Substituted pyrrolo[1,2-b]pyridazines and pyrrolo[2,1-f][1,2,4]triazines as Btk inhibitors

1 . A compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

Ring A is a monocyclic 3- to 7-membered heterocyclyl or bicyclic 7- to 10-membered heterocyclyl, wherein Ring A is optionally substituted with one or more independently selected R 100 substituents;

each R 100 is independently halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(O)R 100a , C(O)NR 100a R 100a , C(O)OR 100a , NR 100a R 100a , NR 100a C(O)R 100a , NR 100a C(O)NR 100a R 100a , NR 100a C(O)OR 100a , NR 100a S(O) 2 R 100a , OR 100a , OC(O)R 100a , OC(O)NR 100a R 100a , SR 100a , S(O)R 100a , S(O)NR 100a R 100a , S(O) 2 R 100a , S(O) 2 NR 100a R 100a , monocyclic 3- to 7-membered carbocyclyl, or monocyclic 4- to 6-membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl, and 4- to 6-membered heterocyclyl is optionally and independently substituted with one or more independently selected R 150 substituents; or

any two R 100 , taken together with their intervening atom(s), independently form a monocyclic 3- to 7-membered carbocyclyl or monocyclic 4- to 6-membered heterocyclyl, wherein each 3- to 7-membered carbocyclyl and 4- to 6-membered heterocyclyl is optionally and independently substituted with one or more independently selected R 150 substituents;

each R 100a is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, monocyclic 3- to 7-membered carbocyclyl, or monocyclic 4- to 6-membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl, and 4- to 6-membered heterocyclyl is optionally and independently substituted with one or more independently selected R 150 substituents;

each R 150 is independently halogen, C 1-6 alkyl, or OR 150a ;

each R 150a is independently H or C 1-6 alkyl;

R 3 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(O)R 3a , C(O)NR 3a R 3a , or C(O)OR 3a , wherein the C 1-6 alkyl, C 2-6 alkenyl, or C 2 -6 alkynyl is optionally substituted with one or more independently selected R 30 substituents;

each R 3a is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2 -6 alkynyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally and independently substituted with one or more independently selected R 30 substituents;

each R 30 is independently halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR 30a , monocyclic 3- to 7-membered carbocyclyl, or monocyclic 4- to 6-membered heterocyclyl;

each R 30a is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, monocyclic 3- to 6-membered carbocyclyl, or monocyclic 4- to 6-membered heterocyclyl;

R 4 is H, halogen, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(O)R 4a , C(O)NR 4a R 4a , C(O)OR 4a , NR 4a R 4a , NR 4a C(O)R 4a , NR 4a C(O)OR 4a , NR 4a S(O) 2 R 4a , OR 4a , OC(O)R 4a , OC(O)NR 4a R 4a , SR 4a , S(O)R 4a , S(O) 2 R 4a , S(O) 2 NR 4a R 4a , monocyclic 3- to 7-membered carbocyclyl, or monocyclic 4- to 6-membered heterocyclyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl, or 4- to 6-membered heterocyclyl is optionally substituted with one or more independently selected R 40 substituents;

each R 4a is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, monocyclic 3- to 7-membered carbocyclyl, or monocyclic 4- to 6-membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl, and 4- to 6-membered heterocyclyl is optionally and independently substituted with one or more independently selected R 40 substituents;

each R 40 is independently halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR 40a , monocyclic 3- to 7-membered carbocyclyl, or monocyclic 4- to 6-membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl, and 4- to 6-membered heterocyclyl is optionally and independently substituted with one or more independently selected R 45 substituents;

each R 40a is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, monocyclic 3- to 7-membered carbocyclyl, or monocyclic 4- to 6-membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl, and 4- to 6-membered heterocyclyl is optionally and independently substituted with one or more independently selected R 45 substituents;

each R 45 is independently halogen, C 1-6 alkyl, or OR 45a ;

each R 45a is independently H or C 1-6 alkyl; or

R 3 and R 4 , taken together with their intervening atoms, form Ring B;

Ring B is a monocyclic 5- to 7-membered carbocyclyl or monocyclic 5- to 7-membered heterocyclyl;

wherein the 5- to 7-membered heterocyclyl contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S; and

wherein Ring B is optionally substituted with one or more independently selected R 300 substituents;

each R 300 is independently halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(O)R 300a , OR 300a , S(O) 2 R 300a , monocyclic 3- to 7-membered carbocyclyl, or monocyclic 4- to 6-membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl, and 4- to 6-membered heterocyclyl is optionally and independently substituted with one or more independently selected R 350 substituents;

each R 300a is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, monocyclic 3- to 7-membered carbocyclyl, or monocyclic 4- to 6-membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl, and 4- to 6-membered heterocyclyl is optionally and independently substituted with one or more independently selected R 350 substituents;

each R 350 is independently halogen, CN, C 1-6 alkyl, CR 350a R 350a NR 350a R 350a , C(O)R 350a , C(O)NR 350a R 350a , or OR 350a ;

each R 350a is independently H or C 1-6 alkyl, wherein each C 1-6 alkyl is optionally and independently substituted with one, two, or three independently selected halogen substituents;

R 5 is H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or OR 5a , wherein the C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with one or more independently selected halogen substituents;

R 5a is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, monocyclic 3- to 7-membered carbocyclyl, or monocyclic 4- to 6-membered heterocyclyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl, or 4- to 6-membered heterocyclyl is optionally substituted with one or more independently selected halogen substituents;

R 6 is H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or OR 6a , wherein the C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with one or more independently selected halogen substituents;

R 6a is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, monocyclic 3- to 7-membered carbocyclyl, or monocyclic 4- to 6-membered heterocyclyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl, or 4- to 6-membered heterocyclyl is optionally substituted with one or more independently selected halogen substituents;

R 7 is H, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(O)R 7a , C(O)NR 7a R 7a , C(O)OR 7a , or OR 7a , wherein the C 1-6 alkyl, C 2-6 alkenyl, or C 2 -6 alkynyl is optionally substituted with one or more independently selected R 70 substituents;

each R 7a is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, monocyclic 3- to 7-membered carbocyclyl, or monocyclic 4- to 6-membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl, and 4- to 6-membered heterocyclyl is optionally and independently substituted with one or more independently selected R 70 substituents;

each R 70 is independently halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR 70a , monocyclic 3- to 7-membered carbocyclyl, or monocyclic 4- to 6-membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl, and 4- to 6-membered heterocyclyl is optionally and independently substituted with one or more independently selected R 75 substituents;

each R 70a is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, monocyclic 3- to 7-membered carbocyclyl, or monocyclic 4- to 6-membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl, and 4- to 6-membered heterocyclyl is optionally and independently substituted with one or more independently selected R 75 substituents;

each R 75 is independently halogen, C 1-6 alkyl, or OR 75a ;

each R 75a is independently H or C 1-6 alkyl;

each R 8 is independently H, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(O)R 8a , C(O)NR 8a R 8a , C(O)OR 8a , NR 8a R 8a , NR 8a C(O)R 8a , NR 8a C(O)NR 8a R 8a , NR 8a C(O)OR 8a , NR 8a S(O) 2 R 8a , OR 8a , OC(O)R 8a ; OC(O)NR 8a R 8a , SR 8a , S(O)R 8a , S(O)NR 8a R 8a , S(O) 2 R 8a , S(O) 2 NR 8a R 8a , monocyclic 3- to 7-membered carbocyclyl, monocyclic 4- to 6-membered heterocyclyl, or bicyclic 7- to 10-membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl, 4- to 6-membered heterocyclyl and 7- to 10-membered heterocyclyl is optionally and independently substituted with one or more independently selected R 80 substituents;

each R 8a is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, monocyclic 3- to 7-membered carbocyclyl, or monocyclic 4- to 6-membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl, and 4- to 6-membered heterocyclyl is optionally and independently substituted with one or more independently selected R 80 substituents; or

any two R 8a , taken together with their intervening atom(s), independently form a monocyclic 4- to 6-membered heterocyclyl, wherein each 4- to 6-membered heterocyclyl is optionally and independently substituted with one or more independently selected R 80 substituents;

each R 80 is independently halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(O)R 80a , C(O)NR 80a R 80a , C(O)OR 80a , NR 80a R 80a , NR 80a C(O)R 80a , NR 80a C(O)NR 80a R 80a , NR 80a C(O)OR 80a , NR 80a S(O) 2 R 80a , OR 80a , OC(O)R 80a , OC(O)NR 80a R 80a , SR 80a , S(O)R 80a , S(O)NR 80a R 80a , S(O) 2 R 80a , S(O) 2 NR 80a R 80a , monocyclic 3- to 7-membered carbocyclyl, or monocyclic 4- to 6-membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered carbocyclyl, and 4- to 6-membered heterocyclyl is optionally and independently substituted with one or more independently selected R 85 substituents; or

any two geminal R 80 , together with the carbon atom to which they are attached, form —C(O)—;

each R 80a is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, monocyclic 3- to 6-membered carbocyclyl, or monocyclic 4- to 6-membered heterocyclyl;

wherein each 4- to 6-membered heterocyclyl independently contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S; and

wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 6-membered carbocyclyl, and 4- to 6-membered heterocyclyl is optionally and independently substituted with one or more independently selected R 85 substituents;

each R 85 is independently halogen, C 1-6 alkyl, or OR 85a ; and

each R 85a is independently H or C 1-6 alkyl.

2 . The compound of claim 1 , wherein the compound is represented by Formula (II):

or a pharmaceutically acceptable salt thereof,

wherein:

A 1 is CR 7 or N; and

R 7 is H.

3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:

Ring A is a monocyclic 5- or 6-membered heterocyclyl or bicyclic 8- to 10-membered heterocyclyl, wherein Ring A is optionally substituted with one, two, or three independently selected R 100 substituents;

each R 100 is independently halogen, CN, C 1-6 alkyl, C(O)R 100a , C(O)NR 100a R 100a , C(O)OR 100a , NR 100a R 100a , NR 100a C(O)R 100a , NR 100a C(O)NR 100a R 100a , NR 100a , C(O)OR 100a , NR 100a S(O) 2 R 100a OR 100a , OC(O)R 100a , OC(O)NR 100a R 100a , SR 100a , S(O)R 100a , S(O)NR 100a R 100a , S(O) 2 R 100a , S(O) 2 NR 100a R 100a , monocyclic C 3-6 cycloalkyl, or monocyclic 4- to 6-membered heterocyclyl, wherein each C 1-6 alkyl, C 3-6 cycloalkyl, and 4- to 6-membered heterocyclyl is optionally and independently substituted with one, two, or three independently selected R 150 substituents; or

any two R 100 , taken together with their intervening atom(s), independently form a monocyclic 3- to 7-membered carbocyclyl or monocyclic 4- to 6-membered heterocyclyl, wherein each 3- to 7-membered carbocyclyl and 4- to 6-membered heterocyclyl is optionally and independently substituted with one or more independently selected R 150 substituents;

each R 100a is independently H, C 1-6 alkyl, monocyclic C 3-6 cycloalkyl, or monocyclic 4- to 6-membered heterocyclyl;

each R 150 is independently halogen, C 1-6 alkyl, or OR 150a , and

each R 150a is independently H or C 1-6 alkyl.

4 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein Ring A is:

wherein Ring A, when unsubstituted, is optionally substituted with one, two, or three independently selected R 100 substituents; or

wherein Ring A, when monosubstituted, is optionally further substituted with one or two additional independently selected R 100 substituents.

5 . The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein Ring A is:

wherein Ring A, when monosubstituted, is optionally further substituted with one or two additional independently selected R 100 substituents; or

wherein Ring A, when disubstituted, is optionally further substituted with one additional R 100 substituent.

6 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein:

each R 100 is independently halogen, CN, C 1-6 alkyl, OR 100a , or monocyclic C 3-6 cycloalkyl, wherein each C 1-6 alkyl and C 3-6 cycloalkyl is optionally and independently substituted with one, two, or three independently selected R 150 substituents;

each R 100a is independently H, C 1-6 alkyl, monocyclic C 3-6 cycloalkyl, or monocyclic 4- to 6-membered heterocyclyl; and

each R 150 is independently halogen or C 1-6 alkyl.

7 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:

R 4 is halogen, CN, C 1-6 alkyl, OR 4a , or monocyclic C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is optionally substituted with one, two, or three independently selected R 40 substituents;

R 4a is C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with one, two, or three independently selected R 40 substituents; and

each R 40 is independently halogen.

8 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 4 is CH 3 , CHF 2 , CF 3 , CH 2 CHF 2 , or cyclopropyl.

9 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H or halogen.

10 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H or halogen.

11 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:

R 8 is H, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(O)R 8a , C(O)NR 8a R 8a , NR 8a R 8a , OR 8a , monocyclic C 3-6 cycloalkyl, monocyclic 4- to 6-membered heterocyclyl, bicyclic 7- to 10-membered heterocyclyl, or phenyl;

wherein the 4- to 6-membered heterocyclyl contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S;

wherein the 7- to 10-membered heterocyclyl contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, 7- to 10-membered heterocyclyl, or phenyl is optionally substituted with one, two, or three independently selected R 80 substituents;

each R 8a is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, monocyclic C 3-6 cycloalkyl, or monocyclic 4- to 6-membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and 4- to 6-membered heterocyclyl is optionally and independently substituted with one, two, or three independently selected R 80 substituents; or

any two R 8a , taken together with their intervening atom(s), independently form a monocyclic 4- to 6-membered heterocyclyl, wherein each 4- to 6-membered heterocyclyl is optionally and independently substituted with one, two, or three independently selected R 80 substituents;

each R 80 is independently halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(O)R 80a , OR 80a , monocyclic C 3-6 cycloalkyl, or monocyclic 4- to 6-membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and 4- to 6-membered heterocyclyl is optionally and independently substituted with one, two, or three independently selected R 85 substituents; or

any two geminal R 80 , together with the carbon atom to which they are attached, form —C(O)—;

each R 80a is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, monocyclic C 3-6 cycloalkyl, or monocyclic 4- to 6-membered heterocyclyl, wherein each 4- to 6-membered heterocyclyl independently contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S;

each R 85 is independently halogen or OR 85a , and

each R 85a is independently H or C 1-6 alkyl.

12 . The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 8 is H, F, Br, CN, CH 2 -tetrahydropyran-4-yl, C(O)N(CH 3 ) 2 , C(O)-azetidin-1-yl, C(O)-piperazin-1-yl, C(O)-morpholin-4-yl, N(CH 3 )CH 2 CH 2 OCH 3 , OCH 2 CH 2 OCH 3 , OCH(CH 3 )OCH 3 , cyclopropyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, 3,6-dihydro-2H-pyranyl, 3,6-dihydro-2H-thiopyranyl, piperazinyl, morpholinyl, 3,6-diazabicyclo[3.1.1]heptanyl, octahydropyrrolo[1,2-a]pyrazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, phenyl, pyrazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazinyl, pyridinyl, pyrazinyl, or pyrimidinyl.

13 . The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein:

each R 80 is independently halogen, CN, C 1-3 alkyl, C(O)R 80a , OR 80a , monocyclic C 3-6 cycloalkyl, or monocyclic 4- to 6-membered heterocyclyl;

wherein each 4- to 6-membered heterocyclyl independently contains 1 or 2 heteroatoms independently selected from the group consisting of N and O; and

wherein each C 1-6 alkyl, C 3-6 cycloalkyl, and 4- to 6-membered heterocyclyl is optionally and independently substituted with one, two, or three independently selected R 85 substituents; or

any two geminal R 80 , together with the carbon atom to which they are attached, form —C(O)—;

each R 80a is independently C 1-4 alkyl or C 2-4 alkenyl;

each R 85 is independently F or OR 85a , and

each R 85a is independently H or C 1-3 alkyl.

14 . The compound of claim 1 , wherein the compound is represented by Formula (IIA) or Formula (IIB):

or a pharmaceutically acceptable salt thereof,

wherein:

Ring A is a monocyclic 5- or 6-membered heterocyclyl or bicyclic 9- or 10-membered heterocyclyl, wherein Ring A is optionally substituted with one or two independently selected R 100 substituents;

each R 100 is independently C 1-6 alkyl or monocyclic C 4-6 cycloalkyl, wherein each C 1-6 alkyl and C 4-6 cycloalkyl is optionally and independently substituted with one, two, or three independently selected R 150 substituents;

each R 150 is independently halogen;

R 4 is C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with one, two, or three independently selected R 40 substituents;

each R 40 is independently halogen;

R 8 is H, halogen, C 1-6 alkyl, C(O)NR 8a R 8a , OR 8a , or monocyclic 5- or 6-membered heteroaryl;

wherein the 5- or 6-membered heteroaryl contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the C 1-6 alkyl or 5- or 6-membered heteroaryl is optionally substituted with one, two, or three independently selected R 80 substituents;

each R 8a is independently C 1-6 alkyl, wherein each C 1-6 alkyl is optionally and independently substituted with one, two, or three independently selected R 80 substituents;

each R 80 is independently halogen, C 1-4 alkyl, or OR 80a ; and

each R 80a is independently H or C 1-3 alkyl.

15 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein:

Ring A is:

each R 100 is independently C 1-6 alkyl or monocyclic C 4-6 cycloalkyl, wherein each C 1-6 alkyl and C 4-6 cycloalkyl is optionally and independently substituted with one, two, or three independently selected R 150 substituents; and

each R 150 is independently halogen.

16 . The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein:

R 8 is H, C(O)NR 8a R 8a , OR 8a , or monocyclic 5-membered heteroaryl;

wherein the 5-membered heteroaryl contains 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S; and

wherein the 5-membered heteroaryl is optionally substituted with one, two, or three independently selected R 80 substituents;

each R 8a is independently C 1-6 alkyl, wherein each C 1-6 alkyl is optionally and independently substituted with one, two, or three independently selected R 80 substituents;

each R 80 is independently halogen, C 1-4 alkyl, or OR 80a ; and

each R 80a is independently H or C 1-3 alkyl.

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

18 . A method for inhibiting Bruton's tyrosine kinase (BTK) activity in a subject, wherein the method comprises administering to the subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

19 . The method of claim 18 , wherein the subject has a disorder responsive to the inhibition of Bruton's tyrosine kinase (BTK) activity selected from the group consisting of atopic dermatitis, an autoimmune disorder, leukemia, lymphoma, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.