Fused heterocyclic or carbocyclic compounds carrying a substituted cycloaliphatic radical and use thereof for treating vasopressin-related diseases

Abstract

The present invention relates to novel fused heterocyclic or carbocyclic compounds of formula I ##STR00001##
wherein the variables are as defined in the claims and the description. The invention further relates to pharmaceutical compositions comprising these compounds, and to their use for the treatment of vasopressin-related disorders.

Claims

1. A compound of the formula (I) ##STR00030## wherein X.sup.1, X.sup.2, X.sup.3, X.sup.4 and X.sup.5, independently of each other, are N or CH; R.sup.1 is C.sub.1-C.sub.4-alkyl which carries a group C(O)R.sup.4 or fluorinated C.sub.1-C.sub.4-alkyl which carries a group C(O)R.sup.4; R.sup.2 is phenyl or a 5- or 6-membered heteroaromatic ring with 1, 2 or 3 heteroatoms selected from the group consisting of O, S and N as ring members, where phenyl or the 5- or 6-membered heteroaromatic ring may carry 1, 2 or 3 substituents R.sup.5; R.sup.3 is a 3-, 4-, 5- or 6-membered saturated or partially unsaturated carbocyclic ring which carries one substituent R.sup.6 and which may additionally carry 1 or 2 substituents R.sup.7; R.sup.4 is OR.sup.8 or NR.sup.9R.sup.10; each R.sup.5 is independently halogen, cyano, nitro, hydroxyl, C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, fluorinated C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, fluorinated C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl, where the 8 last-mentioned aliphatic and cycloaliphatic radicals may carry one or more radicals R.sup.15; C.sub.3-C.sub.8-cycloalkoxy, fluorinated C.sub.3-C.sub.8-cycloalkoxy, C.sub.1-C.sub.6-alkoxy, fluorinated C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylthio, fluorinated C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl, fluorinated C.sub.1-C.sub.6-alkylsulfinyl, C.sub.1-C.sub.6-alkylsulfonyl, fluorinated C.sub.1-C.sub.6-alkylsulfonyl, amino, C.sub.1-C.sub.6-alkylamino, di-(C.sub.1-C.sub.6-alkyl)-amino, C.sub.1-C.sub.6-alkylcarbonyl, fluorinated C.sub.1-C.sub.6-alkylcarbonyl, carboxyl, C.sub.1-C.sub.6-alkoxycarbonyl, fluorinated C.sub.1-C.sub.6-alkoxycarbonyl, C.sub.1-C.sub.6-alkylcarbonyloxy, fluorinated C.sub.1-C.sub.6-alkylcarbonyloxy, aminocarbonyl, C.sub.1-C.sub.6-alkylaminocarbonyl, di-(C.sub.1-C.sub.6-alkyl)-aminocarbonyl, phenyl, phenyl-C.sub.1-C.sub.2-alkyl, or a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups selected from the group consisting of: O, S, N, NO, SO and SO.sub.2 as ring members, where phenyl, phenyl-C.sub.1-C.sub.2-alkyl and the heterocyclic ring may carry one or more radicals R.sup.13; or two radicals R.sup.5, bound on adjacent ring atoms, form together with the ring atoms to which they are bound a saturated or unsaturated 3-, 4-, 5-, 6-, 7-, 8- or 9-membered ring, wherein the ring may contain 1 or 2 heteroatoms or heteroatom groups selected from the group consisting of O, S, N, NO, SO and SO.sub.2 and/or 1 or 2 CO groups as ring members, and wherein the ring may be substituted by one or more radicals R.sup.13; R.sup.6 is C.sub.1-C.sub.4-alkyl which carries a radical NR.sup.11R.sup.12 or fluorinated C.sub.1-C.sub.4-alkyl, which carries a radical NR.sup.11R.sup.12; each R.sup.7 is independently halogen, cyano, hydroxyl, C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, or fluorinated C.sub.1-C.sub.4-alkoxy, or two radicals R.sup.7 bound on the same carbon ring atom form together a group O (oxo); R.sup.8 is hydrogen, C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, fluorinated C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, fluorinated C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl, where the 8 last-mentioned aliphatic and cycloaliphatic radicals may carry one or more radicals R.sup.15; phenyl, phenyl-C.sub.1-C.sub.2-alkyl, or a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups selected from the group consisting of: O, S, N, NO, SO and SO.sub.2 as ring members, where phenyl, phenyl-C.sub.1-C.sub.2-alkyl and the heterocyclic ring may carry one or more radicals R.sup.13; R.sup.9 and R.sup.10, independently of each other, are hydrogen, C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, fluorinated C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, fluorinated C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl, where the 8 last-mentioned aliphatic and cycloaliphatic radicals may carry one or more radicals R.sup.15; C.sub.1-C.sub.6-alkoxy, fluorinated C.sub.1-C.sub.6-alkoxy, phenyl, phenyl-C.sub.1-C.sub.2-alkyl, or a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups selected from the group consisting of: O, S, N, NO, SO and SO.sub.2 as ring members, where phenyl, phenyl-C.sub.1-C.sub.2-alkyl and the heterocyclic ring may carry one or more radicals R.sup.13; or R.sup.9 and R.sup.10, together with the nitrogen atom they are bound to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring, where the heterocyclic ring may additionally contain 1 or 2 heteroatoms or heteroatom groups selected from the group consisting of: O, S, N, NO, SO, SO.sub.2 and CO as ring members, and where the heterocyclic ring may carry 1, 2, 3 or 4 radicals R.sup.13; R.sup.11 and R.sup.12, independently of each other, are hydrogen, C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, fluorinated C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, fluorinated C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl, where the 8 last-mentioned aliphatic and cycloaliphatic radicals may carry one or more radicals R.sup.15; C.sub.1-C.sub.6-alkoxy, fluorinated C.sub.1-C.sub.6-alkoxy, phenyl, phenyl-C.sub.1-C.sub.2-alkyl, or a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups selected from the group consisting of: O, S, N, NO, SO and SO.sub.2 as ring members, where phenyl, phenyl-C.sub.1-C.sub.2-alkyl and the heterocyclic ring may carry one or more radicals R.sup.13; or R.sup.11 and R.sup.12, together with the nitrogen atom they are bound to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring, where the heterocyclic ring may additionally contain 1 or 2 heteroatoms or heteroatom groups selected from the group consisting of: O, S, N, NO, SO, SO.sub.2 and CO as ring members, and where the heterocyclic ring may carry 1, 2, 3 or 4 radicals R.sup.13; each R.sup.13 is independently halogen, cyano, hydroxyl, C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, fluorinated C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, fluorinated C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy, fluorinated C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylthio, fluorinated C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl, fluorinated C.sub.1-C.sub.6-alkylsulfinyl, C.sub.1-C.sub.6-alkylsulfonyl, fluorinated C.sub.1-C.sub.6-alkylsulfonyl, amino, C.sub.1-C.sub.6-alkylamino, di-(C.sub.1-C.sub.6-alkyl)-amino, C.sub.1-C.sub.6-alkylcarbonyl, fluorinated C.sub.1-C.sub.6-alkylcarbonyl, carboxyl, C.sub.1-C.sub.6-alkoxycarbonyl, fluorinated C.sub.1-C.sub.6-alkoxycarbonyl, C.sub.1-C.sub.6-alkylcarbonyloxy, fluorinated C.sub.1-C.sub.6-alkylcarbonyloxy, aminocarbonyl, C.sub.1-C.sub.6-alkylaminocarbonyl, di-(C.sub.1-C.sub.6-alkyl)-aminocarbonyl, phenyl, or phenyl-C.sub.1-C.sub.2-alkyl; or two radicals R.sup.13 bound to the same carbon ring atom together a group O or S; or two radicals R.sup.13 bound to the same carbon ring atom may form together with this carbon ring atom a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring, where the ring may contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected from the group consisting of O, S, N, NO, SO, SO.sub.2 and CO as ring members, and where the ring may be substituted with one or more substituents R.sup.14; or two non-geminal radicals R.sup.13 form together a group (CH.sub.2).sub.k, where k is 1, 2, 3 or 4, where 1 or 2 hydrogen atoms in this group may be replaced by a methyl group; or two vicinal radicals R.sup.13 form together a group CHCHCHCH; each R.sup.14 is independently halogen, cyano, hydroxyl, C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, or fluorinated C.sub.1-C.sub.4-alkoxy; and each R.sup.15 is independently cyano, hydroxyl, nitro, C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.6-alkoxy, fluorinated C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylthio, fluorinated C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl, fluorinated C.sub.1-C.sub.6-alkylsulfinyl, C.sub.1-C.sub.6-alkylsulfonyl, fluorinated C.sub.1-C.sub.6-alkylsulfonyl, amino, C.sub.1-C.sub.6-alkylamino, di-(C.sub.1-C.sub.6-alkyl)-amino, C.sub.1-C.sub.6-alkylcarbonyl, fluorinated C.sub.1-C.sub.6-alkylcarbonyl, carboxyl, C.sub.1-C.sub.6-alkoxycarbonyl, fluorinated C.sub.1-C.sub.6-alkoxycarbonyl, C.sub.1-C.sub.6-alkylcarbonyloxy, fluorinated C.sub.1-C.sub.6-alkylcarbonyloxy, aminocarbonyl, C.sub.1-C.sub.6-alkylaminocarbonyl, di-(C.sub.1-C.sub.6-alkyl)-aminocarbonyl, phenyl, or a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups selected from the group consisting of O, S, N, NO, SO and SO.sub.2 as ring members, where phenyl, phenyl-C.sub.1-C.sub.2-alkyl and the heterocyclic ring may carry one or more radicals R.sup.13; and R.sup.15 as a substituent on a cycloaliphatic ring is additionally C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, fluorinated C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, fluorinated C.sub.2-C.sub.6-alkynyl, or phenyl-C.sub.1-C.sub.2-alkyl, where the phenyl moiety in phenyl-C.sub.1-C.sub.2-alkyl may carry one or more radicals R.sup.13; or an N-oxide, stereoisomer, or a pharmaceutically acceptable salt thereof, or the compound of the formula I, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope.

2. The compound of claim 1, where X.sup.1 is N.

3. The compound of claim 1, where X.sup.2 is N.

4. The compound of claim 1, where X.sup.3, X.sup.4 and X.sup.5 are CH.

5. The compound of claim 1, where R.sup.1 is C.sub.1-C.sub.4-alkyl which carries a group C(O)R.sup.4.

6. The compound of claim 1, where R.sup.4 is OR.sup.8, where R.sup.8 is hydrogen, C.sub.1-C.sub.4-alkyl or fluorinated C.sub.1-C.sub.4-alkyl.

7. The compound of claim 1, where R.sup.4 is NR.sup.9R.sup.10, where R.sup.9 and R.sup.10, independently of each other, are hydrogen, C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.4-alkenyl, fluorinated C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, fluorinated C.sub.2-C.sub.4-alkynyl, C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl, or C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl.

8. The compound of claim 7, where R.sup.9 is hydrogen or C.sub.1-C.sub.4-alkyl; and R.sup.10 is hydrogen, C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, fluorinated C.sub.3-C.sub.6-cycloalkyl, or C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl.

9. The compound of claim 1, where R.sup.2 is phenyl which may carry 1, 2 or 3 substituents R.sup.5.

10. The compound of claim 9, where R.sup.2 is phenyl which carries one substituent R.sup.5 bound in meta-position.

11. The compound of claim 1, where each R.sup.5 is independently halogen, cyano, nitro, hydroxyl, C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, or fluorinated C.sub.1-C.sub.6-alkoxy.

12. The compound of claim 1, where R.sup.3 is C.sub.3-C.sub.4-cycloalkyl or C.sub.3-C.sub.4-cycloalkenyl which carries one substituent R.sup.6.

13. The compound of claim 1, where R.sup.6 is C.sub.1-C.sub.4-alkyl which carries a radical NR.sup.11R.sup.12.

14. The compound of claim 1, where R.sup.11 and R.sup.12, independently of each other, are hydrogen, C.sub.1-C.sub.6-alkyl, or fluorinated C.sub.1-C.sub.6-alkyl; or R.sup.11 and R.sup.12, together with the nitrogen atom they are bound to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated or partially unsaturated heterocyclic ring, where the heterocyclic ring may additionally contain 1 or 2 heteroatoms or heteroatom groups selected from the group consisting of: O, S, N, NO, SO and SO.sub.2 as ring members, and where the heterocyclic ring may carry 1, 2, 3 or 4 radicals R.sup.13.

15. The compound of claim 14, where R.sup.11 and R.sup.12, independently of each other, are hydrogen or C.sub.1-C.sub.6-alkyl; or R.sup.11 and R.sup.12, together with the nitrogen atom they are bound to, form a 4-, 5-, 6- or 7-membered saturated or partially unsaturated heterocyclic ring, where the heterocyclic ring may additionally contain one heteroatom or heteroatom group selected from the group consisting of: O, S, N, NO, SO and SO.sub.2 as ring member, and where the heterocyclic ring may carry 1, 2, 3 or 4 radicals R.sup.13.

16. The compound of claim 15, where R.sup.11 and R.sup.12, independently of each other, are C.sub.1-C.sub.4-alkyl; or R.sup.11 and R.sup.12, together with the nitrogen atom they are bound to, form a 4-, 5-, 6- or 7-membered saturated or partially unsaturated heterocyclic ring, where the heterocyclic ring may additionally contain one heteroatom selected from the group consisting of: O and S as ring member, and where the heterocyclic ring may carry 1, 2, 3 or 4 radicals R.sup.13.

17. The compound of claim 1, where each R.sup.13 is independently halogen, cyano, hydroxyl, C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, or fluorinated C.sub.1-C.sub.4-alkoxy; or two radicals R.sup.13 bound to the same carbon ring atom may form together with this carbon ring atom a 3-, 4-, 5- or 6-membered saturated ring, where the ring may contain 1 or 2 heteroatoms or heteroatom-containing groups selected from the group consisting of: O, S, N, NO, SO and SO.sub.2 as ring members; or two non-geminal radicals R.sup.13 form together a group (CH.sub.2).sub.k, where k is 1, 2, 3 or 4.

18. The compound of claim 17, where each R.sup.13 is independently halogen, cyano, hydroxyl, C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, or fluorinated C.sub.1-C.sub.4-alkoxy; or two radicals R.sup.13 bound to the same carbon ring atom may form together with this carbon ring atom a 4- or 6-membered saturated heterocyclic ring, where the heterocyclic ring contains 1 oxygen atom as ring member; or two non-geminal radicals R.sup.13 form together a group (CH.sub.2).sub.k, where k is 1 or 2.

19. A compound selected from the group consisting of: 2-(2-(3-chlorophenyl)-4-oxo-6-(3-(piperidin-1-ylmethyl)cyclobut-1-en-1-yl)quinazolin-3(4H)-yl)-N-isopropylacetamide; 2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-4-oxo-6-[2-[2-(1-piperidyl)ethyl]cyclopropyl]quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-4-oxo-6-[2-[2-(1-piperidyl)ethyl]cyclopropyl]quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-4-oxo-6-[2-[2-(1-piperidyl)ethyl]cyclopropyl]quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-4-oxo-6-[2-(1-piperidylmethyl)cyclopropyl]quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-4-oxo-6-[2-(1-piperidylmethyl)cyclopropyl]quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-4-oxo-6-[2-(1-piperidylmethyl)cyclopropyl]quinazolin-3-yl]-N-isopropyl-acetamide; methyl 2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]acetate; cis-methyl 2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]acetate; trans-methyl 2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]acetate; 2-[2-(3-chlorophenyl)-4-oxo-6-(3-(piperidin-1-ylmethyl)cyclobutyl]quinazolin-3(4H)-yl]acetic acid; cis-2-[2-(3-chlorophenyl)-4-oxo-6-(3-(piperidin-1-ylmethyl)cyclobutyl]quinazolin-3(4H)-yl]acetic acid; trans-2-[2-(3-chlorophenyl)-4-oxo-6-(3-(piperidin-1-ylmethyl)cyclobutyl]quinazolin-3(4H)-yl]acetic acid; 2-[2-(3-chlorophenyl)-6-[3-[(4-cyano-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[(4-cyano-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[(4-cyano-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-4-oxo-6-[3-(thiomorpholinomethyl)cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(thiomorpholinomethyl)cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(thiomorpholinomethyl)cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-4-oxo-6-[3-(pyrrolidin-1-ylmethyl)cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(pyrrolidin-1-ylmethyl)cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(pyrrolidin-1-ylmethyl)cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[(4-methoxy-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[(4-methoxy-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[(4-methoxy-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[[(3R)-3-fluoropyrrolidin-1-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[[(3R)-3-fluoropyrrolidin-1-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[[(3R)-3-fluoropyrrolidin-1-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[(4,4-difluoro-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[(4,4-difluoro-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[(4,4-difluoro-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-(morpholinomethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-(morpholinomethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-(morpholinomethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[(3-cyano-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[(3-cyano-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[(3-cyano-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-(diethylaminomethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-(diethylaminomethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-(diethylaminomethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[[(3S)-3-fluoropyrrolidin-1-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[[(3S)-3-fluoropyrrolidin-1-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[[(3S)-3-fluoropyrrolidin-1-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-(dimethylaminomethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-(dimethylaminomethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-(dimethylaminomethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-(3,6-dihydro-2H-pyridin-1-ylmethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-(3,6-dihydro-2H-pyridin-1-ylmethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-(3,6-dihydro-2H-pyridin-1-ylmethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[(3-fluoroazetidin-1-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[(3-fluoroazetidin-1-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[(3-fluoroazetidin-1-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[(4-ethoxy-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[(4-ethoxy-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[(4-ethoxy-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[6-[3-(azepan-1-ylmethyl)cyclobutyl]-2-(3-chlorophenyl)-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[6-[3-(azepan-1-ylmethyl)cyclobutyl]-2-(3-chlorophenyl)-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[6-[3-(azepan-1-ylmethyl)cyclobutyl]-2-(3-chlorophenyl)-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[(4-methyl-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[(4-methyl-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[(4-methyl-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[[(3S)-3-methylpyrrolidin-1-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[[(3S)-3-methylpyrrolidin-1-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[[(3S)-3-methylpyrrolidin-1-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-(1,4-oxazepan-4-ylmethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-(1,4-oxazepan-4-ylmethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-(1,4-oxazepan-4-ylmethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; N-tert-butyl-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]acetamide; cis-N-tert-butyl-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]-quinazolin-3-yl]acetamide; trans-N-tert-butyl-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclo-butyl]quinazolin-3-yl]acetamide; 2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-cyclopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-cyclopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-cyclopropyl-acetamide; 2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-propyl-acetamide; cis-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-propyl-acetamide; trans-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-propyl-acetamide; 2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-(cyclopropylmethyl)acetamide; cis-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-(cyclopropylmethyl)acetamide; trans-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-(cyclopropylmethyl)acetamide; 2-[2-(3-chlorophenyl)-6-[3-[(4-fluoro-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[(4-fluoro-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[(4-fluoro-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-(6-oxa-2-azaspiro[3.3]heptan-2-ylmethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-(6-oxa-2-azaspiro[3.3]heptan-2-ylmethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-(6-oxa-2-azaspiro[3.3]heptan-2-ylmethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[(4-hydroxy-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[(4-hydroxy-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[(4-hydroxy-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[[(3R)-3-hydroxy-1-piperidyl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[[(3R)-3-hydroxy-1-piperidyl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[[(3R)-3-hydroxy-1-piperidyl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[[(3R)-3-methylpyrrolidin-1-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[[(3R)-3-methylpyrrolidin-1-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[[(3R)-3-methylpyrrolidin-1-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[(3-methoxyazetidin-1-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[(3-methoxyazetidin-1-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[(3-methoxyazetidin-1-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[(4-hydroxy-4-methyl-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[(4-hydroxy-4-methyl-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[(4-hydroxy-4-methyl-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[[(3S)-3-hydroxy-1-piperidyl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[[(3S)-3-hydroxy-1-piperidyl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[[(3S)-3-hydroxy-1-piperidyl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-4-oxo-6-[3-[[4-(trifluoromethyl)-1-piperidyl]methyl]-cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-4-oxo-6-[3-[[4-(trifluoromethyl)-1-piperidyl]methyl]-cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-4-oxo-6-[3-[[4-(trifluoromethyl)-1-piperidyl]methyl]-cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[(3-fluoro-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[(3-fluoro-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[(3-fluoro-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[(3-hydroxyazetidin-1-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[(3-hydroxyazetidin-1-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[(3-hydroxyazetidin-1-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-(7-oxa-2-azaspiro[3.5]nonan-2-ylmethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-(7-oxa-2-azaspiro[3.5]nonan-2-ylmethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-(7-oxa-2-azaspiro[3.5]nonan-2-ylmethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[[(2S,6R)-2,6-dimethylmorpholin-4-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[[(2S,6R)-2,6-dimethylmorpholin-4-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[[(2S,6R)-2,6-dimethylmorpholin-4-yl]methyl]cyclo-butyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[(2,6-dimethylmorpholin-4-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[(2,6-dimethylmorpholin-4-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[(2,6-dimethylmorpholin-4-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-6-[3-[[(3R)-3-methylmorpholin-4-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-6-[3-[[(3R)-3-methylmorpholin-4-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-6-[3-[[(3R)-3-methylmorpholin-4-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide; 2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide; cis-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide; trans-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide; 2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]acetamide; cis-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]acetamide; trans-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]acetamide; 2-[2-(3-chlorophenyl)-4-oxo-6-[3-[2-(1-piperidyl)ethyl]cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide; cis-2-[2-(3-chlorophenyl)-4-oxo-6-[3-[2-(1-piperidyl)ethyl]cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide; trans-2-[2-(3-chlorophenyl)-4-oxo-6-[3-[2-(1-piperidyl)ethyl]cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide; and 2-[2-(3-chlorophenyl)-4-oxo-6-[3-[2-(1-piperidyl)ethyl]cyclobut-2-en-1-yl]quinazolin-3-yl]-N-isopropyl-acetamide; or an N-oxide, stereoisomer, or a pharmaceutically acceptable salt thereof, or the above compounds, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope.

20. A pharmaceutical composition comprising a compound of claim 1, or an N-oxide, a stereoisomer or at least one pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

21. A method for the treatment of vasopressin-related diseases, comprising administering an effective amount of a compound of claim 1, or an N oxide, a stereoisomer, or pharmaceutically acceptable salt thereof to a subject in need thereof.

22. The method of claim 21, wherein the vasopressin-related diseases are selected from the group consisting of: diabetes; insulin resistance; nocturnal enuresis; incontinence; hypertension; pulmonary hypertension; heart failure; myocardial infarction; coronary spasm; unstable angina; PTCA (percutaneous transluminal coronary angioplasty); ischemias of the heart; edemas; renal vasospasm; necrosis of the renal cortex; hyponatremia; hypokalemia; Schwartz-Bartter syndrome; gastritic vasospasm; hepatocirrhosis; gastric and intestinal ulcers; emesis; emesis occurring during chemotherapy; travel sickness; affective disorders selected from the group consisting of: depressive disorders, anxiety disorders, obsessive-compulsive disorders, trauma and stressor-related disorders, and bipolar disorders; Alzheimer's disease; mild cognitive impairment and cognitive impairment associated with schizophrenia, aging, Alzheimer disease, Parkinson's disease and/or dementia; increased aggression in conditions selected from the group consisting of Alzheimer's disease, schizophrenia, bipolar disorder, frontal lobe injuries and substance use disorders; Cushing's syndrome; sleep disorders; substance-related and addictive disorders; schizophrenia and psychosis; pain; and micturition disorders.

23. The method of claim 22, where substance-related and addictive disorders are selected from the group consisting of: substance use disorder, substance-induced disorder, alcohol use disorder, alcohol intoxication, alcohol withdrawal, caffeine intoxication, caffeine withdrawal, cannabis use disorder, cannabis withdrawal, phencyclidine use disorder, other hallucinogen use disorders, phencyclidine intoxication, hallucinogen persisting perception disorder, inhalant use disorder, inhalant intoxication, opioid use disorder, opioid withdrawal, sedative, hypnotic or anxiolytic use disorder, sedative, hypnotic or anxiolytic withdrawal, stimulant use disorder, stimulant intoxication, stimulant withdrawal, tobacco use disorder, tobacco withdrawal, and gambling disorder.

24. The method of claim 22, where the depressive disorders are selected from the group consisting of: dysthymic disorders, major depression, seasonal depression, treatment-resistant depression disorders, disruptive mood dysregulation disorder, premenstrual dysphoric disorder, substance/medication-induced depressive disorder, and childhood onset mood disorders; the anxiety disorders are selected from the group consisting of: phobias, panic disorders, drug withdrawal-induced anxiety disorders, separation anxiety disorder, selective mutism, social anxiety disorder, agoraphobia, and substance/medication-induced anxiety disorder; the obsessive-compulsive disorders are selected from the group consisting of: obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania, excoriation disorder, and substance/medication-induced obsessive-compulsive and related disorder; the trauma and stressor-related disorders are selected from reactive attachment disorder, disinhibited social engagement disorder, post traumatic stress disorder, acute stress disorder, and adjustment disorder; and the bipolar disorders are selected from the group consisting of: bipolar I disorder, bipolar II disorder, cyclothymic disorder, and substance/medication-induced bipolar disorder.

25. The method of claim 21, where the vasopressin-related diseases are selected from the group consisting of: depressive disorders; anxiety disorders and stress-dependent anxiety disorders; and substance-related and addictive disorders, where the substance-related and addictive disorders are selected from the group consisting of alcohol use disorder, alcohol intoxication, and alcohol withdrawal.

26. The compound of claim 11, where R.sup.5 is halogen.

27. The compound of claim 26, where R.sup.5 is chlorine.

28. The compound of claim 13, where R.sup.6 is C.sub.1-C.sub.2-alkyl which carries a radical NR.sup.11R.sup.12.

29. The compound of claim 5, where R.sup.1 is CH.sub.2C(O)R.sup.4.

Description

EXPERIMENTAL SECTION

(1) TABLE-US-00002 Abbreviations used: rt room temperature (20-25 C.) h hour(s) min minute(s) d day(s) quant. quantitative eq. equivalent(s) conc. concentrated TLC thin layer chromatography RP reversed phase aq. aqueous sat. saturated ACN acetonitrile DCM dichloromethane DIPEA diisopropylethyl amine DMF dimethylformamide DMSO dimethyl sulfoxide EA or ethyl acetate EtOAc Et.sub.3N triethyl amine EtOH ethanol MeOH methanol MeOD deuteromethanol OAc acetate PE petrol ether Pd(PPh.sub.3).sub.4 tetrakis(triphenyl- phosphine)palladium(0) TBAF tetrabutylammonium fluoride TFA trifluoroacetic acid THF tetrahydrofuran p: pseudo (for example pt pseudo triplet) b: broad (for example bs broad singlet) s: singlet d: doublet t: triplet m: multiplet dd: doublet of doublets dt: doublet of triplets tt: triplet of triplets

(2) LC-MS was recorded on Agilent 1200 HPLC/6110 SQ system by the following conditions:

(3) Method A:

(4) Mobile Phase: A: Water (0.05% TFA) B: ACN (0.05% TFA)

(5) Gradient: 5% B for 0.1 min, increase to 95% B within 0.7 min, 95% B for 0.9 min, back to 5% B within 0.01 min.

(6) Flow Rate: 3.0 mL/min

(7) Column: Zorbax SB-C18 Rapid Resolution HT, 4.6*30 mm, 1.8 m

(8) Column Temperature: 45 C.

(9) Method B:

(10) Mobile Phase: A: Water (10 mM NH.sub.4HCO.sub.3) B: ACN

(11) Gradient: 5% B for 0.2 min, increase to 95% B within 1.2 min, 95% B for 1.6 min, back to 5% B within 0.01 min.

(12) Flow Rate: 1.8 mL/min

(13) Column: XBridge C18, 4.6*50 mm, 3.5 m

(14) ColumnTemperature: 50 C.

(15) Method C:

(16) Mobile Phase: A: Water (10 mM NH.sub.4HCO.sub.3) B: ACN

(17) Gradient: 5% for 0.2 min, increase to 95% B within 1.7 min, 95% B for 1.4 min, back to 5% B within 0.01 min

(18) Flow Rate: 2.1 mL/min

(19) Column: XBridge C18, 4.6*50 mm, 3.5 m

(20) Column Temperature: 50 C.

(21) Method D:

(22) Mobile Phase: A: Water (0.01% TFA) B: ACN (0.01% TFA)

(23) Gradient: 5% B increase to 95% B within 1.2 min, 95% B for 1.3 min, back to 5% B within 0.01 min

(24) Flow Rate: 2.0 mL/min

(25) Column: XBridge C18, 4.6*50 mm, 3.5 m

(26) Column Temperature: 50 C.

(27) Method E:

(28) Mobile Phase: A: Water (10 mM NH.sub.4HCO.sub.3) B: ACN

(29) Gradient: 5% B increase to 95% B within 1.3 min, 95% B for 1.5 min, back to 5% B within 0.01 min.

(30) Flow Rate: 1.8 mL/min

(31) Column: XBridge C18, 4.6*50 mm, 3.5 m

(32) ColumnTemperature: 50 C.

(33) Method F:

(34) Mobile phase: A: Water (0.01% TFA) B: ACN (0.01% TFA)

(35) Gradient was 5% B for 0.2 min, and to 95% B within 1.7 min then with a hold at 95% B for 1.3 min, back to 5% B within 0.01 min.

(36) Flow Rate: 2.3 mL/min.

(37) Column: XBridge C18, 4.6*50 mm, 3.5 m

(38) Method G:

(39) Mobile phase: A: Water (10 mM NH.sub.4HCO.sub.3) B: ACN

(40) Gradient was 5% B for 0.2 min, and to 95% B within 1.7 min then with a hold at 95% B for 1.3 min, back to 5% B within 0.01 min.

(41) Flow Rate: 2.3 mL/min.

(42) Column: XBridge C18, 4.6*50 mm, 3.5 m.

(43) Method H:

(44) Mobile Phase: A: Water (0.01% TFA), B: ACN (0.01% TFA)

(45) Gradient: 5% B for increase to 100% B within 1.2 min, 95% B for 1.3 min, back to 5% B within 0.01 min.

(46) Flow Rate: 2.0 mL/min.

(47) Column: SunFire C18, 4.6*50 mm, 3.5 m

(48) Column Temperature: 50 C.

(49) Method I:

(50) Mobile Phase: A: Water (0.01% TFA), B: ACN (0.01% TFA)

(51) Gradient: 5% B for increase to 100% B within 0.8 min, 100% B for 0.9 min,

(52) Flow Rate: 2.0 mL/min.

(53) Column: ZORBAX SB-C18, 4.6*50 mm,

(54) Column Temperature: 50 C.

(55) Method K:

(56) Mobile Phase: A: Water (0.05% TFA), B: ACN (0.05% TFA).

(57) Gradient: 5% B for 0.1 min, and to 95% B within 0.7 min then with a hold at 95% B for 0.9 min, back to 5% B within 0.01 min

(58) Flow Rate: 3.0 mL/min

(59) Column: 4.630 mm Zorbax SB-C18 Rapid Resolution HT column (1.8 m particles).

(60) All mass spectra were taken under electrospray ionisation (ESI) methods.

I. Preparation of Compounds of Formula I

Example 1

2-(2-(3-Chlorophenyl)-4-oxo-6-(3-(piperidin-1-ylmethyl)cyclobut-1-en-1-yl)quinazolin-3(4H)-yl)-N-isopropylacetamide

(61) (Example 1: compound of formula I.24, wherein Q is Q.14, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl)

1.1 2-Amino-5-bromo-N-[2-(isopropylamino)-2-oxoethyl]benzamide

(62) A mixture of 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (6.34 g, 16.66 mmol), 2-amino-N-isopropylacetamide (1.936 g, 16.66 mmol), DIPEA (3.64 mL, 20.83 mmol) and 2-amino-5-bromobenzoic acid (3.0 g, 13.89 mmol) in DCM (80 mL) was stirred at rt for about 4 h. The reaction mixture was washed with water. The organic layer was dried with MgSO.sub.4, filtered, concentrated, and used in the next step directly without further purification.

(63) LC-MS (Method C): m/z 314 [M+H].sup.+, RT: 1.613 min.

1.2 5-Bromo-2-(3-chlorobenzamido)-N-[2-(isopropylamino)-2-oxoethyl]benzamide

(64) A mixture of 2-amino-5-bromo-N-[2-(isopropylamino)-2-oxoethyl]benzamide (4.2 g, 13.41 mmol) and triethylamine (2.71 g, 26.8 mmol) in THF (120 mL) was stirred at 0 C. for about 15 min. 3-Chlorobenzoyl chloride (3.52 g, 20.12 mmol) was added slowly. The reaction mixture was then warmed up to rt and stirring was continued for about 3 h. The reaction mixture was filtered, concentrated to dryness and the residue was recrystallized from MeOH to give white solid (6.0 g, yield: 94%).

(65) LC-MS (Method B): m/z 452 [M+H].sup.+, RT: 1.874 min.

1.3 2-(6-Bromo-2-(3-chlorophenyl)-4-oxoquinazolin-3(4H)-yl)-N-isopropylacetamide

(66) Sodium hydroxide (0.265 g, 6.63 mmol) was added to 5-bromo-2-(3-chlorobenzamido)-N-(2-(isopropylamino)-2-oxoethyl)benzamide (1.0 g, 2.209 mmol) in MeOH (20 mL), and the mixture was stirred at 80 C. for 8 h. The mixture was then cooled and filtered. The title compound was collected as solid (0.46 g, yield: 47.9%).

(67) LC-MS (Method B): m/z 434 [M+H].sup.+, RT: 1.845 min.

1.4 2-[2-(3-Chlorophenyl)-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl]quinazolin-3(4H)-yl]-N-isopropylacetamide

(68) A mixture of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.673 g, 0.920 mmol), 2-(6-bromo-2-(3-chlorophenyl)-4-oxoquinazolin-3(4H)-yl)-N-isopropylacetamide (8.0 g, 18.40 mmol), 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (9.35 g, 36.8 mmol) and potassium acetate (5.42 g, 55.2 mmol) in dioxane (150 mL) was heated at 80 C. over night reflux under nitrogen. Then, the reaction mixture was filtered, concentrated and purified by silica-gel chromatography (EA/PE=1/2) to give the title product (5.7 g, yield: 62%).

(69) LC-MS (Method D): m/z 482 [M+H].sup.+, RT: 1.892 min.

(70) .sup.1H-NMR (DMSO-d6, 400 MHz): 8.51 (s, 1H), 8.07 (dd, J=1.2 Hz, 8.0 Hz, 1H), 7.99 (d, J=7.2 Hz, 1H), 7.70-7.55 (m, 5H), 4.44 (s, 2H), 3.83-3.75 (m, 1H), 1.34 (s, 12H), 1.00 (d, J=6.4 Hz, 6H).

1.5 3-(Hydroxymethyl)cyclobutanol

(71) A solution of 3-oxocyclobutanecarboxylic acid (10 g, 88 mmol) in THF (500 mL) was cooled to about 78 C. in a dry ice/acetone bath. BH.sub.3.DMS (borane dimethyl sulfide complex) (131 mL, 263 mmol) was added dropwise via syringe to the reaction. The resulting solution was stirred at rt for about 16 h. After completion of the reaction, the reaction was cooled to about 0 C. in an ice bath, and MeOH was added to quench the reaction. The solvent was removed under reduced pressure to give white oil. Purification by chromatography onto a silica gel column (elution with 5% MeOH/CH.sub.2Cl.sub.2) gave 3-(hydroxymethyl)cyclobutanol (8.8 g, yield: 98%).

(72) LC-MS (Method D): RT: 1.341 min

1.6 3-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclobutanol

(73) A mixture of 3-(hydroxymethyl)cyclobutanol (6.7 g, 65.6 mmol), 4-(dimethylamino)pyridine (0.801 g, 6.56 mmol) and Et.sub.3N (18.29 mL, 131 mmol) in DCM (180 mL) was stirred at about 0 C. Then, tert-butyldiphenylsilyl chloride (18.87 mL, 73.5 mmol) was added slowly to the reaction. The resulting reaction was stirred at about 0 C. for about 2 h. LC-MS indicated complete conversion to the title compound. The solvent was removed under reduced pressure and the resulting solid was deposited onto silica gel and loaded onto a silica gel column and eluted with 5:1 hexane/EtOAc to give the title compound (10 g, yield: 44.3%).

(74) LC-MS (Method E): m/z 341 [M+H].sup.+, RT: 2.33 min

1.7 3-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclobutanone

(75) To a solution of 3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanol (10 g, 29.4 mmol) in DCM (200 mL) was added Dess-Martin-periodinane (14.95 g, 35.2 mmol) at rt. The reaction mixture was stirred for about 1 h, dried and purified by chromatography on silica-gel (PE/EA=50/1) to give the title compound (6.2 g, yield: 60%).

(76) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.66-7.64 (m, 4H), 7.43-7.39 (m, 6H), 3.80 (d, J=5.6 Hz, 2H), 3.10-3.02 (m, 2H), 3.98-3.90 (m, 2H), 2.64-2.57 (m, 1H), 1.06 (s, 9H).

1.8 3-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclobut-1-en-1-yl trifluoromethanesulfonate

(77) To a solution of 3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanone (2.0 g, 5.91 mmol) in THF (25 mL) was added lithium bis(trimethylsilyl)amide (7.68 mL, 7.68 mmol) at 78 C. The mixture was stirred for about 3 h and then, a solution of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.216 g, 6.20 mmol) in THF (25 mL) was added. The cooling bath was removed 30 minutes after completed addition, and the reaction mixture was stirred for 12 h at rt. The mixture was quenched with tert-butyl methyl ether (50 mL) and washed with 1 M aqueous NaOH solution (3). The organic layers were dried. Purification by TLC (PE/EA=100/1) gave the title compound (0.75 g, yield: 27%).

(78) LC-MS (Method D): RT: 2.68 min.

(79) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.65-7.60 (m, 5H), 7.43-7.30 (m, 5H), 5.42 (s, 1H), 3.69 (d, J=6.0 Hz, 2H), 2.94 (dd, J=4.4 Hz, 13.6 Hz, 1H), 2.79-2.75 (m, 1H), 2.55 (d, J=13.6 Hz, 1H), 1.06 (s, 9H).

1.9 2-(6-(3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobut-1-en-1-yl)-2-(3-chlorophenyl)-4-oxo-quinazolin-3(4H)-yl)-N-isopropylacetamide

(80) A mixture of 3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobut-1-en-1-yl trifluoromethanesulfonate (1.003 g, 1.598 mmol), 2-[2-(3-chlorophenyl)-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl]-N-isopropylacetamide (0.7 g, 1.453 mmol), Na.sub.2CO.sub.3 (0.385 g, 3.63 mmol) and Pd(PPh.sub.3).sub.4 (0.084 g, 0.073 mmol) in toluene (35 mL) was stirred at 60 C. for 5 h. The reaction mixture was filtered through a pad of silica gel, and the solvent was removed under reduced pressure. The sample was deposited onto silica gel and loaded onto a silica gel column and eluted with 1:4 EtOAc/heptane to give the title compound (0.57 g, yield: 53.4%).

(81) LC-MS (Method D): m/z 676 [M+H].sup.+, RT: 2.46 min.

(82) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.19 (s, 1H), 7.81-7.26 (m, 16H), 6.45 (s, 1H), 5.67 (d, J=6.4 Hz, 1H), 4.49 (s, 2H), 4.1 (m, 1H), 3.82 (d, J=4.8 Hz, 1H), 3.07 (m, 1H), 2.93 (m, 1H), 2.50 (d, J=4.8 Hz, 1H), 1.17 (d, J=6.4 Hz, 6H), 1.06 (s, 9H).

1.10 2-[2-(3-Chlorophenyl)-6-(3-(hydroxymethyl)cyclobut-1-en-1-yl)-4-oxo-quinazolin-3(4H)-yl]-N-isopropylacetamide

(83) TBAF in THF (8.13 mL, 8.13 mmol) was dissolved in THF (30 mL), stirred and cooled to about 78 C. for about 20 min under nitrogen. Then, 2-[6-(3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobut-1-en-1-yl)-2-(3-chlorophenyl)-4-oxo-quinazolin-3(4H)-yl]-N-isopropylacetamide (1.1 g, 1.626 mmol) in THF (30 mL) was added dropwise. The cooling-bath was removed and the mixture stirred at rt for 3 h. The reaction mixture was concentrated, water was added and the mixture was extracted with DCM for 3 times. Purification of the organic layers by chromatography on silica-gel (DCM/MeOH=30/1) gave the title compound (0.38 g, yield: 50%).

(84) LC-MS (Method D): m/z 438 [M+H].sup.+, RT: 1.59 min.

1.11 [3-(2-(3-Chlorophenyl)-3-(2-(isopropylamino)-2-oxoethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)cyclobut-2-en-1-yl]methyl methanesulfonate

(85) Methanesulfonyl chloride (145 mg, 1.267 mmol) was added dropwise into the mixture of triethylamine (0.347 mL, 2.53 mmol) and 2-[2-(3-chlorophenyl)-6-(3-(hydroxymethyl)cyclobut-1-en-1-yl]-4-oxo-quinazolin-3(4H)-yl)-N-isopropylacetamide (370 mg, 0.845 mmol) in DCM (100 mL) at 0 C. Then, the reaction mixture was stirred at rt for about 4 h. TLC indicated that the reaction was complete. The reaction mixture was diluted with sat. NaCl solution. The aqueous layer was extracted with methylene chloride (35 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered through a pad of celite and concentrated to give the yellow title compound (0.39 g, yield: 83%). This material was used directly without further purification.

(86) LC-MS (Method D): m/z 516 [M+H].sup.+, RT: 1.845 min.

1.12 2-[2-(3-Chlorophenyl)-4-oxo-6-(3-(piperidin-1-ylmethyl)cyclobut-1-en-1-yl)quinazolin-3(4H)-yl]-N-isopropylacetamide

(87) Under nitrogen, to a solution of [3-(2-(3-chlorophenyl)-3-(2-(isopropylamino)-2-oxoethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)cyclobut-2-en-1-yl]methyl methanesulfonate (115 mg, 0.223 mmol) and piperidine (0.066 mL, 0.669 mmol) in acetonitrile (12 mL), K.sub.2CO.sub.3 (154 mg, 1.114 mmol) was added in one portion. The reaction was heated in a Biotage microwave at 80 C. for 6 h in microwave reactor. The reaction was monitored by LC-MS. After the reaction was completed, the reaction mixture was diluted with sat. NaCl solution. The reaction was extracted with DCM (320 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered through a Bchner funnel and concentrated to give the title compound as a yellow solid.

(88) LC-MS (Method D): m/z 505 [M+H].sup.+, RT: 1.972 min.

(89) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.17 (s, 1H), 7.82-7.45 (m, 7H), 6.51 (s, 1H), 5.60 (d, J=12.4 Hz, 1H), 4.49 (s, 2H), 4.12-4.08 (m, 1H), 3.12-3.02 (m, 2H), 2.64-2.47 (m, 6H), 1.47-1.26 (m, 6H), 1.17 (d, J=6.8 Hz, 6H).

Example 2

cis-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide (example 2a) and trans-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide (example 2b)

(90) (Example 2a: compound of formula I.4, wherein Q is Q.14, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cisconfiguration)

(91) (Example 2b: compound of formula I.4, wherein Q is Q.14, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the trans-configuration)

(92) A mixture of 2-[2-(3-chlorophenyl)-4-oxo-6-(3-(piperidin-1-ylmethyl)cyclobut-1-en-1-yl)quinazolin-3(4H)-yl]-N-isopropylacetamide (600 mg, 1.188 mmol) and Pt/C (150 mg, 10%) in MeOH (10 mL) was stirred at rt under hydrogen overnight. The reaction mixture was filtered and purified by chiral-HPLC to give 102 mg of the compound of example 2a and 25 mg of the compound of example 2b.

(93) Conditions:

(94) Instrument: Waters2767 (PHW-002)

(95) Column: XBridge Prep C18 OBD, 30*100 mm, 5 m

(96) Mobile Phase A: Water (0.1% NH.sub.3H.sub.2O); B: ACN

(97) Gradient 45-75% B in 9 min, stop at 12.7 min

(98) Flow Rate 30.00 mL/min

(99) Detective Wavelength 214/254 nm

(100) Retention Time 6.5 min

Example 2a

(101) LC-MS (Method E): m/z 507 [M+H].sup.+, RT: 1.848 min.

(102) .sup.1H-NMR (DMSO-d6, 400 MHz): 8.11 (s, 1H), 7.69-7.41 (m, 6H), 5.59 (d, J=7.6 Hz, 1H), 4.48 (s, 2H), 4.12-4.04 (m, 1H), 3.57-3.49 (m, 1H), 2.64-2.59 (m, 3H), 2.46-2.39 (m, 6H), 1.87 (d, J=8.4 Hz, 2H), 1.61-1.45 (m, 4H), 1.44-1.40 (m, 2H), 1.17 (d, J=6.4 Hz, 6H).

Example 2b

(103) LC-MS (Method E): m/z 507 [M+H].sup.+, RT: 1.875 min

(104) .sup.1H-NMR (DMSO-d6, 400 MHz): 8.20 (s, 1H), 7.71-7.41 (m, 6H), 5.61 (d, J=7.6 Hz, 1H), 4.49 (s, 2H), 4.14-4.06 (m, 1H), 3.73-3.68 (m, 1H), 2.69-2.59 (m, 3H), 2.47-2.30 (m, 6H), 2.30-2.24 (m, 2H), 1.64-1.55 (m, 4H), 1.49-1.42 (m, 2H), 1.17 (d, J=6.4 Hz, 6H).

Example 3

2-[2-(3-Chlorophenyl)-4-oxo-6-[2-[2-(1-piperidyl)ethyl]cyclopropyl]quinazolin-3-yl]-N-isopropyl-acetamide

(105) (Example 3: compound of the formula I.44, wherein Q is Q.14, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl)

3.1 Methyl 2-[[2-[(3-chlorobenzoyl)amino]-5-iodo-benzoyl]amino]acetate

(106) To a solution of methyl 2-[(2-amino-5-iodo-benzoyl)amino]acetate (20 g, 59.9 mmol) in 400 mL of THF was added triethylamine (16.69 mL, 120 mmol) and 3-chlorobenzoyl chloride (11.00 g, 62.9 mmol) dropwise at 0 C. The reaction mixture was stirred at 0 C. for 2 h. Solvent was evaporated and water was added to the residue. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (25.5 g, 53.9 mmol, 90% yield). LCMS (Method K): m/z 473.0 [M+H].sup.+, RT: 2.03 min.

3.2 2-[[2-[(3-Chlorobenzoyl)amino]-5-iodo-benzoyl]amino]acetic acid

(107) To a solution of compound 3.1 (39 g, 83 mmol) in 600 mL of methanol was added 2M NaOH (250 mL). The mixture was stirred at rt for 3 h. Solvent was evaporated. 1N HCl was added to adjust the reaction mixture to pH=7. The precipitate was collected and dried to give the title compound (33 g, 72.0 mmol, 87% yield).

(108) LCMS (Method G): m/z 459.0 [M+H].sup.+, RT: 1.49 min.

3.3 2-[(3-Chlorobenzoyl)amino]-5-iodo-N-[2-(isopropylamino)-2-oxo-ethyl]benzamide

(109) To a solution of compound 3.2 (22 g, 48.0 mmol) in 800 mL of DCM is added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 18.97 g, 49.9 mmol) and DIPEA (12.57 mL, 72.0 mmol) at 0 C. followed by addition of propan-2-amine (4.93 ml, 57.6 mmol) dropwise. The reaction mixture was stirred at rt for 4 h. Water was added to quench the reaction. The precipitate was collected to give the title compound (21 g, 39.9 mmol, 83% yield) as a white solid.

(110) LCMS (Method G): m/z 500 [M+H].sup.+, RT: 1.96 min

3.4 2-[2-(3-Chlorophenyl)-6-iodo-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(111) To a solution of compound 3.3 (25 g, 50.0 mmol) in 600 mL of DCM was added iodine (25.4 g, 100.0 mmol) and bis(trimethylsilyl)amine (41.9 mL, 200 mmol) dropwise via syringe. The reaction mixture was stirred at 40 C. for 5 h. After cooling to rt, 5% Na.sub.2S.sub.2O.sub.3 solution was added at ice bath. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (14 g, 29.1 mmol, 58.1% yield) as a brown solid.

(112) LCMS (Method G): ESI-MS: m/z: 482.0 [M+H].sup.+; RT=2.00 min.

3.5 2-[2-(3-Chlorophenyl)-6-[4-hydroxybut-1-enyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(113) To a mixture of 2-[2-(3-chlorophenyl)-6-iodo-4-oxo-quinazolin-3-yl]-N-isopropylacetamide (3.8 g, 7.9 mmol), but-3-en-1-ol (0.86 g, 12 mmol) and triethylamine (2.02 g, 20 mmol) were added Pd(OAc).sub.2 (0.19 g, 0.8 mmol) and triphenylphosphine (0.62 g, 2.4 mmol) in CH.sub.3CN (30 mL). The mixture was stirred for 18 h at rt. After adding water (100 mL), the mixture was extracted with EtOAc (50 mL3=150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by a silica gel column chromatography (eluting with: DCM:MeOH=40:1) to give the title compound (2.2 g, 5.2 mmol, 65% yield) as a pale yellow solid.

(114) LC-MS (Method F).: m/z: 426.0 [M+H].sup.+; RT=1.80 min

3.6 2-[2-(3-Chlorophenyl)-6-formyl-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(115) To a solution of 2-[2-(3-chlorophenyl)-6-[4-hydroxybut-1-enyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide (2.0 g, 4.8 mmol) and NaIO.sub.4 (2.1 g, 9.6 mmol) in THF/H.sub.2O=2:1 (150 mL) was added OsO.sub.4 (100 mg, 0.39 mmol). The mixture was stirred for 18 h at rt. Then, water (100 mL) was added to the solution and the mixture was extracted with EtOAc (50 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by a silica gel column chromatography (eluting with: DCM:MeOH=30:1) to give the title compound (2.1 g, 5.5 mmol, 80% yield) as a pale yellow solid.

(116) LC-MS (Method G): m/z: 384.0 [M+H].sup.+; RT=1.13 min

3.7 2-[2-(3-Chlorophenyl)-4-oxo-6-[(p-tolylsulfonylhydrazono)methyl]quinazolin-3-yl]-N-isopropyl-acetamide

(117) To a solution of the compound of example 3.6 (1.73 g, 4.5 mmol) and 4-methylbenzenesulfonohydrazide (0.84 g, 4.5 mmol) in dioxane (10 mL) was added K.sub.2CO.sub.3 (0.94 g, 6.7 mmol). The mixture was stirred for 1 h at 70 C. in a microwave reactor. After water (100 mL) was added to the solution, the mixture was extracted with EtOAc (50 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by a silica gel column chromatography (eluting with: DCM:MeOH=30:1) to give the title compound (2 g, 3.6 mmol, 80% yield) as a pale yellow solid.

(118) LC-MS (Method G): m/z: 552.0 [M+H].sup.+; RT=1.20 min

3.8 [2-[2-[2-(3-Chlorophenyl)-3-[2-(isopropylamino)-2-oxo-ethyl]-4-oxo-quinazolin-6-yl]cyclopropyl]vinyl]acetate

(119) To a solution of buta-1,3-dienyl acetate (0.62 g, 3.9 mmol) and K.sub.2CO.sub.3 (0.16 g, 1.17 mmol) in dioxane (20 mL) was added slowly the compound of example 3.7 (0.431 g, 0.78 mmol) for 6 h. The mixture was allowed to stop at once. After water (100 mL) was added to the solution, the mixture was extracted with EtOAc (50 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by a silica gel column chromatography (eluting with: DCM:MeOH=20:1) to give the title compound (7.5 mg, 0.015 mmol, 2% yield) as a pale yellow solid.

(120) LC-MS (Method F): m/z: 480.0 [M+H].sup.+; RT=1.78 min

3.9 2-[2-(3-Chlorophenyl)-4-oxo-6-[2-(2-oxoethyl)cyclopropyl]quinazolin-3-yl]-N-isopropyl-acetamide

(121) To a solution of the compound of example 3.8 (7.3 mg, 0.015 mmol) in MeOH (2 mL) was added LiOH (1.45 mg, 0.061 mmol). The mixture was stirred for 1 h at rt. After water (2 mL) was added to the solution, the mixture was extracted with EtOAc (10 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated to give the crude title compound (6 mg, 0.013 mmol, 90% yield) as a pale yellow solid, which was used in the next step without purification.

(122) LC-MS (Method F): m/z: 438.0 [M+H].sup.+; RT=1.14 min.

3.10 2-[2-(3-Chlorophenyl)-4-oxo-6-[2-[2-(1-piperidyl)ethyl]cyclopropyl]quinazolin-3-yl]-N-isopropyl-acetamide

(123) To a solution of the compound of example 3.9 (5 mg, 0.011 mmol) and piperidine (1.02 mg, 0.012 mmol), acetic acid (catalytic amount) in 1,2-dichloroethane (2 mL) and NaBH(OAc).sub.3 (3.5 mg, 0.0165 mmol) were added. The mixture was stirred for 16 h at rt and then concentrated to the crude product. The residue was purified by prep-HPLC to give the title compound (3.5 mg, 0.0069 mmol, 60% yield) as a pale white solid.

(124) Conditions for prep-HPLC:

(125) Instrument: waters 2767 (PHW-004)

(126) Column: XBridge Prep C18 OBD, 19*250 mm, 10 m

(127) Mobile Phase A: water (10 mmol/ml NH.sub.4HCO.sub.3); B: ACN

(128) Gradient: 50-80% B in 9.0 min, stop at 12.7 min

(129) Flow Rate: 30.00 mL/min

(130) Detective Wavelength (nm): 214\254

(131) RT: 7.38 min

(132) LC-MS (Method F): m/z: 507.0 [M+H].sup.+; RT=1.47 min.

(133) .sup.1H NMR: (400 MHz, MeOD): 8.05-8.03 (m, 1H), 7.94-7.80 (m, 1H), 7.69-7.52 (m, 5H), 4.57 (s, 2H), 3.93-3.87 (m, 1H), 3.57-3.53 (m, 1H), 3.29-3.23 (m, 2H), 2.94-2.45 (m, 2H), 1.99-1.12 (m, 12H), 1.10 (d, J=6.4 Hz, 6H), 0.92-0.89 (m, 2H).

Example 4

2-[2-(3-Chlorophenyl)-4-oxo-6-[2-(1-piperidylmethyl)cyclopropyl]quinazolin-3-yl]-N-isopropyl-acetamide

(134) (Example 4: compound of the formula I.34, wherein Q is Q.14, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl)

4.1 Ethyl 2-[2-(3-chlorophenyl)-3-[2-(isopropylamino)-2-oxo-ethyl]-4-oxo-quinazolin-6-yl]cyclopropanecarboxylate

(135) To a solution of the compound of example 3.7 (0.2 g, 0.36 mmol) and ethyl acrylate (0.15 g, 1.45 mmol) in dioxane (10 mL) was added K.sub.2CO.sub.3 (0.075 g, 0.54 mmol). The mixture was stirred for 1 h at 150 C. in a microwave reactor. After water (100 mL) was added to the solution, the mixture was extracted with EtOAc (50 mL*3=150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-TLC (eluting with DCM:MeOH=20:1) to give the title compound (34 mg, 0.072 mmol, 20% yield) as a pale yellow solid.

(136) LC-MS (Method H): m/z: 468.0 [M+H].sup.+; RT=1.71 min

4.2 2-[2-(3-Chlorophenyl)-6-[2-(hydroxymethyl)cyclopropyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(137) To a solution of the compound of example 4.1 (33 mg, 0.069 mmol) in DCM (10 mL) was added diisobutylaluminium hydride (1.38 mL, 1.38 mmol) at 78 C. under N.sub.2 atmosphere. The mixture was stirred at 78 C. for 3 h. After water (100 mL) was added to the solution, the mixture was extracted with EtOAc (50 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-TLC (eluting with: DCM: MeOH=40:1) to give the title compound (25 mg, 0.058 mmol, 85% yield) as a pale yellow solid.

(138) LC-MS (Method I): m/z: 426.0 [M+H].sup.+; RT=1.54 min.

4.3 2-[2-(3-Chlorophenyl)-6-(2-formylcyclopropyl)-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(139) To a solution of compound of example 4.2 (25 mg, 0.058 mmol) in DCM (10 mL) was added Dess-Martin Periodinane (29.7 mg, 0.07 mmol). The mixture was stirred for 3 h at rt. Then, sat. aqueous Na.sub.2S.sub.2O.sub.3 solution with NaHCO.sub.3 (10 mL) was added to the solution. The mixture was extracted with EtOAc (10 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated to give the crude title compound (21 mg, 0.049 mmol, 85% yield) as a pale yellow solid.

(140) LC-MS (Method I): m/z: 424.0 [M+H].sup.+, RT=1.61 min.

4.4 2-[2-(3-Chlorophenyl)-4-oxo-6-[2-(1-piperidylmethyl)cyclopropyl]quinazolin-3-yl]-N-isopropyl-acetamide

(141) To a solution of compound of example 4.3 (20 mg, 0.047 mmol) and piperidine (4.2 mg, 0.052 mmol), acetic acid (catalytic amount) in 1,2-dichloroethane (4 mL) and NaBH(OAc).sub.3 (15 mg, 0.07 mmol) were added. The mixture was stirred for 16 h at rt. Then, the mixture was concentrated and the residue was purified by prep-HPLC to give the title compound (14.0 mg, 0.028 mmol, 60% yield) as a pale white solid. LC-MS (Method I): m/z: 493.0 [M+H].sup.+; RT=1.42 min

(142) .sup.1H NMR: (400 MHz, MeOD): 8.11-8.03 (m, 1H), 7.88-7.73 (m, 1H), 7.71-7.54 (m, 5H), 4.60 (s, 2H), 3.95-3.91 (m, 1H), 3.66-3.63 (m, 2H), 3.32-3.24 (m, 2H), 3.04-2.67 (m, 3H), 2.30-2.24 (m, 1H), 1.98-1.27 (m, 9H), 1.13 (d, J=6.4 Hz, 6H).

Example 5

Cis-methyl 2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]acetate

(143) (Example 5: compound of the formula I, wherein X.sup.1N, X.sup.2N, X.sup.3CH, X.sup.4CH, X.sup.5CH, R.sup.1CH.sub.2COOCH.sub.3, R.sup.2=3-chlorophenyl and R.sup.3 is 3-(1-piperidylmethyl)cyclobutyl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

5.1 Methyl 2-(6-(3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobut-1-en-1-yl)-2-(3-chlorophenyl)-4-oxoquinazolin-3(4H)-yl)acetate

(144) A mixture of 3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobut-1-en-1-yl trifluoromethanesulfonate (4.88 g, 7.26 mmol) from example 1.8, methyl 2-(2-(3-chlorophenyl)-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)yl)acetate (3 g, 6.60 mmol) (prepared in analogy to the method described for the preparation of the compound of example 1.4 but starting from ethyl aminoacetate,), Na.sub.2CO.sub.3 (1.748 g, 16.49 mmol) and Pd(PPh.sub.3).sub.4 (0.381 g, 0.330 mmol) in toluene/water (ratio: 4:1, (150 mL) was stirred at 60 C. for 24 h. The reaction mixture was filtered through a pad of silica gel, remove solvent under reduced pressure. The sample was deposited onto silica gel and loaded onto a silica gel column and eluted with 1/10 EtOAc/Heptane. The fractions were collected to give the title compound (1.5 g, yield: 32%). LC-MS (Method D): m/z [M+H].sup.+: 649, RT: 2.455 min.

5.2 cis-Methyl 2-(6-(3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)-2-(3-chlorophenyl)-4-oxoquinazolin-3(4H)-yl)acetate

(145) A mixture of methyl 2-(6-(3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobut-1-en-1-yl)-2-(3-chlorophenyl)-4-oxoquinazolin-3(4H)-yl)acetate (1.4 g, 2.156 mmol) and dihydroxypalladium (700 mg, 4.98 mmol) in 120 mL of MeOH was stirred at room temperature for 100 min under the atmosphere of hydrogen to give the title compound (0.5 g, yield: 35.2%) as the main product.

(146) LCMS (Method D): m/z [M+H].sup.+: 651, RT: 2.63 min.

(147) .sup.1H-NMR (DMSO-d6, 400 MHz): 7.97 (s, 1H), 7.76-7.17 (m, 17H), 4.66 (m, 2H), 3.66 (m, 5H), 3.54-3.49 (m, 1H), 3.17 (s, 1H), 2.44-2.37 (m, 2H), 2.00-1.99 (m, 2H), 1.01 (s, 9H).

5.3 Cis-Methyl 2-[2-(3-chlorophenyl)-6-[3-(hydroxymethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]acetate

(148) TBAF in THF (1.520 mL, 1.520 mmol) was dissolved in 15 mL of THF and then the compound of example 5.2 in 15 mL of THF was added dropwise at 0 C. under stirring. The cooling-bath was removed and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated and then EA was added. The reaction mixture was washed with sat. NaCl for 3 times. The organic layers were purified by chromatography on silica-gel (DCM/MeOH=30/1) to give the title compound (0.26 g, yield: 83%). LCMS (Method D): m/z [M+H].sup.+: 413, RT: 1.677 min.

(149) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.06 (s, 1H), 7.62-7.60 (m, 2H), 7.37-7.35 (m, 4H), 4.57 (m, 2H), 3.70 (m, 3H), 3.58-3.49 (m, 3H), 2.50-2.49 (m, 3H), 1.92-1.90 (m, 2H).

5.4 Cis-methyl 2-[2-(3-chlorophenyl)-6-[3-(methylsulfonyloxymethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]acetate

(150) Methanesulfonyl chloride (229 mg, 1.998 mmol) was added dropwise into the mixture of triethylamine (0.364 ml, 2.66 mmol) and the compound of example 5.3 in DCM (30 mL) at 0 C. The reaction mixture was stirred at rt for about 1 h. TLC indicated that the reaction was completely. The reaction mixture was diluted with sat. aq. NaCl solution. The aqueous layer was extracted with methylene chloride (320 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered through a pad of celite and concentrated to give a yellow solid which was used in the next step directly without further purification.

(151) LCMS (Method D): m/z [M+H].sup.+: 491, RT: 1.78 min.

5.5 Cis-Methyl 2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]-quinazolin-3-yl]acetate

(152) A mixture of K.sub.2CO.sub.3 (507 mg, 3.67 mmol), the compound of example 5.4 (600 mg, 1.222 mmol) and piperidine (624 mg, 7.33 mmol) in ACN (15 mL) was heated in microwave oven at 80 C. for about 6 h. The mixture was extracted with ethyl acetate and water. The solution was concentrated to dryness to give the title compound (600 mg, 1.222 mmol) as a yellow solid.

(153) LCMS (Method D): m/z [M+H].sup.+: 480, RT: 1.47 min

Example 6

cis-2-(2-(3-Chlorophenyl)-4-oxo-6-(3-(piperidin-1-ylmethyl)cyclobutyl)quinazolin-3(4H)-yl)acetic acid

(154) (Example 6: compound of the formula I, wherein X.sup.1N, X.sup.2N, X.sup.3CH, X.sup.4CH, X.sup.5CH, R.sup.1CH.sub.2COOH, R.sup.2=3-chlorophenyl and R.sup.3 is 3-(1-piperidylmethyl)cyclobutyl, and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(155) A mixture of the compound of example 5 (550 mg, 1.146 mmol) and lithium hydroxide (82 mg, 3.44 mmol) in 5 mL of MeOH and 2 ml of water was stirred at rt for 3 h. The solution was acidified with HCl (2 M). The solution was concentrated to dryness. The mixture was transferred in solution onto a silica gel column and eluted with 40% MeOH/CH.sub.2Cl.sub.2 and fractions were collected. The solution was concentrated to dryness to give the title compound.

(156) LC-MS (Method D): m/z (M+H): 466, RT: 1.39 min.

(157) .sup.1H-NMR (MeOD, 400 MHz): 8.17 (s, 1H), 7.90-7.88 (m, 1H), 7.73-7.63 (m, 5H), 4.71 (m, 2H), 3.73 (m, 1H), 3.65-3.51 (m, 2H), 3.33 (m, 2H), 3.26 (m, 2H), 3.04-2.98 (m, 2H), 2.88-2.75 (m, 3H), 2.11-2.09 (m, 2H), 1.99-1.96 (m, 2H), 1.88-1.83 (m, 3H).

Example 7

(158) Cis-2-[2-(3-Chlorophenyl)-6-[3-[(4-cyano-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(159) (Example 7: compound of formula I.4, wherein Q is Q.21, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

7.1 Cis-2-[6-[3-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclobutyl]-2-(3-chlorophenyl)-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(160) A mixture of compound of example 1.9 (1.7 g, 2.51 mmol), Pt/C (0.2 g) and H.sub.2 (balloon) in MeOH was stirred for 8 h. The reaction mixture was filtered through a Bchner funnel and concentrated. The mixture was transferred neat onto a silica gel column and eluted with 5% MeOH/CH.sub.2Cl.sub.2. Fractions were collected and concentrated to give the title compound (0.5 g, 0.737 mmol, 29.3% yield).

(161) LCMS (Method D): m/z 678 (M+H), RT: 2.45 min.

(162) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.07 (s, 1H), 7.68-7.38 (m, 17H), 5.60 (d, J=8.0 Hz, 1H), 4.49 (s, 1H), 4.09-4.05 (m, 1H), 3.64 (d, J=5.2 Hz, 2H), 3.56 (m, 1H), 2.58-2.42 (m, 3H), 2.06-2.03 (m, 2H), 1.15 (d, J=6.4 Hz, 6H), 1.06 (s, 9H).

7.2 Cis-2-[2-(3-chlorophenyl)-6-[3-(hydroxymethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(163) To a solution of compound of example 7.1 (0.6 g, 0.885 mmol) in THF (5 mL) was added TBAF (2.65 mL, 2.65 mmol) at 28 C. The reaction mixture was stirred for about 2 h and concentrated. The mixture was extracted with ethyl acetate and water. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The mixture was transferred in solution onto a silica gel column and eluted with 10% MeOH/CH.sub.2Cl.sub.2. Removal of the solvent under reduced pressure gave the title compound (0.3 g, 0.682 mmol, 77% yield) as a white solid. LCMS (Method D): m/z 440 [M+H].sup.+, RT: 1.59 min.

(164) .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 7.97 (s, 2H), 7.76-7.74 (m, 1H), 7.63-7.53 (m, 5H), 4.53 (m, 2H), 4.43 (s, 2H), 3.82-3.79 (m, 1H), 3.57-3.53 (m, 1H), 3.41-3.40 (m, 2H), 2.43-2.36 (m, 3H), 1.93-1.91 (m, 2H), 1.00 (d, J=6.4 Hz, 6H).

7.3 Cis-2-[2-(3-Chlorophenyl)-6-[3-[(4-cyano-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(165) The title compound was prepared in two steps in analogy to steps 5.4 and 5.5 using 4-cyanopiperidine

(166) ESI-MS: 535.20; [M].sup.+=532.20; 266.60.

(167) The compounds of examples 8 to 25 were prepared in an analogous manner as described in example 7.

Example 8

cis-2-[2-(3-Chlorophenyl)-4-oxo-6-[3-(thiomorpholinomethyl)cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide

(168) (Example 8: compound of formula I.4, wherein Q is Q.33, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(169) ESI-MS: [M+H].sup.+=526.20; 525.20; 263.20

Example 9

cis-2-[2-(3-Chlorophenyl)-4-oxo-6-[3-(pyrrolidin-1-ylmethyl)cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide

(170) (Example 9: compound of formula I.4, wherein Q is Q.6, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(171) ESI-MS: 496.20; 495.20; [M].sup.+=493.20; 247.20.

Example 10

cis-2-[2-(3-Chlorophenyl)-6-[3-[(4-methoxy-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(172) (Example 10: compound of formula I.4, wherein Q is Q.17, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(173) ESI-MS: 540.20; [M+H].sup.+=538.20; 537.20; 269.20.

Example 11

cis-2-[2-(3-Chlorophenyl)-6-[3-[[(3R)-3-fluoropyrrolidin-1-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(174) (Example 11: R-enantiomer of the compound of formula I.4, wherein Q is Q.7, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(175) ESI-MS: 514.20; [M+H].sup.+=512.20; 511.20; 256.20.

Example 12

cis-2-[2-(3-Chlorophenyl)-6-[3-[(4,4-difluoro-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(176) (Example 12: compound of formula I.4, wherein Q is Q.22, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(177) .sup.1H NMR (CDCl.sub.3, 600 MHz): 8.11 (s br., 1H), 7.69 (d, 1H), 7.65 (s, 1H), 7.64 (t, 1H), 7.56 (d, 1H), 7.44 (d, 1H), 7.42 (t, 1H), 5.56-5.59 (m br., 1H), 4.46-4.51 (m, 2H), 4.09 (sext., 1H), 3.56-3.62 (m br., 1H), 2.43-2.69 (m br., 7H), 1.85-2.10 (m br., 6H), 1.21-1.38 (m, 3H), 1.17 (d, 6H).

Example 13

cis-2-[2-(3-Chlorophenyl)-6-[3-(morpholinomethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(178) (Example 13: compound of formula I.4, wherein Q is Q.29, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(179) ESI-MS: 512.20; [M].sup.+=509.20; 255.60.

Example 14

cis-2-[2-(3-Chlorophenyl)-6-[3-[(3-cyano-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(180) (Example 14: compound of formula I.4, wherein Q is Q.26, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(181) ESI-MS: 535.20; [M+H].sup.+=533.20; 532.20; 267.30; 266.70.

Example 15

cis-2-[2-(3-Chlorophenyl)-6-[3-(diethylaminomethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(182) (Example 15: compound of formula I.4, wherein Q is diethylamine, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(183) ESI-MS: 498.20; [M+H].sup.+=496.20; 495.20; 248.20.

Example 16

cis-2-[2-(3-Chlorophenyl)-6-[3-[ [(3S)-3-fluoropyrrolidin-1-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(184) (Example 16: S-enantiomer of the compound of formula I.4, wherein Q is Q.7, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(185) ESI-MS: 514.20; [M].sup.+=511.20; 256.20.

Example 17

cis-2-[2-(3-Chlorophenyl)-6-[3-(dimethylaminomethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(186) (Example 17: compound of formula I.4, wherein Q is dimethylamine, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(187) ESI-MS: 470.20; [M+H].sup.+=468.20; 467.20; 234.20.

Example 18

cis-2-[2-(3-Chlorophenyl)-6-[3-(3,6-dihydro-2H-pyridin-1-ylmethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(188) (Example 18: compound of formula I.4, wherein Q is Q.28, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(189) ESI-MS: 508.20; [M+H].sup.+=506.20; 505.20; 253.20.

Example 19

cis-2-[2-(3-Chlorophenyl)-6-[3-[(3-fluoroazetidin-1-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(190) (Example 19: compound of formula I.4, wherein Q is Q.2, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(191) ESI-MS: 500.20; [M+H].sup.+=498.20; 497.20; 249.20.

Example 20

cis-2-[2-(3-Chlorophenyl)-6-[3-[(4-ethoxy-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(192) (Example 20: compound of formula I.4, wherein Q is Q.18, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(193) ESI-MS: [M+H].sup.+=552.30; 551.30; 504.20; 276.20;

Example 21

cis-2-[6-[3-(Azepan-1-ylmethyl)cyclobutyl]-2-(3-chlorophenyl)-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(194) (Example 21: compound of formula I.4, wherein Q is Q.34, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(195) ESI-MS: 524.20; [M].sup.+=521.20; 261.20.

Example 22

cis-2-[2-(3-Chlorophenyl)-6-[3-[(4-methyl-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(196) (Example 22: compound of formula I.4, wherein Q is Q.19, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(197) ESI-MS: 524.30; [M+H].sup.+=522.30; 521.30; 261.20.

Example 23

cis-2-[2-(3-Chlorophenyl)-6-[3-[(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(198) (Example 23: Compound of formula I.4, wherein Q is Q.37, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(199) ESI-MS: 552.20; [M].sup.+=549.20; 275.20.

Example 24

cis-2-[2-(3-Chlorophenyl)-6-[3-[[(3S)-3-methylpyrrolidin-1-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(200) (Example 24: S-enantiomer of the compound of formula I.4, wherein Q is Q.8, Y is CH,

(201) R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(202) ESI-MS: 510.30; [M+H].sup.+=508.30; 507.30; 254.20.

Example 25

cis-2-[2-(3-Chlorophenyl)-6-[3-(1,4-oxazepan-4-ylmethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(203) (Example 25: Compound of formula I.4, wherein Q is Q.35, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(204) ESI-MS: 526.20; [M].sup.+=523.20; 262.20.

(205) The compounds of examples 26 to 29 were prepared in an analogous manner as described above, starting from the compound of example 6. The amidation reaction was carried out in an analogous manner as described in example 6.

Example 26

cis-N-tert-Butyl-2-[2-(3-chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]-quinazolin-3-yl]acetamide

(206) (Example 26: compound of formula I.6, wherein Q is Q.14, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(207) ESI-MS: 524.30; [M].sup.+=521.20; 261.20.

Example 27

cis-2-[2-(3-Chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-cyclopropyl-acetamide

(208) (Example 27: compound of formula I.9, wherein Q is Q.14, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(209) ESI-MS: 508.20; [M].sup.+=505.20; 253.20.

Example 28

cis-2-[2-(3-Chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-propyl-acetamide

(210) (Example 28: compound of formula I.3, wherein Q is Q.14, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(211) .sup.1H NMR (CDCl.sub.3, 600 MHz): 8.08 (s, 1H), 7.70 (d, 1H), 7.66 (t, 1H), 7.59 (d, 1H), 7.57 (d, 1H), 7.50 (d, 1H), 7.43 (t, 1H), 5.80 (s br., 1H), 4.53 (s, 2H), 3.42-3.70 (2 m, 1+2H), 3.27 (q, 2H), 3.01 (s br., 1H), 2.77 (br. s., 2H), 2.60 (m, 2H), 2.57 (s br., 2H), 1.96 & 1.92 (2 m, 3+2H), 0.93 (t, 2H).

Example 29

cis-2-[2-(3-Chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-(cyclopropylmethyl)acetamide

(212) (Example 29: compound of formula I.10, wherein Q is Q.14, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(213) ESI-MS: 522.20; [M].sup.+=519.20; 261.00; 260.20.

(214) The compounds of examples 30 to 44 were prepared in an analogous manner as described in example 7.

Example 30

cis-2-[2-(3-Chlorophenyl)-6-[3-[(4-fluoro-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(215) (Example 30: compound of formula I.4, wherein Q is Q.15, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(216) ESI-MS: 528.20; [M+H].sup.+=526.20; 525.20; 263.20.

Example 31

cis-2-[2-(3-Chlorophenyl)-6-[3-(6-oxa-2-azaspiro[3.3]heptan-2-ylmethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(217) (Example 31: compound of formula I.4, wherein Q is Q.38, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(218) ESI-MS: [M+H].sup.+=522.20; 521.20; 261.20.

Example 32

cis-2-[2-(3-Chlorophenyl)-6-[3-[(4-hydroxy-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(219) (Example 32: compound of formula I.4, wherein Q is Q.16, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(220) ESI-MS: 526.20; [M].sup.+=523.20; 262.20.

Example 33

cis-2-[2-(3-Chlorophenyl)-6-[3-[[(3R)-3-hydroxy-1-piperidyl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(221) (Example 33: R-enantiomer of the compound of formula I.4, wherein Q is Q.25, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(222) ESI-MS: 526.20; [M+H.sup.+]=524.20; 523.20; 262.20.

Example 34

cis-2-[2-(3-Chlorophenyl)-6-[3-[[(3R)-3-methylpyrrolidin-1-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(223) (Example 34: R-enantiomer of the compound of formula I.4, wherein Q is Q.8, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(224) ESI-MS: 510.20; [M+H].sup.+=508.20; 507.20; 254.20.

Example 35

cis-2-[2-(3-Chlorophenyl)-6-[3-[(3-methoxyazetidin-1-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(225) (Example 35: compound of formula I.4, wherein Q is Q.4, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(226) ESI-MS: 512.20; [M+H].sup.+=510.20; 509.20; 255.20.

Example 36

cis-2-[2-(3-Chlorophenyl)-6-[3-[(4-hydroxy-4-methyl-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(227) (Example 36: compound of formula I.4, wherein Q is Q.23, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(228) ESI-MS: 540.20; [M+H].sup.+=538.20; 537.20; 269.20.

Example 37

cis-2-[2-(3-Chlorophenyl)-6-[3-[ [(3S)-3-hydroxy-1-piperidyl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(229) (Example 37: S-enantiomer of the compound of formula I.4, wherein Q is Q.25, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(230) ESI-MS: 526.20; [M+H].sup.+=524.20; 523.20; 262.20.

Example 38

cis-2-[2-(3-Chlorophenyl)-4-oxo-6-[3-[[4-(trifluoromethyl)-1-piperidyl]methyl]cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide

(231) (Example 38: compound of formula I.4, wherein Q is Q.20, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(232) ESI-MS: 578.40; [M+H].sup.+=576.40; 575.40; 288.20.

Example 39

cis-2-[2-(3-Chlorophenyl)-6-[3-[(3-fluoro-1-piperidyl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(233) (Example 39: compound of formula I.4, wherein Q is Q.24, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(234) .sup.1H NMR (CDCl.sub.3, 600 MHz): =8.11 (s, 1H), 7.69 (d, 1H), 7.65 (s, 1H), 7.63 (t, 1H), 7.56 (d, 1H), 7.49 (d, 1H), 7.43 (t, 1H), 5.59 (d, 1H), 4.71 & 4.62 (2 br. s., 1H), 4.49 (s, 2H), 4.10 (sext, 1H), 3.54 (quint, 1H), 2.79 (br. s., 1H), 2.43-2.68 (m br., 5H), 2.31 (br. s., 1H), 1.83-1.91 (m, 2H), 1.52-1.83 (br. m, 6H), 1.18 (s, 6H).

Example 40

cis-2-[2-(3-Chlorophenyl)-6-[3-[(3-hydroxyazetidin-1-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(235) (Example 40: compound of formula I.4, wherein Q is Q.3, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(236) ESI-MS: 498.20; [M+H].sup.+=496.40; 95.40; 248.20.

Example 41

cis-2-[2-(3-Chlorophenyl)-6-[3-(7-oxa-2-azaspiro[3.5]nonan-2-ylmethyl)cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(237) (Example 41: compound of formula I.4, wherein Q is Q.39, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(238) ESI-MS: 552.20; [M+H].sup.+=550.20; 549.20.

Example 42

cis-2-[2-(3-Chlorophenyl)-6-[3-[[(2S,6R)-2,6-dimethylmorpholin-4-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(239) (Example 42: compound of formula I.4, wherein Q is (2S,6R)-2,6-dimethylmorpholin-4-yl, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(240) ESI-MS: 540.20; [M+H].sup.+=538.20; 537.20.

Example 43

cis-2-[2-(3-Chlorophenyl)-6-[3-[(2,6-dimethylmorpholin-4-yl)methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(241) (Example 43: compound of formula I.4, wherein Q is Q.30, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(242) ESI-MS: 540.20; [M+H].sup.+=538.20; 537.20; 269.20.

Example 44

cis-2-[2-(3-Chlorophenyl)-6-[3-[[(3R)-3-methylmorpholin-4-yl]methyl]cyclobutyl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(243) (Example 44: R-enantiomer of the compound of formula I.4, wherein Q is Q.32, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(244) .sup.1H NMR (CDCl.sub.3, 600 MHz): =8.11 (s, 1H), 7.69 (d, 1H), 7.65 (s, 1H), 7.62 (t, 1H), 7.56 (d, 1H), 7.49 (d, 1H), 7.43 (t, 1H), 5.58 (d, 1H), 4.49 (s, 2H), 4.10 (sext., 1H), 3.81 (br. s., 1H), 3.67 (br. s., 2H), 3.57 (m sym., 1H), 3.26 (br. s., 1H), 2.79 (br. d., 2H), 2.61 (br. s., 3H), 2.28-2.47 (br. m., 3H), 1.89 (br. m., 2H), 1.18 (d, 6H), 1.00 (s. br, 2H).

(245) The compounds of examples 45 and 46 were prepared in analogy to the method described above starting from the compound of example 6.

Example 45

cis-2-[2-(3-Chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]acetamide

(246) (Example 45: S-enantiomer of the cis compound of formula I.7, wherein Q is Q.14, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

(247) ESI-MS: 564.20; [M+H].sup.+=562.20; 561.20; 282.20.

Example 46

cis-2-[2-(3-Chlorophenyl)-4-oxo-6-[3-(1-piperidylmethyl)cyclobutyl]quinazolin-3-yl]-N-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]acetamide

(248) (Example 46: R-enantiomer of the cis-compound of formula I.7, wherein Q is Q.14, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl and where the substituents on the 1,3-cyclobutandiyl radical adopt the cis configuration)

Example 47

2-[2-(3-Chlorophenyl)-4-oxo-6-[3-[2-(1-piperidyl)ethyl]cyclobut-2-en-1-yl]quinazolin-3-yl]-N-isopropyl-acetamide

(249) (Example 47: compound of formula I, where X.sup.1X.sup.2N; X.sup.3X.sup.4X.sup.5CH; R.sup.1CH.sub.2C(O)NHCH(CH.sub.3).sub.2; R.sup.2=3-chlorophenyl; R.sup.3 is 3-[2-(1-piperidyl)ethyl]cyclobut-2-en-1-yl

47.1 But-3-enoxy-tert-butyl-diphenyl-silane

(250) To a solution of but-3-en-1-ol (20 g, 0.28 mol), 1H-imidazole (28.3 g, 0.42 mmol) and N,N-dimethylpyridin-4-amine (3.4 g, 0.028 mol) in DCM (800 mL) was added tert-butyl(chloro)diphenylsilane (84.4 g, 0.31 mol). The mixture was stirred for 24 h at rt. After water (100 mL) was added to the solution, the mixture was extracted with EtOAc (50 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-TLC (eluting with: DCM:MeOH=100:1) to give the title compound (68.8 g, 0.22 mol, 80% yield) as a pale with oil.

(251) .sup.1H NMR: (400 MHz, CDCl.sub.3): 7.68-7.66 (m, 4H), 7.40-7.34 (m, 6H), 5.83-5.82 (m, 1H), 5.07-4.99 (m, 2H), 3.72 (t, J=6.8 Hz, 2H), 2.34-2.30 (m, 2H), 1.05 (s, 9H).

47.2 3-[2-[tert-Butyl(diphenyl)silyl]oxyethyl]-2,2-dichloro-cyclobutanone

(252) To a solution of the compound of example 47.1 (6 g, 0.019 mol) and CuZn (6.8 g, 0.038 mol) in diethyl ether (60 mL) was added 2,2,2-trichloroacetyl chloride (3.4 g, 0.019 mol). The mixture was stirred at 60 C. for 16 h. After water (100 mL) was added to the solution, the mixture was extracted with EtOAc (50 mL*3=150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give the crude title compound (crude 8 g) as a pale yellow oil, which was used in the next step without purification.

(253) .sup.1H NMR: (400 MHz, CDCl.sub.3): 7.68-7.66 (m, 4H), 7.48-7.25 (m, 6H), 3.84-3.74 (m, 2H), 3.33-2.90 (m, 3H), 2.22-2.17 (m, 1H), 1.83-1.81 (m, 1H), 1.08 (s, 9H).

47.3 3-[2-[tert-Butyl(diphenyl)silyl]oxyethyl]cyclobutanone

(254) To a solution of crude compound of example 47.2 (8 g) in CH.sub.3COOH (24 mL) was added Zn (5.4 g, 0.097 mol). The mixture was stirred for 3 h at 60 C., filtered and concentrated. Water (100 mL) was added to the residue, the mixture was extracted with EtOAc (50 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated to give the crude title compound (3.5 g, 0.01 mol, 51% yield) as a pale yellow oil.

(255) .sup.1H NMR: (400 MHz, CDCl.sub.3): 7.74-7.66 (m, 4H), 3.73-3.70 (m, 2H), 3.16-3.10 (m, 2H), 2.70-2.50 (m, 2H), 2.22-2.17 (m, 1H), 1.85 (dd, J.sub.1=2.0 Hz, J.sub.2=6.8 Hz, 2H), 1H), 1.07 (s, 9H).

47.4 [3-[2-[tert-Butyl(diphenyl)silyl]oxyethyl]cyclobut-2-en-1-yl]trifluoromethanesulfonate

(256) To a solution of the compound of example 47.3 (0.5 g, 1.36 mmol) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (1.36 mL, 1.36 mmol) at 78 C. The mixture was allowed to stir for 1 h at 78 C. Then, trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (0.48 g, 1.36 mmol) in THF (4 mL) was added to the solution at 78 C. The mixture was stirred for 16 h at 78 C. to rt. The mixture was concentrated. Then, 2-methoxy-2-methylpropane (50 mL) was added, the mixture was washed with NaOH (1N) and concentrated. The residue was purified by a silica gel column chromatograph (eluting with: PE:EA=75:1) to give the title crude compound (0.8 g) as a pale brown oil which was used in the next step without purification.

47.5 2-[6-[3-[2-[tert-Butyl(diphenyl)silyl]oxyethyl]cyclobut-2-en-1-yl]-2-(3-chlorophenyl)-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(257) To a solution of the crude compound of example 47.4 (0.8 g) and the compound of example 1.4 (0.99 g, 2.1 mmol) in toluene/water=4:1 (50 mL) was added Na.sub.2CO.sub.3 (5.8 g, 4.2 mmol) and Pd(PPh.sub.3).sub.4 (100 mg, 0.021 mmol). The mixture was degassed via N.sub.2 atmosphere for three times and allowed to stir for 16 h at 60 C.

(258) The reaction mixture was poured into water (100 ml), extracted with EA (50 mL*3), and concentrated to give the crude title product. The residue was purified by a silica gel column chromatograph (eluting with: PE:EA=75:1) to give the title compound (215 mg, 0.47 mmol) as a pale white solid.

(259) LCMS: ESI-MS: m/z: 690.0 [M+H].sup.+; RT=2.50 min (Method H).

47.6 2-[2-(3-Chlorophenyl)-6-[3-(2-hydroxyethyl)cyclobut-2-en-1-yl]-4-oxo-quinazolin-3-yl]-N-isopropyl-acetamide

(260) To a solution of the compound of example 47.5 (212 mg, 0.31 mmol) in THF (4 mL) was added TBAF (111 mg, 0.46 mmol). The mixture was stirred for 16 h at rt. Then, the mixture was concentrated to give the crude product. The residue was purified by a silica gel column chromatograph (eluting with: DCM:MeOH=10:1) to give the title compound (125 mg, 0.028 mmol, 90% yield) as a pale yellow oil.

(261) LCMS: ESI-MS: m/z: 452.0 [M+H].sup.+; RT=1.62 min (Method H)

47.7 2-[3-[2-(3-Chlorophenyl)-3-[2-(isopropylamino)-2-oxo-ethyl]-4-oxo-quinazolin-6-yl]cyclobuten-1-yl]ethyl methanesulfonate

(262) The title compound was prepared in analogy to the method described in example 1.11 but the reaction mixture was stirred for 16 h at room temperature. The title compound was obtained as a pale white solid (yield: 80%) and was used in the next step without purification.

(263) LCMS: ESI-MS: m/z: 530.0 [M+H].sup.+; RT=1.70 min (Method H).

(264) .sup.1H NMR: (400 MHz, CDCl.sub.3): 8.17 (s, 1H), 7.80-7.26 (m, 6H), 6.52 (s, 1H), 5.66-5.60 (m, 0.55H), 34.49 (s, 1H), 3.66-3.63 (m, 2H), 4.37-4.33 (m, 1H), 4.07-4.06 (m, 1H), 3.14-3.10 (m, 1H), 3.09 (s, 3H), 2.05-2.03 (m, 1H), 1.40-1.24 (m, 4H), 1.18 (d, J=6.8 Hz, 6H).

47.8 2-[2-(3-Chlorophenyl)-4-oxo-6-[3-[2-(1-piperidyl)ethyl]cyclobut-2-en-1-yl]quinazolin-3-yl]-N-isopropyl-acetamide

(265) To a solution of the compound of example 47.7 (113 mg, 0.21 mmol), piperidine (18.2 mg, 0.21 mmol), and acetic acid (catalytic amount) in CH.sub.3 (10 mL) was added K.sub.2CO.sub.3 (58 mg, 0.42 mmol). The mixture was stirred for 7 h at 80 C. in a microwave reactor. Then, the reaction mixture was concentrated to give the crude product. The residue was purified by a silica gel column chromatograph (eluting with: DCM:MeOH=10:1) to give the title compound (83 mg, 0.16 mmol, 75% yield) as a pale white solid.

(266) LCMS: ESI-MS: m/z: 519.0 [M+H].sup.+; RT=1.18 min (Method I).

(267) .sup.1H NMR: (400 MHz, CDCl.sub.3): 8.16 (s, 1H), 7.79-7.78 (m, 1H), 7.70-7.48 (m, 3H), 7.45-7.26 (m, 2H), 6.51 (s, 1H), 5.64 (d, J=8.0 Hz, 6H), 4.49 (s, 2H), 4.07-4.06 (m, 1H), 3.03-3.02 (m, 1H), 2.87-2.43 (m, 6H), 1.94-1.53 (m, 10H), 1.18 (d, J=6.8 Hz, 6H).

Example 48

2-[2-(3-Chlorophenyl)-4-oxo-6-[3-[2-(1-piperidyl)ethyl]cyclobutyl]quinazolin-3-yl]-N-isopropyl-acetamide

(268) (Example 48: compound of formula I.14, wherein Q is Q.14, Y is CH, R.sup.5a is H, R.sup.5b is H and R.sup.5c is Cl)

(269) To a solution of the compound of example 47.8 (82.6 mg, 0.159 mmol) in MeOH (4 mL) was added Pd(OH).sub.2 (15 mg, 0.07 mmol). The mixture was degassed via N.sub.2 atmosphere and then allowed to stir for 0.5 h at rt. The reaction mixture was filtered and concentrated. The obtained residue was purified by prep-HPLC to give the title compound (50 mg, 0.096 mmol, 60% yield) as a pale white solid, being a mixture of cis and trans isomers in the ratio of about 1.65:1.

(270) LCMS: ESI-MS: m/z: 521.0 [M+H].sup.+; RT=1.14 min (Method E).

(271) .sup.1H NMR: (400 MHz, CDCl.sub.3): 8.09-8.08 (m, 1H), 7.68-7.42 (m, 6H), 5.62-5.60 (m, 1H), 4.48 (s, 2H), 4.11-4.06 (m, 1H), 3.71-3.46 (m, 1H), 2.57-2.56 (m, 1H), 2.37-2.20 (m, 7H), 1.87-1.89 (m, 2H), 1.65-1.61 (m, 7H), 1.44-1.17 (m, 2H), 1.17 (d, J=6.8 Hz, 6H).

II. Determination of the Biological Activity

(272) 1. Vasopressin V1b Receptor Binding Assay:

(273) Substances:

(274) The test substances were dissolved in a concentration of 5 mM in 100% DMSO and further diluted to 510.sup.4 M to 510.sup.9 M. These serial DMSO predilutions were diluted 1:10 with assay buffer. The substance concentration was further diluted 1:5 in the assay mixture resulting in 2% DMSO in the mixture. All dilutions were performed in a Biomek NX automation workstation (Beckman)

(275) Membrane Preparation:

(276) CHO-K1 cells with stably expressed human vasopressin V1b receptor (clone 3H2) were harvested and homogenized in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini #1836170) using a Polytron homogenizer at intermediate setting for 210 seconds, and subsequently centrifuged at 40 000g for 1 h. The membrane pellet was again homogenized and centrifuged as described and subsequently taken up in 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquid nitrogen at 190 C.

(277) Binding Assay:

(278) The binding assay was carried out by the method based on that of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

(279) The incubation buffer was: 50 mM Tris, 10 mM MgCl.sub.2, 0.1% BSA, pH 7.4.

(280) In the assay mixture (200 l), membranes (26 g protein in incubation buffer) from CHO-K1 cells with stably expressed human V1b receptors (cell line hV1b_3H2_CHO) were incubated with 1.5 nM .sup.3H-AVP (8-Arg-vasopressin, PerkinElmer, NET 800) in incubation buffer (50 mM Tris, 10 mM MgCl.sub.2, 0.1% BSA, pH 7.4) (total binding) or additionally with increasing concentrations of test substance (displacement experiment). The nonspecific binding was determined with 1 M AVP (Fluka 94836). All determinations were carried out as duplicate determinations. After incubation (60 minutes at room temperature), the free radioligand was filtered off by vacuum filtration (Tomtec Mach III) through Wathman GF/B glass fiber filter plates (UniFilter, PerkinElmer 6005177). The liquid scintillation measurement took place in a Microbeta TriLux 12 (Wallac).

(281) Analysis:

(282) The binding parameters were calculated by nonlinear regression in SAS. The algorithms of the program operate in analogy to the LIGAND analysis program (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239 (1980)). The Kd of .sup.3H-AVP for the recombinant human V1b receptors is 0.4 nM and was used to determine the Ki.

(283) 2. Vasopressin V1a Receptor Binding Assay:

(284) Substances:

(285) The test substances were dissolved in a concentration of 5 mM M in DMSO. Further dilution of these DMSO solutions took place as described for V1b.

(286) Membrane Preparation:

(287) CHO-K1 cells with stably expressed human vasopressin V1a receptor (clone 5) were harvested and homogenized in 50 mM Tris-HCl and in the presence of protease inhibitors (Roche complete Mini #1836170) using a Polytron homogenizer at intermediate setting for 210 seconds, and subsequently centrifuged at 40 000g for 1 h. The membrane pellet was again homogenized in a High-Pressure-Homogenizer, Polytec 50K at 1500 PSI (Heinemann, Germany) and subsequently taken up in 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquid nitrogen at 190 C.

(288) Binding Assay:

(289) The binding assay was carried out by the method based on that of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

(290) The incubation buffer was: 50 mM Tris, 10 mM MgCl.sub.2, 0.1% BSA, pH 7.4.

(291) In the assay mixture (200 l), membranes (40 g protein in incubation buffer) from CHO-K1 cells with stably expressed human V1a receptors (cell line hV1a_5_CHO) were incubated with 0.04 nM .sup.125I-AVP (8-Arg-vasopressin, PerkinElmer NEX 128) in incubation buffer (50 mM Tris, 10 mM MgCl.sub.2, 0.1% BSA, pH 7.4) (total binding) or additionally with increasing concentrations of test substance (displacement experiment). The nonspecific binding was determined with 1 M AVP (Fluka 94836). Duplicate determinations were carried out.

(292) After incubation (60 minutes at room temperature), the samples were processed as described for V1b.

(293) Analysis:

(294) The binding parameters were calculated by nonlinear regression in SAS. The algorithms of the program operate in analogy to the LIGAND analysis program (Munson PJ and Rodbard D, Analytical Biochem. 107, 220-239 (1980)). The Kd of .sup.125I-AVP for the recombinant hV1a receptors was determined in saturation experiments. A Kd of 1.33 nM was used to determine the Ki.

(295) 3. Oxytocin Receptor Binding Assay

(296) Substances:

(297) The substances were dissolved in a concentration of 5 mM in DMSO and diluted further as described for V1b.

(298) Membrane Preparation:

(299) Confluent HEK-293 cells with transiently expressing recombinant human oxytocin receptors were centrifuged at 750g at room temperature for 5 minutes. The residue was taken up in ice-cold lysis buffer (50 mM Tris-HCl, 10% glycerol, pH 7.4 and Roche complete protease inhibitor) and subjected to an osmotic shock at 4 C. for 20 minutes. Cell lysates were then centrifuged at 750g at 4 C. for 20 minutes, the residue was taken up in incubation buffer (50 mM Tris, 10 mM MgCl.sub.2, 0.1% BSA, pH 7.4), and aliquots corresponding to 10.sup.7 cells/ml were prepared. The aliquots were frozen at 80 C. until use.

(300) Binding Assay:

(301) On the day of the experiment, the cell lysate was thawed, homogenized, and diluted with incubation buffer (50 mM Tris, 10 mM MgCl.sub.2, 0.1% BSA, pH 7.4) to the desired concentration. The reaction mixture of 0.200 ml was composed of cell lysate corresponding to 510.sup.4 cells (HEK-293 cells expressing transiently human OT receptors) and 1 nM 3H-oxytocin (PerkinElmer NET858) in the presence of test substance (displacement experiment) or incubation buffer only (total binding). The nonspecific binding was determined in the presence of 1 M oxytocin (Bachem AG, H2510). Determinations were carried out in duplicates. After 60 minutes incubation at room temperature, bound and free radioligand were separated by filtration under vacuum on GF/B UniFilter plates (Perkin Elmer #6005177) pre-incubated with 0.3% PEI. The bound radioactivity was determined by liquid scintillation measurement in a Microbeta (Perkin Elmer) plate counter.

(302) Analysis:

(303) The binding parameters were calculated by nonlinear regression analysis (SAS) in analogy to the LIGAND program of Munson and Rodbard (Analytical Biochem 1980; 107: 220-239). The Kd of .sup.3H-oxytocin for the recombinant human OT receptors was 7.6 nM and was used to calculate the Ki from competition binding experiments.

(304) 4. Determination of the Microsomal Half-Life

(305) The metabolic stability of the compounds of the invention was determined in the following assay.

(306) The test substances were incubated in a concentration of 0.5 M as follows: 0.5 M test substance are preincubated together with liver microsomes from different species (from rat, human or other species) (0.25 mg of microsomal protein/ml) in 0.05 M potassium phosphate buffer of pH 7.4 in microtiter plates at 37 C. for 5 min. The reaction is started by adding NADPH (1 mg/mL). After 0, 5, 10, 15, 20 and 30 min, 50 l aliquots are removed, and the reaction is immediately stopped and cooled with the same volume of acetonitrile. The samples are frozen until analyzed. The remaining concentration of undegraded test substance is determined by MSMS. The half-life (T) is determined from the gradient of the signal of test substance/unit time plot, it being possible to calculate the half-life of the test substance, assuming first order kinetics, from the decrease in the concentration of the compound with time. The microsomal clearance (mCl) is calculated from mCl=ln 2/T/(content of microsomal protein in mg/ml)1000 [ml/min/mg] (modified from references: Di, The Society for Biomolecular Screening, 2003, 453-462; Obach, D M D, 1999 vol 27. N 11, 1350-1359).

(307) 5. Methods for In Vitro Determination of the Cytochrome P450 (CYP) Inhibition

(308) Luminescent Substrates for 2C9 and 3A4:

(309) 0.4 mg/ml human liver microsomes are preincubated with the test substances to be investigated (0-20 M), the CYP-specific substrates, in 0.05 M potassium phosphate buffer of pH 7.4 at 37 C. for 10 min. The Cyp-specific substrate for CYP 2C9 is luciferin H, and for CYP 3A4 is luciferin BE. The reaction is started by adding NADPH. After incubation at RT for 30 min, the luciferin detection reagent is added, and the resulting luminescence signal is measured (modified from reference: Promega, Technical Bulletin P450-GLO Assays).

(310) Midazolam CYP 3A4 Time-Dependent Inhibition

(311) The assay consists of 2 parts. Firstly, the test substance is preincubated with the liver microsomes (with NADPH=preincubation, then addition of the substrate; in the second part the substrate and the test substance are added simultaneously=coincubation.

(312) Preincubation:

(313) 0.05 mg/ml microsomal protein (human liver microsomes) are preincubated with 0-10 M (or 50 M) test substance in 50 mM potassium phosphate buffer for 5 min. The reaction is started with NADPH. After 30 min 4 M midazolam (final concentration) are added, and incubation is continued for 10 min. 75 l of the reaction solution are removed after 10 min, and stopped with 150 l of acetonitrile solution.

(314) Coincubation:

(315) 0.05 mg/ml microsomal protein (human liver microsomes) are preincubated with 4 m midazolam (final concentration) and 0-10 M (or 50 M) test substance in 50 mM potassium phosphate buffer for 5 min. The reaction is started with NADPH. 75 l of the reaction solution are removed after 10 min and stopped with 150 l of acetonitrile solution. The samples are frozen until the MSMS analysis (modified from references: Obdach, Journal of Pharmacology & Experimental Therapeutics, Vol 316, 1, 336-348, 2006; Walsky, Drug Metabolism and Disposition Vol 32, 6, 647-660, 2004).

(316) 6. Method for Determining the Solubility in Water (in Mg/Ml)

(317) The solubility in water of the compounds of the invention can be determined for example by the so-called shake flask method (as specified in ASTM International: E 1148-02, Standard test methods for measurement of aqueous solubility, Book of Standards Volume 11.05.). This entails an excess of the solid compound being put into a buffer solution with a particular pH (for example phosphate buffer of pH 7.4), and the resulting mixture being shaken or stirred until equilibrium has been set up (typically 24 or 48 hours, sometimes even up to 7 days). The undissolved solid is then removed by filtration or centrifugation, and the concentration of the dissolved compound is determined by UV spectroscopy or high pressure liquid chromatography (HPLC) by means of an appropriate calibration plot.

(318) 7. Results

(319) The results of the receptor binding investigations are expressed as receptor binding constants [K.sub.i(V1b)] or selectivities [K.sub.i(V1a)/K.sub.i(V1b)]. The results of the investigation of the metabolic stability are indicated as microsomal clearance (mCl).

(320) The compounds of the invention show very high affinities for the V1b receptor in these assays (maximally 100 nM, or maximally 10 nM, frequently <1 nM). The compounds also show high selectivities vis--vis the V1a receptor and a good metabolic stability, measured as microsomal clearance.

(321) The results are listed in table B. The numbers of the compounds refer to the synthesis examples.

(322) TABLE-US-00003 TABLE B K.sub.i(h-V1b)* Ex. [nM] K.sub.i(h-V1a)/K.sub.i(h-V1b) 1 + +++ 2a ++ +++ 2b + +++ 3 + ++ 4 + +++ 7 + +++ 8 +++ +++ 9 + +++ 10 ++ +++ 11 ++ +++ 12 ++ +++ 13 ++ +++ 14 ++ +++ 15 + +++ 16 ++ +++ 17 + +++ 18 ++ +++ 19 ++ +++ 20 + +++ 21 ++ +++ 22 ++ +++ 23 ++ +++ 24 + +++ 25 ++ +++ 26 +++ +++ 27 + +++ 28 + +++ 29 + +++ 30 ++ +++ 31 ++ +++ 32 + +++ 33 ++ +++ 34 ++ +++ 35 + +++ 36 ++ +++ 37 ++ +++ 38 ++ +++ 39 ++ +++ 40 ++ +++ 41 ++ +++ 42 ++ +++ 43 + +++ 44 ++ +++ 45 ++ +++ 46 + ++ *h = human Ex. = Example Key: K.sub.i(h-V1b) K.sub.i(h-V1a)/K.sub.i(h-V1b) + >10-100 nM 10-<25 ++ 1-10 nM 25-75 +++ <1 nM >75