EP-4734987-A1 - THIAZOLO TETRAHYDROCHINOLINE COMPOUNDS AS CLASS II PHOSPHOINOSITIDE 3-KINASE INHIBITORS

Abstract

The invention relates to chemical compounds useful as inhibitors of class II phosphoinositide 3- kinase (PI3K) signalling. The invention further relates to the medical use of inhibitors of class II phosphoinositide 3-kinase (PI3K) signalling in the treatment of medical conditions associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, such as stroke, a cardiovascular disease related to endothelial cell dysfunction, cancer, cancer metastasis, myopathy and diabetes.

Inventors

• CIRILLO, Davide
• LO, WEN-TING
• HAUCKE, Volker
• NAZARE, MARC

Assignees

• Forschungsverbund Berlin E.V.

Dates

Publication Date

20260506

Application Date

20240627

Claims (1)

1. CLAIMS 1 . A compound for use in the treatment of a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, according to Formula 1 Formula 1 wherein n is 1 or 2, A is a 5-membered or 6-membered heteroaryl and -N(R4R5) is attached to the C atom adjacent to the N of ring A, R1 is C, S, O or N, R2 is C or N, R3 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl comprising Cl, Br, or F), -CN, carbonyl, carboxyl, carboxy ester, alkoxy, aldehyde, primary, secondary or tertiary amine, amide, imide, carbamate, carboxamide, nitro, sulfide, sulfinyl, sulfonyl, sulfino or sulfonamide, R4 and R5 can be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably comprising Cl, Br or F), C4 to C6 aryl, sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably comprising Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a carbamate or a carbamate ester, or R4 and R5 form a 4-, 5- or 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably N, O and/or S), wherein said hetero cycloalkyl is optionally substituted by alkoxy, R6 is absent or, R1 is C and R6 forms a carbonyl C=O with R1 or, R1 is S and R6 forms a sulfoxide S=O with R1 , R7, R8 and R9 are the same or different, C or N, R10 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl comprising Cl, Br, or F), -CN, carbonyl -, carboxyl, carboxy ester, alkoxy, aldehyde, primary, secondary or tertiary amine, amide, imide, carbamate, carboxamide, nitro, sulfide, sulfinyl, sulfonyl, sulfino or sulfonamide, R11 is H, C3 to C6 cycloalkyl, C4 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), halogen (preferably F, Cl, or Br), sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxyl ester, carboxamide, alkoxy or aryloxy, or R10 and R11 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure D comprising two carbon atoms of B, forming a condensed bicyclic group with B, optionally comprising one or more heteroatoms (preferably N, O and/or S), R14 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), a primary, secondary or tertiary amine or alkyl amine, or R11 and R14 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure C comprising two carbon atoms of B, forming a condensed cyclic group with B, optionally comprising one or more heteroatoms (preferably N, O and/or S), R12 is C1 to C5 alkyl (preferably C1 to C3 alkyl), carbonyl C=O, sulfide, sulfinyl or sulfonyl, R13 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R12 and R13 are absent when R11 is H or halogen, or not forming a ring structure with R10 or R14, or when R11 and R14 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure C and R15 and R16 are present, R15 is C1 to C5 alkyl (preferably C1 to C3 alkyl), carbonyl C=O, sulfide, sulfinyl or sulfonyl, R16 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R15 and R16 are absent when R14 is H, or R11 and R10 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure D, or when R11 and R14 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure C and R12 and R13 are present. The compound for use according to claim 1 , according to Formula 1 Formula 1 wherein n is 1 or 2, A is a 5-membered or 6-membered heteroaryl and -N(R4R5) is attached to the C atom adjacent to N of ring A, R1 is C, S, O or N, R2 is C or N, R3 is H, C1 to C3 alkyl, C3 to C6 cycloalkyl, CX3, wherein X is Cl, Br, or F, R4 and R5 can be the same or different, H, C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), C1 to C3 haloalkyl (preferably comprising Cl, Br or F), C4 to C6 aryl, sulfonyl, or one of or R4 and R5 form together with the atoms they are attached to a 4-, 5- or 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably N, O and/or S), wherein said hetero cycloalkyl is optionally substituted by alkoxy, such as R6 is absent, forms a carbonyl C=O with R1 or, R1 is S and R6 forms a sulfoxide S R7, R8 and R9 are the same or different, C or N, R10 is H or C1 to C3 alkyl, R11 is H, C3 to C6 cycloalkyl, C4 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), halogen (preferably F, Cl, or Br), sulfide, sulfinyl, sulfonyl, carboxyl ester, carboxamide or alkoxy -CH2OR wherein R C1 to C3 alkyl or benzyl, or R10 and R11 form together with the atoms they are attached to a 5- to 7-membered cycloalkyl or aryl ring structure D comprising two carbon atoms of B, forming a condensed bicyclic group with B, optionally comprising one or more heteroatoms (preferably N, O and/or S), R14 is H, C1 to C3 alkyl, a secondary or tertiary amine or alkyl amine, or R11 and R14 form together with the atoms they are attached to a 5- to 7-membered cycloalkyl or aryl ring structure C comprising two carbon atoms of B, forming a condensed cyclic group with B, optionally comprising one or more heteroatoms (preferably N, O and/or S), R12 is C1 to C3 alkyl, carbonyl C=O or sulfonyl, R13 is C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R12 and R13 are absent when R11 is H or halogen, or not forming a ring structure with R10 or R14, or when R11 and R14 form together with the atoms they are attached to a 5- to 7-membered cycloalkyl or aryl ring structure C and R15 and R16 are present, R15 is C1 to C3 alkyl, carbonyl C=O or sulfonyl, R16 is C1 to C3 alkyl, C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, benzyl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R15 and R16 are absent when R14 is H, or R10 and R11 form together with the atoms they are attached to a 5- to 7-membered cycloalkyl or aryl ring structure D, or when R11 and R14 form together with the atoms they are attached to a 5- to 7-membered cycloalkyl or aryl ring structure C and R12 and R13 are present. 3. The compound for use according to any one of the preceding claims, according to Formula 2 Formula 2 wherein R1 to R16 are according to claim 1. 4. The compound for use according to any one of the preceding claims, wherein R11 and R14 form together with the atoms they are attached to a 5- to 7-membered cyclic or aryl ring structure C forming a condensed bicyclic group with B, wherein B and C are one of and wherein R7, R8, R9, R12, R13, R15 and R16 are according to claim 1 , X and Y are the same or different, C, N, S and/or O, R17 may be the same or different, absent (electron pair of X), H, hydroxy, halogen (preferably F, Cl or Br), alkoxy, C1 to C5 alkyl (preferably C1 to C3 alkyl), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl comprising Cl, Br, or F), C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N,0 and/or S and optionally substituted with alkoxy), C4 to C6 aryl, carbonyl C(=O)R, wherein R is C1 to C5 alkyl (preferably C1 to C3 alkyl), carboxyl, carboxy ester, alkoxy (preferably -OCH3, -OCFhCHs or C3 to C6 cycloalkyl alkoxy), aldehyde, primary, secondary or tertiary amine, amide, imide, carbamate, carboxamide, nitro, sulfide (preferably -SCH3, -SCH2CH3), sulfinyl, sulfonyl, sulfino or sulfonamide or when X is C forming a carbonyl C=O with X or when X is S forming sulfoxide S=O or sulfonyl S(=O)2 with X, or two R17 are forming a 4-, 5- or 6-membered cycloalkyl, optionally comprising one or more hetero atoms (preferably N, O and/or S), R18 may be the same or different, H, alkoxy or one R18 is forming a carbonyl C=O with the C atom attached to, or one R17 and one R18 form a 5- or 6-membered cyclic ring structure comprising two carbon atoms of C, forming a condensed cyclic group with C, optionally comprising one or more heteroatoms (preferably N, O and/or S), wherein the 5- or 6-membered cyclic ring structure is optionally substituted with C1 to C3 alkyl or alkoxy carbonyl (preferably at the position of the heteroatom), and R19 may be the same or different, H, C1 to C6 alkyl (preferably C1 to C3 alkyl). 5. The compound for use according to any one of the preceding claims, wherein R10 and R11 form together with the atoms they are attached to a 5- to 7-membered cyclic or aryl ring structure D forming a condensed bicyclic group with B, wherein B and D is and wherein R7, R8, R9, R12 and R13 are according to claim 1 . 6. The compound for use according to any one of the preceding claims wherein R16 is one of wherein R20 may be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and/or Br), alkoxy or E, wherein E is one of R21 may be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and/or Br), alkoxy, primary, secondary or tertiary amine, sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, a secondary hydroxyl group C(- OH)CHs, carbonyl C=OR (wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably comprising Cl, Br or F)), imide, carbamate, carboxamide, amide N=OR (wherein R is C1 to C3 alkyl, C1 to C3 alkenyl, C1 to C3 haloalkyl (preferably comprising Cl, Br or F)), nitro or E, R22 may be the same or different, H or C1 to C5 alkyl (preferably C1 to C3 alkyl), R23 is H, carbonyl, carboxyl or carboxy ester, R24 is H or C1 to C5 alkyl (preferably C1 to C3 alkyl), and R25 may be the same or different, H, C1 to C4 alkyl, C1 to C4 heteroalkyl, C3 to C6 cycloalkyl, C2 to C6 heterocycloalkyl. 7. The compound for use according to any one of the preceding claims, according to Formula 5 Formula 5 wherein R1 to R10, R15 and R16 are according to claim 1 , and R17 to R19 are according to claim 4. 8. The compound for use according to any one of the preceding claims, according to Formula 6 Formula 6 wherein R1 to R10 and R16 are according to claim 1 , and R17 to R19 are according to claim 4. 9. The compound for use according to any one of the preceding claims, selected from the group consisting of: A/-(4-methyl-5-(l-(phenylsulfonyl)-lH-indol-5-yl)thiazol-2-yl)acetamide, A/-(4- methyl-5-(l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(4-methyl- 5-(l-(phenylsulfonyl)indolin-5-yl)thiazol-2-yl)acetamide, A/-(4-methyl-5-(4-(phenylsulfonyl)-3,4- dihydro-2H-benzo[b][l,4]oxazin-7-yl)thiazol-2-yl)acetamide, A/-(5-(l-(phenylsulfonyl)-2, 3,4,5- tetrahydro-lH-benzo[b]azepin-7-yl)thiazol-2-yl)acetamide, A/-(4-methyl-5-(5-(phenylsulfonyl)- 5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl)acetamide, A/-(5-(4-methoxy-l-(phenylsulfonyl)- 1.2.3.4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(4- (phenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]thiazin-7-yl)thiazol-2-yl)acetamide, A/-(4-methyl-5- (l-oxido-4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]thiazin-7-yl)thiazol-2-yl)acetamide, A/-(5- (l,l-dioxido-4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]thiazin-7-yl)-4-methylthiazol-2- yl)acetamide, A/-(4-methyl-5-(8-(phenylsulfonyl)-5,6,7,8-tetrahydro-l,8-naphthyridin-3-yl)thiazol-2- yl)acetamide, A/-(4-methyl-5-(4-oxo-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide, A/-(5-(4-hydroxy-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(2-methyl-l-(phenylsulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(5-(l-(phenylsulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(4-methyl-5-(5-(phenylsulfonyl)-5, 6,7,8- tetrahydro-l,5-naphthyridin-2-yl)thiazol-2-yl)acetamide, A/-(4-methyl-5-(l-(phenylsulfonyl)- 1.2.3.4-tetrahydroquinolin-6-yl)oxazol-2-yl)acetamide, A/-(4-methyl-5-(5-(phenylsulfonyl)- 2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinolin-8-yl)thiazol-2-yl)acetamide, (/?)-/V-(5-(4-methoxy-l- (phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, tert-butyl 6-((4- methyl-5-(l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)amino)-6- oxohexyl)carbamate,A/-(5-(4-acetyl-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinoxalin-6-yl)-4- methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(4-methyl-3-oxo-l-(phenylsulfonyl)-l,2,3,4- tetrahydroquinoxalin-6-yl)thiazol-2-yl)acetamide, A/-(5-(3-methoxy-l-(phenylsulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(4-methoxy-4-methyl-l- (phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl-5- (4-morpholino-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(4- methyl-5-(6-(phenylsulfonyl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-9-yl)thiazol-2- yl)acetamide, A/-(4-methyl-5-(l-(o-tolylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide, A/-(4-methyl-5-(l-(naphthalen-l-ylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol- 2-yl)acetamide, A/-(5-(l-(cyclohexylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, A/-(4-methyl-5-(l-(pyridin-3-ylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide, A/-(4-methyl-5-(l-(methylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide, A/-(4-methyl-5-(l-(thiophen-2-ylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide, A/-(5-(l-((4-fluorophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol- 2-yl)acetamide, A/-(5-(l-((2,4-dichlorophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(l-(naphthalen-2-ylsulfonyl)-l,2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, (S)-/V-(5-(4-methoxy-l-(phenylsulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(l-tosyl-l, 2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(5-(l-((2, 3-dichlorophenyl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-(benzylsulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-((2,3-dihydrobenzofuran-5- yl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, tert-butyl (4-methyl- 5-(l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)carbamate, 4-methyl-5-(l- (phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-amine, A/-(4-ethyl-5-(l-(phenylsulfonyl)- 1.2.3.4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(5-(l-(cyclopropylsulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(2,2-dimethyl-l-(phenylsulfonyl)- 1.2.3.4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(l'- (phenylsulfonyl)-2 , ,3 , -dihydro-l , /-/-spiro[oxetane-3,4 , -quinolin]-6'-yl)thiazol-2-yl)acetamide, A/-(5- (l-((3-methoxyphenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(5-methyl-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide, 5-methyl-4-(l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-A/-(2,2,2- trifluoroethyl)thiazol-2-amine, A/-(5-(4,4-difluoro-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6- yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-(allylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide, A/-allyl-5-methyl-4-(l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin- 6-yl)thiazol-2-amine, A/,5-dimethyl-4-(l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- amine, A/-(5-(l-((3-bromophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, 3-((6-(2-acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin-l(2H)- yl)sulfonyl)benzenesulfonyl fluoride, A/-(5-(l-((3-acetylphenyl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-((3-(2- bromoacetyl)phenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, 2,2,2-trifluoro-/V-(4-methyl-5-(l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide, A/-(5-(l-((3-(l-hydroxyethyl)phenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide, 4-methyl-A/-phenyl-5-(l-(phenylsulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)thiazol-2-amine, A/-(5-(l-((3-aminophenyl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(3-((6-(2-acetamido-4-methylthiazol- 5-yl)-3,4-dihydroquinolin-l(2H)-yl)sulfonyl)phenyl)acetamide, A/-(5-(l-((3- (dimethylamino)phenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)aceamide, A/-(5-(l-((2-chlorophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, A/-(5-(l-((3,4-dimethoxyphenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide, A/-(5-(l-((2,3-dimethoxyphenyl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, Methyl 3-((6-(2-acetamido-4- methylthiazol-5-yl)-3,4-dihydroquinolin-l(2H)-yl)sulfonyl)thiophene-2-carboxylate, A/-(4-methyl- 5-(l-((3-nitrophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(4-methyl- 5-(l-((2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2- yl)acetamide, A/-(4-methyl-5-(l-((3-oxo-3,4-dihydro-2H-benzo[b] [l,4]oxazin-7-yl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(5-(l-((2, 5-difluorophenyl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, methyl 3-((6-(2-acetamido-4- methylthiazol-5-yl)-3,4-dihydroquinolin-l(2H)-yl)sulfonyl)benzoate, A/-(5-(l-((5-chloro-2- fluorophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l- ((2-chloro-5-fluorophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, A/-(5-(l-(benzo[d][l,3]dioxol-5-ylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(l-((l-methyl-lH-indol-5-yl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(5-(l-((2,3-dihydro-lH-inden-5-yl)sulfonyl)- l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-((2,3- dihydrobenzo[b][l,4]dioxin-6-yl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, A/-(4-methyl-5-(l-((5, 6,7, 8-tetrahydronaphthalen-2-yl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(5-(l-(benzofuran-2-ylsulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-(benzo[b]thiophen-3-ylsulfonyl)- 1.2.3.4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-(benzofuran-6- ylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-((2,6- dichlorophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-((5- (l-((2,6-difluorophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(l-((3-oxo-3,4-dihydro-2H-benzo[b] [l,4]thiazin-6-yl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(4-methyl-5-(l-((2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(4- methyl-5-(l-((4-nitrophenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, 3- ((6-(2-acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin-l(2H)-yl)sulfonyl)benzoic acid, A/-(3- ((6-(2-acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin-l(2H)-yl)sulfonyl)phenyl)acrylamide, A/-(3-((6-(2-acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin-l(2H)-yl)sulfonyl)phenyl)-2- chloroacetamide, tert-butyl 7-(2-acetamido-4-methylthiazol-5-yl)-4-(phenylsulfonyl)-3,4- dihydroquinoxaline-l(2H)-carboxylate, A/-(4-methyl-5-(l-(phenylsulfonyl)-l, 2,3,4- tetrahydroquinoxalin-6-yl)thiazol-2-yl)acetamide, A/-(4-methyl-5-(4-methyl-l-(phenylsulfonyl)- 1.2.3.4-tetrahydroquinoxalin-6-yl)thiazol-2-yl)acetamide, A/-(5-(5-(phenylsulfonyl)-5, 6,7,8- tetrahydro-1, 5-naphthyridin-2-yl)thiazol-2-yl)acetamide, A/-(5-(l-(phenylsulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-l,3,4-thiadiazol-2-yl)acetamide, /V-(5-(l-((4-aminophenyl)sulfonyl)- 1.2.3.4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(4-((6-(2-acetamido-4- methylthiazol-5-yl)-3,4-dihydroquinolin-l(2H)-yl)sulfonyl)phenyl)acrylamide, A/-(4-((6-(2- acetamido-4-methylthiazol-5-yl)-3,4-dihydroquinolin-l(2/7)-yl)sulfonyl)phenyl)-2- chloroacetamide, A/-(5-(l-((4-acetylphenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide, A/-(5-(l-((4-(dimethylamino)phenyl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-((4-(2- bromoacetyl)phenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, N- (5-(l-((4-(l-hydroxyethyl)phenyl)sulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2- yl)acetamide, A/-(5-(5-((2,3-dichlorophenyl)sulfonyl)-5,6,7,8-tetrahydro-l,5-naphthyridin-2- yl)thiazol-2-yl)acetamide, A/-(5-(5-((2,3-dichlorophenyl)sulfonyl)-5,6,7,8-tetrahydro-l,5- naphthyridin-2-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(5-((5-chloro-2-fluorophenyl)sulfonyl)- 5,6,7,8-tetrahydro-l,5-naphthyridin-2-yl)thiazol-2-yl)acetamide, A/-(5-(5-((5-chloro-2- fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-l,5-naphthyridin-2-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-benzoyl-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(5-(l-benzyl- l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, tert-butyl 9-(2-acetamido-4- methylthiazol-5-yl)-6-(phenylsulfonyl)-3,4,4a,5,6,10b-hexahydrobenzo[h][l,6]naphthyridine- l(2H)-carboxylate, /V-(4-methyl-5-(6-(phenylsulfonyl)-l,2,3,4,4a,5,6,10b- octahydrobenzo[h][l,6]naphthyridin-9-yl)thiazol-2-yl)acetarnide, /V-(4-methyl-5-(l-methyl-6- (phenylsulfonyl)-l,2,3,4,4a,5,6,10b-octahydrobenzo[h][l,6]naphthyridin-9-yl)thiazol-2- yl)acetamide, A/-(5-(4-ethylthio)-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4- methylthiazol-2-yl)acetamide, A/-(5-(l-((3-chloro-2-fluorophenyl)sulfonyl)-l, 2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(l-(phenylsulfonyl)- 4-(piperidin-l-yl)-l,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)acetamide, A/-(5-(4-(3- isopropoxyazetidin-l-yl)-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)-4-methylthiazol- 2-yl)acetamide, /V-(5-(4-(dimethylamino)-l-(phenylsulfonyl)-l,2,3,4-tetrahydroquinolin-6-yl)- 4-methylthiazol-2-yl)acetamide, A/-(5-(4-cyclobutoxy-l-(phenylsulfonyl)-l,2,3,4- tetrahydroquinolin-6-yl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(3-(methylsulfonyl)- 4-(phenylsulfonamido)phenyl)thiazol-2-yl)acetamide, A/-(5-(4-((2- chlorophenyl)sulfonamido)-3-(methylsulfonyl)phenyl)-4-methylthiazol-2-yl)acetamide, A/- (4-methyl-5-(3-(methylsulfonyl)-4-(naphthalene-1-sulfonamido)phenyl)thiazol-2- yl)acetamide, A/-(4-methyl-5-(2-(phenylsulfonyl)isoindolin-5-yl)thiazol-2-yl)acetamide, A/- (5-(2-((2-chlorophenyl)sulfonyl)isoindolin-5-yl)-4-methylthiazol-2-yl)acetamide A/-(5-(3- fluoro-4-(phenylsulfonamidomethyl)phenyl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl- 5-(3-(methylsulfonyl)-4-(phenylsulfonamidomethyl)phenyl)thiazol-2-yl)acetamide, A/-(5-(3- fluoro-4-((phenylsulfonyl)methyl)phenyl)-4-methylthiazol-2-yl)acetamide, A/-(4-methyl-5-(3- (methylsulfonyl)-4-((phenylsulfonyl)methyl)phenyl)thiazol-2-yl)acetamide, A/-(4-methyl-5- (4-(A/-methylphenylsulfonamido)-3-(methylsulfonyl)phenyl)thiazol-2-yl)acetamide, A/-(4- methyl-5-(3-(methylthio)-4-(phenylsulfonamido)phenyl)thiazol-2-yl)acetamide, A/-(4- methyl-5-(3-(methylsulfinyl)-4-(phenylsulfonamido)phenyl)thiazol-2-yl)acetamide, A/-(4- methyl-5-(4-(phenylsulfonamido)-3-(pyrrolidin-1-yl)phenyl)thiazol-2-yl)acetamide, Methyl 5-(2-acetamido-4-methylthiazol-5-yl)-2-(phenylsulfonamido)benzoate, A/-(5-(3- (benzyloxy)-4-(phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide, A/-(5-(3-fluoro- 4-(phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide, A/-(5-(3-cyclopropyl-4- (phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide, A/-(5-(3-acetamido-4- (phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide, A/-(5-(3-(methoxymethyl)-4- (phenylsulfonamido)phenyl)-4-methylthiazol-2-yl)acetamide. 10. A compound according to Formula 2 Formula 2 wherein R1 is C, S, O or N, R3 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl comprising Cl, Br, or F), -CN, carbonyl, carboxyl, carboxy ester, alkoxy, aldehyde, primary, secondary or tertiary amine, amide, imide, carbamate, carboxamide, nitro, sulfide, sulfinyl, sulfonyl, sulfino or sulfonamide, R4 and R5 can be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl, preferably comprising Cl, Br or F), C4 to C6 aryl, sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, carbonyl C=OR, wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably comprising Cl, Br or F), C4 to C6 aryl, wherein R is optionally substituted with a carbamate or a carbamate ester, wherein when R10 and R11 or R11 and R14 do not form a ring structure, at least one of R4 and R5 is carbonyl C=OR, or R4 and R5 form a 4-, 5- or 6-membered hetero cycloalkyl comprising N and optionally one or more further heteroatoms (preferably N, O and/or S), wherein said hetero cycloalkyl is optionally substituted by alkoxy, R6 is absent or, R1 is C and R6 forms a carbonyl C=O with R1 or, R1 is S and R6 forms a sulfoxide S=O with R1 , R7, R8 and R9 are the same or different, C or N, R10 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), C3 to C6 cycloalkyl, C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl comprising Cl, Br, or F), -CN, carbonyl -, carboxyl, carboxy ester, alkoxy, aldehyde, primary, secondary or tertiary amine, amide, imide, carbamate, carboxamide, nitro, sulfide, sulfinyl, sulfonyl, sulfino or sulfonamide, R11 is C3 to C6 cycloalkyl, C4 to C6 hetero cycloalkyl (preferably comprising N, S and/or O), halogen (preferably F, Cl, or Br), sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxyl ester, carboxamide, alkoxy or aryloxy, or R10 and R11 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure D comprising two carbon atoms of B, forming a condensed cyclic group with B, optionally comprising one or more heteroatoms (preferably N, O and/or S), R14 is H, C1 to C5 alkyl (preferably C1 to C3 alkyl), a primary, secondary or tertiary amine or alkyl amine, or R11 and R14 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure C comprising two carbon atoms of B, forming a condensed bicyclic group with B, optionally comprising one or more heteroatoms (preferably N, O and/or S), wherein B and C is one of R12 is C1 to C5 alkyl (preferably C1 to C3 alkyl), carbonyl C=O, sulfide, sulfinyl or sulfonyl, R13 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R12 and R13 are absent when R11 is halogen, or not forming a ring structure with R10 or R14, or when R11 and R14 form together with the atoms they are attached to a 5- to 8- membered cycloalkyl or aryl ring structure C and R15 and R16 are present, R15 is C1 to C5 alkyl (preferably C1 to C3 alkyl), carbonyl C=O, sulfide, sulfinyl or sulfonyl, when R11 and R14 are not forming a ring structure, or when R11 and R14 form a 5-, 7- or 8-membered ring structure, or R15 is C1 to C5 alkyl (preferably C1 to C3 alkyl), sulfide, sulfinyl or sulfonyl, when R11 and R14 form a 6- membered ring structure, R16 is C1 to C5 alkyl (preferably C1 to C3 alkyl), C2 to C5 alkenyl, C3 to C6 cycloalkyl, C5 or C6 aryl, alkyl aryl, C5 or C6 hetero aryl (preferably comprising N, S and/or O), a bicyclic group (preferably comprising one or two aromatic rings), optionally comprising one or more heteroatoms (preferably N, O and/or S), or R15 and R16 are absent when R14 is H, or R10 and R11 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure D, or when R11 and R14 form together with the atoms they are attached to a 5- to 8-membered cycloalkyl or aryl ring structure C and R12 and R13 are present, X is C, S and/or O, Y is C, N, S and/or O, R17 may be the same or different, absent (electron pair of X), H, hydroxy, halogen (preferably F, Cl or Br), alkoxy, C1 to C5 alkyl (preferably C1 to C3 alkyl), C1 to C5 haloalkyl (preferably C1 to C3 haloalkyl comprising Cl, Br, or F), C3 to C6 cycloalkyl, C3 to C6 hetero cycloalkyl (preferably comprising N,0 and/or S and optionally substituted with alkoxy), C4 to C6 aryl, carbonyl C(=O)R, wherein R is C1 to C5 alkyl (preferably C1 to C3 alkyl), carboxyl, carboxy ester, alkoxy (preferably -OCH3, -OCFhCHs or C3 to C6 cycloalkyl alkoxy), aldehyde, primary, secondary or tertiary amine, amide, imide, carbamate, carboxamide, nitro, sulfide (preferably -SCH3, -SCH2CH3), sulfinyl, sulfonyl, sulfino or sulfonamide or when X is C forming a carbonyl C=O with X or when X is S forming sulfoxide S=O or sulfonyl S(=O)2 with X, or two R17 are forming a 4-, 5- or 6-membered cycloalkyl, optionally comprising one or more hetero atoms (preferably N, O and/or S), R18 may be the same or different, H, alkoxy, or one R17 and one R18 form a 5- or 6-membered cyclic ring structure comprising two carbon atoms of C, forming a condensed cyclic group with C, optionally comprising one or more heteroatoms (preferably N, O and/or S), wherein the 5- or 6-membered cyclic ring structure is optionally substituted with C1 to C3 alkyl or alkoxy carbonyl (preferably at the position of the heteroatom), and R19 may be the same or different, H, C1 to C6 alkyl (preferably C1 to C3 alkyl). 11. The compound according to claim 10, wherein R10 and R11 form together with the atoms they are attached to a 5- to 7-membered cyclic or aryl ring structure D forming a condensed bicyclic group with B, wherein B and D is and wherein R7, R8, R9, R12 and R13 are according to claim 10. 12. The compound according to any one of claims 10 or 11 , wherein R16 is one of wherein R20 may be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and/or Br), alkoxy or E, wherein E is one of R21 may be the same or different, H, C1 to C5 alkyl (preferably C1 to C3 alkyl), halogen (preferably F, Cl and/or Br), alkoxy, primary, secondary or tertiary amine, sulfide, sulfinyl, sulfonyl, sulfino, sulfonamide, carboxyl, carboxy ester, a secondary hydroxyl group C(- OH)CH3, carbonyl C=OR (wherein R is C1 to C10 alkyl (preferably C1 to C5 alkyl), C1 to C3 haloalkyl (preferably comprising Cl, Br or F)), imide, carbamate, carboxamide, amide N=OR (wherein R is C1 to C3 alkyl, C1 to C3 alkenyl, C1 to C3 haloalkyl (preferably comprising Cl, Br or F)), nitro or E, R22 may be the same or different, H or C1 to C5 alkyl (preferably C1 to C3 alkyl), R23 is H, carbonyl, carboxyl or carboxy ester, R24 is H or C1 to C5 alkyl (preferably C1 to C3 alkyl), and R25 may be the same or different, H, C1 to C4 alkyl, C1 to C4 heteroalkyl, C3 to C6 cycloalkyl, C2 to C6 heterocycloalkyl. 13. The compound according to any one of the preceding claims for use as a medicament in the treatment of a medical condition associated with defective and/or pathologic signaling of the beta isoform of class II phosphoinositide 3-kinase (PI3K-C2b). 14. The compound according to any one of the preceding claims for use as a medicament in the treatment of a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, wherein the medical condition is selected from the group consisting of stroke, a cardiovascular disease related to endothelial cell dysfunction, cancer, cancer metastasis, myopathy (preferably myotubular myopathy) and diabetes. 15. A pharmaceutical composition for use as a medicament in the treatment of a medical condition associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling, comprising one or more compounds according to any one of the preceding claims with a pharmaceutically acceptable carrier. 16. An in vitro method for modulating (preferably inhibiting) class II phosphoinositide 3-kinase (PI3K) signaling comprising the administration of a compound according to any one of the preceding claims, or a composition comprising said compound, to a cell in which PI3K signaling is to be modulated.

Description

THIAZOLO TETRAHYDROCHINOLINE COMPOUNDS AS CLASS II PHOSPHOINOSITIDE 3-KINASE INHIBITORS DESCRIPTION The invention is in the field of biochemistry and medicine relates to chemical compounds useful as inhibitors of class II phosphoinositide 3-kinase (PI3K) signalling. The invention further relates to the medical use of inhibitors of class II phosphoinositide 3-kinase (PI3K) signalling in the treatment of medical conditions associated with defective and/or pathologic class II phosphoinositide 3-kinase (PI3K) signaling such as stroke, a cardiovascular disease related to endothelial cell dysfunction, cancer, cancer metastasis, myopathy and diabetes. The invention further relates to the medical use of inhibitors of signalling of the beta isoform of class II phosphoinositide 3-kinase (PI3K-2b) in the treatment of medical conditions associated with defective and/or pathologic signaling of the beta isoform of class II phosphoinositide 3-kinase (PI3K-C2b). BACKGROUND OF THE INVENTION The phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases central to regulating a wide range of important intracellular processes. PI3Ks orchestrate cell responses including mitogenic signaling, cell survival and growth, metabolic control, vesicular trafficking, degranulation, cytoskel- etal rearrangement and migration. PI3Ks catalyze the phosphorylation of the 3-OH group on the inositol ring of phosphatidylinositol. Based on substrate preference, amino acid sequence, and structure, three classes of PI3Ks are identified. Class I PI3Ks are the earliest discovered PI3Ks. They form hetero-dimers by association of a catalytic subunit and a regulatory subunit that produce P I (3 ,4,5)P3. Class I PI3Ks are further classified into class IA (p110a, p, and 5) and class IB (p110y), based on distinct regulatory subunits (Figure 1). The structural similarity between kinase domains of class I PI3Ks and protein kinases implies that PI3Ks have protein kinase activity in addition to lipid kinase activity. Class II phosphoinositide 3-kinases (PI3Ks) control multiple cellular functions ranging from membrane and actin dynamics to cell signaling via synthesis of 3'-phosphorylated inositol phospholipids. In contrast to class I, relatively little is known about class II PI3K. Class II PI3Ks produce PI(3)P or PI(3,4)P2, with varying levels of efficiency that may be related to isoform and cell type. There are three class II PI3K isoforms (PI3KC2oc, PI3KC2P, and PI3KC2y) in vertebrates, but only one member exists in worm and fly. Similar to the catalytic subunit of class I PI3Ks, all class II isoforms contain a Ras binding domain (RBD), a C2 domain (C2), a helical domain (HD), and a kinase domain, but have unique disordered regions in their N-terminus and are extended by two lipid binding domains (PX and C2 domain) at their C-terminus. Unlike class I PI3K, class II PI3K kinases lack regulatory subunits and act as monomers. Class II PI3K isoforms have been demonstrated to couple signaling to membrane traffic. This indicates that distinct mechanisms serve to recruit PI3KII and that their lipid product has unique roles [PI(3)P and/or PI(3,4)P2]. Recently, the a isoform has been shown to synthesize PI(3,4)P2 on endocytic pits at the plasma membrane, where PI(3,4)P2 is required for membrane constriction prior to vesicle fission (Posor et al, Nature, 2013, 499, 233-237) and is required to internalize VEGF receptor in endothelial cells (Yoshioka et al., Nat. Med., 2012, 18, 1560-1569). Besides, PI3KC2oc knock-down impairs autophagy at least in some cells and the maturation of endocytic vesicles. PI3KC2oc can also generate PI(3)P and regulate the formation of a PI(3)P pool at peri- centriolar recycling endosomes (PRE) required for Rabi 1 and Shh pathway activation and primary cilia formation. The activity of the beta isoform of class II PI3K (PI3KC2P, also termed PI3K-C2b) is associated with endocytosis, proliferation and glucose metabolism. Moreover, the beta isoform regulates nutrient signaling by suppressing mTORCI signaling via local production of PI(3,4)P2 at late endosomes or lysosomes (Marat et al, Science, 2017, 356, 968-972). Endothelial-specific PI3KC2a knock-out mice display a vascular barrier function defect indicating that PI3KC2a is involved in angiogenesis (Yoshioka et al., Endothelial PI3K-C2alpha, a class II PI3K, has an essential role in angiogenesis and vascular barrier function. Nat. Med. 2012, 18, 1560-1569). In addition, the liver-specific C2y isoform has recently been shown to produce an endosomal PI(3,4)P2 pool needed for sustained Akt2 activation following insulin stimulation (Braccini et al., Nat. Commun. 2015, 6, 7400). Based on data accumulated to this point in time, class II PI3Ks appear to be involved in cancer, cardiovascular disease, myopathy and diabetes, amongst other diseases (Falasca et al, J. Med. Chem. 2016, 60, 47-65). Cell permeable small-molecule inhibitors of kinases are excellent tools to directly and quickly unrav