HETEROARYL COMPOUNDS, PHARMACEUTICAL COMPOSITIONS THEREOF, AND THEIR THERAPEUTIC USEProvided herein are heteroaryl compounds, for example, a compound of Formula I or IA, and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, ameliorating,or preventing one or more symptoms of a disorder, disease, or condition mediated by a casein kinase 1 (CK1), an interleukin-1 receptor associated kinase (IRAK1), or a cyclin-dependent kinase 9 (CDK9).A compound of the formula i or ia,or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:u and v are each independently-o-and ═ c (r)4) -; or u and v are each independently ═ n-and-n (r)5)-；w, x, y and z are each independently ═ c (r)6) -or ═ n-, with the proviso that at least one of w, x, y and z is ═ n-; or w, x and z are each independently ═ c (r)6)-、-n(r7) -, - (n-, -o-or-s-); and y is a bond;r1and r2each independently is (a) hydrogen or deuterium; (b) c1-6alkyl radical, c2-6alkenyl radical, c2-6alkynyl, c3-12cycloalkyl radical, c6-14aryl radical, c7-15aralkyl, heteroaryl or heterocyclyl; or (c) -c (o) r1a、-c(o)or1a、-c(o)nr1br1c、-c(o)sr1a、-c(nr1a)nr1br1c、-c(s)r1a、-c(s)or1a、-c(s)nr1br1c、-or1a、-oc(o)r1a、-oc(o)or1a、-oc(o)nr1br1c、-oc(o)sr1a、-oc(＝nr1a)nr1br1c、-oc(s)r1a、-oc(s)or1a、-oc(s)nr1br1c、-os(o)r1a、-os(o)2r1a、-os(o)nr1br1c、-os(o)2nr1br1c、-nr1br1c、-nr1ac(o)r1d、-nr1ac(o)or1d、-nr1ac(o)nr1br1c、-nr1ac(o)sr1d、-nr1ac(＝nr1d)nr1br1c、-nr1ac(s)r1d、-nr1ac(s)or1d、-nr1ac(s)nr1br1c、-nr1as(o)r1d、-nr1as(o)2r1d、-nr1as(o)nr1br1c、-nr1as(o)2nr1br1c、-s(o)r1a、-s(o)2r1a、-s(o)nr1br1cor-s (o)2nr1br1c(ii) a or r1and r2together with the n atom to which they are attached form a heteroaryl or heterocyclyl group;each r3、r4and r6independently (a) hydrogen, deuterium, cyano, halo or nitro; (b) c1-6alkyl radical, c2-6alkenyl radical, c2-6alkynyl, c3-12cycloalkyl radical, c6-14aryl radical, c7-15aralkyl, heteroaryl or heterocyclyl; or (c) -c (o) r1a、-c(o)or1a、-c(o)nr1br1c、-c(o)sr1a、-c(nr1a)nr1br1c、-c(s)r1a、-c(s)or1a、-c(s)nr1br1c、-or1a、-oc(o)r1a、-oc(o)or1a、-oc(o)nr1br1c、-oc(o)sr1a、-oc(＝nr1a)nr1br1c、-oc(s)r1a、-oc(s)or1a、-oc(s)nr1br1c、-os(o)r1a、-os(o)2r1a、-os(o)nr1br1c、-os(o)2nr1br1c、-nr1br1c、-nr1ac(o)r1d、-nr1ac(o)or1d、-nr1ac(o)nr1br1c、-nr1ac(o)sr1d、-nr1ac(＝nr1d)nr1br1c、-nr1ac(s)r1d、-nr1ac(s)or1d、-nr1ac(s)nr1br1c、-nr1as(o)r1d、-nr1as(o)2r1d、-nr1as(o)nr1br1c、-nr1as(o)2nr1br1c、-sr1a、-s(o)r1a、-s(o)2r1a、-s(o)nr1br1cor-s (o)2nr1br1c；r5and r7each independently is (a) hydrogen or deuterium; (b) c1-6alkyl radical, c2-6alkenyl radical, c2-6alkynyl, c3-12cycloalkyl radical, c6-14aryl radical, c7-15aralkyl, heteroaryl or heterocyclyl; or (c) -c (o) r1a、-c(o)or1a、-c(o)nr1br1c、-c(o)sr1a、-c(nr1a)nr1br1c、-c(s)r1a、-c(s)or1a、-c(s)nr1br1c、-or1a、-oc(o)r1a、-oc(o)or1a、-oc(o)nr1br1c、-oc(o)sr1a、-oc(＝nr1a)nr1br1c、-oc(s)r1a、-oc(s)or1a、-oc(s)nr1br1c、-os(o)r1a、-os(o)2r1a、-os(o)nr1br1c、-os(o)2nr1br1c、-nr1br1c、-nr1ac(o)r1d、-nr1ac(o)or1d、-nr1ac(o)nr1br1c、-nr1ac(o)sr1d、-nr1ac(＝nr1d)nr1br1c、-nr1ac(s)r1d、-nr1ac(s)or1d、-nr1ac(s)nr1br1c、-nr1as(o)r1d、-nr1as(o)2r1d、-nr1as(o)nr1br1c、-nr1as(o)2nr1br1c、-s(o)r1a、-s(o)2r1a、-s(o)nr1br1cor-s (o)2nr1br1c(ii) a and isr2a、r2b、r2cand r2dis (i) or (ii):(i)r2aand r2beach independently is (a) hydrogen or deuterium; (b) c1-6alkyl radical, c2-6alkenyl radical, c2-6alkynyl, c3-12cycloalkyl radical, c6-14aryl radical, c7-15aralkyl, heteroaryl or heterocyclyl; or (c) -c (o) r 1a、-c(o)or1a、-c(o)nr1br1c、-c(o)sr1a、-c(nr1a)nr1br1c、-c(s)r1a、-c(s)or1a、-c(s)nr1br1c、-or1a、-oc(o)r1a、-oc(o)or1a、-oc(o)nr1br1c、-oc(o)sr1a、-oc(＝nr1a)nr1br1c、-oc(s)r1a、-oc(s)or1a、-oc(s)nr1br1c、-os(o)r1a、-os(o)2r1a、-os(o)nr1br1c、-os(o)2nr1br1c、-nr1br1c、-nr1ac(o)r1d、-nr1ac(o)or1d、-nr1ac(o)nr1br1c、-nr1ac(o)sr1d、-nr1ac(＝nr1d)nr1br1c、-nr1ac(s)r1d、-nr1ac(s)or1d、-nr1ac(s)nr1br1c、-nr1as(o)r1d、-nr1as(o)2r1d、-nr1as(o)nr1br1c、-nr1as(o)2nr1br1c、-s(o)r1a、-s(o)2r1a、-s(o)nr1br1cor-s (o)2nr1br1c(ii) a or r2aand r2btogether with the n atom to which they are attached form a heteroaryl or heterocyclyl group; and isr2cand r2deach independently is (a) hydrogen, deuterium, or cyano; or (b) c1-6alkyl radical, c2-6alkenyl radical, c2-6alkynyl, c3-12cycloalkyl radical, c6-14aryl radical, c7-15aralkyl, heteroaryl or heterocyclyl; or r2cand r2djoined together to form-o-, c1-6alkylene radical, c1-6heteroalkylidene radical, c2-6alkenylene or c2-6an alkynylene group; or(ii)r2aand r2ctogether with the c and n atoms to which they are attached form a heterocyclyl;r2bis (a) hydrogen or deuterium; (b) c1-6alkyl radical, c2-6alkenyl radical, c2-6alkynyl, c3-12cycloalkyl radical, c6-14aryl radical, c7-15aralkyl, heteroaryl or heterocyclyl; or (c) -c (o) r1a、-c(o)or1a、-c(o)nr1br1c、-c(o)sr1a、-c(nr1a)nr1br1c、-c(s)r1a、-c(s)or1a、-c(s)nr1br1c、-or1a、-oc(o)r1a、-oc(o)or1a、-oc(o)nr1br1c、-oc(o)sr1a、-oc(＝nr1a)nr1br1c、-oc(s)r1a、-oc(s)or1a、-oc(s)nr1br1c、-os(o)r1a、-os(o)2r1a、-os(o)nr1br1c、-os(o)2nr1br1c、-nr1br1c、-nr1ac(o)r1d、-nr1ac(o)or1d、-nr1ac(o)nr1br1c、-nr1ac(o)sr1d、-nr1ac(＝nr1d)nr1br1c、-nr1ac(s)r1d、-nr1ac(s)or1d、-nr1ac(s)nr1br1c、-nr1as(o)r1d、-nr1as(o)2r1d、-nr1as(o)nr1br1c、-nr1as(o)2nr1br1c、-s(o)r1a、-s(o)2r1a、-s(o)nr1br1cor-s (o)2nr1br1c；r2dis (a) hydrogen, deuterium or cyano; or (b) c1-6alkyl radical, c2-6alkenyl radical, c2-6alkynyl, c3-12cycloalkyl radical, c6-14aryl radical, c7-15aralkyl, heteroaryl or heterocyclyl; and iseach r1...
헤테로아릴 화합물, 이의 약학 조성물 및 이의 치료적 용도 헤테로아릴 화합물, 예를 들어, 식 I 또는 IA의 화합물, 및 이의 약제학적 조성물이 여기서 제공된다. 또한 카제인 키나제1(CK1), 인터루킨-1 수용체 관련 키나제(IRAK1), 또는 사이클린-의존성 키나제 9(CDK9)에 의해 매개된 장애, 질환, 또는 병태의 하나 이상의 증상의 치료, 완화, 또는 예방을 위한 그의 사용 방법이 여기서 제공된다. 식: (I), (IA)[이미지][이미지]하기 식 I 또는 IA의 화합물, 또는 이의 거울상 이성질체, 거울상 이성질체의 혼합물, 두 개 이상의 부분입체이성질체의 혼합물, 호변체, 두 개 이상의 호변체의 혼합물 또는 동위원소 변형체; 또는 이의 약제학적으로 허용가능한 염, 용매화물, 수화물 또는 프로드럭:[이미지][이미지]식 중,U 및 V는 각각 독립적으로 -O- 및 =C(R4)-이거나; 또는 U 및 V는 각각 독립적으로 =N- 및 -N(R5)-이고;W, X, Y, 및 Z는 각각 독립적으로 =C(R6)- 또는 =N-이되, 단 W, X, Y, 및 Z 중 적어도 하나는 =N-이거나; 또는 W, X, 및 Z는 각각 독립적으로 =C(R6)-, -N(R7)-, =N-, -O-, 또는 -S-이고; 그리고 Y는 결합이고;R1 및 R2는 각각 독립적으로 (a) 수소 또는 중수소; (b) C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C3-12 사이클로알킬, C6-14 아릴, C7-15 아르알킬, 헤테로아릴, 또는 헤테로사이클릴; 또는 (c) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(=NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1aC(O)R1d, -NR1aC(O)OR1d, -NR1aC(O)NR1bR1c, -NR1aC(O)SR1d, -NR1aC(=NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1aC(S)OR1d, -NR1aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1aS(O)2R1d, -NR1aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, 또는 -S(O)2NR1bR1c이거나; 또는 R1과 R2는 이들이 부착되는 N 원자와 함께 헤테로아릴 또는 헤테로사이클릴을 형성하고; 각각의 R3, R4, 및 R6은 독립적으로 (a) 수소, 중수소, 시아노, 할로, 또는 니트로; (b) C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C3-12 사이클로알킬, C6-14 아릴, C7-15 아르알킬, 헤테로아릴, 또는 헤테로사이클릴; 또는 (c) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(=NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1aC(O)R1d, -NR1aC(O)OR1d, -NR1aC(O)NR1bR1c, -NR1aC(O)SR1d, -NR1aC(=NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1aC(S)OR1d, -NR1aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1aS(O)2R1d, -NR1aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, 또는 -S(O)2NR1bR1c이고; R5 및 R7은 각각 독립적으로 (a) 수소 또는 중수소; (b) C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C3-12 사이클로알킬, C6-14 아릴, C7-15 아르알킬, 헤테로아릴, 또는 헤테로사이클릴; 또는 (c) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(=NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1aC(O)R1d, -NR1aC(O)OR1d, -NR1aC(O)NR1bR1c, -NR1aC(O)SR1d, -NR1aC(=NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1aC(S)OR1d, -NR1aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1aS(O)2R1d, -NR1aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, 또는 -S(O)2NR1bR1c이고; 그리고 R2a, R2b, R2c, 및 R2d는 하기 (i) 또는 (ii)이고:(i) R2a 및 R2b는 각각 독립적으로 (a) 수소 또는 중수소; (b) C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C3-12 사이클로알킬, C6-14 아릴, C7-15 아르알킬, 헤테로아릴, 또는 헤테로사이클릴; 또는 (c) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(=NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1aC(O)R1d, -NR1aC(O)OR1d, -NR1aC(O)NR1bR1c, -NR1aC(O)SR1d, -NR1aC(=NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1aC(S)OR1d, -NR1aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1aS(O)2R1d, -NR1aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, 또는 -S(O)2NR1bR1c이거나; 또는 R2a와 R2b는 이들이 부착되는 N 원자와 함께 헤테로아릴 또는 헤테로사이클릴을 형성하고; 그리고 R2c 및 R2d는 각각 독립적으로 (a) 수소, 중수소, 또는 시아노; 또는 (b) C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C3-12 사이클로알킬, C6-14 아릴, C7-15 아르알킬, 헤테로아릴, 또는 헤테로사이클릴이거나; 또는 R2c 및 R2d는 함께 연결되어 -O-, C1-6 알킬렌, C1-6 헤테로알킬렌, C2-6 알케닐렌, 또는 C2-6 알키닐렌을 형성하거나; 또는(ii) R2a와 R2c는 이들이 부착되는 C 및 N 원자와 함께 헤테로사이클릴을 형성하고; R2b는 (a) 수소 또는 중수소; (b) C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C3-12 사이클로알킬, C6-14 아릴, C7-15 아르알킬, 헤테로아릴, 또는 헤테로사이클릴; 또는 (c) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(=NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1aC(O)R1d, -NR1aC(O)OR1d, -NR1aC(O)NR1bR1c, -NR1aC(O)SR1d, -NR1aC(=NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1aC(S)OR1d, -NR1aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1aS(O)2R1d, -NR1aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, 또는 -S(O)2NR1bR1c이고; R2d는 (a) 수소, 중수소, 또는 시아노; 또는 (b) C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C3-12 사이클로알킬, C6-14 아릴, C7-15 아르알킬, 헤테로아릴, 또는 헤테로사이클릴이고; 그리고각각의 R1a, R1b, R1c, 및 R1d는 독립적으로 수소, 중수소, C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C3-12 사이클로알킬, C6-14 아릴, C7-15 아르알킬, 헤테로아릴, 또는 헤테로사이클릴이거나; 또는 R1a와 R1c는 이들이 부착되는 C 및 N 원자와 함께 헤테로사이클릴을 형성하거나; 또는 R1b와 R1c는 이들이 부착되는 N 원자와 함께 헤테로사이클릴을 형성하고;여기서 각각의 알킬, 알킬렌, 헤테로알킬렌, 알케닐, 알케닐렌, 알키닐, 알키닐렌, 사이클로알킬, 아릴, 아르알킬, 헤테로아릴, 및 헤테로사이클릴은 1개 이상, 한 구체예에서, 1, 2, 3, 또는 4개의 치환체 Q로 임의로 치환되고, 여기서 각각의 Q는 (a) 중수소, 시아노, 할로, 및 니트로; (b) C1-6 알킬, C2-6 알케닐, C2-6 알키닐, C3-12 사이클로알킬, C6-14 아릴, C7-15 아르알킬, 헤테로아릴, 및 헤테로사이클릴로부터 독립적으로 선택되고, 이들 각각은 1개 이상, 한 구체예에서, 1, 2, 3, 또는 4개의 치환체 Qa로 추가로 임의로 치환됨; 그리고 (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -OC(=NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OS(O)Ra, -OS(O)2Ra, -O...