MXPA06011715A - Fused ring nk1 antagonists - Google Patents

Abstract

A compound having the general structure shown in Formula (1) or pharmaceutically acceptable salts and/or solvates thereof are useful in treating diseases or conditions mediated by NK1 receptors, for example various physiological disorders, symptoms or diseases, including emesis, depression, anxiety and cough.

Description

ANTIGONISTS OF NEUROQUININE-1 FUSED RING FIELD OF THE INVENTION The present invention relates to novel neurokinin-1 receptor antagonists (NK-i or NK-1), pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds, to treat diseases and conditions mediated by the NK receptor. - ?, Including, for example, emesis, depression, anxiety and cough.

BACKGROUND OF THE INVENTION Tachykinins are peptide ligands for neurokinin receptors. Neurokinin receptors, such as NK-i, NK2 and NK3, are involved in a variety of biological processes. They can be found in the nervous system and in the circulatory system of a mammal, as well as in peripheral tissues. Accordingly, the modulation of these types of receptors has been studied to treat or potentially prevent various disease states in mammals. For example, it has been reported that NK-i receptors are involved in microvascular filtration and mucus secretion. Representative types of neurokinin receptor antagonists and disorders that can be treated therewith include, for example, sleep disorders, pain, migraine, emesis, nociception and inflammation; see, for example, U.S. Patent No. 6,329,401, U.S. Patent No. 5,760,018, U.S. Patent No. 5,620,989, WO 95/19344, WO 94/13639, WO 94/10165, Wu et al., Tetrahedron, 56, 6279-6290 (2000), Rombouts et al., Tetrahedron, 59, 4721-4731 (2003), and Rogiers et al., Tetrahedron, 57, 8971-8981 (2001). It would be advantageous to provide a NK-i antagonist that is potent, selective and possesses beneficial therapeutic and pharmacological properties, and good metabolic stability. It would also be advantageous to provide an NKi antagonist which is effective to treat a variety of physiological disorders, symptoms and diseases while minimizing side effects. This invention provides that type of NK-? Antagonist.

BRIEF DESCRIPTION OF THE INVENTION In one embodiment, the present invention relates to a compound of Formula 1: Formula 1 or a pharmaceutically acceptable salt and / or solvate thereof, Ar1 and Ar2 are each independently selected from the group consisting of (R7) n7-aryl- and (R8) n8-heteroaryl-; G is selected from the group consisting of -O-, -S-, -S (O) -, -S (02) -, -N (R6) -, -N (C (0) R6) -, -N ( S (02) R6) -, -N (S (0) R6) -, -N (C (0) OR6) -, -N (C (0) N (R6) 2) -, -N (R6) S (02) -, -S (02) N (R6) -, -N (R6) SO-, -S (0) N (R6) -, -N (R6) C (0) 0-, -OC (0) N (R6) -, -N (R6) C (0) -, -C (0) N (R6) -, and -N (R6) C (0) N (R6) -; X is - (C (R6) 2) n3-A- (C (R6) 2) n4-, where n3 and n4 may be the same or different; Y is - (C (R6) 2) n5-B- (C (R6) 2) n6-, where n5 and n6 can be the same or different; A is selected from the group consisting of -O-, -S-, -C (R6) 2-, and -N (R14) -, B is selected from the group consisting of -O-, -S-, -C (R6) \ 2 n1, n2, n3, n4, n5, n6, and n8 are individually and independently an integer between 0 and 3; n7 is an integer between 0 and 5; n8 is an integer between 1 and 3; n9 is an integer between 0 and 2; n10 is an integer between 1 and 5 Z is selected from the group consisting of -C (O) -, -C (S) -, -S (O) -, -S (02) -, -C (= NR6) -, -C (= NOR6) - and -C (= NN (R6) 2) -; R and R2 are independently selected from the group consisting of H, alkyl, hydroxyalkyl, cycloalkyl, -CH2F, -CHF2, -CF3, and heterocycloalkyl, wherein each of said alkyl, cycloalkyl, or heterocycloalkyl may be unsubstituted or substituted with one or more substituents which may be the same or different and are independently selected from the group consisting of halogen, alkyl, haloalkyl, -OR6, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -N (R6) 2, -C (0) R6, -C (0) OR6, -OC (0) R6, -C (0) N (R6) 2, -N (R6) C (0) R6, -N (R6) C (0) OR6, -N ( R6) C (0) N (R6) 2, -N02, -CN, -S (02) R6, and -S (02) N (R6) 2; or R1 and R2, taken together with the carbon to which they are shown to be attached in Formula 1, form a carbonyl group with the proviso that G is selected from the group consisting of -O-, -S-, and - N (R6) -; or R1 and R2, taken together with the carbon to which they are shown to be attached in Formula 1, form a cycloalkylene ring, wherein said cycloalkylene ring may be unsubstituted or substituted with one or more substituents which may be equal or and are independently selected from the group consisting of halogen, alkyl, haloalkyl, -OR6, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -N (R6) 2, -C (0) R6, -C (0) OR6, - OC (0) R6, -C (0) N (R6) 2, -N (R6) C (0) R6, -N (R6) C (0) OR6, -N (R6) C (0) N ( R6) 2, -N02, -CN, -S (02) R6, and -S (02) N (R6) 2; R3 and R4 are independently selected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be unsubstituted or substituted with one or more substituents which may be the same or different and are independently selected from the group consisting of halogen, alkyl, haloalkyl, -OR6, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -N (R6) 2 , -C (0) R6, -C (0) OR6, -OC (0) R6, -C (0) N (R6) 2, -N (R6) C (0) R6, -N (R6) C (0) OR6, -N (R6) C (0) N (R6) 2, -N02, -CN, -S (02) R6, and -S (02) N (R6) 2; R5 is selected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and -P (0) (OH) 2, wherein each of said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be unsubstituted or substituted with one or more substituents which may be the same or different and are independently selected from the group consisting of halogen, alkyl, haloalkyl, -OR6, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -N (R6) 2, -C (0 ) R6, -C (0) OR6, -OC (0) R6, -C (0) N (R6) 2, -N (R6) C (0) R6, -N (R6) C (0) OR6, -N (R6) C (0) N (R6) 2, -N02, -CN, -S (02) R6, and -S (02) N (R6) 2; R6 is selected from the group consisting of H, -CN, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be unsubstituted or substituted independently with one or more substituents which they may be the same or different and the substituents are independently selected from the group consisting of halogen, -OH, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, aryl, aryloxy, heteroaryl and heteroaryloxy; each R7 is independently selected from the group consisting of H, alkyl, cycloalkyl, -OH, alkoxy, cycloalkoxy, halogen, -CN, -N02, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -C (0) OR11, -C (0) NR9R10, -N (R9) C (0) R11, -N (R9) C (0) OR12, -N (R9) C (0) NR9R10, -N (R9) S (02) R12, -NR9R10, -S ( 02) NR9R10, -S (0) R12, -S (02) R12, and (R15) n8-heteroaryl-; each R8 is independently selected from the group consisting of H, alkyl, cycloalkyl, -OH, halogen, -CN, -N02, -C (0) CF3, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, alkoxy, cycloalkoxy, -C (0) OR11, - CONR9R10, -NR9R10, -NR9COR12, -NR9C02R11, -NR9CONR9R10, -NR9S02R12, -S (0) R12 , and -S (02) R12; R9 and R10 are each independently selected from the group consisting of H, alkyl, cycloalkyl and bl; or R9 and R10, taken together with the nitrogen to which they are attached, form a 4-7 membered heteroaryl ring containing from 0-3 additional heteroatoms selected from the group consisting of -0-, -S- and - N (R11) -; R11 is selected from the group consisting of H, alkyl and cycloalkyl; R12 is selected from the group consisting of alkyl, cycloalkyl, and -CF3; each R13 is independently selected from the group consisting of - (C (R17) 2) n7-D, where D is H, -CF3, -CHF2, -CH2F, -CN, -OH, -O-alkyl, -OCH2F , -OCHF2, -OCF3, -OCH2CF3, -O-cycloalkyl, -O-alkyl-cycloalkyl, -NR18R19, -SO2NR18R19, -NR11S02R18, -NR11C (0) R19, - NR11C (0) OR18, -NR11 (C (0) NR18R19), -C (0) NR18R19, -C (0) OR18, -cycloalkyl, (R7) n7-aryl-, (R8) n8-heteroaryl-, - OC (0) R19, -OC (0) NR18R19, -C (= NOR19) (R18), -C (0) R18, -C (OR11) (R18) (R19), heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of R21 and R22, R > 1144 is H, alkyl, haloalkyl, aryl, heteroaryl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, -S (0) R6, -S (02) R6, -C (0) OR6, -C (0) R6, and -C ( 0) N (R6) 2; R15 is H, alkyl, cycloalkyl, alkoxy, -OH, -CN, -N02, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, cycloalkoxy, -C (0) OR11, -C (0 ) NR9R10, -N (R9) C (0) R11, -N (R9) C (0) OR12, -N (R9) C (0) NR9R10, -N (R9) S (02) R12, -NR9R10, -S (02) NR9R10, -S (0) R12, -S (02) R12; each R17 is independently H or alkyl; R18 and R19 are each independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, -CH2CF3, aryl, and heteroaryl; or R18 and R19, together with the nitrogen atom to which they are both bound, form a saturated or unsaturated ring of 4 to 7 members which is optionally substituted with -OR11, wherein one of the carbon atoms in the ring is optionally replaced with a heteroatom selected from the group consisting of -O-, -S- and -NR20-; R 20 is H, alkyl, cycloalkyl, cycloalkylalkyl or hydroxyalkyl; R21 and R22, together with the carbon atom to which they are attached, form -C (O) -, -C (S) -, a ring of cyclopropyl or -C (NR23) -; R23 is H, alkyl, cycloalkyl, cycloalkylalkyl, -N02, -CN or OR11; R24 and R25 are each independently selected from the group consisting of H and alkyl; or R24 and R25, together with the carbon atom to which they are both attached, form a -C (O) - or cyclopropyl group; R26 is H, -OH or alkyl; R27 is H, alkyl, cycloalkyl, cycloalkylalkyl, -P (0) (OH) 2, allyl, hydroxyalkyl, alkoxyalkyl, -S02R28 or - (CH2) 2 -N (R11) -S02-R28; R28 is alkyl, cycloalkyl, -CF3 or -CH2CF3; R29 is 1 to 3 substituents independently selected from the group consisting of H, alkyl, -OH, alkoxy and halogen; X1 is -NR27-, -O-, -S-, -S (O) -, -S (02) -, -CH2-, -CF2- or -CR11F-; and X2 is -NR20-, -N (C (0) NR18R19) -, -N (C (0) OR18) -, -N (S (02) R28) -, -N (C (0) R11) -, -N (S (02) NHR18) -, -O-, -S-, -S (O) -, -S (02) -, -CH2-, -CF2 - or -CR11F-. In another embodiment of the compounds of Formula 1, R1 and R2 are independently selected from the group consisting of H, (C -? - C6) alkyl, hydroxyalkyl (CrC3), (C3-C8) cycloalkyl, -CH2F, -CHF2, and -CF3; or R1 and R2, taken together with the carbon to which they are shown to be attached in Formula 1, form a carbonyl group; or R1 and R2, taken together with the carbon to which they are shown to be attached in Formula 1, form a cycloalkylene ring (C3-C6); R3 and R4 are H; R5 is selected from the group consisting of H, (C? -C6) alkyl, hydroxyalkyl (C? -C3), (C3-C8) cycloalkyl, -CH2F, -CHF2, and -CF3; G is -O- or -N (R14) -; R14 is H, (C6) alkyl, hydroxyalkyl (CrC3), (C3-C8) cycloalkyl, -CH2F, -CHF2, -CF3; Ar1 is monosubstituted phenyl; and Ar2 is disubstituted phenyl. In another embodiment of the compounds of Formula 1, Ar1 is a monosubstituted phenyl. In another embodiment of the compounds of Formula 1, Ar1 is phenyl; In another embodiment of the compounds of Formula 1, Ar2 is a disubstituted phenyl. In another embodiment of the compounds of Formula 1, Ar2 is a 3.5-disubstituted phenyl. In another embodiment of the compounds of Formula 1, Ar2 is 3,5-bis (trifluoromethyl) phenyl. In another embodiment of the compounds of Formula 1, Ar 1 is phenyl and Ar 2 is 3,5-bis (trifluoromethyl) phenol. In another embodiment of the compounds of Formula 1, G is -O-. In another embodiment of the compounds of Formula 1, R1 and R2 are each independently H or C6 alkyl. In another embodiment of the compounds of Formula 1, R1 is -CH3; and R2 is -H. In another embodiment of the compounds of Formula 1, at least one of R3 and R4 is H. In another embodiment of the compounds of Formula 1, both R3 and R4 are H. In another embodiment of the compounds of Formula 1 , R5 is H. In another embodiment of the compounds of Formula 1, n1 is 1 or 2. In another embodiment of the compounds of Formula 1, n2 is 0 or 1. In another embodiment of the compounds of Formula 1, n1 and n2 are both 1. In another embodiment of the compounds of Formula 1, n1 is 1 and n2 is 0.

In another embodiment of the compounds of Formula 1, n 1 is 2 and n 2 is 0. In another embodiment of the compounds of Formula 1, X is selected from the group consisting of -N (R 6) - and -O-. In another embodiment of the compounds of Formula 1, X is -N (R6) -. In another embodiment of the compounds of Formula 1, X is -O-. In another embodiment of the compounds of Formula 1, Y is selected from the group consisting of -N (R6) -, -O-, -CH2-, - (CH2) 20-, -0 (CH2) 2-, - ( CH2) 2-, -CH2N (R6) -, and -N (R6) CH2-. In another embodiment of the compounds of Formula 1, Y is -N (R6) -. In another embodiment of the compounds of Formula 1, Y is -O-. In another embodiment of the compounds of Formula 1, Y is -CH2-. In another embodiment of the compounds of Formula 1, Y is - (CH2) 20-. In another embodiment of the compounds of Formula 1, Y is -0 (CH2) 2-. In another embodiment of the compounds of Formula 1, Y is - (CH2) 2-. In another embodiment of the compounds of Formula 1, Y is -CH2N (R6) -.

In another embodiment of the compounds of Formula 1, Y is -N (R6) CH2-. In another embodiment of the compounds of Formula 1, Z is -C (O) -, In another embodiment of the compounds of Formula 1, R 3 is H. In yet another embodiment, the compounds of Formula 1 may be represented through Formula 2: Formula 2 or its pharmaceutically acceptable salt and / or solvate. In yet another embodiment, the compounds of Formula 1 can be represented by Formula 3: Formula 3 or its pharmaceutically acceptable salt and / or solvate. In yet another embodiment, the compounds of Formula 1 can be represented by Formula 4: Formula 4 or its pharmaceutically acceptable salt and / or solvate. In yet another embodiment, the compounds of Formula 1 can be represented by Formula 5: Formula 5 wherein R16 is H, F, alkyl, or each R16 together with the carbon atom to which they are shown to be attached in Formula 5 defines a cycloalkyl ring. In yet another embodiment, the compounds of Formula 1 can be represented by Formula 6: Formula 6 wherein R16 is H, F, alkyl, or each R16 together with the ring carbon atom or atoms to which they are shown to be attached in Formula 6 defines a cycloalkyl ring.

In yet another embodiment, the compounds of Formula 1 can be represented by Formula 7: Formula 7 wherein R 16 is H, F, alkyl, or each R 16 together with the ring carbon atom or atoms to which they are shown to be attached in Formula 7 defines a cycloalkyl ring. In yet another embodiment, the compounds of Formula 1 can be represented by Formula 8: Formula 8 wherein R, 16 is H, F, alkyl, or each R > 16 together with the carbon atom in the ring which are shown to be attached in Formula 8 defines a cycloalkyl ring. In yet another embodiment, the compounds of Formula 1 can be represented by Formula 9: Formula 9 in yet another embodiment, the compounds of Formula 1 can be represented by Formula 10: Formula 10 in yet another embodiment, the compounds of Formula 1 can be represented by Formula 11: Formula 11 in yet another embodiment, the compounds of Formula 1 can be represented by Formula 12: Formula 12 In yet another embodiment, the compounds of Formula 1 can be represented by Formula 13: Formula 13 wherein R 16 is H, F, alkyl, or each R 16 together with the carbon atom in the ring to which they are attached in Formula 13 defines a cycloalkyl ring. In yet another embodiment, the compounds of Formula 1 can be represented by Formula 14: Formula 14 wherein R 16 is H, F, alkyl, or each R 16 together with the ring carbon atom or atoms to which they are shown to be attached in Formula 14 defines a cycloalkyl ring.

In yet another embodiment, the compounds of Formula 1 can be represented by Formula 15: Formula 15 wherein R16 is H, F, alkyl, or each R16 together with the ring carbon atom or atoms to which they are shown to be attached in Formula 15 defines a cycloalkyl ring. In yet another embodiment, the compounds of Formula 1 can be represented by Formula 16: Formula 16 wherein R is H, F, alkyl, or each R, 16 together with the carbon atom in the ring to which they are shown to be attached in Formula 16 defines a cycloalkyl ring. In yet another embodiment, the compounds of Formula 1 can be represented by Formula 17: Formula 17 in yet another embodiment, a compound of Formula 1 is selected from the compounds of the formulas: or a pharmaceutically acceptable salt and / or solvate thereof. In yet another embodiment, the compound of Formula 1 is a compound of the Formula: or its pharmaceutically acceptable salt and / or solvate. In yet another embodiment, the compound of Formula 1 is a compound of the Formula: or its pharmaceutically acceptable salt and / or solvate. In yet another embodiment, the compound of Formula 1 is a compound of the Formula: or its pharmaceutically acceptable salt and / or solvate. In yet another embodiment, the compound of Formula 1 is a compound of the Formula: or its pharmaceutically acceptable salt and / or solvate. In yet another embodiment, the compound of Formula 1 is a compound of the Formula: or its pharmaceutically acceptable salt and / or solvate. In yet another embodiment, the compound of Formula 1 is a compound of the Formula: or its pharmaceutically acceptable salt and / or solvate. In yet another embodiment, the compound of Formula 1 is a compound of the Formula: or its pharmaceutically acceptable salt and / or solvate. In yet another embodiment, the compound of Formula 1 is a compound of the Formula: or its pharmaceutically acceptable salt and / or solvate. In yet another embodiment, the compound of Formula 1 is a compound of the Formula: or its pharmaceutically acceptable salt and / or solvate. In yet another embodiment, the compound of Formula 1 is a compound of the Formula: or its pharmaceutically acceptable salt and / or solvate. In yet another embodiment, the compound of Formula 1 is a compound of the Formula: or its pharmaceutically acceptable salt and / or solvate. In yet another embodiment, the compound of Formula 1 is a compound of the Formula: or its pharmaceutically acceptable salt and / or solvate. In yet another embodiment, the compound of Formula 1 is a compound of the Formula: or its pharmaceutically acceptable salt and / or solvate. In yet another embodiment, the compound of Formula 1 is a compound of the Formula: or its pharmaceutically acceptable salt and / or solvate. In yet another embodiment, the compound of Formula 1 is a compound of the Formula: or its pharmaceutically acceptable salt and / or solvate. In yet another embodiment, the compound of Formula 1 is a compound of the Formula: or its pharmaceutically acceptable salt and / or solvate. In a further embodiment, the present invention relates to a pharmaceutical composition comprising an effective amount of at least one compound of Formula 1, or its pharmaceutically acceptable salt and / or solvate. acceptable, and at least one pharmaceutically acceptable carrier. In a further embodiment, this invention relates to a device comprising two or more containers in a single package, wherein each container in the package comprises a pharmaceutical composition. At least one container of the package comprises an effective amount of the compound of Formula I, or its pharmaceutically acceptable salt and / or solvate in a pharmaceutically acceptable carrier, and at least one other container in the package comprises another therapeutic agent in a pharmaceutically acceptable carrier. The pharmaceutical compositions of the equipment can be used in combination. In a further embodiment, the present invention relates to a method for affecting an NK-i receptor in a patient comprising administering to the patient an effective amount of at least one compound of Formula 1 or its pharmaceutically acceptable salt and / or solvate. acceptable. In an additional mode, the present invention relates to a method for treating a condition or disease mediated by the NK-i receptor (i.e., a disease associated with an NKi receptor, or a disease involving an NKi receptor in part of the process). of the disease) in a patient in need of such a treatment comprising administering to the patient an effective amount of at least one compound of Formula 1 or its pharmaceutically acceptable salt and / or solvate. In yet a further embodiment, the present invention relates to a method for the treatment of a disease (or disorder or condition) in a patient in need of such treatment, where the disease is selected from the group consisting of: (1) respiratory diseases (eg, chronic lung disease, bronchitis, pneumonia, asthma, allergy, cough and bronchospasm), (2) inflammatory diseases (for example, arthritis and psoriasis), (3) skin disorders (eg, atopic dermatitis and contact dermatitis), (4) ophthalmological disorders (eg, retinitis, ocular hypertension and cataracts), (5) conditions of the central nervous system, such as depressions (eg, neurotic depression), anxieties (eg, general anxiety, social anxiety and panic anxiety disorders), phobias (eg, social phobia), and bipolar disorder, (6) addictions (for example, alcohol dependence and psychoactive substance abuse), (7) epilepsy, (8) nociception, (9) psychosis, (10) schizophrenia, (11) Alzheimer's disease, (12) AIDS-related dementia, ( 13) Towne's bad, (14) disorders r stress-related (for example, post-traumatic stress disorder), (15) obsessive / compulsive disorders, (16) eating disorders (for example, bulimia, anorexia nervosa, and "binge-eating" disorder), (17) sleep disorders, (18) mania, (19) premenstrual syndrome, (20) gastrointestinal disorders (eg, irritable bowel syndrome, Crohn's disease, colitis, and emesis), (21) atherosclerosis, (22) fibrosing disorders (eg, fibrosis) pulmonary), (23) obesity, (24) type II diabetes, (25) pain-related disorders (eg, headaches, such as migraines, neuropathic pain, postoperative pain and chronic pain syndromes), ( 26) bladder and genitourinary disorders (eg, cystitis) interstitial and urinary incontinence), (27) emesis (for example, induced by chemotherapy (for example, induced by cisplatin, doxorubicin, and taxane), induced by radiation, dizziness, induced by ethanol, and postoperative nausea and vomiting), and (28) nausea, which comprises administering to the patient an effective amount of at least one (e.g., a) compound of Formula 1 or a pharmaceutically acceptable salt and / or solvate thereof. In yet a further embodiment, the present invention relates to a method for treating a disease (or disorder or condition) in a patient in need of such treatment, wherein the disease is selected from the group consisting of: respiratory diseases (e.g. cough), depression, anxiety, phobia, bipolar disorder, alcohol dependence, psychoactive substance abuse, nociception, psychosis, schizophrenia, stress-related disorders, obsessive / compulsive disorder, bulimia, anorexia nervosa, binge-eating disorder, sleep, mania, premenstrual syndrome, gastrointestinal disorders, obesity, pain-related disorders (eg, headaches, such as migraines, neuropathic pain, postoperative pain, and chronic pain syndromes), bladder disorders, genitourinary disorders, emesis and nausea, which comprises administering to the patient an effective amount of at least one compound of Formula 1 or a salt and / or olvate thereof pharmaceutically acceptable. In still a further embodiment, the present invention also relates to a method for the treatment of a disease (or disorder or condition) wherein there is microvascular filtration and mucus secretion in a patient in need of such treatment, comprising administering to the patient an effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt and / or solvate thereof. In yet a further embodiment, the present invention also relates to a method for the treatment of asthma, emesis, nausea, depressions, anxieties, cough and pain-related disorders in a patient in need of such treatment comprising administering to the patient a effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt and / or solvate thereof. In still an additional modality, the present invention also relates to a method for the treatment of emesis, depression, anxiety and cough in a patient in need of such treatment comprising administering to the patient an effective amount of at least one compound of Formula 1 or a salt and or solvate thereof pharmaceutically acceptable. In yet a further embodiment, the present invention also relates to a method for antagonizing an effect of a Substance P at a neurokinin-1 receptor site in a patient in need of such a treatment, comprising administering to the patient at least one compound of Formula 1 or a pharmaceutically acceptable salt and / or solvate thereof. In still a further embodiment, the present invention also relates to a method for blocking NK-i receptors in a a patient in need of said treatment, comprising administering to the patient at least one compound of Formula 1 or a pharmaceutically acceptable salt and / or solvate thereof. In yet a further embodiment, the present invention also relates to a method for treating depression and / or anxiety in a patient in need of such treatment comprising administering to the patient an effective amount of one or more compounds of Formula 1 or a salt and / or pharmaceutically acceptable solvate thereof, in combination with an effective amount of one or more antidepressant agents and / or one or more anti-anxiety agents. In yet a further embodiment, the present invention also relates to a method for the treatment of a disease mediated by NKi receptors (or disorder or condition) in a patient in need of such treatment comprising administering to the patient an effective amount of one or more compounds of Formula 1 or a pharmaceutically acceptable salt and / or solvate thereof, in combination with an effective amount of one or more selective serotonin reuptake inhibitors (SSRIs, abbreviation of the English expression "reuptake inhibitors"). selective serotonin "). In yet a further embodiment, the present invention also relates to a method for the treatment of depression and / or anxiety in a patient in need of such treatment comprising administering to the patient an effective amount of one or more compounds of Formula 1 or one pharmaceutically acceptable salt and / or solvate thereof, in combination with an effective amount of one or more selective serotonin reuptake inhibitors. In yet a further embodiment, the present invention also relates to a method for the treatment of a disease mediated by NK-? (or disorder or condition) in a patient in need of such treatment comprising administering to the patient an effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt and / or solvate thereof, in combination with at least one therapeutic agent selected from the group consisting of: other types of NKi receptor antagonists (eg, NKi receptor antagonists other than those according to Formula 1 of the present invention), prostanoids, Hi-receptor antagonists , agonists of a-adrenergic receptors, dopamine receptor agonists, melanocortin receptor agonists, endothelin receptor antagonists, endothelin-converting enzyme inhibitors, angiotensin II receptor antagonists, inhibitors of angiotensin converting enzyme, neutral metalloendopeptidase inhibitors, ETA antagonists, renin inhibitors, antagonist of serotonin 5-HT3 receptors (eg, ondansetron), serotonin 5-HT2c receptor agonists, nociceptin receptor agonists, glucocorticoids (eg, dexamethasone), rho kinase inhibitors, modulators of the channels of potassium and inhibitors of protein 5 of resistance to multiple drugs. In yet a further embodiment, the invention also relates to a method for treating a disease mediated by NK-i (or disorder or condition) in a patient in need of such treatment comprising administering to the patient an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt and / or solvate thereof, in combination with at least one therapeutic agent selected from the group consisting of: prostanoids, such as prostaglandin E1; a-adrenergic agonists, such as phentolamine mesylate; dopamine receptor agonists, such as apomorphine; angiotensin II antagonists, such as losartan, irbesartan, valsartan and candesartan; ETA antagonists, such as bosentan and ABT-627; 5-HT3 serotonin receptor antagonists, such as ondansetron; and glucocorticoids, such as dexamethasone. In yet a further embodiment, the invention also relates to a method for the treatment of an NKi-mediated disease (or disorder or condition) in a patient in need of such a treatment comprising administering to the patient an effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt and / or solvate thereof, in combination with an effective amount of at least one therapeutic agent selected from the group consisting of: other types of NKi receptor antagonists, SSRIs, agonists of the dopamine receptors, serotonin 5-HT3 receptor antagonists, serotonin 5-HT2c receptor agonists, nociceptin receptor agonists, glucocorticoids and inhibitors of protein 5 of resistance to multiple drugs. In yet a further embodiment, the invention also relates to a method for the treatment of emesis, nausea and / or vomiting in a patient in need of such treatment comprising administering to the patient an effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt and / or solvate thereof, in combination with an effective amount of at least one serotonin 5-HT3 receptor antagonist (e.g., ondansetron) and / or at least one glucocorticoid (e.g. dexamethasone). In a further embodiment, the present invention also relates to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat a disease mediated by NK-i receptors (or disorder or condition), where A container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt and / or solvate thereof, in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising another therapeutic agent. in a pharmaceutically acceptable carrier, the therapeutic agent being selected from the group consisting of: SSRIs, other types of NK ^ prostanoid receptor antagonists, Hi receptor antagonists, a-adrenergic receptor agonists, dopamine receptor agonists, melanocortin receptor agonists, endothelin receptor antagonists, endothelin-converting enzyme inhibitors, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, neutral metalloendopeptidase inhibitors, ETA antagonists, renin inhibitors, 5-HT3 serotonin receptor antagonists, serotonin 5-HT2c receptor agonists, nociceptin receptor agonists, glucocorticoids, rho kinase inhibitors, potassium channel modulators, and multiple resistance protein 5 inhibitors drugs. In still another embodiment, the present invention also relates to an equipment comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat depression and / or anxiety, wherein a container comprises a pharmaceutical composition comprising a effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt and / or solvate thereof, in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an antidepressant agent in a pharmaceutically acceptable carrier, and / or wherein a separate container comprises a pharmaceutical composition comprising an anti-anxiety agent in a pharmaceutically acceptable carrier. In yet another embodiment, the present invention also relates to an equipment comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat a disease mediated by NKi receptors, wherein a container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt and / or solvate thereof, in a pharmaceutically carrier acceptable, and where, a separate container comprises a pharmaceutical composition comprising an SSRI in a pharmaceutically acceptable carrier. In still another embodiment, the present invention also relates to an equipment comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat depression and / or anxiety, wherein a container comprises a pharmaceutical composition comprising a effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt and / or solvate thereof, in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an SSRI in a pharmaceutically acceptable carrier. In yet another embodiment, the present invention also relates to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat emesis and / or nausea, wherein a container comprises a pharmaceutical composition comprising a effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt and / or solvate thereof, in a pharmaceutically acceptable carrier, and wherein, a separate container it comprises a pharmaceutical composition comprising a serotonin 5-HT3 receptor antagonist in a pharmaceutically acceptable carrier, and / or wherein a separate container comprises a pharmaceutical composition comprising a glucocorticoid in a pharmaceutically acceptable carrier. In still another embodiment, the present invention also relates to an equipment comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat emesis and / or nausea, wherein a container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt and / or solvate thereof, in a pharmaceutically acceptable carrier, and wherein, a separate container comprises ondansetron, and / or wherein a separate container comprises dexamethasone. Other features and advantages of the invention will be apparent from the following detailed description and from the claims.

DETAILED DESCRIPTION OF THE INVENTION Except where otherwise indicated, the following definitions apply throughout the specification and the claims. When any variable appears more than once in any portion, its definition in each occurrence is independent of its definition in each other occurrence.

The chemical names, common denominations and chemical structures can be used interchangeably to describe the same structure. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Thus, the definition of "alkyl" is applied to "alkyl" as well as to the "alkyl" portions of "hydroxyalkyl," "haloalkyl," "alkoxy," etc. Ac means acetyl. Boc means -butoxycarbonyl.

Bu means butyl. t-Bu or Buf means tertiary butyl. Cbz means carbobenzoxy (i.e., Ph-CH2-0-C (0) -). DIEA means disopropylethylamine. DMPU means N, N H -dimethylpropyleneurea. DPPA means diphenylphosphorazide. Et means ethyl. HOTs means p-toluenesulfonic acid. HPLC stands for High Performance Liquid Chromatography. LiHMDS means lithium hexamethyldisilazide. It means methyl. EM means mass spectroscopy. Ni (Ra) means Ni Raney.

DO stands for optical density. Ph means phenyl / -PA (or IPA or iPA) means / so-propyl. PPTS means p-toluenesulfonic acid of pyridinium.

PTSA means p-toluenesulfonic acid.

THF means tetrahydrofuran.

TLC stands for Thin Layer Chromatography.

"Patient" includes both humans and animals. "Mammals" means humans and other mammalian animals. The portions of the chemical formulas that are in parentheses and / or brackets denote pending groups. For example, -C (O) - is refers to a carbonyl group (ie, OR II-C-), -N (alkyl) - refers to a divalent amine group with a pendant alkyl group (ie, Rc i alkyl Q = C-N- and -N [C (0) R6] - refers to a. - N- "Alkyl" means an aliphatic hydrocarbon group, which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. The most preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. The term "substituted alkyl" means that the alkyl group may be substituted with one or more substituents which may be the same or different., each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH (alkyl), -NH (cycloalkyl), -N (alkyl) 2, carboxy and - C (0) 0-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl. "Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to an alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain, which may be straight or branched. The term "alkenyl" includes substituted alkenyl which means that the alkenyl group may be substituted with one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, alkoxy and -S (alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl (i.e., vinyl), propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl. "Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have from about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. The term "substituted alkynyl" means that the alkynyl group may be substituted with one or more substituents which may be the same or different, each substituent being selected from the group consisting of alkyl, aryl and cycloalkyl. "Aryl" means a monocyclic or multicyclic aromatic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group may be optionally substituted with one or more "ring system substituents" which may be the same or different and are as defined in the present invention. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Heteroaryl" means a system of monocyclic or aromatic multicyclic rings comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, wherein one or more of the atoms in the ring is a distinct element carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" may be optionally substituted with one or more "substituents in the ring system" which may be identical or different, and are as defined in the present invention. The prefix aza, oxa or tia prefixed to the heteroaryl root name means that at least one nitrogen, oxygen or sulfur atom respectively, is present as an atom in the ring. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, thiadiazolyl 1.2.4 , pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo [1.2- ajpyridinyl, imidazo [2,1-b] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl, tetrazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. "Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The link to the mother portion is through the alkyl. "Alkylaryl" means an alkyl-aryl group in which the alkyl and the aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. A non-limiting example of a suitable alkylaryl group is tolyl. The link to the mother portion is through the aril. "Cycloalkyl" means a system of mono- or multicyclic aromatic rings comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl may be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined previously. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like, as well as partially saturated species such as, for example, indanyl, tetrahydronaphthyl and the like. "Halogen" means fluorine, chlorine, bromine, or iodine. The preferred halogens are fluorine, chlorine and bromine. The groups substituted with "halogen" or "halo" (for example, haloalkyl groups) refer to groups substituted with one or more fluorine, chlorine, bromine and / or iodine atoms. "Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system, which, for example, replaces a hydrogen available in the ring system. The substituents of the ring system may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy , aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocycloalkyl, -C (= N-CN) - NH2, -C (= NH) -NH2, -C (= NH) -NH (alkyl), Y? Y2N-, Y ^ N-alkyl-, Y ^ NO) -, Y1Y2NS02- and -S02NY1Y2, where Yi and Y2 can be the same or different and are selected independently of the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may also mean a single portion which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) in a ring system. Examples of such a portion are methylenedioxy, ethylenedioxy, -C (CH3) 2- and the like which form portions such as, for example: "Heterocycloalkyl" means a saturated non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, wherein one or more of the atoms in the ring system is a element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and / or sulfur atoms present in the ring system. Preferred heterocycloalkyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocycloalkyl root name means that at least one nitrogen, oxygen or sulfur atom respectively is present as an atom in the ring. Any -NH in a heterocycloalkyl ring may be present in protected form such as, for example, a group -N (Boc), -N (CBz), -N (Tos) and the like; such protected functional groups are also considered part of this invention. The heterocycloalkyl may be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined in the present invention. The nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable monocyclic heterocycloalkyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone and the like. It should be noted that in ring systems containing heteroatoms of this invention, there are no hydroxyl groups on the carbon atoms adjacent to N, O or S, as well as there are no N or S groups on the carbon adjacent to another hetero atom. Therefore, for example, in the ring: there is no -OH attached directly to the carbons marked 2 and 5. It should also be noted that the tautomeric forms such as, for example, the portions: they are considered equivalent in certain embodiments of this invention. "Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and the alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkynyl group and a lower alkyl group. The link to the mother portion is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl. "Heteroaralkyl" means a heteroaryl-alkyl- group in which heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl and quinolin-3-ylmethyl. The link to the mother portion is through the alkyl. "Hydroxyalkyl" means an HO-alkyl- group in which the alkyl is as previously defined. The "alkyl" portion of the hydroxyalkyl is preferably a lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. "Acyl" means a group H-C (O) -, alkyl-C (O) - or cycloalkyl-C (O) -, in which the various groups are as previously described. The link to the mother portion is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propane. "Aroyl" means an aryl-C (O) - group in which the aryl group is as previously described. The link to the mother portion is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1-naphthoyl. "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The link to the mother portion is through ether oxygen. "Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of aryloxy groups include phenoxy and naphthoxy. The link to the mother portion is through ether oxygen. "Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The link to the mother portion is through ether oxygen. "Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The link to the mother portion is through sulfur. "Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The link to the mother portion is through sulfur. "Aralkylthio" means an aralkyl-S- group in which the group Aralkyl is as previously described. A non-limiting example of a suitable aralkylthio group is benzylthio. The link to the mother portion is through sulfur. "Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The link to the mother portion is through the carbonyl. "Aryloxycarbonyl" means an aryl-O-C (O) - group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The link to the mother portion is through the carbonyl. "Aralkoxycarbonyl" means an aralkyl-O-C (O) - group. A non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The link to the mother portion is through the carbonyl. "Alkylsulfonyl" means an alkyl-S (02) - group. Preferred groups are those in which the alkyl group is lower alkyl. The link to the mother portion is through the sulfonyl. "Ariisulfonyl" means an aryl-S (02) - group. The link to the mother portion is through the sulfonyl. The term "substituted" means that one or more hydrogens in the designated atom is replaced with a selection of the indicated group, provided that the normal valence of the designated atom under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are allowed only if such combinations result in compounds stable By "stable compound" or "stable structure" is meant a compound that is strong enough to survive the isolation to a useful degree of purity of a reaction mixture, and the formulation into an effective therapeutic agent. The term "optionally substituted" means the optional substitution with the groups, radicals or specified portions. The term "isolated" or "in isolated form" for a compound refers to a synthetic process or natural source or combination thereof. The term "purified" or "in purified form" for a compound refers to the physical state of said compound after it is obtained from a process or from various purification methods described in the present invention or well known to the person skilled in the art, in sufficient purity to be characterized by conventional analytical techniques described in the present invention or known to the person skilled in the art. It should be noted that any heteroatom with valences not satisfied in the text, schemes and examples of the present invention is presumed to have the hydrogen atom (s) to satisfy the valences. When a ring system (eg, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) is substituted with an amount of substituents that varies within an expressly defined range, it is understood that the total number of substituents does not exceed the normal available valencies under the existing conditions. Thus, for example, a phenyl ring substituted with "n" substituents (where "n" ranges from 0 to 5) may have 0 to 5 substituents, while it is understood that a pyridinyl ring substituted with "n" substituents has an amount of substituents ranging from 0 to 4. When a functional group in a compound is termed "protected" ", this means that the group is in modified form to avoid unwanted side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those skilled in the art as well as by reference to standard textbooks such as, for example, TW Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York, incorporated into the present invention as a reference. When any variable (for example, aryl, heterocycloalkyl, R2, etc.) appears more than once in any constituent or in Formula I, its definition in each occurrence is independent of its definition in each other occurrence. As used in the present specification, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which is the result, direct or indirect, of combinations of the ingredients specified in the specified quantities. "Alkylheteroaryl" means an alkyl group attached to a parent portion by means of a heteroaryl group.

"Alkylsulfinyl" means an alkyl-S (O) - group. Preferred groups are those in which the alkyl group is lower alkyl. The link to the mother portion is through sulfinil. "Aralkenyl" means an aryl-alkenyl group in which aryl and alkenyl are as previously described. Preferred aralkenyls contain a lower alkenyl group. Non-limiting examples of suitable aralkenyl groups include 2-phenetenyl and 2-naphthylethenyl. The link to the mother portion is through the alkenyl. "Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. A non-limiting example of a suitable aralkylthio group is benzylthio. The link to the mother portion is through sulfur. "Aryloxycarbonyl" means an aryl-O-C (O) - group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The link to the mother portion is through the carbonyl. "Arylsulfinyl" means an aryl-S (O) - group. Non-limiting examples of suitable arylsulfinyl groups include phenylsulfinyl and naphthylsulfinyl. The link to the mother portion is through sulfinil. A carbamate group means a group -0-C (0) -N (alkyl aryl) -, and a urea group means a group -N (alkyl or aryl) -C (0) -N (alkyl or aryl) - . Representative carbamate and urea groups may include the following: "Cycloalkenyl" means a system of mono or multicyclic non-aromatic rings comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl may be optionally substituted with one or more "ring system substituents" which may be identical or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl and the like. A non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl. "Cycloalkylamino" means a cycloalkyl group as defined in the present invention attached to the parent portion through a nitrogen atom. "Cycloalkylaminocarbonyl" means a cyclic alkyl group attached to a nitrogen atom, which is attached to a carbonyl group; the Totality can be called substituted amide. "Heteroalkyl" means an alkyl as defined in the present invention, in which one or more of the atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. "Heteroaralkenyl" means a heteroaryl-alkenyl- group in which heteroaryl and alkenyl are as previously described. Preferred heteroaralkenyls contain a lower alkenyl group. Non-limiting examples of suitable heteroaralkenyl groups include 2- (pyrid-3-yl) ethenyl and 2- (quinolin-3-yl) ethenyl. The link to the mother portion is through the alkenyl. "Heteroaralkyl" means a heteroaryl-alkyl- group in which heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, 2- (furan-3-yl) ethyl and quinolin-3-methylmethyl. The link to the mother portion is through the alkyl. "Heteroaralkylthio" means a heteroaryl-alkyl-S group where the group is attached to the mother portion through the sulfur. "Heteroarylsulfinyl" means a heteroaryl-S (O) - group wherein the heteroaryl is as defined in the present invention and the heteroarylsufinyl group is attached to the mother portion through the sulfinyl. "Heteroarylsulfonyl" means a heteroaryl-S (02) - group wherein the heteroaryl is as defined in the present invention and the heteroarylsulfonyl group is attached to the mother portion through the sulfonyl.

"Heteroarylthio" means a heteroaryl-S- group where the heteroaryl is as defined in the present invention and the heteroarylsulfinyl group is attached to the mother portion through the sulfur. "Heterocycloalkenyl" means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is a element other than carbon, for example a nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or a carbon-nitrogen double bond. There are no adjacent oxygen and / or sulfur atoms present in the ring system. Preferred heterocycloalkenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or tia prefixed to the heterocycloalkenyl root name means that at least one nitrogen, oxygen or sulfur atom, respectively, is present as an atom in the ring. The heterocycloalkenyl may be optionally substituted with one or more substituents of the ring system, where "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocycloalkenyl may be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable monocyclic azaheterocycloalkenyl groups include 1.2.3.4-tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1.2.3.6- tetrahydropyridine, 1.4.5.6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Non-limiting examples of suitable oxaheterocycloalkenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluordihydrofuranyl, and the like. A non-limiting example of a suitable multicyclic oxaheterocycloalkenyl group is 7-oxabicyclo [2.2.1] heptenyl. Non-limiting examples of suitable monocyclic thiaheterocycloalkenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like. "Heterocyclic" means, in addition to the heteroaryl groups defined below, saturated and unsaturated cyclic organic groups having at least one O, S and / or N atom interrupting a carbocyclic ring structure consisting of a ring or two fused rings , where each ring is 5, 6 or 7 members and may or may not have double bonds lacking delocalized pi electrons, whose ring structure has from 2 to 8, preferably from 3 to 6 carbon atoms, for example 2- or 3-piperidinyl, 2- or 3-piperazinyl, 2- or 3-morpholinyl, or 2- or 3-thiomorpholinyl. "Sulfonamide" means a sulfonyl group attached to a mother portion through an amide. As is well known in the art, a bond drawn from a particular atom where no portion is shown at the terminal end of the bond indicates a methyl group linked through that bond to the atom. For example: It should also be noted that throughout the specification and the appended Claims, that any formula, compound, portion or chemical illustration with unsatisfied valences is presumed to have the hydrogen atom to satisfy the valences unless the context indicates a link. The term "substituted" means substitution with specified groups other than hydrogen, or with one or more groups, portions or radicals which may be the same or different, each being, for example, independently selected. The term "optionally substituted" means optional substitution with specified groups other than hydrogen, or with one or more groups, portions or radicals which may be the same or different, each being, for example, independently selected. With reference to the number of portions (for example, substituents, groups or rings) in a compound, unless otherwise defined, the phrases "one or more" and "at least one" mean that there may be as many portions as is chemically allowed, and the determination of the maximum number of such portions is within the knowledge of those skilled in the art. As used in the present invention, the term "composition" is intended to encompass a product that comprises the specified ingredients in the specified amounts, as well as any product which is the direct or indirect result of the combination of the specified ingredients in the specified amounts. The wavy line l? Mj as A bond generally indicates a mixture of, or either, the possible isomers, for example, containing stereochemistry (R) - and (S) -. For example, when the stereochemistry in a structure is not expressly indicated, the structure may have a mixture of, or any of the possible individual stereoisomers. The lines drawn in the ring systems, such as, for example: they indicate that the indicated line (link) can be attached to any of the substitutable ring carbon atoms. It should also be noted that any heteroatoms with valences not satisfied in the text, in the schemes, examples, and any structural formulas of the present invention are presumed to have the hydrogen atom or atoms to satisfy the valences.

The prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug", as used in the present invention, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to provide a compound of Formula 1 or a salt and / or solvate thereof. A description of prodrugs is provided in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both documents are incorporated herein by reference. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent binding, including hydrogen bonding. In certain cases, the soivate will be capable of isolation, for example when one or more solvent molecules are incorporated into the crystalline lattice of the crystalline solid. "Solvate" covers both solvates in the solution phase and solvates that can be isolated. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. A "hydrate" is a solvate where the solvent molecule is H20. An "effective amount" or a "therapeutically effective amount" is for the purpose of describing an amount of compound or a composition of the present invention effective in antagonizing the neurokinin-1 and thus produce the desired therapeutic effect in a suitable patient. The compounds of Formula 1 form salts that are also within the scope of this invention. It is understood that reference to a compound of Formula 1 in the present invention includes reference to its salts, unless otherwise indicated. The term "salt (s)", as used in the present invention, denotes acid salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. Additionally, when a compound of Formula 1 contains both a basic portion, such as, but not limited to a pyridine or imidazole, and an acid portion, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may formed and are included within the term "salt (s)" as used in the present invention. Pharmaceutically acceptable salts (ie, non-toxic, physiologically acceptable) are preferred, although other salts are also useful. Salts of the compounds of Formula 1 can be formed, for example, by reacting a compound of Formula 1 with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or an aqueous medium followed by lyophilization. Examples of acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, iodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulphonates, methylsulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulphates, 3- phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned in the present invention), tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) undecanoates and the like. Examples of basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts as organic bases. (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N, N-bis (dehydroabiethyl) ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butylamines, piperazine, phenylcyclohexylamine, choline, tromethamine and salts with amino acids such as arginine, lysine and the like. The basic nitrogen containing groups can be quaternized with agents such as lower alkyl halides (for example methyl, ethyl, propyl and butylchlorides, bromides and iodides), dialkylsulfates (for example dimethyl, diethyl, dibutyl and diamiisulfates), chain halides long (for example chlorides, bromides and iodides of decyl, lauryl, myristyl and stearyl), aralkyl halides (for example benzyl and phenethylbromides), and others. The acids (and bases) which are generally considered Suitable for the formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are described, for example, by S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food &Drug Administration, Washington, D.C. on its website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Puré and Applied Chemistry, pp. 330-331, each of which is incorporated herein by reference. All salts of acids and bases of that type are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for the purposes of the invention. nvention The compounds of Formula 1 and the salts, solvates and prodrugs thereof, can exist in their tautomeric form (for example, as an amide or a minoether). All such tautomeric forms are contemplated herein as part of the present invention. The polymorphic forms of the compounds of Formula 1, and of the salts, solvates, and / or prodrugs thereof, are intended to be included in the present invention. All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those which may exist due to asymmetric carbons in various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated as being within the scope of this invention. The individual stereoisomers of the compounds of the invention may be, for example, substantially free of other isomers, or may be mixed, for example, as racemates or with all other stereoisomers or other selected thereof. The chiral centers of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "prodrug" and the like, is intended to be equally applied to the salt, solvate and prodrug of the enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the compounds of the invention. "At least one", the examples include 1-3, 1-2 or 1. The compounds of Formula 1 are effective antagonists of the NK-1 receptor, and have an effect on their endogenous agonist, Substance P, in the NK-? receptor site and therefore, may be useful in the treatment of diseases, disorders or conditions caused or aggravated by receptor activity.

The activities of NK- ?, NK2 and NK3 in vitro and in vivo of the compounds of Formula 1 can be determined by various methods known in the art, such as an assay for their ability to inhibit the activity of the NK-? Agonist. Substance P. Percent inhibition of neurokinin agonist activity is the difference between the percentage of maximum specific binding ("UEM") and 100%. The percentage of EMU is defined by the following equation, where "dpm" represents "disintegrations per minute":% EMU = (dpm of unknown) - (non-specific binding dpm) X 100. (total union dpm) - ( nonspecific binding dpm) The concentration at which the compound produces 50% inhibition of binding is then used to determine an inhibition constant ("K") using the Chang-Prusoff equation. The activity it? Live can be measured by inhibiting a light tap of an agonist-induced leg in a gerbil, as described in Science, 281, 1640-1695 (1998), which is incorporated herein by reference in its entirety. It will be recognized that the compounds of Formula 1 can exhibit NK-i antagonist activities of varying degrees. For example, certain compounds may exhibit N i antagonist activities stronger than others. The compounds of the present invention exhibit potent affinities for the NK-i receptor as measured by the K i values (in nM).

The activities (potencies) for the compounds of the invention are determined by measuring their K i values. The smaller the value K i, the more active is a compound for antagonizing the NK-? Receptor. The compounds of the invention exhibit a wide range of activities. The average K K values of NK-? for compounds of Formula 1 they generally range from 0.01 nM to about 1000 nM, preferably, from about 0.01 nM to about 500 nM, with values between about 0.01 nM and about 100 nM being more preferred. Even more preferred are the compounds having average K i values between 0.01 nM and about 10 nM for the NK-? Receptor. Especially preferred compounds have average Ki values of NKi between 0.01 nM and about 3 nM. Even more especially the preferred compounds have average NKi K values of 0.01 nM to about 0.3 nM. The compounds 1 a, 4 a, 4 b, 5a, 6a, 7, 8, and 9a (see the examples, which appear below) have K i values, respectively, of 0.23, 0.62, 0.32, 0.23, 0.14, 0.3, 0.36, and 0.28 nM. The compounds of Formula 1 have a number of utilities. For example, the compounds of the invention may be useful as antagonists of neurokinin receptors, particularly, NKi receptors in a mammal, such as a human. As such, they may be useful for the treatment or prevention of one or more of a variety of disease states in mammals (human and animal) (physiological disorders, symptoms and diseases) in a patient in need of said treatment, where the disease states are selected from the group consisting of: (1) respiratory diseases (eg, chronic lung disease, bronchitis, pneumonia, asthma, allergy, cough and bronchospasm), (2) inflammatory diseases (eg, , arthritis and psoriasis), (3) skin disorders (eg, atopic dermatitis and contact dermatitis), (4) ophthalmological disorders (eg, retinitis, ocular hypertension and cataracts), (5) central nervous system disorders , such as depressions (eg, neurotic depression), anxieties (eg, general anxiety, social anxiety and panic anxiety disorders), phobias (eg, social phobia), and bipolar disorder, (6) addictions (eg. , alcohol dependence and abuse of psychoactive substances), (7) epilepsy, (8) nociception, (9) psychosis, (10) schizophrenia, (11) Alzheimer's disease, (12) AIDS-related dementia, (13) malignancy of Towne, (14) disorders related to stress (eg, post-traumatic stress disorder), (15) obsessive / compulsive disorders, (16) eating disorders (eg, bulimia, anorexia nervosa, and binge-eating disorder), (17) sleep disorders, (18) ) mania, (19) premenstrual syndrome, (20) gastrointestinal disorders (eg, irritable bowel syndrome, Crohn's disease, colitis, and emesis), (21) atherosclerosis, (22) fibrosing disorders (eg, pulmonary fibrosis) , (23) obesity, (24) type II diabetes, (25) pain-related disorders (eg, headaches, such as migraines, neuropathic pain, postoperative pain and chronic pain syndromes), (26) bladder and genitourinary disorders (eg, cystitis interstitial and urinary incontinence), (27) emesis (for example, induced by chemotherapy (for example, induced by cisplatin, doxorubicin, and taxane), induced by radiation, dizziness, induced by ethanol, and postoperative nausea and vomiting), and (28) nausea. Preferably, the compounds of the invention may be useful in the treatment or prevention of one of the following disease states in mammals (e.g., humans) in a patient in need of such treatment: respiratory diseases (e.g., cough), depression , anxiety, phobia, and bipolar disorder, alcohol dependence, psychoactive substance abuse, nociception, psychosis, schizophrenia, stress-related disorders, obsessive / compulsive disorder, bulimia, anorexia nervosa and binge-eating disorder, sleep disorders, mania , premenstrual syndrome, gastrointestinal disorders, obesity, disorders related to pain, bladder disorders, genitourinary disorders, emesis and nausea. In particular, the compounds according to Formula 1 are useful for treating disease states related to microvascular filtration and mucus secretion. Accordingly, the compounds of the invention are especially useful in the treatment and prevention of asthma, emesis, nausea, depressions, anxieties, coughs and pain-related disorders, more especially, emesis, depression, anxiety and cough. In another aspect, the invention relates to pharmaceutical compositions comprising at least one compound (e.g., one to three compounds, preferably, a compound) represented by Formula 1 and at least one excipient or carrier pharmaceutically acceptable. The invention also relates to the use of that type of pharmaceutical compositions in the treatment of disease states of a mammal (eg, a human), such as those indicated above. In yet another aspect of the invention, there is provided a method for antagonizing the effects of a Substance P at a neurokinin-1 receptor site or for blocking one or more neurokinin-1 receptors in a mammal (i.e. a patient, for example, a human) in need of such treatment, which comprises administering to the mammal an effective amount of at least one (e.g., one) composed according to Formula 1. In another aspect of the invention, an effective amount of one or more of the NK-? receptor antagonists can be combined. of the invention with an effective amount of one or more antidepressant agents and / or one or more anxiolytic agents (e.g., gepirone, gepirone hydrochloride, nefazodone, and nefazodone hydrochloride (e.g., Serzone®)) to treat depression and / or anxiety. U.S. Patent No. 6,117,855 (2000), the disclosure of which is incorporated herein by reference, discloses a method for treating or preventing depression or anxiety with a combination therapy of an NK receptor antagonist. -i specific together with an antidepressant and / or anxiolytic agent. Therefore, antidepressant and / or anxiolytic agents, such as those described in U.S. Patent No. 6,117,855 (2000), can be combined with one or more compounds (e.g., one) of Formula 1 to treat the disease states of depression and / or anxiety in a mammal, preferably a human. In yet another aspect of the invention, an effective amount of one or more (eg, one) of the antagonists of the NK-i receptors of the invention can be combined with an effective amount of one or more (eg, one) inhibitors. of selective serotonin reuptake ("SSRIs") to treat a variety of disease states in mammals, such as those described above. SSRIs alter the synaptic availability of serotonin through its inhibition of presynaptic reuptake of neuronally released serotonin. U.S. Patent No. 6,162,805 (2000), the disclosure of which is incorporated herein by reference, discloses a method of treating obesity with a combination therapy of an NKi receptor antagonist and an SSRI. One or more compounds of the invention of Formula 1 may be combined together with an SSRI (s) in a single pharmaceutical composition, or may be administered concurrently, concurrently or sequentially with an SSRI. This combination may be useful in the treatment and prevention of obesity or other disease states in humans and animals previously identified. In particular, an effective amount of at least one compound (e.g., one) having Formula 1, alone or together with an effective amount of at least one (e.g., a) selective reuptake inhibitor is selective serotonin, It can be useful in the treatment and prevention of depression and / or anxiety. Many chemical substances are known to alter the Synaptic availability of serotonin through its inhibition of neuronally released presynaptic reuptake of serotonin. Representative SSRIs include, without limitation, the following: fluoxetine, fluoxetine hydrochloride (e.g., Prozac®), fluvoxamine, fluvoxamine maleate (e.g., Luvox®), paroxetine, paroxetine hydrochloride (e.g., Paxil®), sertraline, sertraline hydrochloride (eg, Zoloft®), citalopram, citalopram hydrobromide (eg, Celexa ™), duloxetine, duloxetine hydrochloride, venlafaxine, and venlafaxine hydrochloride (eg, Effexor®). Other SSRIs include those described in U.S. Patent No. 6,162,805 (2000). Other compounds can be easily evaluated for their ability to selectively inhibit serotonin reuptake. Therefore, one aspect of the invention relates to a pharmaceutical composition comprising at least one (for example, one) NK- receptor antagonist? having the Formula 1, at least one (e.g., an) SSRI, and at least one pharmaceutically acceptable excipient or carrier. Another aspect of the invention relates to a method for the treatment of disease states in mammals (eg, a human) identified above, the method comprising administering to a patient in need of such treatment an effective amount of a pharmaceutical composition that comprises at least one (eg, one) NKi receptor antagonist having Formula 1 in combination with at least one (eg, one) SSRI, such as one of those mentioned above, and at least one excipient or carrier pharmaceutically acceptable. In a preferred aspect, the invention relates to a method for the treatment of depression and anxiety, the method comprising administering to a patient in need of such treatment an effective amount of at least one (eg, one) antagonist of the NKi receptor having Formula 1 in combination with at least one (eg, one) SSRI, such as one of those described above. When an antagonist of the NK-i receptor of the invention is combined with an SSRI for administration to a patient in need of such treatment, the two active ingredients can be administered simultaneously, consecutively (one after the other within a period of relatively short time), or sequentially (first one and then the other during a period of time). In general, when the two active ingredients are administered sequentially or sequentially, the NK-i receptor antagonist is preferably administered prior to administration of the SSRI. Another embodiment of the invention for treating a patient suffering from multiple diseases with a combination therapy, the therapy comprising administering to a patient (e.g., a mammal, preferably a human being) in need of such treatment at least one compound of Formula 1, and at least one other active ingredient (ie, drug) used to treat one or more diseases that the patient is suffering from. The compounds of Formula 1 and the other active ingredients can be administered sequentially, concurrently and / or simultaneously. The compounds of Formula 1 and the other active ingredients can be administered separately in any suitable dosage form. Preferably, administration is achieved using an oral dosage form or using transdermal patches. The compounds of Formula 1 and the other active ingredients can be formulated together and administered in a combined dosage form. Therefore, the compounds of the invention can be used alone or in combination with other active agents. The combination therapy includes the administration of two or more active ingredients to a patient in need of treatment. In addition to the combination therapy of the NK ^ SSRI receptor antagonist described above, the compounds having the Formula 1 can be combined with one or more other active agents, such as the following: other types of N i receptor antagonists (e.g. those which are described in the aforementioned patents on neurokinin receptor antagonists), prostanoids, Hi receptor antagonists, a-adrenergic receptor agonists, dopamine receptor agonists, melanocortin receptor agonists, receptor antagonists, endothelin, endothelin-converting enzyme inhibitors, angiotensin II receptor antagonists, angiotensin-converting enzyme inhibitors, neutral metalloendopeptidase inhibitors, ETA antagonists, renin inhibitors, serotonin 5-HT3 receptor antagonists (e.g. , ondansetron, ondansetron hydrochloride (for example, Zolfran®), palonosetron, granisetron, and granisetron hydrochloride (eg, Kytril®), serotonin 5-HT2c receptor agonists, nociceptin receptor agonists, glucocorticoids (eg, dexamethasone), rho inhibitors kinase, modulators of potassium channels and / or inhibitors of multidrug resistance protein 5. The preferred therapeutic agents for combination therapy with the compounds of the invention are the following: prostanoids, such as prostaglandin E-i; a-adrenergic agonists, such as phentolamine mesylate; dopamine receptor agonists, such as apomorphine; angiotensin II antagonists, such as losartan, irbesartan, valsartan and candesartan; ETA antagonists, such as bosentan and ABT-627; 5-HT3 serotonin receptor antagonists, such as ondansetron; and glucocorticoids, such as dexamethasone. In preferred embodiments of the invention, the inventive compounds can be combined with: other types of NK-i receptor antagonists, SSRIs, dopamine receptor agonists, serotonin 5-HT3 receptor antagonists, serotonin 5-HT2c receptor agonists, Nociceptin receptor agonists, glucocorticoids and / or inhibitors of multidrug resistance protein 5. A preferred embodiment of the invention relates to a method for the treatment of emesis and / or nausea in a patient in need of such treatment using a combination therapy comprising administering to the patient an effective amount of at least one (e.g. a) compound having the Formula 1 in combination with an effective amount of at least one (eg, a) serotonin 5-HT3 receptor antagonist (eg, ondansetron) and / or at least one (eg, a) glucocorticoid (for example, dexamethasone). Preferably, the compound of Formula 1 is administered orally or by IV. Another embodiment of this invention relates to a method for treating a physiological disorder, symptom or disease in a patient in need of such treatment, comprising administering to the patient an effective amount of at least one compound of Formula 1, and an effective amount of at least one active ingredient selected from the group consisting of: other NK-? receptor antagonists.selective serotonin reuptake inhibitors, dopamine receptor agonists, serotonin 5-HT3 receptor antagonists, serotonin 5-HT2c receptor agonists, nociceptin receptor agonists, glucocorticoids and multiple resistance protein 5 inhibitors drugs, where the physiological disorder, symptom or disease is selected from the group consisting of: a respiratory disease, depression, anxiety, phobia, bipolar disorder, alcohol dependence, psychoactive substance abuse, nociception, psychosis, schizophrenia, stress-related disorder, obsessive / compulsive disorder, bulimia, anorexia nervosa, binge-eating disorder, sleep disorder, mania, premenstrual syndrome, gastrointestinal disorder, obesity, headache, neuropathic pain, postoperative pain, chronic pain syndrome, bladder disorder , genitourinary disorder, cough, emesis and nausea.

Another aspect of the invention is to provide a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat a disease mediated by NK-i receptors, wherein a container comprises a pharmaceutical composition comprising a effective amount of a compound of Formula 1 in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising another therapeutic agent in a pharmaceutically acceptable carrier, the therapeutic agent being selected from the group consisting of: SSRIs, other types of NK-i receptor antagonists, prostanoids, Hi receptor antagonists, a-adrenergic receptor agonists, dopamine receptor agonists, melanocortin receptor agonists, endothelin receptor antagonists, endothelin-converting enzyme inhibitors, antagonists of angio receptors tensin II, angiotensin-converting enzyme inhibitors, neutral metalloendopeptidase inhibitors, ETA antagonists, renin inhibitors, serotonin 5-HT3 receptor antagonists, serotonin 5-HT2c receptor agonists, agonists of serotonin nociceptin receptors, glucocorticoids, rho kinase inhibitors, potassium channel modulators and inhibitors of multidrug resistance protein 5. Another aspect of the invention is to provide a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat the depression and / or anxiety, wherein a container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula 1 in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an antidepressant agent in a pharmaceutically carrier acceptable, and / or where a separate container comprises a pharmaceutical composition comprising an anti-anxiety agent in a pharmaceutically acceptable carrier. Another aspect of the invention is to provide a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat a disease mediated by NKi receptors, wherein a container comprises a pharmaceutical composition comprising an effective amount. of a compound of Formula 1 in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an SSRI in a pharmaceutically acceptable carrier. Another aspect of the invention is to provide a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat depression and / or anxiety, wherein a container comprises a pharmaceutical composition comprising an effective amount. of a compound of Formula 1 in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition that comprises an SSRI in a pharmaceutically acceptable carrier. Another aspect of the invention is to provide a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat emesis and / or nausea, wherein a container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula 1 in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising a serotonin 5-HT3 receptor antagonist in a pharmaceutically acceptable carrier, and / or wherein a separate container comprises a pharmaceutical composition comprising a glucocorticoid in a pharmaceutically acceptable carrier. Another aspect of the invention is to provide an equipment comprising, in separate containers in a single container, pharmaceutical compositions for use in combination to treat emesis and / or nausea, wherein a container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula 1 in a pharmaceutically acceptable carrier, and wherein , a separate container comprises ondansetron, and / or where a separate container comprises dexamethasone. Another aspect of the invention is to provide a kit comprising, in separate containers in a single package, pharmaceutical compositions to be used in combination to treat a receptor-mediated disease NK1 t wherein a container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula 1 in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising a therapeutic agent in a pharmaceutically carrier acceptable, being the therapeutic agent selected from the group consisting of: other types of NK- receptor antagonists, SSRIs, dopamine receptor agonists, serotonin 5-HT3 receptor antagonists, serotonin 5-HT2c receptor agonists, agonists of nociceptin receptor, glucocorticoids and inhibitors of multidrug resistance protein 5. The pharmaceutical compositions may contain between about 0.1 and about 99.9 percent by weight, or between about 5 and about 95 percent by weight, or about 20 to about 80 percent by weight of active ingredient (compound of Formula 1). To prepare the pharmaceutical compositions from the compounds described by this invention, the inert, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, seals and suppositories. The powders and tablets may consist of about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, for example magnesium carbonate, stearate magnesium, talc, sugar or lactose. The tablets, powders, seals and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions can be found in A. Gennaro (ed.), Remington: The Science and Pharmacy Practice, 20th Edition, (2000), Lippincott Williams & Wiikins, Baltimore, MD, incorporated herein by reference. Liquid form preparations include solutions, suspensions and emulsions, for example, water or water solutions - propylene glycol for parenteral injection or addition of sweeteners and opacifiers for solutions, suspensions and oral emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, for example nitrogen. Also included are solid form preparations which are intended to be converted, immediately before use, to liquid form preparations for oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The compounds of the invention can also be administered transdermally. The transdermal compositions can adopt the form of creams, lotions, aerosols and / or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. Preferably the compound is administered orally. Preferably, the pharmaceutical preparation is in a unit dosage form. In that type of form, the preparations are subdivided into appropriately sized unit doses containing appropriate amounts of the active component, for example, an effective amount to achieve the intended purpose. The amount of active compound in a unit dose of preparation may vary or may be adjusted between about 0.01 mg and about 4000 mg, preferably between about 0.02 mg and about 1000 mg, more preferably between about 0.3 mg and about 500 mg, and more preferably between approximately 0.04 mg and approximately 250 mg according to the particular application. The actual dose used can be varied depending on the requirements of the patient and the severity of the condition being treated. The determination of the appropriate dosage regimen for a particular situation is within the skill of the expert. For convenience, the total daily dose can be divided and administered in portions during the day as required. The amount and frequency of administration of the compounds of the invention and / or the pharmaceutically acceptable salts thereof will be regulated according to the criteria of the professional in charge considering factors such as the age, condition and measures of the patient as well as the severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 0.02 mg / day to about 2000 mg / day, in two to four divided doses. The pharmaceutical compositions of the invention can be administered from about 1 to about 5 times per day, or alternatively, as a continuous infusion. That type of administration can be used as a chronic or acute therapy. The amount of NK-? Receptor antagonist in combination with a selective serotonin reuptake inhibitor ("SSRI") in a unit dose of preparation can be from about 10 to about 300 mg of NI i receptor antagonist combined with about 10 to about 100 mg of SSRI. In another combination the amount of NK-i receptor antagonist in combination with an SSRI in a unit dose of preparation can be from about 50 to about 300 mg of NK-? Receptor antagonist. combined with between about 10 and about 100 mg of SSRI. In another combination, the amount of NKi receptor antagonist in combination with SSRI in a unit dose of preparation can be from about 50 to about 300 mg of NK-i receptor antagonist combined with about 20 to about 50 mg of SSRI. The actual dose used can be varied depending on the requirements of the patient and the severity of the condition being treated. The determination of the appropriate dosage regimen for a particular situation is within the skill of the expert. For convenience, the total daily dose can be divided and administered in portions during the day as required. After the improvement of a patient's condition, a maintenance dose of a compound, composition or combination of the invention may be administered, if necessary. Subsequently, the dose or frequency of administration, or both, can be reduced, depending on the symptoms, to a level at which the improved condition is retained, when the symptoms have been alleviated to the desired level, the treatment should be interrupted. However, patients may require long-term intermittent treatment after any recurrence of disease symptoms. Dosage and treatment regimens specific to any particular patient can be varied and will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health status, dryness and the patient's diet, the time of administration, the rate of excretion, the specific combination of drugs, the severity and course of the symptoms being treated, the patient's disposition to the condition being treated and the criteria of the attending physician . The determination of the regime of Appropriate dosing for a particular situation is within the knowledge of the art.

EXAMPLES The invention described herein is exemplified by the following preparations and examples, which should not be construed as limiting the scope of the description. Alternative mechanistic routes and analogous structures may be apparent to those skilled in the art. The compounds 1-4 shown below can be prepared by the methods described in WO03 / 051840 (ie, compounds 23, 46, 45, and 42, respectively). WO03 / 051840 is incorporated herein by reference.

PREPARED EXAMPLE 1 Example? A Example ib Example ic Example d Step A: Compound 1 (13.13 g, 23.7 mmol) was dissolved in 40 ml of anhydrous CH 2 Cl 2 and kept under an atmosphere of N 2. Then (R) -f-butylsulfinamide (3.0g) was added, 23.7 mmol), followed by the addition of 13.7 ml of Ti (iPrO) 4. The resulting solution was stirred for 18 h. Under vigorous stirring, 100 ml of EtOAc and 100 ml of brine were added to the solution. The resulting suspension was filtered through a pad of Celite (i.e., diatomaceous earth) and the Celite was washed three times with 100 ml of EtOAc. The combined filtrate was separated from the water layer. The organic layer was dried with Na 2 SO 4, filtered and concentrated to give 10.9g (70%) of compound 5 as a yellow oil.

Step B: The N- (diphenylmethylene) glycine ethyl ester was dissolved in 15 ml of THF and was maintained under an atmosphere of N2 at 0 ° C. LiHMDS (1.0M in THF, 5.3 ml) was added, and the resulting solution was stirred for 5 min. A solution of compound 5 (1.16g, 1.78 mmol) in 5mL of anhydrous THF was then cannulated in aforementioned enolate solution. After 1 h at 0 ° C, the reaction mixture was warmed by the addition of 10 ml of saturated NH 4 Cl solution. The resulting organic and aqueous phases were separated and the aqueous phase was extracted three times with 10 mL of EtOAc. The organic phases were combined and washed with a saturated solution of NaHCO 3, then a brine solution. Then, the washed organic phase was dried and concentrated. After purification by flash chromatography on silica gel (eluent: 20% EtOAc / Hexanes), three isomers were obtained: compounds 6a, 6b and 6c.

Step C: B A solution of compound 6a (230 mg, 0.25 mmol) in absolute MeOH (2.5 mL) was treated with 2N HCL solution (2.5 mL), and stirred at 23 ° C for 18 h. The reaction mixture was diluted with Et20, and basified by adding a 2N NaOH solution until a pH of 12 was obtained. The resulting aqueous and organic phases were separated. The aqueous phase was extracted three times with 10 ml of Et20. The organic phases were combined, and then dried with anhydrous K2CO3 and concentrated. The resulting residue was dissolved in 3 ml of EtOH and 0.05 ml of 1,4-cyclohexadiene, to which Pd on carbon (10%, 100 mg) was added. The resulting suspension was heated at 80 ° C for 1 h. The suspension was filtered through Celite and concentrated. The resulting residue was dissolved in 2.5 ml of CH2Cl2 to which 0.5 ml of DIEA and triphosgene (36 mg, 0.12 mmol) was added. The mixture was stirred for 1 h, and then partitioned between 10 mL of EtOAc and 10 mL of 1 N HCl solution. The resulting organic phase was washed sequentially with a solution of NaHCO 3 and brine solution, then dried and concentrated . The resulting concentrate was purified by preparative TLC (silica gel: 5% methanol / CH 2 Cl 2) to provide compound 7a as a product (EM by electrospray [M + 1] + 487.1). A similar procedure was used to convert compounds 6b and 6c to compounds 7b and 7c (EM by electrospray [M + 1] + compound 6b: 487; compound 6c: 487.1).

Step D: A solution of compound 7b (90 mg, 0.06 mmol) in MeOH (2 mL) was treated with 0.2 mL of 30% NaOMe in MeOH and stirred overnight. The reaction mixture was warmed by the addition of 4 drops of 4 N HCl in dioxane, and then the solution was concentrated under reduced pressure. The residue was purified using preparative TLC (silica gel: 5% methanol / CH 2 Cl 2) to give compound 7d. Step E: Compound-LiAIH4 (1 M in Et20, 0.268 ml) was added to AICI3 (solid) at 0 ° C, and the mixture was stirred for 10 min. Then a solution of compound 7a in 1 ml of THF was cannulated into the mixture. The reaction mixture was allowed to warm to 23 ° C and stirring was continued for 5 h. Then, the mixture was diluted with 10mL of THF. Then 5 ml of Na, K tartrate solution was added carefully and the mixture was stirred overnight. The phases The resulting organic and aqueous phases were separated, and the aqueous phase was extracted five times with 15 ml of EtOAc. The organic phases were combined, then washed with brine, dried and concentrated. The resulting residue was purified using preparative TLC (silica gel: 5% methanol / CH 2 Cl 2) to give Example 1a (EM by electrospray [M + 1] + 488.1). A similar procedure was used to convert compounds 7b-7d in Examples 1b-1d (EM by electrospray [M + 1] + compound 1b: 488.1, compound 1c: 488.1, compound 1d: 488.1).

PREPARED EXAMPLE 2 Example 2 Step A: Compound 5 (2.0 g, 3.05 mmol) was dissolved in 15 ml of CH2Cl2 and maintained at -78 ° C. AliIMgBr (1M in Et20, 9.1 mmol) was added, and the solution was allowed to warm to 23 ° C overnight. The mixture of The reaction was warmed with a solution of NH CI and extracted with EtOAc. The resulting organic phase was washed with brine, dried and concentrated. The crude product was purified by flash chromatography (silica gel: 5-20% EtOAc / hexane) to give compound 6.

Step B: compue sto e coiTiDüesto Compound 6 (430 mg, 0.62 mmol) was dissolved in 2 mL of CH2Cl2 and cooled to -78 ° C. Ozone was bubbled into the solution for 20 min, then a stream of nitrogen was introduced into the reaction mixture until the solution became colorless. Then, the solution was treated with tetrabutylammonium iodide (457.3 mg, 1.24 mmol) and stirred overnight. The solution was concentrated, and the resulting residue was dissolved in 2 ml of toluene. Then 2 crystals of p-toluenesulfonic acid of pyridinium were added and the solution was heated at 80 ° C for 30 min. The solution was loaded onto a column of silica gel and eluted with 2% -5% EtOAc / Hexanes to give compound 7.

Step C: compound 7 compound g Compound 7 (120 mg, 0.176 mmol) was dissolved in 2 mL of THF, and cooled to 0 ° C. A solution of BH3-Me2S in THF (264 ml, 2.0M solution, 0.528 mmol) was added and the resulting reaction mixture was stirred overnight at 23 ° C. The reaction mixture was warmed by diluting it with 2 mL of THF followed by the addition of 2 mL of 2N NaOH and 2 mL of 30% H202, then stirred for 6 h. The organic and aqueous phases were separated, and the aqueous phase was extracted three times with 10 ml of Et20. The combined organic phases were dried and concentrated. The resulting residue was purified by preparative TLC (silica gel; 2: 1 EtOAc / hexane) to give the product, compound 8.

Step D: composed Compound 8 (30 mg, 0.043 mmol) was dissolved in 0.5 ml of MeOH, and kept at 0 ° C. HCl (4N in dioxane, 0.5 ml) was added and the The mixture was stirred at 23 ° C for 2 h. The solvents were removed and the resulting residue was dissolved in 2 ml of CH2Cl2 and cooled to 0 ° C. DIEA (0.1 ml) and triphosgene (6.4 mg, 0.021 mmol) were then added, and the solution was stirred for 2 h, then passed through a pad of silica gel and washed with 50% EtOAc. The eluent was concentrated and the resulting residue was dissolved in 2mL of MeOH. Then Pd / C (10% Pd on carbon, 4.6 mg) and 0.5 ml of 1,4-cyclohexadiene were added. The resulting mixture was heated for 20 min, then filtered through a pad of Celite, concentrated and applied to a TLC prep plate (silica gel), and eluted with 50% EtOAc / hexanes to provide Example 2 (EM by electrospray [M + 1] + 489.1).

PREPARED EXAMPLE 3 Example 3a Example 3b Step A: J NHCbz CFa compound -i eomcuesto Sa comcueslo 9b Compound 1 (3.0 g, 5.4 mmol) was dissolved in 27 ml of THF, and kept at 0 ° C. BF3-Et20 (755 μL, 6.0 mmol) was added, and the mixture was stirred for 10 min. Vinylmagnesium bromide (1.0M in THF, 16.2 mL, 16.2 mmol) was added rapidly, and the reaction mixture was stirred at 0 ° C for 2 h. The reaction mixture was then quenched with a solution of NH CI. The organic phase was separated, dried and concentrated. The resulting crude product was purified by column chromatography (silica gel) using 5% EtOAc in 1: 1 Hexane / CH CI2 as the eluent, to give two isomers of compounds 9a and 9b.

Step B: Compound 9a Compound 10a Compound 9a (380 mg, 0.65 mmol) was dissolved in 6.5 ml of CH2Cl2 and the resulting solution was kept at 0 ° C. Then CI3CC (0) NCO (0.094 mL, 0.784 mmol) was added, and the solution was stirred for 2 h. Another portion of CI3CC (0) NCO (0.045 mL, 0.35 mmol) was added, and the reaction mixture was allowed to warm to 23 ° C. After 1 h, the reaction mixture was concentrated and the resulting residue was dissolved in 9 ml of MeOH and 1.5 ml of H20. Then, 750 mg of K2C03 was added, and the mixture was stirred at 23 ° C for 1 h. Then, the solvent was removed and the mixture was partitioned between EtOAc and H20. The aqueous phase was extracted three times with 10 ml of EtOAc. Then, the combined organic phases were dried and concentrated. Column chromatography (silica gel; 5% EtOAc in 1: 1 hexane / CH2Cl2) of the crude product afforded compound 10a.

Step C: CF3 co mpuesto -? oa co oa Compound 10a (140 mg, 0.224 mmol) was dissolved in 1.5 mL of CH2Cl2 and cooled to -78 ° C. Then ozone was bubbled through the solution. After the solution acquired a light blue color, nitrogen was introduced until the solution became colorless. The reaction mixture was treated with 1 ml of Me2S, heated to 23 ° C and stirred for 3 h. Then, the solvent was removed. The resulting residue was dissolved in 2 ml of toluene, and then 5 mg of p-toluenesulfonic acid was added and the solution was heated to 65-70 ° C and kept at that temperature overnight. The reaction mixture was then loaded onto a column of silica gel and eluted with EtOAc to provide compound 11a.

Step D: Compound 11a (47 mg, 0.077 mmol) was dissolved in 1 mL of EtOH. Pd (OH) 2 / C (8 mg, 20% Pd) was added and a hydrogen balloon was adhered to the flask containing the mixture. The hydrogenation was carried out overnight. The reaction mixture was then filtered and purified by preparative TLC (silica gel; EtOAc) to give Example 3a (MS by electrospray [M + 1] + 475.1). A similar procedure was used to convert compound 9b to Example 3b (EM by electrospray [M + 1] + 475.1).

PREPARED EXAMPLE 4 Example 4a and 4 b Step A: Following a procedure similar to that described in Example 3, Step B, mentioned above, compound 2 was converted to the corresponding carbamate compound 12.

Step B: compound 12 like 13 Compound 12 (300 mg, 0.48 mmol) was dissolved in 4.8 ml of CH2Cl2 and then treated with Phl (OAc) 2 (216.5 mg, 0.67 mmol), Rh2 (OAc) 4 (42 mg, 0.096 mmol) and MgO (44.5 mg, 1.1 mmol). The resulting mixture was heated at 40-46 ° C for 24 h, then filtered through a pad of Celite 545, concentrated and purified using column chromatography (silica gel; 20-50% EtOAc / hexane), to give compound 13.

Step C: compound 3 Example 4a and 4b Compound 13 (185 mg, 0.3 mmol) was dissolved in 3 mL of EtOH. 20% Pd (OH) 2 / C (25 mg) was added to the solution, and the hydrogenation was carried out overnight by adhering a hydrogen balloon to the reaction vessel. Then, the reaction mixture was filtered, concentrated and purified using an HPLC OD column with an eluent of 1: 9 iPA: hexanes. The first product fraction Example 4a had a retention time retention time of 80.6 min and a second isomer of the product, Example 4b had a retention time of 93.1 min (EM by electrospray [M + 1] + Example 4a: 489.1; Example 4b: 489.1).

PREPARED EXAMPLE 5 Example 5a Example Sb Method 1: Step A: Compound 3 (20.0 g, 35.5 mmol) was dissolved in 300 mL of THF and cooled to -30 ° C. Then N02BF (9.5 g, 68.8 mmol) was added in one portion. The solution was allowed to warm to 23 ° C and was stirred for 3 h. Then 200 ml of saturated NaHCO 3 solution was added, and the mixture was stirred for 30 min. Then the organic and aqueous phases were separated. The aqueous phase was extracted three times with 30 ml of Et20. The combined organic phases were dried and concentrated to give compound 14, which was used without further purification.

Step B: compound i -14 compound 15th compound igj A 25 ml pear-shaped bottle was charged with compound 14 (1.4 g, 2.30 mmol, 1.0 equiv.), Anhydrous THF (9 ml), dry EtOAc (0.45 ml, 4.60 mmol, 2.0 equiv.) And DMPU (OJ ml). The resulting brown solution was cooled to -78 ° C. A 1.OM solution of LiHMDS in THF (4.6 mL, 4.60 mmol, 2.0 equiv.) Was dripped into the flask. Then, the solution was stirred at -78 ° C for 2 hours. The reaction mixture was warmed with saturated NH CI solution at -78 ° C, and then allowed to warm to room temperature. The mixture was diluted with diethyl ether, and then the organic and aqueous phases were separated. The aqueous phase was further extracted with diethyl ether. The combined organic phase was dried over anhydrous MgSO4, filtered and concentrated to give a crude product. The crude product was purified on a silica column (10% to 15% eluent EtOAc / hexane) to provide compound 15a (eluted second) (562 mg, 35% yield) and compound 15b (eluted first) (300 mg, yield 18.8%).

Step C: «C. '1 zY"' ,, H P2d '(eOoHM) 2 < • »r'Y? CF?'" L 2) K2C03 TT '"' N02 C02Et fe8 HH ^ O Compound 15a Example 5a A 250 ml Parr shaker bottle was charged with compound 15a (300 mg, 0.44 mmol, 1.0 equiv.) And MeOH (10 ml). After dry nitrogen gas was bubbled through this reaction mixture, it was they added Pd (OH) 2 / C (63 mg, 20% by weight, 0.088 mmol, 0.2 equiv.) and an approximately equal volume of Ni Raney. Then, the agitator bottle was stirred under a hydrogen atmosphere (408 kPa) (60 psi) for 48 hours. The reaction mixture was diluted with MeOH, and then carefully passed through a funnel packed with Celite. The Celite pad was thoroughly washed with MeOH. The filtrate was treated with MeONa (25 mg, 0.46 mmol, 1.05 equiv.) And heated at 70 ° C for 3 hours. TLC analysis (5% MeOH / CH2Cl2, silica gel) showed only one product. The mixture was concentrated to dryness and then redissolved in diethyl ether, washed with a saturated sodium bicarbonate solution, and then the organic and aqueous phases were separated. The aqueous phase was further extracted with diethyl ether. The combined organic phases were dried over anhydrous MgSO 3, filtered and concentrated to give the crude product, which was purified on a silica gel chromatography column (3% MeOH / CH 2 Cl 2) to give Example 5a (112 mg, yield 52%), EM by electrospray (M + 1) + 487.1. Similar procedures were used to convert compound 15b to Example 5b (EM by electrospray (M + 1) + 487.1).

Method 2: Step A: compound 14 comp Xuesto? Sc To a mixture of compound 14 (145 mg, 0.238 mmol) and 2- (1'-methyl-1'-phenyl-ethyl) -cyclohexyl ester of (1S.2R) -acetic acid (124 mg, 0.476 mmol) in anhydrous THF (2 mL) at -78 ° C was added a 1.0M solution of LiHMDS in THF (0.476 mL, 0.476 mmol) by dripping through a syringe. The solution was then stirred at -78 ° C for 2 hours. The reaction mixture was warmed with a saturated NaHCO 3 solution at -78 ° C, and then warmed to room temperature, then stirred for 16 h. The mixture was diluted with EtOAc, and then the organic and aqueous phases were separated. The aqueous phase was further extracted with EtOAc. The combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated to provide a crude product. The crude product was purified on a silica column (10% to 15% EtOAc / hexane as eluent) to provide compound 15c (135 mg, 65%).

Step B: _.? ' ! - 1 SC -.si '.., .I.¡Í: 1 $ ß To compound 15c (50 mg, 0.057 mmol) in 1 mL of HOAc was added Zn powder (77 mg) and the mixture was then stirred for 16 h. The mixture was diluted with 10 mL of Et20 and washed with 5 mL of H2O, 5 mL of saturated NaHCO3 (aq) and 5 mL of brine. The organic layer was dried and concentrated. The resulting residue was dissolved in 2 ml of MeOH followed by the addition of NaOMe (50 mg), and then heated for 16 h. The reaction mixture was concentrated and then partitioned between 5 mL of EtOAc and 5 mL of 1 N HCl (aq). The organic layer was washed with NaHCO 3 (aq) and brine, and then concentrated. TLC on preparative silica gel of the residue using 1: 1 EtOAc / Hexane gave compound 15d (MS by electrospray [M + 1] + 621.1).

Step C: trorpou this 15 ^ Eterpp le 5a Using the procedure of Preparative Example 3, step D, compound 15d was hydrogenated to give Example 5a (MS by electrospray [M + 1] + 487.1).

PREPARED EXAMPLE 6 Step A: corp uosto ^ Qg I ran DU this 16 A 25 ml bottle was charged with compound 15a (250 mg, 0.36 mmol, 1.0 equiv.) And dry THF (3.6 ml). This colorless solution was cooled to 0 ° C. Then a solution of LiAIH4 1.0M (0.72 ml, 0.72 mmol, 2.0 equiv.) was introduced with a syringe drip into the bottle. The resulting cloudy solution was stirred at 0 ° C for 1.5 h. The reaction mixture was warmed with saturated sodium potassium tartrate solution, and then extracted with EtOAc. The organic phase was separated, dried over anhydrous Na 2 SO 4, filtered and concentrated to give a crude product. The crude product was dissolved in EtOH (20 ml) and hydrogenated on a Parr shaker (408 kPa (60 psi) of hydrogen) for 16 h with Ni Raney as the hydrogenation catalyst. The reaction mixture was then diluted with MeOH, and passed through a funnel containing Celite. The filtrate was concentrated to give the crude product, compound 16.

Step B: The crude compound 16 (53 mg, 0.085 mmol) was dissolved in anhydrous CH 2 Cl 2 (4 mL). The resulting almost colorless solution was cooled to 0 ° C, disopropylethylamine (0.1 ml, 0.57 mmol) and triphosgene (12 mg, 0.040 mmol) were added, and then the mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated sodium bicarbonate solution, and extracted with EtOAc. The combined organic phases were dried over Na 2 SO 4, filtered, concentrated to give the crude product, which it was purified with Prep-TLC (5% MeOH / CH2Cl2; silica gel) to give compound 17 (10 mg, yield 18%).

Step C: cort? DUesís? Example 6 Using the procedure of Preparative Example 3, step D, compound 17 was hydrogenated to give Example 6a (MS by electrospray [M + 1] + 517.1). A similar procedure was used to convert compound 15b to Example 6b (EM by electrospray [M + 1] + 489.1).

PREPARED EXAMPLE 7 Step A: Figure 18: Compound 15 Compound 15a (1.2 g, 1.42 mmol) was mixed with 14 mL of HOAc at 0 ° C. Zn powder (1.2 g, 18.3 mmol) was added to the mixture and stirred at 23 ° C overnight. The reaction mixture was diluted with CH2Cl2 and filtered through a pad of Celite. The filtrate was washed with a saturated NaHCO 3 solution, brine, dried and concentrated. The concentrated filtrate was redissolved in 10 mL of CH2Cl2, and then Et3N (0.4 mL, 2.86 mmol) and (Boc) 20 (433 mg, 1.5 mmol) were added and the solution was stirred overnight. The solution was diluted with Et20, washed with 1 N H 4 Cl, saturated NaHCO 3 solution, brine and concentrated. The resulting crude product was purified by chromatography on silica gel (silica gel: 10-30% EtOAc / hexane) to give compound 18.

Step B: corn DU this ig corporation 19 LiAIH (1 M in Et20, 1.2 mL, 1.2 mmol) was added to a solution of compound 18 (560 mg, 0.73 mmol) in THF at 0 ° C. The resulting reaction mixture was stirred at 0 ° C for 3 h, quenched by adding NH 4 Cl solution and then extracted with Et 20. The organic phase was separated, dried and concentrated. The crude product was purified by chromatography on silica gel (silica gel) to provide compound 19.

Step C: compound 9 with ouTsto 20 Cyanomethylenetributylphosphine (140 mg, 0.552 mmol) was added to compound 19 (100 mg, 0.138 mmol), then acetone cyanohydrin (0.025 mL, 0.276 mmol) and anhydrous toluene (0.65 mL) were added. The resulting mixture was heated at 100-105 ° C for 3 h. Then, the mixture was concentrated and the resulting residue was purified by column chromatography (silica gel) using an eluent of 20-30% EtOAc / hexanes to provide compound 20.

Step D: The compound 20 prepared in step C was then dissolved in 2 ml of MeOH in a glass tube, and then 4N HCl in dioxane (3 ml) was added. The tube was sealed and heated at 60-65 ° C for 16 h. Then N2 was bubbled into this solution for 1 h. Then, the solution was treated with NaOMe in MeOH (25% w / w, 1 ml) and heated to 60-65 ° C for 3 h. Then, the solvent was removed and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic phases were dried and concentrated. The crude product was purified by preparative TLC (silica gel; 2: 1 EtOAc / hexane) to provide compound 21.

Step E: CoiKjjuosío 21 Example 1 Using the procedure of Preparative Example 4, step C, compound 21 was hydrogenated to provide Example 7 (MS per electrospray [M + 1] + 501.1).

PREPARED EXAMPLE 8 Example 8 Step A: eroded 18 corpouosto 22 4N NaOH (1 ml) was added to a solution of compound 18 (750 mg, 0.98 mmol) in 5 ml MeOH, and stirred for 4 h. Then, the solution was concentrated and the resulting residue was partitioned between EtOAc and water. The mixture was then treated with 10% HCl until the aqueous phase was acidified to a pH of 1-2. The organic and aqueous phases were separated, and the aqueous layer was extracted three times with 10 ml of EtOAc. The combined organic phases were dried and concentrated to provide the crude compound 22.

Step B: compound 22 C? rpou this 23 The crude compound 22 (280 mg, 0.38 mmol) was dissolved in 10 ml of toluene, and then Et3N (0.76 mL, 5.45 mmol) and DPPA (0.478 mL, 2.27 mmol) were added. The mixture was heated at 100 ° C for 3 h. The solvent was removed and the resulting residue was dissolved in 10 ml of THF and 10 ml of saturated NaHCO 3 solution and stirred overnight. The organic phase was separated from the aqueous phase and the aqueous phase was extracted with EtOAc. The combined organic phases were concentrated to give crude compound 23.

Step C: corpoucsto 23 corpoues The crude compound 23 was treated with 5 ml of 4N HCl in dioxane and stirred for 4 h. Then, the mixture was concentrated, and the resulting residue was dissolved in 8 ml of CH2Cl2, cooled to 0 ° C followed by the addition of DIEA (0.33 ml, 1.9 mmol) and triphosgene (56 mg, 0.57 mmol) and stirred during the night at 23 ° C. The reaction mixture was concentrated and the residue was purified using preparative TLC (silica gel) eluted with 1: 1 EtOAc / hexanes to provide compound 24.

Step D: oorpoUDSt? 24 Example 8 Using the procedure of Preparative Example 4, step C, compound 24 was hydrogenated to provide Example 8 (MS by electrospray [M + 1] + 502.1).

PREPARED EXAMPLE 9 Example 9a E; & 9b Step A: Toluenesulfonic acid monohydrate (146 mg, 0.77 mmol) was added to a solution of compound 4 (9.83 g, 15 mmol) in 150 mL of EtOH, and the resulting mixture was heated at 80 ° C for 16 h. The reaction mixture was then treated with 1 ml of Et3N, stirred for 30 min, and then concentrated. The resulting crude product was purified by chromatography on silica gel (silica gel 2-10% EtOAc / hexane) to provide compound 25 (5.6 g, 65% yield).

Step B: compound 25 compound 26 N02BF4 (1.3 g, 9.8 mmol) was added in one portion to a solution of compound 25 (4.6 g, 8.2 mmol) in 80 mL of THF maintained at -35 ° C. After stirring for 5 min, the reaction mixture was allowed to warm to 23 ° C and stirring was continued for 10 min. Half of the solution of saturated NaHC03 (40 ml) was then added, and the mixture was extracted three times with 50 ml of EtOAc. The combined organic layers were dried with Na 2 SO and concentrated. The crude material was purified using silica gel column chromatography (silica gel, 0-10% EtOAc / hexane) to provide compound 26.

Step C: compound 26 compound 27 Compound 26 (4.7 g, 7.73 mmol) was dissolved in 80 mL of EtOH, and then NaBH (309 mg, 7.7 mmol) was added. The reaction was stirred for 2 h and quenched with a saturated NH CI solution. The volatiles were removed under vacuum, and the resulting residue was partitioned between EtOAc and a saturated solution of NaHCO 3. The organic phase was dried, concentrated and purified using silica gel chromatography. The organic phase was dried, concentrated and purified using silica gel chromatography (silica gel 5-10% EtOAc / hexane) to provide the compound 27 Step D: -cbz a ^^^ - Jcbz F3 H0 NHBoc (- com ou esto 27 compound 28 Zn powder (OJg) was added to a solution of compound 27 (500 mg, 0.82 mmol) in 8 ml of acetic acid, and the mixture was stirred overnight. The resulting suspension was diluted with 20 ml of CH2Cl2 and filtered through a pad of Celite. The Celite was washed with 30 ml of CH2Cl2. 0 50% NaOH was added to the combined filtrate and the phases were washed to adjust the alkalinity to a pH of 11. The organic phase was then washed with brine, dried and concentrated. The resulting residue was dissolved in 8 ml of CH2Cl2. Then Boc20 (178 mg, 0.83 mmol) and Et3N (160 mL, 1.14 mmol) were added, and the solution was stirred at 23 ° C overnight. The resulting reaction mixture was diluted with 30 ml of Et.sub.20 and washed sequentially with 10 ml of 1 N HCl, 10 ml of saturated NaHCO 3 and 10 ml of brine. The organic layer was dried and concentrated. The crude product was purified by column chromatography on silica gel (10-20% EtOAc / hexane) to provide compound 28.

Step E: compound 28 compound 29a compound 29b BH3-THF (1 M in THF, 2.1 mL, 2.1 mmol) was added to a solution of compound 28 in 4 mL of THF maintained at 0 ° C. The solution was allowed to warm to 23 ° C, and stirred overnight. The reaction mixture was then diluted with 10 ml of THF, cooled to 0 ° C. 2N NaOH (25 ml) was added dropwise to the solution, and then 25 ml of 30% H202 was added. The mixture was stirred at 23 ° C for 4 h, then extracted three times with 20 ml of Et20. The organic phases were combined, dried and concentrated. The resulting crude product was purified using preparative thin layer chromatography (1: 1 EtOAc / hexane) to provide compound 29a and compound 29b.

Step F: Using the procedure of Preparative Example 8, step C, compound 29a was cyclized to provide compound 30a.

Step G: Using the procedure of Preparative Example 4, step C, compound 30a was hydrogenated to provide Example 9a (MS by electrospray [M + 1] + 489.1). Using similar procedures, compound 29b was converted to Example 9b (EM by electrospray [M + 1] + 489.1). While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those skilled in the art. All such alternatives, medications and variations are intended to fall within the spirit and scope of the present invention.

Claims (30)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound of Formula 1: Formula 1 or a pharmaceutically acceptable salt and / or solvate thereof, Ar1 and Ar2 are each independently selected from the group consisting of (R7) n7-aryl- and (R8) n8-heteroaryl-; G is selected from the group consisting of -O-, -S-, -S (O) -, -S (02) -, -N (R6) -, -N (C (0) R6) -, -N ( S (02) R6) -, -N (S (0) R6) -, -N (C (0) OR6) -, -N (C (0) N (R6) 2) -, -N (R6) S (02) -, -S (02) N (R6) -, -N (R6) SO-, -S (0) N (R6) -, -N (R6) C (0) 0-, -OC (0) N (R6) -, -N (R6) C (0) -, -C (0) N (R6) -, and -N (R6) C (0) N (R6) -; X is - (C (R6) 2) n3-A- (C (R6) 2) n4-, where n3 and n4 may be the same or different; Y is - (C (R6) 2) n5-B- (C (R6) 2) n6-, where n5 and n6 can be the same or different; A is selected from the group consisting of -O-, -S-, -C (R6) 2-, and -N (R14) -; B is selected from the group consisting of -O-, -S-, -C (R6) 2-, and -N (R14) -; n1, n2, n3, n4, n5, n6, and n8 are individually and independently an integer between 0 and 3; n7 is an integer between 0 and 5; n8 is an integer between 1 and 3; n9 is an integer between 0 and 2; n10 is a whole number between 1 and 5; Z is selected from the group consisting of -C (O) -, -C (S) -, -S (O) -, -S (02) -, -C (= NR6) -, -C (= NOR6) - and -C (= NN (R6) 2) -; R1 and R2 are independently selected from the group consisting of H, alkyl, hydroxyalkyl, cycloalkyl, -CH2F, -CHF2, -CF3, and heterocycloalkyl, wherein each of said alkyl, cycloalkyl, or heterocycloalkyl may be unsubstituted or substituted with one or more substituents which may be identical or different and are independently selected from the group consisting of halogen, alkyl, haloalkyl, -OR6, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -N (R6) 2, -C (0) R6 , -C (0) OR6, -OC (0) R6, -C (0) N (R6) 2, -N (R6) C (0) R6, -N (R6) C (0) OR6, -N (R6) C (0) N (R6) 2, -N02, -CN, -S (02) R6, and -S (02) N (R6) 2; or R1 and R2, taken together with the carbon to which they are shown to be attached in Formula 1, form a carbonyl group with the proviso that G is selected from the group consisting of -O-, -S-, and - N (R6) -; or R1 and R2, taken together with the carbon to which they are shown to be attached in Formula 1, form a cycloalkylene ring, wherein said cycloalkylene ring may be unsubstituted or substituted with one or more substituents which may be the same or and are independently selected from the group consisting of halogen, alkyl, haloalkyl, -OR6, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -N (R6) 2, -C (0) R6, -C (0) OR6, - OC (0) R6, -C (0) N (R6) 2, -N (R6) C (0) R6, -N (R6) C (0) OR6, -N (R6) C (0) N ( R6) 2, -N02, -CN, -S (02) R6, and -S (02) N (R6) 2; R3 and R4 are independently selected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be unsubstituted or substituted by one or more substituents which may be the same or different and are independently selected from the group consisting of halogen, alkyl, haloalkyl, -OR6, haloalkoxy, cycloalkyl, heterocycloalkyl , aryl, heteroaryl, -N (R6) 2, -C (0) R6, -C (0) OR6, -OC (0) R6, -C (0) N (R6) 2, -N (R6) C (0) R6, -N (R6) C (0) OR6, -N (R6) C (0) N (R6) 2, -N02, -CN, -S (02) R6, and -S (02) N (R6) 2; R5 is selected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and -P (0) (OH) 2, wherein each of said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be unsubstituted or substituted with one or more substituents which may be the same or different and are independently selected from the group consisting of halogen, alkyl, haloalkyl, -OR6, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -N (R6) 2, -C (0 ) R6, -C (0) OR6, -OC (0) R6, -C (0) N (R6) 2, -N (R6) C (0) R6, -N (R6) C (0) OR6, -N (R6) C (0) N (R6) 2, -N02, -CN, -S (02) R6, and -S (02) N (R6) 2; R6 is selected from the group consisting of H, -CN, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may be unsubstituted or substituted independently with one or more substituents which they can be the same or different and the substituents are independently selected from the group consisting of halogen, -OH, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, aryl, aryloxy, heteroaryl and heteroaryloxy; each R7 is independently selected from the group consisting of H, alkyl, cycloalkyl, -OH, alkoxy, cycloalkoxy, halogen, -CN, -N02, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -C (0) OR11, -C (0) NR9R10, - N (R9) C (0) R11, -N (R9) C (0) OR12, -N (R9) C (0) NR9R10, -N (R9) S (02) R12, -NR9R10, -S (02) ) NR9R10, -S (0) R12, -S (02) R12, and (R15) n8-heteroaryl-; each R8 is independently selected from the group consisting of H, alkyl, cycloalkyl, -OH, halogen, -CN, -N02, -C (0) CF3, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, alkoxy, cycloalkoxy, -C (0) OR11, -CONR9R10, -NR9R10, -NR9COR12, -NR9C02R11, -NR9CONR9R10, -NR9S02R12, -S (0) R12, and -S (02) R12; R9 and R10 are each independently selected from! group consisting of H, alkyl, cycloalkyl and benzyl; or R9 and R10, taken together with the nitrogen to which they are attached, form a 4-7 membered heteroaryl ring containing from 0-3 additional heteroatoms selected from the group consisting of -O-, -S- and - N (R11) -; R11 is selected from the group consisting of H, alkyl and cycloalkyl; R12 is selected from the group consisting of alkyl, cycloalkyl, and -CF3; each R13 is independently selected from the group consisting of - (C (R17) 2) n7-D, where D is H, -CF3, -CHF2, -CH2F, -CN, -OH, -O-alkyl, -OCH2F , -OCHF2, -OCF3, -OCH2CF3, -O-cycloalkyl, -O-alkyl-cycloalkyl, -NR18R19, -S02NR18R19, -NR11S02R18, -NR11C (0) R19, -NR11C (0) OR18, -NR1 (C ( 0) NR18R19), -C (0) NR18R'19, -C (0) OR18, -cycloalkyl, (R7) n7-aryl-, (R8) n8-heteroaryl-, -OC (0) R19, -OC ( 0) NR18R19, -C (= NOR19) (R18), -C (0) R18, -C (OR11) (R18) (R19), heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of R21 and R22, R14 is H, alkyl, haloalkyl, aryl, heteroaryl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, -S (0) R6, -S (02) R6, -C (0) OR6, -C (0) R6, and -C ( 0) N (R6) 2; R15 is H, alkyl, cycloalkyl, alkoxy, -OH, -CN, -N02, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, cycloalkoxy, -C (0) OR11, -C (0 ) NR9R10, -N (R9) C (0) R11, -N (R9) C (0) OR12, -N (R9) C (0) NR9R10, -N (R9) S (02) R12, -NR9R10, -S (02) NR9R10, -S (0) R12, -S (02) R12; each R17 is independently H or alkyl; R18 and R19 are each independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, -CH2CF3, aryl, and heteroaryl; or R18 and R19, together with the nitrogen atom to which both are attached, form a saturated or unsaturated ring of 4 to 7 members which is optionally substituted with -OR11, where one of the carbon atoms in the ring is optionally replaced with a heteroatom selected from the group consisting of -O-, -S- and -NR20-; R 20 is H, alkyl, cycloalkyl, cycloalkylalkyl or hydroxyalkyl; R21 and R22, together with the carbon atom to which they are attached, form -C (O) -, -C (S) -, a cyclopropyl ring or -C (NR23) -; R23 is H, alkyl, cycloalkyl, cycloalkylalkyl, -N02, -CN or OR11; R24 and R25 are each independently selected from the group consisting of H and alkyl; or R24 and R25, together with the carbon atom to which they are both bound, form a -C (O) - or cyclopropyl group; R26 is H, -OH or alkyl; R27 is H, alkyl, cycloalkyl, cycloalkylalkyl, -P (0) (OH) 2, allyl, hydroxyalkyl, alkoxyalkyl, -S02R28 or - (CH2) 2-N (R11) -S02-R28; R28 is alkyl, cycloalkyl, -CF3 or -CH2CF3; R29 is 1 to 3 substituents independently selected from the group consisting of H, alkyl, -OH, alkoxy and halogen; X1 is -NR27-, -O-, -S-, -S (O) -, -S (02) -, -CH2-, -CF2- or -CR11F-; and X2 is -NR20-, -N (C (0) NR18R19) -, -N (C (0) OR18) -, -N (S (02) R28) -, -N (C (0) R11) - , -N (S (02) NHR18) -, -O-, -S-, -S (O) -, -S (02) -, -CH2-, -CF2- or -CR11F-.
2. 2. The compound according to claim 1, further characterized in that R1 and R2 are independently selected from the group consisting of H, alkyl (CrC6), hydroxyalkyl (C3), cycloalkyl (C3-C8), -CH2F, -CHF2, and -CF3; or R1 and R2, taken together with the carbon to which they are shown to be attached in Formula 1, form a carbonyl group; or R1 and R2, taken together with the carbon to which they are shown to be attached in Formula 1, form a cycloalkylene ring (C3-C6); R3 and R4 are H; R5 is selected from the group consisting of H, alkyl (C -? - C6), hydroxyalkyl (CrC3), cycloalkyl (C3-C8), -CH2F, -CHF2, and -CF3; n1 + n2 < 4; G is -O- or -N (R14) -; R14 is H, (C6) alkyl, hydroxyalkyl (C3), (C3-C8) cycloalkyl, -CH2F, -CHF2, -CF3; Ar 1 is unsubstituted or monosubstituted phenyl; and Ar2 is unsubstituted, monosubstituted or disubstituted phenyl.
3. 3. The compound according to claim 1, further characterized in that Ar1 is a monosubstituted phenyl.
4. 4. The compound according to claim 1, further characterized in that Ar1 is a disubstituted phenyl.
5. 5. The compound according to claim 1, further characterized in that Ar2 is 3,5-bis (trifluoromethyl) phenyl.
6. 6. The compound according to claim 1, further characterized in that Ar1 is phenyl and Ar2 is 3,5-bis (trifluoromethyl) phenyl.
7. 7. The compound according to claim 1, further characterized in that G is -O-.
8. 8. The compound according to claim 1, further characterized in that R1 is -CH3 and R2 is H. The compound according to claim 1, further characterized in that both R3 and R4 are H. 10. The compound in accordance with claim 1, further characterized in that R5 is H. The compound according to claim 1, further characterized in that n1 is 1 or 2. 12. The compound according to claim 1, further characterized in that n2 is 0 or The compound according to claim 1, further characterized in that n1 and n2 are both 1. The compound according to claim 1, further characterized in that n1 is 1 and n2 is 0. 15. The compound of according to claim 1, further characterized in that n1 is 2 and n2 is 0. 16. The compound according to claim 1, further characterized in that X is -N (R14) - or -O-. 17. The compound according to claim 1, further characterized in that Y is selected from the group consisting of -N (R14) -, -O-, -CH2-, - (CH2) 20-, -0 (CH2) 2- , - (CH2) 2-, -CH2N (R14) -, and -N (R14) CH2-. 18. The compound according to claim 1, further characterized in that Z is -C (O) -. 19. The compound according to claim 1, further characterized in that it is represented by one of Formulas 2-8: Formula 2 Formula 3 Formula 4 Formula 5 Formula 6 Formula 7 Formula 8 wherein R 16 is H, F, alkyl, or each R 16 together with the ring carbon atom or atoms to which they are shown to be attached in Formulas 5-8 define a cycloalkyl ring. 20. The compound according to claim 1, represented by one of Formulas 9-16: Formula 9 Formula 10 Formula Formula 12 Formula 13 Formula 14 Formula 1 £ > Formula 16 Fómula 17 wherein R16 is H, F, alkyl, or each R6 together with the ring carbon atom (s) to which they are shown to be attached in Formulas 13-16 define a cycloalkyl ring. 21. The compound according to claim 2, further characterized in that it is represented by Formula 9: Formula 9 or its pharmaceutically acceptable salt and / or solvate. 22. The compound according to claim 2, further characterized in that it is represented by Formula 10: or its pharmaceutically acceptable salt and / or solvate. 23. The compound according to claim 2, further characterized in that it is represented by formula 11: Formula 11 or its pharmaceutically acceptable salt and / or solvate 24. The compound according to claim 2, further characterized in that it is represented by formula 12: Formula 2 or its pharmaceutically acceptable salt and / or solvate 25. The compound according to claim 2, further characterized in that it is represented by formula 13: Formula 13 or its pharmaceutically acceptable salt and / or solvate, wherein R 16 is H, F, alkyl, or each R 16 together with the carbon atom in the ring to which they are shown to be attached in formula 13 defines a cycloalkyl ring. 26. The compound according to claim 2, further characterized in that it is represented by formula 14: Formula 14 or its pharmaceutically acceptable salt and / or solvate, wherein R16 is H, F, alkyl, or each R16 together with the carbon atom or atoms in the ring to which they are shown attached in formula 14 defines a cycloalkyl ring. 27. The compound according to claim 2, further characterized in that it is represented by formula 15: Formula 15 or its pharmaceutically acceptable salt and / or solvate, wherein R16 is H, F, alkyl, or each R16 together with the ring carbon atom or atoms to which they are shown attached in formula 15 defines a ring cycloalkyl. 28. The compound according to claim 2, further characterized in that it is represented by formula 16: Formula 16 or its pharmaceutically acceptable salt and / or solvate, wherein R 16 is H, F, alkyl, or each R 16 together with the carbon atom in the ring to which they are shown to be attached in formula 16 define a cycloalkyl ring. 29. The compound according to claim 2, further characterized in that it is represented by formula 17: Formula 17 or its pharmaceutically acceptable salt and / or solvate 30. The compound according to claim 1, characterized further because it is selected from the group consisting of the compounds of the following formulas: or its pharmaceutically acceptable salt and / or solvate 31. A compound represented by the following formula: or its pharmaceutically acceptable salt and / or solvate. 32. A compound represented by the following formula: or its pharmaceutically acceptable salt and / or solvate 33. A compound represented by the following formula: or its pharmaceutically acceptable salt and / or solvate. 34. A compound represented by the following formula: or its pharmaceutically acceptable salt and / or solvate. 35. A compound represented by the following formula: or its pharmaceutically acceptable salt and / or solvate. 36. A compound represented by the following formula: or its pharmaceutically acceptable salt and / or solvate. 37. A pharmaceutical composition comprising: at least one compound according to claim 1 or its pharmaceutically acceptable salt and / or solvate, and at least one pharmaceutically acceptable carrier. 38. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, at least one serotonin reuptake inhibitor, and at least one compound according to claim 1. 39. The use of at least one compound in accordance with claim 1 or its pharmaceutically acceptable salt and / or solvate in the manufacture of a medicament for the treatment of a physiological disorder, symptom or disease in a patient wherein the physiological disorder, symptom or disease is selected from the group consisting of respiratory diseases, inflammatory disorders, skin disorders, ophthalmological disorders, central nervous system disorders, depression, anxiety, phobia, bipolar disorder, addictions, alcohol dependence, psychoactive substance abuse, epilepsy, nociception, psychosis, schizophrenia, Alzheimer's disease, related dementia with AIDS, Towne's disease, disorders related to stress, obsessive / compulsive disorders, eating disorders, bulimia, anorexia nervosa, binge eating disorder, sleep disorders, mania, premenstrual syndrome, gastrointestinal disorders, atherosclerosis, fibrosing disorders, obesity, type II diabetes, disorders related to pain, headache, neuropathic pain, postoperative pain, chronic pain syndrome, bladder disorders, genitourinary disorders, cough, emesis, and nausea. 40. The use of at least one compound of claim 1 or its pharmaceutically acceptable salt and / or solvate, and at least one active ingredient selected from the group consisting of other selective NKi receptor antagonists, selective serotonin reuptake inhibitors, dopamine receptor agonists, serotonin 5-HT3 receptor antagonists, serotonin 5-HT2c receptor agonists, nociceptin receptor agonists, glucocorticoids, and inhibitors of multidrug resistance protein 5; in the preparation of a medicament for treating a psychological disorder, symptom or disease in a patient wherein the physiological disorder, symptom or disease is selected from the group consisting of: a respiratory disease, depression, anxiety, phobia, bipolar disorder, alcohol dependence , psychoactive substance abuse, nociception, psychosis, schizophrenia, dementia related to stress, obsessive / compulsive disorder, bulimia, anorexia nervosa, binge eating disorder, sleep disorder, mania, premenstrual syndrome, gastrointestinal disorder, obesity, pain head, neuropathic pain, postoperative pain, chronic pain syndrome, bladder disorder, genitourinary disorder, cough, emesis, and nausea. 41. The use of at least one compound according to claim 1 or its pharmaceutically acceptable salt and / or solvate in combination with at least one serotonin 5-HT3 receptor antagonist and / or at least one glucocorticoid in the preparation of a medication for the treatment of emesis and / or nausea in a patient. 42. The use claimed in claim 41, wherein the serotonin 5-HT3 receptor antagonist is ondansetron and the glucocorticoid is dexamethasone. 43. The use claimed in claim 39, wherein the physiological disorder, symptom or disease is emesis, depression, anxiety or cough. 44. The use claimed in claim 43, wherein the physiological disorder, symptom or disease is depression or anxiety. 45. The use claimed in claim 43, wherein the physiological disorder, symptom or disease is emesis. 46. The use claimed in claim 44, wherein at least one anti-depressant agent and / or at least one anti-anxiety agent is additionally administrable. 47. The use claimed in claim 43, wherein at least one selective serotonin reuptake inhibitor is additionally administrable and wherein the physiological disorder, symptom or disease is depression. 48. The use of at least one compound according to claim 1 or its pharmaceutically acceptable salt and / or solvate in the manufacture of a medicament for antagonizing an effect of a Substance P at a neurokinin-1 receptor site or blocking at least one neurokinin-1 receptor in a patient. 49. A kit, comprising: two or more separate containers in a single container, wherein each container comprises a pharmaceutical composition; wherein a first container of said container comprises a first pharmaceutical composition comprising an effective amount of a compound according to claim 1 and / or its pharmaceutically acceptable salt and / or solvate in a pharmaceutically acceptable carrier, a second container of said container comprises a second pharmaceutical composition comprising another therapeutic agent in a pharmaceutically acceptable carrier, and the other therapeutic agent is selected from the group consisting of SSRIs, other types of NKi receptor antagonists, prostanoids, Hi receptor antagonists, receptor agonists a-adrenergics, dopamine receptor agonists, melanocortin receptor agonists, endothelin receptor antagonists, endothelin-converting enzyme inhibitors, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, inhibitors of Neutral metalloendopeptidase, antago ETA agents, renin inhibitors, antagonists of the 5-HT3 receptors of serotonin, serotonin 5-HT2c receptor agonists, nociceptin receptor agonists, glucocorticoids, rho kinase inhibitors, potassium channel modulators, and multidrug resistance protein 5. 50. The purified compound according to the claim 30.