Substituted quinoxaline derivatives as interleukin-8 receptor antagonists

A compound which is selected from the group consisting of:

• N-(1-Azabicyclo[2.2.2]octanyl-3-pyridinyl)-3-(2-pyridinyl)-2-quinoxalinamine;
• N-[3-(1H-Imidazol-1-yl)propyl]-3-(2-pyridinyl)-2-quinoxalinamine;
• N-[2-(1-Methyl pyrrolidinyl)ethyl]-3-(2-pyridinyl)-2-quinoxalinamine;
• 1-[3-[[3-Pyridinyl-2-quinoxalinamine]amino]propyl]-2-pyrrolidinone;
• N-[4-(4-Morpholinyl)phenyl]-3-(2-pyridinyl)quinoxalinamine;
• N-(4-Piperidinylmethyl)-3-(2-pyridinyl)-2-quinoxalinamine;
• N-[4-(Dimethylamino)phenyl]-3-(2-pyridinyl)-2-quinoxalinamine;
• N-Methyl-N-[4-[[3-(2-pyridinyl)-2-quinoxalinyl]amino]phenyl]-acetamide;
• N-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-cyclohexane-1,4-diamine;
• 2-[1,4′]Bipiperidinyl-1′-yl-6,7-dichloro-3-pyridin-2-yl-quinoxaline;
• (6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-(4-diethylaminomethyl-phenyl)amine;
• N′-(6,7-Dichloro-3-furan-2-yl-quinoxalin-2-yl)-N,N-dimethyl-propane-1,3-diamine;
• N′-(6,7-Dichloro-3-thiophen-2-yl-quinoxalin-2-yl)-N,N-dimethyl-propane-1,3-diamine;
• N′-(6,7-Difluoro-3-thiophen-2-yl-quinoxalin-2-yl)-N,N-dimethyl-butane-1,4-diamine;
• N′-[6,7-Dichloro-3-(1H-indol-2-yl)-quinoxalin-2-yl]-N,N-diethyl-butane-1,4-diamine;
• N′-(3-Benzo[b]thiophen-2-yl-6,7-dichloro-quinoxalin-2-yl)-N,N-diethyl-butane-1,4-diamine;
• N,N-Diethyl-N′-(3-thiophen-2-yl-7-trifluoromethyl-quinoxalin-2-yl)-butane-1,4-diamine;
• N′-[6,7-Dichloro-3-(5-methyl-thiophen-2-yl)-quinoxalin-2-yl]-N,N-diethyl-butane-1,4-diamine;
• N′-(6,7-Dichloro-3-thiazol-2-yl-quinoxalin-2-yl)-N,N-dimethyl-propane-1,3-diamine;
• N′-(3-[2.2′]Bithiophenyl-5-yl-6,7-dichloro-quinoxalin-2-yl)-N,N-diethyl-butane-1,4-diamine;
• N′-[6,7-Dichloro-3-(5-chloro-thiophen-2-yl)-quinoxalin-2-yl]-N,N-diethyl-butane-1,4-diamine;
• N′-[6,7-Dichloro-3-(5-methoxy-thiophen-2-yl)-quinoxalin-2-yl]-N,N-diethyl-butane-1,4-diamine;
• N′-[6,7-Dichloro-3-(5-propyl-thiophen-2-yl)-quinoxalin-2-yl]-N,N-diethyl-butane-1,4-diamine;
• N′-(3-Benzofuran-2-yl-6,7-dichloro-quinoxalin-2-yl)-N,N-diethyl-butane-1,4-diamine;
• N′-[6,7-Dichloro-3-dibenzothiophen-4-yl-quinoxalin-2-yl)-N,N-diethyl-butane-1,4-diamine;
• [6,7-Dichloro-3-(5-phenyl-oxazol-2-yl)-quinoxalin-2-yl-(4-pyrrolidin-1-yl-butyl)-amine;
• [6,7-Dichloro-3-(5-thiophen-2-yl-oxazol)-quinoxalin-2-yl]-(4-pyrrolidin-1-yl-butyl)-amine;
• N-(6,7-Dichloro-3-pyridinyl-3-quinoxalin-2-yl)-N′,N′-dimethyl-cyclohexane-1,4-diamine;
• N-(6,7-Dichloro-3-pyridin-4-yl-quinoxalin-2-yl)-N′,N′-dimethyl-cyclohexane-1,4-diamine;
• N-(6,7-Dimethoxy-3-pyridin-2yl-quinoxalin-2-yl)-N′,N′-dimethyl-cyclohexane-1,4-diamine;
• N,N-Dimethyl-N′-(3-pyridin-2-yl-7,8-dihydro-6H-cyclopenta[g]quinoxalin-2-yl)-cyclohexane-1,4-diamine;
• N′-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-N,N-dimethyl-butane-1,4-diamine;
• N′-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-N,N-dimethyl-pentane-1,5-diamine;
• N-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-pentane-1,5-diamine;
• N′-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-N,N-dimethyl-hexane-1,6-diamine;
• [3-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-ylsulfanyl)-propyl]-dimethylamine;
• (6,7-Dichloro-2-pyridin-2-yl-quinoxalin-2-yl)-(3-morpholin-4-yl-propyl)-amine;
• (6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-(3-methoxypropyl)-amine;
• N′-1-[3-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-ylamino)-propyl]-N′-1-methylpropane-1,3-diamine;
• 2-{[3-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-ylamino)-propyl]-(2-hydroxy-ethyl)-amino}-ethanol;
• {4-[4-(2-Chloro-phenyl)-piperidin-1-yl]-butyl-(6,7-dichloro-3-pyridin-2-yl-quinoxalin-2-yl)}amine;
• (6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-(1-phenyl-4-piperidin-1-yl-butyl)-amine;
• [6,7-Dichloro-3-(1-ethyl-5-phenyl-imidazol-2-yl)-quinoxalin-2-yl]-(4-pyrrolidin-1-yl-butyl)-amine;
• [6,7-Dichloro-3-(1-phenyl-imidazol-2-yl)-quinoxalin-2-yl]-(4-pyrrolidin-1-yl-butyl)-amine;
• [6,7-Dichloro-3-[1-ethyl-5-(5-methyl-thiophene-2-yl)-imidazol-5-yl]-quinoxalin-2-yl]-(4-pyrrolidin-1-yl-butyl)-amine;
• and
• [6,7-Dichloro-3-(1-phenyl-pyrazolo-5-yl)-quinoxalin-2-yl]-(4-pyrrolidin-1-yl-butyl)-amine;
• or a pharmaceutically acceptable salt thereof.

A compound of Formula I:

• wherein A is
• wherein R3, R3a, and R3b are each independently the same or different and are hydrogen,
• aryl-SO2—,
• aryl,
• heteroaryl,
• —OR4 wherein R4 is hydrogen,
• alkyl,
• aryl,
• aralkyl,
• acetyl, or
• wherein
• R5 and R6 are each the same or different and are hydrogen, alkyl, cycloalkyl, acetyl, —(CH2)m—OH, or R5 and R6 are taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or N—R4 wherein R4 is as defined above and m is an integer of 2 to 5,
• wherein n is zero or an integer of 1 and R7 and R8 are each independently the same or different and are hydrogen,
• alkyl,
• aryl,
• aralkyl,
• acetyl, or
• wherein R5 and R6 are as defined above or R7 and R8 taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or N—R4 wherein R4 and m are as defined above,
• wherein R7, R8, and n are as defined above,
• wherein R7, R8, and n are as defined above,
• —(CH2)n—SO2OR4 wherein R4 and n are as defined above,
• —(CH2)n—CO2R4 wherein R4 and n are as defined above,
• —CH2OR4 wherein R4 is as defined above,
• CF3,
• CBr3,
• CCl3, or
• NO2;
• wherein R3, R3a, and R3b are each independently the same or different and are hydrogen,
• alkyl,
• aryl-SO2—,
• aryl,
• heteroaryl,
• —OR4 wherein R4 is hydrogen,
• alkyl,
• aryl,
• aralkyl,
• acetyl, or
• wherein
• R5 and R6 are each the same or different and are hydrogen, alkyl, cycloalkyl, acetyl, —(CH2)m—OH, or R5 and R6 are taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or N—R4 wherein R4 is as defined above and m is an integer of 2 to 5,
• wherein n is zero or an integer of 1 and R7 and R8 are each independently the same or different and are hydrogen,
• alkyl,
• aryl,
• aralkyl,
• acetyl, or
• wherein R5 and R6 are as defined above or R7 and R8 taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or N—R4 wherein R4 and m are as defined above,
• wherein R7, R8, and n are as defined above,
• wherein R7, R8, and n are as defined above,
• —(CH2)n—SO2OR4 wherein R4 and n are as defined above,
• —(CH2)n—CO2R4 wherein R4 and n are as defined above,
• —CH2OR4 wherein R4 is as defined above,
• halogen,
• CF3,
• CBr3,
• CCl3, or
• NO2;
• R2 is CF3,
• CCl3,
• CBr3, or
• wherein R10 is hydrogen,
• alkyl, or
• aralkyl, and
• wherein n, R5, and R6 are as defined above,
• wherein R5, R6, and m are as defined above,
• wherein R12 and R12a are each independently the same or different and are hydrogen, alkyl, or aryl, or taken together can form a 5- to 7-membered ring, and
• R13 is hydrogen or alkyl, and
• m is as defined above,
• wherein m, R12, R12a, and R13 are as defined above,
• wherein R9 and m are as defined above,
• wherein R9 and m are as defined above,
• wherein m and o are as defined above,
• wherein n, o, R5, and R6 are as defined above,
• wherein n and R9 are as defined above,
• wherein n is as defined above,
• wherein n is as defined above,
• wherein m is as defined above, or
• R10 and R11 when taken together can form a 5- to 7-membered ring optionally containing an oxygen atom or N—R4 wherein R4 is as defined above;
• or a pharmaceutically acceptable salt thereof.

A method for preparing a compound having the Formula Ia:

• wherein A is
• wherein R3, R3a and R3b are each independently the same or different and are hydrogen,
• alkyl,
• aryl-SO2—,
• aryl,
• heteroaryl,
• —OR4 wherein R4 is hydrogen,
• alkyl,
• aryl,
• aralkyl,
• acetyl, or
• wherein
• R5 and R6 are each the same or different and are hydrogen, alkyl, cycloalkyl, acetyl, —(CH2)m—OH, or R5 and R6 are taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or N—R4 wherein R4 is as defined above and m is an integer of 2 to 5,
• wherein n is zero or an integer of 1 and R7 and R8 are each independently the same or different and are hydrogen,
• alkyl,
• aryl,
• aralkyl,
• acetyl, or
• wherein R5 and R6 are as defined above or R7 and R8 taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or N—R4 wherein R4 and m are as defined above,
• wherein R7, R8, and n are as defined above,
• wherein R7, R8, and n are as defined above,
• —(CH2)n—SO2OR4 wherein R4 and n are as defined above,
• —(CH2)n—CO2R4 wherein R4 and n are as defined above,
• —CH2OR4 wherein R4 is as defined above,
• halogen,
• CF3,
• CBr3,
• CCl3, or
• NO2,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R14 is hydrogen, alkyl, aryl, or aralkyl, and R3 and R3a are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3 and R3a are as defined above,
• wherein R3, R3a, and R14 are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3 is as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a and R3b are as defined above,
• wherein R3 and R3a are as defined above,
• wherein R3 and R3a are as defined above,
• wherein R3 and R3a are as defined above,
• wherein R3, R3a and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above, or
• wherein R3, R3a, and R3b are as defined above;
• and
• R10 is hydrogen,
• alkyl, or
• aralkyl, and
• wherein n, R5, and R6 are as defined above,
• wherein R5, R6, and m are as defined above,
• wherein R12 and R12a are each independently the same or different and are hydrogen, alkyl, or aryl, or taken together can form a 5- to 7-membered ring, and
• R13 is hydrogen or alkyl, and
• m is as defined above,
• wherein m, R12, R12a, and R13 are as defined above,
• wherein R9 and m are as defined above,
• wherein R9 and m are as defined above,
• wherein m and o are as defined above,
• wherein n, o, R5, and R6 are as defined above,
• wherein n and R9 are as defined above,
• wherein n is as defined above,
• wherein n is as defined above,
• wherein m is as defined above, or
• R10 and R11 when taken together can form a 5- to 7-membered ring optionally containing an oxygen atom or N—R4 wherein R4 is as defined above;
• or a pharmaceutically acceptable salt thereof, comprises reacting a compound of Formula III
• wherein A and R1 are as defined above with a compound of Formula IV
• wherein R10 and R11 are as defined above in a solvent to afford a compound of Formula Ia.

A pharmaceutical composition adapted for administration as an agent for treating psoriasis, atopic dermatitis, disease associated with pathologicalangiogenesis, cancer, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, gastric ulcer, septic shock, endotoxicshock, gram-negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulo-nephritis, or thrombosis, Alzheimer's disease, graft versus host reaction, allograft rejections, or allergic diseases comprising a therapeutically effective amount of a compound of Formula I in admixture with a pharmaceutically acceptable excipient, diluent, or carrier, wherein said compound of Formula I is:

• wherein A is
• wherein R3, R3a, and R3b are each independently the same or different and are hydrogen,
• alkyl,
• aryl-SO2—,
• aryl,
• heteroaryl,
• —OR4 wherein R4 is hydrogen,
• alkyl,
• aryl,
• aralkyl,
• acetyl, or
• wherein
• R5 and R6 are each the same or different and are hydrogen, alkyl, cycloalkyl, acetyl, —(CH2)m—OH, or R5 and R6 are taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or N—R4 wherein R4 is as defined above and m is an integer of 2 to 5,
• wherein n is zero or an integer of 1 and R7 and R8 are each independently the same or different and are hydrogen,
• alkyl,
• aryl,
• aralkyl,
• acetyl, or
• wherein R5 and R6 are as defined above or R7 and R8 taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or N—R4 wherein R4 and m are as defined above,
• wherein R7, R8, and n are as defined above,
• wherein R7, R8, and n are as defined above,
• —(CH2)n—SO2OR4 wherein R4 and n are as defined above,
• —(CH2)n—CO2R4 wherein R4 and n are as defined above,
• —CH2OR4 wherein R4 is as defined above,
• halogen,
• CF3,
• CBr3,
• CCl3, or
• NO2,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R14 is hydrogen, alkyl, aryl, or aralkyl, and R3 and R3a are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3 and R3a are as defined above,
• wherein R3 and R3a are as defined above,
• wherein R3, R3a, and R14 are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3 is as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3 and R3a are as defined above,
• wherein R3 and R3a are as defined above,
• wherein R3 and R3a are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above, or
• wherein R3, R3a, and R3b are as defined above;
• and
• R2 is CF3,
• CCl3,
• CBr3, or
• wherein R10 is hydrogen,
• alkyl, or
• aralkyl, and
• wherein n, R5, and R6 are as defined above,
• wherein R5, R6, and m are as defined above,
• wherein R12 and R12a are each independently the same or different and are hydrogen, alkyl, or aryl, or taken together can form a 5- to 7-membered ring, and
• R13 is hydrogen or alkyl, and
• m is as defined above,
• wherein m, R12, R12a, and R13 are as defined above,
• wherein R9 and m are as defined above,
• wherein R9 and m are as defined above,
• wherein m and o are as defined above,
• wherein n, o, R5, and R6 are as defined above,
• wherein n and R9 are as defined above,
• wherein n is as defined above,
• wherein n is as defined above,
• wherein m is as defined above, or
• R10 and R11 when taken together can form a 5- to 7-membered ring optionally containing an oxygen atom or N—R4 wherein R4 is as defined above;
• or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition suitable for oral administration comprising a compound of Formula I in admixture with a pharmaceutically acceptable excipient, diluent, or carrier for oral dosage, wherein said compound of Formula I is:

• wherein A is
• wherein R3, R3a, and R3b are each independently the same or different and are hydrogen,
• alkyl,
• aryl-SO2—,
• aryl,
• heteroaryl,
• —OR4 wherein R4 is hydrogen,
• alkyl,
• aryl,
• aralkyl,
• acetyl, or
• wherein
• R5 and R6 are each the same or different and are hydrogen, alkyl, cycloalkyl, acetyl, —(CH2)m—OH, or R5 and R6 are taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or N—R4 wherein R4 is as defined above and m is an integer of 2 to 5,
• wherein n is zero or an integer of 1 and R7 and R8 are each independently the same or different and are hydrogen,
• alkyl,
• aryl,
• aralkyl,
• acetyl, or
• wherein R5 and R6 are as defined above or R7 and R8 taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or N—R4 wherein R4 and m are as defined above,
• wherein R7, R8, and n are as defined above,
• wherein R7, R8, and n are as defined above,
• —(CH2)n—SO2OR4 wherein R4 and n are as defined above,
• —(CH2)n—CO2R4 wherein R4 and n are as defined above,
• —CH2OR4 wherein R4 is as defined above,
• halogen,
• CF3,
• CBr3,
• CCl3, or
• NO2,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R14 is hydrogen, alkyl, aryl, or aralkyl, and R3 and R3a are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3 and R3a are as defined above,
• wherein R3 and R3a are as defined above,
• wherein R3, R3a, and R14 are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3 is as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3 and R3a are as defined above,
• wherein R3 and R3a are as defined above,
• wherein R3 R3a are as defined above,
• wherein R3, R3a, and R3b are as defined above,
• wherein R3, R3a, and R3b are as defined above, or
• wherein R3, R3a, and R3b are as defined above;
• and
• R2 is CF3,
• CCl3,
• CBr3, or
• wherein R10 is hydrogen,
• alkyl, or
• aralkyl, and
• wherein n, R5, and R6 are as defined above,
• wherein R5, R6, and m are as defined above,
• wherein R12 and R12a are each independently the same or different and are hydrogen, alkyl, or aryl, or taken together can form a 5- to 7-membered ring, and
• R13 is hydrogen or alkyl, and
• m is as defined above,
• wherein m, R12, R12a, and R13 are as defined above,
• wherein R9 and m are as defined above,
• wherein R9 and m are as defined above,
• wherein m and o are as defined above,
• wherein n, o, R5, and R6 are as defined above,
• wherein n and R9 are as defined above,
• wherein n is as defined above,
• wherein n is as defined above,
• wherein m is as defined above, or
• R10 and R11 when taken together can form a 5- to 7-membered ring optionally containing an oxygen atom or N—R4 wherein R4 is as defined above;
• or a pharmaceutically acceptable salt thereof.