IP Library › Granted Patent US 9,834,571

Granted Patent B2

US 9,834,571 · App. 15/044,382 · Granted Dec 5, 2017

Compounds for inhibiting cell proliferation in EGFR-driven cancers

Inventors: Xiaotian Zhu (Newton, MA); Yihan Wang (Newton, MA); William C. Shakespeare (Southborough, MA); Wei-Sheng Huang (Acton, MA); David C. Dalgarno (Brookline, MA)

Assignee: ARIAD Pharmaceuticals, Inc.

C07F9/65127 A61K31/505 A61K31/506 A61K31/675 A61K45/06 C07D239/42 C07D239/48 C07D403/12 C07F9/28 C07F9/6561 C07F9/6584 C07F9/65217 C07F9/65583 C07F9/65586 C07F9/65846

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Quick Facts

Patent No.: US 9,834,571
App. No.: 15/044,382
Granted: Dec 5, 2017
Kind: B2

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Abstract

The invention features compounds, pharmaceutical compositions and methods for treating patients who have an EGFR-driven cancer of Formula I: wherein the variables are as defined herein.

Claims (438)

1. A compound of the Formula:

or a pharmaceutically acceptable salt thereof, wherein

R d is H, CI, F, Br, I, CN, CH 3 CF 3 —CH 2 CH═CH 2 , or cyclopropyl;

R g is —P(O)(R 3A )(R 3B ) or —S(O) 2 R 3E ;

each R 3A , R 3B , and R 3E is, independently, selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heteroalkyl;

R g2 is H, F, C 1-6 alkyl, or C 1-6 alkoxy;

R g1 is H, —P(O)(R 3A )(R 3B ) or —OR 2 ;

R b2 is H;

R b4 is W 1 ;

R a1 is of the Formula:

wherein:

J 1 and J 2 are independently H, halo or R J ; or J 1 and J 2 together with the atom to which each is attached form an optionally substituted ring which is C 3-8 cycloalkyl, 3- to 7-membered heterocyclic, or heteroaryl;

J 3 and J 4 are independently H or R J ; or J 3 and J 4 together with the atom to which each is attached form an optionally substituted ring which is 3- to 7-membered heterocyclic or heteroaryl ring;

R J C 1-6 alkyl, C 3-8 cycloalkyl, C 1-8 heteroalkyl, or 3- to 7-membered heterocyclyl, wherein each R J is independently selected from halo, haloalkyl, hydroxyl, hydroxyalkyl, amino, alkylamino, dialkylamino, cycloalkyl, alkoxy, cycloalkoxy and heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups on R J are optionally substituted with one or more halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, amino, alkylamino, dialkylamino or cycloalkyl groups; and,

z is 1- 3

R a2 is H, halo, —CH 3 , —CF 3 , —CH 2 CH 3 , —OCH 3 , —OCF 3 , —OCH 2 CH 3 , —OCH 2 CH 2 N(CH 3 ) 2 , or —O-heterocyclyl;

W 1 is —NHC(O)CH═CH 2 or is

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R a1 is selected from the following:

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R b4 is —NHC(O)CH═CH 2 or is selected from the following:

4. A method for treating an EGFR-driven cancer in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said EGFR-driven cancer is a non-small cell lung cancer (NSCLS); pancreatic cancer; head and neck cancer; or colorectal cancer.

5. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

6. A compound selected from the group consisting of:

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl)acrylamide (Example 1);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)acrylamide (Example 2);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpiperidin-4-yl)methoxy)phenyl)acrylamide (Example 3);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-morpholinoethoxy)phenyl)acrylamide (Example 4);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-morpholinopropoxy)phenyl)acrylamide (Example 5);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)acrylamide (Example 6);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpiperidin-2-yl)methoxy)phenyl)acrylamide (Example 7);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(piperidin-1-yl)ethoxy)phenyl)acrylamide (Example 8);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(oxetan-3-yloxy)phenyl)acrylamide (Example 9);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(pyridin-3-ylmethoxy)phenyl)acrylamide (Example 10);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(pyridin-4-ylmethoxy)phenyl)acrylamide (Example 11);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpiperidin-3-yl)oxy)phenyl)acrylamide (Example 12);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin-3-yl)oxy)phenyl)acrylamide (Example 13);

rel-(R)-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpiperidin-3-yl)oxy)phenyl)acrylamide (Example 14);

N-(2-((1-(azetidin-1-yl)-3-methoxypropan-2-yl)oxy)-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Example 15);

rel-(R)-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpiperidin-3-yl)oxy)phenyl)acrylamide (Example 16);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylazetidin-3-yl)oxy)phenyl)acrylamide (Example 17);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin-2-yl)methoxy)phenyl)acrylamide (Example 18);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((4-methyl-1,4-oxazepan-6-yl)oxy)phenyl)acrylamide (Example 19);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin-3-yl)methoxy)phenyl)acrylamide (Example 20);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)cyclohexyl)oxy)-4-methoxyphenyl)acrylamide (Example 21);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (Example 22);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(4-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide (Example 23);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (Example 24);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide (Example 25);

rac-(R)-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (Example 26);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)acrylamide (Example 27);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-morpholinopyrrolidin-1-yl)phenyl)acrylamide (Example 28);

rac-(R)-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (Example 29);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide (Example 30);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-(pyrrolidin-1-yl)azetidin-1-yl)phenyl)acrylamide (Example 31);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-hydroxypyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (Example 32);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)phenyl)acrylamide (Example 33);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(diethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (Example 34);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-hydroxy-[1,3′-bipyrrolidin]-1′-yl)-4-methoxyphenyl)acrylamide (Example 35);

N-(2-([1,3′-bipyrrolidin]-1′-yl)-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Example 36);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl)phenyl)acrylamide (Example 37);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-((2-(diethylamino)ethyl)(methypamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (Example 38);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(4-hydroxypiperidin-1-yl)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (Example 39);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(4-(2-hydroxyethyl)piperazin-1-yl)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (Example 40);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-((2-methoxyethyl)(methyl)amino)pyrrolidin-1-yl)phenyl)acrylamide (Example 41);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-(pyrrolidin-1-ylmethyl)acrylamide (Example 42);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-(piperidin-1-ylmethyl)acrylamide (Example 43);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((4-(methylsulfonyl)piperazin-1-yl)methyl)acrylamide (Example 44);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((4-(4-methylpiperazin-1-yl)piperidin-1-yl)methyl)acrylamide (Example 45);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((1,1-dioxidothiomorpholino)methyl)acrylamide (Example 46);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((3-oxopiperazin-1-yl)methyl)acrylamide (Example 47);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-(morpholinomethyl)acrylamide (Example 48);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((4-methylpiperazin-1-yl)methyl)acrylamide (Example 49);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((4-isopropylpiperazin-1-yl)methyl)acrylamide (Example 50);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((4-morpholinopiperidin-1-yl)methyl)acrylamide (Example 51);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)acrylamide (Example 52);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((3-hydroxypyrrolidin-1-yl)methyl)acrylamide (Example 53);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-fluorophenyl)acrylamide (Example 54);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy -2-((4-methylpiperazin-1-yl)methyl)phenyl)acrylamide (Example 55);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy -2-(4-methylpiperazine-1-carbonyl)phenyl)acrylamide (Example 56);

N-(2-(3-aminopyrrolidin-1-yl)-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Example 57);

N1-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N4-(2-(dimethylamino)ethyl)fumaramide (Example 58);

(E)-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-enamide (Example 59);

N1-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N4,N4-dimethylfumaramide (Example 60);

(Z)-4-((3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)amino)-4-oxobut-2-enoic acid (Example 61);

N1-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N4,N4-dimethylmaleamide (Example 62);

(Z)-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-enamide (Example 63);

N1-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N4-(2-(dimethylamino)ethyl)maleamide (Example 64);

N-(2-(3-amino-3-methylbut-1-yn-1-yl)-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Example 65);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-3-hydroxypropoxy)-4-methoxyphenyl)acrylamide (Example 66);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-((2-fluoroethyl)(methyl)amino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (Example 67);

N-(2-(3-(azetidin-1-yl)pyrrolidin-1-yl)-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Example 68);

N-(2-([1,4′-bipiperidin]-1′-yl)-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Example 69);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-morpholinopiperidin-1-yl)phenyl)acrylamide (Example 70);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)acrylamide (Example 71);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)acrylamide (Example 72);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)cyclopropyl)ethynyl)-4-methoxyphenyl)acrylamide (Example 73);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)acrylamide (Example 74);

(E)-ethyl 4-((3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)amino)-4-oxobut-2-enoate (Example 75);

(E)-tert-butyl (1-(3-((3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)amino)-3-oxoprop-1-en-1-yl)cyclopropyl)carbamate (Example 76);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-fluoroacrylamide (Example 77);

(E)-3-chloro-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Example 78);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)cyclohex-1-enecarboxamide (Example 79);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl)but-2-ynamide (Example 80);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(dimethylamino)but-2-ynamide (Example 81);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-(trifluoromethyl)acrylamide (Example 82);

N-(3-((5-chloro-2-((4-(dimethylphosphoryl)-2-methoxyphenyl)amino)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-ynamide (Example 83);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-1-methyl-1,2,5,6-tetrahydropyridine-3-carboxamide (Example 84);

(E)-3-chloro-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)acrylamide (Example 85);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4-(2-methoxyethoxy)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Example 86);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-ynamide (Example 87);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-5-(piperidin-1-yl)pent-2-ynamide (Example 88);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(pyrrolidin-1-yl)but-2-ynamide (Example 89);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-methyl-4-(pyrrolidin-1-yl)pent-2-ynamide (Example 90);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-methyl-4-(pyrrolidin-1-yl)pent-2-ynamide (Example 91);

(E)-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(piperidin-1-yl)but-2-enamide (Example 92);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-3-phenylpropiolamide (Example 93);

(E)-3-(1-aminocyclopropyl)-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Example 94);

(E)-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(pyrrolidin-1-yl)but-2-enamide (Example 95);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(diethylamino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide (Example 96);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-methoxybut-2-ynamide (Example 97);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)acrylamide (Example 98);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4-((tetrahydrofuran-3-yl)oxy)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Example 99);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Example 100);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-5-(piperidin-1-yl)pent-2-ynamide (Example 101);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)but-2-ynamide (Example 102);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(oxetan-3-yloxy)phenyl)but-2-ynamide (Example 103);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-4-(dimethylamino)but-2-ynamide (Example 104);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-4-methoxybut-2-ynamide (Example 105);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)but-2-ynamide (Example 106);

N-(4-((5-chloro-4-((2-(dimethylphosphoryl)-3-(2-(piperidin-1-yl)ethoxy)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)acrylamide (Example 107);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4-(2-(piperidin-1yl)ethoxy)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Example 108);

N1-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N4-methylfumaramide (Example 109);

N1-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N4-methylmaleamide (Example 110);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)-4-methoxybut-2-ynamide (Example 111);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)but-2-ynamide (Example 112);

rac-(R)-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)methacrylamide (Example 113);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-5-(dimethylamino)pent-2-ynamide (Example 114);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-5-methoxypent-2-ynamide (Example 115);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-methyl-3-(pyrrolidin-1-yl)but-1-yn-1-yl)phenyl)acrylamide (Example 116);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-(2-(dimethylamino)ethoxy)phenyl)acrylamide (Example 117);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-5-(4-methylpiperazin-1-yl)pent-2-ynamide (Example 118);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(pyrrolidin-1-yl)phenyl)-5-(4-methylpiperazin-1-yl)pent-2-ynamide (Example 119);

N-(5-((5-cyclopropyl-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(diethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (Example 120);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(diethylamino)-3-fluoropropan-2-yl)oxy)-4-methoxyphenyl)acrylamide (Example 121);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-5-(2-(methoxymethyl)pyrrolidin-1-yl)pent-2-ynamide (Example 122);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-(2-methoxyethyl)piperidin-3-yl)oxy)phenyl)acrylamide (Example 123);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide (Example 124);

N-(3-((5-chloro-4-((4-(2-(dimethylamino)ethoxy)-2(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Example 125);

N-(3-((5-chloro-4-((4-(3-(dimethylamino)propoxy)-2(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Example 126);

1-(6-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxylndolin-1-yl)prop-2-en-1-one (Example 127);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(4-(dimethylamino)but-1-yn-1-yl)-4-methoxyphenyl)acrylamide (Example 128);

(R)-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)-4-methoxyphenyl)acrylamide (Example 129);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)-4-methoxyphenyl)acrylamide (Example 130);

N-(3-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methoxypyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Example 131);

2-chloro-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4methoxyphenyl)acrylamide (Example 132);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-methylphenyl)acrylamide (Example 133);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-(trifluoromethoxy)phenyl)acrylamide (Example 134);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-ethylphenyl)acrylamide (Example 135);

N-(4-chloro-3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2yl)amino)phenyl)acrylamide (Example 136);

2-chloro-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acetamide (Example 137);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-(oxetan-3-yloxy)phenyl)acrylamide (Example 138);

N-(3-((5-cyano-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Example 139);

2-chloro-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-methylphenyl)acetamide (Example 140);

2-chloro-N-(3-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-4-methoxyphenyl)acetamide (Example 141);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)-3-ethoxypropan-2-yl)oxy)-4-methoxyphenyl)acrylamide (Example 142);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)-4-methylphenyl)acrylamide (Example 143);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)-4-methylphenyl)acrylamide (Example 144);

N-(4-chloro-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)phenyl)acrylamide (Example 145);

N-(4-chloro-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)phenyl)acrylamide (Example 146);

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-fluoroacetamide (Example 147);

2-chloro-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methylphenyl)acetamide (Example 148);

2-chloro-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)acetamide (Example 149);

1-chloro-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)methanesulfonamide (Example 150);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4-methylphenyl)acrylamide (Example 151);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4-ethylphenyl)acrylamide (Example 152);

N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide (Example 153);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(diethylamino)-3-methylbut-1-yn-1-yl)-4-methoxyphenyl)acrylamide (Example 154);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)-3-methylbut-1-yn-1-yl)-4-methoxyphenyl)acrylamide (Example 155);

N-(4-chloro-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)acrylamide (Example 156);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)phenyl)acrylamide (Example 157);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(diisopropylamino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide (Example 158);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-(4-methylpiperazin-1-yl)prop-1-yn-1-yl)phenyl)acrylamide (Example 159);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-(methylamino)prop-1-yn-1-yl)phenyl)acrylamide (Example 160);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-((2-methoxyethyl)(methyl)amino)prop-1-yn-1-yl)phenyl)acrylamide (Example 161);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(ethyl(methyl)amino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide (Example 162);

N-(3-((6-((3-(dimethylphosphoryl)pyridin-2-yl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide (Example 163);

N-(3-((5-chloro-4-((4-(dimethylphosphoryl)pyridin-3-yl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Example 164);

N-(2-(3-(azepan-1-yl)prop-1-yn-1-yl)-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Example 165);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(isopropyl(methyl)amino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide (Example 166);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-(piperidin-1-yl)prop-1-yn-1-yl)phenyl)acrylamide (Example 167);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(cyclopentyl(methyl)amino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide (Example 168);

N-(3-((4-((2-(dimethylphosphoryl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-4-methoxyphenyl)acrylamide (Example 169);

N-(3-((4-((2-(dimethylphosphoryl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-4-(trifluoromethoxy)phenyl)acrylamide (Example 170);

N-(3-((6-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide (Example 171);

(1S,2R,3S,4R)-3-((2-((5-acrylamido-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)bicyclo[2.2.1]heptane-2-carboxamide (Example 172);

2-((2-((5-acrylamido-4-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)benzamide (Example 173);

N-(5-((5-chloro-4-((2-cyanophenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (Example 174);

N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (Example 175);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)methyl)-4-methoxy-2-(3-(4-methylpiperidin-1-yl)prop-1-yn-1-yl)phenyl)acrylamide (Example 176);

N-(2-(3-(tert-butyl(methyl)amino)prop-1-yn-1-yl)-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)methyl)-4-methoxyphenyl)acrylamide (Example 177);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)methyl)-2-(3-(2-(dimethylamino)pyrrolidin-1-yl)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide (Example 178);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)methyl)-4-methoxy-2-(3-(2-methylpiperidin-1-yl)prop-1-yn-1-yl)phenyl)acrylamide (Example 179);

(Z)-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)methyl)-2-(3-(dimethylamino)prop-1-en-1-yl)-4-methoxyphenyl)acrylamide (Example 180);

(E)-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)methyl)-2-(3-(dimethylamino)prop-1-en-1-yl)-4-methoxyphenyl)acrylamide (Example 181);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)methyl)-2-(3-(4-fluoropiperidin-1-yl)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide (Example 182);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)methyl)-4-methoxy-2-(3-(methyl(tetrahydro-2H-pyran-4-yl)amino)prop-1-yn-1-yl)phenyl)acrylamide (Example 183);

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)methyl)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4-methoxyphenyl)but-2-ynamide (Example 184); and

N-(3-((5-chloro-2-(2-methoxy-4-(1-methyl-4-oxido-1,4-azaphosphinan-4-yl)benzyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (Example 185);

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 , selected from the group consisting of: