N-substituted oxazinopteridines and oxazinopteridinones
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IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/5383
C07D-498/14
출원번호
US-0404958
(2012-02-24)
등록번호
US-8791107
(2014-07-29)
발명자
/ 주소
Chang, Edcon
Gibson, Tony
Jin, Bohan
Scorah, Nicholas
Dong, Qing
출원인 / 주소
Takeda Pharmaceutical Company Limited
대리인 / 주소
Russo, Matthew J.
인용정보
피인용 횟수 :
2인용 특허 :
7
초록▼
Disclosed are compounds of Formula 1, and pharmaceutically acceptable salts thereof, wherein Ar, R1, R2, R3, G1, G2, and m are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula 1, to pharmaceutical compositions which contain them,
Disclosed are compounds of Formula 1, and pharmaceutically acceptable salts thereof, wherein Ar, R1, R2, R3, G1, G2, and m are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula 1, to pharmaceutical compositions which contain them, and to their use for treating inflammatory disorders, cardiovascular disease, cancer, and other conditions associated with PI3Kδ.
대표청구항▼
1. A compound of Formula 1 or a pharmaceutically acceptable salt therefore, wherein:G1 is selected from N and CR7;G2 is selected from C═O and CH2;Ar is C1-10 heteroaryl;m is 0, 1, 2, 3, or 4;n is 0, 1, 2 or 3;each R1 is independently selected from cyano, halo, hydroxy, nitro, oxo, optionally substit
1. A compound of Formula 1 or a pharmaceutically acceptable salt therefore, wherein:G1 is selected from N and CR7;G2 is selected from C═O and CH2;Ar is C1-10 heteroaryl;m is 0, 1, 2, 3, or 4;n is 0, 1, 2 or 3;each R1 is independently selected from cyano, halo, hydroxy, nitro, oxo, optionally substituted C1-6 alkyl, optionally substituted C1-4 alkoxy, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-6 heterocyclyl, optionally substituted C6-14 aryl, optionally substituted C6-14 aryloxy, optionally substituted C1-10 heteroaryl, optionally substituted C1-10 heteroaryloxy, —C(O)OR4, —OC(O)R4, —N(R4)R5, —NHC(O)N(R)R9, —S(O)2R6, —S(O)2N(R4)R5, —C(O)N(R8)R9, —NHC(O)OR10, —NHS(O)2NHR8, —NHS(O)2R6, —NHC(O)NHN(R8)R9, —NHC(S)N(R8)R9, —NHC(═NR11)N(R)R9, —NHC(SR12)N(R)R9, and —NHC(═NR11)OR13;R2 is selected from hydrogen, cyano, halo, hydroxy, nitro, optionally substituted C1-6 alkyl, optionally substituted C1-4 alkoxy, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C3-6 heterocyclyl, optionally substituted C6-14 aryl, optionally substituted C6-14 aryloxy, optionally substituted C1-10 heteroaryl, —C(O)OR4, —OC(O)R4, —N(R4)R5, and —S(O)2R6;R3 is selected from hydrogen, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-6 heterocyclyl, optionally substituted C6-14 aryl, optionally substituted C1-10 heteroaryl, —(CH2)nN(R4)R5, —(CH2)nC(O)N(R4)R5, and —S(O)2R6;each R4 and R5 is independently selected from hydrogen, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted phenyl, optionally substituted C3-6 heterocyclyl, and optionally substituted C1-10 heteroaryl;each R6 is independently selected from optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted phenyl, optionally substituted C3-6 heterocyclyl, and optionally substituted C1-10 heteroaryl;R7 is selected from hydrogen, cyano, halo, hydroxy, nitro, optionally substituted C1-4 alkyl, optionally substituted C1-4 alkoxy, —C(O)OR4, —C(O)N(R4)R5, —N(R4)R5, —NHC(O)R4, —NHC(O)N(R4)R5, —OC(O)N(R4)R5, —NHC(O)OR6, —S(O)2R6, —NHS(O)2R6, and —S(O)2N(R4)R5;each R8 and R9 is independently selected from hydrogen, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted C3-6 heterocyclyl, and optionally substituted C1-10 heteroaryl;each R10 is independently selected from optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-14 aryl, optionally substituted C3-6 heterocyclyl, and optionally substituted C1-10 heteroaryl;each R11 is independently selected from hydrogen, cyano, nitro, optionally substituted C1-6 alkyl, optionally substituted C1-4 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C3-6 heterocyclyl, optionally substituted C6-14 aryl, and optionally substituted C1-10 heteroaryl;each R12 is independently selected from optionally substituted C1-6 alkyl and optionally substituted phenyl;each R13 is independently selected from optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C6-14 aryl;each R14 and R15 is independently selected from hydrogen, C1-6 alkyl, C3-8 cycloalkyl, optionally substituted phenyl, C3-6 heterocyclyl, and C1-10 heteroaryl; andeach R16 is independently selected from C1-6 alkyl, C3-8 cycloalkyl, optionally substituted phenyl, C3-6 heterocyclyl, and C1-10 heteroaryl;wherein:each optionally substituted C1-6 alkyl is independently substituted with from 0 to 7 substituents independently selected from cyano, halo, hydroxy, oxo, optionally substituted C1-4 alkyl, C1-4 alkoxy, C2-4 alkenyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-6 heterocyclyl, optionally substituted C1-10 heteroaryl, optionally substituted phenyl, optionally substituted C6-14 aryloxy, —SR14, —C(O)OR14, —N(R14)R15, —C(O)N(R14)R15, and —S(O)2R16;each optionally substituted C1-4 alkoxy is independently substituted with from 0 to 6 substituents independently selected from cyano, halo, hydroxy, oxo, C2-4 alkenyl, C1-4 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted phenyl, —C(O)N(R14)R15, and —C(O)OR14;each optionally substituted C2-4 alkenyl is independently substituted with from 0 to 3 substituents independently selected from cyano, halo, hydroxy, oxo, C1-4 alkoxy, C3-8 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted phenyl, —C(O)N(R14)R15, and —C(O)OR14;each optionally substituted C2-4alkynyl is independently substituted with from 0 to 3 substituents independently selected from cyano, halo, hydroxy, oxo, C1-4alkoxy, C3-8 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted phenyl, —C(O)N(R14)R15, and —C(O)OR14;each optionally substituted C3-8 cycloalkyl is independently substituted with from 0 to 6 substituents independently selected from cyano, halo, hydroxy, nitro, oxo, optionally substituted C1-4 alkyl, C1-4alkoxy, C2-4 alkenyl, C3-8 cycloalkyl, C3-8 cycloalkoxy, optionally substituted C1-10 heteroaryl, optionally substituted phenyl, —C(O)N(R14)R15, —C(O)N(R14)R15, —N(R14)R15, —NHC(O)R14, —NHC(O)OR14, and —C(O)OR14;each optionally substituted C1-10 heteroaryl is independently substituted with from 0 to 5 substituents independently selected from cyano, halo, hydroxy, oxo, nitro, optionally substituted C1-4 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, optionally substituted C3-6 heterocyclyl, C1-10 heteroaryl, optionally substituted phenyl, —C(O)N(R14)R15, —N(R14)R15, —C(O)N(R14)R15, —OC(O)NR14R15, —NHC(O)OR16, —NHS(O)2R16, —S(O)2N(R14)R15, —NHC(O)N(R14)R15, —C(O)OR14, and —S(O)2R16;each optionally substituted C1-10 heteroaryloxy is independently substituted with from 0 to 5 substituents independently selected from cyano, halo, hydroxy, nitro, oxo, optionally substituted C1-4 alkyl, C1-4 alkoxy, trifluoromethyl, optionally substituted phenyl, and —S(O)2R16;each optionally substituted C3-6 heterocyclyl is independently substituted with from 0 to 4 substituents independently selected from cyano, halo, hydroxy, nitro, oxo, optionally substituted C1-4 alkyl, optionally substituted C1-4 alkoxy, C2-4 alkenyl, optionally substituted C3-8 cycloalkyl, C3-8 cycloalkoxy, C3-6 heterocyclyl, C1-10 heteroaryl, optionally substituted phenyl, —C(O)N(R14)R15, —C(O)N(R14)R15, —N(R14)R15, and —C(O)OR14;each optionally substituted C1-4 alkyl is independently substituted with from 0 to 5 substituents independently selected from cyano, halo, hydroxy, nitro, oxo, optionally substituted C1-4 alkoxy, C2-4 alkenyl, C3-8 cycloalkyl, C3-8 cycloalkoxy, C3-6 heterocyclyl, C1-10 heteroaryl, phenyl, —SR14, —C(O)N(R14)R5, —N(R14)R5, —C(O)OR14, and —S(O)2R16;each optionally substituted C6-14 aryl is independently substituted with from 0 to 5 substituents independently selected from cyano, halo, hydroxy, nitro, oxo, optionally substituted C1-4 alkyl, C1-4 alkoxy, C2-4 alkenyl, C1-10 heteroaryl, trifluoromethyl, trifluoromethoxy, —N(R14)R15, —C(O)N(R14)R5, —OC(O)N(R14)R5, —NHC(O)OR16, —NHS(O)2R16, —S(O)2N(R14)R5, —NHC(O)N(R14)R15, —C(O)OR14, and —S(O)2R16;each optionally substituted C6-14 aryloxy is independently substituted with from 0 to 5 substituents independently selected from cyano, halo, hydroxy, nitro, oxo, optionally substituted C1-4 alkyl, C1-4 alkoxy, C2-4 alkenyl, trifluoromethyl, trifluoromethoxy, —N(R14)R15, C(O)N(R14)R15, —OC(O)N(R14)R15, —NHC(O)OR16, —NHS(O)2R16, —S(O)2N(R14)R15, —NHC(O)N(R14)R15, —C(O)OR14, and —S(O)2R16;each optionally substituted phenyl is independently substituted with from 0 to 5 substituents independently selected from cyano, halo, hydroxy, nitro, optionally substituted C1-4 alkyl, C1-4 alkoxy, C2-4 alkenyl, C1-10 heteroaryl, trifluoromethyl, trifluoromethoxy, —N(R14)R15, —C(O)N(R14)R15, —OC(O)N(R14)R15, —NHC(O)OR16, —NHS(O)2R16, —S(O)2N(R14)R15, —NHC(O)N(R14)R15, —C(O)OR14, and —S(O)2R16;each of the aforementioned heteroaryl and heteroaryloxy moieties has independently one to four ring heteroatoms independently selected from N, O, and S, and each of the aforementioned heterocyclyl moieties is independently saturated or partially unsaturated and has one or two ring heteroatoms independently selected from N, O, and S. 2. A compound or pharmaceutically acceptable salt according to claim 1, wherein G1 is N. 3. A compound or pharmaceutically acceptable salt according to claim 1, wherein G2 is CH2. 4. A compound or pharmaceutically acceptable salt according to claim 1, wherein Ar is a bicyclic C5-9 heteroaryl having from 1 to 4 nitrogen heteroatoms. 5. A compound or pharmaceutically acceptable salt according to claim 4, wherein Ar is a bicyclic C7-9 heteroaryl having from 1 to 2 nitrogen heteroatoms. 6. A compound or pharmaceutically acceptable salt according to claim 5, wherein Ar is selected from indolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, benzimidazolyl, and indazolyl. 7. A compound or pharmaceutically acceptable salt according to claim 6, wherein Ar is selected from indol-4-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, 1H-pyrrolo[2,3-c]pyridin-4-yl, and 1H-pyrrolo[3,2-c]pyridin-4-yl. 8. A compound or pharmaceutically acceptable salt according to claim 1, wherein R3 is selected from optionally substituted C1-6 alkyl, optionally substituted C6-14 aryl, optionally substituted C1-10 heteroaryl, and —S(O)2R6. 9. A compound or pharmaceutically acceptable salt according to claim 1, wherein R2 is hydrogen. 10. A compound according to claim 1, which is selected from the following compounds: 5-(5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)pyrimidin-2-amine;2-(1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;5-(cyclopropylmethyl)-2-(1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;5-(5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)pyrimidin-2-amine;5-(2-chloro-4-(methylsulfonyl)benzyl)-2-(1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;5-(5-(2-chloro-4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)pyrimidin-2-amine;2-(6-methoxy-1H-indol-3-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(7-methoxy-1H-indol-3-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(1H-benzo[d]imidazol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(7-chloro-1H-indol-3-yl)-5,6,6a,7,9,1-hexahydro-[,4]oxazino[3,4-h]pteridine;4-(5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)-1H-indol-2-ol;2-(4-((2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)phenyl)propan-2-ol;2-(2-methoxypyridin-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(7-fluoro-3-methyl-1H-indol-4-yl)-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(7-fluoro-1H-indol-4-yl)-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(1H-indol-4-yl)-5-tosyl-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(1H-indol-4-yl)-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;1-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-(4-methoxyphenyl)ethanone;5-(4-(methylsulfonyl)benzyl)-2-(2-(trifluoromethyl)-1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(1H-indazol-4-yl)-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;5-(4-(methylsulfonyl)benzyl)-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;5-(4-(methylsulfonyl)benzyl)-2-(1H-pyrrolo[3,2-b]pyridin-6-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;5-(4-(methylsulfonyl)benzyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(1H-indol-4-yl)-4-methyl-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;5-(cyclopropylmethyl)-2-(1H-indol-4-yl)-4-methyl-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;(S)-2-(1H-indol-4-yl)-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-2-(1H-indol-4-yl)-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-5-(4-(methylsulfonyl)benzyl)-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-5-((5-ethyl-1,3,4-oxadiazol-2-yl)methyl)-2-(1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(1H-indol-4-yl)-5-(2-phenoxyethyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(1H-indol-4-yl)-5-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;3-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-(furan-2-ylmethyl)propanamide;5-((5-ethyl-1,3,4-oxadiazol-2-yl)methyl)-2-(1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;5-((1-cyclopropyl-1H-tetrazol-5-yl)methyl)-2-(1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(1H-indol-4-yl)-5-((2-phenyloxazol-4-yl)methyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(1H-indol-4-yl)-5-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)-5,6,6a,7,9,1-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(1H-indol-4-yl)-5-(oxazol-2-ylmethyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(1H-indol-4-yl)-5-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-5,6,6a,7,9,1-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-(2-methylbenzyl)acetamide;2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-isopropylacetamide;2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N,N-dimethylacetamide;2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-isopropyl-N-methylacetamide;2-((2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)benzonitrile;2-((2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)-4-fluorobenzonitrile;4-((2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)-3-methoxybenzonitrile;1-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-phenylethanone;1-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-(thiophen-2-yl)ethanone;1-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-(3-methoxyphenyl)ethanone;1-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-(thiophen-3-yl)ethanone;1-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-(benzofuran-3-yl)ethanone;benzyl 2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridine-5(6H)-carboxylate;2-(2,6-difluorophenyl)-1-(2-(indolin-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)ethanone;1-(2-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)ethanone;1-(2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)ethanone;tert-butyl ((1r,4r)-4-((2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)cyclohexyl)carbamate;(1r,4r)-4-((2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)cyclohexanamine;3-((2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)benzonitrile;3-((2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)-4-fluorobenzonitrile;2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(benzo[d][1,3]dioxol-4-yl)-5,6,6a,7,9,1-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-2-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-tert-butyl 2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetate;(R)-2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid;(R)-2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-(cyclopropylmethyl)acetamide;(R)-2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-(2-hydroxy-2-methylpropyl)acetamide;(R)-2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-((1H-pyrazol-3-yl)methyl)acetamide;(R)-2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide;2-((2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)benzamide;2-((2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)-4-fluorobenzamide;3-((2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)benzamide;3-((2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)-4-fluorobenzamide;4-((2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)benzamide;4-((2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)-3-methoxybenzamide;2-(1H-indol-4-yl)-5-((6-methylpyridin-2-yl)methyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;5-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-2-(1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;5-((S)-2,3-dihydro-1H-inden-1-yl)-2-(1H-pyrazol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;5-((S)-1-phenylethyl)-2-(1H-pyrazol-3-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(1H-indol-6-yl)-5-(4-(methylsulfonyl)benzyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;ethyl 5-(5-(4-(methylsulfonyl)benzyl)-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)nicotinate;2-(6-aminopyridin-3-yl)-5-(4-(methylsulfonyl)benzyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;5-(4-(methylsulfonyl)benzyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;N-methyl-5-(5-(4-(methylsulfonyl)benzyl)-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)picolinamide;2-(1H-indazol-5-yl)-5-(4-(methylsulfonyl)benzyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;N-(5-(5-(4-(methylsulfonyl)benzyl)-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)pyridin-2-yl)acetamide;5-(4-(methylsulfonyl)benzyl)-2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;5-(4-(methylsulfonyl)benzyl)-2-(1H-pyrrolo[3,2-b]pyridin-6-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(1H-indol-4-yl)-5-(4-(methylsulfonyl)benzyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(1H-indazol-6-yl)-5-(4-(methylsulfonyl)benzyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(2-aminopyrimidin-5-yl)-5-(4-(methylsulfonyl)benzyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(1-methyl-1H-pyrazol-5-yl)-5-(4-(methylsulfonyl)benzyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(1H-indol-5-yl)-5-(4-(methylsulfonyl)benzyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(3-methyl-1H-pyrazol-4-yl)-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(7-chloro-1H-indol-3-yl)-5-(4-(methylsulfonyl)benzyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(2-hydroxy-1H-indol-4-yl)-5-(4-(methylsulfonyl)benzyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(6-methoxy-1H-indol-3-yl)-5-(4-(methylsulfonyl)benzyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;5-(4-(methylsulfonyl)benzyl)-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(7-methoxy-1H-indol-3-yl)-5-(4-(methylsulfonyl)benzyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(1H-benzo[d]imidazol-4-yl)-5-(4-(methylsulfonyl)benzyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(2-methoxypyridin-4-yl)-5-(4-(methylsulfonyl)benzyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(4-aminopyridin-2-yl)-5-(4-(methylsulfonyl)benzyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(7-fluoro-1H-indol-4-yl)-5-(4-(methylsulfonyl)benzyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(7-fluoro-3-methyl-1H-indol-4-yl)-5-(4-(methylsulfonyl)benzyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;5-(4-(methylsulfonyl)benzyl)-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;5-benzyl-2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;5-(6-chloro-2,3-dihydro-1H-inden-1-yl)-2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;(R)-2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;(S)-2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(benzo[d][1,3]dioxol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(1H-benzo[d]imidazol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;(S)-2-(1H-indol-4-yl)-5-((S)-1-p-tolylethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;(R)-2-(1H-indol-4-yl)-5-((S)-1-p-tolylethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;5-(4-(methylsulfonyl)benzyl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(2-methyl-1H-imidazol-1-yl)-5-(4-(methylsulfonyl)benzyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-5-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(2-aminopyrimidin-5-yl)-5-((S)-1-(4-chlorophenyl)ethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;5-((S)-1-(4-chlorophenyl)ethyl)-2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one;2-(1H-indol-4-yl)-5-(pyrimidin-2-ylmethyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-methyl 2-((2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)-4-methylbenzoate;(R)-(2-((2-(1H-indol-4-yl)-6a,7,9,19,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)-4-methylphenyl)methanol;(R)-5-((5-ethyl-1,3,4-oxadiazol-2-yl)methyl)-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-5-(5-((5-ethyl-1,3,4-oxadiazol-2-yl)methyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)pyridin-2-ol;(R)-4-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methylbutan-2-ol;(R)-4-(2-(1H-pyrrolo[2,3-c]pyridin-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methylbutan-2-ol;(R)-2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)ethanol;(R)-2-(2-(1H-pyrrolo[2,3-c]pyridin-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide;(6aR)-2-(1H-indol-4-yl)-5-(1-(5-isobutyl-1,3,4-oxadiazol-2-yl)ethyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;(6aR)-5-(1-(5-ethyl-1,3,4-oxadiazol-2-yl)ethyl)-2-(1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-5-((5-ethyl-1,3,4-oxadiazol-2-yl)methyl)-2-(1H-pyrrolo[3,2-c]pyridin-1-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;2-(1H-indol-4-yl)-5-phenyl-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-2-(1H-indol-4-yl)-5-((1-methyl-1H-pyrazol-4-yl)methyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-5-(3-ethylphenyl)-2-(1H-indol-4-yl)-5,6,6a,7,9,1-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-5-(2-ethylphenyl)-2-(1H-indol-4-yl)-5,6,6a,7,9,1-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-2-(1H-indol-4-yl)-5-(oxazol-5-ylmethyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)benzonitrile;(R)-2-(1H-indol-4-yl)-5-(o-tolyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-5-((3-ethylisoxazol-5-yl)methyl)-2-(1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-4-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)cyclohexanol;(R)-ethyl 3-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)benzoate;(R)-2-(1H-indol-4-yl)-5-(3-(methylsulfonyl)phenyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-2-(1H-indol-4-yl)-5-(tetrahydro-2H-pyran-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-2,5-di(1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-5-(2-(1,3-dioxolan-2-yl)ethyl)-2-(1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-methyl 4-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)butanoate;(R)-4-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)butanoic acid;(1R,4r)-4-(((R)-2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)cyclohexanamine;(R)-ethyl 5-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)nicotinate;(R)-methyl 5-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)nicotinate;(R)-methyl 2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)isonicotinate;(R)-2-(1H-indol-4-yl)-5-(5-methoxypyridin-3-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine;(R)-methyl 5-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methoxynicotinate;(R)-2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-(pyridin-4-yl)acetamide;(R)-2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-(2-methoxyethyl)acetamide;(R)-2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide;(R)-2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-(1-methyl-1H-pyrazol-4-yl)acetamide;(R)-2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-cyclopropylacetamide;(R)-2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-(2-cyanopropan-2-yl)acetamide;2-((R)-2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-(tetrahydrofuran-3-yl)acetamide;((R)-2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-4,4-dimethylpentan-3-amine;(R)-2-(2-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide;(R)-2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide;(S)-tert-butyl 2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetate;(R)-2-(2-(6-aminopyridin-3-yl)-6a,7,9,1-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide;(R)—N-((tetrahydro-2H-pyran-4-yl)methyl)-2-(2-(thiophen-3-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetamide;(R)-2-(2-(1-methyl-1H-pyrazol-5-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-(6H)-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide;(R)-2-(2-(5-(hydroxymethyl)thiophen-2-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide;(R)-5-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methylpentan-2-ol;2-((2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)-4-methylbenzamide; a stereoisomer of any of the aforementioned compounds; and a pharmaceutically acceptable salt of any of the aforementioned compounds or stereoisomers. 11. A pharmaceutical composition comprising: a compound or pharmaceutically acceptable salt as defined in claim 1; anda pharmaceutically acceptable excipient. 12. A method of treating a disease or condition in a subject, the method comprising administering to the subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt as defined in claim 1, wherein the disease or condition is selected from allergic rhinitis, asthma, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, immune thrombocytopenic purpura, inflammatory bowel disease, chronic obstructive pulmonary disease, Sjögren's syndrome, ankylosing spondylitis, Behcet's disease, atherosclerosis, myocardial infarction, and thrombosis. 13. A combination comprising an effective amount of a compound or pharmaceutically acceptable salt as defined in claim 1 and a disease modifying antirheumatic drug.
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