http://rdf.ncbi.nlm.nih.gov/pubchem/patent/AR-099934-A1
Outgoing Links
| Predicate | Object |
|---|---|
| assignee | http://rdf.ncbi.nlm.nih.gov/pubchem/patentassignee/MD5_7d01227a7111c7565c8a5a1906a182c9 |
| classificationIPCInventive | http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61K31-437 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61P35-00 |
| filingDate | 2015-04-01-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| publicationDate | 2016-08-31-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| publicationNumber | AR-099934-A1 |
| titleOfInvention | THERAPEUTIC COMBINATION OF A PI3K INHIBITOR AND A BTK INHIBITOR |
| abstract | A therapeutic combination of a 3-kinase phosphoinositide inhibitor (PI3K), which includes selective PI3K inhibitors for the g and d isoforms, and selective for the g and d isoforms, and a Bruton tyrosine kinase inhibitor (BTK). Therapeutic methods for using a BTK inhibitor and a PI3K-d inhibitor to treat solid tumors through tumor microenvironment modulation, including macrophages, monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory T cells, natural killer cells , myeloid-derived suppressor cells, regulatory B cells, neutrophils, dendritic cells and fibroblasts. Claim 1: A composition that a phosphoinositide 3-kinase inhibitor (Pl3K-d) and a Bruton tyrosine kinase inhibitor (BTK), wherein the Pl3K-d inhibitor is a compound of formula (1) or a salt, pharmaceutically acceptable solvate, hydrate, co-crystal or prodrug thereof, wherein: X¹ is C (R⁹) or N; X² is C (R¹⁰) or N; Y is N (R¹¹), O or S; Z is CR⁸ or N; n is 0, 1, 2 or 3; R¹ is a monocyclic ring with direct bond or oxygen bond, saturated, partially saturated or unsaturated, of 5, 6 or 7 members, containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but which does not contain more than one O or S, where the available carbon atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups, where the ring is substituted by 0 or 1 R² substituents, and the ring is additionally substituted by 0, 1, 2 or 3 substituents independently selected from halo, nitro, cyano, C₁₋₄ alkyl, OC₁₋₄ alkyl, O-haloalkyl C₁₋₄, NHC₁₋₄, N (C₁₋₄ alkyl) C₁₋₄ alkyl and C₁₋₄ haloalkyl; R² is selected from halo, haloalkyl C₁₋₄, cyano, nitro, -C (= O) Rᵃ, -C (= O) ORᵃ, -C (= O) NRᵃRᵃ, -C (= NRᵃ) NRᵃRᵃ, -ORᵃ, -OC (= O) Rᵃ, -OC (= O) NRᵃRᵃ, -OC (= O) N (Rᵃ) S (= O) ₂Rᵃ, -O-alkyl C₂₋₆NRᵃRᵃ, -O-alkyl C₂₋₆ORᵃ, - SRᵃ, OS (= O) Rᵃ, -S (= O) ₂Rᵃ, -S (= O) ₂NRᵃRᵃ, -S (= O) ₂N (Rᵃ) C (= O) Rᵃ, -S (= O) ₂N ( Rᵃ) C (= O) ORᵃ, -S (= O) ₂N (Rᵃ) C (= O) NRᵃRᵃ, -NRᵃRᵃ, -N (Rᵃ) C (= O) Rᵃ, -N (Rᵃ) C (= O ) ORᵃ, -N (Rᵃ) C (= O) NRᵃRᵃ, -N (Rᵃ) C (= NRᵃ) NRᵃRᵃ, -N (Rᵃ) S (= O) ₂Rᵃ, -N (Rᵃ) S (= O) ₂NRᵃRᵃ , -NRᵃ-C₂₋₆NRᵃRᵃ alkyl and -NRᵃ-C₂₋₆ORᵃ alkyl; or R² is selected from C₁₋₆ alkyl, phenyl, benzyl, heteroaryl, heterocycle, - (C₁₋₃ alkyl) heteroaryl, - (C₁₋₃ alkyl) heterocycle, -O (C₁₋₃ alkyl) heteroaryl, -O (alkyl C₁₋₃) heterocycle, -NRᵃ (C₁₋₃ alkyl) heteroaryl, -NRᵃ (C₁₋₃ alkyl) heterocycle, - (C₁₋₃ alkyl) phenyl, -O (C₁₋₃ alkyl) phenyl and -NRᵃ (C₁ alkyl ₋₃) phenyl, all of which are substituted by 0, 1, 2 or 3 substituents selected from C₁₋₄ haloalkyl, O-C₁₋₄ alkyl, Br, Cl, F, I and C₁₋₄ alkyl; R³ is selected from H, halo, haloalkyl C₁₋₄, cyano, nitro, -C (= O) Rᵃ, -C (= O) ORᵃ, -C (= O) NRᵃRᵃ, -C (= NRᵃ) NRᵃRᵃ, - ORᵃ, -OC (= O) Rᵃ, -OC (= O) NRᵃRᵃ, -OC (= O) N (Rᵃ) S (= O) ₂R², -O-alkyl C₂₋₆NRᵃRᵃ, -O-alkyl C₂₋₆ORᵃ , -SRᵃ, -S (= O) Rᵃ, -S (= O) ₂Rᵃ, -S (= O) ₂NRᵃRᵃ, -S (= O) ₂N (Rᵃ) C (= O) Rᵃ, -S (= O ) ₂N (Rᵃ) C (= O) ORᵃ, -S (= O) ₂N (Rᵃ) C (= O) NRᵃRᵃ, -NRᵃRᵃ, -N (Rᵃ) C (= O) Rᵃ, -N (Rᵃ) C (= O) ORᵃ, -N (Rᵃ) C (= O) NRᵃRᵃ, -N (Rᵃ) C (= NRᵃ) NRᵃRᵃ, -N (Rᵃ) S (= O) ₂Rᵃ, -N (Rᵃ) S (= O) ₂NRᵃNRᵃRᵃ, -NRᵃ-C₂₋₆ORᵃ alkyl, C₁₋₆ alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein C₁₋₆ alkyl, phenyl, benzyl, heteroaryl and heterocycle are further substituted by 0, 1, 2 or 3 substituents selected from C₁₋₆ haloalkyl, O-C₁₋₆ alkyl, Br, Cl, F, l and C₁₋₆ alkyl; R⁴ is, independently, in each instance, halo, nitro, cyano, C₁₋₄ alkyl, O-C₁₋₄ alkyl, O-haloalkyl C₁₋₄, NH-C₁₋₄ alkyl, N (C₁₋₄ alkyl) C₁ alkyl ₋₄ or C₁₋₄ haloalkyl; R⁵ is, independently, in each instance, H, halo, C₁₋₆ alkyl, C₁₋₄ haloalkyl or C₁₋₆ alkyl substituted by 1, 2 or 3 substituents selected from halo, cyano, OH, O-C₁₋₄ alkyl, C₁₋₄ alkyl, C₁₋₃ haloalkyl, O-C₁₋₄ alkyl, NH₂, NH-C₁₋₄ alkyl, N (C₁₋₄ alkyl) C₁₋₄ alkyl; or both R⁵ groups together form a C₃₋₆ spiroalkyl substituted by 0, 1, 2 or 3 substituents selected from halo, cyano, OH, O-C₁₋₄ alkyl, C₁₋₄ alkyl, C₁₋₃ haloalkyl, O-C₁ alkyl ₋₄, NH₂, NH-C₁₋₄ alkyl, N (C₁₋₄ alkyl) C₁₋₄ alkyl; R⁶ is selected from H, halo, C₁₋₆ alkyl, C₁₋₄ haloalkyl, cyano, nitro, -C (= O) Rᵃ, -C (= O) ORᵃ, -C (= O) NRᵃRᵃ, -C (= NRᵃ) NRᵃRᵃ, -S (= O) Rᵃ, -S (= O) ₂Rᵃ, -S (= O) ₂NRᵃRᵃ, -S (= O) ₂N (Rᵃ) C (= O) Rᵃ, -S (= O ) ₂N (Rᵃ) C (= O) ORᵃ, -S (= O) ₂N (Rᵃ) C (= O) NRᵃRᵃ; R⁷ is selected from H, halo, C₁₋₆ alkyl, C₁₋₄ haloalkyl, cyano, nitro, -C (= O) Rᵃ, -C (= O) ORᵃ, -C (= O) NRᵃRᵃ, -C (= NRᵃ) NRᵃRᵃ, -S (= O) Rᵃ, -S (= O) ₂Rᵃ, -S (= O) ₂NRᵃRᵃ, -S (= O) ₂N (Rᵃ) C (= O) Rᵃ, -S (= O ) ₂N (Rᵃ) C (= O) ORᵃ, -S (= O) ₂N (Rᵃ) C (= O) NRᵃRᵃ; R⁸ is selected from H, C₁₋₆ haloalkyl, Br, Cl, F, l, ORᵃ, NRᵃRᵃ, C₁₋₆ alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein C₁₋₆ alkyl, phenyl, benzyl, heteroaryl and heterocycles are additionally substituted by 0, 1, 2 or 3 substituents selected from C₁₋₆ haloalkyl, O-C₁₋₆ alkyl, Br, Cl, F, and C₁₋₆ alkyl; R⁹ is selected from H, halo, haloalkyl C₁₋₄, cyano, nitro, -C (= O) Rᵃ, C (= O) ORᵃ, -C (= O) NRᵃRᵃC (= NRᵃ) NRᵃRᵃ, -ORᵃ, -OC (= O) Rᵃ, -OC (= O) NRᵃRᵃ, -OC (= O) N (Rᵃ) S (= O) ₂Rᵃ, -O-alkyl C₂₋₆ORᵃ, -SRᵃ, S (= O) Rᵃ, - S (= O) ₂Rᵃ, -S (= O) ₂NRᵃRᵃ, -S (= O) ₂N (Rᵃ) C (= O) Rᵃ, S (= O) ₂N (Rᵃ) C (= O) ORᵃ, -S (= O) ₂N (Rᵃ) C (= O) NRᵃRᵃ, NRᵃRᵃ, -N (Rᵃ) C (= O) Rᵃ, -N (Rᵃ) C (= O) ORᵃ, -N (Rᵃ) C (O) NRᵃRᵃN (RᵃC (= NRᵃ) NRᵃRᵃ, -N (Rᵃ) S (= O) ₂Rᵃ, -N (Rᵃ) S (= O) ₂NRᵃRᵃ, -NRᵃ-alkyl C₂₋₆NRᵃRᵃ, -NRᵃ-alkyl C₁₋₆, phenyl , benzyl, heteroaryl and heterocycle, wherein C₁₋₆ alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1, 2 or 3 substituents selected from halo, C₁₋₄ haloalkyl, cyano, nitro, -C ( = O) Rᵃ, -C (= O) ORᵃ, -C (= O) NRᵃRᵃ, C (= NRᵃ) NRᵃRᵃ, -ORᵃ, -OC (= O) Rᵃ, OC (= O) NRᵃRᵃ, OC (= O ) N (Rᵃ) S (= O) ₂Rᵃ, -O-C₂₋₆NRᵃRᵃ alkyl, -O-C₂₋₆ORᵃ alkyl, - SRᵃ, S (= O) Rᵃ, -S (= O) ₂Rᵃ, -S (= O) ₂NRᵃRᵃ, -S (= O) ₂N (Rᵃ) C (= O) Rᵃ, S (= O) ₂N (Rᵃ ) C (= O) ORᵃ, -S (= O) ₂N (Rᵃ) C (= O) NRᵃRᵃ, NRᵃRᵃ, -N (Rᵃ) C (= O) Rᵃ, -N (Rᵃ) C (= O) ORᵃ , -N (Rᵃ) C (= O) NRᵃRᵃ, -N (Rᵃ) C (= NRᵃ) NRᵃRᵃ, -N (Rᵃ) S (= O) ₂Rᵃ, -N (Rᵃ) S (= O) ₂NRᵃRᵃ, - NRᵃ-C₂₋₆ORᵃ alkyl, -NRᵃ-C₂₋₆ORᵃ alkyl; or R⁹ is a monocyclic ring of 5, 6 or 7 members, saturated, partially saturated or unsaturated, containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but not containing more than one O or S, wherein the available carbon atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2, 3 or 4 substituents selected from halo, C₁₋₄ haloalkyl, cyano, nitro, -C (= O) Rᵃ, -C (= O) ORᵃ, -C (= O) NRᵃRᵃ, -C (= NRᵃ) NRᵃRᵃ, -ORᵃ, -OC (= O) Rᵃ, -OC ( = O) NRᵃRᵃ, -OC (= O) N (Rᵃ) S (= O) ₂Rᵃ, -O-C₂₋₆NRᵃRᵃ alkyl, -O-C₂₋₆ORᵃ alkyl, -SRᵃ, -S (= O) Rᵃ, - S (= O) ₂Rᵃ, -S (= O) ₂NRᵃRᵃ, -S (= O) ₂N (Rᵃ) C (= O) Rᵃ, -S (= O) ₂N (Rᵃ) C (= O) ORᵃ, - S (= O) ₂N (Rᵃ) C (= O) NRᵃRᵃ, -NRᵃRᵃ, -N (Rᵃ) C (= O) Rᵃ, -N (Rᵃ) C (= O) ORᵃ, -N (Rᵃ) C ( = O) NRᵃRᵃ, -N (Rᵃ) C (= NRᵃ) NRᵃRᵃ, -N (Rᵃ) S (= O) ₂Rᵃ, -N (Rᵃ) S (= O) ₂NRᵃRᵃ, -NRᵃ-alkyl C₂₋₆NRᵃRᵃ and - NRᵃ-C₂₋₆ORᵃ alkyl; R¹⁰ is H, C₁₋₃ alkyl, C₁₋₃ haloalkyl, cyano, nitro, CO₂Rᵃ, C (= O) NRᵃRᵃ, -C (= NRᵃ) NRᵃRᵃ, -S (= O) ₂N (Rᵃ) C (= O) Rᵃ, -S (= O) ₂N (Rᵃ) C (= O) ORᵃ, -S (= O) ₂N (Rᵃ) C (= O) NRᵃRᵃ, -S (= O) Rᵇ, S (= O) ₂Rᵇ or S (= O) ₂NRᵃRᵃ; R¹¹ is H, C₁₋₄ alkyl; Rᵃ is independently, in each instance, H or Rᵇ; and Rᵇ is independently, in each instance, phenyl, benzyl or C₁₋₆ alkyl, wherein the phenyl, benzyl and C₁₋₆ alkyl are substituted by 0, 1, 2 or 3 substituents selected from halo, C₁₋₄ alkyl, haloalkyl C₁₋₃, -O-C₁₋₄ alkyl, -NH₂, -NH-C₁₋₄ alkyl, -N (C₁₋₄ alkyl) C₁₋₄ alkyl; and wherein the BTK inhibitor is a compound of formula (2) or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof, wherein X is CH, N, O or S; Y is C (R⁶), N, O or S; Z is CH, N or a bond; A is CH or N; B¹ is N or C (R⁷); B² is N or C (R⁸); B³ is N or C (R⁹); B⁴ is N or C (R¹⁰); R¹ is R¹¹C (O), R¹²S (O), R¹³SO₂ or C₁₋₆ alkyl optionally substituted with R¹⁴; R² is H, C₁₋₃ alkyl or C₃₋₇ cycloalkyl; R³ is H, C₁₋₆ alkyl or C₃₋₇ cycloalkyl; or R² and R³ together with the N and C atom to which they are attached, a C₃₋₇ heterocycloalkyl optionally substituted with one or more fluorine, hydroxyl, C₁₋₃ alkyl, C₁₋₃ alkoxy or oxo; R⁴ is H or C₁₋₃ alkyl; R⁵ is H, halogen, cyano, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₃₋₆ cycloalkyl, any alkyl group of which is optionally substituted with one or more halogen; or R⁵ is C₆₋₁₀ aryl or C₂₋₆ heterocycloalkyl; R⁶ is H or C₁₋₃ alkyl; or R⁵ and R⁶ together can form a C₃₋₇ cycloalkenyl or C₂₋₆ heterocycloalkenyl; each optionally substituted with C₁₋₃ alkyl, or one or more halogens; R⁷ is H, halogen, CF₃, C₁₋₃ alkyl or C₁₋₃ alkoxy; R⁸ is H, halogen, CF₃, C₁₋₃ alkyl or C₁₋₃ alkoxy; or R⁷ and R⁸, together with the carbon atoms to which they are attached, form C₆₋₁₀ aryl or C₁₋₉ heteroaryl; R⁹ is H, halogen, C₁₋₃ alkyl or C₁₋₃ alkoxy; R¹⁰ is H, halogen, C₁₋₃ alkyl or C₁₋₃ alkoxy; R¹¹ is independently selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl, wherein each alkyl, alkenyl or alkynyl is optionally substituted with one or more groups selected from hydroxyl, C₁₋₄ alkyl, cycloalkyl C₃₋₇, [C₁₋₄ alkyl] amino, di [C₁₋₄ alkyl] amino, C₁₋₃ alkoxy, C₃₋₇ cycloalkoxy, C₆₋₁₀ aryl or C₃₋₇ heterocycloalkyl; or R¹¹ is C₁₋₃-C (O) -S-C₁₋₃ alkyl; or R¹¹ is C₁₋₅ heteroaryl optionally substituted with one or more groups selected from halogen or cyano; R¹² and R¹³ are independently selected from the group consisting of C₂₋₆ alkenyl or C₂₋₆ alkynyl, both optionally substituted with one or more groups selected from hydroxyl, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, [C₁₋₄ alkyl] amino , di [C₁₋₄ alkyl] amino, C₁₋₃ alkoxy, C₃₋₇ cycloalkoxy, C₆₋₁₀ aryl or C₃₋₇ heterocycloalkyl; or C₁₋₅ heteroaryl optionally substituted with one or more groups selected from halogen or cyano; and R¹⁴ is independently selected from the group consisting of halogen, cyano or C₂₋₆ alkenyl or C₂₋₆ alkynyl, both optionally substituted with one or more groups selected from hydroxyl, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₁₋₄ alkylamino , di [C₁₋₄ alkyl] amino, C₁₋₃ alkoxy, C₃₋₇ cycloalkoxy, C₆₋₁₀ aryl, C₁₋₅ heteroaryl or C₃₋₇ heterocycloalkyl. |
| priorityDate | 2014-04-03-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| type | http://data.epo.org/linked-data/def/patent/Publication |
Incoming Links
Total number of triples: 32.