1 Hz, 1H), 7.63 - 7.44 (m, 5H), 7.39 (d, J = 2.5 Hz, 1H), 7.26 (dd, J = 8.7, 2.5 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 5.1 Hz, 1H), 4.35 (s, 2H), 4.26 (t, J = 5.6 Hz, 2H), 4.07 (dd, J = 12.0, 4.6 Hz, 2H), 3.84 (s, 3H), 3.69 (t, J = 6.8 Hz, 2H), 3.53 - 3.40 (m, 3H), 2.29 - 2.21 (m, 2H), 2.14 - 2.05 (m, 2H), 1.80- 1.65 (m, 2H).
242	LC-MS: (ES, m/z): RT = 1.067 min, LCMS 33: m/z = 483 [M+l], 1H NMR (300 MHz, Deuterium Oxide) δ 7.87 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.93 6.82 (m, 2H), 6.12 (d, J = 2.5 Hz, 1H), 4.27 (d, J = 12.9 Hz, 1H), 4.08 (t, J = 5.6 Hz, 2H), 3.92 - 3.58 (m, 6H), 3.34 (t, J = 7.5 Hz, 2H), 3.16 - 2.95 (m, 5H), 2.59 (dd, J = 14.1, 11.3 Hz, 1H), 2.25- 1.60 (m, 12H), 1.20-0.90 (m, 2H).
243	LC-MS: (ES, m/z): UFLC 06:RT = 6.901 min, LCMS 53: m/z = 440.3 [M+l], 1H NMR (300 MHz, Deuterium Oxide) δ 7.42 (d, J = 7.3 Hz, 1H), 7.00 (d, J = 1.6 Hz, 2H), 6.85 - 6.71 (m, 1H), 6.05 (dd, J = 7.4, 1.7 Hz, 1H), 4.64 - 4.56 (m, 1H), 4.33 (t, J = 12.7, 2.3 Hz, 2H), 4.08 - 3.97 (m, 2H), 3.96 - 3.82 (m, 2H), 3.77 (s, 3H), 3.46 - 3.25 (m, 2H), 3.25 - 3.12 (m, 2H), 2.89 - 2.72 (m, 5H), 2.46 - 2.31 (m, 2H), 1.88 - 1.72 (m, 1H), 1.50 (d, J = 13.2 Hz, 2H), 1.25 - 1.06 (m, 2H).

469

244	LC-MS: (ES, m/z): RT = 0.95min, LCMS33: m/z = 346 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.66 (d, J = 7.3 Hz, 1H), 7.45 (dd, J = 6.3, 3.0 Hz, 1H), 7.22 (m, 1H), 6.93 (m, J = 9.2, 3.5 Hz, 1H), 6.25 (d, J = 7.3 Hz, 1H), 4.14 (t, J = 5.8 Hz, 2H), 3.72 (d, J = 5.8 Hz, 2H), 3.50 - 3.33 (m, 2H), 3.15 (t, J = 13.0 Hz, 2H), 3.02 (s, 3H), 2.24 (m, 4H), 2.16 - 2.02 (m, 2H).
245	LC-MS: (ES, m/z): RT = 1.004 min, LCMS 07: m/z = 344.15 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.65 (d, J = 7.3 Hz, 1H), 7.16 (s, 1H), 7.07 (d, J = 1.3 Hz, 2H), 6.20 (d, J = 7.3 Hz, 1H), 4.21 (t, J = 5.5 Hz, 2H), 3.90 (s, 3H), 3.81 (s, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.29 - 3.02 (m, 2H), 2.34 - 2.01 (m, 6H).
246	LC-MS: (ES, m/z): RT = 0.907 min, LCMS 07: m/z = 358.05 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.01 (d, J = 2.5 Hz, 1H), 7.25 - 7.14 (m, 1H), 6.94 (d, J = 1.3 Hz, 2H), 5.96 (d, J = 2.4 Hz, 1H), 4.09 (t, J = 6.1 Hz, 2H), 3.84 (s, 3H), 2.78 (s, 5H), 2.70 (s, 4H), 2.12-1.99 (m, 2H), 1.90 - 1.80 (m, 4H).
247	LC-MS: (ES, m/z): RT = 1.41 min, LCMS 07: m/z = 358 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.44 (d, J = 2.5 Hz, 1H), 7.30 - 7.13 (m, 3H), 7.07 - 6.98 (m, 1H), 4.22 (t, J = 5.5 Hz, 2H), 4.02 - 3.77 (m, 5H), 3.50 (t, J = 7.0 Hz, 2H), 3.223.12 (m, 2H), 3.03 (s, 3H), 2.37 - 2.02 (m, 6H).
248	LC-MS: (ES, m/z):RT = 0.871 min, LCMS 07: m/z = 358 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.03 (s, 1H), 7.77 (d, J = 6.9 Hz, 1H), 7.27 (s, 1H), 6.81 (s, 1H), 6.73 (d, J = 7.2 Hz, 1H), 4.53 (s, 2H), 4.00 (s, 3H), 3.89 - 3.75 (m, 2H), 3.49 (t, J = 7.0 Hz, 2H), 3.18-3.10 (m, 2H), 3.00 (s, 3H), 2.40 - 2.39 (m, 2H), 2.30 2.06 (m, 4H).
249	LC-MS: (ES, m/z): RT = 0.577 min, LCMS 30: m/z = 368.2 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.30 (s, 1H), 7.56 (d, J = 7.1 Hz, 1H), 7.26 - 7.07 (m, 4H), 4.23 (t, J = 5.6 Hz, 2H), 3.96 (s, 3H), 3.82 (s, 2H), 3.49 (t, J = 7.2 Hz, 2H), 3.21 3.15 (m, 2H), 2.38-2.23 (m, 2H), 2.21 - 2.14 (m, 4H).
250	LC-MS: (ES, m/z): RT = 0.974 min, LCMS 33: m/z = 367.21 [M+l], 1HNMR (300 MHz, Methanol-d4) δ 7.90 (d, J = 7.1 Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 8.2 Hz, 2H), 6.81 - 6.69 (m, 2H), 4.21 (t, J = 5.5 Hz, 2H), 3.94 (s, 3H), 3.90 - 3.76 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.25 - 3.10 (m, 2H), 2.37-2.04 (m, 6H)
251	LC-MS: (ES, m/z): RT = 1.07 min, LCMS 53: m/z = 374.2 [M+l], 1H NMR (300 MHz, Chloroform-d) δ 7.94 (d, J = 5.7 Hz, 1H), 7.40 (t, J = 2.2 Hz, 1H), 7.17 (t, J = 8.1 Hz, 1H), 7.08 - 7.04 (m, 1H), 6.99 (s, 1H), 6.55 - 6.51 (m, 1H), 5.84 (d, J = 5.7 Hz, 1H), 5.30 - 5.05 (m, 1H), 4.66 (d, J = 7.8 Hz, 1H), 4.06 (t, J = 6.3 Hz, 3H), 3.03 - 2.64 (m, 5H), 2.57 - 2.42 (m, 1H), 2.32 - 1.95 (m, 4H), 1.28 (d, J = 6.3 Hz, 6H).
252	LC-MS: (ES, m/z): RT = 0.943 min, LCMS 28: m/z = 344 [M+l], 1H-NMR: (300 MHz, Methanol-d4) δ 7.74 (d, J = 6.0 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.22 - 7.09 (m, 2H), 6.64 - 6.52 (m, 1H), 5.94 (d, J = 6.0 Hz, 1H), 4.18-4.06 (m, 1H), 4.04 3.89 (m, 2H), 2.94 (s, 3H), 2.84 - 2.78 (m, 1H), 2.77 - 2.57 (m, 5H), 1.96 - 1.74 (m, 4H).
253	LC-MS: (ES, m/z): RT = 0.943 min, LCMS 28: m/z = 344 [M+l], 1H-NMR: (300 MHz, Methanol-d4) δ 7.74 (d, J = 5.7 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.22 - 7.05 (m, 2H), 6.61 - 6.52 (m, 1H), 5.94 (d, J = 6.0 Hz, 1H), 4.19 - 4.06 (m, 1H), 4.05 3.90 (m, 2H), 2.94 (s, 3H), 2.84 - 2.96 (m, 1H), 2.76 - 2.57 (m, 5H), 1.93 - 1.75 (m, 4H).
256	LC-MS: (ES, m/z): RT = 0.83min, LCMS33: m/z = 414 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.75 (d, J = 6.7 Hz, 1H), 7.21 (s, 1 H), 7.16 - 7.04 (m, 2H), 6.41 (d, J = 6.5 Hz, 1H), 4.39-4.36 (m, 1H), 4.22 (t, J = 5.5 Hz, 2H), 3.99-3.92 (m, 4H), 3.89 - 3.64 (m, 5H), 3.51-3.42 (m, 3H), 3.27 - 3.09 (m, 2H), 2.60-2.07 (m,

470

	7H).
257	LC-MS: (ES, m/z): RT = 1.22min, LCMS 33: m/z = 382 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.20 (s, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.30 (dd, J = 8.7, 2.4 Hz, 1H), 7.06 (d, J = 8.7 Hz, 1H), 6.81 (d, J = 9.1 Hz, 1H), 4.25 (t, J = 5.5 Hz, 2H), 4.09 (s, 3H), 3.90 (s, 5H), 3.50 (t, J = 7.0 Hz, 2H), 3.25 - 3.09 (m, 2H), 2.39 - 2.04 (m, 6H).
258	LC-MS: (ES, m/z): RT = 0.871 min, LCMS 33: m/z = 382 [M+l], 1H NMR (Methanol-d4, ppm): δ 8.75 (s, 1H), 8.59 (s, 1H), 7.19 - 6.98 (m, 4H), 4.23 (t, J = 5.6 Hz, 2H), 3.98 - 3.76 (m, 8H), 3.49 (t, J = 7.1 Hz, 2H), 3.25 - 3.10 (m, 2H), 2.38 - 2.02 (m, 6H).
259	LC-MS: (ES, m/z): RT= 1.801 min, LCMS 31, m/z = 482.5 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.57 (d, J = 7.3 Hz, 1H), 7.09 (d, J = 17.2 Hz, 3H), 6.17 (d, J = 7.3 Hz, 1H), 4.53 - 4.24 (m, 1H), 4.07 - 3.82 (m, 5H), 3.82 - 3.50 (m, 2H), 3.49 3.35 (m, 4H), 3.30 - 3.15 (m, 1H), 2.96 (d, J = 4.1 Hz, 4H), 2.25 - 1.18 (m, 15H).
260	LC-MS: (ES, m/z): RT = 1.069 min; m/z = 468.35 [M+l], 1H NMR (300 MHz, Deuterium Oxide) δ 7.37 (d, J = 7.3 Hz, 1H), 6.99 - 6.84 (m, 2H), 6.82 - 6.70 (m, 1H), 5.97 (d, J = 7.5 Hz, 1H), 4.15 - 3.92 (m, 3H), 3.88 - 3.61 (m, 7H), 3.37 - 3.13 (m, 2H), 3.12-2.98 (m, 2H), 2.81 (s, 3H), 2.05 - 1.81 (m, 2H), 1.85- 1.23 (m, 9H), 1.22-0.91 (m, 2H).
261	LC-MS: (ES, m/z): RT = 0.720 min, LCMS 32: m/z = 388 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.56 (d, J = 2.4 Hz, 1H), 7.10-7.06 (m, 1H), 6.86 (d, J = 8.7 Hz, 1H), 5.25 (s, 1H), 4.08 (t, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 2.87 (s, 3H), 2.77 - 2.68 (m, 2H), 2.62 (d, J = 5.7 Hz, 4H), 2.08-2.00 (m, 2H), 1.88-1.80 (m, 4H).
262a	LC-MS: (ES, m/z): RT = 0.964 min ; m/z = 334 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.59 (d, J = 6.2 Hz, 1H), 5.91 (d, J = 6.6 Hz, 1H), 3.91 (d, J = 8.6 Hz, 1H), 3.73 - 3.39 (m, 3H), 3.35 - 3.18 (m, 4H), 2.92 (s, 3H), 2.38 - 2.25 (m, 1H), 2.17-1.78 (m, 10H), 1.50- 1.20 (m, 5H).
262b	LC-MS: (ES, m/z): RT = 0.964 min; m/z = 334 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.59 (d, J = 6.2 Hz, 1H), 5.87 (d, J = 6.6 Hz, 1H), 3.91 - 3.69 (m, 1H), 3.73 - 3.39 (m, 3H), 2.85 (s, 3H), 2.78 - 2.61 (m, 6H), 2.32 - 2.21 (m, 1H), 2.00 - 1.75 (m, 9H), 1.50 - L11 (m, 4H).
263	LC-MS: (ES, m/z): RT = 1.07min, LCMS07: m/z = 408.15[M+l], 1HNMR (400 MHz, Methanol-d4) δ 8.12-8.09 (m,lH), 7.84-7.80 (m, 1H), 7.61 - 7.53 (m, 1H), 7.48-7.46 (m, 1H), 7.25 (s, 1H), 7.20 - 7.07 (m, 2H), 4.22 (t, J = 5.5 Hz, 2H), 3.93 (s, 3H), 3.89 - 3.78 (m, 2H), 3.50 (t, J = 7.1 Hz, 2H), 3.19-3.14 (m, 5H), 2.36 - 2.16 (m, 4H), 2.10-2.07 (m, 2H).
264	LC-MS: (ES, m/z): RT=0.695min, LCMS 40, m/z =367 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.35 (d, J = 2.4 Hz, 1H), 7.75 - 7.60 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 6.22 (d, J = 7.3 Hz, 1H), 3.96 (t, J = 6.1 Hz, 2H), 3.90 - 3.80 (m, 2H), 3.73 (t, J = 6.7 Hz, 2H), 3.53 (t, J = 6.0 Hz, 2H), 3.27 - 3.08 (m, 4H), 3.06 (s, 3H), 2.29 1.98 (m, 4H).
265	LC-MS: (ES, m/z): RT = 2.07min, LCMS07: m/z = 366.20 [M+l], 1H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.38 (s, 1H), 7.70 (s, 1H), 7.31 7.15 (m, 1H), 6.90 (dd, J = 7.7, 3.0 Hz, 3H), 6.74 (d, J = 2.5 Hz, 1H), 6.68 - 6.65 (m, 1H), 6.55 (t, J = 2.5 Hz, 1H), 3.99 (t, J = 5.8 Hz, 2H), 3.74 (s, 3H), 3.62 (s, 2H), 3.34-3.26 (m, 2H), 3.06-3.03 (m, 2H), 2.19-1.98 (m, 4H), 1.93 - 1.79 (m, 2H).
266	LC-MS: (ES, m/z): RT = 1.021 min, LCMS 33: m/z = 367 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.51 - 7.38 (m, 2H), 7.24 - 7.04 (m, 4H), 6.92 (d, 1H), 4.20 (t, J = 5.5 Hz, 2H), 3.95 (s, 3H), 3.82 (s, 2H), 3.49 (t, J = 7.2 Hz, 2H), 3.17 (t, J =

471

	13.2 Hz, 2H), 2.36 - 2.02 (m, 6H).
267	LC-MS: (ES, m/z): RT= 1.04 min, LCMS 45: m/z = 328 [M+l], 1H-NMR: (Methanol-d4, ppm): δ 7.88-7.86 (m, 2H), 7.29 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.52 (s, 1H), 6.11 (s, 1H), 4.83 (s, 2H), 4.01 - 3.91 (m, 2H), 3.84-3.68 (m, 2H), 3.59 - 3.49 (m, 2H), 3.28 - 3.13 (m, 2H), 2.95 (s, 3H), 2.25 - 2.01 (m, 4H).
268	LC-MS: (ES, m/z): RT= 0.94 min, LCMS 28: m/z = 328 [M+l], 1H-NMR: (Methanol-d4, ppm): δ 7.71 (d, J = 6.0 Hz, 1H), 7.62-7.58 (m, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.98 (dd, J = 7.4, 1.1 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 6.69 (dd, J = 6.0, 2.0 Hz, 1H), 4.59 (s, 2H), 3.81-3.63 (m, 2H), 2.87 (s, 3H), 2.85-2.72 (m, 2H), 2.70 2.58 (m, 4H), 1.85-1.68 (m, 4H).
272	LC-MS: (ES, m/z): RT = 0.985 min, LCMS 07: m/z = 375 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.62 (d, J = 5.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.02 - 6.90 (m, 2H), 5.96 (d, J = 7.2 Hz, 1H), 4.20 (t, J = 5.6 Hz, 2H), 3.91 (s, 3H), 3.85-3.75 (m, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.25 - 3.09 (m, 2H), 2.92 (s, 3H), 2.37 - 2.02 (m, 6H).
276	LC-MS: (ES, m/z): RT=1.529 min, LCMS 33, m/z =346.0 [M+l], 1H NMR (300 MHz, Deuterium Oxide) δ 7.49 (d, J = 7.4 Hz, 1H), 7.43 - 7.34 (m, 1H), 7.25 - 7.05 (m, 2H), 3.95 - 6.88 (m, 1H), 6.36 - 5.98 (m, 1H), 5.13 - 4.98 (m, 1H), 4.96 - 4.80 (m, 1H), 4.57 - 4.33 (m, 2H), 4.10 - 3.90 (m, 1H), 3.89 - 3.59 (m, 2H), 3.47 - 3.22 (m, 2H), 2.94 (s, 3H), 2.28 - 1.83 (m, 4H).
277	LC-MS: (ES, m/z): RT = 1.348 min, LCMS 27: m/z = 364 [M+l], 1H-NMR: (Methanol-d4, ppm): δ 7.64 (d, J = 7.3 Hz, 1H), 7.46 - 7.27 (m, 3H), 6.97 - 6.84 (m, 1H), 6.22 (d, J = 7.3 Hz, 1H), 4.48 (t, J = 12.2 Hz, 2H), 4.23 - 4.06 (m, 2H), 3.78 - 3.33 (m, 4H), 3.06 (s, 3H), 2.17 (s, 4H).
279	LC-MS: (ES, m/z): RT=1.221min, LCMS 30, m/z =342 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.68 - 7.58 (m, 3H), 7.53 - 7.40 (m, 1H), 7.30 - 7.20 (m, 1H), 6.21 (d, J = 7.3 Hz, 1H), 4.58 (q, J = 6.4 Hz, 1H), 3.75 - 3.54 (m, 4H), 3.48 3.34 (m, 2H), 3.22 - 2.99 (m, 5H), 2.20 - 1.99 (m, 4H), 1.53 (d, J = 6.5 Hz, 3H).
280	LC-MS: (ES, m/z): RT=0.969min, LCMS 15, m/z =360 [M+1].1H NMR (300 MHz, Methanol-d4) δ 7.57 (d, J = 7.3 Hz, 1H), 7.22 (s, 1H), 7.10 (d, J = 1.9 Hz, 2H), 6.19 (d, J = 7.3 Hz, 1H), 4.21 (t, J = 5.6 Hz, 2H), 3.91 (s, 3H), 3.51 - 3.28 (m, 6H), 3.03 (s, 3H), 2.36 - 2.20 (m, 2H), 1.39 (t, J = 7.3 Hz, 6H).
283	LC-MS: (ES, m/z): RT=0.651min, LCMS 07, m/z =388.4 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.72 (d, J = 6.1 Hz, 1H), 7.52 - 7.43 (m, 1H), 7.08 (dd, J = 8.7, 2.5 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 4.18 - 3.90 (m, 3H), 3.81 (s, 3H), 3.29 (s, 3H), 2.93 (s, 3H), 2.83 -2.48 (m, 6H), 2.18-1.94 (m, 3H), 1.88- 1.76 (m, 1H).
285	LC-MS: (ES, m/z): RT = 0.57min, LCMS48: m/z = 426 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.56 (d, J = 7.3 Hz, 1H), 7.20 (s, 1H), 7.04-7.10 (m, 2H), 6.17 (d, J = 7.3 Hz, 1H), 4.19 (t, J = 5.4 Hz, 3H), 3.99 - 3.87 (m, 5H), 3.69-3.42 (m, 4H), 3.03 (s, 3H), 2.51 - 2.26 (m, 4H).
286	LC-MS: (ES, m/z): RT = 0.934 min, LCMS 07: m/z = 374 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.72 (d, J = 5.9 Hz, 1H), 7.47 (d, J = 2.3 Hz, 1H), 7.08 (dd, J = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 4.40-4.30 (m, 1H), 4.14 - 4.03 (m, 2H), 3.82 (s, 3H), 2.97 - 2.47 (m, 9H), 2.24 - 1.92 (m, 3H), 1.80-1.70 (m, 1H).
287	LC-MS: (ES, m/z): RT = 1.021 min, LCMS 33: m/z = 383 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.56 (d, 1H), 7.20 (s, 1H), 7.09 (d, 2H), 6.18 (d, 1H), 4.35-4.10(m, 3H), 4.10-3.92 (m, 4H), 3.90-3.48 (s, 5H), 3.03 (s, 3H), 2.872.36 (s, 2H), 2.32 (s, 2H).

472

288	LC-MS: (ES, m/z): RT = 2.22 min, LCMS 27: m/z = 358 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.80-7.70 (m, 1H), 7.50 (s, 1H), 7.10 - 7.00 (m, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.96 (d, J = 7.2 Hz, 1H), 4.15-4.05 (m, 2H), 3.80 (s, 3H), 3.15-3.05 (m,lH), 2.95 (s, 3H), 2.50 - 2.40 (m, 4H), 2.35 - 2.20 (m, 2H), 2.20 - 2.10 (m, 1H), 1.85- 1.55 (m, 4H).
289	LC-MS: (ES, m/z): RT = 0.92min, LCMS07: m/z = 344.10 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.72 (s, 1H), 7.52 (s, 1H), 7.08 (dd, J = 8.7, 2.5 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.04 (d, J = 5.8 Hz, 2H), 3.82 (s, 3H), 3.21 - 3.08 (m, 1H), 2.94 (s, 3H), 2.94-2.83(m, 1H), 2.59 (d, J = 1.3 Hz, 3H), 2.40 (q, J = 9.0 Hz, 1H), 2.19-2.06 (m, 1H), 1.90-1.82 (m, 2H), 1.77-1.68 (m, 1H).
290	1H NMR (300 MHz, Methanol-d4) δ 7.56 (d, J = 7.3 Hz, 1H), 7.29 - 7.18 (m, 1H), 7.09 (d, J = 1.0 Hz, 2H), 6.18 (d, J = 7.3 Hz, 1H), 4.30 - 4.12 (m, 2H), 3.94 - 3.49 (m, 6H), 3.30-3.20(m, 2H), 3.03 (s, 3H), 2.48-2.03 (m, 5H), 1.90- 1.70 (m, 1H), 1.51 (d, J = 6.5 Hz, 3H).
291	LC-MS: (ES, m/z): RT = 1.412 min, LCMS 34: m/z = 273 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 8.73 (s, 2H), 8.26 (s, 1H), 7.90 (d, J = 7.3 Hz, 1H), 6.51 (d, J = 7.3 Hz, 1H), 3.53 (q, J = 7.3 Hz, 2H), 3.20 (s, 3H), 1.30 (t, J = 7.3 Hz, 3H).
293	LC-MS: (ES, m/z): RT =1.055 min, LCMS 28: m/z = 372 [M+l]. 1H NMR (400 MHz, Methanol-d4) δ 7.72 (s, 1H), 7.48 (s, 1H), 7.08 (d, J = 6.4 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.10 (t, J = 6.0 Hz, 2H), 3.82 (s, 3H), 3.02 (d, J = 8.8 Hz, 1H), 2.93 (s, 3H), 2.87 (s, 1H), 2.79 (d, J = 8.0 Hz, 2H), 2.68 (s, 1H), 2.34-2.28 (m, 1 H), 2.21 (d, J = 8.0 Hz, 1H), 2.13 - 2.01 (m, 3H), 1.45 (d, J =8.0 Hz, 1H), 1.09 (d, J = 6.8 Hz, 3H).
298	LC-MS: (ES, m/z): RT = 0.978 min, LCMS15: m/z = 370.2 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.72 (s, 1H), 7.50 - 7.44 (m, 1H), 7.08 - 7.06 (m, 1H), 6.89 (d, J = 8.6 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.10 - 4.02 (m, 2H), 3.82 (s, 3H), 3.08 (d, J = 9.2 Hz, 2H), 2.93 (s, 3H), 2.68 (t, J = 7.6 Hz, 2H), 2.46 (d, J = 9.2 Hz, 2H), 2.01-1.95 (m, 2H), 1.49-1.41 (m, 2H), 0.68 (q, J = 4.1 Hz, 1 H), 0.43 (q, J = 7.2 Hz, 1H).
299	LC-MS: (ES, m/z): RT=0.590min, LCMS 30, m/z =374 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.72 (d, J = 6.0 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.09 (dd, J = 8.7, 2.5 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.22 - 4.09 (m, 1H), 4.09 - 3.91 (m, 2H), 3.85 (s, 3H), 2.94 (s, 3H), 2.90 - 2.65 (m, 6H), 1.92 1.78 (m, 4H).
300	LC-MS: (ES, m/z): RT=0.592min, LCMS 30, m/z =374 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.72 (d, J = 6.0 Hz, 1H), 7.53 (s, 1H), 7.09 (dd, J = 8.7, 2.5 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.23 - 3.90 (m, 3H), 3.85 (s, 3H), 2.94 (s, 3H), 2.89 - 2.64 (m, 6H), 1.92- 1.78 (m, 4H).
301	LC-MS: (ES, m/z): RT = 1.302min, LCMS 27: m/z = 390 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.35 - 7.23 (m, 2H), 5.85 (s, 1H), 4.02 (t, J = 6.1 Hz, 2H), 3.87 (s, 3H), 2.94 (s, 3H), 2.84 - 2.75 (m, 2H), 2.72 - 2.62 (m, 4H), 2.20 (s, 3H), 2.03 - 1.81 (m, 6H).
302	LC-MS: (ES, m/z): RT =1.013 min; LCMS15: m/z = 390 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.10 (s, 1H), 6.86 (d, J = 12.4 Hz, 1H), 5.85 (s, 1H), 4.07 (t, J = 6.2 Hz, 2H), 3.83 (s, 3H), 2.93 (s, 3H), 2.71 - 2.66 (m, 2H), 2.59 (s, 4H), 2.19 (s, 3H), 2.05 - 1.96 (m, 2H), 1.93 - 1.77 (m, 4H).
303	LC-MS: (ES, m/z): RT = 0.529 min, LCMS48: m/z = 373.3 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.00 (s, 1H), 6.73 (s, 1H), 6.16 (d, J = 1.2 Hz, 1H), 4.28 (t, J = 5.6 Hz, 2H), 3.94 (s, 3H), 3.86 - 3.76 (m, 2H), 3.47 (t, J = 7.2 Hz, 2H), 3.22 3.10 (m, 2H), 3.04 (s, 3H), 2.47 - 2.42 (m, 3H), 2.41 - 2.29 (m, 2H), 2.26 - 2.24

473

	(m, 2H), 2.24-2.19 (m, 2H).
304	LC-MS: (ES, m/z): RT = 1.019 min, LCMS15: m/z = 368.2 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.05 (s, 1H), 7.90 (d, J = 6.9 Hz, 1H), 7.60 (d, J = 3.3 Hz, 1H), 7.37 (d, J = 7.0 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.11 (s, 1H), 4.35 (t, J = 5.6 Hz, 2H), 3.98 (d, J= 1.1 Hz, 3H), 3.88-3.78 (m, 2H), 3.50 (t, J = 7.3 Hz, 2H), 3.243.13 (m, 2H), 2.43 - 2.36 (m, 2H), 2.28 - 2.23 (m, 2H), 2.19 - 2.04 (m, 2H).
305	LC-MS: (ES, m/z): RT =0.958min, LCMS 28: m/z = 358 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.92 (s, 1H), 7.70 (s, 1H), 6.59 (s, 1H), 6.45 (d, J = 9.1 Hz, 1H), 6.00 (s, 1H), 4.26 (t, J = 5.5 Hz, 2H), 3.93 (s, 3H), 3.89 - 3.74 (m, 2H), 3.47 (t, J = 7.3 Hz, 2H), 3.24 - 3.08 (m, 2H), 2.93 (s, 3H), 2.46 - 2.30 (m, 2H), 2.23 (q, J = 9.0, 2H), 2.09 - 2.06 (m, 2H).
306	LC-MS: (ES, m/z): RT = 1.30 min, LCMS 53: m/z = 372.3 [M+l]. 1H NMR (400 MHz, Methanol-d4) δ 7.95 (d, J = 1.3 Hz, 1H), 6.61 (s, 1H), 6.26 (s, 1H), 5.91 (s, 1H), 4.26 (t, J = 5.5 Hz, 2H), 3.93 (s, 3H), 3.87 - 3.76 (m, 2H), 3.47 (t, J = 7.3 Hz, 2H), 3.22 - 3.10 (m, 2H), 2.92 (s, 3H), 2.55 - 2.45 (m, 3H), 2.40 - 2.16 (m, 4H), 2.16-2.00 (m, 2H).
307	LC-MS: (ES, m/z): RT = 1.30 min, LCMS 53: m/z = 372.3 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.95 (d, J = 1.3 Hz, 1H), 6.61 (s, 1H), 6.26 (s, 1H), 5.91 (s, 1H), 4.26 (t, J = 5.5 Hz, 2H), 3.93 (s, 3H), 3.87 - 3.76 (m, 2H), 3.47 (t, J = 7.3 Hz, 2H), 3.22 - 3.10 (m, 2H), 2.92 (s, 3H), 2.55 - 2.45 (m, 3H), 2.40 - 2.16 (m, 4H), 2.16-2.00 (m, 2H).
308	LC-MS: (ES, m/z): RT = 2.72 min, LCMS 33: m/z = 372.3 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.95 (d, J = 1.3 Hz, 1H), 7.43 (s, 1H), 6.66 (s, 1H), 4.92 (s, 1H), 4.26 (t, J = 5.5 Hz, 2H), 3.93 (s, 3H), 3.83 - 3.78 (m, 2H), 3.47 (t, J = 7.3 Hz, 2H), 3.19-3.14 (m, 2H), 3.00 (s, 3H), 2.61 - 2.41 (m, 3H), 2.40 - 2.30 (m, 4H), 2.26-2.21 (m, 2H).
309	LC-MS: (ES, m/z): RT = 1.107 min; LCMS53: m/z = 390 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.95 (s, 1H), 6.62 (s, 1H), 6.07 (d, J = 6.5 Hz, 1H), 4.29 (t, J = 5.5 Hz, 2H), 3.93 (s, 3H), 3.82 (s, 2H), 3.47 (t, J = 7.3 Hz, 2H), 3.16 (q, J = 8.6 Hz, 2H), 2.97 (s, 3H), 2.51 (d, J = 3.2 Hz, 3H), 2.39 - 2.37 (m, 2H), 2.21 (q, J = 6.7 Hz, 2H), 2.14-2.02 (m, 2H).
310	LC-MS: (ES, m/z): RT = 1.802 min ; m/z = 382.2 [M+l], 1H NMR (300 MHz, Deuterium Oxide) δ 6.97 - 6.72 (m, 2H), 6.46 - 6.15 (m, 2H), 6.01 — 5.82 (m, 1H), 3.75 - 2.65 (m, 11H), 2.29 - 1.66 (m, 9H).
311	LC-MS: (ES, m/z): RT = 2.10 min, LCMS 53: m/z = 319.2 [M+l], 1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.70 (s, 1H), 7.20 (q, J = 8.7 Hz, 1H), 6.93 (s, 1H), 6.82 (d, J = 8.8 Hz, 1H), 5.75 (s, 1H), 4.08 - 3.98 (m, 2H), 3.73 - 3.62 (m, 5H), 3.32 (s, 3H), 2.82 (d, J = 4.5 Hz, 3H), 2.11 (s, 3H).
312	LC-MS: (ES, m/z): RT = 1.221 min, LCMS 33: m/z = 333 [M+Hl], 1H NMR (400 MHz, Methanol-d4) δ 7.60 (s, 1H), 7.06-7.02 (m, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.81 (d, J = 0.8 Hz, 1H), 4.11 (t, J = 6.4 Hz, 2H), 3.82 (s, 3H), 3.61 (t, J = 6.2 Hz, 2H), 3.37 (s, 3H), 2.93 (s, 3H), 2.19 (s, 3H), 2.10-2.04 (m, 2H).
313	UPLC: (ES, m/z): RT = 2.42 min, UPLC 07: m/z = 382 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.26 (d, J = 2.0 Hz, 1H), 7.12 - 7.06 (m, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.03 (d, J = 1.1 Hz, 1H), 4.19 (t, J = 5.8 Hz, 2H), 3.81 - 3.72 (m, 2H), 3.55 - 3.46 (m, 2H), 3.22 - 3.12 (m, 2H), 3.03 (s, 3H), 2.39 - 2.28 (m, 5H), 2.23 - 2.03 (m, 5H), 0.99 - 0.91 (m, 2H), 0.70 - 0.63 (m, 2H).
314	LC-MS: (ES, m/z): RT = 1.167 min, LCMS 28: m/z = 368 [M+l], 1H-NMR: (400 MHz, Methanol-d4) δ 7.58 (d, J = 7.3 Hz, 1H), 7.18 (s, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.18 (d, J = 7.3 Hz, 1H), 4.18 (t, J = 5.7 Hz, 2H), 3.74

474

	(s, 2H), 3.54 - 3.45 (m, 2H), 3.25 - 3.12 (m, 2H), 3.05 (s, 3H), 2.36 - 3.28 (m, 2H), 2.22 - 2.12 (m, 5H), 1 - 0.90 (m, 2H), 0.73 - 0.60 (m, 2H).
315	LC-MS: (ES, m/z): RT =1.160min, LCMS 33: m/z =412 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.67 (d, J = 7.3 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.45 - 7.27 (m, 2H), 6.24 (d, J = 7.3 Hz, 1H), 4.24 (t, J = 5.7 Hz, 2H), 3.75 - 3.69 (m, 2H), 3.50 - 3.39 (m, 2H), 3.15 (q, J = 8.4 Hz, 2H), 3.07 (s, 3H), 2.31 - 2.29 (m, 2H), 2.20 (d, J = 9.1 Hz, 2H), 2.07 (t, J = 6.6 Hz, 2H).
317	LC-MS: (ES, m/z): RT=12min, LCMS 31, m/z =358 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.22 (dd, J = 8.7, 2.4 Hz, 1H), 7.12 - 6.99 (m, 2H), 6.01 (d, J = 1.0 Hz, 1H), 4.67-4.49 (m, 1H), 3.86 (s, 3H), 3.60 - 3.44 (m, 1H), 3.11 - 2.95 (m, 5H), 2.87 (s, 6H), 2.50 - 2.27 (m, 5H).
318	LC-MS: (ES, m/z): RT = 0.99min, LCMS33: m/z = 372 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.36 (d, J = 2.4 Hz, 1H), 7.10 (dd, J = 8.7, 2.5 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 5.81 (s, 1H), 4.68-4.65 (m, 1H), 3.82 (s, 3H), 2.93 (s, 3H), 2.78 -2.69 (m, 2H), 2.62 (d, J = 6.9 Hz, 2H), 2.36 (s, 6H), 2.36-2.13 (m, 4H), 1.991.79 (m, 2H).
319	LC-MS: (ES, m/z): RT= 0.83 min, LCMS 45: m/z = 404 [M+l], 1H-NMR: (Methanol-d4, ppm): δ 7.26 (d, J = 2.4 Hz, 1H), 7.14 (dd, J = 8.7, 2.4 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 4.20 (t, J = 5.5 Hz, 2H), 3.90-3.80 (m, 5H), 3.50 (t, J = 7.1 Hz, 2H), 3.07 (s, 5H), 2.78-2.56 (m, 2H), 2.37 - 2.02 (m, 6H), 1.33 (t, J = 7.6 Hz, 3H).
320	LC-MS: (ES, m/z): RT=1.780min, LCMS 31, m/z =398 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.34 (d, J = 2.4 Hz, 1H), 7.17 (dd, J = 8.7, 2.5 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 5.86 (s, 1H), 4.20 (t, J = 5.5 Hz, 2H), 3.89 (s, 3H), 3.87 - 3.78 (m, 2H), 3.49 (t, J = 7.0 Hz, 2H), 3.25 - 3.09 (m, 2H), 3.00 (s, 3H), 2.35 - 2.16 (m, 4H), 2.15-2.02 (m, 2H), 1.99- 1.86 (m, 1H), 1.32 - 1.11 (m, 2H), 1.09-0.95 (m, 2H).
321	LC-MS: (ES, m/z): RT = 0.758 min, LCMS 33: m/z = 368 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.71-8.59 (m,lH), 8.31-8.19 (m, 1H), 8.18-8.00(m, 2H), 7.65-7.55(m, 1H),7.61 - 7.50 (m, 1H), 6.88- 6.75 (m, 1H), 4.30 (s, 2H), 3.90 (s, 3H), 3.89-3.75 (m, 2H), 3.42 (s, 2H), 3.20-3.09 (m, 2H), 2.30 (s, 2H),2.28 - 2.02 (m, 4H).
322	LC-MS: (ES, m/z): RT = 0.96min, LCMS33: m/z = 359.00 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.08 (s, 1H), 8.01 (s, 1H), 6.68 (s, 1H), 6.18 (s, 1H), 4.28 (t, J = 5.5 Hz, 2H), 3.95 (s, 3H), 3.95-3.75 (m, 2H), 3.48 (t, J = 7.4 Hz, 2H), 3.17 (s, 2H), 2.98 (s, 3H), 2.42 - 2.30 (m, 2H), 2.26-2.23 (m, 2H), 2.08 (t, J = 6.5 Hz, 2H).
323	LC-MS: (ES, m/z): RT=0.836min, LCMS 15, m/z =359.2 [M+l], 1H NMR (300 MHz, Deuterium Oxide) δ 8.08 - 7.92 (m, 2H), 7.09 (s, 1H), 6.26 (d, J = 2.4 Hz, 1H), 4.22 (t, J = 5.6 Hz, 2H), 3.89 (s, 3H), 3.73 - 3.56 (m, 2H), 3.36 (d, J = 17.0 Hz, 5H), 3.10 - 2.95 (m, 2H), 2.32 - 1.78 (m, 6H).
324	LC-MS: (ES, m/z): RT = 0.888min, LCMS 33: m/z = 359 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.40 (s, 1H), 7.92 (s, 1H), 6.70 (s, 1H),6.10-5.90 (m, 1H), 4.31 (t, J = 5.6 Hz, 2H), 3.94 (s, 3H), 3.85-3.75 (m, 2H), 3.47 (t, J = 7.4 Hz, 2H), 3.25-3.15 (m, 2H), 3.05-2.95 (m, 3H), 2.40-2.30 (m, 2H), 2.22 (s, 2H), 2.10-2.00 (m, 2H).
325	LC-MS: (ES, m/z): RT = 0.918 min, LCMS 33: m/z = 373 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.99 (s, 1H), 6.67 (s, 1H), 6.00 (s, 1H), 4.28 (s, 2H), 3.94 (s, 3H), 3.80 (s, 2H), 3.47 (s, 2H), 3.21 - 3.08 (m, 2H), 2.99 (s, 3H), 2.59 (s, 3H), 2.35 (s, 2H), 2.22 (s, 2H), 2.08 (s, 2H)
326	LC-MS: (ES, m/z): RT = 0.958 min, LCMS 33: m/z = 383 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 8.14 (s, 1H), 7.48 (d, J = 3.6 Hz, 1H), 7.09 - 6.98 (m, 2H),

475

	4.36 (t, J = 5.5 Hz, 2H), 4.00 (s, 3H), 3.90-3.80 (m, 2H), 3.50 (t, J = 7.4 Hz, 2H), 3.19 (s, 2H), 2.83 (s, 3H), 2.45-2.35 (m, 2H), 2.30-2.20 (m, 2H), 2.15-2.05 (m, 2H).
328	LC-MS: (ES, m/z): RT = 1.196 min; m/z = 398.3[M+l], 1H NMR (300 MHz, Deuterium Oxide) 67.22 - 7.12 (m, 1H), 7.07 - 6.92 (m, 2H), 4.05 (t, J = 5.6 Hz, 2H), 3.79 (s, 3H), 3.75 - 3.58 (m, 2H), 3.33 (t, J = 7.5 Hz, 2H), 3.11 - 2.95 (m, 2H), 2.89 (s, 3H), 2.72 (t, J = 7.7 Hz, 2H), 2.55 - 2.42 (m, 2H), 2.23 - 1.89 (m, 8H).
329	LC-MS: (ES, m/z): RT=L021min, LCMS 31, m/z =358 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.18 (dd, J = 8.7, 2.4 Hz, 1H), 7.14 - 6.96 (m, 2H), 6.04 5.96 (m, 1H), 4.13 - 3.96 (m, 1H), 3.87 (s, 3H), 3.37 - 3.34 (m, 1H), 3.04 - 2.97 (m, 3H), 2.91 - 2.75 (m, 8H), 2.71 - 2.59 (m, 2H), 2.31 (d, J = 0.9 Hz, 3H).
330	LC-MS: (ES, m/z): RT = 1.115 min ; m/z = 372.0 [M+l]. 1HNMR (300 MHz, Deuterium Oxide) 6 7.19 - 7.06 (m, 1H), 6.96 - 6.29 (m, 2H), 5.86 - 5.40 (m, 1H), 3.95 - 3.76 (m, 1H), 3.76 - 3.38 (m, 5H), 2.79 - 2.43 (m, 9H), 2.41 - 2.25 (m, 2H), 2.25 - 2.02 (m, 2H), 1.97 - 1.83 (m, 3H).
331	LC-MS: (ES, m/z): RT = 0.99min, LCMS33: m/z =372 [M+l], 1H NMR (300 MHz, Methanol-d4) 6 7.24 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.81 (s, 1H), 4.83 - 4.75 (m, 1H), 3.83 (s, 3H), 2.92 (s, 3H), 2.68 (d, J = 4.7 Hz, 3H), 2.53 - 2.24 (m, 10H), 2.19 (s, 3H).
332	LC-MS: (ES, m/z): RT = 2.247 min; m/z = 373.2 [M+l]. 1H NMR (300 MHz, Deuterium Oxide) δ 7.76 - 7.65 (m, 1H), 7.53 - 7.09 (m, 1H), 6.07 - 5.83 (m, 1H), 4.17 - 3.95 (m, 2H), 3.91 - 3.80 (s, 3H), 3.74 - 3.48 (m, 2H), 3.38 - 3.23 (m, 2H), 3.11 - 2.94 (m, 2H), 2.94 - 2.74 (m, 3H), 2.26 - 2.00 (m, 7H), 1.97 - 1.82 (m, 2H).
333	LC-MS: (ES, m/z): RT = 1.032 min, LCMS 28: m/z = 355 [M+l], 1H-NMR-PHEPI-K-351-100: (300 MHz, Methanol-d4) δ 12.19 (s, 1H), 7.90 (d, J = 7.1 Hz, 1H), 7.64-7.49 (m, 1H), 7.35-7.25 (m, 1H), 7.21-7.13 (m, 1H), 6.32 (s, 1H), 4.76 (s, 2H), 4.33 (q, J = 7.2 Hz, 2H), 3.93 - 3.85 (m, 2H), 3.74 -3.66 (m, 2H), 3.53 - 3.45 (m, 2H), 3.24 - 3.08 (m, 2H), 2.25 -2.11 (m, 2H), 2.11 - 1.96 (m, 2H), 1.53 (t, J = 7.2 Hz, 3H).
334	LC-MS: (ES, m/z): RT=0.955min, LCMS 40, m/z =358 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.42 - 7.29 (m, 1H), 7.27 - 6.99 (m, 2H), 6.06 - 5.98 (m, 1H), 4.52 - 4.04 (m, 6H), 3.95 - 3.86 (m, 3H), 3.49 (q, J = 7.3 Hz, 2H), 3.40 - 3.33 (m, 1H), 3.05-2.95 (m, 3H), 2.31 (s, 3H), 1.37-1.21 (m, 3H).
335	LC-MS: (ES, m/z): RT= 0.90 min, LCMS 33:m/z = 368 [M+l], 1H-NMR: (Methanol-d4, ppm): δ 8.27 (dd, J = 7.3, 2.2 Hz, 1H), 8.12 - 8.00 (m, 2H), 7.41 (d, J = 3.6 Hz, 1H), 7.09 - 6.98 (m, 2H), 4.30 (t, J = 5.5 Hz, 2H), 3.97 (s, 3H), 3.92-3.77 (m, 2H), 3.49 (t, J = 7.3 Hz, 2H), 3.24 - 3.09 (m, 2H), 2.43 - 2.01 (m, 6H).
336	LC-MS: (ES, m/z): RT= 1.73 min, LCMS 53:m/z = 382 [M+]. 1H-NMR: (Methanol-d4, ppm):ô 8.14 (s, 1H), 7.48 - 7.35 (m, 3H), 6.92 (d, J = 3.5 Hz, 1H), 4.50-4.40 (m, 2H), 4.05 (s, 3H), 3.92-3.75 (m, 2H), 3.49 (t, J = 7.2 Hz, 2H), 3.223.05 (m, 2H), 2.74 (s, 3H), 2.47 - 2.36 (m, 2H), 2.22 - 2.09 (m, 4H).
388	LC-MS: (ES, m/z): RT =0.859 min, LCMS 33: m/z = 326 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.45 (d, J = 0.9 Hz, 1H), 8.09 (s, 1H), 7.84 (dd, J = 9.0, 0.8 Hz, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.22 (dd, J = 8.9, 1.8 Hz, 1H), 6.26 (d, J = 7.3 Hz, 1H), 4.99 - 4.87 (m, 2H), 3.29 - 3.17 (m, 2H), 3.10 (s, 3H), 2.92 (s, 6H), 2.48 (s, 2H).
404	LC-MS: (ES, m/z): RT = 0.598 min; m/z = 312.2 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.53 (d, J = 0.9 Hz, 1H), 8.13 - 8.06 (m, 1H), 7.93 -7.77 (m, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.26 (dd, J = 9.0, 1.8 Hz, 1H), 6.27 (d, J = 7.3 Hz, 1H), 5.00 (t, J = 6.7, 5.1 Hz, 2H), 3.88 (t, J = 5.9 Hz, 2H), 3.12(s, 3H), 3.09 - 3.01(m, 6H).

476

407	LC-MS: (ES, m/z): RT = 0.942 min, LCMS33: m/z = 344 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.61 - 7.37 (m, 3H), 7.12 - 7.08 (m, 1H), 6.19 - 6.17 (m, 1H), 4.70 - 4.62 (m, 2H), 4.45 (d, J = 5.4 Hz, 1H), 3.97 - 3.84 (m, 3H), 3.84 - 3.70 (m, 2H), 3.34 -3.11 (m, 2H), 3.09 - 2.92 (m, 6H), 2.57 - 2.33 (m, 1H), 2.34 - 2.09 (m, 1H).
408	LC-MS: (ES, m/z): RT = 0.95min, LCMS07: m/z = 358.20 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.55 (dd, J = 7.3, 1.8 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.09 (dd, J = 4.7, 1.3 Hz, 2H), 6.18 (d, J = 7.3 Hz, 1H), 4.20 - 4.07 (m, 2H), 3.96-3.84 (m, 4H), 3.75-3.70 (m, 1H), 3.38 (d, J = 7.4 Hz, 2H), 3.30 - 3.05 (m, 2H), 3.19-2.89 (m, 4H), 2.53 -2.25 (m, 1H), 2.23 - 1.94 (m, 1H), 1.38 (t, J = 7.3 Hz, 3H).
409	LC-MS: (ES, m/z):RT = 0.981 min, LCMS 33: m/z = 372 [M+l],
410	LC-MS: (ES, m/z): RT = 0.94 min, LCMS 07: m/z = 388 [M+l], 1H-NMR: (Methanol-d4, ppm): δ 7.57 (d, J = 7.3 Hz, 1H), 7.25 (s, 1H), 7.16 (d, J = 9.4 Hz, 1H), 7.05 (d, J = 8.9 Hz, 1H), 6.16 (d, J = 7.3 Hz, 1H), 4.19 - 4.00 (m, 2H), 4.00 3.65 (m, 7H), 3.58 - 3.35 (m, 6H), 3.32 - 3.14 (m, 1H), 3.03-2.85 (m, 4H), 2.411.90 (m, 2H).
411	LC-MS: (ES, m/z): RT=1.285min, LCMS 40, m/z =370 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.56 (d, J = 7.3 Hz, 1H), 7.29 - 6.99 (m, 3H), 6.17 (d, J = 7.3 Hz, 1H), 4.23 -4.00 (m, 2H), 3.98-3.41 (m, 7H), 3.03 (s, 5H), 2.62 - 1.60 (m, 2H), 1.11-0.89 (m, 4H).
412	LC-MS: (ES, m/z): RT = 0.919 min, LCMS07: m/z = 358.15 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.57 (d, J = 7.2 Hz, 1H), 7.20 (s, 1H), 7.13 - 7.01 (m, 2H), 6.26 - 6.13 (m, 1H), 4.09 - 4.04 (m, 1H), 3.99 - 3.84 (m, 4H), 3.75 - 3.71 (m, 1H), 3.57-3.53 (m, 1H), 3.07 - 2.90 (m, 8H), 2.42 (s, 1H), 2.10 - 1.89 (m, 3H), 1.591.40 (m, 1H).
413	LC-MS: (ES, m/z): RT = 0.969 min, LCMS07: m/z = 372.20 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.58 (s, 1H), 7.08 - 7.06 (m, 1H), 6.88 (d, J = 8.4Hz, 1H), 5.81 (s, 1H), 3.96 - 3.94 (m, 1H), 3.90 - 3.79 (m, 4H), 3.16 - 3.14 (m, 1H), 2.93 (s, 4H), 2.36 (d, J = 2.8 Hz, 3H), 2.18 (s, 5H), 2.00- 1.97 (m, 1H), 1.92 - 1.76 (m, 2H), 1.72- 1.67 (m, 1H), 1.23 - 1.09 (m, 1H).
414	LC-MS: (ES, m/z): RT = 1.020 min, LCMS53: m/z = 360.2 [M+l], 1H NMR (300 MHz, Deuterium Oxide) δ 7.65 - 7.29 (m, 1 H), 7.18 - 6.82 (m, 3H), 7.06 (s, 2H), 6.20 - 5.87 (m, 1H), 4.60 - 4.37 (m, 2H), 4.25 - 3.88 (m, 4H), 3.88 - 3.68 (m, 4H), 3.48 - 3.25 (m, 2H), 2.98 - 2.68 (m, 3H), 2.10 - 1.82 (m, 2H).
415	LC-MS: (ES, m/z): RT = 1.77 min, LCMS 07: m/z = 344.3 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.72 (s, 1H), 7.50 (s, 1H), 7.08 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 3.96 - 3.86 (m, 2H), 3.82 (s, 3H), 2.94 (s, 3H), 2.86 (d, J = 9.1 Hz, 1H), 2.81 - 2.73 (m, 1H), 2.67 (t, J = 7.1 Hz, 2H), 2.56 (q, J = 7.7 Hz, 1 H), 2.43 (s, 3H), 2.20 - 2.04 (m, 1 H), 1.69 - 1.67 (m, 1 H).
416	LC-MS: (ES, m/z): RT = 1.71 min, LCMS 07: m/z = 344.3 [M+l]. 1H NMR (400 MHz, Methanol-d4) δ 7.74 (s, 1H), 7.55 (s, 1H), 7.09 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 5.97 (d, J = 6.0 Hz, 1H), 3.96 - 3.83 (m, 2H), 3.82 (s, 3H), 2.94 (s, 3H), 2.88 (d, J = 9.1 Hz, 1H), 2.84 - 2.72 (m, 1H), 2.66 (t, J = 7.1 Hz, 2H), 2.57 (q, J = 7.7 Hz, 1H), 2.41 (s, 3H), 2.22 - 2.01 (m, 1H), 1.68- 1.64 (m, 1H).
417	LC-MS: (ES, m/z): RT = 1.64 min, LCMS 53: m/z = 358.3 [M+l], 1HNMR (300 MHz, Chloroform-d) δ 7.54 (d, J = 2.5 Hz, 1H), 7.21 (s, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H), 5.73 (d, J = 0.8 Hz, 1H), 4.94 (s, 1H), 4.00 (d, J = 6.5 Hz, 2H), 3.84 (s, 3H), 3.35 - 2.57 (m, 8H), 2.49 (s, 3H), 2.28 (s, 3H), 2.16-2.13 (m, 1H), 1.73-1.71 (m, 1H).

477

418	LC-MS: (ES, m/z): RT = 1.15 min, LCMS 53: m/z = 358.3 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.60 (s, 1H), 7.08 (d, J = 8.7 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.81 (s, 1H), 3.96 - 3.90 (m, 2H), 3.82 (s, 3H), 2.93 (s, 3H), 2.85 - 2.83 (m, 1H), 2.82-2.70 (m, 1H), 2.71 - 2.60 (m, 2H), 2.53 - 2.49 (m, 1H), 2.41 (d, J = 1.1 Hz, 3H), 2.18 (s, 3H), 2.16-2.03 (m, 1H), 1.67- 1.60 (m, Hz, 1H).
419	LC-MS: (ES, m/z): RT =1.01min, LCMS33: m/z = 372 [M+l], 1H NMR (300 MHz, DMSO-d6) δ 7.41 (s, 1H), 7.19 - 6.95 (m, 2H), 6.03 (s, 1H), 4.1-3.92 (m, 2H), 3.85-3.7 (m, 3H), 3.63-3.52 (m, 1H), 3.32 - 2.98 (m, 4H), 2.95 - 2.72 (m, 5H), 2.42 - 2.05 (m, 4H), 1.98-1.67 (m, 1H), 1.25 (t, J = 7.2 Hz, 3H).
420	LC-MS: (ES, m/z): RT=0.774min, LCMS 40, m/z =372 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.56 (d, J = 7.3 Hz, 1H), 7.28 - 6.98 (m, 3H), 6.17 (d, J = 7.3 Hz, 1H), 4.19 - 3.99 (m, 2H), 3.89 (s, 4H), 3.78 - 3.65 (m, 1H), 3.46 - 3.36 (m, 1H), 3.30-3.10 (m, 3H), 3.08 - 2.87 (m, 4H), 2.53 - 1.91 (m, 2H), 1.89-1.71 (m, 2H), 1.07 (t, J = 7.4 Hz, 3H).
421	1H NMR (400 MHz, Methanol-d4) δ 7.69 - 7.63 (m, 1H), 7.57 - 7.55 (m, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.79 (d, J = 0.8 Hz, 1H), 4.57 - 4.45 (m, 2H), 4.24 - 4.21 (m, 1H), 3.83 (s, 3H), 2.92 (s, 3H), 2.85 - 2.67 (m, 3H), 2.55 - 2.51 (m, 1H), 2.38 (s, 3H), 2.24-2.10 (m, 4H), 1.96- 1.94 (m, 1H).
422	LC-MS: (ES, m/z): RT = 0.979 min, LCMS 45: m/z = 384.2 [M+l], 1H NMR (300 MHz, Deuterium Oxide) δ 7.65 - 7.33 (m, 1H), 7.24 - 7.12 (s, 1H), 7.03 - 6.89 (m, 2H), 6.19 - 5.98 (m, 1H), 4.08 - 3.52 (m, 7H), 3.39 - 2.80 (m, 8H), 2.38 - 2.07 (m, 1H), 2.05- 1.72 (m, 1H), 1.12-0.95 (m, 1H), 0.70-0.53 (m, 2H), 0.29 - 0.21 (m, 2H).
423	LC-MS: (ES, m/z): RT = 0.94min, LCMS07: m/z = 358.15 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.87-7.5 (m, 1H), 7.29 - 7.01 (m, 3H), 6.38-6.11 (m, 1H), 4.43 (t, J = 9.4 Hz, 1H), 4.27 - 4.10 (m, 3H), 4.08 - 4.00 (m, 1H), 3.94 (d, J = 2.2 Hz, 3H), 3.79 (t, J = 9.8 Hz, 1H), 3.50-3.41 (m, 2H), 3.10-2.9 (m, 4H), 2.2-2.02 (m, 2H), 1.41 (d, J = 7.1 Hz, 1H), 1.30 (d, J = 6.7 Hz, 2H).
424	LC-MS: (ES, m/z): RT = 0.97min, LCMS07: m/z = 372.20 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.9-7.54 (m, 1H), 7.29 - 7.05 (m, 3H), 6.4-6.16 (m, 1H), 4.20 (t, J = 5.6 Hz, 2H), 3.91 (s, 3H), 3.62 - 3.49 (m, 1H), 3.48 - 3.39 (m, 1H), 3.29-3.19 (m, 1H), 3.17-2.9 (m, 7H), 2.31-2.27 (m, 2H), 1.31 - 1.15 (m, 1H), 0.83-0.80 (m, 2H), 0.59 - 0.39 (m, 2H).
425	LC-MS: (ES, m/z): RT= 0.96 min, LCMS 45: m/z = 374 [M+l], 1H-NMR: (Methanol-d4, ppm): δ 7.57 (d, J = 7.3 Hz, 1H), 7.24 - 7.03 (m, 3H), 6.17 (d, J = 7.3 Hz, 1H), 4.65-4.60 (m, 1H), 4.33 (s, 3H), 4.16-4.10 (m, 2H), 4.08-3.90 (m, 4H), 3.59-3.45 (m, 2H), 3.40-3.35 (m, 3H), 3.03 (s, 3H), 2.25-2.11 (m, 2H).
426	LC-MS: (ES, m/z): RT = 1.34 min, LCMS 33: m/z = 368 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.53 (d, J = 7.4 Hz, 1H), 7.23 (s, 1H), 7.07 (s, 2H), 6.25 6.12 (m, 2H), 5.14 (s, 2H), 3.89 (s, 3H), 3.02 (s, 3H), 2.15-2.05 (m, 1H), 1.19 - 1.03 (m, 2H), 1.04-0.89 (m, 2H).
428	LC-MS: (ES, m/z): RT = 1.111 min, LCMS 33: m/z = 440 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.62 (s, 1H), 7.10 - 7.04 (m, 1H), 6.88 (d, J = 8.7 Hz, 1H), 5.96 (s, 1H), 4.09 (t, J = 6.2 Hz, 2H), 3.82 (s, 3H), 3.42 - 3.38 (m,lH), 3.31-3.28 (m, 1H), 2.94 (s, 3H), 2.80 - 2.70 (m, 2H), 2.68 - 2.60 (m, 4H), 2.10-2.02 (m, 2H), 1.90-1.80 (m, 4H).
429	LC-MS: (ES, m/z): RT=0.996min, LCMS 31, m/z = 358 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.56 (d, J = 7.3 Hz, 1H), 7.24 - 7.00 (m, 3H), 6.17 (d, J = 7.3 Hz, 1H), 4.62 - 4.47 (m, 1H), 4.29 - 4.10 (m, 3H), 4.08 - 3.89 (m, 4H), 3.58 - 3.33 (m, 2H), 3.03 (s, 3H), 2.69 - 2.54 (m, 1H), 2.43 - 2.23 (m, 1H), 2.22 - 2.07 (m,

478

	2H), 1.62 (d, J = 6.6 Hz, 3H).
430	LC-MS: (ES, m/z): RT = 1.02min, LCMS33: m/z = 372 [M+l], 1H NMR (300 MHz, DMSO-d6) δ 8.1-7.8 (m, 1H), 7.71 (s, 1H), 7.05 (d, J = 9.0 Hz, 1H), 6.76 (dd, J = 9.0, 3.0 Hz, 1H), 6.4-6.2 (m, 1H), 4.14 - 3.93 (m, 4H), 3.63 - 3.49 (m, 2H), 3.32 - 3.19 (m, 2H), 3.08 - 2.85 (m, 5H), 2.19 - 1.83 (m, 6H), 1.32 (t, J = 6.9 Hz, 3H).
432	LC-MS: (ES, m/z): RT = 1.06min, LCMS33: m/z = 386 [M+l], 1H NMR (300 MHz, DMSO-d6) δ 7.96 - 7.89 (m, 1H), 7.04 (d, J = 9.0 Hz, 1H), 6.70 (dd, J = 9.0, 3.0 Hz, 1H), 6.37-6.09 (m, 1H), 4.11-3.98 (m, 4H), 3.62-3.56 (m, 2H), 3.31-3.19 (m, 2H), 3.08 - 2.85 (m, 5H), 2.39 - 2.24 (m, 3H), 2.19-1.76 (m, 6H), 1.36 (t, J = 6.9 Hz, 3H).
433	LC-MS: (ES, m/z): RT = 1.34 min, LCMS 33: m/z = 368 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.64 (s, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.11 (dd, J = 8.9, 2.5 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 6.01 (d, J = 6.5 Hz, 1H), 5.14 (s, 2H), 3.84 (s, 3H), 2.95 (s, 3H), 2.35-2.25 (m, 1H), 1.35 - 1.13 (m, 4H).
435	LC-MS: (ES, m/z): RT= 1.15 min, LCMS 53: m/z = 372 [M+l], 1H-NMR: (Methanol-d4, ppm): δ 7.27 (s, 1H), 7.16 — 6.97 (m, 2H), 6.01 (s, 1H), 3.95-3.90 (m, 2H), 3.86 (s, 3H), 3.65 - 3.53 (m, 2H), 3.01-2.95 (m, 5H), 2.90 (s, 3H), 2.31 (s, 3H), 2.22-2.11 (m, 3H), 1.87-1.56 (m, 2H).
436	LC-MS: (ES, m/z): RT= 1.08 min, LCMS53:m/z = 412 [M+l], 1H-NMR: (MethanoLd4, ppm): δ 7.27 (d, J = 2.4 Hz, 1H), 7.11 (dd, J = 8.7, 2.5 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.04 - 5.97 (m, 1H), 3.96 (d, J = 5.4 Hz, 2H), 3.85 (d, J = 3.7 Hz, 3H), 3.76 (d, J = 12.4 Hz, 2H), 3.17 - 2.97 (m, 6H), 2.32 - 2.20 (m, 5H), 1.911.76 (m, 2H), 1.33-1.05 (m, 1H), 0.87-0.74 (m, 2H), 0.56-0.36 (m, 2H).
437	LC-MS: (ES, m/z): RT = 0.957 min, LCMS15: m/z = 330.2 [M+l], 1H NMR (400 MHz, DMSO-d6) δ 8.80 - 8.58 (m, 2H), 7.69 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.84 (s, 1H), 4.11 (d, J = 6.2 Hz, 2H), 4.06 (d, J = 9.7 Hz, 2H), 3.91 - 3.71 (m, 6H), 3.28 - 3.18 (m, 1H), 2.86 (s, 3H), 2.16 (s, 3H).
438	LC-MS: (ES, m/z): RT = 1.54 min, LCMS 28: m/z = 358 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.72 (d, J = 5.8 Hz, 1H), 7.51 (s, 1H), 7.07 (dd, J = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 4.08 - 3.90 (m, 2H), 3.82 (s, 3H), 2.98 - 2.62 (m, 6H), 2.37 (d, J = 2.5 Hz, 3H), 2.30-2.20 (m, 2H), 2.102.00 (m, 1H), 1.18 (d, J = 6.8 Hz, 3H).
439	LC-MS: (ES, m/z): RT = 1.56 min, LCMS 28: m/z = 358 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.72 (s, 1H), 7.51 (s, 1H), 7.08 (dd, J = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.09 - 3.90 (m, 2H), 3.82 (s, 3H), 2.94 (s, 4H), 2.90-2.80 (m, 2H), 2.39 (d, J = 4.9 Hz, 3H), 2.27 (d, J = 8.3 Hz, 2H), 2.08 (s, 1H), 1.18 (d, J = 6.8 Hz, 3H).
440	LC-MS: (ES, m/z): RT = 1.400 min, LCMS 33: m/z = 359 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.53 (d, J = 7.2 Hz, 1H), 7.20 (s, 1H), 7.03 (d, J = 2.7 Hz, 2H), 6.16 (d, J = 7.3 Hz, 1H), 4.20 - 4.00 (m, 3H), 3.91 - 3.73 (m, 5H), 3.03 (s, 3H), 1.85- 1.49 (m, 9H).
441	LC-MS: (ES, m/z): RT= 0.831 min, LCMS 32, m/z = 402.4 [M+l], 1H NMR (400 MHz, Deuterium Oxide) δ 7.15 (d, J = 2.1 Hz, 1H), 7.09 - 6.90 (m, 2H), 6.02 (d, J = 1.7 Hz, 1H), 4.27 (s, 2H), 4.14 - 3.98 (m, 2H), 3.77 (s, 3H), 3.70 - 3.55 (m, 2H), 3.32 (d, J = 4.4 Hz, 5H), 3.08 - 2.92 (m, 2H), 2.83 (s, 3H), 2.24 - 1.73 (m, 6H).
442	LC-MS: (ES, m/z): RT = 0.930 min, LCMS07: m/z = 344.15 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.33 - 7.29 (m, 1H), 7.26 - 7.04 (m, 2H), 6.02 (d, J = 1.2 Hz, 1H), 4.63 - 4.40 (m, 2H), 4.26 - 4.03 (m, 4H), 3.93 (d, J = 1.5 Hz, 3H), 3.32 - 3.31 (m, 1H), 3.08 - 2.95 (m, 6H), 2.32 (s, 3H).

479

444	LC-MS: (ES, m/z): RT =0.957 min, LCMS 07: m/z = 358 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.35 (d, J = 14.3 Hz, 1H), 7.27 - 7.14 (m, 1H), 7.09 (q, J = 8.8 Hz, 1H), 6.01 (d, J = 1.1 Hz, 1H), 4.54-4.35 (m, 2H), 4.31 -4.08 (m, 4H), 3.92 (s, 3H), 3.70 - 3.47 (m, 2H), 3.47 (s, 1H), 3.01 (s, 3H), 2.48 - 2.24 (m, 3H), 1.28 (t, J = 7.3 Hz, 3H).
445	LC-MS: (ES, m/z): RT = 1.067 min, LCMS15: m/z = 384.2 [M+1].1H NMR (400 MHz, Methanol-d4) δ 7.36 - 7.06 (m, 3H), 5.99 (s, 1H), 4.53 - 4.35 (m, 2H), 4.32 4.07 (m, 4H), 3.91 (s, 3H), 3.36 (d, J = 7.0 Hz, 2H), 3.18 (d, J = 7.3 Hz, 1H), 3.03 2.95 (m, 3H), 2.31 (s, 3H), 1.09 - 1.06 (m, 1H), 0.77 - 0.72 (m, 2H), 0.50 - 0.41 (m, 2H).
446	LC-MS: (ES, m/z): RT = 1.99 min, LCMS 33: m/z = 398.3 [M+l], 1HNMR (300 MHz, Methanol-d4) δ 7.33 - 7.17 (m, 2H), 7.04 (d, J = 8.8 Hz, 1H), 5.98 (s, 1H), 4.26 - 3.86 (m, 6H), 3.80 - 3.46 (m, 2H), 2.99 (d, J = 11.3 Hz, 6H), 2.51-2.12 (m, 9H), 1.97 (q, J = 9.4 Hz, 2H).
447	LC-MS: (ES, m/z): RT = 0.85 min, LCMS 33: m/z = 359.0 [M+l], 1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.28 (s, 1H), 7.31 (s, 2H), 6.89 (d, J = 8.7 Hz, 1H), 5.59 (s, 1H), 3.96 (t, J = 6.5 Hz, 2H), 3.73 (s, 3H), 2.54 (d, J = 7.1 Hz, 2H), 2.42 - 2.39 (m, 4H), 2.05 (s, 3H), 1.89 - 1.84 (m, 2H), 1.68 - 1.63 (m, 4H).
448	LC-MS: (ES, m/z): RT = 0.88 min, LCMS 33: m/z = 359.0 [M+l], 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.67 - 7.41 (m, 1H), 7.05 (q, J = 8.7 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 5.63 (s, 1H), 3.99 (t, J = 6.5 Hz, 2H), 3.72 (s, 3H), 2.57 (t, J = 7.1 Hz, 2H), 2.48 (s, 5H), 2.09 (s, 3H), 1.91 - 1.85 (m, 2H), 1.77 - 1.45 (m, 4H).
449	LC-MS: (ES, m/z): RT = 1.226 min; LCMS34: m/z = 400 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.35 - 7.29 (m, 1H), 7.23 (d, J = 8.7 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 5.98 (d, J= 1.1 Hz, 1H), 5.01-4.91 (m, 3H), 4.79-4.77 (m, 2H), 4.69 (s, 1H), 4.13 - 4.11 (m, 2H), 3.90 (s, 4H), 3.80 - 3.50 (m, 2H), 3.04 - 2.97 (m, 4H), 2.40 - 2.30 (m, 1H), 2.30 (d, J = 0.9 Hz, 3H), 2.17 (s, 1H).
450	LC-MS: (ES, m/z): RT = 1.18min, LCMS33: m/z = 427 [M+l], 1H NMR (300 MHz, DMSO-d6) δ 10.86-10.48 (m, 2H), 8.04-7.95 (m, 1H), 7.45 (d, J = 15.1 Hz, 1H), 7.08-6.91 (m, 2H), 5.04 (s, 1H), 4.07 (d, J = 6.6 Hz, 2H), 3.76 (s, 3H), 3.743.25 (m, 8H), 3.10-2.97 (m, 2H), 2.91 - 2.79 (m, 3H), 2.19 (q, J = 7.4, 6.8 Hz, 2H), 2.06- 1.81 (m, 8H).
451	LC-MS: (ES, m/z): RT =1.016min, LCMS 07: m/z = 442 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.30 - 7.12 (m, 2H), 7.05 (q, J = 4.9 Hz, 1H), 6.05 - 5.97 (m, 1H), 4.09 - 4.75 (m, 2H), 4.05 - 3.75 (m, 6H), 3.72 (m, 1H), 3.40 (q, J = 2.3 Hz, 3H), 3.28-3.00 (m, 5H), 2.99 - 2.89 (m, 1H), 2.54-2.41 (m, 1H),2.31 (d, J = 0.9 Hz, 3H), 1.88-1.81 (m, 1H), 1.80- 1.78 (m, 1H), 1.75- 1.73 (m, 1H), 1.72-1.57 (m, 2H), 1.29- 1.25 (m, 2H).
452	LC-MS: (ES, m/z): RT = 1.245 min, LCMS 33: m/z = 345 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.26 (s, 1H), 7.03 (d, 2H), 6.29-5.99 (m, 1H), 4.30(s, 1H), 4.11-3.82 (m, 7H), 3.00(s, 3H), 2.42-2.22 (m,3H), 2.18-1.81(m, 4H).
453	LC-MS: (ES, m/z): RT = 1.25min, LCMS33: m/z = 331 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.76-7.50 (m, 1H), 7.16-7.11 (m, 1H), 7.10-7.01 (m, 2H), 6.39-6.1 (m, 1H), 4.2-4.02 (m, 2H), 3.93 - 3.83 (m, 5H), 3.52 - 3.44 (m, 1H), 3.062.95 (m, 3H), 0.67 - 0.55 (m, 2H), 0.52 (dd, J = 6.8, 4.6 Hz, 2H).
456	LC-MS: (ES, m/z): RT =0.764min, LCMS48: m/z = 412 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.33 (s, 1H), 7.24 - 7.20 (m, 1H), 7.04 (q, J = 3.5 Hz, 1H), 5.99 (q, J = 1.2 Hz, 1H), 4.10 - 4.06 (m, 2H), 4.01 - 3.86 (m, 4H), 3.86 - 3.57 (m, 2H), 3.54-3.38 (m, 1H), 3.23 - 3.18 (m, 1H), 3.00 (d, J = 12.0 Hz, 4H), 2.53 1.96 (m, 7H), 1.94 - 1.65 (m, 6H).

480

458	LC-MS: (ES, m/z): RT=3.213min, LCMS 28, m/z =426.3 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.35 (d, J = 2.4 Hz, 1H), 7.18 (dd, J = 8.7, 2.5 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.05 (s, 1H), 4.21 (t, J = 5.5 Hz, 2H), 3.86 (d, J = 19.0 Hz, 5H), 3.49 (t, J = 7.0 Hz, 2H), 3.25-2.88 (m,6H), 2.44 - 1.98 (m, 8H), 1.98 - 1.56 (m, 6H).
459	LC-MS: (ES, m/z): RT= 1.100min, LCMS 28, m/z = 442.2 [M+l], 1H NMR (300 MHz, Deuterium Oxide) δ 7.16 (d, J = 1.8 Hz, 1H), 7.11 — 6.92 (m, 2H), 5.93 (s, 1H), 4.18 - 3.92 (m, 4H), 3.80 (s, 3H), 3.74 - 3.58 (m, 2H), 3.57 - 3.27 (m, 4H), 3.15 - 2.62 (m, 6H), 2.28 - 1.52 (m, 10H).
460	LC-MS: (ES, m/z): RT = 0.998 min, LCMS 33: m/z = 383 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.64 (s, 1H), 8.14 (s, 1H), 7.20(s, 1H), 7.03 (s, 1H), 4.35 (t, J = 5.5 Hz, 2H), 4.00 (s, 3H), 3.82 (s, 2H), 3.50 (t, J = 7.4 Hz, 2H), 3.18 (s, 2H), 2.73 (s, 3H), 2.45-2.35 (m, 2H), 2.30-2.20 (m, 2H), 2.15-2.05 (m, 2H).
461	LC-MS: (ES, m/z): RT = 0.63 min, LCMS 53: m/z = 388.3 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.29 (d, J = 2.8 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.09 - 6.99 (m, 1H), 5.99 (s, 1H), 4.20 - 4.02 (m, 2H), 4.00 - 3.63 (m, 7H), 3.61 - 3.41 (m, 3H), 3.26 - 3.19 (m, 1H), 3.01 - 2.98 (m, 4H), 2.31 - 2.26 (m, 4H), 2.23 - 1.99 (m, 1H).
462	LC-MS: (ES, m/z): RT =1.069min, LCMS07: m/z =468 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.36 - 7.11 (m, 2H), 7.03 (d, J = 8.6 Hz, 1H), 5.99 (s, 1H), 4.13 (s, 2H), 4.04 - 3.52 (m, 9H), 3.50 - 3.35 (m, 3H), 3.30 - 3.16 (m, 1H), 3.04 (d, J = 3.6 Hz, 2H), 2.31 (s, 5H), 1.88- 1.82 (m, 1H), 1.73 - 1.52 (m, 2H), 1.44-1.18 (m, 2H), 1.13-0.68 (m, 4H).
463	LC-MS: (ES, m/z): RT=0.986 min, LCMS 07, m/z =372.20 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.46 - 6.91 (m, 3H), 6.02 (s, 1H), 4.19 (t, J = 5.6 Hz, 2H), 3.90 (s, 3H), 3.75 - 3.45 (m, 2H), 3.18-2.76 (m, 7H), 2.53 - 2.12 (m, 5H), 1.31 0.86 (m, 4H).
464	LC-MS: (ES, m/z): RT =1.128 min, LCMS 33: m/z = 456 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.96 (s, 1H),6.52-6.61 (m, 1H),6.20-6.40 (m, 1H), 5.90-6.08 (m, 1H), 4.28 (t, J = 5.6 Hz, 2H), 4.05 - 3.90 (m,5H), 3.81 (s, 2H), 3.52 - 3.41 (m, 4H), 3.21-3.11 (s, 4H), 2.59-2.40 (m, 3H), 2.35 (t, J = 6.6 Hz, 2H), 2.22 (s, 2H), 2.10 (s, 2H), 1.93 (s, 1H), 1.74 (s, 2H), 1.40 (s, 2H).
465	LC-MS: (ES, m/z): RT = 1.68min, LCMS28: m/z = 374 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.29 (d, J = 2.4 Hz, 1H), 7.20 (dd, J = 8.7, 2.6 Hz, 1H), 7.067.04 (m, 1H), 6.2-5.99 (m, 1H), 4.76 - 4.52 (m, 2H), 4.39 - 4.11 (m, 4H), 4.05-3.85 (m, 4H), 3.61-3.43 (m, 2H), 3.05-2.9 (m, 3H), 2.45-2.23 (m, 3H), 2.20-2.06 (m, 2H).
466	LC-MS: (ES, m/z): RT = 1.64min, LCMS33: m/z = 384 [M+l], 1HNMR (300 MHz, Methanol-d4) δ 7.40 - 7.27 (m, 2H), 7.12-6.95 (d, J = 9.1 Hz, 1H), 6.25-5.97 (m, 1H), 4.89-4.67 (m, 1H), 3.90 (d, J = 4.4 Hz, 3H), 3.77-3.45 (m, 4H), 3.09-2.94 (m, 4H), 2.40 (s, 1H), 2.33-2.23 (m, 4H), 2.14-1.9 (m, 2H), 1.25-0.9 (m,4H).
473	LC-MS: (ES, m/z): RT = 0.962min, LCMS28: m/z = 359 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.05 (s, 1H), 7.09 (s, 1H), 6.30 (s, 1H), 4.60 - 4.24 (m, 2H), 4.12 - 3.62 (m, 5H), 3.44 - 3.34 (m, 1H), 3.28 - 2.95 (m, 8H), 2.78 (s, 3H), 2.60 2.30 (m, 1H), 2.27- 1.85 (m, 1H).
478	LC-MS: (ES, m/z): RT = 1.062 min, LCMS 53: m/z = 368.2 [M+l], 1H NMR (400 MHz, DMSO-d6) δ 13.63 (s, 1H), 8.74 (s, 1H), 7.78 (s, 1H), 7.71 (s, 1H), 7.45 7.19 (m, 1H), 7.19 - 6.95 (m, 1H), 6.95 - 6.66 (m, 1H), 5.87 (d, J = 5.8 Hz, 1H), 4.88 (s, 2H), 3.69 (s, 3H), 2.82 (s, 3H), 2.04 (dd, J = 9.7, 5.2 Hz, 1H), 1.13 - 0.97 (m, 2H), 0.90 (d, J = 5.9 Hz, 5H).

481

480	LC-MS: (ES, m/z): RT = 1.114 min ; m/z = 368.3 [M+l], 1H NMR (300 MHz, Deuterium Oxide) δ 8.75 - 8.38 (m, 1H), 7.28 (dd, J = 7.3, 4.6 Hz, 1H), 7.17 - 7.00 (m, 1H), 6.86 - 6.66 (m, 2H), 6.12 -5.89 (m, 1H), 4.98 - 4.75 (m, 2H), 3.75 - 3.42 (m, 4H), 2.85 - 2.46 (m, 3H), 1.09 - 0.93 (m, 4H).
481	LC-MS: (ES, m/z): RT = 1.03 min, LCMS 33: m/z = 384.3 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.37 (d, J = 2.5 Hz, 1H), 7.13 (q, J = 8.7, 1H), 6.99 (d, J = 8.7 Hz, 1H), 5.94 (s, 1H), 4.05 - 4.01 (m, 2H), 3.86 (s, 3H), 3.48 (t, J = 9.9 Hz, 1H), 3.30 - 3.12 (m, 2H), 2.98 (s, 3H), 2.88 (q, J = 7.2 Hz, 1H), 2.55 (d, J = 8.4 Hz, 1H), 2.27 (s, 4H), 1.93 - 1.91 (m, 6.9 Hz, 1H), 0.80 (q, J = 5.1 Hz, 4H).
482	LC-MS: (ES, m/z): RT = 1.20 min, LCMS 27: m/z = 384.0 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.49 (s, 1H), 7.09 (q, J = 8.7 Hz, 1H), 7.00 - 6.91 (m, 1H), 5.87 (d, J = 2.9 Hz, 1H), 4.09 - 3.96 (m, 2H), 3.84 (s, 3H), 3.26 - 2.69 (m, 8H), 2.22 (s, 5H), 1.79- 1.69 (m, 1H), 0.63 (q, J = 7.7 Hz, 4H).
483	LC-MS: (ES, m/z): RT = 1.16min, LCMS28: m/z = 400 [M+l], 1H NMR (300 MHz, Deuterium Oxide) δ 7.27 (s, 1H), 6.92 (s, 2H), 5.84 (s, 1H), 4.14 - 4.02 (m, 2H), 3.75 (s, 3H), 3.26 (d, J = 7.8 Hz, 6H), 2.75 (s, 3H), 2.62 - 2.52 (m, 1H), 2.21 2.05 (m, 2H), 1.97 (s, 4H), 1.10 (d, J = 6.9 Hz, 6H).
486	LC-MS: (ES, m/z): RT = 0.902 min, LCMS33: m/z = 382 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.08 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.21 - 7.19 (m, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 0.8 Hz, 1H), 4.14 (t, J = 6.0 Hz, 2H), 3.84 (s, 3H), 2.82 - 2.73 (m, 2H), 2.66 (d, J = 4.8 Hz, 4H), 2.50 (d, J = 0.8 Hz, 3H), 2.16 2.04 (m, 2H), 1.89- 1.85 (m, 4H).
490	LC-MS: (ES, m/z): RT = 0.969 min, LCMS 33: m/z = 358 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.25 (s, 1H), 7.20-7.11 (m, 1 H),7.07 - 6.95 (s, 1H), 6.035.96 (m, 1H), 4.39 - 4.28 (m, 2H), 4.25 - 4.08 (m, 4H), 3.95 (s, 3H), 3.64 - 3.48 (m, 2H), 3.01 (s, 3H), 2.65 - 2.51 (m, 1H), 2.52 - 2.38 (m, 1H), 2.41 - 2.22 (m, 3H), 2.14-2.00 (m , 2H).
496	LC-MS: (ES, m/z): RT = 1.471min, m/z = 406.2 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.45 (d, J = 2.4 Hz, 1H), 7.41 - 7.21 (m, 1H), 6.23 - 6.07 (m, 1H), 4.23 (q, J = 5.9 Hz, 2H), 3.90 - 3.70 (m, 5H), 3.53 - 3.42 (m, 2H), 3.18 (m, 2H), 3.02 (s, 3H), 2.46 - 2.03 (m, 9H).
497	LC-MS: (ES, m/z): RT = 2.041 min, LCMS33: m/z = 370 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.29 - 7.09 (m, 3H), 6.29 - 5.89 (m, 1H), 4.17 (t, J = 5.7 Hz, 2H), 3.82 - 3.70 (m, 2H), 3.53 - 3.41 (m, 2H), 3.18 - 3.04 (m, 2H), 3.04 (s, 3H), 2.68 (q, J = 7.5 Hz, 2H), 2.45 - 2.17 (m, 7H), 2.17 - 2.03 (m, 2H), 1.29 - 1.14 (m, 3H).
498	LC-MS: (ES, m/z): RT= 1.120 min, LCMS 28, m/z =398.2 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.30 (d, J = 2.4 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.05 (d, J = 8.8 Hz, 1H), 5.99 (d, J = 1.2 Hz, 1H), 4.20 (t, J = 5.5 Hz, 2H), 4.04 - 3.85 (m, 4H), 3.62 - 3.36 (m, 4H), 3.29 - 3.25 (m, 1H), 3.01 (s, 3H), 2.51 - 1.89 (m, 7H), 0.95 - 0.60 (m, 4H).
502	LC-MS: (ES, m/z): RT = 0.98min, LCMS33: m/z = 360 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.27 (s, 1H), 7.16 (dd, J = 8.7, 2.5 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 5.98 (s, 1H), 4.11 (t, J = 5.6 Hz, 2H), 3.88 (s, 3H), 3.35 - 3.30 (m, 2H), 2.97 - 2.88 (m, 9H), 2.30 (s, 3H), 2.06 - 1.89 (m, 4H).
503
503	LC-MS: (ES, m/z): RT =1.140 min; LCMS27: m/z = 372 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.25 (d, J = 2.9 Hz, 1H), 7.16 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 5.98 (s, 1H), 4.16-4.13 (m, 1H), 4.13-4.05 (m, 1H), 3.87 (s, 4H),

482

	3.79 - 3.62 (m, 1H), 3.54 - 3.42 (m, 1H), 3.26 - 3.05 (m, 1H), 3.04 - 2.77 (m, 7H), 2.75 - 2.55 (m, 1H), 2.35 (s, 3H), 2.10 - 1.75 (m, 3H).
504	LC-MS: (ES, m/z): RT= 1.03 min, LCMS 15:m/z = 386 [M+l], 1H-NMR: (Methanol-d4, ppm): δ 7.34 - 7.26 (m, 1H), 7.16 (dd, J = 8.9, 2.3 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 6.02 (s, 1H), 4.35-4.18 (m, 2H), 3.98 - 3.78 (m, 4H), 3.74-3.65 (m, 1H), 3.65-3.50 (m, 1H), 3.42-3.08 (m, 2H), 3.05-2.99 (m, 3H), 2.30-2.40 (m, 6H), 2.24-2.05 (m, 2H), 1.93-1.75 (m, 1H), 1.61-1.51 (m, 3H).
506	LC-MS: (ES, m/z): RT = 1.03min, LCMS33: m/z = 384 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.37 - 7.17 (m, 2H), 7.11 - 7.01 (m, 1H), 5.98 (s, 1H), 4.17 (d, J = 5.4 Hz, 2H), 3.91 - 3.81 (m, 5H), 3.51 - 3.77 (m, 4H), 3.00 (s, 3H), 2.44 2.17 (m, 5H), 2.03 - 1.89 (m, 2H), 0.92 (q, J = 7.6 Hz, 1H), 0.73-0.58 (m, 1H).
507	LC-MS: (ES, m/z): RT = 1.023min; LCMS33: m/z = 380 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.06 (s, 1H), 7.90 (d, J = 7.0 Hz, 1H), 7.61 (d, J = 3.4 Hz, 1H), 7.38 (d, J = 0.9 Hz, 1H), 7.26 (d, J = 0.9 Hz, 1H), 7.01 (s, 1H), 4.30 (t, J = 5.4 Hz, 2H), 3.99 (s, 3H), 3.97 - 3.80 (m, 2H), 3.48 - 3.40 (m, 4H), 2.35 - 2.33 (m, 2H), 1.91 - 1.89 (m, 2H), 1.01-0.87 (m, 1H), 0.73 - 0.62 (m, 1H).
508	LC-MS: (ES, m/z): RT = 0.97 min, LCMS 53: m/z = 358.0 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.23 (t, J = 3.1 Hz, 1H), 7.15 (t, J = 8.9 Hz, 1H), 7.01 (t, J = 1.3 Hz, 1H), 6.01 - 5.96 (m, 1H), 4.45 - 4.25 (m, 2H), 4.09 (q, J = 5.8 Hz, 3H), 3.97 (q, J = 9.3 Hz, 1H), 3.87 (d, J = 2.1 Hz, 3H), 3.27 - 3.06 (m, 1H), 2.99 (d, J = 5.0 Hz, 4H), 2.92 (s, 2H), 2.30 (d, J = 0.9 Hz, 3H), 2.25 - 2.11 (m, 2H).
509	LC-MS: (ES, m/z): RT = 1.102 min; LCMS53: m/z = 402 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.93 (s, 1H), 6.62 (s, 1H), 6.09 (d, J = 6.5 Hz, 1H), 4.25 (t, J = 5.5 Hz, 2H), 3.94 (s, 3H), 3.89 - 3.87 (m, 2H), 3.50 - 3.38 (m, 4H), 2.96 (s, 3H), 2.50 (d, J = 3.1 Hz, 3H), 2.37 - 2.26 (m, 2H), 1.95 - 1.86 (m, 2H), 0.91 (q, J = 7.7 Hz, 1H), 0.69- 0.62 (m, 1H).
510	LC-MS: (ES, m/z): RT = 1.075 min, LCMS28: m/z = 370 [M+l]. 1H-NMR: (300 MHz, Methanol-d4) δ 7.25-6.95 (m, 3H), 6.10 - 5.86 (m, 1H), 4.49 - 3.93 (m, 6H), 3.79 (s, 3H), 3.34 - 2.98 (m, 2H), 2.82 (s, 3H), 2.14 (s, 3H), 0.93 - 0.62 (m, 4H).
514	LC-MS: (ES, m/z): RT = 1.197 min, LCMS 27: m/z = 385 [M+l], 1H-NMR: (300 MHz, Methanol-d4) δ 7.95 (d, J = 2.2 Hz, 1H), 7.81 (s, 1H), 5.82 (d, J = 0.8 Hz, 1H), 4.05 (t, J = 6.2 Hz, 2H), 3.91 (s, 3H), 3.08 (d, J = 9.1 Hz, 2H), 2.91 (s, 3H), 2.74 - 2.64 (m, 2H), 2.50 - 2.44 (m, 2H), 2.18 (s, 3H), 2.04 - 1.94 (m, 2H), 1.49 1.41 (m, 2H), 0.70-0.32 (m, 1H), 0.46 - 0.38 (m, 1H).
515	LC-MS: (ES, m/z): RT =0.870min, LCMS 33: m/z = 371 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.44 (s, 1H), 7.91 (d, J = 2.0 Hz, 1H), 5.98 (s, 1H), 4.20 (q, J = 6.2 Hz, 2H), 3.71 - 3.41 (m, 6H), 3.00 (s, 3H), 2.83 (q, J = 7.5 Hz, 2H), 2.41 2.25 (m, 5H), 2.20 - 2.09 (m, 4H), 1.26 (t, J = 7.6 Hz, 3H).
517a	LC-MS: (ES, m/z): RT=1.041 min, LCMS 53, m/z =398 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.29 (d, J = 2.4 Hz, 1H), 7.20 - 6.98 (m, 2H), 6.01 (s, 1H), 4.12 - 3.81 (m, 6H), 3.75- 3.63 (m, 1H), 3.24 - 3.08 (m, 2H), 3.01 (s, 3H), 2.94 2.81 (m, 1H), 2.46-2.35 (m, 1H), 2.31 (d, J = 0.9 Hz, 3H), 2.14 - 1.78 (m, 3H), 1.63 - 1.43 (m, 1H), 1.17-0.95 (m, 4H).
517b	LC-MS: (ES, m/z): RT = 1.094min, LCMS28: m/z = 398.2 [M+l], 1H NMR (400 MHz, Deuterium Oxide) δ 7.28 - 6.78 (m, 3H), 6.19 - 5.72 (m, 1H), 3.96 (dd, J = 9.8, 4.7 Hz, 1H), 3.85 (dd, J = 9.8, 7.4 Hz, 1H), 3.80 - 3.70 (m, 4H), 3.58 (d, J = 13.7 Hz, 1H), 3.10 - 2.89 (m, 2H), 2.82 (s, 3H), 2.72 - 2.62 (m, 1H), 2.38 - 2.04 (m, 4H), 1.95 (s, 3H), 1.83 (d, J = 13.1 Hz, 1H), 1.70- 1.56 (m, 1H), 1.44-1.20 (m, 1H), 0.94-0.75 (m, 4H).

483

518	LC-MS: (ES, m/z): RT = 1.22min, m/z = 385 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.59 (s, 1H), 7.48-7.05 (m, 1H), 4.37 (t, J = 5.4 Hz, 2H), 4.20 - 3.80 (m, 4H), 3.92 - 3.72 (m, 2H), 3.50 (t, J = 7.3 Hz, 2H), 3.25 - 3.10 (m, 5H), 2.61 1.60 (m, 14H).
523	LC-MS: (ES, m/z): RT = 1.27 min, LCMS 53: m/z = 399.0 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.54 (s, 1H), 7.31- 7.20 (m, 1H), 4.37 (t, J = 5.5 Hz, 2H), 4.03 (s, 3H), 3.84 - 3.82 (m, 2H), 3.71 - 3.44 (m, 3H), 3.18 (s, 5H), 2.40 - 2.36 (m, 2H), 2.32-2.03 (m, 4H), 2.04 - 1.51 (m, 9H), 1.39- 1.40 (m, 1H).
527	LC-MS: (ES, m/z): RT = 0.932min, LCMS28: m/z = 454.3 [M+l], 1H-NMR: (CDC13, ppm): 1H NMR (300 MHz, Deuterium Oxide) δ 7.43-7.31 (m, J = 11.7 Hz, 1H), 7.09 (s, 1H), 4.30-4.20 (m, 2H), 3.83-3.90 (m, 3H), 3.80 (s, 3H), 3.71-3.60 (m, 3H), 3.56 (d, J = 10.7 Hz, 2H), 3.30-3.39 (m, 3H), 3.24 - 3.11 (m, 2H), 3.11 — 2.94 (m, 2H), 2.80-2.90 (m, 3H), 2.30-2.20 (m, 3H), 2.20 - 2.02 (m, 7H), 2.00 1.84 (m, 4H).
528	LC-MS: (ES, m/z): RT= 0.69 min, LCMS 15:m/z = 504 [M+l]. 1H-NMR: (Methanol-d4, ppm): δ 7.55 (s, 1H), 7.33 (s, 1H), 4.37 (t, J = 5.5 Hz, 2H), 4.26 4.15 (m, 4H), 4.05 (s, 3H), 3.98 - 3.89 (m, 1H), 3.85 - 3.81 (m, 2H), 3.71 - 3.70 (m, 2H), 3.50 (t, J = 7.2 Hz, 2H), 3.34 - 3.32 (m, 1H), 3.32 - 3.30 (m, 3H), 2.98 (s, 3H), 2.45-2.03 (m, 14H).
529	LC-MS: (ES, m/z): RT=4.170min LCMS53, m/z =468 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.76 (s, 1H), 7.29 (s, 1H), 4.60 - 4.22 (m, 3H), 4.12-3.89 (m, 4H), 3.88 - 3.76 (m, 2H), 3.75 - 3.62 (m, 2H), 3.61 - 3.39 (m, 3H), 3.23 - 3.05 (m, 2H), 2.96 (s, 3H), 2.45 - 1.58 (m, 19H).
538	LC-MS: (ES, m/z): RT = 0.666min, m/z = 368.2 [M+l]: 1H NMR (300 MHz, Methanol-d4) δ 8.60 (s, 1H), 7.83 (s, 1H), 7.72 (d, J = 6.9 Hz, 1H), 6.85 (s, 1H), 6.30 (d, J = 6.8 Hz, 1H), 4.38 (s, 2H), 3.78 (s, 2H), 3.55 (s, 2H), 3.21 (s, 2H), 3.14 (s, 3H), 2.41 (s, 2H), 2.22 - 2.10 (m, 4H).
541	LC-MS: (ES, m/z): RT = 1.64 min, LCMS 27: m/z = 208.0 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.64 (d, J = 6.9 Hz, 1H), 6.07 (d, J = 6.9 Hz, 1H), 4.55 - 4.45 (m, 1H), 3.96 - 3.92 (m, 1H), 3.63 - 3.51 (m, 1H), 3.49 - 3.33 (m, 2H), 2.95 (s, 3H), 2.27-2.17 (m, 1H), 1.97-1.91 (m,lH), 1.89- 1.69 (m, 2H).
542	LC-MS: (ES, m/z): RT = 1.21 min, LCMS 27: m/z = 208.0 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.67 (d, J = 6.0 Hz, 1H), 5.76 (d, J = 6.0 Hz, 1H), 4.69 - 4.57 (m, 2H), 2.95-2.83 (m, 6H), 1.89- 1.85 (m, 2H), 1.37- 1.25 (m, 2H).
543	LC-MS: (ES, m/z): RT = 1.15 min, LCMS 07: m/z =181.1 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.61 (d, J = 6.0 Hz, 1H), 5.77 (d, J = 6.0 Hz, 1H), 3.34 (t, J = 4.5 Hz, 1H), 3.32 (t, J = 1.5 Hz, 1H), 2.87 (s, 3H), 1.63 - 1.53 (m, 2H), 1.48 - 1.36 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H).
545	LC-MS: (ES, m/z): RT = 0.86min, LCMS15: m/z = 250 [M+l], 1H-NMR (300 MHz, Methanol-d4) δ 7.67 (d, J = 6.0 Hz, 1H), 5.75 (d, J = 6.0 Hz, 1H),4.07-3.88 (m, 2H), 3.76-3.54(m, 2H), 2.86 (s, 3H), 1.74- 1.30 (m, 8H), 1.04-0.80 (m, 3H).
546	LC-MS: (ES, m/z): RT = 1.31 min, LCMS 27: m/z = 222.0 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.67 (d, J = 6.0 Hz, 1H), 5.76 (d, J = 6.0 Hz, 1H), 3.86 - 3.80 (m, 1H), 3.69 - 3.58 (m, 1H), 3.57 - 3.48 (m, 2H), 2.88 (s, 3H), 1.76 - 1.55 (m, 4H), 1.14 (s, 3H).
547	LC-MS: (ES, m/z): RT = 0.67 min, LCMS 27: m/z = 222.0 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.67 (d, J = 6.0 Hz, 1H), 5.76 (d, J = 6.0 Hz, 1H), 3.92 - 3.84 (m, 2H), 3.71 - 3.62 (m, 2H), 2.87 (s, 3H), 1.61 - 1.49 (m, 4H), 1.22 (s, 3H).
548	LC-MS: (ES, m/z): RT = 0.98 min, LCMS28: m/z = 208.1 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.62 (s, 1H), 5.89 (d, J = 6.3 Hz, 1H), 4.31 (t, J = 7.2 Hz,

484

	1H), 3.70-3.55 (m, 1H), 2.91 (s, 3H), 2.68-2.56 (m, 1H), 2.18-2.12 (m, 2H), 1.99 - 1.88 (m, 2H), 1.62 - 1.55 (m, 1H).
549	LC-MS: (ES, m/z): RT = 1.12 min, LCMS 27: m/z = 278.1 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.62 (d, J = 7.2 Hz, 1H), 6.17 (d, J = 7.2 Hz, 1H), 4.14 - 4.02 (m, 2H), 3.79 - 3.71 (m, 1H), 3.68 - 3.54 (m, 1H), 3.34 - 3.32 (m, 2H), 3.24 - 3.01 (m, 3H), 2.00 - 1.91 (m, 4H), 1.72 - 1.65 (m,2H), 1.52 - 1.39(m, 5H), 1.02 (t, J = 7.3 Hz, 3H).
550	LC-MS: (ES, m/z): RT = 1.13 min, LCMS 27: m/z = 278.1 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.68 (s, 1H), 5.78 (d, J = 6.0 Hz, 1H), 4.32 - 4.25 (m, 2H), 3.67 - 3.27 (m, 2H), 2.87 (s, 3H), 2.71 - 2.65 (m, 2H), 1.65 (t, J = 5.1 Hz, 4H), 1.59 - 1.49 (m, 2H), 1.49- 1.39 (m, 2H), 1.29 (s, 3H), 0.98 (t, J = 7.2 Hz, 3H).
551	LC-MS: (ES, m/z): RT = 1.04 min, LCMS33: m/z = 387 [M+l], 1H NMR (300 MHz, Deuterium Oxide) δ 7.18 (d, J = 2.0 Hz, 1H), 7.08 - 6.95 (m, 2H), 6.04-5.89 (m, 1H), 4.07 (t, J = 5.5 Hz, 2H), 3.85 - 3.77 (m, 3H), 3.68 (t, J = 8.1 Hz, 1H), 3.353.25 (m, 1H), 3.05-2.98 (m, 1H), 2.84 (d, J = 2.1 Hz, 3H), 2.69 (s, 3H), 2.35-2.19 (m, 3H), 2.19-2.07 (m, 6H), 1.72 (q, J = 9.3 Hz, 2H).
552	LC-MS: (ES, m/z): RT = 0.681min, LCMS 27: m/z = 306 [M+l], 1H-NMR (300 MHz, Methanol-d4) δ 8.27 (s, 2H), 4.20 - 4.03 (m, 3H), 3.74 - 3.69 (m, 2H), 3.55 3.37 (m, 4H), 3.25-3.06 (m, 4H), 2.33-2.13 (m, 6H), 2.07-2.03 (m, 2H), 1.93 1.73 (m, 2H).
553	LC-MS: (ES, m/z): RT = 0.87 min, LCMS 33: m/z = 307 [M+l]. 1H NMR (400 MHz, Methanol-d4) δ 8.24 (s, 2H), 4.17-3.94 (m, 4H), 3.92 - 3.66 (m, 2H), 3.49 3.36 (m, 2H), 3.30 (d, J = 7.0 Hz, 2H), 3.27 - 2.88 (m, 6H), 2.50 - 2.22 (m, 1H), 2.19-1.86 (m, 2H), 1.71-1.58 (m, 2H), 1.33 - 1.08 (m, 2H).
554	LC-MS: (ES, m/z): RT= 1.24 min, LCMS 28:m/z = 291 [M+l], 1H-NMR: (Methanol-d4, ppm): δ 7.94 - 7.78 (m, 1H), 7.56 (t, J = 3.1 Hz, 1H), 7.19 - 7.11 (m, 1H), 4.20 - 3.98 (m, 3H), 3.92 - 3.65 (m, 2H), 3.58 - 3.44 (m 2H), 3.32 - 3.14 (m, 3H), 3.14 - 2.93 (m, 5H), 2.53 - 2.24 (m, 3H), 2.20 - 1.81 (m, 3H).
555	LC-MS: (ES, m/z): RT = 0.80 min, LCMS 53: m/z = 292.3 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.20 (s, 2H), 4.17-3.95 (m, 3H), 3.94 - 3.66 (m, 2H), 3.46 (q, J = 3.8 Hz, 2H), 3.29 - 2.83 (m, 8H), 2.48 - 1.97 (m, 4H), 1.85 - 1.73 (m, 2H).
556	LC-MS: (ES, m/z): RT =0.763min, LCMS33: m/z = 318 [M+l], 1H-NMR (400 MHz, Methanol-d4) δ 8.20 (s, 2H), 4.04 - 3.99 (m, 3H), 3.76 (s, 2H), 3.46 - 3.41 (m, 3H), 3.15 - 3.05 (m, 3H), 2.95- 8.83 (m, 2H), 2.50 - 2.00 (m, 4H), 1.95 - 1.76 (m, 2H), 1.13-0.90 (m, 4H).
557	LC-MS: (ES, m/z): RT =1.315min, LCMS 28: m/z =319 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.09 (s, 2H), 3.94-3.89 (m, 5H), 3.54-3.49 (m, 2H), 2.97 2.93 (m, 1H), 2.90-2.52 (m, 4H), 2.15-1.91 (m, 3H), 1.83 - 1.48 (m, 4H), 0.590.40 (m, 4H).
559	LC-MS: (ES, m/z): RT = 1.030 min, LCMS 33: m/z = 372 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.40 - 7.29 (m, 1H), 7.27 - 7.11 (m, 1 H), 7.11 - 6.99 (m, 1H), 6.29 -5.99 (m, 1H), 4.45 - 4.08 (m, 6H), 3.90 (s, 3H), 3.88 - 3.55 (m, 1H), 3.21-3.11 (m, 1H), 3.09 - 2.91 (m, 3H), 2.44- 2.28 (m, 3H), 1.40-1.21 (m, 6H).
563	LC-MS: (ES, m/z): RT = 1.05 min, LCMS 53: m/z = 398 [M+l]. 1H NMR (400 MHz, Methanol-d4) δ 7.59 (s, 1H), 7.09 - 6.96 (m, 1H), 6.90 (q, J = 8.7, 1H), 5.81 (s, 1H), 3.99 - 3.96 (m, 2H), 3.83 (d, J = 1.1 Hz, 3H), 3.30 - 2.96 (m, 2H), 2.94 (s, 3H), 2.80 (q, J = 8.0 Hz, 3H), 2.63 (s, 1H), 2.19 (s, 3H), 2.17 - 1.97 (m, 5H), 1.89 1.68 (m, 3H).
565	LC-MS: (ES, m/z): RT = 0.926 min, LCMS 33: m/z = 382 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.64 - 7.50 (m, 1H), 7.21 - 7.09 (m, 3H), 6.90 (s, 1H), 4.28 -

485

	4.18 (m, 2H), 3.96 (s, 3H), 3.88 - 3.71 (m, 2H), 3.57 - 3.48 (m, 2H), 3.21 - 3.08 (m, 2H), 2.53 (s, 3H), 2.31 - 2.10 (m, 6H).
570	LC-MS: (ES, m/z): RT = 0.999 min, LCMS07: m/z = 386.25 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.59 (s, 1H), 7.12 - 7.05 (m, 1H), 6.90 - 6.86 (m, 1H), 5.80 (s, 1H), 4.00 - 3.91 (m, 2H), 3.81 (d, J = 1.7 Hz, 3H), 3.10 - 2.92 (m, 4H), 2.77 2.70 (m, 3H), 2.55-2.44 (m, 2H), 2.17-2.06 (m, 4H), 1. 70- 1.66 (m, 1H), 1.221.10 (m, 6H).
571	LC-MS; (ES, m/z): RT = 1.000 min, LCMS33: m/z = 372 [M+l]. 1H NMR (400 MHz, Methanol-d4) δ 7.60 (s, 1H), 7.09 - 7.06 (m, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.81 (d, J = 0.8 Hz, 1H), 4.04 - 3.90 (m, 2H), 3.82 (s, 3H), 2.94 (s, 4H), 2.75 - 2.72 (m, 2H), 2.72 - 2.49 (m, 4H), 2.18 (s, 3H), 2.12 - 2.09 (m, 1H), 1.71 - 1.66 (m, 1H), 1.18 (t, J = 7.2 Hz, 3H).
576	LC-MS: (ES, m/z): RT=1.784min, LCMS 33, m/z =384 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.37 - 7.26 (m, 1H), 7.27 - 7.03 (m, 2H), 6.00 (d, J = 1.1 Hz, 1H), 4.48 - 4.03(m, 7H), 3.97- 3.84 (m, 3H), 3.32- 3.26 (m, 1H), 2.99 (s, 3H), 2.43 - 2.14 (m, 7H), 2.00- 1.88 (m, 2H).
580	LC-MS: (ES, m/z): RT= 0.96 min, LCMS 27:m/z = 400 [M+l], 1H-NMR: (Methanol-d4, ppm): δ 7.59 (s, 1H), 7.15-7.01 (m, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.82 (s, 1H), 4.13 (d, J = 6.2 Hz, 2H), 4.00 - 3.58 (m, 7H), 3.57 - 3.44 (m, 2H), 3.31 - 3.14 (m, 3H), 2.94-2.92 (m, 4H), 2.19 (s, 3H), 2.10 - 1.90 (m, 1H), 1.82-1.71 (m, 1H).
590	LC-MS: (ES, m/z): RT = 1.073min, LCMS53: m/z = 456.4 [M+l], 1H NMR (300 MHz, Deuterium Oxide) δ 7.29 — 6.72 (m, 3H), 6.22 - 5.67 (m, 1H), 4.06 (t, J = 5.6 Hz, 2H), 3.90 - 3.70 (m, 5H), 3.68 - 3.58 (m, 2H), 3.41 - 3.18 (m, 4H), 3.12 (d, J = 6.9 Hz, 2H), 3.06 - 2.92 (m, 2H), 2.02 - 1.62 (m, 1 OH), 1.63 - 1.32 (m, 2H), 1.26 1.00 (m, 2H).
524	LC-MS: (ES, m/z): RT=1.553 min, LCMS53, m/z=400 [M+l], 1HNMR: (300 MHz, Methanol-d4) δ 7.45 (d, J = 4.3 Hz, 2H), 6.82 (s, 1H), 4.32 (t, J = 5.5 Hz, 2H), 4.17 - 3.97 (m, 5H), 3.90 - 3.69 (m, 4H), 3.67 - 3.37 (m, 3H), 3.16 (s, 5H), 2.47 - 1.75 (m, 10H).
535	LC-MS: (ES, m/z): RT=0.825 min,LCMS53, m/z=413 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.60 (s, 1H), 7.49 (s, 1H), 6.89 (s, 1H), 4.36 (t, J = 5.6 Hz, 2H), 4.06 (s, 3H), 3.91 - 3.64 (m, 5H), 3.58 -3.41(m, 4H), 3.26 - 3.07 (m, 5H), 2.98 (s, 3H), 2.47 - 1.99 (m, 10H).
599	LC-MS: (ES, m/z): RT = 1.078 min, LCMS28: m/z = 373.2 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.04 - 7.88 (m, 1H), 7.69 - 7.49 (m, 1H), 6.07 (s, 1H), 4.20-4.10 (m, 2H), 4.06 - 3.91 (m, 2H), 3.91 - 3.65 (m, 2H), 3.48 - 3.24 (m, 2H), 3.24 - 3.12 (m, 1H), 3.12 2.92 (m, 6H), 2.54-2.43 (m, 1H), 2.43-2.24 (m, 3H), 2.25 - 1.90 (m, 1H), 1.43 (t, J = 9 Hz, 3H).
604	LC-MS: (ES, m/z): RT=1.325min, LCMS 28, m/z =321.3 [M+l]. 1H NMR (400 MHz, D2O-d6) 67.30 (d, J = 4.2, 1H), 6.25 (s, 1H), 4.05 - 3.50 (m, 8H), 3.48 - 3.38 (m, 2H), 3.30 - 2.80 (m, 8H), 2.40 - 1.70 (m, 6H).
613	LC-MS: (ES, m/z): RT = 0.15min, LCMS28: m/z =368.20 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.14 (d, J = 3.3 Hz, 1H), 7.52 (d, J = 3.3 Hz, 1H), 7.27 - 7.13 (m, 2H), 7.08-7.01 (m, 1H), 4.57-4.41 (m, 2H), 4.45-4.35 (m, 1H), 4.30 - 4.17 (m, 2H), 4.16-4.09 (m, 1H), 4.01 (d, J = 9.7 Hz, 3H), 3.53 - 3.47 (m, 2H), 3.4-3.35 (m, 1H), 2.73 (s, 3H), 1.31 - 1.26 (m, 3H).
622	LC-MS: (ES, m/z): RT = 0.886 min, LCMS33: m/z = 383 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 9.27 (s, 1H), 8.81 (s, 1H), 6.99 (d, J = 1.5 Hz, 1H), 6.08 (d, J = 1.1 Hz, 1H), 4.41 (t, J = 5.5 Hz, 2H), 3.83 - 3.73 (m, 2H), 3.62 - 3.50 (m, 2H), 3.25 - 3.15 (m, 2H), 3.07 (s, 3H), 2.48 - 2.31 (m, 5H), 2.30 - 2.15 (m, 2H), 2.15 - 2.00 (m, 2H).
625	LC-MS: (ES, m/z): RT=0.876 min,LCMS53, m/z=453 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.52 (s, 1H), 7.47 (s, 1H), 6.82 (s, 1H),4.32 (t, J = 5.5 Hz, 2H), 4.03 (s,

486

	3H), 3.91 - 3.64 (m, 9H), 3.49 (t, J = 7.2 Hz, 2H), 3.45 - 3.32 (m, 2H), 3.24 - 3.08 (m, 2H), 2.98 (s, 3H), 2.46- 1.95 (m, 14H).
628	LC-MS: (ES, m/z): RT = 2.127min; LCMS33: m/z = 383 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 9.30 (d, J = 2.9 Hz, 1H), 8.39 (s, 1H), 6.82 (s, 1H), 6.20 (s, 1H), 4.61 (t, J = 5.9 Hz, 2H), 3.77 (s, 2H), 3.60 - 3.51 (m, 2H), 3.21 - 3.19 (m, 5H), 2.51 - 2.38 (m, 5H), 2.23 (q, J = 7.7 Hz, 2H), 2.14 - 2.05 (m, 2H).
641	LC-MS: (ES, m/z): RT = 0.868 min, LCMS28: m/z = 345.1 [M+l],
642	LC-MS: (ES, m/z): RT = 0.903 min, LCMS07: m/z = 359.20 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.97 (d, J = 2.4 Hz, 1H), 7.84 (s, 1H), 5.82 (d, J = 0.9 Hz, 1H), 4.04 - 3.87 (m, 5H), 2.92 (s, 3H), 2.86 - 2.75 (m, 2H), 2.75 - 2.59 (m, 2H), 2.57 - 2.47 (m, 1H), 2.40 (s, 3H), 2.21 -2.02 (m, 4H), 1.71 - 1.61 (m, 1H).
644	LC-MS: (ES, m/z): RT =1.961 min, HPLC05: m/z = 371 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.90-7.75 (m, 1H), 7.72-7.49 (m, 1H), 7.25-7.09 (m, 1H), 6.04 - 5.97 (m, 1H), 4.34 (s, 2H), 3.97 (s, 3H), 3.70 - 3.43 (m, 8H), 2.99 (s, 3H), 2.49-2.25 (m, 3H), 2.212.03 (m, 4H).
906	LC-MS: (ES, m/z): RT=1.001 min, LCMS28, m/z=388 [M+l]. 1H NMR: (300 MHz, Methanol-d4) δ 7.61 (d, J = 2.4 Hz, 1H), 7.07 (dd, J = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.79 (d, J = 0.8 Hz, 1H), 4.18 - 4.08 (m, 1H), 4.08 - 3.90 (m, 2H), 3.83 (s, 3H), 3.01 2.73 (m, 4H), 2.70-2.55 (m, 5H), 2.17 (s, 3H), 1.83-1.79 (m, 4H).
949	LC-MS: (ES, m/z): RT = 1.509min; LCMS15: m/z = 358 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.97 (d, J = 2.2 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 5.82 (d, J = 0.8 Hz, 1H), 4.04 (t, J = 6.2 Hz, 2H), 3.92 (s, 3H), 3.33 - 3.28 (m, 4H), 2.91 (s, 3H), 2.67 (q, J = 8.1, 2H), 2.21 - 2.05 (m, 5H), 1.77 - 1.86 (m, 6.2 Hz, 2H).
965	LC-MS: (ES, m/z): RT = 0.834min, LCMS07: m/z = 357 [M+l]. 1H NMR: (400 MHz, Methanol-d4) δ 7.61 - 7.53 (m, 2H), 6.92 (d, J = 8.6 Hz, 1H), 5.80 (s, 1H), 3.86 (s, 3H), 3.74 (s, 2H), 3.22 (t, J = 6.8 Hz, 4H), 2.91 (s, 3H), 2.57 - 2.56 (m, 4H), 2.18 (s, 3H), 2.09 2.05 (m, 2H).
1038	LC-MS: (ES, m/z): RT=0.97min, LCMS28, m/z=374.21 [M+l]. 1H-NMR: (Methanol-d4) δ 7.30 (d, J = 2.4 Hz, 1H), 7.19 (dd, J = 8.7, 2.5 Hz, 1H), 7.10-7.01 (m, 1H), 6.25-5.92 (m, 1H), 4.40 - 4.15 (m, 5H), 4.13 - 3.98 (m, 2H), 3.92-3.88 (m, 3H), 3.54 (dd, J = 12.9, 3.2 Hz, 1H), 3.45-3.38 (m, 1H), 3.06-2.93 (m, 3H), 2.78-2.56 (m, 1H), 2.52-2.39 (m, 1H), 2.31 (d, J= 1.0 Hz, 3H).

Table IB

Cpd No.	Data
648	LC-MS: (ES, m/z): RT=1.015 min,LCMS28, m/z=369 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.25 (d, J = 0.9 Hz, 1H), 8.18 (dd, J = 9.1, 1.0 Hz, 1H), 7.94 (s, 1H), 7.18 (d, J = 9.1 Hz, 1H), 6.83 (s, 1H), 4.24 (t, J = 5.6 Hz, 2H), 4.11 (s, 3H), 3.86 - 3.76 (m, 2H), 3.47 (dd, J = 8.1, 6.8 Hz, 2H), 3.23 -3.08 (m, 2H), 2.40-2.02 (m, 6H), 1.29 (s, 1H).
652	LC-MS: (ES, m/z): RT=0.541min LCMS 32, m/z =416 [M+l]. 1H NMR (400 MHz, Methanol-d4) δ 7.66 (s, 1H), 7.52 (s, 1H), 4.38 (t, J = 5.5 Hz, 2H), 4.12 (s, 3H), 4.02 - 3.90 (m, 1H), 3.90 - 3.79 (m, 2H), 3.77 - 3.68 (m, 2H), 3.51 (t, J = 7.2 Hz, 2H), 3.42 - 3.32 (m, 2H), 3.24 - 3.10 (m, 2H), 2.99 (s, 3H), 2.79 - 2.73 (m, 3H), 2.68 - 2.52 (m, 2H), 2.45 2.34 (m, 2H), 2.30 - 2.02 (m, 6H).
656	LC-MS: (ES, m/z): RT = 1.488 min; LCMS53: m/z = 370 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.59 (s, 1H), 8.23 (d, J = 8.1, 1H), 8.16 (s, 1H), 7.84 (d,J = 8.8, 1H), 7.42 (d, J = 8.8, 1.0 Hz, 1H), 4.65 (t, J = 5.7 Hz, 2H), 3.95 (s, 3H), 3.86 - 3.63 (m, 2H), 3.48 (t, J = 7.6 Hz, 2H), 3.18 (q, J = 9.0 Hz, 2H), 2.42 - 2.31 (m, 2H), 2.22 (q, J = 9.4 Hz, 2H), 2.08 (d, J = 3.7 Hz, 2H).

487

659	LC-MS: (ES, m/z): RT = 0.99min, LCMS28: m/z = 427.31 [M+l], 1H NMR (300 MHz, Deuterium Oxide) δ 7.55 (s, 1H), 7.26 (s, 1H), 4.36 (t, J = 5.6 Hz, 2H), 4.18-3.95 (m, 4H), 3.76 - 3.43 (m, 5H), 3.42 - 3.12 (m, 4H), 3.1-2.96 (m, 2H), 2.91-2.81 (m, 3H), 2.35 - 2.15 (m, 6H), 2.13-1.79 (m, 4H) , 1.41-1.19 (m, 6H).
662	LC-MS: (ES, m/z): RT = 1.087 min, LCMS 31, m/z = 398.27 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.80 - 7.68 (m, 2H), 7.53 (d, J = 2.2 Hz, 1H), 4.48 - 4.31 (m, 2H), 4.16 (d, J = 2.6 Hz, 3H), 4.14 - 3.79 (m, 2H), 3.80 - 3.65 (m, 3H), 3.57 - 3.35 (m, 5H), 3.27 - 3.05 (m, 2H), 3.00 (s, 3H), 2.93 (s, 3H), 2.62 - 1.96 (m, 6H), 1.49 - 1.35 (m, 3H).
663	LC-MS: (ES, m/z): RT = 1.047 min, LCMS 30, m/z = 426.3 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.76-7.64 (m, 2H), 7.57 (s, 1H), 4.47-4.25 (m, 2H), 4.19-3.80 (m, 5H), 3.84 - 3.59 (m, 4H), 3.56 - 3.12 (m,6H), 2.92 (s, 3H), 2.63 - 1.93 (m, 7H), 1.52 1.27 (m, 10H).
664	LC-MS: (ES, m/z): RT = 0.786 min; LCMS07: m/z = 385 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.67 (d, J = 5.7 Hz, 1H), 7.42 (d, J = 7.1 Hz, 1H), 4.61 - 4.41 (m, 2H), 4.40 - 4.24 (m, 2H), 4.26 - 3.87 (m, 7H), 3.83 - 3.56 (m, 2H), 3.49 (q, J = 7.3 Hz, 3H), 3.35 (d, J = 2.5 Hz, 1H), 2.98 (s, 3H), 2.83 (d, J = 1.5 Hz, 3H), 2.55 - 2.29 (m, 2H), 2.20 (d, J = 8.2 Hz, 2H), 1.76-0.93 (m, 3H).
670	LC-MS: (ES, m/z): RT=0.856 min,LCMS28, m/z=427 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.95 (s, 1H), 7.69 (s, 1H), 4.76 (t, J = 5.7 Hz, 2H), 4.14 (s, 3H), 4.04 - 3.90 (m, 1H), 3.79 (s, 2H), 3.74 - 3.58 (m, 3H), 3.54 - 3.35 (m, 4H), 3.16 (s, 2H), 2.89 (s, 3H), 2.47- 1.96 (m, 10H), 1.46 (d, J = 6.7 Hz, 6H).
673	LC-MS: (ES, m/z): RT = 0.815 min; LCMS15: m/z = 399 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.43 (s, 1H), 7.19 (s, 1H), 4.23 - 4.06 (m, 2H), 4.02 (s, 3H), 3.62 - 3.49 (m, 1H), 3.09 (d, J = 5.9 Hz, 2H), 2.99 - 2.91 (m, 1H), 2.89 - 2.42 (m, 9H), 2.42 - 2.25 (m, 5H), 2.26-2.01 (m, 3H), 1.99 - 1.80 (m, 2H), 1.81-1.70 (m, 1H), 1.16 (t, J = 7.3 Hz, 3H).
681	LC-MS: (ES, m/z): RT = 1.013 min, LCMS 28, m/z=451.2 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.41 (s, 2H), 7.57 (s, 1H), 7.41 (d, J = 2.2 Hz, 1H), 4.39 (t, J = 5.5 Hz, 2H), 4.09 (s, 3H), 4.02 -3.92 (m, 1H), 3.90 - 3.80 (m, 2H), 3.78 - 3.68 (m, 2H), 3.64 - 3.47 (m, 2H), 3.43 - 3.33 (m, 2H), 3.26 - 3.10 (m, 2H), 2.99 (s, 3H), 2.52 - 2.34 (m, 4H), 2.33 2.17 (m, 4H), 2.15-2.02 (m, 2H).
737	LC-MS: (ES, m/z): RT = 0.920 min, LCMS 30, m/z = 331 [M+l]. 1H NMR (400 MHz, Methanol-d4) δ 7.49 (s, 1H), 7.24 (s, 1H), 4.41-4.33 (m, 2H), 4.02 (s, 3H), 3.84 (s, 2H), 3.54 - 3.45 (m, 2H), 3.16 (s, 5H), 2.89 (s, 3H), 2.45 - 2.33 (m, 2H), 2.23 (s, 2H), 2.13 2.05 (m, 2H).
739	LC-MS: (ES, m/z): RT = 0.898 min, LCMS 07: m/z = 386 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.47 (s, 1H), 7.39 (s, 1H), 4.38 (t, J = 5.6 Hz, 2H), 4.30 (t, J = 5.2 Hz, 4H), 4.03 (s, 3H), 3.85 (d, J = 9.8 Hz, 2H), 3.55 - 3.39 (m, 6H), 3.25 - 3.15 (m, 2H), 2.89 (s, 3H), 2.39 (p, J = 6.5 Hz, 2H), 2.23 (q, J = 7.5, 7.1 Hz, 2H), 2.10 (d, J = 7.8, 4.9 Hz, 2H).
743	LC-MS: (ES, m/z): RT = 0.88min, LCMS33: m/z = 399.27 [M+l], 1HNMR (400 MHz, Deuterium Oxide) δ 7.59-7.45 (m, 1H), 7.26 (d, J = 1.4 Hz, 1H), 4.44 - 4.05 (m, 3H), 4.023.89(m, 3H), 3.72 - 3.59 (m, 2H), 3.57 - 3.31 (m, 5H), 3.10 - 2.97 (m, 3H), 2.95 - 2.79 (m, 6H), 2.33 - 2.02 (m, 6H), 2.01 - 1.46 (m, 4H).
745	LC-MS: (ES, m/z): RT = 0.89min, LCMS07: m/z = 385.28 [M+l], 1H NMR (400 MHz, Deuterium Oxide) δ 7.54 (s, 1H), 7.26 (d, J = 2.5 Hz, 1H), 4.89-4.78 (m, 1H), 4.36 (t, J = 5.6 Hz, 2H), 4.25-4.17 (m, 1H), 4.12-3.95 (m, 3H), 3.89 - 3.76 (m, 1H), 3.72 - 3.61 (m, 2H), 3.52-3.41 (m, 1H), 3.39 - 3.34 (m, 2H), 3.32-3.21 (m, 1H), 3.11-2.95 (m, 5H), 2.942.79 (m, 4H), 2.37 - 2.19 (m, 2H), 2.14-2.01 (m, 3H), 2.01-1.82 (m, 2H).
746	HPLC: (ES, m/z): RT = 4.51min, HPLC07: m/z =414.28 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.58-7.42 (m, 1H), 7.29 (s, 1H), 4.45-4.31 (m, 2H), 4.21-4.01 (m, 4H), 3.95 - 3.57 (m, 4H), 3.57 - 3.43 (m, 3H), 3.26 - 3.05 (m, 6H), 3.18-2.98 (m, 3H), 2.472.32 (m, 2H), 2.31-2.02 (m, 7H), 1.93-1.82 (m, 1H).
755	LC-MS: (ES, m/z): RT= 0.94 min, LCMS 28: m/z = 468 [M+l]. 1H-NMR: (Methanol-d4, ppm):3 7.69 (d, J = 8.1 Hz, 2H), 7.56 (s, 1H), 4.44 (t, J = 5.5 Hz, 2H), 4.21 - 4.10 (m, 5H), 4.09 - 3.96 (m, 1H), 3.87-3.81 (m, 4H), 3.64 - 3.38 (m, 7H), 3.26 - 3.10 (m, 2H), 2.93 (s,

488

	3H), 2.46-2.42 (m, 2H), 2.35 - 2.20 (m, 6H), 2.19 - 2.09 (m, 4H), 2.07-1.92 (m, 2H).
756	LC-MS: (ES, m/z): RT = 1.316 min; LCMS53: m/z = 454 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.68 (d, J = 6.4 Hz, 2H), 7.54 (s, 1H), 4.43 (t, J = 5.5 Hz, 2H), 4.28 (d, J = 8.1 Hz, 1H), 4.14 (s, 6H), 3.62 - 3.96 (m, , 6H), 3.42 - 3.58 (m, 4H), 3.25 - 3.09 (m, 2H), 2.91 (s, 3H), 2.57 - 2.01 (m, 12H).
757	LC-MS: (ES, m/z): RT=0.887 min,LCMS53, m/z=483 [M-+1]. 1H NMR (300 MHz, Methanol-d4) δ 7.46 (s, 2H), δ 6.87 (s, 1 H),4.33 (t, J = 5.5 Hz, 2H), 4.18-4.07 (m, 2H), 4.03 (s, 3H), 3.90 - 3.69 (m, 5H), 3.61 - 3.34 (m, 7H), 3.17 (s, 5H), 2.44 - 1.99 (m, 12H), 1.98 - 1.79 (m, 2H).
758	LC-MS: (ES, m/z): RT=0.877 min,LCMS53, m/z=469 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.46 (s, 2H), 6.88 (s, 1H), 4.38 - 4.20 (m, 3H), 4.19 - 3.99 (m, 5H), 3.97 3.56 (m, 7H), 3.55 - 3.36 (m, 4H), 3.17 (s, 5H), 2.55-2.01 (m, 12H).
759	HPLC: (ES, m/z): RT=3.82 min, HPLC07: m/z = 471 [M+l], 1H-NMR: (Methanol-d4): δ 7.59 (s, 1H), 7.29 (s, 1H), 4.37 (t, J = 5.5 Hz, 2H), 4.28 - 3.95 (m, 7H), 3.96 - 3.59 (m, 6H), 3.54 - 3.38 (m, 4H), 3.27 - 3.08 (m, 5H), 2.68 - 2.01 (m, 12H).
762	LC-MS: (ES, m/z): RT = 1.130 min, LCMS 28, m/z = 387 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.50 (s, 1H), 7.31 (s, 1H), 4.37 (t, J = 5.5 Hz, 2H), 4.05 - 3.98 (m, 7H), 3.91 - 3.78 (m, 6H), 3.50 (t, J = 7.2 Hz, 2H), 3.23 - 3.11 (m, 2H), 2.91 (s, 3H), 2.45 - 2.34 (m, 2H), 2.30-2.16 (m, 2H), 2.15- 2.05 (m, 2H).
763	LC-MS: (ES, m/z): RT = 1.107 min; LCMS53: m/z = 424.3 [M+l], 1H NMR (300 MHz, MethanoLd4) δ 7.87 (s, 1H), 7.66 (s, 1H), 7.50 (s, 1H), 4.60 - 4.38 (m, 4H), 4.12 (s, 3H), 3.98 (s, 4H), 3.90 - 3.76 (m, 2H), 3.31 - 3.69 (m , 6H), 3.25 - 3.10 (m, 2H), 2.85 (s, 3H), 2.35 - 2.45 (m, 2H), 2.29 - 2.03 (m, 4H).
786	LC-MS: (ES, m/z): RT = 1.025 min, LCMS 33: m/z = 352 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.78 (d, J = 2.7 Hz, 1H), 7.54 (d, J = 2.7 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 5.81 (d, J = 0.9 Hz, 1H), 3.84 (s, 3H), 3.68 (s, 2H), 2.91 (s, 3H), 2.85 - 2.72 (m, 4H), 2.22 - 2.15 (m, 3H), 1.97 - 1.81 (m, 4H).
787	LC-MS: (ES, m/z): RT = 1.399 min; LCMS53: m/z = 455 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.33 (d, J = 2.5 Hz, 1H), 7.19 (d, J = 8.7, 1H), 6.92 (d, J = 8.7 Hz, 1H), 5.80 (s, 1H), 4.10 (t, J = 6.0 Hz, 3H), 3.82 (s, 3H), 2.99 (s, 1H), 2.88 - 2.34 (m, 7H), 2.29 (s, 3H), 2.17 (s, 3H), 2.13-2.01 (m, 3H), 1.95 (s, 2H), 1.91-1.75 (m, 5H), 1.69 (d, J = 3.6 Hz, 1H), 1.31 (d, J = 10.8 Hz, 1H).
788	LC-MS: (ES, m/z): RT = 1.041 min; LCMS07: m/z = 442 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.54 (s,lH), 7.03 - 6.94 (m,lH), 6.89 (d, J = 5.6 Hz, 1H), 5.81 (s, 1H), 4.11 (t, J = 7.2 Hz, 4H), 3.83 (d, J = 6.1 Hz, 4H), 3.45 (t, J = 3.2 Hz, 1H), 3.22 - 3.13 (m, 1H), 2.76 (d, J = 8.9 Hz, 6H), 2.14 (s, 3H), 2.05 (s, 3H), 1.86 (d, J = 7.6 Hz, 5H), 2.73 2.51 (m, 2H).
789	LC-MS: (ES, m/z): RT= 1.15 min, LCMS28: m/z = 428 [M+l], 1H-NMR: (Methanol-d4, ppm):ô 7.42 (d, J = 2.5 Hz, 1H), 7.11 (dd, J = 8.7, 2.5 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 5.82 (d, J = 0.8 Hz, 1H), 4.56 (s, 1H), 4.12 - 3.77 (m, 8H), 3.68 - 3.53 (m, 1H), 2.80 - 2.57 (m, 6H), 2.37 - 2.25 (m, 1H), 2.22 (s, 3H),2.12 - 1.76 (m, 7H).
790	LC-MS: (ES, m/z): RT = 0.924 min, LCMS 07: m/z = 409 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 4.41 (t, J = 5.4 Hz, 2H), 4.18 (s, 3H), 3.92 - 3.82 (m, 1H), 3.81 (d, J = 10.9 Hz, 2H), 3.73 (d, J = 11.2 Hz, 2H), 3.51 (q, J = 9.9, 8.4 Hz, 4H), 3.19 (d, J = 14.4, 7.7 Hz, 2H), 3.01 (d, J = 2.7 Hz, 3H), 2.41 (q, J = 6.1 Hz, 2H), 2.33 - 2.18 (m, 4H), 2.19 - 2.06 (m, 4H).
791	LC-MS: (ES, m/z):RT = 1.673 min; LCMS53: m/z=367 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 8.01 (s, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.26 (d, J = 8.6 Hz, 1H), 5.94 (s, 1H), 4.23 (t, J = 6.0 Hz, 2H), 2.93 (s, 3H), 2.86 - 2.81 (m, 2H), 2.73 - 2.70 (m, 4H), 2.20 (s, 3H), 2.15-2.08 (m, 2H), 1.96- 1.85 (m, 4H).

489

793	LC-MS: (ES, m/z): RT=1.706 min,LCMS53, m/z=383 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.56 (d, J = 2.5 Hz, IH), 7.42 (d, J = 2.5 Hz, IH), 6.00 (s, IH), 4.28 (t, J = 5.5 Hz, 2H), 3.62 - 3.38 (m, 6H), 2.99 (s, 3H), 2.33 - 2.05 (m, 9H).
794	LC-MS: (ES, m/z): RT = 0.958 min, m/z = 382.15 [M+l], IH NMR (400 MHz, Chloroform-d) δ 8.85 (d, J = 1.2 Hz, IH), 8.23 (d, J = 5.6 Hz, IH), 7.59 - 7.49 (m, IH), 7.17 (d, J = 2.7 Hz, IH), 7.11 (dd,J = 8.6, 2.6 Hz, IH), 6.88 (d, J = 8.7 Hz, IH), 6.56 (s, IH), 4.15 (t, J = 6.2 Hz, 2H), 4.07 (s, 3H), 3.86 (s, 3H), 3.11 (s, 6H), 2.42 - 2.26 (m, 2H), 2.06 (d, J = 7.1 Hz, 4H).
795	LC-MS: (ES, m/z): RT = 0.8 min, m/z = 383.25 [M+l]. IH NMR (400 MHz, Methanold4) δ 9.74 (s, IH), 8.79 (d, J = 6.5, 1.0 Hz, IH), 8.50 (d, J = 6.4 Hz, IH), 7.91 (s, IH), 7.26 (s, IH), 4.53 (t, J = 5.7 Hz, 2H), 4.43 (s, 3H), 3.99 (s, 3H), 3.87 - 3.76 (m, 2H), 3.51 (t, J = 7.4 Hz, 2H), 3.26 - 3.11 (m, 2H), 2.49 - 2.38 (m, 2H), 2.29 - 2.17 (m, 2H), 2.16 - 2.01 (m, 2H).
796	LC-MS: (ES, m/z): RT = 0.982min, LCMS33: m/z = 331 [M+l]. IH NMR (300 MHz, Methanol-d4) δ 7.00 (d, J = 8.7 Hz, IH), 6.90 (d, J = 2.3 Hz, IH), 6.83 (dd, J = 8.5, 2.5 Hz, IH), 4.19 (t, J = 5.5 Hz, 2H), 3.91 -3.73 (m, 5H), 3.49 (t, J = 7.0 Hz, 2H), 3.25 - 3.02(m, 2H), 2.34 (s, 3H), 2.29 - 2.04 (m, 7H).
797	LC-MS: (ES, m/z): RT = 1.218 min, LCMS28: m/z = 344 [M+l], IH NMR (400 MHz, Methanol-d4) δ 6.98 - 6.90 (m, 2H), 6.78 (dd, J = 8.6, 2.5 Hz, IH), 4.18 (t, J = 5.5 Hz, 2H), 3.87 - 3.74 (m, 5H), 3.69 (s, 3H), 3.48 (t, J = 6.9 Hz, 2H), 3.22 - 3.11 (m, 2H), 2.32 2.17 (m, 7H), 2.10-2.01 (m, 2H).
798	LC-MS: (ES, m/z): RT= 1.103 min; LCMS15: m/z = 399 [M+l]. 1HNMR (300 MHz, Methanol-d4) δ 7.98 (d, J = 2.2 Hz, IH), 7.85 (s, IH), 5.83 (d, J = 0.8 Hz, IH), 4.21 - 3.65 (m, 5H), 3.13 - 2.76 (m, 5H), 2.76 - 2.49 (m, 3H), 2.39 (d, J = 9.7, 6.2 Hz, IH), 2.19 (s, 3H), 2.15-1.86 (m, 5H), 1.86 - 1.53 (m, 3H).
799	LC-MS: (ES, m/z): RT = 1.478 min; LCMS07: m/z = 402 [M+l]. IH NMR (400 MHz, Methanol-d4) δ 7.18 (d, J = 2.4 Hz, IH), 6.94 (d, J = 2.4 Hz, IH), 6.02 (d,J= 1.1 Hz, IH), 4.19 (t, J = 5.6 Hz, 2H), 3.89 (s, 3H), 3.82 (s, 3H), 3.78 (s, 2H), 3.58 - 3.39 (m, 2H), 3.23 (s, 2H), 3.06 (s, 3H), 2.33 (d, J = 1.0 Hz, 3H), 2.30 - 2.13 (m, 4H), 2.07 (d, J = 8.8 Hz, 2H).
800	LC-MS: (ES, m/z): RT = 2.007 min; LCMS53: m/z = 372 [M+l]. IH NMR (300 MHz, Methanol-d4) δ 7.48 (d, J = 2.4 Hz, IH), 7.12 (d, J = 8.7, 2.4 Hz, IH), 6.89 (d, J = 8.7 Hz, IH), 5.77 (d, J = 0.8 Hz, IH), 4.15 (s,lH), 4.08 - 4.02(m,lH), 3.98 - 3.92 (m,lH), 3.8 (s, 3H), 3.31-3.19 (m,2H),3.18 - 3.00 (m, 2H), 2.81 - 2.70 (m, IH), 2.23-2.07 (m, 4H), 1.82 (d, J = 6.8 Hz, IH), 1.23 (d, J = 6.5 Hz, 6H).
802	LC-MS: (ES, m/z): RT=1.843min LCMS 31, m/z =372 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.49 - 7.43 (m, 2H), 6.83 (s, IH), 4.35 - 4.27 (m, IH), 4.27 - 4.18 (m, IH), 4.17-4.08 (m, 2H), 4.02 (s, 3H), 3.83 - 3.72 (m, 2H), 3.66 - 3.51 (m, 3H), 3.46 3.28 (m, 2H), 3.18 (s, 3H), 3.07 - 2.95 (m, IH), 2.43 - 2.29 (m, IH), 2.14 - 2.00 (m, IH), 1.98- 1.82 (m, 4H).
803	LC-MS: (ES, m/z): RT=0.672min LCMS 32, m/z =386 [M+l], IH NMR (400 MHz, Methanol-d4) δ 7.27 (s, IH), 7.19 (s, IH), 6.55 (s, 1 H), 4.15 - 3.99 (m, 4H), 3.94 (s, 3H), 3.80 - 3.69 (m, 2H), 3.52 - 3.36 (m, IH), 2.99 (s, 3H), 2.96 - 2.90 (m, IH), 2.89 - 2.76 (m, IH), 2.76 - 2.66 (m, 2H), 2.63 - 2.55 (m, IH), 2.44 (s, 3H), 2.24 - 2.10 (m, IH), 1.95 1.70 (m, 5H).
806	LC-MS: (ES, m/z): RT=0.983 min,LCMS28, m/z=308 [M+l], IH NMR (300 MHz, Methanol-d4) δ 7.45 (s, IH), 6.44 (s, IH), 4.12 - 3.92 (m, 7H), 3.90 - 3.80 (m, IH), 3.63 3.33 (m, 5H), 3.25 (dd, J = 11.9, 7.0 Hz, IH), 2.97 - 2.77 (m, IH), 2.35 - 2.18 (m,lH), 2.10-1.90 (m, 3H), 1.70-1.50 (m, 2H).
808	LC-MS: (ES, m/z): RT = 0.85min, LCMS33: m/z = 322.21 [M+l], IH NMR (400 MHz, Methanol-d4) δ 7.50 (s, IH), 6.64 (s, IH), 4.31-4.15 (m, IH), 4.14 - 3.95 (m, 7H), 3.71 3.55 (m, 2H), 3.54 - 3.42 (m, 2H), 3.41 - 3.35 (m, IH), 3.28-3.21 (m, IH), 3.10 (s, 3H), 2.95 - 2.87 (m, IH), 2.41-2.22 (m, IH), 2.09 - 1.92 (m, 3H), 1.80 - 1.70 (m, 2H).

490

809	LC-MS: (ES, m/z): RT=0.991 min,LCMS53, m/z=441 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.46 (d, J = 6.9 Hz, 2H), 6.79 (s, 1H), 4.82 - 4.68 (m, 1H), 4.33 (t, J = 5.5 Hz, 2H), 4.19-4.06 (m, 1H), 4.02 (s, 3H), 3.91-3.75 (m, 2H), 3.71 - 3.35 (m, 4H), 3.16 (s, 5H), 2.93 (td, J = 13.0, 2.6 Hz, 1H), 2.45- 1.96 (m, 11H), 1.85- 1.55 (m, 2H).
810	LC-MS: (ES, m/z): RT =1.842min, LCMS15, m/z = 384 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.46 (s, 1H), 7.37 (s, 1H), 7.25 (d, J = 1.2 Hz, 1H), 4.33 (t, J = 5.5 Hz, 2H), 4.02 (s, 3H), 3.91 - 3.82 (m, 6H), 3.51 (t, J = 7.2 Hz, 2H), 3.23 - 3.10 (m, 2H), 2.73 (d, J = 1.0 Hz, 3 H), 2.46 - 2.31 (m, 2H), 2.27 - 2.20 (m, 2H), 2.15 - 2.04 (m, 2H), 1.87 - 1.78 (m, 6H).
812	HPLC: (ES, m/z): RT = 8.367 min; HPLC07: m/z = 467 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.55 - 7.46 (m, 2H), 7.09 (s, 1H), 4.32 (t, J = 5.5 Hz, 2H), 4.03 (s, 3H), 3.92 - 3.66 (m, 9H), 3.55 - 3.32 (m, 3H), 3.20 - 3,12 (m, 2H), 2.97 (s, 4H), 2.44 - 2.00 (m, 10H), 1.82 (s, 6H).
816	LC-MS: (ES, m/z): RT = 1.246 min; LCMS15: m/z = 398 [M+l], 1HNMR (400 MHz, Methanol-d4) δ 7.20 (d, J = 8.8 Hz, 2H), 6.52 (s, 1H), 4.18 (t, J = 6.1 Hz, 2H), 3.92 (s, 3H), 3.24 - 3.04 (m, 1H), 2.98 (s, 3H), 2.85 - 2.71 (m, 2H), 2.73 - 2.53 (m, 4H), 2.26 - 2.07 (m, 2H), 2.07 - 1.90 (m, 4H), 1.90 - 1.74 (m, 5H), 1.72 - 1.45 (m, 4H), 1.45 - 1.24 (m, 1H).
817	LC-MS: (ES, m/z): RT=2.004 min,LCMS28, m/z=358 [M+l], 1HNMR (300 MHz, Methanol-d4) δ 7.53 (s, 1H), 7.46 (s, 1H), 6.85 (s, I H), 4.37 (t, J = 5.5 Hz, 2H), 4.02 (s, 3H), 3.93 - 3.79 (m, 2H), 3.68 (p, J = 6.8 Hz, 1H), 3.53 (t, J = 7.2 Hz, 2H), 3.20 (s, 5H), 2.50 - 2.02 (m, 6H), 1.42 (d, J = 6.8 Hz, 7H).
820	LC-MS: (ES, m/z): RT = 0.695 min, LCMS 30, m/z =317 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.42 (s, 1H), 7.19 (s, 1H), 6.90 (d, J = 1.1 Hz, 1H), 4.37 (t, J = 5.6 Hz, 2H), 4.03 (s, 3H), 3.92 - 3.78 (m, 2H), 3.52 (t, J = 7.2 Hz, 2H), 3.27 - 3.11 (m, 2H), 2.77 (s, 3H), 2.48 - 2.33 (m, 2H), 2.32 - 2.03 (m, 4H).
821	LC-MS: (ES, m/z): RT = 1.047 min; LCMS07: m/z = 331 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.53 (s, 1H), 7.47 (s, 1H), 7.33 (s, 1H), 4.42 (t, J = 5.5 Hz, 2H), 4.34 (s, 3H), 4.08 (s, 3H), 3.90 - 3.80 (m, 2H), 3.52 (t, J = 7.2 Hz, 2H), 3.22 - 3.17 (m, 2H), 2.94 (s, 3H), 2.45 - 2.39 (m, 2H), 2.30 - 2.17 (m, 2H), 2.16 - 2.08 (m, 2H).
822	LC-MS: (ES, m/z): RT=1.815 min, LCMS53, m/z=387 [M+l], 1HNMR (400 MHz, Methanol-d4) δ 7.59 (s, 1 H), 7.31 (d, J= 1.1 Hz, 1 H), 7.03 (d, J= 1.7 Hz, 1 H), 4.41 (t, J = 5.7 Hz, 2H), 4.18 - 4.05 (m, 5H), 3.90 - 3.75 (m, 5H), 3.52 (t, J = 7.2 Hz, 2H), 3.25 - 3.14 (m, 2H), 2.48 - 2.36 (m, 2H), 2.31 - 2.02 (m, 4H), 2.00 - 1.83 (m, 4H).
823	LC-MS: (ES, m/z): RT = 1.008 min, LCMS 07: m/z = 414 [M+l], 1H NMR (400 MHz, D2O) δ 7.19-7.07 (m, 2H), 7.01-6.93 (m, 1H), 4.31-4.21 (m, 2H), 3.91 (td, J = 10.3, 9.5, 4.7 Hz, 5H), 3.73 (d, J = 10.9, 5.2 Hz, 2H), 3.38 (d, J = 37.3, 8.9 Hz, 4H), 3.16 - 2.98 (m, 5H), 2.81 (s, 2H), 2.36 - 2.24 (m, 2H), 2.15 (d, J = 9.6, 5.6 Hz, 2H), 2.07 - 1.88 (m, 3H), 1.61 - 1.52 (m, 2H), 1.35 (q, J = 11.6 Hz, 2H).
824	LC-MS: (ES, m/z): RT=1.339 min,LCMS15, m/z=454 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.51 (s, 1H), 7.47 (s, 1H), 7.05 (s, 1 H), 4.33 (t, J = 5.5 Hz, 2H), 4.18 - 4.09 (m, 2H), 4.03 (s, 3H), 3.91 - 3.73 (m, 8H), 3.70 - 3.55 (m, 1H), 3.50 (t, J = 7.2 Hz, 2H), 3.17 (dd, J = 11.5, 6.7 Hz, 2H), 2.44 - 2.33 (m, 2H), 2.30 - 2.16 (m, 2H), 2.16 - 2.02 (m, 2H), 2.02 - 1.87 (m, 4H), 1.86 - 1.72 (m, 6H).
825	LC-MS: (ES, m/z): RT=1.172 min,LCMS28, m/z=414 [M+l], 1HNMR (400 MHz, Deuterium Oxide) 57.30 - 7.10 (m, 2H), 6.72 - 6.60 (m, 1H), 4.30 - 4.10 (m, 2H), 4.07 3.99 (m, 2H), 3.90 - 3.85 (m, 3H), 3.75 - 3.60 (m, 4H), 3.45 - 3.30 (m, 3H), 3.30 - 3.20 (m, 6H), 3.10 - 3.00 (m, 2H), 2.30 - 1.70 (m, 10H).
826	LC-MS: (ES, m/z): RT=1.099 min,LCMS28, m/z=428 [M+l], 1H NMR (400 MHz, Methanol-d4) 5 7.61 (s, 1H), 7.45 (s, 1H), 6.83 (s, 1H), 4.36 (t, J = 5.5 Hz, 2H), 4.30 - 4.20 (m, 1H), 4.17 - 4.07 (m, 2H), 4.02 (s, 3H), 3.89 - 3.75 (m, 4H), 3.60 - 3.45 (m, 3H), 3.20 - 3.10 (m, 2H), 2.42 - 2.30 (m, 2H), 2.30 - 2.17 (m, 2H), 2.17 - 2.02 (m, 2H), 1.96-1.81 (m, 4H), 1.40 (d, J = 6.3 Hz, 6H).

491

832	LC-MS: (ES, m/z): RT = 1.385 min; LCMS07: m/z = 495 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.49 - 7.41 (m, 2H), 6.87 (s, 1H), 4.33 (t, J = 5.5 Hz, 2H), 4.03 (s, 3H), 3.85 - 3.79 (m, 4H), 3.72 - 3.66 (m, 1H), 3.58 - 3.36 (m, 6H), 3.17 (s, 5H), 2.92 - 2.86 (m, 2H), 2.45-2.03 (m, 10H).
833	LC-MS: (ES, m/z): RT = 1.462 min; LCMS07: m/z = 481 [M+l]. 1HNMR (300 MHz, Methanol-d4) δ 7.46 - 7.41 (m, 2H), 7.43 (s, 1H), 4.32 (t, J = 5.5 Hz, 2H), 4.01 (s, 3H), 3.86 - 3.77 (m, 2H), 3.69 - 3.60 (m, 2H), 3.52 - 3.42 (m, 5H), 3.24 - 3.01 (m, 7H), 2.39 2.35 (m, 2H), 2.28 - 1.92 (m, 8H).
839	LC-MS: (ES, m/z): RT = 0.858 min; LCMS07: m/z = 457 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.22 - 7.17(m, 2H), 6.53 (s, 1H), 4.17 (t, J = 6.1 Hz, 2H), 3.91 (s, 3H), 3.63 - 3.57 (m, 2H), 3.37 (s, 3H), 3.23 - 3.06 (m, 3H), 2.97 (s, 3H), 2.83 - 2.60 (m, 8H), 2.39 - 2.33 (m, 2H), 2.15 - 2.10 (m, 2H), 2.01 - 1.75 (m, 8H).
844	LC-MS: (ES, m/z): RT = 1.012 min, LCMS28: m/z = 353.2 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.02 (s, 1H), 6.01 (s, 1H), 4.41 (s, 2H), 4.01 (s, 3H), 3.91 3.32 (m, 4H), 2.95 (s, 3H), 2.32 (s, 3H), 2.21 - 2.01 (m, 4H).
846	LC-MS: (ES, m/z): RT = 0.981 min, LCMS15: m/z = 338.3 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.74 (d, J = 2.7 Hz, 1H), 7.65 - 7.55 (m, 1H), 6.94 (d, J = 9.0 Hz, 1H), 5.81 (s, 1H), 4.33 - 4.32 (m, 1H), 3.84 (s, 3H), 3.32 - 3.31 (m, 1H), 3.30 - 3.07 (m, 1H), 2.90 (s, 3H), 2.32 - 2.30 (m, 1H), 2.28 - 2.02 (m, 6H).
847	LC-MS: (ES, m/z): RT = 1.003 min, LCMS 33: m/z = 352 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.64 - 7.45 (m, 2H), 7.06 (d, J = 8.8 Hz, 1H), 5.99 -5.96 (m, 1H), 3.89 (s, 6H), 3.45 (s, 1H), 3.27 (s, 1H), 2.99 (s, 6H), 2.63 (s, 1H), 2.44 - 2.14 (m, 4H).
848	LC-MS: (ES, m/z): RT = 1.655 min, LCMS28: m/z = 352.2 [M+l], 1H NMR (300 MHz, MethanoLd4) δ 7.78 (s, 1H), 7.54 (d, J = 8.9 Hz, 1H), 6.93 (d, J = 9.0 Hz, 1H), 5.81 (s, 1H), 3.84 (s, 3H), 3.44 (t, J = 6.9 Hz, 1H), 3.03 - 2.88 (m, 4H), 2.30 - 2.92 (m, 4H), 2.35 2.08 (m, 4H), 2.00 - 1.92 (m, 3H).
854	LC-MS: (ES, m/z): RT = 1.18min, LCMS33: m/z = 400.14 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.50 (d, J = 2.5 Hz, 1H), 7.24 (s, 1H), 7.19 (dd, J = 8.7, 2.5 Hz, 1H), 6.97 (d, J = 8.7 Hz, 1H), 4.16 (t, J = 5.9 Hz, 2H), 3.86 (s, 3H), 3.12-3.02 (m, 2H), 3.01-2.91 (m, 7H), 2.49 (s, 3H), 2.23-2.12 (m, 2H), 2.04 - 1.87 (m, 4H).
855	LC-MS: (ES, m/z): RT=1.033min, LCMS15, m/z=366.3 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.66 (d, J = 7.4 Hz, 2H), 7.14 (d, J = 9.5 Hz, 1H), 6.02 (s, 1H), 4.32 (s, 2H), 3.93 (s, 3H), 3.72 (s,3H), 3.57 (d, J = 1.6 Hz, 3H), 2.99 (s, 3H), 2.32 (s, 3H), 1.88 (s,7H).
863	LC-MS: (ES, m/z): RT = 1.256 min; LCMS53: m/z = 454 [M+l], 1H-NMR (300 MHz, Methanol-d4) δ7.68 - 7.64 (m, 2H), 7.52 (s, 1H), 4.42 (t, J = 6.0 Hz, 2H), 4.28 - 4.22 (m, 1H), 4.18 - 3.98 (m, 6H), 3.97 - 3.62 (m, 6H), 3.52 - 3.39 (m, 4H), 3.22-3.08 (m, 2H), 2.91 (s, 3H), 2.55 - 2.01 (m, 12H).
864	LC-MS: (ES, m/z): RT = 0.813 min; LCMS53: m/z = 454 [M+l]. 1H NMR (300 MHz, Methanol-d4) Ô7.38 (s, 1H), 7.34 (s, 1H), 7.20 (s, 1H), 4.23 (t, J = 6.0 Hz, 2H), 4.06 - 3.88 (m, 5H), 3.87 - 3.65 (m, 2H), 3.43 - 3.32 (m, 1H), 3.26 - 3.08 (m, 4H), 3.02 - 3.00 (m, 2H), 2.91-2.71 (m, 4H), 2.64 (s, 3H), 2.59-2.38 (m, 2H), 2.27-2.09 (m, 3H), 2.05 - 1.80 (m, 8H).
866	LC-MS: (ES, m/z): RT = 1.406 min; LCMS07: m/z = 469 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.23 - 7.18 (m, 2H), 6.65 (s, 1H), 4.18 (t, J = 6.1 Hz, 2H), 4.06 - 3.88 (m, 5H), 3.87 - 3.65 (m, 2H), 3.24 - 2.92 (m, 7H), 2.81 - 2.75 (m, 2H), 2.80 - 2.30 (m, 6H), 2.25-2.05 (m, 3H), 2.01 - 1.72 (m, 9H).
867	LC-MS: (ES, m/z): RT = 1.405 min; LCMS07: m/z = 469 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.25 - 7.16 (m, 2H), 6.64 (s, 1H), 4.21 (t, J = 6.1 Hz, 2H), 4.05 - 3.87 (m, 5H), 3.87 - 3.65 (m, 2H), 3.24 - 2.86 (m, 7H), 2.81 - 2.75 (m, 2H), 2.70 - 2.33 (m, 6H), 2.26 - 2.08 (m, 3H), 2.06 - 1.72 (m, 9H).
870	LC-MS: (ES, m/z): RT = 1.182 min, LCMS 28: m/z = 427 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.64 (d, J = 2.5 Hz, 1H), 7.17 (dd, J = 8.8, 2.4 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.72 (s, 1H), 4.24 (t, J = 5.5 Hz, 2H), 4.11 - 4.01 (m, 2H), 3.95 - 3.79 (m, 5H), 3.73 -

492

	3.54 (m, 2H), 3.53 - 3.46 (m, 2H), 3.23 - 3.14 (m, 2H), 3.06 - 2.83 (m, 1H), 2.43 (s, 3H), 2.35 - 2.16 (m, 4H), 2.16-2.01 (m, 2H), 2.01 - 1.79 (m, 4H).
871	LC-MS: (ES, m/z): RT=1.383min, LCMS 15, m/z=378.2 [M+l], 1H-NMR: δ 8.24 (d, J = 2.7 Hz, 1H), 7.65 (s, 1H), 7.45 - 7.17 (m, 4H), 6.03 (d, J = 1.3 Hz,2H), 5.09 (s, 1H), 4.65 (s, 2H), 4.01 (d, J = 1.6 Hz, 3H), 2.99 (s, 3H), 2.32 (d, J = 1.0 Hz, 3H).
872	LC-MS: RT=1.675min, LCMS15, m/z=365.3 [M+l], 1H-NMR: δ 8.51 - 8.39 (m, 3H), 7.86 - 7.76 (m, 3H), 7.16 (dd, J = 9.0, 1.2 Hz, 1H), 5.84 (s, 1H), 4.05 (s, 3H), 2.95 (s, 3H), 2.21 (s, 3H).
873	LC-MS: (ES, m/z): RT = 0.939 min, LCMS 27: m/z = 385 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.19 (dd, J = 21.0, 2.9 Hz, 1H), 7.69 (dd, J = 8.9, 2.9 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 6.27 - 5.97 (m, 1H), 4.25 - 4.10 (m, 1H), 4.00 (s, 3H), 3.62 (d, J = 12.8 Hz, 2H), 3.29 - 3.14(m 2H), 3.17 - 3.07 (m, 6H), 2.52 - 2.06 (m, 5H), 1.70 - 1.90 (m, 2H).
874	LC-MS: (ES, m/z): RT = 1.864 min, LCMS 07: m/z = 382 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.26 (d, J = 10.6 Hz, 2H), 8.38 (d, J = 12.4 Hz, 1H), 7.76 - 7.64 (m, 1H), 7.32 - 7.22 (m, 1H), 6.04 (q, J = 1.0 Hz, 1H), 4.34 (q, J = 14.2, 10.4 Hz, 2H), 4.07 (d, J = 5.2 Hz, 3H), 3.00 (d, J = 9.2 Hz, 3H), 2.33 (s, 3H), 1.59 - 1.49 (m, 3H).
876	LC-MS: (ES, m/z): RT=1.300min, LCMS15, m/z=378.2 [M+l]. 1HNMR (300 MHz, Methanol-d4) δ 7.93 - 7.82 (m, 2H), 7.63 - 7.39 (m, 3H), 7.31 (d, J = 8.2 Hz, 1H), 7.07 (dd, J = 8.1, 2.0 Hz, 1H), 6.03 (s, 1H), 4.59 (s, 1H), 3.94 (s, 3H), 3.03 (s, 3H), 2.32 (s, 3H).
877	LC-MS: (ES, m/z): RT=1,375min, LCMS15, m/z=378.3 [M+l], 1HNMR (300 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.83 (s, 1H), 8.68 - 8.57 (m, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.72 (s, 1H), 7.39 - 7.10 (m, 6H), 6.08 (s, 1H), 4.51 (d, J = 6.1 Hz, 2H), 3.92 (s, 3H), 2.96 (d, J = 4.5 Hz, 3H), 2.28 (s, 3H).
881	LC-MS: (ES, m/z): RT=0.963min, LCMS28, m/z=389.2 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.03 (s, 1H), 7.57 (d, J = 2.3 Hz, 1H), 6.04 (d, J= 1.5 Hz, 1H), 4.43-4.31 (m, 1H), 4.14 - 3.98 (m, 2H), 3.78 (d, J = 10.2 Hz, 3H), 3.47 (d, J = 9.6 Hz, 2H), 3.23 (s,2H), 3.01 (s,2H), 2.33 (s, 3H), 2.21 (s, 3H), 2.15 - 2.01 (m, 4H).
882	LC-MS: (ES, m/z): RT=0.947min, LCMS28, m/z=389.2 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.05 (s, 1H), 7.58 (s, 1H), 6.07-6.00 (m, 1H), 4.43-4.31 (m, 1H), 4.09 (d, J = 4.8 Hz, 2H), 4.01 (s, 3H), 3.81 - 3.71 (m, 2H), 3.52 - 3.39 (m, 2H), 3.24 (s, 2H), 3.01 (s, 3H), 2.33 (s, 2H), 2.21 (s, 3H), 2.15 - 2.03 (m, 2H).
883	LC-MS: (ES, m/z): RT=0.897min, LCMS28, m/z=445.3 [M+l], 1H NMR (300 MHz, MethanoLd4) δ 8.13 (s, 1H), 7.62 (d, J = 2.3 Hz, 1H), 6.24 (s, 1H), 4.44-4.20 (m, 2H), 4.17 - 4.03 (m, 2H), 3.99 (s, 3H), 3.94 - 3.37 (m, 8H), 3.35 - 3.15 (m, 3H), 2.47 (s, 4H), 2.28 - 2.15 (m, 2H), 2.14 - 2.03 (m, 2H).
884	LC-MS: (ES, m/z): RT=1.373min, LCMS28, m/z=445.2 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.14 (d, J = 2.1 Hz, 1H), 7.61 (s, 1H), 6.23 (s, 1H), 4.44 - 4.20 (m, 2H), 4.11 (dd, J = 5.1, 2.5 Hz, 2H), 3.99 (s, 3H), 3.94 - 3.38 (m, 8H), 3.24 (s, 3H), 2.47 (s, 3H), 2.40 (s, 2H), 2.09 (m, J = 9.2 Hz, 3H).
885	LC-MS: (ES, m/z): RT=0.962 min, LCMS 07, m/z=389 [M+l], 1H NMR (400 MHz, Chloroform-d) δ 8.33 (s, 1H), 7.82 (s, 1H), 5.80 (s, 1H), 4.28 (d, J = 24.4, 9.5, 4.8 Hz, 2H), 4.16 (d, J = 9.9, 5.5 Hz, 1H), 3.88 (s, 3H), 3.01 - 2.87 (m, 6H), 2.779 (d, 3H) , 2.30 (s, 3H), 1.94 - 1.86 (m, 4H), 1.21 (s, 1H).
886	LC-MS: (ES, m/z): RT=0.962 min, LCMS27, m/z=389 [M+l], 1H NMR (400 MHz, Chloroform-d) δ 8.33 (s, 1H), 7.82 (s, 1H), 5.80 (s, 1H), 4.28 (d, J = 24.4, 9.5, 4.8 Hz, 2H), 4.16 (d, J = 9.9, 5.5 Hz, 1H), 3.88 (s, 3H), 3.01 - 2.87 (m, 6H), 2.779 (d, 3H) , 2.30 (s, 3H), 1.94 - 1.86 (m, 4H), 1.21 (s, 1H).
887	LC-MS: (ES, m/z): RT = 0.983 min; LCMS33: m/z = 444 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.94 (d, J = 2.2 Hz, 1H), 7.78 (d, J = 2.3 Hz, 1H), 5.83 (s, 1H), 4.10 (t, J = 6.1 Hz, 2H), 3.92 (s, 3H), 3.64 (t, J = 6.8 Hz, 2H), 2.85 - 2.75 (m, 2H), 2.71 (d, J = 4.6 Hz, 7H), 2.48 (t, J = 6.8 Hz, 2H), 2.17 (s, 3H), 2.09 - 2.07 (m, 2H), 1.95 - 1.79 (m, 4H).

493

888	LC-MS: (ES, m/z): RT = 1.38 min, LCMS 33: m/z = 485.3 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.96 (d,J = 2.1 Hz, 1 H), 7.55 (d, J = 2.1 Hz, 1 H), 6.03 (d, J = 1.2 Hz, 1H), 4.21 (t, J = 5.4 Hz, 2H), 3.99 (d, J = 5.7 Hz, 5H), 3.84 (t, J = 8.4 Hz, 2H), 3.75 - 3.55 (m, 4H), 3.48 (t, J = 7.2 Hz, 2H), 3.17 (q, J = 9.3 Hz, 2H), 2.92 - 2.79 (m, 1H), 2.67 (s, 3H), 2.38 (s, 3H), 2.28 - 2.07 (m, 6H).
890	LC-MS: (ES, m/z): RT=1.059 min, LCMS27, m/z=403 [M+l]. 1HNMR (400 MHz, Methanol-d4) δ 7.46 (s, 1H), 7.27 (d, J = 2.5 Hz, 1H), 7.21-7.13 (m, 1H), 6.97 (d, J = 8.7 Hz, 1H), 5.97 (d, J = 1.1 Hz, 1H), 4.13 (t, J = 5.5 Hz, 2H), 3.83 (s, 3H), 3.16 (t, J = 7.0 Hz, 2H), 2.99 (s, 3H), 2.42 - 2.26 (m, 5H).
891	LC-MS: (ES, m/z): RT=2.388 min, LCMS07, m/z=417 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.30 (s, 1H), 7.22 (d, J = 2.5 Hz, 1H), 7.16 - 7.04 (m, 1H), 6.98 (d, J = 8.8 Hz, 1H), 5.97 (d, J = 0.9 Hz, 1H), 4.10 (t, J = 5.6 Hz, 2H), 3.83 (s, 3H), 3.73 (s, 3H), 3.08 (t, J = 7.1 Hz, 2H), 2.97 (d, J = 4.8 Hz, 3H), 2.34 - 2.19 (m, 5H).
892	LC-MS: (ES, m/z): RT=0.983min, LCMS15, m/z=479.3 [M+l], 1HNMR (300 MHz, Methanol-d4) δ 7.40 (d, J = 2.5 Hz, 1H), 7.14 (dd, J = 8.7, 2.5 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 5.85 (s, 1H), 4.20 - 4.10 (m, 2H), 3.90 - 3.75 (m, 5H), 3.36 (s, 1H), 3.32 (d, J = 3.6 Hz, 1H), 3.08 - 2.91 (m, 6H), 2.65 (s, 3H), 2.23 - 2.07 (m, 5H), 2.05 - 1.89 (m, 4H).
893	LC-MS: (ES, m/z): RT=1.072min, LCMS28, m/z=493.3 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.39 (d, J = 2.5 Hz, 1H), 7.15 (dd, J = 8.7, 2.4 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 5.85 (s, 1H), 4.22 - 4.11 (m, 2H), 3.88 - 3.77 (m, 5H), 3.34 - 3.24 (m, 2H), 3.10 2.97 (m, 6H), 2.81 (s, 6H), 2.18 (d, J = 9.3 Hz, 5H), 2.04- 1.93 (m, 4H).
894	LC-MS: (ES, m/z): RT = 1.798 min, LCMS33: m/z = 415 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 8.15 (s, 1H), 8.01 (s, 1H), 6.77 (s, 1H), 6.41 (s, 1H), 4.32-4.29 (m, 2H), 3.96 (s, 3H), 3.88 - 3.76 (m, 4H), 3.73 - 3.70 (m, 2H), 3.48 - 4.44 (m, 4H), 3.26 - 3.10 (m, 2H), 2.37-2.34 (m, 2H), 2.32 - 2.17 (m, 3H), 2.10 - 2.06 (m, 2H).
895	LC-MS: (ES, m/z): RT =1.221 min; LCMS33: m/z = 326 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 8.51 (s, 1H), 7.30 (d, J = 5.6 Hz, 2H), 4.25 (t, J = 6.1 Hz, 2H), 3.98 (s, 3H), 2.86 - 2.71 (m, 5H), 2.70 - 2.59 (m, 4H), 2.21 - 2.12 (m, 2H), 1.94 - 1.77 (m, 4H).
896	LC-MS: (ES, m/z): RT=0.715min LCMS30, m/z =319 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.28 (d, J = 9.7 Hz, 1H), 7.53 - 7.41 (m, 2H), 4.37 (t, J = 5.5 Hz, 2H), 4.04 (s, 3H), 3.94 - 3.75 (m, 2H), 3.51 (t, J = 7.2 Hz, 2H), 3.25 - 3.09 (m, 2H), 2.77 (d, J = 2.6 Hz, 3H), 2.46 - 2.33 (m, 2H), 2.31 - 2.01 (m, 4H).
897	LC-MS: (ES, m/z): RT=0.990min LCMS 07, m/z =334 [M+l]. 1H NMR (400 MHz, Methanol-d4) δ 8.08 (d, J = 11.2 Hz, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 4.32 (t, J = 5.5 Hz, 2H), 3.98 (s, 3H), 3.90 - 3.80 (m, 2H), 3.51 (t, J = 7.2 Hz, 2H), 3.27 - 3.11 (m, 5H), 2.44 2.32 (m, 2H), 2.30-2.17 (m, 2H), 2.16- 2.03 (m, 2H).
900	LC-MS: (ES, m/z): RT=1.28min, LCMS33: m/z=329.19 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.18 (s, 1H), 6.90 (s, 1H), 6.57 (s,lH), 3.94 (s, 3H), 3.88 - 3.76 (m, 2H), 3.73 - 3.64 (m, 2H), 3.15-3.04 (m, 4H), 2.78 (s, 3H), 2.61 (d, J = 1.0 Hz, 3H), 2.32 - 2.13 (m, 2H).
904	LC-MS: (ES, m/z): RT=1.447 min, LCMS07, m/z=368 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.77 (s, 1H), 7.51 (dd, J = 9.0, 2.8 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 5.82 (s, 1H), 3.83 (s, 3H), 3.76 (t, J = 4.7 Hz, 4H), 3.57 (s, 2H), 2.92 (s, 3H), 2.70 (dd, J = 5.7, 3.6 Hz, 4H), 2.19 (s, 3H).
905	LC-MS: (ES, m/z): RT=1.720 min, LCMS28, m/z=388 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.66 - 7.58 (m, 1H), 7.08 (dd, J = 8.7, 2.5 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 5.81 (d, J = 0.8 Hz, 1H), 4.19-4.11 (m, 1H), 4.04 (dd, J = 9.7, 4.4 Hz, 1H), 3.96 (dd, J = 9.7, 6.3 Hz, 1H), 3.84 (s, 3H), 2.93 (s, 3H), 2.82 (dd, J = 12.6, 4.4 Hz, 1H), 2.75 - 2.59 (m, 5H), 2.19 (s, 3H), 1.91 - 1.75 (m, 4H).
906	LC-MS: (ES, m/z): RT=1.001 min, LCMS28, m/z=388 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.61 (d, J = 2.4 Hz, 1H), 7.07 (dd, J = 8.7, 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.79 (d, J = 0.8 Hz, 1H), 4.18-4.08 (m, 1H), 4.08-3.90 (m, 2H), 3.83 (s, 3H), 3.01 - 2.73 (m, 4H), 2.70 - 2.55 (m, 5H), 2.17 (s, 3H), 1.83-1.79 (m, 4H).

494

907	LC-MS: (ES, m/z): RT=1.01min, LCMS33: m/z=360.15[M+l], 1H-NMR: (Methanol-d4) δ 7.72 (d, J = 5.8 Hz, 1H), 7.50 (d, J = 2.5 Hz, 1H), 7.09 (dd, J = 8.7, 2.5 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.05 - 3.90 (m, 3H), 3.85 (s, 3H), 3.44 (t, J = 7.2 Hz, 4H), 2.94 (s, 3H), 2.82 (dd, J = 12.5, 3.7 Hz, 1H), 2.74 - 2.63 (m, 1H), 2.25-2.10(m, 2H).
908	LC-MS: (ES, m/z): RT=0.94min, LCMS28 : m/z=360.12 [M+l], 1H-NMR: (Methanold4) δ 7.67-7.45 (m, 1H), 7.32 - 7.02 (m, 3H), 6.44 - 6.10 (m, 1H), 4.43 - 4.15 (m, 5H), 4.10 - 3.99 (m, 2H), 3.92-3.78 (m, 3H), 3.61 - 3.47 (m, 1H), 3.45-3.35 (m, 1H), 3.1-2.95 (m, 3H), 2.74 - 2.59 (m, 1H), 2.53-2.31 (m, 1H).
911	LC-MS: (ES, m/z): RT = 0.614 min; LCMS32: m/z = 359 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.96 (d, J = 2.2 Hz, 1H), 7.79 - 7.71 (m, 2H), 5.94 (d, J = 6.0 Hz, 1H), 4.10 (t, J = 6.1 Hz, 2H), 3.93 (s, 3H), 2.93 (s, 3H), 2.91-2.65 (m, 6H), 2.14-2.03 (m, 2H), 1.95- 1.82 (m, 4H).
912	LC-MS: (ES, m/z): RT = 0.961 min; LCMS27: m/z = 345 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.96 (d, J = 2.2 Hz, 1H), 7.79 (s, 1H), 7.73 (s, 1H), 5.94 (d, J = 6.0 Hz, 1H), 4.03 - 3.90 (m, 5H), 2.94 (s, 3H), 2.91 - 2.62 (m, 4H), 2.68 - 2.44(m, 1H), 2.41 (s, 3H), 2.32 - 2.05(m, 1H), 1.75 - 1.62 (m, 1H).
914	LC-MS: (ES, m/z): RT= 0.96 min, LCMS 27: m/z = 345 [M+l], 1H-NMR: (Methanol-d4, ppm): δ 7.97 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H), 6.20 (d, J = 7.3 Hz, 1H), 4.45 - 4.30 (m, 2H), 4.24 - 4.07 (m, 4H), 4.03 (s, 3H), 3.45 (t, J = 6.9 Hz, 2H), 3.02 (s, 3H), 2.84 - 2.31 (m, 2H), 2.30 - 2.15 (m, 2H).
915	LC-MS: (ES, m/z): RT = 1.076 min; LCMS27: m/z = 371 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 8.03 - 7.86 (m, 1H), 7.79 (s, 1H), 7.74 (s, 1H), 5.94 (d, J = 6.0 Hz, 1H), 4.04 - 3.90 (m, 5H), 3.24 - 2.96 (m, 1H), 2.94 (s, 3H), 2.88 - 2.64 (m, 3H), 2.65 - 2.56 (m, 1H), 2.21 -1.89 (m, 1H), 1.76 (d, J = 5.5 Hz, 1H), 1.69- 1.62 (m, 1H), 0.56 - 0.41 (m, 4H).
916	LC-MS: (ES, m/z): RT = 1.124 min; LCMS39: m/z = 318 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.72 (s, 1H), 7.47 (s, 1H), 7.09 (dd, J = 8.7, 2.5 Hz, 1H), 6.99 - 6.73(m, 1H), 5.91 (d, J = 6.0 Hz, 1H), 4.11 (t, J = 6.0 Hz, 2H), 3.83 (s, 3H), 2.93 (s, 3H), 2.81 (t, J = 6.8 Hz, 2H), 2.44 (s, 3H), 2.03 (p, J = 6.4 Hz, 2H).
917	LC-MS: (ES, m/z): RT= 0.90 min, LCMS 28: m/z = 319 [M+l], 1H-NMR: (Methanol-d4, ppm): δ 7.97 (d, J = 2.2 Hz, 1H), 7.81 - 7.71 (m, 2H), 5.95 (d, J = 6.0 Hz, 1H), 4.15 (t, J = 5.9 Hz, 2H), 3.95 (s, 3H), 2.98 - 2.80 (m, 5H), 2.55 (s, 3H), 2.20 - 2.03 (m,2H).
918	LC-MS: (ES, m/z): RT=0.837 min, LCMS 07, m/z=344.0[M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.60 - 7.53 (m, 1H), 7.25 (s, 1H), 7.16-7.03 (m, 2H), 6.17 (d, J = 7.3 Hz, 1H), 4.28 (t, J = 8.5, 4.2 Hz, 1H), 4.15-4.04 (m, 2H), 3.91 (d, J = 2.0, 1.1 Hz, 3H), 3.23 (d, J = 12.7, 8.4 Hz, 1H), 3.03 (s, 4H), 2.80 (s, 3H).
919	LC-MS: (ES, m/z): RT = 1.006 min, LCMS28: m/z = 388 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.57 (d, J = 7.3 Hz, 1H), 7.28 - 7.00 (m, 3H), 6.18 (d, J = 7.3 Hz, 1H), 4.31 - 4.10 (m, 2H), 4.02 (dq, J = 8.0, 3.8 Hz, 1H), 3.90 (s, 3H), 3.80 - 3.70 (m, 2H), 3.59 (s, 4H), 3.49 (dd, J= 13.2, 3.2 Hz, 1H), 3.24 (s, 2H), 3.04 (s, 3H), 2.21 (s, 2H), 2.11 (d, J = 8.4 Hz, 2H).
920	LC-MS: (ES, m/z): RT = 0.997 min, LCMS28: m/z = 388 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.56 (d, J = 7.3 Hz, 1H), 7.27 - 7.00 (m, 3H), 6.17 (d, J = 7.3 Hz, 1H), 4.30 - 4.09 (m, 2H), 4.08 - 3.95 (m, 1H), 3.89 (s, 3H), 3.74 (s, 2H), 3.58 (s, 4H), 3.48 (dd, J = 13.2, 3.2 Hz, 1H), 3.24 (t, J = 8.6 Hz, 2H), 3.04 (s, 3H), 2.24 - 2.03 (m, 4H).
922	LC-MS: (ES, m/z): RT = 0.966 min, LCMS28: m/z = 348 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.56 (d, J = 7.2 Hz, 1H), 7.24 (s, 1H), 7.20 - 7.03 (m, 2H), 6.17 (d, J = 7.3 Hz, 1H), 4.29 (dd, J = 10.4, 4.3 Hz, 1H), 4.16 (dd, J = 10.4, 3.6 Hz, 1H), 3.91 (s, 4H), 3.56 (s, 3H), 3.39 (td, J = 10.8, 8.8, 5.6 Hz, 2H), 3.03 (s, 3H), 2.80 (s, 3H).
927	LC-MS: (ES, m/z): RT = 1.437 min, LCMS 07: m/z = 358 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.57 (d, J = 3.2 Hz, 1H), 7.33 - 7.28 (m, 3H), 6.19 (d, J = 2.4 Hz, 1H), 4.13 - 4.10 (m, 2H), 4.00 - 3.78 (m, 4H), 3.72 - 3.68 (m, 1H), 3.44 - 3.35 (m, 2H), 3.29 - 3.10 (m, lH),3.16-3.09(m, 1H) 3.03 (s, 4H), 2.53 - 1.93 (m, 2H), 1.41 - 1.39 (m, 3H).

495

928	LC-MS: (ES, m/z): RT = 1.369 min, LCMS 33: m/z = 370 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.56 (d, J = 2.4 Hz, 1H), 7.21 (s, 1H), 7.08 (d, J = 1.2 Hz, 2H), 6.18 (d, J = 1.8 Hz, 1H), 4.20-4.05 (m, 2H), 4.02 - 3.79 (m, 4H), 3.78-3.67 (m, 1H), 3.61-3.58 (m, 1H), 3.53-3.36 (m, 1H), 3.13 (s, 1H), 3.03 (s, 4H), 2.26-2.23 (m, 2H), 1.04-1.01 (m, 4H).
931	LC-MS: (ES, m/z): RT = 1.86 min, LCMS 53: m/z = 360 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.72 (d, J = 6.3 Hz, 1H), 7.51 (s, 1H), 7.09 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.14 - 3.87 (m, 4H), 3.82 (s, 3H), 3.71 (t, J = 2.4 Hz, 1H), 3.04-2.90 (m, 4H), 2.74 (q, J = 1.8 Hz, 1H), 2.35 (s, 3H), 2.29-2.07 (m, 1H) , 2.05 -2.00 (m, 1H).
932	LC-MS: (ES, m/z): RT = 0.92 min, LCMS 33: m/z = 374 [M+l]. 1H NMR (300 MHz, Methanol-d4) δ 7.72 (d, J = 6.0 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.15 - 3.88 (m, 4H), 3.86 - 3.65 (m, 4H), 3.09 - 3.05 (m, 1H), 2.94 (s, 3H), 2.89 - 2.77 (m, 1H), 2.50 (q, J = 7.2 Hz, 2H), 2.26 - 1.97 (m, 2H), 1.15 (t, J = 7.2 Hz, 3H).
933	LC-MS: (ES, m/z): RT = 1.86 min, LCMS 53: m/z = 346 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.71 (d, J = 6.3 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.09 (q, J = 2.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.12 - 3.99 (m, 4H), 3.84 (s, 3H), 3.69 3.64 (m, 1H), 3.10-3.08 (m, 1H), 2.97 (s, 3H), 2.90-2.71 (m, 3H).
936	LC-MS: (ES, m/z): RT = 0.912 min; LCMS33: m/z = 360 [M+l],1H NMR (300 MHz, Methanol-d4) δ 7.55 (d, J = 7.3 Hz, 1H), 7.22 (s, 1 H), 7.18 - 6.99 (m, 2H), 6.17 (d, J = 7.3 Hz, 1H), 4.26 - 4.09 (m, 4H), 3.89 (s, 4H), 3.70 - 3.68(m, 1H), 3.51 - 3.50 (m, 1H), 3.22 3.20 (m, 2H), 3.02 (d, J = 7.7 Hz, 6H).
937	LC-MS: (ES, m/z): RT = 0.931 min; LCMS33: m/z = 374 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.72 (d, J = 5.9 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 5.94 (d, J = 6.1 Hz, 1H), 4.20 - 4.05 (m, 1H), 4.04 - 3.90 (m, 3H), 3.84 (s, 3H), 3.74 - 3.72 (m, 1H), 3.15 - 3.04 (m, 1H), 2.95 (s, 3H), 2.86 - 2.84 (m, 1H), 2.52 (q, J = 7.2 Hz, 2H), 2.29 - 2.00 (m, 2H), 1.16 (t, J = 7.2 Hz, 3H).
938	LC-MS: (ES, m/z): RT = 0.907 min; LCMS33: m/z = 346 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.72 (d, J = 6.0 Hz, 1H), 7.51 (s, 1H), 7.09 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 6.0 Hz, 1H), 4.05 - 4.03 (m, 1H), 4.00 - 3.84 (m, 3H), 3.82 (s, 3H), 3.67 - 3.64 (m, 1H), 3.12 - 3.01 (m, 1H), 2.94 (s, 3H), 2.88 - 2.79 (m, 2H), 2.72 2.68 (m, 1H).
949	LC-MS: (ES, m/z): RT = 1.509min; LCMS15: m/z = 358 [M+l], 1H NMR (300 MHz, Methanol-d4) δ 7.97 (d, J = 2.2 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 5.82 (d, J = 0.8 Hz, 1H), 4.04 (t, J = 6.2 Hz, 2H), 3.92 (s, 3H), 3.33 - 3.28 (m, 4H), 2.91 (s, 3H), 2.67 (q, J = 8.1, 2H), 2.21 - 2.05 (m, 5H), 1.77 - 1.86 (m, 6.2 Hz, 2H).
1005	LC-MS: (ES, m/z): RT = 0.611min, LCMS 32, m/z = 374.2 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.58 (d, J = 7.3 Hz, 1H), 7.32 - 7.26 (m, 1H), 7.21 - 7.05 (m, 2H), 6.17 (d, J = 7.3 Hz, 1H), 4.50 - 4.19 (m, 4H), 4.06 - 3.92 (m, 5H), 3.57 (d, J = 13.3 Hz, 1H), 3.39 (d, J= 13.3 Hz, 1H), 3.04 (s, 3H), 2.75 - 2.60 (m, 1H), 2.50-2.35 (m, 1H), 1.36 (s, 3H).
1011	LC-MS: (ES, m/z): RT=0.982 min, LCMS 28, m/z =332.2 [M+l], 1H NMR (400 MHz, Methanol-d4) δ 7.58 (d, J = 7.3 Hz, 1H), 7.29 - 7.17 (m, 2H), 7.10 (d, J = 8.7 Hz, 1H), 6.17 (d, J = 7.3 Hz, 1H), 4.60 - 4.49 (m, 1H), 3.92 (s, 3H), 3.32 - 3.25 (m, 2H), 3.02 (s, 3H), 2.78 (s, 3H), 2.17 - 2.00 (m, 2H), 1.37 (d, J = 6.1 Hz, 3H).
1014	LC-MS: (ES, m/z): RT=1.00min, LCMS28 : m/z=358.14 [M+l], 1H-NMR (Methanol-d4) δ 7.95-7.52 (m, 1H), 7.45-6.89 (m, 3H), 6.44 - 6.10 (m, 1H), 4.59-4.37 (m,lH), 4.35 - 4.09 (m, 5H), 3.97-3.88 (m, 3H), 3.75-3.52 (m, 1H), 3.12-2.94 (m, 3H), 2.71 - 2.57 (m, 1H), 2.48-2.27 (m, 1H), 2.26-2.01 (m, 2H), 1.34 (d, J = 6.5 Hz, 3H).
1019	LC-MS: (ES, m/z): RT = 6.569 min; LCMS53: m/z = 343[M+1], 1H NMR (300 MHz, Methanol-d4) δ 7.80 - 7.55 (m, 3H), 7.19 (d,lH), 6.19 (d, J = 7.3 Hz, 1H), 4.36 (s, 2H), 4.12-3.92 (m, 4H), 3.67-3.31 (m, 4H), 3.02 (s, 3H), 2.46 - 2.29 (m, 1H), 2.24 - 1.98 (m, 2H), 1.89- 1.84 (m, 1H).

496

1020	LC-MS: (ES, m/z): RT = 8.458 min; LCMS53: m/z = 343[M+1], 1H NMR (300 MHz, Methanol-d4) δ 7.82 - 7.55 (m, 3H), 7.19 (d, J = 8.9 Hz, 1H), 6.19 (d, J = 7.3 Hz, 1H), 4.36 (s, 2H), 4.10-3.92 (m, 4H), 3.64 - 3.35 (m, 5H), 3.02 (s, 3H), 2.38 (m, 1H), 2.22 - 1.98 (m, 2H), 1.86 - 1.83 (m, 1H).
1031	LC-MS: (ES, m/z): (ES, m/z): RT = 0.908min, LCMS07: m/z =372 [M +1]. 1H NMR (400 MHz, Methanol-d4) δ 8.67 - 8.62 (m, 1H), 8.02 (d, J = 2.6 Hz, 1H), 6.03 (d, J = 1.1 Hz, 1H), 4.35 (s, 2H), 4.06 (d, J = 7.1 Hz, 3H), 3.71 - 3.55 (m, 4H), 3.48 (s, 4H), 2.99 (s, 3H), 2.33 (d, J= LO Hz, 3H), 2.18-2.10 (m, 4H).
1032	LC-MS: (ES, m/z): RT = 0.868 min, LCMS28: m/z =357 [M+l], 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 7.82 - 7.74 (m, 2H), 7.68 (d, J = 8.9 Hz, 1H), 7.10 (s, 1H), 6.96 (d, J = 8.9 Hz, 1H), 5.89 (d, J = 5.9 Hz, 1H), 3.95 (s, 2H), 3.79 (s, 3H), 2.96 - 2.78 (m, 7H), 2.77 - 2.69 (m, 4H), 1.84 - 1.72 (m, 4H).

Example 156: Bioactivity Assays

Materials and Equipment:

[0518] Recombinant purified human EHMT2 913-1193 (55 μΜ) synthesized by Viva was used for ail experiments. Biotinylated histone peptides were synthesized by Biopeptide and HPLC-purified to > 95% purity. Streptavidin Flashplates and seals were purchased from PerkinElmer and 384 Well V-bottom Polypropylene Plates were from Greiner. H-labeled 5adenosylmethionine (³H-SAM) was obtained from American Radiolabeled Chemicals with a spécifie activity of 80 Ci/mmol. Unlabeled SAM and 5-adenosylhomocysteine (SAH) were obtained from American Radiolabeled Chemicals and Sigma-Aldrich respectively. Flashplates were washed in a Biotek ELx-405 with 0.1% Tween. 384-well Flashplates and 96-well filter binding plates were read on a TopCount microplate reader (PerkinElmer).

Compound serial dilutions were performed on a Freedom EVO (Tecan) and spotted into assay plates using a Thermo Scientific Matrix PlateMate (Thermo Scientific). Reagent cocktails were added by Multidrop Combi (Thermo Scientific).

[0519] MDA-MB-231 cell line was purchased from ATCC (Manassas, VA, USA). RPMI/Glutamax medium, Penicillin-Streptomycin, Heat Inactivated Fêtai Bovine Sérum, and D-PBS were purchased from Life Technologies (Grand Island, NY, USA). Odyssey blocking buffer, 800CW goat anti-mouse IgG (H+L) antibody, and Licor Odyssey Infrared Scanner were purchased from Licor Biosciences, Lincoln, NE, USA. H3K9me2 mouse monoclonal antibody (Cat #1220) was purchased from Abcam (Cambridge, MA, USA). 16% Paraformaldéhyde was purchased from Electron Microscopy Sciences, Hatfield, PA, USA).MDA-MB-231 cells were maintained in complété growth medium (RPMI supplemented with 10% v/v heat inactivated fêtai bovine sérum) and cultured at 37°C under

5% CO₂. UNC0638 was purchased from Sigma-Aldrich (St. Louis, MO, USA).

497

[0520] General Procedure for EHMT2 Enzyme Assay on Histone Peptide Substrate.

I0-point curves of test compounds were made on a Freedom EVO (Tecan) using serial 3-fold dilutions in DMSO, beginning at 2.5 mM (final top concentration of compound was 50 μΜ and the DMSO was 2%). A 1 μΕ aliquot of the inhibitor dilution sériés was spotted in a polypropylene 384-well V-bottom plate (Greiner) using a Thermo Scientific Matrix PlateMate (Thermo Scientific). The 100% inhibition control consisted of 1 mM final concentration of the product inhibitor S-adenosylhomocysteine (SAH, Sigma-Aldrich). Compounds were incubated for 30 minutes with 40 pL per well of 0.031 nM EHMT2 (recombinant purified human EHMT2 913-1193, Viva) in IX assay buffer (20 mM Bicine

[pH 7.5], 0.002% Tween 20, 0.005% Bovine Skin Gelatin and 1 mM TCEP). 10 pL per well of substrate mix comprising assay buffer, ³H-SAM (³H-labeled 5-adenosylmethionine, American Radiolabeled Chemicals, spécifie activity of 80 Ci/mmol), unlabeled SAM (American Radiolabeled Chemicals), and peptide representing histone H3 residues 1-15 containing C-terminal biotin (appended to a C-terminal amide-capped lysine, synthesized by

Biopeptide and HPLC-purified to greater than 95% purity) were added to initiate the reaction (both substrates were présent in the final reaction mixture at their respective K_m values, an assay format referred to as “balanced conditions”). Reactions were incubated for 60 minutes at room température and quenched with 10 pL per well of 400 pM unlabeled SAM, then transferred to a 384-well streptavidin Flashplate (PerkinElmer) and washed in a Biotek ELx-

405 well washer with 0.1% Tween after 60 minutes. 384-well Flashplates were read on a

TopCount microplate reader (PerkinElmer).

[0521] General Procedure for MDA-MB-231 HEK9me2 in-cell Western Assay.

Compound (100 nL) was added directly to 384-well cell plate. MDA-MB-231 cells (ATCC) were seeded in assay medium (RPMFGlutamax supplemented with 10% v/v heat inactivated fêtai bovine sérum and 1% Penicillin/Streptomycin, Life Technologies) at a concentration of 3,000 cells per well to a Poly-D-Lysine coated 384-well cell culture plate with 50 pL per well. Plates were incubated at 37°C, 5% CO2 for 48 hours (BD Biosciences 356697). Plates were incubated at room température for 30 minutes and then incubated at 37°C, 5% CO₂ for additional 48 hours. After the incubation, 50 pL per well of 8% paraformaldéhyde (Electron

Microscopy Sciences) in PBS was added to the plates and incubated at room température for 20 minutes. Plates were transferred to a Biotek 406 plate washer and washed 2 times with 100 pL per well of wash buffer (IX PBS containing 0.3% Triton X-100 (v/v)). Next, 60 pL per well of Odyssey blocking buffer (Licor Biosciences) was added to each plate and incubated for 1 hour at room température. Blocking buffer was removed and 20 pL of

498 monoclonal primary antibody a-H3K9me2 (Abcam) diluted 1:800 in Odyssey buffer with 0.1% Tween 20 (v/v) were added and plates were incubated ovemight (16 hours) at 4 °C. Plates were washed 5 times with 100 pL per well of wash buffer. Next 20 pL per well of secondary antibody was added (1:500 800CW donkey anti-mouse IgG (H+L) antibody (Licor Biosciences), 1:1000 DRAQ5 (Cell Signaling Technology) in Odyssey buffer with 0.1 % Tween 20 (v/v)) and incubated for 1 hour at room température. The plates were washed 5 times with 100 pL per well wash buffer then 2 times with 100 pL per well of water. Plates were allowed to dry at room température then imaged on a Licor Odyssey Infrared Scanner (Licor Biosciences) which measured integrated intensity at 700nm and 800nm wavelengths. Both 700 and 800 channels were scanned.

[0522] % Inhibition Calculation. First, the ratio for each well was determined , /H3K9me2 SOOnm value\ by: -------------------------).

\ DRAQ3 700nm value /

Each plate included fourteen control wells of DMSO only treatment (Minimum Inhibition) as well as fourteen control wells (background wells) for maximum inhibition treated with control compound UNC0638 (Background wells).

The average of the ratio values for each well was calculated and used to détermine the percent inhibition for each test well in the plate. Control compound was serially diluted threefold in DMSO for a total of 10 test concentrations beginning at 1 pM. Percent inhibition was calculated as: Percent Inhibition = 100- l----------------—, : ~---------------- ) * 100 \ Smoj- {Background Average Ratio)/ !

IC50 curves were generated using triplicate wells per concentration of compound. The IC50 is the concentration of compound at which measured méthylation is inhibited by 50% as interpolated from the dose response curves. IC50 values were calculated using a non-linear régression (variable slope-four parameter fit model) with by the following formula:

/ Top - Bottom \ ( % inhibition = Bottom + —7777777“ ) \ ( ( 50 L J, ) / _{? w}h_ere Tqp is fixed at 100% and

Bottom is fixed to 0%, [I] = concentration of inhibitor, /C50 = half maximal inhibitory concentration , and n = Hill Slope.

[0523] The IC50 values are listed in Tables II-VII below (“A” means IC50 <100nM; “B” means IC50 ranging between 100 nM and 1 pM; “C” means IC50 ranging between >1 pM and 10 pM; “D” means ICso + 10 pM; “ND” means not determined).

499

Table II

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
I	A	A	A
2	A	A	B
3	A	A	B
4	A	B	B
5	B	B	B
6	A	B	C
7	A	A	C
8	B	B	C
9	C	D	D
10	A	B	D
11	A	A	ND
12	C	C	D
13	D	D	D
14	D	D	D
15	A	A	D
16	B	B	D
17	B	B	D
18	B	B	C
19	A	A	B
20	A	B	B
21	A	B	B
22	A	A	B
23	B	B	B
24	A	A	B
25	A	A	B
26	A	B	B
27	B	B	B
28	A	A	B
29	A	A	B
30	A	B	B

500

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
31	B	B	B
32	A	A	B
33	A	B	B
34	A	B	B
35	B	B	B
36	A	B	B
37	B	B	B
38	A	B	B
39	A	A	B
40	B	B	C
41	B	B	C
42	B	B	C
43	B	B	C
44	B	B	C
45	B	B	C
46	A	B	C
47	A	A	C
48	B	B	C
49	B	B	C
50	B	B	C
51	B	B	C
52	C	C	C
53	C	C	C
54	B	B	C
55	B	B	C
56	C	C	C
57	C	C	C
58	D	D	ND
59	D	D	ND
60	C	C	ND
61	D	D	ND

501

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
62	D	D	ND
63	D	D	ND
64	D	D	ND
65	D	D	ND
66	D	D	ND
67	D	D	ND
68	D	D	ND
69	D	D	ND
70	D	D	ND
71	D	D	ND
72	D	D	ND
73	D	D	ND
74	D	D	ND
75	D	D	ND
76	D	D	ND
77	D	D	ND
78	D	D	ND
79	D	C	ND
80	D	D	ND
81	D	D	ND
82	D	D	ND
83	D	D	ND
84	D	D	ND
85	D	D	ND
86	C	C	ND
87	C	C	ND
88	B	B	C
89	D	D	ND
90	A	A	D
91	D	C	ND
92	D	D	ND

502

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
93	D	D	ND
94	C	C	ND
95	D	D	ND
96	C	C	ND
97	C	C	ND
98	D	D	ND
99	D	D	ND
100	D	D	ND
101	C	D	ND
102	D	D	ND
103	B	B	D
104	D	D	ND
105	C	D	ND
106	C	B	ND
107	D	D	ND
108	C	C	ND
109	C	C	ND
110	C	C	ND
111	D	D	ND
112	D	D	ND
113	C	C	ND
114	D	D	ND
115	D	D	ND
116	C	C	ND
117	C	C	ND
118	B	B	ND
119	D	D	ND
120	C	B	ND
121	C	C	ND
122	D	D	ND
123	D	D	ND

503

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
124	C	C	ND
125	C	C	ND
126	D	D	D
127	D	D	D
128	D	D	D
129	D	D	D
130	D	D	D
131	D	D	D
132	D	D	D
133	C	D	D
134	D	D	D
135	C	C	D
136	C	C	D
137	C	C	D
138	C	D	D
139	D	D	D
140	C	C	D
141	D	D	D
142	C	C	D
143	C	C	D
144	D	D	D
145	C	C	D
146	D	D	C
147	C	C	D
148	C	D	D
149	D	D	D
150	B	C	D
151	D	D	D
152	C	C	D
153	C	C	D
154	C	D	D

504

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
155	C	D	D
156	C	C	D
157	C	C	D
158	D	D	D
159	D	D	C
160	D	D	D
161	D	D	D
162	D	D	D
163	D	D	D
164	D	D	D
165	B	B	D
166	D	D	D
167	B	B	B
168	D	D	C
169	D	D	D
170	D	D	D
171	C	C	C
172	C	C	D
173	C	C	D
174	D	D	D
175	D	D	D
176	D	D	D
177	C	D	D
178	B	B	B
179	D	D	D
180	D	D	D
181	D	D	D
182	B	B	D
183	C	C	C
184	D	D	D
185	C	C	D

505

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
186	B	B	B
187	C	C	C
188	B	B	D
190	C	C	ND
191	A	A	B
192	B	B	C
193	B	B	B
194	D	D	ND
195	C	C	C
196	D	D	ND
197	D	D	ND
199	B	B	C
200	D	D	ND
201	D	D	ND
202	D	D	ND
203	B	B	B
204	C	C	D
205	A	A	A
206	B	B	D
207	C	C	C
208	B	B	C
209	B	B	C
210	C	C	C
211	C	C	ND
212	C	C	ND
213	D	D	ND
214	D	D	D
215	D	D	D
216	B	B	D
217	D	D	D
218	D	D	D

506

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
219	D	D	D
220	D	D	D
221	D	D	D
222	D	D	D
223	C	C	D
224	D	D	D
225	C	C	C
226	B	C	C
227	D	D	D
228	D	D	D
229	B	B	C
230	C	C	C
231	B	B	B
232	D	D	D
233	D	D	D
234	D	D	D
235	D	D	D
236	B	B	B
237	C	C	D
238	D	D	D
239	D	D	D
240	A	A	B
241	D	D	D
242	C	C	D
243	D	D	D
244	D	D	D
245	B	B	C
246	B	B	D
247	C	C	C
248	A	A	B
249	D	D	D

507

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
250	C	C	D
251	D	D	D
252	C	C	C
253	D	D	D

Table III

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
256	D	D	ND
257	D	D	D
258	D	D	D
259	D	D	D
260	D	D	D
261	D	D	D
262a and 262b	D	D	D
263	A	A	ND
264	D	D	D
265	D	D	D
266	C	C	C
267	D	D	D
268	D	D	D
270	A	A	B
271	C	B	D
272	B	C	C
273	D	D	D
274	C	C	D
275	D	D	D
276	D	C	D
277	D	D	D
278	A	A	C
279	D	D	D

508

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
280	C	C	C
281	A	ND	B
282	D	D	D
283	A	A	B
284	D	D	D
285	D	D	D
286	A	B	B
287	D	D	D
288	B	B	C
289	B	A	B
290	B	B	C
291	D	D	D
293	C	B	C
295	D	D	D
296	D	D	D
297	C	D	D
298	A	A	B
299	A	A	B
300	B	B	B
301	D	D	D
302	C	C	D
303	A	B	C
304	A	A	B
305	A	A	B
306	C	D	D
307	A	A	B
308	B	B	C
309	A	A	B
310	B	B	D
311	D	D	D
312	D	D	D

509

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
313	B	B	C
314	B	B	C
315	C	C	ND
316	C	B	C
317	C	D	C
318	D	D	D
319	B	B	C
320	A	A	B
321	C	C	D
322	A	A	B
323	D	D	D
324	C	C	D
325	C	C	C
326	B	B	C
328	B	B	C
329	C	C	D
330	D	C	D
331	D	D	D
332	A	A	B
333	C	C	D
334	A	A	B
335	B	B	C
336	B	B	C
337	C	B	C
338	D	D	D
339	D	D	D
340	B	B	D
341	D	D	D
342	D	D	D
343	D	D	D
344	D	D	D

510

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
345	D	D	D
346	D	D	D
347	C	C	D
348	D	D	D
349	C	C	C
350	B	B	C
351	D	D	D
352	D	D	D
353	B	B	C
354	C	B	C
355	A	A	B
356	D	D	D
357	D	D	D
358	D	D	D
359	D	D	D
360	B	B	B
361	C	C	D
362	D	D	D
363	D	D	D
364	A	A	B
365	D	D	D
366	C	C	D
367	D	D	D
368	D	D	D
369	B	B	C
370	B	B	D
371	C	C	D
372	A	A	B
373	D	D	D
374	C	C	D
375	D	D	D

511

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
376	C	C	C
377	C	D	D
378	B	B	B
379	B	C	C
380	D	D	ND
381	C	D	D
382	B	B	B
383	C	C	D
384	D	D	D
385	B	B	C
386	D	D	D
387	B	A	B
388	D	D	D
389	D	D	D
390	B	B	B
391	B	B	C
392	B	B	C
393	B	A	B
394	D	D	D
395	D	D	D
396	D	C	D
397	D	D	D
398	B	B	C
399	ND	ND	B
400	C	D	D
402	D	D	D
404	D	D	D
405	D	D	D
407	B	B	B
408	B	B	B
409	A	A	B

512

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
410	C	C	D
411	A	A	B
412	B	B	C
413	B	B	B
414	A	A	B
415	C	B	C
416	A	A	B
417	B	B	C
418	A	A	A
419	A	A	B
420	B	B	C
421	B	B	C
422	B	B	C
423	B	B	C
424	C	C	C
425	B	B	C
426	D	D	D
427	D	D	D
428	C	C	C
429	B	B	C
430	D	D	D
431	D	D	D
432	D	D	D
433	D	C	D
434	D	D	D
435	C	C	C
436	C	D	D
437	B	A	C
438	D	D	D
439	B	B	B
440	D	D	D

513

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
441	B	B	C
442	A	A	B
443	D	D	D
444	A	A	B
445	B	B	C
446	A	A	B
447	D	D	D
448	D	D	D
449	B	B	B
450	C	D	D
451	B	A	C
452	D	C	D

Table IV

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
453	D	D	D
455	D	D	D
456	C	C	D
457	A	A	A
458	B	B	C
459	C	C	D
460	A	A	B
461	A	A	B
462	A	A	B
463	A	A	B
464	B	B	C
465	A	A	B
466	D	D	D
468	C	B	C
470	D	C	D

514

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
471	C	C	D
473	C	B	C
475	B	A	B
477	B	B	C
478	D	D	D
480	D	D	D
481	A	A	A
482	B	B	C
483	A	A	B
485	A	A	B
486	D	D	D
487	C	B	C
488	B	A	B
489	C	B	C
490	A	A	A
491	B	A	C
492	B	A	B
494	A	A	A
494a	B	A	B
495	B	A	B
496	C	B	C
497	B	B	B
498	C	B	C
502	C	B	C
503	C	C	C
504	B	B	B
506	A	A	B
507	A	A	B
508	C	C	D
509	B	A	B

515

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
510	B	A	B
512	A	A	A
514	B	A	B
515	C	C	C
516	C	C	C
517a	B	B	B
517b	B	B	B
518	C	C	C
519	B	C	D
520	A	A	C
521	C	C	C
522	C	C	C
523	C	C	C
524	A	A	A
526	A	A	B
527	A	A	B
528	B	B	C
529	A	A	B
530	A	A	C
532	A	A	B
533	A	A	B
534	C	C	D
535	A	A	A
536	A	A	B

Table V

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
538	B	B	D
539	C	D	D
540	ND	ND	ND

516

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
541	D	D	D
542	D	D	D
543	D	D	D
544	D	D	D
545	D	D	D
546	D	D	D
547	D	D	D
548	D	D	D
549	D	D	D
550	D	D	D
551	B	B	B
552	D	D	D
553	D	D	D
554	D	D	D
555	D	D	D
556	D	D	D
557	D	D	D
558	B	A	B
559	B	A	B
560	B	B	B
561	D	D	D
562	C	C	C
563	A	A	A
564	A	A	D
565	C	C	C
566	C	C	D
567	C	C	D
568	B	A	B
569	B	A	B
570	C	C	C

517

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
571	A	A	B
572	D	D	D
573	C	C	D
574	C	C	D
575	C	B	C
576	B	A	B
577	C	B	D
578	C	C	D
579	C	C	D
580	D	D	D
581	C	D	D
582	D	D	D
583	C	C	D
584	D	D	D
585	C	C	C
586	C	C	D
587	A	A	B
588	D	D	D
589	D	D	D
590	A	A	B
591	A	A	B
592	B	B	B
593	B	B	B
594	B	A	B
595	B	B	B
596	C	C	D
597	D	D	D
598	D	D	D
599	B	A	B
600	A	A	A

518

Compound No.	EHMT2 PEP (IC50 μΜ)	EHMT1 PEP (IC50 μΜ)	EHMT2 ICW (IC50 μΜ)
601	B	A	B
602	B	B	B
603	A	A	B

Table VI

Compound No.	EHMT2 PEP IC50 (μΜ)	EHMT1 PEP IC50 (μΜ)	EHMT2 ICW IC50 (μΜ)
604	B	B	D
605	D	D	D
607	B	A	C
609	B	B	C
610	D	D	C
611	C	C	C
613	B	A	C
616	C	B	C
618	C	B	D
619	D	D	D
620	D	D	D
621	D	C	D
622	C	C	D
623	C	C	C
624	B	A	C
625	A	A	B
628	D	D	D
629	B	A	D
630	D	D	D
631	D	D	D
632	D	D	D
633	D	D	D
634	B	B	D
635	C	C	D

519

Compound No.	EHMT2 PEP IC50 (μΜ)	EHMT1 PEP IC50 (μΜ)	EHMT2 ICW IC50 (μΜ)
636	D	D	D
637	D	D	D
638	D	D	D
640	D	D	D
641	A	A	B
642	B	A	B
643	D	D	D
644	A	A	B
645	D	C	C
646	C	C	C
647	D	C	D
648	C	c	D
649	B	B	B
650	D	D	D
651	D	C	D
652	B	A	C
654	D	D	D
655	D	D	D
656	D	D	D
658	B	B	D
659	B	B	D
660	A	A	C
661	A	A	C
662	A	A	B
663	A	A	B
664	C	C	D
665	C	C	D
667	B	A	B
668	B	B	B
670	B	B	D

520

Compound No.	EHMT2 PEP IC50 (μΜ)	EHMT1 PEP IC50 (μΜ)	EHMT2 ICW IC50 (μΜ)
671	B	A	B
672	A	A	B
673	B	B	D
674	C	C	D
676	D	D	D
677	A	A	D
678	B	B	C
679	C	C	C
680	C	C	D
681	C	B	C
682	A	A	B
686	D	D	D
687	C	C	C
736	A	A	A
737	C	C	D
738	B	B	C
739	C	D	D
740	A	A	C
741	B	B	C
742	A	A	C
743	C	C	D
745	B	B	D
746	B	B	D
747	B	B	C
748	B	B	D
753	A	A	C
754	C	C	D
755	A	A	B
756	A	A	B
757	A	A	A

521

Compound No.	EHMT2 PEP IC50 (μΜ)	EHMT1 PEP IC50 (μΜ)	EHMT2 ICW IC50 (μΜ)
758	A	A	A
759	A	A	C
760	C	C	D
761	C	C	C
762	D	D	D
763	D	D	C
784	C	C	D
786	A	A	B
787	A	A	B
788	B	A	B
789	A	A	B
790	B	A	C
791	C	B	C
793	D	D	D
794	D	D	D
795	D	D	D
796	D	D	D
797	D	D	D
798	B	A	B
800	A	A	B
801	D	D	D
802	A	A	C
803	B	A	C
806	C	C	D
808	D	C	D
809	A	A	B
810	B	A	C
811	D	D	D
812	A	A	B
813	C	B	D

522

Compound No.	EHMT2 PEP IC50 (μΜ)	EHMT1 PEP IC50 (μΜ)	EHMT2 ICW IC50 (μΜ)
814	C	C	D
816	A	A	B
817	A	A	B
822	D	D	D
823	A	A	B
824	B	B	C
825	B	B	C
832	A	A	A
833	A	A	B
834	B	B	C
836	B	B	C
837	B	B	C
838	A	A	B
839	A	A	A
841	D	D	D
844	B	B	C
845	B	A	B
846	A	A	B
847	B	A	C
848	A	A	B
854	D	D	D
855	A	A	B
859	A	A	B
860	D	D	D
863	A	A	B
864	A	A	B
865	A	A	B
866	A	A	A
867	A	A	A
870	D	D	D

523

Compound No.	EHMT2 PEP IC50 (μΜ)	EHMT1 PEP IC50 (μΜ)	EHMT2 ICW IC50 (μΜ)
871	D	D	D
873	D	D	D
876	D	D	D
877	D	D	D
881	B	B	B
882	B	B	C
883	D	D	D
884	D	D	D
885	C	C	D
886	C	C	D
887	B	B	C
888	B	B	D
890	D	D	D
891	D	D	D
892	A	A	C
893	B	A	B
894	B	B	D
895	D	D	D
896	D	D	D
897	D	C	D
900	D	D	B
902	A	A	B
903	C	B	C
904	D	C	D
905	B	B	B
906	A	A	B
907	C	B	C
908	A	A	B
911	B	A	B
912	B	A	B

524

Compound No.	EHMT2 PEP IC50 (μΜ)	EHMT1 PEP IC50 (μΜ)	EHMT2 ICW IC50 (μΜ)
914	B	A	B
915	A	A	A
916	B	A	C
917	C	B	C
918	C	B	C
919	C	C	D
920	B	B	B
921	D	D	D
922	C	C	D
927	B	A	B
928	B	A	A
931	D	D	D
932	D	C	D
933	D	C	D
936	D	D	D
937	D	D	D
938	D	D	D
943	C	C	C
945	B	A	B
947	A	A	C
949	B	A	B
950	B	B	C
951	B	A	C
961	C	C	D
962	B	B	C
963	A	A	B
964	B	A	C
965	A	A	A
974	B	A	B
985	B	A	B

525

Compound No.	EHMT2 PEP IC50 (μΜ)	EHMT1 PEP IC50 (μΜ)	EHMT2 ICW IC50 (μΜ)
986	B	B	C
990	A	A	B
1005	C	C	C
1006	B	A	B
1007	D	C	D
1008	B	A	B
1009	C	C	C
1011	C	C	C
1014	C	B	C
1016	C	B	C
1019	C	B	D
1020	C	C	D
1021	C	B	C
1022	C	B	D
1028	A	A	B
1030	B	A	B
1031	B	A	B
1032	A	A	B
1033	A	A	B
1034	B	B	C
1035	B	B	C
1036	B	B	C
1037	B	B	B
1038	A	A	A
1040	B	B	A
1041	B	B	D
1042	C	C	D

Table VII

526

Compound No.	EHMT2 PEP IC50 (μΜ)	EHMT1 PEP IC50 (μΜ)	EHMT2 ICWIC50 (μΜ)
1043	C	B	C
1044	B	B	B
1045	A	A	B
1046	C	C	C
1047	A	A	B
1048	B	A	B
1049	B	A	B
1050	B	A	B
1051	A	A	A
1052	B	B	C
1053	C	B	C
1054	C	B	C
1055	B	A	B
1056	B	A	A
1057	B	B	B
1058	D	D	D
1059	C	C	C
1060	C	B	C
1061	C	B	D
1062	C	C	D
1063	B	B	B
1064	A	A	B
1065	B	A	B
1066	C	C	D
1067	D	D	D
1068	D	D	D
1069	D	C	D
1070	D	D	D
1071	D	D	D
1072	D	D	D
1073	C	B	C

527

Compound No.	EHMT2 PEP IC50 (μΜ)	EHMT1 PEP IC50 (μΜ)	EHMT2 ICWIC50 (μΜ)
1074	C	B	D
1075	A	A	B
1076	B	B	C
1077	B	B	C
1078	A	A	A
1079	B	B	C
1080	B	A	C
1081	A	A	A
1082	C	C	D
1083	B	B	B
1084	D	D	D
1085	B	A	B
1086	C	C	C
1087	C	B	C
1088	A	A	B
1089	B	A	B
1090	B	B	B
1091	B	A	B
1092	C	C	C
1093	B	A	B
1094	B	A	B
1095	B	B	C
1096	D	D	D
1097	D	C	D
1098	A	A	B
1099	B	A	B
1100	B	B	C
1101	A	A	B
1102	A	A	B
1103	C	C	C
1104	A	A	B

528

Compound No.	EHMT2 PEP IC50 (μΜ)	EHMT1 PEP IC50 (μΜ)	EHMT2 ICWIC50 (μΜ)
1105	B	B	C
1106	A	A	B
1107	A	A	B
1108	A	A	B
1109	C	B	C
1110	B	A	B
1111	A	A	B
1112	B	A	C
1113	B	A	C
1114	D	D	D
1115	C	C	ND
1116	C	D	ND
1117	C	D	ND
1118	C	D	ND
1119	C	C	ND

Exampie 157: Bioactivity Assays

The following procedure and Figures 1A-1D, 2, and 3 describe the induction of fêtai hemoglobin following treatment of cells with EHMT2 inhibitors defined herein.

Cell Culture

Peripheral Blood Mononuclear Cells (PBMCs) where isolated from whole blood of healthy donors by Ficoll gradients. CD34+ cells were then magnetically isolated from the PBMC fraction. Cells were differentiated in vitro toward the erythroid lineage for 14 days using the first two weeks of the 3-phase culture method described by jo Giarratana, et al (Blood 2011). After isolation, cells were seeded at a density of 1x10⁵ cells/mL in phase 1 media. At day 7, cells were split in a ratio of 1:5 into Phase 2 media.

Drug Treatment

Compounds were dissolved in Dimethyl sulfoxide (DMSO), and 1 μΜ stocks were prepared and diluted in a 1:3 sériés to generate an 11-point dose curve. 100 % DMSO served as control. Compound dilutions were added to cells on day 1 as 1:1000 dilutions. DMSO was equally added to control cells for a final concentration of

529

0.001%. Compound dilutions and DMSO were re-added on day 7, after the cell split described above.

Flow cytometry

At day 14, around 10⁶ cells were fixed, permeabilized, and stained for cell surface markers CD235a, CD71, Human Fêtai Hemoglobin, Human Histone 3, and Dimethyl-Lysine 9 Histone 3.

RT-qPCR

At day 14, around 10⁶ cells were pelleted. RNA was isolated by traditional spin column methods and gene expression analysis carried out by 2-step RT-qPCR. Standard curves were generated using plasmids encoding each of Human Globin HBA, HBB and HBG and were used to calculate individual globin copy numbers. HBB and HBG were added to calculate the total β-Locus Globins copies. Reported results represent % HBG/Total mRNA copies.

Mass Spectrometry

At day 14, around 10⁶ cells were pelleted. Protein was isolated, digested, and quantified by LC-PRM mass spectrometry analysis. Globin-specific label peptides were used for quantification of individual globins. HBB and HBG were added to calculate the total β-Locus Globin protein levels. Reported results represent % HBG/Total protein.

There was good corrélation between in-cell Western (ICW) and fluorescenceactivated cell sorting (FACs) data for K9 lysine dimethylation, and between fluorescence-activated cell sorting data for K9 lysine dimethylation and percent of cells containing fêtai hemoglobin (HbF+ cells), as shown in Figures 1A-1D. As shown in Figures 2 and 3, ail tested compounds showed around 30% Hbb-γ per total β-globins at the mRNA and protein level, with a 1:1 corrélation between protein and mRNA data. A good corrélation between potency, target engagement, and induction of HbF+ cells was observed. More potent compounds were shown to hâve a more sustained induction of Hbb-γ, which also correlated with the sustained induction of HbF+ cells as observed by FACs analysis. The data suggests that sickle-cell disease (SCD)-relevant levels of around 30% HbF/ total β-globins might be achievable for ail tested EHMT2 inhibitors. The following procedure and Figures 4 and 5 describe the inhibition of MV4-11 human acute monocytic leukemia cells following treatment with an EHMT2 inhibitor defined herein.

Materials and Equipment:

530

MV-4-11 leukemia cells were purchased from ATCC. IMDM, FBS, and Calcein-AM were purchased from Invitrogen. Fiat 96-well plates were purchased from Corning, and Poly-D-Lysine 96-well Microplates, black/clear were purchased from BD BIOCOAT.

A 3-fold serial dilution of Compound 205 (“3*compounds”) was prepared as follows: Compound 205 was dissolved in DMSO to give a 10 mM solution and stored at -20 °C. A 3-fold serial dilution of Compound 205 in DMSO to give solutions ranging in concentration from 5 mM to 0.25 μΜ.

The 3*compounds solutions were added to the cell plate via the foilowing procedure: 1.2 μΐ of the compound solutions were transferred to a 96-well plate with 200 μΐ of media in each well, then mixed well by pipetting up and down to give 3* compounds in media. 50 μΐ of 3*compounds in media were then transferred to the cell plate.

Day 0

In a fiat bottom 96-well plate, 100pL of cells were added per well at a density of 1x10⁵ cells/mL. (Note: Only internai wells were used. PBS was placed in ail outer wells to avoid évaporation of the internai wells.) 50 pL of 3*compounds were added to each well, to give a final volume of 150 pL per well.

Days 1-3

The plates were incubated for 96 hours.

Day 4

Cells were pipetted up and down to mix in each well. 20 pL of the cell suspension was aspirated from each well and added to a V-bottom plate. 80 pL of HBSS was added to each well of the V-bottom plate and mixed.

Next, 50 pL of cell suspension in the V-bottom plate was aspirated and added to a poly-D-lysine coated 96-well plate. To this was added 50 pL of HBSS containing 2 pM Calcein-AM, to give a final concentration of 1 pM. The cells were allowed to sit at room température for 10 minutes, then centrifuged to settle the cells on the bottom of the wells.

The plate was then incubated for an additional 40 minutes in the incubator to load Calcein AM and to give cells more time to attach.

The plate was removed and read on an Acumen plate reader, and cell numbers were calculated, taking into account the dilution factors. The master plate was split by taking the total viable cell count calculated, and cells were pipetted up and down in

531 each well in order to mix. Then, cell suspension was aspirated from each well and added to a V-bottom plate.

The plate was centrifuged at 1100 rpm for 5 minutes, then the media was removed, being careful not to disturb the cell pellet.

The pellet was then resuspended in 200 pL fresh media. The cells were mixed in each well by pipetting up and down, then 100 pL of cell suspension was aspirated from each well and added to a new 96-well fiat bottom plate, and 50 pL of 3*compounds solution was added.

Days 4-6

The plates were incubated for 72 hours.

Day 7

Cells were pipetted up and down to mix in each well. 20 pL of the cell suspension was aspirated from each well and added to a V-bottom plate. 80 pL of HBSS was added to each well of the V-bottom plate and mixed.

Next, 40 pL of cell suspension in the V-bottom plate was aspirated and added to a poly-Dlysine coated 96-well plate. To this was added 40 pL of HBSS containing 2 pM Calcein-AM, to give a final concentration of 1 pM. The cells were allowed to sit at room température for 10 minutes, then centrifuged to settle the cells on the bottom of the wells.

The plate was then incubated for an additional 40 minutes in the incubator to load Calcein AM and to give cells more time to attach.

The plate was removed and read on an Acumen plate reader, and cell numbers were calculated, taking into account the dilution factors. The master plate was split by taking the total viable cell count calculated, and cells were pipetted up and down in each well in order to mix. Then, 1.2* of the calculated cell suspension was aspirated from each well and added to a V-bottom plate.

The plate was centrifuged at 1100 rpm for 5 minutes, then the media was removed, being careful not to disturb the cell pellet.

The pellet was then resuspended in 120 pL fresh media. The cells were mixed in each well by pipetting up and down, then 100 pL of cell suspension was aspirated from each well and added to a new 96-well fiat bottom plate, and 50 pL of 3*compounds solution was added.

Days 7-10

The plates were incubated for 96 hours.

Day 11

532

Cells were pipetted up and down to mix in each well. 20 pL of the cell suspension was aspirated from each well and added to a V-bottom plate. 80 pL of HBSS was added to each well of the V-bottom plate and mixed.

Next, 50 pL of cell suspension in the V-bottom plate was aspirated and added to a poly-Dlysine coated 96-well plate. To this was added 50 pL of HBSS containing 2 pM Calcein-AM, to give a final concentration of 1 pM. The cells were allowed to sit at room température for 10 minutes, then centrifuged to settle the cells on the bottom of the wells.

The plate was then incubated for an additional 40 minutes in the incubator to load Calcein AM and to give cells more time to attach.

The plate was removed and read on an Acumen plate reader, and cell numbers were calculated, taking into account the dilution factors. The master plate was split by taking the total viable cell count calculated, and cells were pipetted up and down in each well in order to mix and reduce variation caused by pipetting. Then, 1.2* of the calculated cell suspension was aspirated from each well and added to a V-bottom plate.

The plate was centrifuged at 1100 rpm for 5 minutes, then the media was removed, being careful not to disturb the cell pellet.

The pellet was then resuspended in 120 pL fresh media. The cells were mixed in each well by pipetting up and down, then 100 pL of cell suspension was aspirated from each well and added to a new 96-well fiat bottom plate, and 50 pL of 3*compounds solution was added.

Days 11-13

The plates were incubated for 72 hours.

Day 14

Cells were pipetted up and down to mix in each well. 20 pL of the cell suspension was aspirated from each well and added to a V-bottom plate. 80 pL of HBSS was added to each well of the V-bottom plate and mixed.

Next, 40 pL of cell suspension in the V-bottom plate was aspirated and added to a poly-Dlysine coated 96-well plate. To this was added 40 pL of HBSS containing 2 pM Calcein-AM, to give a final concentration of 1 pM. The cells were allowed to sit at room température for 10 minutes, then centrifuged to settle the cells on the bottom of the wells.

The plate was then incubated for an additional 40 minutes in the incubator to load Calcein AM and to give cells more time to attach.

The plate was removed and read on an Acumen plate reader, and cell numbers were calculated, taking into account the dilution factors.

533

Growth was calculated for days 4, 7, H, and 14 as follows: the split factor was calculated for day 4 to 7, day 7 to 11, and day 11-14 The split factor is the number of viable cells/mL on Day X (either 4, 7, or 11) divided by the density the cells are being split back to.

For growth of cells from day 4 to 7, the day 7 viable cells/mL density was multiplied by the 5 split factor from day 4.

For growth of cells from day 7 to 11, the day 11 viable cells/mL density was multiplied by the day 4 and day 7 split factors.

For growth of cells from day 11 to 14, the day 14 viable cells/mL density was multiplied by the day 4, day 7, and day 11 split factors.

Growth was plotted on semi-log chart (viable cells/mL on Y axis, in log, and days on X axis). The invention can be embodied in other spécifie forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in ail respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and ail changes that corne within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims (5)

What is claimed is:

1. A compound of Formula (I):

^Rl (i), or a tautomer thereof, or a pharmaceutically acceptable sait of the compound or the tautomer, 5 wherein ring A is phenyl or a 5- or 6-membered heteroaryl;

X¹ is N, CR², or NR²’ as valency permits;

X² is N, CR³, or NR³’ as valency permits;

X³ is N, CR⁴, or NR⁴’ as valency permits;

10 X⁴ is N or CR⁵, or X⁴ is absent such that ring A is a 5-membered heteroaryl containing at least one N atom;

X⁵ is C or N as valency permits;

B is absent or a ring structure selected from the group consisting of Cô-Cio aryl, C₃Cio cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 12-membered heterocycloalkyl

15 containing 1-4 heteroatoms selected from N, O, and S;

T is a bond or Ci-Cô alkylene, C₂-C₆ alkenylene, or C₂-Cô alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo; or Ci-Cô alkoxy when B is présent; or T is H and n is 0 when B is absent; or T is Ci-Cô alkyl optionally substituted with (R⁷)n when B is absent; or when B is absent, T and R¹ together with the atoms to which 20 they are attached optionally form a 4-7 membered heterocycloalkyl or 5-6 membered y heteroaryl, each of which is optionally substituted with (R )n;

R¹ is H or C1-C4 alkyl;

each of R², R³, and R⁴, independently is selected from the group consisting of H, halo, cyano, C]-C6 alkoxyl, C6-Ci0 aryl, NR^aR^b, C(O)NR^aR^b, NR^aC(O)R^b, C3-C₈ cycloalkyl, 4- to 25 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, and Ci-Cô alkyl, wherein Ci-Cô alkoxyl and Ci-Cô alkyl are optionally substituted with one or more of halo, OR^a, or NR^aR^b, in which each of R^a and R^b independently is H or Ci-C6 alkyl, or R³ is -Q’-T¹, in which Q¹ is a bond or Ci-Cô alkylene, C2-Cô alkenylene, or C₂-Cô alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or Cj-Cô alkoxyl, and T¹ is H, halo, cyano, 30 NR⁸R⁹, C(O)NR⁸R⁹, OR⁸, OR⁹, or R^S1, in which R^SI is C₃-C₈ cycloalkyl, phenyl, 4- to 12535 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R^SI is optionally substituted with one or more of halo, Ci-Cô alkyl, hydroxyl, oxo, -C(O)R⁹, -SO2R⁸, -SO2N(R⁸)₂, -NR⁸C(O)R⁹, amino, mono- or dialkylamino, or Ci-Cô alkoxyl;; or when ring A is a 5-membered heteroaryl containing at least 5 one N atom, R⁴ is a spiro-fused 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S;

each of R²’, R³’ and R⁴’ independently is H or C1-C3 alkyl;

R⁵ is selected from the group consisting of H, F, Br, cyano, Ci-Cô alkoxyl, Cô-Cio aryl, NR^aR^b, C(O)NR^aR^b, NR^aC(O)R^b, C3-C8 cycloalkyl, 4- to 12-membered heterocycloalkyl 10 containing 1-4 heteroatoms selected from N, O, and S, Ci-C6 alkyl optionally substituted with one or more of halo, OR^a or NR^aR^b, and C2-Cô alkynyl optionally substituted with 4- to 12membered heterocycloalkyl; wherein said C3-C8 cycloalkyl or 4- to 12-membered heterocycloalkyl are optionally substituted with one or more of halo, C(O)R^a, OR^a, NR^aR^b, 4to 7-membered heterocycloalkyl, -Ci-Cô alkylene-4- to 7-membered heterocycloalkyl, or Ci15 C4 alkyl optionally substituted with one or more of halo, OR^a or NR^aR^b, in which each of R^a and R^b independently is H or Ci-Cô alkyl; or

R⁵ and one of R³ or R⁴ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R⁵ and one of R³’or R⁴’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 20 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl;

R⁶ is absent when X⁵ is N and ring A is a 6-membered heteroaryl; or R⁶ is -Q'-T¹, in which Q¹ is a bond or Ci-Cô alkylene, C2-Cô alkenylene, or C2-Cô alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or Ci-Cô alkoxyl, and 25 T¹ is H, halo, cyano, NR⁸R⁹, C(O)NR⁸R⁹, C(O)R⁹, OR⁸, OR⁹, or R^S1, in which R^S1 is C3-C₈ cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R^S1 is optionally substituted with one or more of halo, Ci-Cô alkyl, hydroxyl, oxo, -C(O)R⁹, -SO2R⁸, -SO2N(R⁸)₂, -NR⁸C(O)R⁹, NR⁸R⁹, or Ci-Cô alkoxyl; and R⁶ is not NR⁸C(O)NR¹²R¹³; or

30 R⁶ and one of R² or R³ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R and one of R ’or R ’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6-membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl, oxo (=O), C1-C3 alkoxyl, or -Q'-T¹;

536 each R⁷ is independently oxo (=O) or -Q²-T², in which each Q² independently is a bond or Ci-Cô alkylene, C2-Cô alkenylene, or C2-Cô alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or Cj-Cô alkoxyl, and each T² independently is H, halo, cyano, OR¹⁰, OR¹¹, C(O)R^U, NR¹⁰R^h, C(O)NR¹⁰Rⁿ, NR^CCOjR¹¹, 5- to 10-membered heteroaryl, C3-C₈ cycloalkyl, or 4- to 12membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the 5- to 10-membered heteroaryl, C₃-C₈ cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, Cj-Cô alkyl optionally substituted with NR^xR^y, hydroxyl, oxo, N(R⁸)2, cyano, Cj-Cô haloalkyl, -SO2R⁸, or Cj-Cô alkoxyl, each of R^x and R^y independently being H or Cj-C6 alkyl; and R₇ is not H or C(O)OR^g; or optionally, when B is présent, one R⁷ and R⁵ together form a C₃-Cjo alkylene, C₂-Cjo heteroalkylene, C₄-Cj₀ alkenylene, C₂-Cj₀ heteroalkenylene, C₄-Cio alkynylene or C₂Cio heteroalkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or Cj-Cô alkoxyl;

each R⁸ independently is H or Cj-Cô alkyl;

each R⁹ is independently -Q³-T³, in which Q³ is a bond or Cj-Cô alkylene, C2-Cô alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or Cj-Cô alkoxyl, and T³ is H, halo, OR¹², OR¹³, NR¹²R¹³, NR¹²C(O)R¹³, C(O)NR¹²R¹³, C(O)R¹³, S(O)2R¹³, S(O)2NR¹²R¹³, or R^S2, in which R^S2 is C3-C₈ cycloalkyl, Cô-Cjo aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and R^S2 is optionally substituted with one or more -Q⁴-T⁴, wherein each Q⁴ independently is a bond or Cj-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Cj-Cô alkoxy, and each T⁴ independently is selected from the group consisting of H, halo, cyano, Cj-Cô alkyl, C3-C₈ cycloalkyl, Cô-Cjo aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^C, C(O)R^c, S(O)₂R^C, NR^cR^d, C(O)NR^cR^d, and NR^cC(O)R^d, each of R^c and R^d independently being H or Cj-Cô alkyl; or -Q⁴-T⁴ is oxo; or

R⁸ and R⁹ taken together with the nitrogen atom to which they are attached form a 4to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, which is optionally substituted with one or more of-Q⁵-T⁵, wherein each Q⁵ independently is a bond or Cj-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Cj-Cô alkoxy, and each T⁵ independently is selected from the group consisting of H, halo, cyano, Cj-Cô alkyl, C3-C₈

537 cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing l-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^e, C(O)R^e, S(O)2R^e, S(O)2NR^eR^f, NR^eR^f, C(O)NR^eR^f, and NR^eC(O)R^f, each of R^e and R^f independently being H or Ci-Cô alkyl; or -Q⁵-T⁵ is oxo;

R¹⁰ is selected from the group consisting of H and Ci-Cô alkyl;

R¹¹ is -Q⁶-T⁶, in which Q⁶ is a bond or Ci-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or Ci-Cô alkoxyl, and T⁶ is H, halo, OR^g, NR^gR^h, NR^gC(O)R^h, C(O)NR^gR^h, C(O)R^g, S(O)2R^g, or R^S3, in which each of R^g and R^h independently is H, phenyl, C3-C8 cycloalkyl, or Ci-Cô alkyl optionally substituted with C3-C8 cycloalkyl, or R^g and R^h together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and R^S3 is C3-C₈ cycloalkyl, Cô-Cio aryl, 4- to 12membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, or a 5- to 10-membered heteroaryl, and R^S3 is optionally substituted with one or more -Q⁷-T⁷, wherein each Q⁷ independently is a bond or C|-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁷ independently is selected from the group consisting of H, halo, cyano, Ci-C6 alkyl, C₃-C₈ cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR\ C(O)Rj NRR^k, C(O)NR^JR^k, S(O)₂R^j, and NR^jC(O)R^k, each of R and R^k independently being H or Ci-Cô alkyl optionally substituted with one or more halo; or -Q -T is oxo; or

R¹⁰ and R¹¹ taken together with the nitrogen atom to which they are attached form a 4to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, which is optionally substituted with one or more of halo, Ci-Cô alkyl, hydroxyl, or Ci-Cô alkoxyl;

R¹² is H or Ci-Cô alkyl;

R¹³ is Ci-Cô alkyl, C3-C8 cycloalkyl, Cô-Cio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more -Q -T , wherein each Q independently is a bond or Ci-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁸ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C3-C₈ cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl; or-Q⁸-T⁸ is oxo; and

538 n is 0, 1, 2, 3, or 4, optionally provided that (1) the compound of Formula (I) is not 4-(((2-(( 1 -acetylindolin-6-yl)amino)-6(trifluoromethyl)pyrimidin-4-yl)amino)methyl)benzenesulfonamide,

5-bromo-N⁴-(4-fluorophenyl)-N²-(4-methoxy-3-(2-(pyrrolidin-lyl)ethoxy)phenyl)pyrimidine-2,4-diamine,

N²-(4-methoxy-3-(2-(pyrrolidin-l-yl)ethoxy)phenyl)-N⁴-(5-(tert-pentyl)-lH-pyrazol3-yl)pyrimidine-2,4-diamine,

2. A compound of Formula (IX-1):

or a tautomer thereof, or a pharmaceutically acceptable sait of the compound or the 25 tautomer, wherein,

X⁶ is N or CH;

X⁷ is N or CH;

X³ is N or CR⁴;

R⁴ is selected from the group consisting of H, halo, cyano, Cj-Cô alkoxyl, Cg-Cio aryl, 30 NR^aR^b, C(O)NR^aR^b, NR^aC(O)R^b, C₃-C₈ cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, and Ci-Cô alkyl, wherein Ci-Cealkoxyl and Ci-CJ alkyl are

540 optionally substituted with one or more of halo, OR^a, or NR^aR^b, in which each of R^a and R^b independently is H or Ci-Cô alkyl;

each Q¹ is independently a bond or Cj-Cô alkylene, C₂-Cô alkenylene, or C₂-Cô alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or 5 Ci-Cô alkoxyl;

each T¹ is independently H, halo, cyano, NR⁸R⁹, C(O)NR⁸R⁹, C(O)R⁹, OR⁸, OR⁹, or R^S1, in which R^S1 is C3-C8 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R^S1 is optionally substituted with one or more of halo, Ci-Cô alkyl, hydroxyl, oxo, -C(O)R⁹, 10 SO2R⁸, -SO2N(R⁸)2, -NR⁸C(O)R⁹, NR⁸R⁹, or Ci-C₆ alkoxyl; and -Q'-T¹ is not NR⁸C(O)NR¹²R¹³;

Q each R independently is H or Ci-Cô alkyl;

each R⁹ is independently -Q³-T³, in which Q³ is a bond or Ci-Cô alkylene, C2-Cô alkenylene, or C2-Cô alkynylene linker optionally substituted with one or more of halo, 15 cyano, hydroxyl, or CrC6 alkoxyl, and T³ is H, halo, OR¹², OR¹³, NR¹²R¹³, NR¹²C(O)R¹³, C(O)NR¹²R¹³, C(O)R¹³, S(O)2R¹³, S(O)2NR¹²R¹³, or R^S2, in which R^S2 is C3-C₈ cycloalkyl, Cô-Cio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and R is optionally substituted with one or more -Q⁴-T⁴, wherein each Q⁴ independently is a bond or Ci-C3 alkylene, C2-C3 alkenylene, 20 or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁴ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C3-C₈ cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^C, C(O)R^c, S(O)₂R^C, NR^cR^d, C(O)NR^cR^d, and NR^cC(O)R^d, each of R^c and R^d

25 independently being H or Ci-Cô alkyl; or -Q⁴-T⁴ is oxo; or

R¹² is H or C]-C₆ alkyl;

R is Ci-Cô alkyl, C₃-C₈ cycloalkyl, Cô-Cio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more -Q⁸-T⁸, wherein each Q⁸

30 independently is a bond or Ci-C₃ alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cg alkoxy, and each o

T independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C₃-C₈ cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl; or -Q -T is oxo;

541

R¹⁵· is CN, C(O)H, C(O)R^1!, OH, OR^IS, Ci-Cs alkyl, NHR¹⁷, C₃-Q cycloalkyl, C₆Cio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or 5- to 10-membered heteroaryl, wherein each of said Ci-Cô alkyl, C₃-Cs cycloalkyl, Cô-Cio aryl, 4- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl is

5 optionally substituted with one or more -Q⁹-T⁹, wherein each Q⁹ independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy, and each T⁹ independently is selected from the group consisting of H, halo, cyano, Ci-Cô alkyl, C3-Cs cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 510 to 6-membered heteroaryl; or -Q⁹-T⁹ is oxo;

R^16a is -Qⁿ-R¹⁶ in which Q¹¹ is a bond, O, NR^a, Ci-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Ci-Cô alkoxy; and R¹⁶ is H, Ci-Cô alkyl, C2-Cô alkenyl, C₂-Cô alkynyl, C₃-C$ cycloalkyl, C₆-Cio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms

15 selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more -Q¹⁰-T¹⁰, wherein each Q¹⁰ independently is a bond or Ci-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Cj-Cô alkoxy, and each T¹⁰ independently is selected from the group consisting of H, halo, cyano, C(O)H, C(O)R¹⁸, S(O)PR¹⁸, OH, OR¹⁸, Ci-Cô

20 alkyl, C₃-Cs cycloalkyl, C₆-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl; or -Q^l0-T¹⁰ is oxo;

R¹⁷ is H or Ci-Cô alkyl;

each R¹⁸ is independently Ci-Cô alkyl, C₂-Cô alkenyl or C₂-Cô alkynyl;

p is 0, 1, or 2; and

25 v is 0, 1, or 2.

(2) when T is a bond, B is substituted phenyl, and R⁶ is NR⁸R⁹, in which R⁹ is -Q³R^S2, and R^S2 is optionally substituted 4- to 7-membered heterocycloalkyl or a 5- to 6membered heteroaryl, then B is substituted with at least one substituent selected from (i) -Q OR¹¹ in which R¹¹ is -Q⁶-R^S3 and Q⁶ is optionally substituted C₂-Cô alkylene, C₂-Cô alkenylene, or C₂-Cô alkynylene linker and (ii) -Q²-NR¹⁰Rⁿ in which R¹¹ is -Q⁶-R^S3;

2-cyclohexyl-6-methoxy-N-[ 1 -( 1 -methylethyl)-4-piperidinyl]-7-[3-( 1 pyrrolidinyl)propoxy]-4-quinazolinamine,

3. A compound of Formula (liai):

R⁵

Γ\ γλ1 ^R (liai), or a tautomer thereof, or a pharmaceutically acceptable sait of the compound or the tautomer 30 thereof, wherein

542

R¹ is H or C1-C4 alkyl;

R³ is selected from the group consisting of H and Ci-Cô alkyl;

R⁵ is selected from the group consisting of H and Cj-Cô alkyl;

each R⁷ is independently oxo (=O) or -Q²-T², in which each Q² independently is a

5 bond or Cj-C₆ alkylene, C₂-Cô alkenylene, or C₂-Cô alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or Ci-Cô alkoxyl, and each T² independently is H, halo, cyano, OR¹⁰, OR¹¹, C(O)Rⁿ, NR^1OR^U, C(O)NR¹⁰Rⁿ, NR¹⁰C(O)R^h, 5- to 10-membered heteroaryl, C₃-C₈ cycloalkyl, or 4- to 12membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and

10 wherein the 5- to 10-membered heteroaryl, C₃-C₈ cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, Ci-Cô alkyl optionally substituted with NR^xR^y, hydroxyl, oxo, N(R^x)₂, cyano, Cj-Cô haloalkyl, -SO₂R^X, or Ci-Cô alkoxyl, each of R^x and R^y independently being H or Cj-Cô alkyl; and -Q²-T² is not H or C(O)OR^g;

15 R⁸ is H or Cj-Cô alkyl;

R⁹ is -Q³-T³, in which Q³ is a bond or Ci-C₆ alkylene and T³ is H;

each R¹⁰ is independently selected from the group consisting of H and Cj-Cô alkyl;

each R¹¹ is independently -Q⁶-T⁶, in which Q⁶ is a bond or Cj-Cô alkylene, C2-Cô alkenylene, or C2-Cô alkynylene linker optionally substituted with one or more of halo, 20 cyano, hydroxyl, oxo, or Cj-Cô alkoxyl, and T⁶ is H, halo, OR^g, NR^gR^h, NR^gC(O)R^h, C(O)NR^gR^h, C(O)R^g, S(O)2R^g, or R^S3, in which each of R^g and R^h independently is H, phenyl, C3-C8 cycloalkyl, or Cj-Cô alkyl optionally substituted with C3-C8 cycloalkyl, or R^g and R^h together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and R is C3-C₈

25 cycloalkyl, Cô-Cio aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, or a 5- to 10-membered heteroaryl, and R is optionally substituted with one or more -Q⁷-T⁷, wherein each Q⁷ independently is a bond or Cj-C₃ alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or Cj-Cô alkoxy, and each T⁷ independently is selected

30 from the group consisting of H, halo, cyano, Cj-Cô alkyl, C₃-C₈ cycloalkyl, C₆-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6membered heteroaryl, OR^J, C(O)RJ, NR'R^k, C(O)NR^JR^k, S(O)₂R\ and NRjC(O)R^k, each of R^J and R^k independently being H or Cj-Cô alkyl optionally substituted with one or more halo; or -Q⁷-T⁷ is oxo; or

543 one of R¹⁰ and one of R¹¹ taken together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, which is optionally substituted with one or more of halo, C]-Cô alkyl, hydroxyl, or Ci-Cô alkoxyl; and

5 n is 2, 3, or 4.

(3) when T is a bond and B is optionally substituted phenyl, then R⁶ is not OR⁹ or NR⁸R⁹ in which R⁹ is optionally substituted naphthyl;

539

3-(l -cyano-1 -methylethyl)-7V-[3-[(3,4-dihydro-3-methyl-4-oxo-6quinazolinyl)amino]-4-methylphenyl]benzamide,

6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-l-ylpyridin-2-yl)amino]pyrido[2,3d]pyrimidin-7-one,

IV-[2-[[4-(Diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3d]pyrimidin-7-yl]-7V-( 1,1 -dimethylethyl)urea, or

6-[[2-[[4-(2,4-dichlorophenyl)-5-(5-methyl-lH-imidazol-2-yl)-2pyrimidinyl] amino] ethyl] amino] -3 -pyridinecarbonitrile;

4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, or a

15 5- to 10-membered heteroaryl, and R is optionally substituted with one or more -Q -T , wherein each Q⁷ independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or CiCô alkoxy, and each T⁷ independently is selected from the group consisting of H, halo, cyano, 20 Ci-Cô alkyl, C3-C8 cycloalkyl, Cô-Cio aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR\ C(O)R\ NR*R^k, C(O)NR^JR^k, S(O)2R^j, and NR^jC(0)R^k, each of R^J and R^k independently being H or C]-Cô alkyl optionally substituted with one or more halo; or -Q -T is oxo; or

25 one of R¹⁰ and one of R¹¹ taken together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from

N, O, and S, which is optionally substituted with one or more of halo, Ci-Cô alkyl, hydroxyl, or

30 Ci-Cô alkoxyl.

32. The compound of claim 31, being of the following formula:

549

or a tautomer thereof, or a pharmaceutically acceptable sait of the compound or the tautomer thereof.

5 33. The compound of claim 32, wherein R¹ is H.

□

34. The compound of claim 33, wherein R is H.

35. The compound of claim 34, wherein R⁵ is Cj-Cô alkyl.

10 g

36. The compound of claim 35, wherein each R is H.

37. The compound of claim 36, wherein R⁹ is -Q³-T³, in which Q³ is Cj-Cô alkylene, and T³ is H.

15 7 2 2 7 · 2

38. The compound of claim 37, wherein R is -Q -T , in which Q“ is a bond, and T is OR¹¹.

39. The compound of claim 38, wherein R¹¹ is -Q⁶-T⁶, in which Q⁶ is Cj-Cô alkylene 20 optionally substituted with one or more hydroxyl, and T⁶ is NR^sR^h.

40. The compound of claim 39, wherein R^s and R^h, together with the nitrogen atom to which they are attached, form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S.

41. A compound being selected from:

Compound No. Structure

550 Compound No. Structure 1 HH 1 \ IX U, -'_O-' 6 HH 1 > Χγ IY 20 Q ZI 3 0 171 1 H YY IJ UJ 176 HH i \ N N N \ N ^/ TT TT γγ χχχ^ζ 186 XX /Y IY ÏY J HH 205 /0. Y%. ΥΊ xT \ J HH 207 HH T) χι χτ 210 Υτ 0 I ο ο 0

551

552 Compound No. Structure 252 OH r—\ H H f 1 > k/ N N ^N -X Uu 253 OH i--\ H H ï 1 ) XIX^ 269 HH \ X,_p ,N. z?_x 7./ Y Y XX° X^N XX 271 HH I >........_. .N. ¹ XIXI/ 274 Jz I ZI Z--. οχχ Z T M 275 Jz o ZI Z---. οχχ ^z^ 276 F 7\ H H 1 । > N,N,NO\X\^-^N-X XI xi 277 H H V O N N N K^ÿ^K/O^XX/ N .y XIXI 279 H H | \ \ .N. /N. /\ /-/ _XN_X/ T y γγγ^ XX

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581 Compound No. Structure 905 XX XX \ / i ^{H H} V-X OH 906 /0. XX xx \ 1 ^{H H} \___' OH 907 XX XX N N N / / j ^H H OH 908 ,o. X^\ X^\ XX ^X n^ ^X XXXXz X^N^ X^ ^0^ ^hX ^hX ^hT Il ^{H H} ÔH 913 ^Ίι ^X N] ^X r^- N N N / / HH 916 xX\ ^X\ ^°\ HH H 918 x^°\ X^ ^N X^ jp N ^N N N HH i H OH 919 \ / oui...../ o ^o iz χ ^Z\ /7 920 r^\ N ^N N \/^V/ ^N ''''··' XX XX/ Xd^

582

583

584

585

586

587

588 Compound No. Structure 1009 XXXX '''''''N N HH H 1010 .x-x. \ XX XX λ HH H 1011 il i ^XXXX1 HH H 1012 XXXX ’ HH H 1013 i XXXX / / HH 1014 1 ^Îl ^N| Γ~^~~ N N N j HH 1015 XXXX ^! HH H 1016 XXXX Λ HH H 1017 ’ XXXX ! HH

589 Compound No. Structure 1018 XXXX i HH H 1019 /X YX / -NH Y^ ^X ^X <1 « I 1 ii 1 \^X /^N\ ^Y\ X\ XX JX\ /Y '//Y Y/ ^Y ^N^ H H 1020 JL /Y\ X--NH Y X; ^X _N^ ^X < 1 h ] 1 il ] H H 1021 .0. /Y /¼. /~~~~NH Υτ| N| H H 1022 H H 1023 / 'N jf^ |1 ^N| N\\V' /^/X'/ \ X \ ' O N N N = HH ÔH 1024 Ξ HH ÔH 1029 ^ïi ^X h 1 1 Ji 1 ^^N\ yXzXx ^XX <?X\ Flllim,./ i H H 1030 Xn ^X n^ ^X h 1111 ^^N\ ^γΧ. χίΧ\ /X xX / ^Y ^F^X / H H

590

591

592

593

594

595

596

597

598

599

600

42.

A compound which is

or a pharmaceutically acceptable sait thereof.

43. A compound which is

10 or a pharmaceutically acceptable sait thereof.

44. A compound which is

601 or a pharmaceutically acceptable sait thereof.

45. The compound of any one of claims 1-44, wherein the compound inhibits a kinase with an enzyme inhibition IC₅₀ value of about 100 nM or greater, 1 μΜ or greater, 10 μΜ or greater, 100 μΜ or greater, or 1000 μΜ or greater, or about 1 mM or greater; and/or wherein the compound inhibits a kinase with an enzyme inhibition IC₅₀ value of 1 μΜ or greater, 2 μΜ or greater, 5 μΜ or greater, or 10 μΜ or greater, wherein the kinase is one or more of the following: Abl, AurA, CHK1, MAP4K, IRAK4, JAK3, EphA2, FGFR3, KDR, Lck, MARK1, MNK2, PKCb2, SIX, and Src.

46. A pharmaceutical composition comprising a compound of any one of claims 1-45 or a pharmaceutically acceptable sait thereof and a pharmaceutically acceptable carrier.

47. A compound of any one of claims 1-45 for use in a method of preventing or treating a blood disorder via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound.

48. The compound for use of claim 47, wherein the blood disorder is sickle cell anémia or β-thalassemia; or wherein the blood disorder is a hematological cancer including acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL).

602

Abstract

The présent disclosure relates to amine-substituted aryl or heteroaryl compounds. The présent disclosure also relates to pharmaceutical compositions containing these compounds and methods of treating a disorder (e.g., sickle cell anémia) via inhibition of a

4. The compound of claim 3, wherein R¹ is H or CH₃.

7 2 11

5. The compound of claim 3 or 4, wherein n is 2, and at least one of R is-Q-OR in 10 which R¹¹ is -Q⁶-R^S3 and Q⁶ is optionally substituted C₂-Cô alkylene, C₂-C₆ alkenylene, or C₂-Cô alkynylene linker.

6. The compound of claim 5, wherein Q⁶ is C₂-Cô alkylene, C₂-Cô alkenylene, or C₂-Cô

S 3 alkynylene linker optionally substituted with a hydroxyl and R is 4- to 7-membered 7 7

15 heterocycloalkyl optionally substituted with one or more -Q -T .

7. The compound of claim 6, wherein Q⁶ is C₂-Cô alkylene, C₂-Cô alkenylene, or C₂-Cô alkynylene linker optionally substituted with a hydroxyl and R^S3 is C₃-Cô cycloalkyl optionally substituted with one or more -Q -T .

8. The compound of claim 7, wherein each Q⁷ is independently a bond or a Ci-C₃ alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker and each T⁷ is independently H, halo, Ci-Cô alkyl, or phenyl.

25 9. The compound of any one of claims 5 to 8, wherein Q² is a bond or a Ci-C₄ alkylene,

C₂-C₄ alkenylene, or C₂-C₄ alkynylene linker.

y

10. The compound of any one of claims 3-9, wherein at least one R is

544

11. The compound of claim 10, wherein n is 2, and one of R⁷ is selected from halo and methoxy.

15 12. The compound of any one of claims 3-11, wherein R¹ is H.

545

13. The compound of any one of claims 3-12, wherein R⁵ is C]-C₆ alkyl.

14. The compound of any one of claims 3-13, wherein R is H.

7 211 11 6

15. The compound of claim 3, wherein at least one of R is -Q -OR in which R is -Q R^S3 and Q⁶ is optionally substituted C₂-Cô alkylene linker.

16. The compound of claim 15, wherein R is -Q -R , in which Q is a Ci-Cô alkylene linker substituted with a hydroxyl and R^S3 is 4 to 12-membered heterocycloalkyl.

17. The compound of claim 15, wherein R¹¹ is -Q⁶-R^S3, in which Q⁶ is a Ci-Cô alkylene linker substituted with a hydroxyl and R^S3 is a 4-membered heterocycloalkyl.

18. The compound of any one of claims 15-17, wherein n is 2.

19. The compound of claim 3, wherein n is 2, one of R is-Q-OR in which R is-QR^S3 and Q⁶ is optionally substituted C₂-Cô alkylene linker; and one of R⁷ is selected from halo and methoxy.

20. The compound of claim 3, wherein the compound is

546

or a pharmaceutically acceptable sait thereof.

β

21. The compound of claim 12, wherein R is H.

22. The compound of claim 21, wherein R⁵ is Ci-Cô alkyl.

O io 23. The compound of claim 22, wherein each R is H.

9 3 3 3

24. The compound of claim 23, wherein R is -Q -T , in which Q is Ci-Cô alkylene, and T³ is H.

15 25. The compound of claim 24, wherein at least one of R⁷ is -Q²-T², in which Q² is a bond, and T² is OR¹¹.

26. The compound of claim 25, wherein R¹¹ is -Q⁶-T⁶, in which Q⁶ is Ci-Cô alkylene optionally substituted with one or more hydroxyl, and T⁶ is NR^gR^h.

27. The compound of claim 26, wherein R^g and R^h, together with the nitrogen atom to which they are attached, form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S.

547

28. The compound of claim 27, wherein n is 2.

29. The compound of claim 28, wherein one of R⁷ is methoxy.

5 30. The compound of claim 29, wherein the R⁷ being methoxy is at the para-position to NR¹.

31. A compound of the foilowing formula:

or a tautomer thereof, or a pharmaceutically acceptable sait of the compound or the tautomer thereof, wherein

R¹ is H or C1-C4 alkyl;

R³ is selected from the group consisting of H and Ci-Cô alkyl;

15 R⁵ is selected from the group consisting of H and Cj-Cô alkyl;

R⁷ is oxo (=O) or -Q²-T², in which each Q² independently is a bond or Ci-Cô alkylene,

C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or Ci-Cô alkoxyl, and each T”

20 independently is H, halo, cyano, OR¹⁰, OR¹¹, C(O)R^1], NR^1OR^U, C(O)NR¹⁰R^u, NR¹⁰C(O)Rⁿ, 5- to 10membered heteroaryl, C3-C8 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 14 heteroatoms selected from N, O, and S, and wherein the 5- to 10-membered heteroaryl, C3-C8

25 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, Ci-Cô alkyl optionally substituted with NR^xR^y, hydroxyl, oxo, N(R^X)2, cyano, Ci-Cô haloalkyl, -SO₂R^X, or Ci-Cô alkoxyl, each of R^x and R^y independently being H or Ci-Cô alkyl;

and -Q²-T² is not H or C(O)OR^g;

30 R⁸ is H or Ci-Cô alkyl;

548

R⁹ is -Q³-T³, in which Q³ is a bond or Ci-Cô alkylene, and T³ is H;

each R¹⁰ is independently selected from the group consisting of H and Ci-Cô alkyl; and each R¹¹ is independently -Q⁶-T⁶, in which Q⁶ is a bond or Ci-Ce alkylene, C₂-Cô 5 alkenylene, or C₂-Ce alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or Ci-C₆ alkoxyl, and T⁶ is H, halo, OR^g, NR^gR^h, NR^gC(O)R^h, C(O)NR^gR^h, C(O)R^g, S(O)₂R^g, or R^S3, in which each of R^g and R^h independently is H, phenyl, C3-C8 cycloalkyl, or Ci-Ce alkyl optionally substituted with C3-C8 cycloalkyl, or R^g and R^h together 10 with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and R^S3 is C3-C8 cycloalkyl, Cô-Cio aryl,

(4) when T is a bond and B is optionally substituted phenyl, naphthyl, indanyl or 1,2,3,4-tetrahydronaphthyl, then R⁶ is not NR⁸R⁹ in which R⁹ is optionally substituted phenyl, naphthyl, indanyl or 1,2,3,4-tetrahydronaphthyl;

(5) when T is a bond and B is optionally substituted phenyl or thiazolyl, then R⁶ is not 5 optionally substituted imidazolyl, pyrazolyl, pyridyl, pyrimidyl, or NR⁸R⁹ in which R⁹ is optionally substituted imidazolyl or 6- to 10-membered heteroaryl; or

(6) when T is a C]-Cô alkylene linker and B is absent or optionally substituted Cô-Cio aryl or 4- to 12-membered heterocycloalkyl; or when T is a bond and B is optionally substituted C3-C10 cycloalkyl or 4- to 12-membered heterocycloalkyl, then R⁶ is not

10 NR⁸C(O)R¹³;

(7) when X¹ and X³ are N, X² is CR³, X⁴ is CR⁵, X⁵ is C, R⁵ is 4- to 12-membered heterocycloalkyl substituted with one or more Ci-Cô alkyl, and R⁶ and R³ together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted C1-C3 alkoxyl, then B is absent, Cô-Cio aryl, C3-C10 cycloalkyl, or 5- to

15 10-membered heteroaryl, or (8) when X² and X³ are N, X¹ is CR², X⁴ is CR⁵, X⁵ is C, R⁵ is C₃-C₈ cycloalkyl or 4to 12-membered heterocycloalkyl, each optionally substituted with one or more Ci-C₆ alkyl, and R⁶ and R² together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted C1-C3 alkoxyl, then B is absent, Cô-Cjo

20 aryl, C3-C10 cycloalkyl, or 5- to 10-membered heteroaryl.

4-((2,4-dichloro-5-methoxyphenyl)amino)-2-((3-(2-(pyrrolidin-lyl) ethoxy)phenyl) amino)pyrimidine- 5 - carbonitrile,

N-(naphthalen-2-yl)-2-(piperidin-l-ylmethoxy)pyrimidin-4-amine, N-(3,5-difluorobenzyl)-2-(3-(pyrrolidin-l-yl)propyl)pyrimidin-4-amine, N-(((4-(3-(piperidin-l-yl)propyl)pyrimidin-2-yl)amino)methyl)benzamide, N-(2-((2-(3-(dimethylamino)propyl)pyrimidin-4-yl)amino)ethyl)benzamide, 2-(hexahydro-4-methyl-1 H-1,4-diazepin-1 -yl)-6,7-dimethoxy-N-[ 1 -(phenylmethyl)-4piperidinyl] -4-quinazolinamine,

5 methyltransferase enzyme selected from EHMTl and EHMT2, by administering an aminesubstituted aryl or heteroaryl compound disclosed herein or a pharmaceutical composition thereof to subjects in need thereof. The présent disclosure also relates to the use of such compounds for research or other non-therapeutic purposes.