WO2023034466A1

WO2023034466A1 - Cgrp antagonists for treating psoriasis

Info

Publication number: WO2023034466A1
Application number: PCT/US2022/042282
Authority: WO
Inventors: Robert CROOP; Daniel FRANJIC
Original assignee: Pfizer Ireland Pharmaceuticals
Priority date: 2021-09-02
Filing date: 2022-09-01
Publication date: 2023-03-09
Also published as: AR126954A1

Abstract

Provided for are methods of treating psoriasis with one or more CGRP receptor antagonists and/or pharmaceutical compositions thereof. Such methods are useful for treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis in a mammalian subject, such as a human. In particular, CGRP receptor antagonists such as those according to Formula I, Formula II, and/or Formula III as described herein are useful in methods of treating psoriasis in a subject in need thereof.

Description

CGRP ANTAGONISTS FOR TREATING PSORIASIS

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to United States Provisional patent application number 63/240,064, filed September 2, 2021 , which is hereby incorporated by reference in its entirety.

FIELD OF THE DISCLOSURE

Provided for are methods of treating psoriasis with one or more calcitonin gene- related peptide (CGRP) receptor antagonists and/or pharmaceutical compositions thereof. Such methods are useful for treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis in a mammalian subject, such as a human. In particular, CGRP receptor antagonists such as those according to Formula I, Formula II, and/or Formula III as described herein are useful in methods of treating psoriasis in a subject in need thereof.

BACKGROUND OF THE DISCLOSURE

Psoriasis is a chronic skin disease affecting 2-4% of the population globally. There are several categories of psoriasis including plaque, guttate, inverse, pustular, and erythrodermic, and a patient may have one or more types concurrently or throughout their life. A hallmark symptom of most types of psoriasis is raised areas of abnormal skin that are red-purple in color and scaly in texture. Individuals suffering from psoriasis, particularly plaque psoriasis, may develop white plaques on top of red patches. Further symptoms may include small pus-filled blisters, red patches, and irregularities on the toenails and/or fingernails. Furthermore, approximately 30% of psoriasis patients develop psoriatic arthritis, which is a chronic inflammatory arthritis of joints and surrounding connective tissue. Psoriasis can vary from being localized to being widespread to any part of the body and may change or worsen over time for a given patient.

The cause of psoriasis is, to date, not known. It is believed to have an autoimmune component and is thought to be associated with certain genetic risk factors. There is compelling evidence that psoriasis also involves a neurological component, or that psoriasis is at least partly neurogenic. The onset of psoriasis has been linked with psychological stress or may follow after skin trauma. In some patients, lesions or plaques are distributed symmetrically on the body and psoriatic skin has been found to harbor an increase in nerve fibers and their neuropeptides. It has been reported that denervation or administration of local anesthetics leads to improvement of psoriatic leasions or even remission in cases of permanent nerve damage. (Zhu et al., Am J Clin Dermatol 2016, 17:3, pp. 257-263; Farber et al, Int. J. Dermatol. 1990, 29:6, pp. 418-420; Perlman, H.H. Arch Dermatol.1972, 105:1 , pp. 128-129).

A neuropeptide whose expression or overexpression has been reported to be associated with psoriasis is the calcitonin gene-related peptide (CGRP). CGRP is a naturally occurring 37-amino-acid peptide first identified in 1982 (Amara, S. G. et al, Science 1982, 298, 240-244). Two forms of the peptide are expressed (aCGRP and βCGRP) which differ by one and three amino acids in rats and humans, respectively. The peptide is widely distributed in both the peripheral (PNS) and central nervous system (CNS), principally localized in sensory afferent and central neurons, and displays a number of biological effects, including vasodilation.

When released from the cell, CGRP binds to specific cell surface G protein-coupled receptors and exerts its biological action predominantly by activation of intracellular adenylate cyclase (Poyner, D. R. et al, Br J Pharmacol 1992, 105, 441 -7; Van Valen, F. et al, Neurosci Lett 1990, 119, 195-8.). Two classes of CGRP receptors, CGRP1 and CGRP2, have been proposed based on the antagonist properties of the peptide fragment CGRP(8-37) and the ability of linear analogues of CGRP to activate CGRP2 receptors (Juaneda, C. et al. TiPS 2000, 21 , 432-438). However, there is lack of molecular evidence for the CGRP2 receptor (Brain, S. D. et al, TiPS 2002, 23, 51 -53). The CGRP1 receptor has three components: (i) a 7 transmembrane calcitonin receptor-like receptor (CRLR);

(ii) the single transmembrane receptor activity modifying protein type one (RAMP1 ); and

(iii) the intracellular receptor component protein (RCP) (Evans B. N. et al., J Biol. Chem. 2000, 275, 31438-43). RAMP 1 is required for transport of CRLR to the plasma membrane and for ligand binding to the CGRP-receptor (McLatchie, L. M. et al, Nature 1998, 393, 333-339). RCP is required for signal transduction (Evans B. N. et al., J Biol. Chem. 2000, 275, 31438-43). There are known species-specific differences in binding of small molecule antagonists to the CGRP-receptor with typically greater affinity seen for antagonism of the human receptor than for other species (Brain, S. D. et al, TiPS 2002, 23, 51 -53). The amino acid sequence of RAMP1 determines the species selectivity, in particular, the amino acid residue Trp74 is responsible for the phenotype of the human receptor (Mallee et al. J Biol Chem 2002, 277, 14294-8). In a preclinical model of psoriatic dermatitis, both surgical denervation or administration of a small molecule CGRP antagonist led to reduction of immune cell infiltration and improvement of acanthosis. In psoriasis patients, plasma CGRP levels are elevated compared to controls and CGRP content is increased in psoriatic leasions. (Ostrowski et al, J Invest. Dermatol. 2011 , 131 :7, pp. 1530-1538; Reich et al, Experimental Dermatology 2007, 16:5, pp. 421 -428; He et al, Chinese Medical Journal 2000, 113:8, pp. 747-751 ). Moreover, psoriasis is a IL-17/Th-17 cell mediated disease and it has been shown that treatment of endothelial cells with CGRP biases antigen presentation towards the Th17- and away from Th1 - mediated immune response. (Ding et al, Journal of Immunology 2016, 196:5, pp. 2181-2194).

Inhibitors at the receptor level to CGRP are postulated herein to be useful in pathophysiologic conditions where excessive CGRP receptor activation has occurred. Some of these include neurogenic vasodilation, neurogenic inflammation, migraine, cluster headache and other headaches, thermal injury, circulatory shock, and asthma, as well as various skin conditions having a neurogenic component including psoriasis, redness, rosatia, discrete erythema, flushing, menopausal flushing, rash, and hyperseborrhoea. CGRP antagonists or inhibitors are also contemplated to be useful in subjective sensations of itching, pruritus, sensations of burning or heating, sensations of stinging, tingling, discomfort, tightness, and other such sensations having either a neurogenic component or a neurogenic origin.

CGRP antagonists have shown efficacy for various indications in human clinical trials. See Davis C D, Xu C. Curr Top Med. Chem. 2008 8(16): 1468-79; Benemei S, Nicoletti P, Capone J G, Geppetti P. Curr Opin Pharmacol. 2009 9(1 ):9-14. Epub 2009 Jan. 20; Ho T W, Ferrari M D, Dodick D W, Galet V, Kost J, Fan X, Leibensperger H, Froman S, Assaid C, Lines C, Koppen H, Winner P K. Lancet. 2008 372:2115. Epub 2008 Nov. 25; Ho T W, Mannix L K, Fan X, Assaid C, Furtek C, Jones C J, Lines C R, Rapoport A M; Neurology 2008 70:1304. Epub 2007 Oct. 3.

CGRP receptor antagonists, including small molecule CGRP-receptor antagonists, have been disclosed in PCT publications WO 97/09046, WO 98/09630, WO 98/1128, WO 98/56779, WO 00/18764, WO 00/55154, WO 01/32649, WO 01/49676, WO 01/032648, WO 2004/092166, WO 2004/092168, and WO 2007/120590. See also U.S. Pat. No. 6,344,449, U.S. Pat. No. 6,313,097, U.S. Pat. No. 6,521 ,609, U.S. Pat. No. 6,552,043, US 20030181462, US 20030191068 and WO 03/076432 and related applications. CGRP receptor antagonists have also been disclosed in US Pat. No. 8,314,117, US Pat. No. 8,759,372, US Pat. No. 7,200,862, US Pat. No. 8,481 ,546, and US Pat. No. 9,808,457, each of which are incorporated by reference herein in their entirety.

The disclosure provides technical advantages, for example, methods to treat, ameliorate, and/or prevent psoriasis with compounds that inhibit CGRP. Additionally, the methods and compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.

SUMMARY OF THE DISCLOSURE

The disclosure generally relates to methods of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, comprising administering to a subject in need thereof one or more CGRP receptor antagonists.

In an embodiment, the disclosure describes methods of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, comprising administering to a subject in need thereof one or more CGRP receptor antagonists according to one or more of a compound according to Formula (I), Formula (II), and/or Formula (III), or pharmaceutically acceptable salts or optical isomers thereof:

wherein, in Formula (I), Ri is hydrogen, cyano, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl;

R² is piperidinyl substituted with 1 substituent selected from the group consisting of:

R³ is hydrogen, halo, cyano, alkyl, haloalky I , alkoxy, or haloalkoxy;

R⁴ is hydrogen, halo, cyano, alkyl, haloalky I , alkoxy, or haloalkoxy;

R⁵ is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;

R⁶ is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;

R⁷ is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;

R⁸ is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;

R⁹ is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;

R¹⁰ is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;

R¹¹ is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, dialkylamino, alkoxycarbonyl, or benzyloxycarbonyl; or R¹⁰ and R¹¹ taken together is 0 or N — OH; provided that at least one of R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, or R¹¹ is not hydrogen;

Ar¹ is phenyl substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalky I , alkoxy, haloalkoxy, and alkylSO2;

X is 0, CH2, or NH; and

Y is a bond, 0, CH2, or NH; wherein, in Formula (II), V is — N(R¹)(R²) or OR⁴; R⁴ is H, C_1-6alkyl, C_1-4haloalkyl or (C_1-4alkylene)_0-1R⁴'

R⁴' is C_3-7cycloalkyl, phenyl, adamantyl, quinucidyl, azabicyclo[2.2.1 ]heptyl, azetidinyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino or dioxolanyl; and

R⁴' is optionally substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, C_1-4alkyl, C_1-4haloalkyl, C_1-4alkoxy, hydroxy, amino, C_3-7cycloalkyl, C_1-3alkylamino, C_1-3dialkylamino, (C_1-3alkyl)o-2ureido, phenyl and benzyl; and

R⁴' optionally contains 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of the ring structure of R⁴';

R¹ and R² are each independently L¹, wherein L¹ is selected from the group consisting of H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, — C_1-6alkylene-amino ( C_1-3alkyl)2, C3-7cycloalkyl, phenyl, azetidinyl, adamantyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino and dioxolmnyl; and

R¹ and R² are each optionally and independently substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, C₁- 4alkyl, C_1-4haloalkyl, C_1-4alkoxy, hydroxy, amino, C3-7cycloalkyl, C_1-3alkylamino, C₁- 4dialkylamino, (C_1-3alkyl)o-2ureido, phenyl and benzyl;

R¹ and R² optionally and independently contain 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of the heterocycles comprising R¹ and R²; wherein L¹ is optionally and independently interrupted from the nitrogen to which it is attached by L², wherein L² is independently C_1-3alkylene or C_1-3alkylidene; or

R¹ and R² together with the nitrogen to which they are attached form X, wherein X is azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolizyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, piperazinyl, piperidinyl, morpholino or thiomorpholino; wherein X is optionally substituted with Y, wherein Y is dioxolanyl, C_{1 -9}alkyl, C2- galkenyl, C2-9alkynyl, C_1-4alkylamino, C_1-4dialkylamino, C_1-4alkoxy, C_3-7cycloalkyl, phenyl, azetidinyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, imidazolinyl, imidazolidinyl, imidazolidinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, pyridyl, pyrimidinyl, dihaydrobenzimidazolonyl, piperazinyl, piperidinyl, morpholino, benzothiazolyl, benzisothiazolyl or thiomorpholino; and wherein X and Y are optionally interrupted with Z, wherein Z is — NHC(O)O — , — NHC(O)NH— , NC(Q)NH₂,— NH— , — C_1-3alkylene— , C_1-3alkenylene-NHC(O)O— C_1-3alkylene-; and optionally and independently substituted with 1 or 2 of the same or different substituents selected from the group consisting of C_1-4alkyl, amino, C_1-3alkylamino, — C_1-3alkylene-amiao(C_1-3alkyl)2, (C_1-3alkyl)o-2ureido, phenyl and benzyl;

X and Y optionally and independently contain 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of the heterocycles comprising X and Y; provided that if X is substituted with Y, and if X and Y are not interrupted with Z, then X and Y optionally share one carbon atom and together form a spirocyclic moiety;

Q is Q' or Q"; wherein

Q' is (S^y)sR³; and

Q" is NH(S^y)sR³, NHC(O)(S^y)sR³, NHC(O)O(S^y)sR³, NHC(O)NH(S^y) _SR³, O(S^y)sR³, (S^y)₃NHR³, (S^y)sNHC(O)R³,(S^y)sNHC(O)OR³, (S^y)sNHC(O)NHR³; or (S^y)sOR³; wherein S^y is C_1-3alkylene or C_1-3alkylidene and a is 0 or 1 ;

U is CH₂ or NH; provided that if Q is Q", then U is CH2;

R³ is R^3a or R^3b wherein R^3a is (i) a heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle containing one to five of the same or different beteroatoms selected from the group consisting of O, N and S, and said heterocycle optionally containing 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of said fused rings;

(ii) a 4 to 6 membered heterocycle containing one to three of the same or different heteroatoms selected from the group consisting of O, N and S, optionally containing 1 to 2 carbonyls, wherein the carbon atom of said carbonyl is a member of said 4 to 6 membered heterocycle;

(iii) C_3-7cycloalkyl;

(iv) carbazolyl, fluorenyl, phenyl, — O-phenyl, — O — C_1-4alklylene-phenyl, or napthyl; or

(v) C_1-8alkyl, C_2-7alkenyl, — C(O)R³', CHC(O)O— R³', CH(CH₃)C(O)O— R³',— C(O)O — R³'or C_2-7alkynyl; and wherein R^3a is optionally substituted with 1 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, — O-phenyl, — O — C_1-3alkylenephenyl, — C_1-3alkylene-O — C(O)-phenyl, cyano, amino, nitro, halo, C_1- ₆alkyl, C_1-3mono-bi-tri-haloalkyl, C_1-3mono-bi-tri-haloalkyloxy, (C_1-3alkyl)i-2amine, — OR³', — C(O)R³', — C(O)O— R³', — O— C(O)R³', — N(R³')₂, — C(O)N(R³')₂, — N(R³')C(O)(R³')2, — N(R³')C(O)N(R³')2, — N(R³')C(O)OR³', — 0— C(O)N(R³')₂, — N(R³')SO₂R³', — SO₂N(R³')₂ and — SO2R³'; R³'is H or — C_1-6alkyl; provided that if R^3a is , — C(O)R³', CHC(O)O— R³', CH(CH₃)C(O)O— R³'or — C(O)O— R³', then said — C(O)R³', CHC(O)O— R³', CH(CH₃)C(O)O— R³'or — C(O)O— R³'are unsubstituted;

R^3b is R^3a but is not phenyl, 1 -naphthyl, 2-naphthyl, 1 ,2, 3, 4-tetrahydro-1 -naphthyl, 1 H-indol-3-yl, 1 -methyl-1 H-indol-3-yl, 1 -formyl-1 H-indol-3-yi, 1 -(1 ,1- dirnethylethoxycarbonyl)- 1 H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, 1 H-indazol-3-yl, 1-methyl-1 H-indazol-3-yl, benzo[b]fur-3-yl, benzo[b]thien-3-yl, pyridinyl, quinolinyl or isoquinolinyl; optionally substituted in the carbon skeleton with mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by branched or unbranched alkyl groups, C_3-8-cycloalkyl groups, phenylalkyl groups, alkenyl, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycoarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, dialkylaminoalkoxy, hydroxy, nitro, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, methylsulphonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups; wherein said substituents may be the same or different and the above-mentioned benzoyl, benzoylaznino- and benzoylmnethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom, or by an alkyl, trifluoromethyl, amino or acetylamino group;

D is 0, NCN or NSO₂C_1-3alkyl;

A is CH; m and n are each 1 ;

E is N, CE or C; p is 1 ;

G, J and E together form A^x;

A^x is a fused heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle containing one to four of the same or different heteroatoms selected from the group consisting of O, N and S; and optionally containing 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of said fused heterocycle; and further provided that if Q is Q", then R³ is R^3a; and if Q is Q', then

R³ is R^3b; and wherein, in Formula (III), R¹ is H or Q-(C₁-C₆)alkyl; where Q is a bond, C(O) or C(O)O and where the (C₁-C₆)alkyl can be optionally substituted by N(C₁-C3alkyl)2 or CO2H;

R² is H or forms a spirocyclic heterocyclic ring with R³; R³ forms a spirocyclic heterocyclic ring with R² or is a heterocyclic ring if R² is H; and

R⁴ is an optionally substituted aryl group which may be monocyclic or fused to a further ring.

In another embodiment, the disclosure describes methods of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, comprising administering to a subject in need thereof a pharmaceutical composition comprising one or more CGRP receptor antagonists according to one or more of a compound according to Formula (I), Formula (II), and/or Formula (III).

In another embodiment, the disclosure describes methods of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, comprising administering to a subject in need thereof a pharmaceutical composition comprising one or more CGRP receptor antagonists according to one or more of a compound according to Formula (I), Formula (II), and/or Formula (III) via an oral administration route, an injection administration route, and/or a topical administration route.

In another embodiment, the disclosure provides for the use of one or more of a compound according to Formula (I), Formula (II), and/or Formula (III) in methods of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis.

In another embodiment, the disclosure provides for the use of a compound according to Formula (I), Formula (II), and/or Formula (III) in the manufacture of a medicament for the treatment of psoriasis. In some embodiments, the treatment includes treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis.

These and further embodiments will become apparent to a person of skill in the art based upon the disclosure herein.

DETAILED DESCRIPTION OF THE DISCLOSURE

Psoriasis is known to be associated with overexpression of neuropeptides, some of which may play a role in psoriasis. CGRP is one such neuropeptide that is thought to play a role in psoriasis. The disclosure provides for methods to treat, ameliorate and/or prevent psoriasis with compounds and therapeutic or pharmaceutical compositions that inhibit the CGRP receptor. Inhibition of the CGRP receptor with one or more CGRP receptor antagonists may prevent symptoms or disease associated with overexpression of CGRP, including psoriasis.

CGRP Receptor Antagonists

CGRP Receptor Antagonists useful for the methods of the present invention may be small molecule (molecular weight < about 2 kDa, or < about 1 kDa) or a larger construct (molecular weight > about 2 kDa, or > 1 kDa) such as a peptide, biologic, antibody, etc. In particular, the present disclosure is drawn to methods of treating psoriasis comprising administering to a mammalian or human subject one or more CGRP receptor antagonists. Such CGRP receptor antagonists may be described by various generic or specific chemical formulas. In the following exemplary chemical formulas, the general structure broadly describes a number of chemical structures in the alternative and it can be appreciated that each alternative structure is contemplated.

Formula I

In some embodiments, a method of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, may comprise administering to a subject in need thereof a CGRP receptor antagonist according to Formula (I):

where:

R¹ is hydrogen, cyano, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl; R² is piperidinyl substituted with 1 substituent selected from the group consisting of:

R³ is hydrogen, halo, cyano, alkyl, haloalky I , alkoxy, or haloalkoxy;

R⁴ is hydrogen, halo, cyano, alkyl, haloalky I , alkoxy, or haloalkoxy;

R⁶ is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R⁷ is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino;

R¹¹ is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, dialkylamino, alkoxycarbonyl, or benzyloxycarbonyl; or R¹⁰ and R¹¹ taken together is 0 or N— OH; provided that at least one of R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, or R¹¹ is not hydrogen;

X is 0, CH2, or NH; and

Y is a bond, 0, CH2, or NH; or a pharmaceutically acceptable salt thereof.

In some embodiments, the CGRP receptor antagonists described by general Formula I may be selected from any of the following specific formulas:

(6R,9R)-6-(2,3-Difluorophenyl)-6-hydroxy-5-oxo-6,7,8,9-tetrahydro-5H-cycl- ohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1 -yl)piperidine-1- carboxylate;

(9R)-6-(2,3-difluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-cyclohepta[b]p- yridin-9- yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1 -yl)piperidine-1 -carboxylate;

(5S,6R,9R)-6-(2,3-difluorophenyl)-5,6-dihydroxy-6,7,8,9-tetrahydro-5H-- cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1 -y l)piperidine- 1 -carboxylate;

(5S,6S,9R)-6-(2,3-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cycl- ohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1 -yl)piperidine-1- carboxylate;

(5S,6S,9R)-6-(2,3-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cycl- ohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1 -yl)piperidine-1- carboxylate; (5S,6R,9R)-6-(2,3-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cycl- ohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1 -yl)piperidine-1- carboxylate;

(5S,6S,9R)-5-azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloh- epta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1-yl)piperidine-1 - carboxylate;

(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloh- epta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1-yl)piperidine-1 - carboxylate;

(6S,9R)-6-(2,3-difluorophenyl)-6-hydroxy-6,7,8,9-tetrahydro-5H-cyclohe- pta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1-yl)piperidine-1- carboxylate;

(5S,6S,9R)-5-amino-6-(3,5-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloh- epta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1-yl)piperidine-1 - carboxylate;

(5S,6S,9R)-6-(3,5-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cycl- ohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1 -yl)piperidine-1- carboxylate;

(6S,8R,9S)-6-(2,3-difluorophenyl)-8-hydroxy-6,7,8,9-tetrahydro-5H-cycl- ohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1 -yl)piperidine-1- carboxylate;

(5S,6S,9R)-6-(2,3-difluorophenyl)-5-(methylamino)-6,7,8,9-tetrahydro-5- H- cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1 -y l)piperidine- 1 -carboxylate;

(5S,6S,9R)-6-(2,3-difluorophenyl)-5-(dimethylamino)-6,7,8,9-tetrahydro- -5H- cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1 -y l)piperidine- 1 -carboxylate;

(5S,9R,Z)-6-(2,3-difluorophenyl)-5-(hydroxyimino)-6,7,8,9-tetrahydro-5- H- cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1 -y l)piperidine- 1 -carboxylate;

(6S,9R,E)-6-(2,3-difluorophenyl)-5-(hydroxyimino)-6,7,8,9-tetrahydro-5- H- cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1 -y l)piperidine- 1 -carboxylate; (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloh- epta[b]pyridin-9-yl 2'-oxo-1 , 1 ',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridine]-5- yl- carbamate; tert-butyl(5S,6S,9R)-9-amino-6-(2,3-difluorophenyl)-6,7,8,9-tet- rahydro-5H- cyclohepta[b]pyridin-5-ylcarbamate; tert-butyl (5S,6S,9S)-6-(2,3-difluorophenyl)-9-(2- oxo-2-(4-(2-oxo-2,3-dihydro-1 H-imi- dazo[4,5-b]pyridin-1 -y l)piperid in-1 -yl)ethyl)-6, 7,8,9- tetrahydro-5H-cycloh- epta[b]pyridin-5-yl-carbamate; tert-butyl (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(2-oxo-2-(4-(2-oxo-2,3-dihydro-1 H- imi- dazo[4,5-b]pyridin-1-yl)piperidin-1 -yl)ethyl)-6,7,8,9-tetrahydro-5H-cycloh- epta[b]pyridin-5-ylcarbamate; and

1 -(1 -(2-((5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H- cyclohepta[b]pyridin-9-yl)acetyl)piperidin-4-yl)-1 H-imidazo[4,5-b]pyridin-2(3H)-one; or a pharmaceutically acceptable salt thereof.

In some embodiments, the CGRP receptor antagonist may be Rimegepant, which has the formula (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H- cyclohepta[b]pyridine-9-yl-4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridine-1- yl)piperidine-1 -carboxylate, and which has the following structure

or a pharmaceutically acceptable salt thereof, including the hemisulfate salt and the hemisulfate sesquihydrate.

Formula II

In some embodiments, a method of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, may comprise administering to a subject in need thereof a CGRP receptor antagonist according to Formula (II):

or a pharmaceutically acceptable salt thereof, wherein

V is — N(R¹)(R²) or OR⁴;

R⁴ is H, C_1-6alkyl, C_1-4haloalkyl or (C_1-4alkylene)o-iR⁴'

R¹ and R² are each independently L¹, wherein L¹ is selected from the group consisting of H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, — C_1-6alkylene-amino (C_1-3alkyl)2, C3- 7cycloalkyl, phenyl, azetidinyl, adamantyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino and dioxolmnyl; and

R¹ and R² are each optionally and independently substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, Ci- ₄alkyl, C_1-4haloalkyl, C_1-4alkoxy, hydroxy, amino, C_3-7cycloalkyl, C_1-3alkylamino, C_1- ₄dialkylamino, ( C_1-3alkyl)o-2ureido, phenyl and benzyl;

R¹ and R² together with the nitrogen to which they are attached form X, wherein X is azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolizyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, piperazinyl, piperidinyl, morpholino or thiomorpholino; wherein X is optionally substituted with Y, wherein Y is dioxolanyl, C_{1 -9}alkyl, C_2- ₉alkenyl, C2-9alkynyl, C_1-4alkylamino, C_1-4dialkylamino, C_1-4alkoxy, C_3-7cycloalkyl, phenyl, azetidinyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, imidazolinyl, imidazolidinyl, imidazolidinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, pyridyl, pyrimidinyl, dihaydrobenzimidazolonyl, piperazinyl, piperidinyl, morpholino, benzothiazolyl, benzisothiazolyl or thiomorpholino; and wherein X and Y are optionally interrupted with Z, wherein Z is — NHC(O)O — , — NHC(O)NH— , NC(Q)NH₂,— NH— , — C_1-3alkylene— , C_1-3alkenylene-NHC(O)O— C_1- ₃alkylene-; and optionally and independently substituted with 1 or 2 of the same or different substituents selected from the group consisting of C_1-4alkyl, amino, C_1-3alkylamino, — C_1- ₃alkylene-amiao(C_1-3alkyl)2, (C_1-3alkyl)o-2ureido, phenyl and benzyl;

X and Y optionally and independently contain 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of the heterocycles comprising X and Y; provided that if X is substituted with Y, and if X and Y are not interrupted with Z, then X and Y optionally share one carbon atom and together form a spirocyclic moiety; Q is Q' or Q"; wherein

Q' is (S^y)sR³; and

U is CH₂ or NH; provided that if Q is Q", then U is CH₂;

R³ is R^3a or R^3b wherein R^3a is

(i) a heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle containing one to five of the same or different beteroatoms selected from the group consisting of 0, N and S, and said heterocycle optionally containing 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of said fused rings;

(iii) C_3-7cycloalkyl;

(v) Ci-salkyl, C_2-7alkenyl, — C(O)R³', CHC(O)O— R³', CH(CH₃)C(O)O— R³',— C(O)O — R³'or C_2-7alkynyl; and wherein R^3a is optionally substituted with 1 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, — O-phenyl, — O — C_1- ₃alkylenephenyl, — C_1-3alkylene-O — C(O)-phenyl, cyano, amino, nitro, halo, C_1-6alkyl, C_1- ₃mono-bi-tri-haloalkyl, C_1-3mono-bi-tri-haloalkyloxy, (C_1-3alkyl)_1-2amine, — OR³', — C(O)R³', — C(O)O— R³', — O— C(O)R³', — N(R³')₂, — C(O)N(R³')₂, — N(R³')C(O)(R³')₂, — N(R³')C(O)N(R³')₂, — N(R³')C(O)OR³', — 0— C(O)N(R³')₂, — N(R³')SO₂R³', — SO₂N(R³')₂ and — SO₂R³'; R³'is H or — C_1-6alky I ; provided that if R^3a is , — C(O)R³', CHC(O)O— R³', CH(CH₃)C(O)O— R³'or — C(O)O— R³', then said — C(O)R³', CHC(O)O— R³', CH(CH₃)C(O)O— R³'or — C(O)O— R³'are unsubstituted;

R^3b is R^3a but is not phenyl, 1 -naphthyl, 2-naphthyl, 1 ,2, 3, 4-tetrahydro-1 -naphthyl, 1 H-indol-3-yl, 1 -methyl-1 H-indol-3-yl, 1 -formyl-1 H-indol-3-yi, 1 -(1 ,1- dirnethylethoxycarbonyl)- 1 H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3- thienyl, thiazolyl, 1 H-indazol-3-yl, 1 -methyl-1 H-indazol-3-yl, benzo[b]fur-3-yl, benzo[b]thien-3-yl, pyridinyl, quinolinyl or isoquinolinyl; optionally substituted in the carbon skeleton with mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by branched or unbranched alkyl groups, C_3-8-cycloalkyl groups, phenylalkyl groups, alkenyl, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycoarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, dialkylaminoalkoxy, hydroxy, nitro, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, methylsulphonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups; wherein said substituents may be the same or different and the above-mentioned benzoyl, benzoylaznino- and benzoylmnethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom, or by an alkyl, trifluoromethyl, amino or acetylamino group;

D is O, NCN or NSO₂C_1-3alkyl;

A is CH; m and n are each 1 ;

E is N, CE or C;

P is 1 ;

G, J and E together form A^x; A^x is a fused heterocycle having two fused rings with 5 to 7 members in each of said rings, said heterocycle containing one to four of the same or different heteroatoms selected from the group consisting of O, N and S; and optionally containing 1 or 2 carbonyls wherein the carbon atom of said carbonyl is a member of said fused heterocycle; and further provided that if Q is Q", then R³ is R^3a; and if Q is Q', then

R³ is R^3b

In some embodiments, the CGRP receptor antagonists described by general Formula II may be selected from any of the following specific formulas:

(±)-3-(1 H-lndazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 - carbonyl]-amino}-propionic acid;

(R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [2-

[1 , 4']bipiperid iny 1-1 '-y 1-1 -(1 H-indazol-5 -ylmethyl)-2-oxo-ethyl]-amide;

(±)-4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1 -carboxylic acid [2-

[1 , 4']bipiperid iny 1-1 '-y 1-1 -(1 H-indol-5-ylmethyl)-2-oxo-ethyl]-am- ide;

(±)-4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1 -carboxyl- ic acid [2-

[1 , 4']bipiperid iny 1-1 '-y 1-1 -(1 H-indazol-5-ylmethyl)-2-oxo-ethyl- ]-amide;

(±)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carb- oxylic acid [2-

[1 , 4']bipiperid iny 1-1 '-y 1-1 -(1 H-indol-5-ylmethyl)-2-oxo-ethyl]-amide;

(±)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [2-

[1 , 4']bipiperid iny 1-1 '-y 1-1 -(1 H-indazol-5-ylmethyl)-2-oxo-ethyl]-- amide;

(±)-4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1 -carbox- ylic acid [1-(1 H- indol-5 -ylmethyl)-2-(4-isobutyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

(±)-4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1 -carboxylic acid [2-(1 ,4- dioxa-8-aza-spiro[4.5]dec-8-yl)-1-(1 H-indol-5-ylmethyl)-2-ox- o-ethyl]-amide;

(±)-4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1 -carboxylic acid [1-(1 H- indazol-5-ylmthyl) -2-(4-isobutyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

(±)-4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1 -carboxylic acid [2-(1 ,4- dioxa-8-aza -spiro[4.5]dec-8-yl)-1-(1 H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide; (±)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [2-(1 ,4- dioxa-8-aza -spiro[4.5]dec-8-yl)-1-(1 H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide;

(±)-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino}-propionic acid methyl ester;

(±)-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino}-propionic acid;

[1 , 4']bipiperid iny 1-1 '-y 1-1 -(7-methyl-1 H-indazol-5-ylmethyl)-2-ox- o-ethyl]-amide;

(±)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [1 -(7- methyl-1 H-indazol-5-ylmethyl)-2-oxo-2-piperidin-1 -yl-ethyl]-am- ide;

(±)4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxyli- c acid [1 - dimethylcarbamoyl-2-(7-methyl-1 H-indazol-5-yl)-ethyl]-amide;

(±)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [1 -1 -(7- methyl-1 H-indazol-5-ylmethyl)-2-(4-methyl-piperazin-1-yl)-2-- oxo-ethyl]-amide;

(±)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [1 -1 -(7- methyl-1 H-indazol-5-ylmethyl)-2-oxo-2-pyrrolidin-1 -yl-ethyl]- -amide;

(±)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carbo- xylic acid [1 -(7- methyl-1 H-indazol-5-ylmethyl)-2-oxo-2-(4-pyridin-4-yl-pip- erazin-1 -yl)-ethyl]-amide;

(±)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [1 -(7- methyl-1 H-indazol-5-ylmethyl)-2-oxo-2-(4-pyridin-2-yl-piperazi- n-1 -yl)-ethyl]-amide;

4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid {1 -(1 -1 H- indazol-5-ylmethyl)-2-oxo-2-[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-- 3-y l)-piperid ine-1 -yl]- ethyl}-amide;

4-(3-(1 H-lndazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piper- idine-1 - carbonyl]-amino}-propionyl)-piperazine-1 -carboxylic acid benzyl ester;

4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [1 -(1 H-indazol- 5-ylmethyl)-2-oxo-2-piperazin-1 -yl-ethyl]-am ide;

4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid {1 -(1 H-indazol- 5-ylmethyl)-2-[4-(2-methyl-butyl)-piperazin-1 -yl]-2-oxo-et- hyl}-amide;

3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)- - piperidine-1-carbonyl]-amino}-propionic acid cyclohexyl ester; 3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)- - piperidine-1-carbonyl]-amino}-propionic acid 1-benzyl-piperidin-4-yl ester;

3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino}-propionic acid 1 -methyl-piperidin-4-yl ester,

3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)- - piperidine-1-carbonyl]-amino}-propionic acid 4-phenyl-cyclohexyl ester; 3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)- - piperidine-1-carbonyl]-amino}-propionic acid (R)-1 -pyridin-4-yl-etyl ester;

3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino}-propionic acid (S)-1 -pyridin-4-yl-ethyl ester;

(±)-3-(7-Chloro-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino}-propionic acid methyl ester;

(±)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-pipeine-1 -carboxylic acid [2-

[1 , 4']bipiperid iny 1-1 '-y 1-1 -(7-chloro-1 H-indazol-5-ylmethyl)-2-oxo-eth- yl]-amide;

(±)-3-(7-Ethyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-- quinazolin-3- yl)piperidine-1 -carbonyl]-amino}-propionic acid methyl ester

[1 , 4']bipiperid iny 1-1 '-y 1-1 -(7-ethy 1-1 H-indazol-5-ylmethyl)-2oxo-- ethyl]-amide;

(R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [2-

[1 , 4']bipiperid iny 1-1 '-y 1-1 -(2-methyl-1 H-benzoimidazol-5-ylmethyl)-2-o- xo-ethyl]-amide;

(R)-4(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [2-

[1 , 4']bipiperid iny 1-1 '-yl-2-oxo-1 -(2-oxo-2,3-dihydro-benzooxazol-6-ylm- ethy l)-ethy I]- amide;

(R)-3-(1 H-Benzotriazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)- -piperid ine- 1 -carbonyl]-amino}-propionic acid methyl ester;

(R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [1 -(1 H- benzotriazol-5-ylmethyl)-2-[1 , 4']bipiperid iny 1-1 '-yl-2-oxo-ethyl]-- amide;

(R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxyli- c acid

[2[1 ,4']bipiperidinyl-1 '-yl-2-oxo-1-(2-oxo-2,3-dihydro-1 H-indol-5-y- lmethyl)-ethyl]-amide;

(±)-4(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [1-(4- benzyloxy-2-oxo-2H pyridin-1 -ylmethyl)-2-[1 ,4']bipiperidinyl-T-yl-2-oxo-ethyl]-amide;

[1 ,4'bipiperidnyl-T-yl-1 -(4-hydroxy-2-oxo-2H-pyridin-1-ylmethyl)- -2-oxo-ethyl]-amide;

[1 , 4'bipiperid iny 1-1 '-y 1-1 -(4-hydroxy-piperidin-1 -ylmethyl)-2-oxo- -ethy]-amide;

[1 , 4']bipiperid iny 1-1 '-yl-2-oxo-1 -(1 ,4,6,7-tetrahydro-pyrazolo[4,- 3-c]pyridin-5-ylmethyl)- ethyl]-amide;

(±)-3-(7,7-Dimethyl-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-- {[4-(2-oxo-1 ,4- dihydro-2H -quinazolin-3-yl)-piperidine-1 -carbonyl]-amino}-propionic acid methyl ester; (±)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carbo- xylic acid

[2[1 , 4'bipiperidiny 1-1 '-y 1-1 -(7,7-dimethyl-1 ,4,6,7-tetrahydro-p- yrazolo[4,3-c]pyridin-5- ylmethyl)-2-oxo-ethyl]-amide;

(±)-4(2Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid

[2[1 , 4']bipiperidiny 1-1 '-y 1-1 -(6methoxy-pyridin-3-ylmethyl)-2-oxo-et- hyl]-amide;

[1 , 4']bipiperid iny 1-1 '-y 1-1 -(2-methoxy-pyrimidin-5-ylmethyl)-2-ox- o-ethyl]-amide;

(±)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [(1 -(6- benzyloxy-pyridin-3-ylmethyl)-2-[1 , 4' bipiperid iny 1-1 '-yl-2-ox- o-ethyl]-amide;

[1 ,4']bipiperidinyl-1 '-yl-2-oxo-1 -(6-oxo-1 ,6-dihydro-pyridin-3-yl- methyl)-ethyl]-amide;

(±)-2-(7-Methyl-1 H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1 ,4-dihydro-2- H- quinazolin-3-yl)-piperidin-1 -yl]-butyric acid methyl ester;

(±)-1 -[1 , 4'] B ipiperid iny 1-1 '-yl-2-(7-methyl-1 H-indazol-5-ylmethyl)-4-[- 4-(2-oxo-1 ,4- dihydro-2H -quinazolin-3-yl)-piperidin-1 -yl]butane-1 ,4-dione;

(±)-1 -(1 ,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-2-(7-methyl-1 H-indazol-5-yl- methyl)-4-[4-

(2-oxo-1 ,4-dihydro -2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1 ,4-dione;

(±)-N,N-Dimethyl-2-(7-methyl-1 H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo-- 1 ,4-dihydro- 2H-quinazolin-3-yl)-piperidin-1-yl]-butyramide;

(±)-1 -(2,6-Dimethyl-morpholin-4-yl)-2-(7-methyl-1 H-indazol-5-ylmethyl)- -4-[4-(2-oxo- 1 ,4-dihydro-2H -quinazolin-3-yl)-piperidin-1-yl]-butane-1 ,4-dione;

(±)-2-(7-Methyl-1 H-indazol-5-ylmethyl)-1 -(4-methyl-piperidin-1 -yl)-4-[- 4-(2-oxo-1 ,4- dihydro-2H -quinazolin-3-yl)-piperidin-1 -yl]-butane-1 ,4-dione;

(±)-2-(7-Methyl1 H-indazol-5-ylmethyl)-1 -morpholin-4-yl-4-[4-(2-oxo-1 ,4- -dihydro-2H- quinazolin-3-yl) -piperid in-1 -yl]-butane-1 ,4-dione;

(±)-2-(7-Methyl-1 H-indazol-5-ylmethyl)-4-[4-(2-oxo-1 ,4-dihydro-2H-quin- azolin-3-yl)- piperid in-1 -y l]-1 -piperidin-1 -yl-butane-1 ,4-dione;

(±)-1-(1 ,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-2-(1 H-indazol-5-ylmethyl)-4- -[4-(2-oxo-

1 ,4-dihydro-2H -quinazolin-3-yl)-piperidin-1-yl]-butane-1 ,4-dione;

(±)-2-(1 H-lndazol-5-ylmethyl)-N,N-dimethyl-4-oxo-4-[4-(2-oxo-1 ,4-dihyd- ro-2H- quinazolin-3-yl) -piperid ine-1 -yl]-butyramide;

(±)-5-{2-([1 ,4']Bipiperidinyl-1'-carbonyl)-4-oxo-4-[4-(2-oxo-1 ,4-dihyd- ro-2H- quinazolin-3-yl)-piperidin -1 -yl]-butyl}-indazole-1 -carboxylic acid tert-butyl ester; (±)-2-(7- Methyl-1 H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1 ,4-dihydro-2- H-quinazolin-3-yl)- piperidin-1yl]-N-prop-2-ynyl-butyramide;

(L)-{1 -([1 , 4'] B ipiperid iny 1-1 '-carbonyl)-3-oxo-3-[4-(2-oxo-1 ,4-dihydro-2H- -quinazolin-

3-yl)-piperidin-1-yl]-propyl}-carbamic acid tert-butyl ester;

(L)-1 -[1 , 4'] Bipiperidiny 1-1 '-yl-2-(1 H-indol-5-ylamino)-4-[4-(2-oxo-1 ,4-di- hydro-2H- quinazolin-3-yl) -piperid in-1 -yl]-butane-1 ,4-dione;

(L)-1 -[1 , 4'] Bipiperidiny 1-1 '-yl-2-(5-chloro-2-nitro-phenylamino)-4-[4-(2-- oxo-1 ,4- dihydro-2H-quinazolin -3-y l)-piperid in-1 -yl]-butane-1 ,4-dione;

(L)-1 -[1 , 4' B ipiperidiny 1-1 '-yl-2-(6-chloro-pyrimidin-4-ylamino)-4-[4-(2-o- xo-1 ,4- dihydro-2H-quinazolin -3-y l)-piperid in-1 -yl]-butane-1 ,4-dione;

(L)-1 -[1 , 4'] Bipiperidiny 1-1 '-yl-2-(2-chloro-9H-purin-6-ylamino)-4-[4-(2-o- xo-1 ,4- dihydro-2H-quinazolin -3-y l)-piperid in-1 -yl]-butane-1 ,4-dione;

(L)-2-(4-Amino-6-methyl-5-nitro-pyrimidin-2-ylamino)-1 -[1 ,4']bipiperidiny- 1-1 '-yl-4-[4-

(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidin-1 -yl]-butane- -1 ,4-dione;

(L)-1 -[1 , 4'] Bipiperidiny 1-1 '-yl-2-(4,5-diamino-6-methyl-pyrimidin-2-ylami- no)-4-[4-(2- oxo-1 ,4-dihydro -2H-quinazolin-3-yl)-piperidin-1 -yl]-butane-1 ,4-dione;

(L)-1 -[1 , 4'] Bipiperidiny 1-1 '-yl-2-(7-methyl-1 H-[1 ,2,3]triazo[4,5-d]pyrimi- din-5-ylamino)-

4-[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]- -butane-1 ,4-dione;

(L)-1 -[1 , 4'] Bipiperidiny 1-1 '-yl-2-((2'-pyridyl)-methyl-amino)-4-]4-(2-oxo- -1 ,4-dihydro-

2H-quinazolin-3-yl)-piperidin-1 -yl]-butane-1 ,4-dione;

(L)-1 -[1 , 4'] Bipiperidiny 1-1 '-yl-2-((5'-indazolyl)-methyl-amino)-4-[4-(2-o- xo-1 ,4-dihydro-

2H-quinazolin-3-yl)-piperidin-1 -yl]-butane-1 ,4-dione;

(L)-1 -[1 , 4'] Bipiperidiny 1-1 '-yl-2-((3'-methyl-phenyll)-methyl-amino)-4-[4- -(2-oxo-1 ,4- dihydro-2H -quinazolin-3-yl)-piperidin-1 -yl]-butane-1 ,4-dione;

(L)-1 -[1 , 4'] B ipiperid iny 1-1 '-yl-4-[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-y- l)-piperid in-1 - yl]-2-(pyrim idin -4-ylamino)-butane-1 ,4-dione;

(L)-1 -[1 , 4'] Bipiperidiny 1-1 '-yl-2-(4-hydroxy-cyclohexylamino-4-[4-(2-oxo-- 1 ,4-dihydro-

2H-quinazolin-3-yl)-piperidin-1 -yl]-butane-1 ,4-dione;

(L)-1 -[1 , 4'] Bipiperidiny 1-1 '-y l-2-[( 1 H-imidazol-4-ylmethyl)-amino]-4-[4-(- 2-oxo-1 ,4- dihydro-2H -quinazolin-3-yl)piperidin-1 -yl]-butane-1 ,4-dione;

(L)-N-{1 -([1 , 4'] B ipiperidiny 1-1 '-carbonyl)-3-oxo-3-[4-(2-oxo-1 ,4-dihydro- 2H- quinazolin-3-yl)-piperidin-1 -yl]-propyl}-4-hydroxy-benzamide;

(L)-N-{1 -([1 , 4'] B ipiperidiny 1-1 '-carbonyl)-3-oxo-3-[4-(2-oxo-1 ,4-dihydro- 2H- quinazolin-3-yl)-piperidin-1 -yl]-propyl}-4-hydroxy-benzamide; (L)-1 H-Pyrazole-3-carboxylic acid{1-([1 ,4']bipiperidinyl-1 '-carbonyl)-3-oxo-3-[4-(2- oxo-1 ,4-dihydro-2H- -quinazolin-3-yl)-piperidin-1-yl]-propyl}-amide;

(±)-1-[1 ,4']Bipiperidinyl-1 '-yl-2-(1 H-indazol-5-ylamino)-4-[4-(2-oxo-1- , 4-di hydro-2 H- quinazolin-3-yl)-piperidin-1 -yl]-butane-1 ,4-dione;

(±)-3-(3-Cyano-1 H-indol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3- -yl)-piperidin- 1 -carbonyl]-amino}-propionic acid methyl ester;

[1 , 4']bipiperid iny 1-1 '-y I -1 -(3-cyano-1 H-indol-5-yl-methyl)-2-oxo-ethyl]-amide; (±)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [2-

[1 , 4']bipiperid iny 1-1 '-y 1-1 (3-cyano-7-methyl-1 H-indol-5-yl-methyl- )-2-oxo-ethyl]-amide;

(±)-3-(7-lsopropyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dibydro-2H-quinaz- olin-3-yl)- piperidin-1-carbonyl]-amino}-propionic acid methyl ester; (±)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [2-

[1 , 4']bipiperid iny 1-1 '-y 1-1 (7-isopropyl-1 H-indazol-5-yl-methyl)-2- -oxo-ethyl]-amide;

[1 , 4']bipiperid iny 1-1 '-y 1-1 (7-ethy 1-1 H-indazol-5-yl-methyl)-2-oxo- -ethyl]-amide; (±)-4-(2,2- Dioxo-1 ,4-dihydro-2H-2.lamda..sup.6-benzo[1 ,2,6]thiadiazin— 3-yl)-piperidine-1 - carboxylic acid [2-[1 , 4']bipiperid iny 1-1 '-y 1-1 (7-methyl-1 H-indazol-5-yl-methyl)-2-oxo-eth- yl]-amide;

(±)-4-(2,2-Dioxo-1 ,4-dihydro-2H-2.lamda..sup.6-benzo[1 ,2,6]t- hiadiazin-3-yl)- piperid in-1 -carboxylic acid [2-[1 , 4'bipiperid iny 1-1 '-y 1-1 (7-ethyl-3-methyl-1 H-indazol-5-yl- methyl)-2-- oxo-ethyl]-amide;

(±)-2-[4-(6-Cyano-2-oxo-1 ,4-dihydro-2H-qinazolin-3-yl)piperidine-1 -car- bonyl]- amino]-3-(7-methyl-1 H-indazol-5-yl)-propionic acid methyl ester;

(±)-4-(6-Cyano-2-oxo-1 ,4-dihydro-2H-qinazolin-3-yl)-piperidine-1 -carbo- xylic acid{2- [1 ,4'bipiperidinyl-1 '-yl-1 -(7-methyl-1 H-indazol-5-yl methyl)-2-oxo-ethyl}-amide;

(±)-4-(2-Oxo-1 ,2,4,5-tetrahydro-benzo[d][1 ,3]diazepin-3-yl-1 -carboxyli- c acid{2-

[1 , 4']bipiperid iny 1-1 '-yl-1 -(7-methyl-1 H-indazol-5-yl methyl)-2-oxo-ethyl}-amide;

(±)-4-(6-Hydroxy-2-oxo-1 ,4-dihydro-2H-qinazolin-3-yl)-piperidine-1 -car- boxylic acid{2-[1 , 4']bipiperid iny 1-1 '-yl-1 -(7-methyl-1 H-indazol-5-yl methyl)-2-oxo-ethyl}-amide;

(±)-4-(8-Methoxy-2-oxo-1 ,4-dihydro-2H-qinazolin-3-yl)-piperidine-1 -car- boxylic acid{2-[1 , 4']bipiperid iny 1-1 '-yl-1 -(7-methyl-1 H-indazol-5-yl methyl)-2-oxo-ethyl}-amide;

(±)-4(8-Chloro-2-oxo-1 ,4-dihydro-2H-qinazolin-3-yl)-piperidine-1 -carbo- xylic acid{2-

(±)-N-(3-(7-Ethyl-1 H-indazol-5-yl)-1 -(6,7-dihydro-1 H-pyrazolo[4,3-c]py- ridin-5(4H)- yl)-1 -oxopropan-2-yl)-4-(1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)- piperidine-1 - carboxamide;

(±)-Methyl 2-(4-(8-fluoro-1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1 - carboxam- ide)-3-(7-methyl-1 H-indazol-5-yl)propanoate;

(±)-4-(8-Fluoro-1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-methyl-1 - H-indazol-5- yl)-1 -oxo-1 -(4-(piperidi n-1 -y l)piperid in-1 -yl)propan-2-yl)piperidine-1 -carboxamide;

(±)4-(8-Fluoro-1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-methyl-1 H- -indazol-5- yl)-1 -oxo-1 -(4-phenylpiperazin-1 -yl)propan-2-yl)piperidine-1 -carboxam ide;

(±)-4-(8-Fluoro-1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(1 -(- 4-(4- fluorophenyl)piperazin-1 -yl)-3-(7-methy-1 H-indazol-5-yl)-1 -oxopropan-- 2-y l)piperid ine-1 - carboxamide; (±)-4-(8-Fluoro-1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(1 -(4-(2-fluor- ophenyl)piperazin-1 -yl)-3-(7-methyl-1 H-indazol-5-yl)-1 -oxopropan-2-yl)pipe- rid ine-1 - carboxamide;

(±)-4-(8-Fluoro-1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-methyl-1 - H-indazol-5- yl)-1 -oxo-1 -(4-o-tolylpiperazin-1-yl)propan-2-yl)piperidine-1 -- carboxamide;

(±)-Methyl 2-(4-(8-fluoro-1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1 - carboxam- ide)-3-(7-ethyl -3-methyl-1 H-indazol-5-yl)propanoate;

(±)-N-(3-(7-Ethyl-3-methyl-1 H-indazol-5-yl)-1 -oxo-1 -(4-(piperid in-1 -y l)piperid in-1 - yl)propan-2-yl)-4-(8-fluoro-1 ,2-dihydro-2-oxoquinazolin-3(4H)- -yl)piperid ine-1 - carboxamide;

(R)-N-((R)-3-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)-1 -oxo-1 -(4-(piperidin-1 - - yl)propan-2-yl)-4-(8-fluoro-1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidi- ne-1 - carboxamide;

(±)-4-(8-Fluoro-1 ,2-dihydro-2,4-dioxoquinazolin-3(4H)-yl)-N-(3-(7-meth- y 1-1 H- indazol-5-yl)-1 -oxo-1 -(4-(piperid in-1 -y l)piperid in-1 -yl)propan-2-yl)- piperid ine-1 - carboxamide;

N-((R)-3-(2-(trifluoromethyl)-1 H-benzo[d]imidazol-5-yl)-1 -oxo-1 -(4-(piper- id in-1 - y l)piperid in-1 -yl)propan-2-yl)-4-(1 ,2-dihydro-2-oxoquinazolin-3(4H)- -yl)piperid ine-1 - carboxamide;

N-((R)-1-(dimethylcarbamoyl)-2-(2-trifluoromethyl)-1 H-benzo[d]imidazol-5-- yl)ethyl)- 4-(1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1 -carboxamide- ;

(R)-methyl 2-(4-(1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1 -carboxam ide)-3- (2- ,3-dihydro-2-oxo-1 H-benzo[d]imidazol-6-yl)propanoate;

N-((R)-3-(2,3-dihydro-2-oxo-1 H-benzo[d]imidazol-6-yl)-1 -oxo-1 (4-piperid ine-1 - yl)propan-2-yl)-4-(1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1 -c- arboxamide;

N-((R)-1-(dimnethylcarbamoyl)-2-(2,3-dihydro-2-oxo-1 H-benzo[d]imidazol-6-- y l)ethy l)-4-( 1 ,2-dihydro-2-oxoquinazolin-3(4H))-yl)piperidine-1 -carboxamid- e;

4-(1 ,2-dihydro-2,4-dioxoquinazolin-3-(4H)-yl)-N-((R)-3-(7-methyl-1 H-ben- zo[d][1 , 2 , 3]triazol-5-y 1-1 -oxo-1 -(4-(piperid in-1 -y l)piperidi n-1 -yl)propan-- 2-y l)piperidine-1 - carboxamide;

(R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid[2-(4- cyclohexyl-piperazin-1 -yl)-2-oxo-1 -(2-oxo-2,3-dihydro-benzooxaz- ol-6-ylmethyl)-ethyl]- amide; (R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid[2-(4- isopropyl-piperazin-1 -yl)-2-oxo-1 -(2-oxo-2,3-dihydro-benzooxazo- l-6-y Im ethy l)-ethy I]- amide;

(R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid[2-

[1 , 4']bipiperid iny 1-1 '-y 1-1 -(4-chloro-2-oxo-2,3-dihydro-benzooxazo- l-6-ylmethyl)-2-oxo- ethyl]-amide;

(R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid[2-

[1 , 4']bipiperid iny 1-1 '-y 1-1 -(5-chloro-2-oxo-2,3-dihydro-benzooxazo- l-6-ylmethyl)-2-oxo- ethyl]-amide;

(R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid[2-

[1 , 4']bipiperid iny 1-1 '-y 1-1 -(4-bromo-2-oxo-2,3-dihydro-benzooxazol- -6-ylmethyl)-2-oxo- ethyl]-amide;

(R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid[2-

[1 , 4']bipiperid iny 1-1 '-y 1-1 -(5-bromo-2-oxo-2,3-dihydro-benzooxazol- -6-ylmethyl)-2-oxo- ethyl]-amide;

(R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid[2-

[1 , 4']bipiperid iny 1-1 '-y 1-1 -(4-iodo-2-oxo-2,3-dihydro-benzooxazol-- 6-ylmethyl)-2-oxo- ethyl]-amide;

(±)-N-(1 -Benzyl-2-hydroxy-ethyl)-2-(7-methyl-1 H-indazol-5-ylmethyl)-4-- oxo-4-[4-(2- oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidin-1 -yl]-butyramide- ;

(4Phenyl-acetic acid N'-{2-(7-methyl-1 H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1 ,4- dihydro 2H -quinazolin-3-yl)-piperidin-1 -yl)-butyryl}-hydrazide;

(±)-1-[1 ,4']Bipiperidinyl-1 '-yl-4-[4-(8-fluoro-2-oxo-1 ,4-dihydro-2H-qu- inazolin-3-yl)- piperid in-1 -yl]-2-(7-methyl-1 H-indazol-5-ylmethyl)-butane-1 - ,4-dione;

(±)1 -(4-Cyclohexyl-piperazin-1 -yl)-2-(2-oxo-2,3-dihydro-benzo- oxazol-6-ylmethyl)-4- [4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidin-1 - -yl]-butane-1 ,4-dione;

(±)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)piperidine-1 -carboxylic acid[2-(4- cyclohexyl -piperazin-1 -yl)-1 -(7-methyl-1 H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide;

(±)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid[2-[4-(4- fluoro-phenyl)-piperazin-1 -y l]-1 -(7-methyl-1 H-indazol-5-ylme- thyl)-2-oxo-ethyl]-amide;

(±)-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino)}-propionic acid tert-butyl ester;

(±)-3-(7-Methyl-1 H-indazol-5-yl)-2-}[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino}-propionic acid 1-methyl cyclohexyl ester; (±)-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-qu- inazolin-3-yl)- piperidine-1-carbonyl}-amino}-propionic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester;

(±)-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino}-propionic acid piperidin-4-yl ester;

(±)-4-(3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinaz- olin-3-yl)- piperidine-1-carbonyl[-amino}-propionyloxy)-piperidine-1 -carbox- ylic acid tert-butyl ester,

(±)-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino}-propionic acid 3,4,5,6-tetrahydro-2H-[1 ,4']bipyridinyl-4-yl ester,

(±)-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino)-propionic acid 1-diethylamino-1-methyl-ethyl ester;

(±)-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino}-propionic acid 1 ,1-dimethyl-2-phenyl-ethyl ester;

(±)-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino)-propionic acid 1 ,1-dimethyl-3-phenyl-propyl ester;

(±)-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino}-propionic acid ethyl ester; and

(R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 d-carboxylic acid[2- [1 , 4']bipiperid iny 1-1 '-y 1-1 -(7-methyl-1 H-indazol-5-ylmethyl)-2-oxo- -ethyl]amide.

In some embodiments, the CGRP receptor antagonist may be Zavegepant, which has the formula (R) — N-(3-(7-methyl-1 H-indazol-5-yl)-1-(4-(1-methylpiperidin-4- yl)piperazin-1 -yl)-1 -oxopropan-2-yl)-4-(2-oxo-1 , 2-dihydroqu inol in-3-y l)piperid ine-1 - carboxamide, and which has the following structure

or a pharmaceutically acceptable salt thereof.

Formula III

In some embodiments, a method of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, may comprise administering to a subject in need thereof a CGRP receptor antagonist according to Formula (III):

or a salt thereof or an optical isomer thereof, wherein

R¹ is H or Q-(C₁-C₆)alkyl; where Q is a bond, C(O) or C(O)O and where the (C-i- C₆)alkyl can be optionally substituted by N(C₁-C3alkyl)2 or CO2H;

R² is H or forms a spirocyclic heterocyclic ring with R³;

R³ forms a spirocyclic heterocyclic ring with R² or is a heterocyclic ring if R² is H; and

In some embodiments, the CGRP receptor antagonists described by general Formula III may be selected from any of the following specific formulas:

N-[(2R)-3-(7-methyl-1 H-indazol-5-yl)-1 -oxo-1 -({(2S)-1 -oxo-3-(piperidin-4-yl)-1 -[4- (pyridin-4-yl)piperazin-1 -yl]propan-2-yl}amino)propan-2-yl]-4-(2-- oxo-2,3-dihydro-1 H- imidazo[4,5-b]pyridin-1 -yl)piperidine-1 -carboxamide; tert-butyl 4-{(2S)-2-{[(2R)-3-(7-methyl-1 H-indazol-5-yl)-2-({[[4-(2-oxo-1 ,2- dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoyl]amino}-3-oxo-3-[4-(py- rid in-4-y l)piperazin-1 -y l]propy IJpiperid ine-1 -carboxylate;

N-[(2R)-3-(7-methyl-1 H-indazol-5-yl)-1 -oxo-1 -({(2S)-1 -oxo-3-(piperidin-4-- yl)-1 - [4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-- oxo-1 ,2- dihydroquinolin-3-yl)piperidine-1 -carboxamide;

N-[(2R)-3-(7-methyl-1 H-indazol-5-yl)-1 -oxo-1 -({(2S)-1 -oxo-3-(1 -propylpiperidin-4- yl)-1-[4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-y- l]-4-(2-oxo-1 ,2- dihydroquinolin-3-yl)piperidine-1 -carboxamide;

3.5-dibromo-Na-{[4-(2-oxo-1 ,2-dihydroquinolin-3-yl)piperidin-1 -yl]carbonyl}-N- {(2S)-1 -oxo-3-(piperidin-4-yl)-1 -[4-(pyridin-4-yl)piperazin-1 -y- l]propan-2-yl}-D- tyrosinamide;

N-[(2R)-3-(7-methyl-1 H-indazol-5-yl)-1 -oxo-1 -({(2S)-1 -oxo-3-(1 - pentanoylpiperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1 -yl]propan-2-yl}amino)propan-2-yl]- 4-(2-oxo-1 ,2-dihydroquinolin-3-yl)piperidine-1 -carboxamide;

N-[(2R)-1 -({(2S)-3-(1 -ethy Ipiperid in-4-y l)-1 -oxo-1 -[4-(pyridin-4-yl)piperazin-1 - yl]propan-2-yl}amino)-3-(7-methyl-1 H-indazol-5-yl)-1-oxopropan-2-yl- ]-4-(2-oxo-1 ,2- dihydroquinolin-3-yl)piperidine-1 -carboxamide;

3.5-dibromo-Na-{[4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1 -yl)piperidin-1- yl]carbonyl}-N-{(2S)-1 -oxo-3-(piperidin-4-yl)-1 -[4-(pyridin-4- -yl)piperazin-1 -yl]propan-2- yl}-D-tyrosinamide;

3.5-dibromo-Na-{[4-(2-oxo-1 ,4-dihydroquinazolin-3(2H)-yl)piperidin-1- yl]carbonyl}-N-{(2S)-1 -oxo-3-(piperidin-4-yl)-1 -[4-(pyridin-4-yl)piperaz- in-1 -yl]propan-2- yl}-D-tyrosinamide;

N-[(2R)-3-(7-methyl-1 H-indazol-5-yl)-1 -oxo-1 -({(2S)-1 -oxo-3-(piperidin-4-- yl)-1 - [4-(pyridin-4-yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-4-(2-- oxo-1 ,4- dihydroquinazolin-3(2H)-yl)piperidine-1 -carboxamide;

N-[(2R)-3-(7-methyl-1 H-indazol-5-yl)-1 -oxo-1 -({(2S)-1 -oxo-3-(piperidin-4-yl)-1 -[4- (pyridin-4-yl)piperazin-1 -yl]propan-2-yl}amino)propan-2-yl]-2'-oxo-1 ' ,2'-d ihydro-1 H- spiro[piperidine-4,4'-pyrido[2,3-d][1 ,3]oxazine]-1 -carboxamide;

N-[(2R)-1-({(2S)-3-{1 -[2-(dimethylamino)ethyl]piperidin-4-yl}-1 -oxo-1 -[4-(pyridin-4- yl)piperazin-1-yl]propan-2-yl}amino)-3-(7-methyl-1 H-ind- azol-5-yl)-1 -oxopropan-2-yl]-4- (2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin- -1 -yl)piperidine-1 -carboxamide; 3-(4-{(2S)-2-{[(2R)-3-(7-methyl-1 H-indazol-5-yl)-2-({[4-(2-oxo-2,3-dihydro-1 H- imidazo[4,5-b]pyridin-1 -y l)piperid in-1 -yl]carbonyl}amino)propanoyl]am- ino}-3-oxo-3-[4- (pyridin-4-yl)piperazin-1 -yl]propyl}piperidin-1 -yl)-3-oxop- ropanoic acid, ammonium salt; and

3, 5-dibromo-Na-[(2'-oxo-T,2'-dihydro-1 H-spiro[piperidine-4,4'-pyrido- [2,3- d][1 ,3]oxazin]-1 -yl)carbonyl]-N-{(2S)-1 -oxo-3-(piperidin-4-yl)-1 -[4-(- pyridin-4- yl)piperazin-1 -yl]propan-2-yl}-D-tyrosinam ide; or a salt thereof or an optical isomer thereof.

In some embodiments, the CGRP receptor antagonist may be BHV-3100, which has the formula N-[(2R)-3-(7-methyl-1 H-indazol-5-yl)-1 -oxo-1-({(2S)-1-oxo-3-(piperidin- 4-yl)-1 -[4-(pyridin-4-yl)piperazin-1 -yl]propan-2-yl}amino)propan-2-yl]-2'-oxo-T,2'-dihydro- 1 H-spiro[piperidine-4,4'-pyrido[2,3-d][1 ,3]oxazine]-1 -carboxamide, and which has the following structure:

or a pharmaceutically acceptable salt thereof.

Pharmaceutical Compositions and Methods of Treatment

The compounds of Formula I, Formula II, and/or Formula III inhibit the CGRP receptor. As such, they are useful for treating conditions or disorders associated with aberrant CGRP levels or where modulating CGRP levels may have therapeutic benefit.

Accordingly, another aspect of the disclosure is a pharmaceutical composition comprising a compound of Formula I with a pharmaceutically acceptable adjuvant, carrier, or diluent. Accordingly, another aspect of the disclosure is a pharmaceutical composition comprising a compound of Formula II with a pharmaceutically acceptable adjuvant, carrier, or diluent.

Accordingly, another aspect of the disclosure is a pharmaceutical composition comprising a compound of Formula III with a pharmaceutically acceptable adjuvant, carrier, or diluent.

Compounds are generally given as pharmaceutical compositions comprised of a therapeutically effective amount of one or more of a compound of Formula I, Formula II, and/or Formula III, or pharmaceutically acceptable salt(s) thereof, and a pharmaceutically acceptable carrier, further optionally containing conventional excipients. A therapeutically effective amount is the amount needed to provide a meaningful patient benefit as determined by practitioners in that art. Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles. Compositions encompass all common solid and liquid forms including capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Solid compositions may by formed in timed or sustained released formulations. Compositions are made using common formulation techniques and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols).

The disclosure and methods encompass all conventional modes of administration including oral, parenteral, intranasal, sublingual, topical, and transdermal methods. Typically, the daily dose may be 0.01 -100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regime, however, should be determined by a physician using sound medical judgement.

Among other routes of administration, the standard routes of administration described by the FDA are contemplated herein as shown in Table 1 below (FDA Routes of Administration; retrieved from www.fda.gov: content current as of 11/14/2017).

Table 1 : FDA Routes of Administration

In some embodiments, the route of administration may be oral, intranasal, inhalation, intravenous, topical, injectable and/or transdermal.

The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating. Pharmaceutical compositions may comprise one or more pharmaceutically acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985), the entire disclosure of which is incorporated by reference herein for all purposes. As used herein, “pharmaceutically acceptable” refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient. Accordingly, pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

Compounds of the present teachings can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tabletdisintegrating agents, or encapsulating materials. Oral formulations containing a compound disclosed herein can comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. In powders, the carrier can be a finely divided solid, which is an admixture with a finely divided compound. In tablets, a compound disclosed herein can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets can contain up to 99% of the compound.

Capsules can contain mixtures of one or more compound(s) disclosed herein with inert filler(s) and/or diluent(s) such as pharmaceutically acceptable starches (e.g., com, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.

Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, ion exchange resins, benzyl alcohol, eucalyptol, gelatin, limonene, mannitol, menthol, menthone, menthyl acetate, sucralose, and vanillin. Surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the compound(s). The oral formulation can also consist of administering a compound disclosed herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.

Liquid carriers can be used in preparing solutions for oral or parenteral administration (such as intravenous, intramuscular, or other injections), including suspensions, emulsions, syrups, elixirs, and additionally for inhaled delivery. A compound of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (particularly containing additives as described herein, e.g., cellulose derivatives such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants.

Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile injectable solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.

Preferably the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the pharmaceutical composition can be further sub-divided to contain appropriate quantities of the compound. The unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. Alternatively, the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Such doses can be administered in any manner useful in directing the compound(s) to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally.

When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that an effective dosage can vary depending upon the particular compound utilized, the pharmaceutical composition formulated, the mode of administration, and severity of the condition being treated, as well as the various physical factors related to the individual being treated. In therapeutic applications, a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician. The variables involved include the specific condition and its state as well as the size, age and response pattern of the patient.

In some cases it may be desirable to administer a compound directly to the airways of the patient, using devices such as, but not limited to, metered dose inhalers, breath- operated inhalers, multidose dry-powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal or intrabronchial inhalation, the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition. The liquid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a squeeze-actuated nebulized spray dispenser. The solvents can be, for example, isotonic saline or bacteriostatic water. The solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation. The aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfactants, and co-solvents, and can be administered by, for example, a metered device. The propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable.

Compounds described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or a pharmaceutically acceptable salts, hydrates, or esters thereof can be prepared in water suitably mixed with a surfactant such as hydroxyl-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms.

The pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form can sterile and its viscosity permits it to flow through a syringe. The form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts, hydrates, or esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

Transdermal administration can be accomplished through the use of a transdermal patch containing a compound, such as a compound disclosed herein, and a carrier that can be inert to the compound, can be non-toxic to the skin, and can allow delivery of the compound for systemic absorption into the blood stream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous liquid or semisolid emulsions of either the oil- in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the compound can also be suitable. A variety of occlusive devices can be used to release the compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the compound with or without a carrier, or a matrix containing the compound. Other occlusive devices are known in the literature.

Compounds described herein can be administered rectally or vaginally in the form of a conventional suppository. Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used.

Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.

Inhibitors at the receptor level to CGRP are postulated to be useful in pathophysiologic conditions where excessive CGRP receptor activation has occurred. Such excessive CGRP receptor activation occurs in psoriasis.

Another aspect of the disclosure is a method of inhibiting the CGRP receptor comprising contacting the CGRP receptor with a compound of formula I, formula II, formula III, or a pharmaceutically acceptable salt(s) thereof.

Another aspect of the disclosure is a method for treating conditions associated with aberrant levels of CGRP comprising the administration of a therapeutically effective amount of a compound of formula I, formula II, and/or formula III to a patient.

Another aspect of the disclosure is the use of a compound of formula I, formula II, and/or formula III in the manufacture of a medicament for the treatment of conditions related to aberrant levels of CGRP, such as psoriasis. Another aspect of the disclosure is a compound according to formula I, formula II, and/or formula III useful for the treatment of conditions related to aberrant levels of CGRP, such as psoriasis. Another aspect of the disclosure is a method of treating psoriasis. Another aspect of the disclosure relates to a method of treating inflammation (particularly neurogenic inflammation), pain, and other conditions or symptoms related to psoriasis, the treatment of which can be effected by the antagonism of the CGRP receptor by the administration of pharmaceutical compositions comprising one or more compounds of Formula I, Formula II, and/or Formula III as defined herein. Another aspect of the disclosure relates to a method of treatment using combinations of one or more of Formulas I, Formula II, and/or Formula III with one or more therapeutic agents selected from corticosteroids, calcipotriol, anthralin, coal tar, biologies, monoclonal antibodies, secukinumab, brodalumab, guselkumab, certolizumab, usetkinumab, ciclosporin, methotrexate, retinoids, vitamin D, fumaric acid esters paricalcitol , dithranol, desoximetasone, and fluocinonide. Methods of treatment may also comprise combinations with moisturizers and emollients such as mineral oil, petroleum jelly, and decubal. Methods of treatment may also comprise PLIVA and/or UVB phototherapy treatments. Methods of treatment may also comprise systemic agents such as methotrexate, ciclosporin, hydroxycarbamide, vitamin A, fumarates such as dimethyl fumarate, and retinoids. It can be appreciated that a CGRP receptor antagonist may be used alone or in combination with any known treatment in order to treat, ameliorate, and/or prevent psoriasis or symptoms associated therewith.

In some embodiments, a method of treating psoriasis with a CGRP receptor antagonist may further comprise an analysis of genetic susceptibility or risk. Such a genetic analysis may include, genome analysis of PSORS1 , PSORS2, PSORS3, PSORS4, PSORS5, PSORS6, PSORS7, PSORS8, PSORS9, interleukin-12, interleukin- 12 subunit [3, IL23R. in some embodiments, a susceptibility or risk analysis may also include hereditary factors. In some embodiments, a genetic or hereditary analysis may inform dosing with a CGRP receptor antagonist. In some embodiments, a genetic or hereditary analysis may inform prophylaxis in patients with no symptoms or limited symptoms.

In some embodiments, the disclosure is directed to treating varying severities of psoriasis by the administration of pharmaceutical compositions comprising one or more compounds of Formula I, Formula II, and/or Formula III as defined herein. The psoriasis area and seventy index (PASI) may be used to evaluate the severity of psoriasis in a patient. The PASI score may range from 0 to 72. A score of 0 means no psoriasis. A PASI score of 5 to 10 is considered moderate disease and a score over 10 is considered severe. A score over 40 is rare. In some embodiments, the disclosure is directed to treating moderate plaque psoriasis. In alternative embodiments, the disclosure is directed to treating severe plaque psoriasis.

Pharmacokinetics and Dosing In some embodiments, a method of treating psoriasis may be characterized by one or more pharmacokinetic parameters such as AUC, Cmax, Tmax, and others known and understood to persons of skill in the art. The term “pharmacokinetic” (PK) as used herein is used in its ordinary sense to mean the pharmacokinetic aspects of drug delivery. By definition pharmacokinetics (PK) is the study of how an organism affect a drug, e.g. how and how fast it metabolizes the drug. The pharmacokinetics typically vary based upon the dosage amount of one or more of Formula I, Formula II, and/or Formula III The pharmacokinetics may or may not vary as a function of administration route.

In some embodiments, a method of treating psoriasis may be characterized by an AUC for a compound according to Formula I, Formula II, and/or Formula III. In some embodiments, the AUCo-t and/or AUCo-inf (collectively referred to in the alternative as, simply, AUC) may be from about 80 - 125% of a given AUC value. In some embodiments, the AUC may be within 80 - 125 % of about 25, 50, 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000, 1300, 1600, 1900, 2500, 3500, 5000, 7500, 10,000, 15,000, 20,000, 30,000, 50,000, and/or 100,000 hr*ng/mL. In some embodiments, a systemic treatment may have a larger AUC than a localized (such as topical or subdermal) treatment.

In some embodiments, a method of treating psoriasis may be characterized by a Cmax for a compound according to Formula I, Formula II, and/or Formula III. In some embodiments, the Cmax may be from about 80 - 125% of a given Cmax value. In some embodiments, the Cmax may be within 80 - 125 % of about 1 , 2, 3, 4, 5, 8, 10, 20, 35, 50, 80,100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000, 1300, 1600, 1900, 2500, 3500, 5000, 7500, 10,000, 15,000, 20,000, 30,000, 50,000, and/or 100,000 ng/mL. In some embodiments, a systemic treatment may have a larger Cmax than a localized (such as topical or subdermal) treatment.

In some embodmients, a ratio Cmax/AUC may be used to characterize a method of treating psoriasis wherein one or more of a compound according to Formula I, Formula II, and/or Formula III are administered to a subject. In some embodiments, the Cmax/AUC ratio may be from about 80 - 125 % of a given Cmax/AUC ratio. In some embodiments, the Cmax/AUC ratio may be from about 80 - 125 % of about 0.01 , 0.03, 0.05, 0.08, 0.1 , 0.13, 0.17, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, and 0.9.

In some emboidments, the Tmaxmay range from about 0.1 - 16 hours, or from about 0.3 - 8 hours, or from about 0.5 - 4 hours, or from 0.5 - 2 hours, or from about 1 - 2 hours. In some embodiments, the route of administration, which may be any route described herein or known to a person of skill in the art, may affect the Tmax of a compound according to Formula I, Formula II, and/or Formula III. Excipients or other pharmaceutically acceptable carriers in pharmaceutical compositions of one or more compounds according to Formula I, Formula II, and/or Formula III may alter the Tmax value by making it larger or smaller than a pharmaceutical composition having the excipient or carrier excluded.

Solid compositions are normally formulated in dosage units providing from about 0.1 to about 1000 mg of the active ingredient per dose. Some examples of solid dosage units are 0.1 mg, 1 mg, 10 mg, 100 mg, 500 mg, and 1000 mg. Liquid compositions are generally in a unit dosage range of 0.1 -100 mg/mL. Some examples of liquid dosage units are 0.1 mg/mL, 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL.

In some embodiments, a dose is daily. In some embodiments, a dose is twice daily. In some embodiments, a does is one, two, three, four, or five times daily. In some embodiments, a dose is once every other day, once every second day, once every third day, once every fourth day, once every fifth day, once every sixth day, weekly, bi-weekly, or monthly. Typically, a dose may be from 0.01 -100 mg/kg body weight, or from .05 - 50 mg/kg body weight, or from 0.1 - 10 mg/kg body weight, or from 0.15 - 5 mg/kg body weight, or from 0.2 - 2 mg/kg body weight, or from 0.5 - 1 .5 mg/kg body weight, or from 1 - 1.5 mg/kg body weight. In some embodiments, the dosing regimen may comprise one or more optional loading doses and a subsequent maintenance dose regimen. A loading dose may be larger than the doses given in a subsequent maintenance dose regimen.

In some embodiments, the dosage is adjusted based upon psoriasis symptoms observed in the patient. A symptom-dependent regimen may have a larger treatment dose while symptoms are present and a smaller preventative dose while symptoms are lessened, in remission, controlled, etc. In some embodiments, a treatment dose may comprise a unit dosage of about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, or 200 mg of a CGRP receptor antagonist compound according to one or more of Formula I, Formula II, and/or Formula III. In some embodiments, a preventative dose may comprise a unit dosage of about 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 100 mg, 120 mg, or 140 mg of a CGRP receptor antagonist compound according to one or more of Formula I, Formula II, and/or Formula III. In some embodiments, the preventative dose is an amount that is about 7/8, 3/4, 5/8, 1/2, 3/8, 1/4, or about 1/8 of the amount of the treatment dose. In some embodiments, if a patient receiving a preventative dosing regimen experiences recurrence or onset of symptoms, a treatment dosing regimen may replace the preventative dosing regimen until symptoms have lessened or subsided. Each of the treatment and/or preventative doses may be adjusted during the regimen based upon the severity of psoriasis symptoms.

Definitions

"Therapeutically effective" means there is a meaningful patient benefit as understood by medical practitioners.

"Patient" means a person who may benefit from treatment as determined by medical practitioners.

“Psoriasis” as used herein, generally refers to any form of or indication related to psoriasis including but not limited to, plaque psoriasis, pustular psoriasis, inverse psoriasis, napkin psoriasis, guttate psoriasis, erythrodermic psoriasis, mouth psoriasis, seborrheic-like psoriasis, and other forms of psoriasis. In some embodiments, the term “psoriasis” may also encompass psoriatic arthritis, dactylitis, spondylitis, sacroiliitis, and other inflammation of joints and/or connective tissue associated with psoriasis.

“CGRP Receptor Antagonist” as used herein generally may refer to any small molecule antagonist of the CGRP receptor that is useful for treating, ameliorating, and/or preventing a disease or indication. In some embodiments, a CGRP receptor antagonist may be given as a pharmaceutical composition. In some embodiments, one or more CGRP receptor antagonists may be included in a pharmaceutical composition.

The terms "treating" and its derivatives such as “treat” or "treatment," as used herein, may be used with respect to a particular condition, for example, a condition due to or associated with CGRP and/or abberant levels thereof, such as psoriasis. In reference to a particular condition, “treating” and its derivatives are inclusive of several meanings, including (1 ) to alleviate one or more symptoms, effects, or side effects associated with the condition, (2) to ameliorate the condition and/or one or more of the biological manifestations or underlying causes of the condition, (3) to interfere with one or more of the biological manifestations or underlying causes of the condition or with one or more points in the biological cascade(s) associated with the condition, (4) to slow the progression of, or arrest the development of, the condition or of one or more of the biological manifestations of the condition, (5) to prevent or reduce the risk of a subject developing the condition, in some cases prophylactically when the subject has one or more risk factors for the condition (6) to cause regression of the condition, or improvement or reversal of, the biological manifestations or underlying causes of the conditions. It can be appreciated that “treating” may encompass one or more of these meanings simultaneously and that a subject’s condition may change over time or throughout the course of treatment such that the meaning of “treating” as applied to a given subject may change over time or throughout the course of treatment. “Treating” as used herein may also refer to any beneficial effect of administering a CGRP receptor antagonist compound and/or a pharmaceutical composition comprising a CGRP receptor antagonist to a subject or patient having or being at risk for developing psoriasis. “Treating” therefore may encompass alleviating psoriasis and/or the symptoms of psoriasis, prophylaxis or prevention of psoriasis or of the worsening of psoriasis, and reducing the risk that a subject or patient may develop new or worsening psoriasis. “Treatment” may be in combination with other therapies or alone.

The term “AUC” (area under the curve) typically refers to a total amount of drug absorbed or exposed to a subject. Generally , AUC may be obtained from mathematical method in a plot of drug concentration in the subject over time until the concentration is negligible . The term “ AUC ” may also refer to partial AUC at specified time intervals. The AUC may be determined within a certain time period (such as from time 0 to time t; AUCo- t) or may be extrapolated from the last measured point to the point where drug concentration in the subject is zero (AUCinf).

The term "Cmax” refers to a maximum concentration of a drug in blood , serum , a specified compartment or test area of a subject after administration of a dose or between administration of a first dose and administration of a second dose. The term Cmax could also refer to dose normalized ratios, if specified.

The term “Tmax” refers to a time or period after administration of a drug when the maximum concentration (Cmax) is reached in blood, serum, a specified compartment or test area of a subject.

The term “dosing interval” refers to the amount of time that elapses between multiple doses of a formulation disclosed herein being administered to a subject. Dosing interval can thus be indicated as ranges.

The term “dosing frequency” refers to the frequency of administering doses of a formulation disclosed herein in a given time. Dosing frequency can be indicated as the number of doses per a given time, e.g., once a day (daily), twice a day (twice daily), once a week (weekly) or once in two weeks, etc. For the purposes of the present disclosure, the term “excipient” and “carrier” are used interchangeably throughout the disclosure and said terms are defined herein as, “ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition.”

Examples

The following examples further describe and demonstrate embodiments within the scope of the present disclosure. The Examples are given solely for purpose of illustration and are not to be construed as limitations of the present disclosure, as many variations thereof are possible without departing from the spirit and scope of the disclosure.

Example 1 - Rimegepant Oral Treatment for Psoriasis

An ongoing phase 2 clinical trial is examining the use of a new investigational medication for the treatment of moderate plaque-type psoriasis. The study medication is rimegepant, an orally administered small molecule competitive inhibitor of the calcitonin gene-related peptide (CGRP) receptor. This medication, rimegepant, has been approved by the FDA under the trade name Nurtec for the treatment of acute migraine. However, rimegepant has not been studied in the treatment of moderate plaque-type psoriasis and is investigational for this indication.

Primary outcome measures:

The trial/study is investigating the change in seventy of psoriasis as measured with the psoriasis area and severity index instrument [Time Frame: Baseline and Week 16 ] with Rimegepant or placebo intervention. Total score of Psoriasis Area and Seventy Index ranges from 0 to 72. Change = (Week 16 score - Baseline score). A low score means less severe disease while a high score reflects more severe disease. A score of 0 means no psoriasis. A PASI score of 5 to 10 is considered moderate disease and a score over 10 is considered severe. A score over 40 is rare.

Secondary outcome measures:

Average Change in Psoriasis Area and Severity Index Instrument Score [ Time Frame: Baseline and Week 16 ] To Score Whether the Average PASI Score Improves by at Least 50% by Week 16 (Week 16 average score - Baseline average score) PASI range is 0-72 although PASI must be at least 5 for entry into the study. A score of 0 means no psoriasis. A PASI score of 5 to 10 is considered moderate disease and a score over 10 is considered severe. A score over 40 is rare.

• Change in Severity of Psoriasis as Assessed by the Investigator's Global Assessment Instrument. [ Time Frame: Baseline and Week 16 ]

Score of the Investigator's Global Assessment instrument ranges from 0 to 4. Average Change in Score of Each Group= (Week 16 average score - Baseline average score) 0=Clear, 1 =Almost Clear, 2=Mild, 3=Moderate, 4=Severe.

• Change in Dermatology Quality of Life Index [ Time Frame: Baseline and Week 16 ]

Dermatology Quality of Life Index score ranges from 0-30. Average Change in Score of Each Group= (Week 16 average score - Baseline average score). 0 - 1 no effect at all on patient's life, 2 - 5 small effect on patient's life, 6 - 10 moderate effect on patient's life, 11 - 20 very large effect on patient's life, 21 - 30 extremely large effect on patient's life.

• Change in Degree of Itching Assessed by the Visual Analogue Scale [ Time Frame: Baseline and Week 16 ]

The Visual Analogue Scale ranges from 0 to 10. 0= no pruritus, < 3= mild pruritus, > 3- <7= moderate pruritus, > 7-<9 = severe pruritus, > 9= very severe pruritus.

Inclusion Criteria:

• Male or female patients with at least 3% body surface are involved with psoriasis and a PASI score >5.

• Between 18 and 75 years of age.

• Documentation of a definite diagnosis of psoriasis by a dermatologist or biopsy.

• For women of childbearing potential, a negative urine pregnancy test within 48 hours of randomization. Female subjects should not have attempted to become pregnant in the month prior to exposure to rimegepant and agree not to attempt to become pregnant for 8 weeks after exposure to rimegepant. A valid form of contraception must be documented for men and women of child-bearing potential. o The two methods for women of childbearing potential should include:

■ One barrier method (for example, Diaphragm with spermicidal gel, condom with spermicidal gel, cervical caps or intrauterine devices placed for at least four weeks before sexual intercourse); AND

■ One additional method. The other method could include hormonal contraceptives, or second barrier method as listed above. o The two options for men of childbearing potential should include:

■ Simultaneous use of male condom, and for the female partner, hormonal contraceptives (for example, birth control pills, implants, patch, depot injection, used since at least 4 weeks) or intra-uterine contraceptive device (placed since at least 4 weeks) before sexual intercourse; OR simultaneous use of male condom, and for the female partner, diaphragm with intravaginally applied spermicide.

Exclusion Criteria:

• Any ongoing medical illness or condition that places the participant at higher risk for adverse outcomes or inability to complete study procedures in the opinion of the study investigator.

• Pregnancy or breastfeeding.

• Known autoimmune disorders other than psoriasis.

• Current use of corticosteroids or immunosuppressive medications (for any reason).

• Immunodeficiency diseases.

• Use of any biologic agent/monoclonal antibody within 5 half-lifes prior to baseline.

• Ultraviolet light treatment, cyclosporine, oral corticosteroids, methotrexate, oral retinoids, mycophenolate mofetil, thioguanine, hydroxyurea, sirolimus or azathioprine within the 4 weeks prior to baseline or had topical psoriasis treatment within the previous 2 weeks prior to baseline.

• Participation in another clinical trial involving an investigational drug within the last 30 days prior to baseline. • Inability for woman of child-bearing potential to use an effective form of contraception if sexually active.

• Use of any medication that is a strong or moderate inhibitor of CYP3A, a strong or moderate inducer of CYP3A, or an inhibitor of glycoprotein (P-gp) or Breast Cancer Resistance Protein (BCRP). Please see Section 7.8 for more information.

• Body Mass Index greater than 31 .0 kg/m2

• Subject history with current evidence of uncontrolled, unstable or recently diagnosed cardiovascular disease, such as ischemic heart disease, coronary artery vasospasm, and cerebral ischemia. Subjects with myocardial infarction (Ml), acute coronary syndrome (ACS), percutaneous coronary intervention (PCI), cardiac surgery, stroke or transient ischemic attack (TIA) during 6 months (24 weeks) prior to screening.

• Uncontrolled hypertension or uncontrolled diabetes (however, subjects can be included who have stable hypertension and/or diabetes for 3 months (12 weeks) prior to screening). Blood pressure greater than 150 mm Hg systolic or 100 mm Hg diastolic after 10 minutes of rest is exclusionary

• Subjects with an active episode of major depressive episode within the last 6 months are ineligible. Subjects with major depressive disorder or any anxiety disorder are eligible only if they are on stable medication for each disorder for at least 3 months prior to the Screening visit.

• Subject has a history or diagnosis of Gilbert's Syndrome or any other active hepatic or biliary disorder

• Hematologic or solid malignancy diagnosis within 5 years prior to screening. Subjects with a history of localized basal cell or squamous cell skin cancer are eligible for the study if they are cancer-free prior to the screening visit in this study.

• Subject has current diagnosis of major depressive disorder requiring treatment with atypical antipsychotics, schizophrenia, bipolar disorder, or borderline personality disorder.

• History of gallstones or cholecystectomy.

• Subject has current diagnosis of major depressive disorder requiring treatment with atypical antipsychotics, schizophrenia, bipolar disorder, or borderline personality disorder. • The use of CGRP antagonists (biologic [e.g. Aimovig™, Emgality® and Ajovy™, VyeptiTM] or small molecule [ e.g. Ubrelvy™ {ubrogepant]]) other than rimegepant is prohibited during the study.

• Concomitant use of atypical antipsychotics such as Ability (aripiprazole), Zyprexa (olanzapine), Seroquel (quetiapine), Geodon (ziprasidone), or Risperdal (risperidone).

• Depakote/Depakene (divalproex/valproic acid/valproate) is prohibited during the study.

• Concomitant use of LAMICTAL (lamotrigine) is prohibited during the study.

• Concomitant use of Modafinil (PROVIGIL®) is prohibited during the study.

• Exclusionary screening lab test findings: o Serum bilirubin (Total, Direct or Indirect) > 1 x ULN (Only abnormal values of between 1-1 ,5x ULN may be repeated once for assessment of eligibility prior to randomization) o AST or ALT > 1 x ULN (Only abnormal values of between 1 -1 ,5x ULN may be repeated once for assessment of eligibility prior to randomization) o Neutrophil count < 1000/pL (or equivalent) o HbA1c > 6.5%

Administration of Interventions

• Experimental: Rimegepant

Participants receive a rimegepant 75 mg tablet orally every other day for 16 weeks.

Intervention: Drug: Rimegepant

• Placebo Comparator: Placebo

Participants receive a placebo tablet matching rimegepant orally every other day for 16 weeks.

Intervention: Drug: Placebo

Example 2 - Oral Pharmaceutical Compositions for Treating Psoriasis

The CGRP receptor antagonists of one or more of a compound according to Formula I, Formula II, and/or Formula III can be formulated as an oral treatment for psoriasis. Such oral treatments are expected to be useful for the treatment, prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis.

The oral pharmaceutical compositions of one or more of a compound according to Formula I, Formula II, and/or Formula III can be prepared in any appropriate oral dosage form, including but not limited to as pills, tablets including oral disintegrating tablets, or capsules. The pharmaceutical compositions may be formulated with one or more pharmaceutically acceptable excipients as disclosed herein or as known to a person of skill in the art.

In a study, the oral pharmaceutical compositions of one or more of a compound according to Formula I, Formula II, and/or Formula III can be administered to patients having psoriasis using a dosing regimen described herein. The patients can be monitored for improvement of symptoms associated with psoriasis. In some patients, treatment may continue beyond the treatment of psoriasis to prophylactically treat, prevent, and/or prevent the risk of symptom recurrence. Subgroups of patients having a history of psoriasis and symptom flares but no current or currently limited symptoms can be treated prophylactically with the expectation that further psoriasis symptom flares can be reduced or avoided. As described herein, a treatment dose may differ in the amount of one or more of a compound according to Formula I, Formula II, and/or Formula III administered compared to a preventative dose, where the amount of one or more of Formula I, Formula II, and/or Formula III administered in the preventative dose may be, but is not necessarily, lower. The dosage amounts and particular dosage regimen applied to each patient can be decided upon by a medical professional using sound judgement according to the disclosure herein.

It is expected that such oral therapies can treat psoriasis with varying degrees of success in different patients having different types of psoriasis and psoriasis symptoms, and that, guided by these developed therapies, physicians can identify an effective course of psoriasis treatment using the compounds, compositions, and methods of the present disclosure.

Example 3 - Topical Pharmaceutical Compositions for Treating Psoriasis

The CGRP receptor antagonists of one or more of a compound according to Formula I, Formula II, and/or Formula III can be formulated as a topical treatment for psoriasis. Such topical treatments are expected to be useful for the treatment, prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis.

The topical pharmaceutical compositions of one or more of a compound according to Formula I, Formula II, and/or Formula III can be prepared in any appropriate dosage form, including but not limited to as lotions, creams, ointments, foams, patches, pastes, gels, suspensions, and solutions. The pharmaceutical compositions may be formulated with one or more pharmaceutically acceptable excipients as disclosed herein or as known to a person of skill in the art.

In a study, the topical pharmaceutical compositions of one or more of a compound according to Formula I, Formula II, and/or Formula III can be administered to patients having psoriasis using a dosing regimen described herein. The patients can be monitored for improvement of symptoms associated with psoriasis. In some patients, treatment may continue beyond the treatment of psoriasis to prophylactically treat, prevent, and/or prevent the risk of symptom recurrence. Subgroups of patients having a history of psoriasis and symptom flares but no current or currently limited symptoms can be treated prophylactically with the expectation that further psoriasis symptom flares can be reduced or avoided. As described herein, a treatment dose may differ in the amount of one or more of a compound according to Formula I, Formula II, and/or Formula III administered compared to a preventative dose, where the amount of one or more of a compound according to Formula I, Formula II, and/or Formula III administered in the preventative dose may be, but is not necessarily, lower. The dosage amounts and particular dosage regimen applied to each patient can be decided upon by a medical professional using sound judgement according to the disclosure herein.

In some patients, topical pharmaceutical compositions can be applied directly onto, or adjacent to psoriatic lesions for treatment of active psoriasis symptoms having a visible and active lesion on the skin. In some patients, topical pharmaceutical compositions can be applied as a preventative to regions of the skin having a prior psoriatic lesion or a region of the skin at risk for a psoriatic lesion. In some patients, topical pharmaceutical compositions can be applied on or adjacent to a joint for treatment of psoriatic arthritis or related indications.

It is expected that such topical therapies can treat psoriasis with varying degrees of success in different patients having different types of psoriasis and psoriasis symptoms, and that, guided by these developed therapies, physicians can identify an effective course of psoriasis treatment using the compounds, compositions, and methods of the present disclosure.

Example 4 - Injectable Pharmaceutical Compositions for Treating Psoriasis The CGRP receptor antagonists of one or more of a compound according to Formula I, Formula II, and/or Formula III can be formulated as an injectable treatment for psoriasis. Such injectable treatments are expected to be useful for the treatment, prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis.

The injectable pharmaceutical compositions of one or more of a compound according to Formula I, Formula II, and/or Formula III can be prepared in any appropriate dosage form, including but not limited to as sterile solutions, suspensions, dispersions, or emulsions. The pharmaceutical compositions may be formulated with one or more pharmaceutically acceptable excipients as disclosed herein or as known to a person of skill in the art.

In a study, the injectable pharmaceutical compositions of one or more of a compound according to Formula I, Formula II, and/or Formula III can be administered to patients having psoriasis using a dosing regimen described herein. The patients can be monitored for improvement of symptoms associated with psoriasis. In some patients, treatment may continue beyond the treatment of psoriasis to prophylactically treat, prevent, and/or prevent the risk of symptom recurrence. Subgroups of patients having a history of psoriasis and symptom flares but no current or currently limited symptoms can be treated prophylactically with the expectation that further psoriasis symptom flares can be reduced or avoided. As described herein, a treatment dose may differ in the amount of one or more of a compound according to Formula I, Formula II, and/or Formula III administered compared to a preventative dose, where the amount of one or more of a compound according to Formula I, Formula II, and/or Formula III administered in the preventative dose may be, but is not necessarily, lower. The dosage amounts and particular dosage regimen applied to each patient can be decided upon by a medical professional using sound judgement according to the disclosure herein.

In some patients, injectable pharmaceutical compositions can be injected intravenously, intramuscularly, subcutaneously, or via any other appropriate route for a systemic treatment of psoriasis. In some patients, injectable pharmaceutical compositions can be injected locally at or adjacent to a psoriatic lesion or region at risk for development of a psoriatic lesion.

It is expected that such injectable therapies can treat psoriasis with varying degrees of success in different patients having different types of psoriasis and psoriasis symptoms, and that, guided by these developed therapies, physicians can identify an effective course of psoriasis treatment using the compounds, compositions, and methods of the present disclosure.

Example 5 - Intranasal Pharmaceutical Compositions for Treating Psoriasis

The CGRP receptor antagonists of one or more of a compound according to Formula I, Formula II, and/or Formula III can be formulated as an intranasal treatment for psoriasis. Intranasal pharmaceutical compositions are described generally in WO 2021/112707A1 published June 24, 2021 , which is incorporated by reference in its entirety herein. Such intranasal treatments are expected to be useful for the treatment, prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis.

The intranasal pharmaceutical compositions of one or more of a compound according to Formula I, Formula II, and/or Formula III can be prepared in any appropriate dosage form, including but not limited to as sterile solutions, saline solutions, isotonic solutions, buffered solutions, suspensions, dispersions, and emulsions. The pharmaceutical compositions may be formulated with one or more pharmaceutically acceptable excipients as disclosed herein or as known to a person of skill in the art.

In a study, the intranasal pharmaceutical compositions of one or more of a compound according to Formula I, Formula II, and/or Formula III can be administered to patients having psoriasis using a dosing regimen described herein. The patients can be monitored for improvement of symptoms associated with psoriasis. In some patients, treatment may continue beyond the treatment of psoriasis to prophylactically treat, prevent, and/or prevent the risk of symptom recurrence. Subgroups of patients having a history of psoriasis and symptom flares but no current or currently limited symptoms can be treated prophylactically with the expectation that further psoriasis symptom flares can be reduced or avoided. As described herein, a treatment dose may differ in the amount of one or more of a compound according to Formula I, Formula II, and/or Formula III administered compared to a preventative dose, where the amount of one or more of a compound according to Formula I, Formula II, and/or Formula III administered in the preventative dose may be, but is not necessarily, lower. The dosage amounts and particular dosage regimen applied to each patient can be decided upon by a medical professional using sound judgement according to the disclosure herein. It is expected that such intranasal therapies can treat psoriasis with varying degrees of success in different patients having different types of psoriasis and psoriasis symptoms, and that, guided by these developed therapies, physicians can identify an effective course of psoriasis treatment using the compounds, compositions, and methods of the present disclosure.

Example 6 - Combination Treatments for Treating Psoriasis

Some patients having active psoriasis symptoms can be treated in a study with one or more of an oral, topical, intranasal and/or injectable pharmaceutical composition according to Examples 2 - 5 simultaneously, alternatively, or initially via one route initially in a first treatment phase followed by a second route in a second treatment phase.

In a first subset of patients, a local topical treatment can be applied in a first treatment phase followed by an oral, intranasal, or injectable systemic treatment in a second treatment phase following the first. The local topical treatment, i.e. the first treatment phase, can be applied for a set period of time or until a change or improvement of symptoms is observed, after which a second treatment phase can be applied. The systemic oral, intranasal, or injectable treatment, i.e. the second treatment phase, would then be applied either i) until symptoms have been reduced or cleared and/or ii) for a prolonged period for prophylaxis, prevention, and reduction in the risk that the patient has further symptom flares.

In a second subset of patients, systemic oral, intranasal, or injectable treatment can be applied in a first treatment phase followed by a topical local treatment in a second treatment phase following the first. The systemic oral, intranasal, or injectable, i.e. the first treatment phase, can be applied for a set period of time or until a change or improvement of symptoms is observed, after which a second treatment phase can be applied. The local topical treatment, i.e. the second treatment phase, would then be applied either i) until symptoms have been reduced or cleared and/or ii) for a prolonged period for prophylaxis, prevention, and reduction in the risk that the patient has further symptom flares. In a third subset of patients, systemic oral, intranasal, or injectable treatment can be applied concurrently with a topical local treatment. Within the subset, after a set period of time or after improvement of symptoms is observed, some patients can discontinue the local topical treatment and continue receiving the systemic oral, intranasal, or injectable treatment either i) until symptoms have been reduced or cleared and/or ii) for a prolonged period for prophylaxis, prevention, and reduction in the risk that the patient has further symptom flares. For other patients within the subset, after a set period of time or after improvement of symptoms is observed, some patients can discontinue the oral, intranasal, or injectable systemic treatment and continue receiving the local topical treatment either i) until symptoms have been reduced or cleared and/or ii) for a prolonged period for prophylaxis, prevention, and reduction in the risk that the patient has further symptom flares.

It is expected that such combination therapies can treat psoriasis with varying degrees of success in different patients having different types of psoriasis and psoriasis symptoms, and that, guided by these developed therapies, physicians can identify an effective course of psoriasis treatment using the compounds, compositions, and methods of the present disclosure.

Incorporation by Reference

The entire disclosure of each of the patent documents, including certificates of correction, patent application documents, scientific articles, governmental reports, websites, and other references referred to herein is incorporated by reference herein in its entirety for all purposes. In case of a conflict in terminology, the present specification controls.

Equivalents

The invention can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are to be considered in all respects illustrative rather than limiting on the invention described herein. In the various embodiments of the present invention, where the term comprises is used with respect to the recited components or methods, it is also contemplated that the invention consists essentially of, or consists of, the recited components or methods. Furthermore, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

In the specification, the singular forms also include the plural forms, unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the case of conflict, the present specification will control.

All percentages and ratios used herein, unless otherwise indicated, are by weight.

It is recognized the mass of an object is often referred to as its weight in everyday usage and for most common scientific purposes, but that mass technically refers to the amount of matter of an object, whereas weight refers to the force experienced by an object due to gravity. Also, in common usage the “weight” (mass) of an object is what one determines when one “weighs” (masses) an object on a scale or balance.

Claims

What is claimed is:

1 . A method of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, the method comprising administering to a subject in need thereof a CGRP receptor antagonist according to Formula (I):

where:

R¹ is hydrogen, cyano, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl;

R³ is hydrogen, halo, cyano, alkyl, haloalky I , alkoxy, or haloalkoxy;

R⁴ is hydrogen, halo, cyano, alkyl, haloalky I , alkoxy, or haloalkoxy;

X is 0, CH2, or NH; and

Y is a bond, 0, CH2, or NH; or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 where:

R¹ is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl; R² is piperidinyl substituted with 1 substituent selected from the group consisting of

R³ is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

R⁴ is hydrogen, halo, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

R¹⁰ is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; R¹¹ is hydrogen, hydroxy, alkoxy, haloalkoxy, azido, amino, alkylamino, or dialkylamino; or

R¹⁰ and R¹¹ taken together is oxo; provided that at least one of R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, or R¹¹ is not hydrogen; Ar¹ is phenyl substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalky I , alkoxy, haloalkoxy, and alky ISO2;

X is 0, CH2, or NH; and

Y is a bond, O, CH2, or NH; or a pharmaceutically acceptable salt thereof. 3. The method of claim 1 with the designated stereochemistry:

4. The method of claim 3 where R¹ is hydrogen, halo, cyano, amino, alkylamino, or dialkylamino;

R² is piperidinyl substituted with 1 substituent selected from the group consisting of

R³ is hydrogen or halo;

R⁴ is hydrogen or halo;

R⁵ is hydrogen or hydroxy;

R⁶ is hydrogen;

R⁷ is hydrogen;

R⁸ is hydrogen;

R⁹ is hydrogen or hydroxy;

R¹⁰ is hydrogen, hydroxy, azido, amino, alkylamino, or dialkylamino;

R¹¹ is hydrogen; or R¹⁰ and R¹¹ taken together is oxo; provided that at least one of R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, or R¹¹ is not hydrogen;

Ar¹ is phenyl substituted with 0-2 halo substituents;

X is O, CH2, or NH; and Y is O; or a pharmaceutically acceptable salt thereof. The method of claim 4 where

R¹ is hydrogen;

R⁵ is hydrogen or hydroxy;

R⁶ is hydrogen;

R⁷ is hydrogen; R⁸ is hydrogen;

R⁹ is hydrogen or hydroxy;

R¹⁰ is hydroxy, azido, or amino;

Ar¹ is phenyl or difluorophenyl;

X is 0, CH2, or NH; and

Y is O; or a pharmaceutically acceptable salt thereof.

6. The method of claim 1 where R¹ is hydrogen, cyano, halo, alkyl, haloalky I , alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl.

7. The method of claim 1 where R² is N-piperidinyl and is 4-substituted.

8. The method of claim 7 where the substituent is:

9. The method of claim 1 where:

R⁵ is hydrogen, R⁶ is hydrogen, R⁷ is hydrogen, R⁸ is hydrogen, R⁹ is hydrogen, R¹⁰ is hydroxy, azido, or amino, and R¹¹ is hydrogen; or where R⁵ is hydrogen, R⁶ is hydrogen, R⁷ is hydrogen, R⁸ is hydrogen, R⁹ is hydrogen or hydroxy, and R¹⁰ and R¹¹ taken together is oxo; or where R⁵ is hydrogen, R⁶ is hydrogen, R⁷ is hydrogen, R⁸ is hydrogen, R⁹ is hydroxy, R¹⁰ is hydrogen or hydroxy, and R¹¹ is hydrogen; or where R⁵ is hydroxy, R⁶ is hydrogen, R⁷ is hydrogen, R⁸ is hydrogen, R⁹ is hydrogen,

R¹⁰ is hydrogen, and R¹¹ is hydrogen.

10. The method of claim 1 where Ar¹ is phenyl substituted with 2 halo substituents.

11 . The method of claim 10 where Ar¹ is 2,3-difluorophenyl.

12. The method of claim 1 where X is O.

13. The method of claim 1 , wherein the CGRP antagonist is selected from the group consisting of: (6R,9R)-6-(2,3-Difluorophenyl)-6-hydroxy-5-oxo-6,7,8,9-tetrahydro-5H-cycl- ohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1 -yl)piperidine-1- carboxylate;

(5S,6R,9R)-6-(2,3-difluorophenyl)-5-hydroxy-6,7,8,9-tetrahydro-5H-cycl- ohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1 -yl)piperidine-1- carboxylate;

(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloh- epta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1-yl)piperidine-1 - carboxylate; (6S,9R)-6-(2,3-difluorophenyl)-6-hydroxy-6,7,8,9-tetrahydro-5H-cyclohe- pta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1-yl)piperidine-1- carboxylate;

(6S,9R,E)-6-(2,3-difluorophenyl)-5-(hydroxyimino)-6,7,8,9-tetrahydro-5- H- cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-1 -y l)piperidine- 1 -carboxylate;

(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloh- epta[b]pyridin-9-yl 2'-oxo-1 , 1 ',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridine]-5- yl- carbamate; tert-butyl(5S,6S,9R)-9-amino-6-(2,3-difluorophenyl)-6,7,8,9-tet- rahydro-5H- cyclohepta[b]pyridin-5-ylcarbamate; tert-butyl (5S,6S,9S)-6-(2,3-difluorophenyl)-9-(2- oxo-2-(4-(2-oxo-2,3-dihydro-1 H-imi- dazo[4,5-b]pyridin-1 -y l)piperid in-1 -yl)ethyl)-6, 7,8,9- tetrahydro-5H-cycloh- epta[b]pyridin-5-yl-carbamate; tert-butyl (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(2-oxo-2-(4-(2-oxo-2,3-dihydro-1 H- imi- dazo[4,5-b]pyridin-1-yl)piperidin-1 -yl)ethyl)-6,7,8,9-tetrahydro-5H-cycloh- epta[b]pyridin-5-ylcarbamate; and 1 -(1 -(2-((5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H- cyclohepta[b]pyridin-9-yl)acetyl)piperidin-4-yl)-1 H-imidazo[4,5-b]pyridin-2(3H)-one; or a pharmaceutically acceptable salt thereof.

14. A method of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, the method comprising administering to a subject in need thereof a CGRP receptor antagonist, wherein CGRP receptor antagonist is the compound (5S,6S,9R)-5-amino-6- (2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-9-yl-4-(2-oxo-2,3- dihydro-1 H-imidazo[4,5-b]pyridine-1 -yl)piperidine-1 -carboxylate, which has the following structure:

or a pharmaceutically acceptable salt thereof.

15. The method of claim 14, wherein the pharmaceutically acceptable salt thereof isa hemisulfate salt.

16. The method of claim 15, wherein the hemisulfate salt is a sesquihydrate.

17. The method of any one of claims 1 - 16, wherein the CGRP antagonist is administered in a unit dosage selected from the group consisting of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg

18. The method of any one of claims 1 - 16, wherein the CGRP antagonist is administered in a dosage of 0.01 -100 mg/kg body weight, or from .05 - 50 mg/kg body weight, or from 0.1 - 10 mg/kg body weight, or from 0.15 - 5 mg/kg body weight, or from 0.2 - 2 mg/kg body weight, or from 0.5 - 1 .5 mg/kg body weight, or from 1 - 1.5 mg/kg body weight.

19. The method of any one of claims 1 - 16, wherein the CGRP antagonist is administered in an amount corresponding to an area under curve (AUC) within about 80 - 125 % of about 25, 50, 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000, 1300, 1600, 1900, 2500, 3500, 5000, 7500, 10,000, 15,000, 20,000, 30,000, 50,000, or 100,000 hr*ng/mL.

20. The method of any one of claims 1 - 16, wherein the CGRP antagonist is administered in an amount corresponding to a Cmax value within about 80 - 125 % of about 1 , 2, 3, 4, 5, 8, 10, 20, 35, 50, 80,100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000, 1300, 1600, 1900, 2500, 3500, 5000, 7500, 10,000, 15,000, 20,000, 30,000, 50,000, and/or 100,000 ng/mL.

21 . The method of any one of claims 19 and 20, wherein the CGRP antagonist is administered in an amount corresponding to a Cmax/AUC ratio within about 80 - 125 % of about 0.01 , 0.03, 0.05, 0.08, 0.1 , 0.13, 0.17, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, and 0.9

22. The method of any one of claims 1 - 21 , wherein the CGRP antagonist is administered at an interval of daily, twice daily, once every other day, once every two days, once every three days, once every four days, once every five days, once every six days, or once weekly.

23. The method of any one of claims 1 - 22, wherein the CGRP antagonist is administered by a route selected from oral, intrabuccal, intranasal, inhalation, parenteral, intravenous, topical, injectable and/or transdermal.

24. The method of any one of claims 1 - 16, wherein the CGRP antagonist is administered in a unit dosage of 75 mg.

25. The method of claim 24, wherein the CGRP antagonist is administered orally.

26. A method of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, the method comprising administering to a subject in need thereof a CGRP receptor antagonist according to Formula (II):

or a pharmaceutically acceptable salt thereof, wherein

V is — N(R¹)(R²) or OR⁴;

R⁴ is H, C_1-6alkyl, C_1-4haloalkyl or (C_1-4alkylene)o-iR⁴'

R¹ and R² are each independently L¹, wherein L¹ is selected from the group consisting of H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, — C_1-6alkylene-amino (C_1-3alkyl)2, C3- cycloalkyl, phenyl, azetidinyl, adamantyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino and dioxolmnyl; and

R¹ and R² are each optionally and independently substituted with 1 or 2 of the same or different substituents selected from the group consisting of halo, cyano, C1- 4alkyl, C_1-4haloalkyl, C_1-4alkoxy, hydroxy, amino, C3-7cycloalkyl, C_1-3alkylamino, C1- 4dialkylamino, (C_1-3alkyl)o-2ureido, phenyl and benzyl;

R¹ and R² together with the nitrogen to which they are attached form X, wherein X is azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolizyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, piperazinyl, piperidinyl, morpholino or thiomorpholino; wherein X is optionally substituted with Y, wherein Y is dioxolanyl, C_{1 -9}alkyl, C2- galkenyl, C2-9alkynyl, C_1-4alkylamino, C_1-4dialkylamino, C_1-4alkoxy, C3-7cycloalkyl, phenyl, azetidinyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, imidazolinyl, imidazolidinyl, imidazolidinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, pyridyl, pyrimidinyl, dihaydrobenzimidazolonyl, piperazinyl, piperidinyl, morpholino, benzothiazolyl, benzisothiazolyl or thiomorpholino; and wherein X and Y are optionally interrupted with Z, wherein Z is — NHC(O)O — , — NHC(O)NH— , NC(Q)NH₂,— NH— , — C_1-3alkylene— , C_1-3alkenylene-NHC(O)O— Cisalkylene-; and optionally and independently substituted with 1 or 2 of the same or different substituents selected from the group consisting of C_1-4alkyl, amino, C_1-3alkylamino, — Ci- ₃alkylene-amiao(C_1-3alkyl)2, (C_1-3alkyl)o-2ureido, phenyl and benzyl;

Q is Q' or Q"; wherein

Q' is (S^y)sR³; and

U is CH₂ or NH; provided that if Q is Q", then U is CH₂;

R³ is R^3a or R^3b wherein R^3a is

(iii) C_3-7cycloalkyl;

(v) Ci-salkyl, C_2-7alkenyl, — C(O)R³', CHC(O)O— R³', CH(CH₃)C(O)O— R³',— C(O)O — R³'or C_2-7alkynyl; and wherein R^3a is optionally substituted with 1 to 3 of the same or different substituents selected from the group consisting of benzyl, phenyl, — O-phenyl, — O — Ci- salkylenephenyl, — C_1-3alkylene-O — C(O)-phenyl, cyano, amino, nitro, halo, C_1-6alkyl, Ci- smono-bi-tri-haloalkyl, C_1-3mono-bi-tri-haloalkyloxy, (C_1-3alkyl)i-2amine, — OR³', — C(O)R³', — C(O)O— R³', — O— C(O)R³', — N(R³')₂, — C(O)N(R³')₂, — N(R³')C(O)(R³')₂, — N(R³')C(O)N(R³')2, — N(R³')C(O)OR³', — O— C(O)N(R³')₂, — N(R³')SO₂R³', — SO₂N(R³')₂ and — SO2R³'; R³'is H or — C_1-6alky I ; provided that if R^3a is , — C(O)R³', CHC(O)O— R³', CH(CH₃)C(O)O— R³'or — C(O)O— R³', then said — C(O)R³', CHC(O)O— R³', CH(CH₃)C(O)O— R³'or — C(O)O— R³'are unsubstituted;

R^3b is R^3a but is not phenyl, 1 -naphthyl, 2-naphthyl, 1 ,2, 3, 4-tetrahydro-1 -naphthyl, 1 H-indol-3-yl, 1 -methyl-1 H-indol-3-yl, 1 -formyl-1 H-indol-3-yi, 1 -(1 ,1- dirnethylethoxycarbonyl)- 1 H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3- thienyl, thiazolyl, 1 H-indazol-3-yl, 1 -methyl-1 H-indazol-3-yl, benzo[b]fur-3-yl, benzo[b]thien-3-yl, pyridinyl, quinolinyl or isoquinolinyl; optionally substituted in the carbon skeleton with mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by branched or unbranched alkyl groups, Cs-s-cycloalkyl groups, phenylalkyl groups, alkenyl, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycoarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, dialkylaminoalkoxy, hydroxy, nitro, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, methylsulphonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups; wherein said substituents may be the same or different and the above-mentioned benzoyl, benzoylaznino- and benzoylmnethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom, or by an alkyl, trifluoromethyl, amino or acetylamino group;

D is 0, NCN or NSO₂C_1-3alkyl;

A is CH; m and n are each 1 ;

E is N, CE or C; p is 1 ;

G, J and E together form A^x;

R³ is R^3b

27. The method of claim 26, wherein Q is Q¹ and R³ is R^3b.

28. The method of claim 26, wherein Q is Q".

29. The method of claim 28, wherein Q" is NH(S^y)sR³.

30. The method of claim 28, wherein Q" is NHC(O)(S^y)sR³.

31. The method of claim 28, wherein Q" is NHC(O)O(S^y)sR³.

32. The method of claim 28, wherein Q" is NHC(O)NH(S^y)sR³.

33. The method of claim 28, wherein Q" is O(S^y)sR³.

34. The method of claim 28, wherein Q" is (S^y)sNHR³.

35. The method of claim 28, wherein Q" is (S^y)sNHC(O)R³.

36. The method of claim 28, wherein Q" is (S^y)sNHC(O)OR³.

37. The method of claim 28, wherein Q" is (S^y)sNHC(O)NHR³.

38. The method of claim 28, wherein Q" is (S^y)sOR³.

39. The method of claim 26, wherein V is OR⁴.

40. The method of claim 26, wherein V is -N(R¹)(R²).

41. The method of claim 26, wherein R⁴ is H, C_1-6alkyl or (C_1-4alkylene)o-iR⁴' and R⁴' is C3-7cycloalkyl.

42. The method of claim 26, wherein V is -N(R¹)(R²) and R¹ and R² are each independently L¹, wherein L¹ is selected from the group consisting of H, C_1-6alkyl, -Ci- 6alkylene-amino(C_1-3alkyl)2, C_3-7cycloalkyl, phenyl, azetidinyl, adamantyl, tetrahydrofuranyl, furanyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, isoxazolyl, thiazoiyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, piperidinyl. , piperazinyl, morpholino, thiomorpholino and dioxolanyl; or R¹ and R² together with the nitrogen to which they are attached form X, wherein X is azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, piperazinyl, piperidinyl, morpholino or thiomorpholino; wherein x is substituted with Y, wherein Y is dioxolanyl, C_1-4alkyl, C_1-4alkoxy, C3-7cycloalkyl, phenyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, irnidazolinyl, imidazolidinyl, imidazolidinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, azepinyl, diazepinyl, pyridyl, pyrimidinyl, dihydrobenzimidazolonyl, piperazinyl, piperidinyl, morpholino, benzothiazolyl, benzisothiazolyl or thiomorpholino; and wherein X and Y optionally share one carbon atom and together form a spirocyclic moiety.

43. The method of claim 26, wherein V is -N(R¹)(R²) and R¹ and R² are each independently L¹, wherein L¹ is selected from the group consisting of H, C_1-6alkyl, or R¹ and R² together with the nitrogen to which they are attached form X, wherein X is piperidinyl or morpholino; wherein X is substituted with Y, wherein Y is dioxolanyl, Ci- 4alkyl or piperidinyl; and wherein X and Y optionally share one carbon atom and together form a spirocydic moiety.

44. The method of claim 26, wherein V is -N(R¹)(R²) and wherein R¹ and R² are each independently L¹, wherein L¹ is selected from the group consisting of H, C_1-6alkyl.

45. The method of claim 26, wherein V is -N(R¹)(R⁾ and wherein R¹ and R² together with the nitrogen to which they are attached form X, wherein X is piperidinyl or morpholino; wherein X is substituted with Y, wherein Y is dioxolanyl, C_1-4alkyl or piperidinyl; and wherein X and Y optionally share one carton atom and together form a spirocyclic moiety.

46. The method of claim 26, wherein V is -N(R¹)(R²) and wherein R¹ and R² together with the nitrogen to which they are attached form X, wherein X is piperidinyl; wherein X is substituted with Y, wherein Y is piperidinyl.

47. The method of claim 26, wherein V is -N(R¹)(R²) and wherein R¹ and R² together with the nitrogen to which they are attached form X, wherein X is morpholino; wherein X is substituted with Y, wherein Y is C_1-4alkyl.

48. The method of claim 26, wherein V is -N(R¹)(R²) and wherein R¹ and R² together with the nitrogen to which they are attached form X, wherein X is piperidinyl; wherein X is substituted with Y, wherein Y is C_1-4alkyl.

49. The method of claim 26, wherein V is -N(R¹)(R²) and wherein R¹ and R² together with the nitrogen to which they are attached form X, wherein X is piperidiny I ; wherein X is substituted with Y, wherein Y is dioxolanyl; and wherein X and Y share one carbon atom and together form a spirocyclic moiety.

50. The method of claim 26, wherein R³ is R^3a and R^3a is substituted or unsubstituted phenyl, hydroxyphenyl, azetidinyl, napthyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynl, dihydroquinolinonyl, hydroquinolinonyl, quinolinyl, dihydroisoquinolinonyl, hydroisoquinolinonyl, isoquinolinyl, diydroquinazolinonyl, hydroquinazolinonyl, quinazolinyl, dihydroquinoxalinonyl, hydroquinoxalinonyl, quinoxalinyl, benzimidazolyl, indazolyl, dihydrobenzimiidazolonyl, hydrobenzimidazolonyl, benzimidazolinyl, dihydro- benzthiazolonyl, hydrobenztblazolonyl, benzthiazolyl, dihydrobenzoxazolyl, benzotriazolyl, dihydrobeuzotbiophenonyl, hydrobeuzothiophenonyl, beuzothienyl, dihydrobenzofuranonyl, hydrobenzofuranonyl, benzofuranyl, benzdioxolanyl, dihydroindolonyl, hydroindolonyl, indolyl, indolizinyl, isoindolyl, indoliny, indazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, purinyl, carbazolyl, pyrimidinyl, piperidinyl, triazolopyrim idinyl, tetrahydropyrazolopyridinyl, piperazinyl or morpholino.

51 . The method of claim 26, wherein R³ is R^3b and R^3b is substituted or unsubstituted dihydrobenzimidazolonyl, hydrobenzimidazolonyl, benzimidazolinyl, dihydro- benzthiazolonyl, hydrobenzthiazolonyl, benzthiazolyl, dihydrobenzothiophenonyl, hydrobenzothiophenonyl, dihydrobeuzofuranonyl, hydrobenzofuranonyl, 1 H-indazol-5-yl, benzdioxalanyl, dihydrobeuzoxazolyl, benzotriazolyl, dihydroindolonyl, hydroindolonyl, indolizinyl, isoindolyl, indolinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, purinyl, carbazolyl, pyrimidinyl, piperidinyl, piperazinyl or morpholino.

52. The method of claim 26, wherein D is O and m and n are each 1 .

53. The method of claim 26, wherein p is 1 ; and G, J and E together form A^x.

54. The method of claim 26 wherein R³ is R^3b and R^3b is:

1 H-lndol-5-yl

H-lndazol-5-yl

H-Benzotriazol-5-yl

,3-Dihydro-indol-2-on-5-yl

H-Benzooxazol-2-on-6-yl

,3-Dihydro-benzoimidazol-2-on-5-yl

-Methyl-1 ,3-dihydro-benzoimidazol-2-on-6-yl

,4-Dihydro-1 H-quinolin-2-on-6-yl

,4-Dihydro-benzo[d][1 ,3]oxazin-2-on-6-yl

,4-Dihydro-1 H-quinazolin-2-on-6-yl

-Methyl-3,4-dihydro-1 H-quinazolin-2-on-6-yl

H-Benzo[1 ,4]oxazin-3-on-7-yl

wherein T^y is H, C_1-4alkyl, F, Cl, Br or nitrile.

55. A method of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising a CGRP receptor antagonist according to Formula (II):

or a pharmaceutically acceptable salt thereof, wherein V is -N(R¹)(R²); R¹ and R² together with the nitrogen to which they are attached form X, wherein X is piperazinyl; wherein X is substituted with Y, wherein Y is piperidinyl;

Q is Q'; wherein Q'is (S^y)sR³; wherein S_y is C-i-alkylene and s is 1 ; U is NH;

R³ is R^3b; wherein R^3b is 3H-Benzooxazol-2-on-6-yl

wherein T^y is H;

D is 0;

A is CH; m and n are each 1 ;

E is N; p is 1 ;

G, J and E together form A^x; A^x is a fused heterocycle having two fused rings with 6 members in each of said rings, said heterocyole containing two nitrogen atoms; and containing 1 carbonyl wherein the carbon atom of said carbonyl is a member of said fused heterocycle.

56. A method of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising a CGRP receptor antagonist according to Formula (II)

or a pharmaceutically acceptable salt thereof wherein

V is -N(R¹)(R²);

R¹ and R² together with the nitrogen to which they are attached form X, wherein X is piperazinyl; wherein X is substituted with Y, wherein Y is piperidinyl;

Q is Q'; wherein Q' is (S^y)sR³; wherein S^y is C-i-alkylene and s is 1 ;

U is NH;

R³ is R^3b wherein R^3b is 1 H-Benzotriazol-5-yl

wherein T^y is H;

D is 0; A is CH; m and n are each 1 ;

E is N; p is 1 ;

G, J and E together form A^x; A^x is a fused heterocycle having two fused rings with 6 members in each of said rings, said heterocycle containing two nitrogen atoms; and containing 1 carbonyl wherein the carbon atom of said carbonyl is a member of said fused heterocycle.

57. A method of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising a CGRP receptor antagonist according to Formula (II)

or a pharmaceutically acceptable salt thereof wherein

V is -N(R¹)(R²);

R¹ and R² together with the nitrogen to which they are attached form X, wherein X is piperazinyl; wherein X is substituted with Y, wherein Y is piperidinyl; and wherein X and Y are optionally and independently substituted with 1 or 2 of the same or different sub stituents selected from the group consisting of C_1-4alkyl;

Q is Q'; wherein Q'is (S^y)_sR³; wherein S_y is C-i-alkylene and s is 1 ;

U is NH;

R³ is R^3b wherein

R^3b is 1 H-lndazol-5-yl

wherein T^y is C_1-4alkyl;

D is 0;

A is CH; m and n are each 1 ;

E is C; p is 1 ;

G, J and E together form A^x;

A^x is a fused hetero cycle having two fused rings with 6 members in each of said rings, said heterocycle containing one nitrogen atom; and containing 1 carbonyl wherein the carbon atom of said carbonyl is a member of said fused heterocycle.

58. A method of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising a CGRP receptor antagonist selected from the group consisting of

( ± )-3-(1 H-lndazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 - carbonyl]-amino}-propionic acid;

(R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [2-

(±)-4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1 -carboxylic acid [2-

[1 , 4']bipiperid iny 1-1 '-y 1-1 -(1 H-indol-5-ylmethyl)-2-oxo-ethyl]-am- ide;

[1 , 4']bipiperid iny 1-1 '-y 1-1 -(1 H-indol-5-ylmethyl)-2-oxo-ethyl]-amide;

[1 , 4']bipiperid iny 1-1 '-y 1-1 -(1 H-indazol-5-ylmethyl)-2-oxo-ethyl]-- amide; ( ± )-4-(2-Oxo-2,3-dihydro-benzoimidazol-1 -y l)-piperid ine-1 -carbox- ylic acid [1 -(1 H- indol-5 -ylmethyl)-2-(4-isobutyl-piperazin-1 -yl)-2-oxo-ethyl]-amide;

( ± )-4-(2-Oxo-2,3-dihydro-benzoimidazol-1 -yl)-piperid ine-1 -carboxylic acid [1 -(1 H- indazol-5-ylmthyl) -2-(4-isobutyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

(±)-4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1 -carboxylic acid [2-(1 ,4- dioxa-8-aza -spiro[4.5]dec-8-yl)-1-(1 H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide;

( ± )-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [2-(1 ,4- dioxa-8-aza -spiro[4.5]dec-8-yl)-1-(1 H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide;

( ± )-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino}-propionic acid methyl ester;

( ± )-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino}-propionic acid;

( ± )-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [1 -(7- methyl-1 H-indazol-5-ylmethyl)-2-oxo-2-piperidin-1 -yl-ethyl]-am- ide;

( ± )-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [1 -1 -(7- methyl-1 H-indazol-5-ylmethyl)-2-(4-methyl-piperazin-1-yl)-2-- oxo-ethyl]-amide;

( ± )-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [1 -1 -(7- methyl-1 H-indazol-5-ylmethyl)-2-oxo-2-pyrrolidin-1 -yl-ethyl]- -amide;

( ± )-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carbo- xylic acid [1 -(7- methyl-1 H-indazol-5-ylmethyl)-2-oxo-2-(4-pyridin-4-yl-pip- erazin-1 -yl)-ethyl]-amide;

( ± )-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [1 -(7- methyl-1 H-indazol-5-ylmethyl)-2-oxo-2-(4-pyridin-2-yl-piperazi- n-1 -yl)-ethyl]-amide;

4-(3-(1 H-lndazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piper- idine-1 - carbonyl]-amino}-propionyl)-piperazine-1 -carboxylic acid benzyl ester; 4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [1 -(1 H-indazol--ylmethyl)-2-oxo-2-piperazin-1 -yl-ethyl]-am ide;

4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid {1 -(1 H-indazol--ylmethyl)-2-[4-(2-methyl-butyl)-piperazin-1 -yl]-2-oxo-et- hyl}-amide;

3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)- - piperidine-1-carbonyl]-amino}-propionic acid cyclohexyl ester;

3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)- - piperidine-1-carbonyl]-amino}-propionic acid 1-benzyl-piperidin-4-yl ester;

3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)- - piperidine-1-carbonyl]-amino}-propionic acid 4-phenyl-cyclohexyl ester;

3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)- - piperidine-1-carbonyl]-amino}-propionic acid (R)-1 -pyridin-4-yl-etyl ester;

(±)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-pipeine-1 -carboxylic acid [2-

( ± )-3-(7-Ethy 1-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-- quinazolin-3- yl)piperidine-1 -carbonyl]-amino}-propionic acid methyl ester

(R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [2-

(R)-4(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [2-

(R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxyli- c acid [2[1 ,4']bipiperidinyl-1 '-yl-2-oxo-1-(2-oxo-2,3-dihydro-1 H-indol-5-y- lmethyl)-ethyl]-amide;

( ± )-4(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [1 -(4- benzyloxy-2-oxo-2H pyridin-1 -ylmethyl)-2-[1 ,4']bipiperidinyl-T-yl-2-oxo-ethyl]-amide; (±)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [2-

(±)-3-(7,7-Dimethyl-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-- {[4-(2-oxo-1 ,4- dihydro-2H -quinazolin-3-yl)-piperidine-1 -carbonyl]-amino}-propionic acid methyl ester;

( ± )-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carbo- xylic acid

[2[1 , 4' bipiperid iny 1-1 '-y 1-1 -(7,7-dimethyl-1 ,4,6,7-tetrahydro-p- yrazolo[4,3-c]pyridin-5- ylmethyl)-2-oxo-ethyl]-amide;

( ± )-4(2Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid

[2[1 , 4']bipiperid iny 1-1 '-y 1-1 -(6methoxy-pyridin-3-ylmethyl)-2-oxo-et- hyl]-amide;

( ± )-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [(1 -(6- benzyloxy-pyridin-3-ylmethyl)-2-[1 , 4' bipiperid iny 1-1 '-yl-2-ox- o-ethyl]-amide;

( ± )-2-(7-Methyl-1 H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1 ,4-dihydro-2- H- quinazolin-3-yl)-piperidin-1 -yl]-butyric acid methyl ester;

( ± )-1 -[1 , 4']B ipi perid iny 1-1 '-yl-2-(7-methyl-1 H-indazol-5-ylmethyl)-4-[- 4-(2-oxo-1 ,4- dihydro-2H -quinazolin-3-yl)-piperidin-1 -yl]butane-1 ,4-dione;

( ± )-1 -(1 ,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-2-(7-methyl-1 H-indazol-5-yl- methyl)-4-[4-

(2-oxo-1 ,4-dihydro -2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1 ,4-dione;

(±)-N,N-Dimethyl-2-(7-methyl-1 H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo-- 1 ,4- dihydro-2H-quinazolin-3-yl)-piperidin-1 -yl]-butyramide;

( ± )-1 -(2,6-Dimethyl-morpholin-4-yl)-2-(7-methyl-1 H-indazol-5-ylmethyl)- -4-[4-(2- oxo-1 ,4-dihydro-2H -quinazolin-3-yl)-piperidin-1 -yl]-butane-1 ,4-dione;

( ± )-2-(7-Methyl-1 H-indazol-5-ylmethyl)-1 -(4-methyl-piperidin-1 -yl)-4-[- 4-(2-oxo-1 ,4- dihydro-2H -quinazolin-3-yl)-piperidin-1 -yl]-butane-1 ,4-dione; ( ± )-2-(7-Methyl1 H-indazol-5-ylmethyl)-1 -morpholin-4-yl-4-[4-(2-oxo-1 ,4- -dihydro- 2H-quinazolin-3-yl) -piperid in-1 -yl]-butane-1 ,4-dione;

( ± )-2-(7-Methyl-1 H-indazol-5-ylmethyl)-4-[4-(2-oxo-1 ,4-dihydro-2H-quin- azolin-3- y l)-piperidi n-1 -y l]-1 -piperid in-1 -yl-butane-1 ,4-dione;

(±)-1 -(1 ,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-2-(1 H-indazol-5-ylmethyl)-4- -[4-(2-oxo- 1 ,4-dihydro-2H -quinazolin-3-yl)-piperidin-1-yl]-butane-1 ,4-dione;

(±)-5-{2-([1 ,4']Bipiperidinyl-1 '-carbonyl)-4-oxo-4-[4-(2-oxo-1 ,4-dihyd- ro-2H- quinazolin-3-yl)-piperidin -1 -yl]-butyl}-indazole-1 -carboxylic acid tert-butyl ester; (±)-2- (7-Methyl-1 H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1 ,4-dihydro-2- H-quinazolin-3-yl)- piperidin-1yl]-N-prop-2-ynyl-butyramide;

3-yl)-piperidin-1-yl]-propyl}-carbamic acid tert-butyl ester;

(L)-1 -[1 , 4'] B ipiperid iny 1-1 '-yl-2-(1 H-indol-5-ylamino)-4-[4-(2-oxo-1 ,4-di- hydro-2H- quinazolin-3-yl) -piperid in-1 -yl]-butane-1 ,4-dione;

(L)-2-(4-Amino-6-methyl-5-nitro-pyrimidin-2-ylamino)-1 -[1 ,4']bipiperidiny- 1-1 '-yl-4-[4- (2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidin-1 -yl]-butane- -1 ,4-dione;

(L)-1 -[1 , 4'] Bipiperidiny 1-1 '-yl-2-((2'-pyridyl)-methyl-amino)-4-]4-(2-oxo- -1 ,4-dihydro- 2H-quinazolin-3-yl)-piperidin-1 -yl]-butane-1 ,4-dione;

(L)-1 -[1 , 4'] Bipiperidiny 1-1 '-yl-2-((5'-indazolyl)-methyl-amino)-4-[4-(2-o- xo-1 ,4-dihydro- 2H-quinazolin-3-yl)-piperidin-1 -yl]-butane-1 ,4-dione;

(L)-1 -[1 , 4'] Bipiperidiny 1-1 '-yl-2-((3'-methyl-phenyll)-methyl-amino)-4-[4- -(2-oxo-1 ,4- dihydro-2H -quinazolin-3-yl)-piperidin-1 -yl]-butane-1 ,4-dione; (L)-1 -[1 , 4'] B ipiperid iny 1-1 '-yl-4-[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-y- l)-piperid in-1 - yl]-2-(pyrim idin -4-ylamino)-butane-1 ,4-dione;

(L)-1 -[1 , 4'] Bipiperidiny 1-1 '-yl-2-(4-hydroxy-cyclohexylamino-4-[4-(2-oxo-- 1 ,4-dihydro- 2H-quinazolin-3-yl)-piperidin-1 -yl]-butane-1 ,4-dione; (L)-1 -[1 , 4'] Bipiperidiny 1-1 '-y l-2-[( 1 H-imidazol-4-ylmethyl)-amino]-4-[4-(- 2-oxo-1 ,4- dihydro-2H -quinazolin-3-yl)piperidin-1 -yl]-butane-1 ,4-dione;

(L)-1 H-Pyrazole-3-carboxylic acid{1-([1 ,4']bipiperidinyl-1 '-carbonyl)-3-oxo-3-[4-(2- oxo-1 ,4-dihydro-2H- -quinazolin-3-yl)-piperidin-1-yl]-propyl}-amide;

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( ± )-1 -[1 , 4']B ipi perid iny 1-1 '-y l-2-( 1 H-indazol-5-ylamino)-4-[4-(2-oxo-1 - , 4-di hydro-2 H- quinazolin-3-yl)-piperidin-1 -yl]-butane-1 ,4-dione; ( ± )-3-(3-Cyano-1 H-indol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3- -yl)- piperidin-1-carbonyl]-amino}-propionic acid methyl ester;

[1 , 4']bipiperid iny 1-1 '-y I -1 -(3-cyano-1 H-indol-5-yl-methyl)-2-oxo-ethyl]-amide;

(±)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [2- [1 , 4']bipiperid iny 1-1 '-y 1-1 (3-cyano-7-methyl-1 H-indol-5-yl-methyl- )-2-oxo-ethyl]-amide;

(±)-3-(7-lsopropyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dibydro-2H-quinaz- olin-3-yl)- piperidin-1-carbonyl]-amino}-propionic acid methyl ester;

[1 , 4']bipiperid iny 1-1 '-y 1-1 (7-isopropyl-1 H-indazol-5-yl-methyl)-2- -oxo-ethyl]-amide; (±)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [2-

[1 ,4']bipiperidinyl-1 '-yl-1 (7-ethyl-1 H-indazol-5-yl-methyl)-2-oxo- -ethyl]-amide; (±)-4- (2,2-Dioxo-1 ,4-dihydro-2H-2.lamda..sup.6-benzo[1 ,2,6]thiadiazin-- 3-yl)-piperidine-1 - carboxylic acid [2-[1 , 4']bipiperid iny 1-1 '-y 1-1 (7-methyl-1 H-indazol-5-yl-methyl)-2-oxo-eth- yl]-amide; (±)-4-(2,2-Dioxo-1 ,4-dihydro-2H-2.lamda..sup.6-benzo[1 ,2,6]t- hiadiazin-3-yl)- piperid in-1 -carboxylic acid [2-[1 , 4'bipiperid iny 1-1 '-y 1-1 (7-ethyl-3-methyl-1 H-indazol-5-yl- methyl)-2-- oxo-ethyl]-amide;

( ± )-2-[4-(6-Cyano-2-oxo-1 ,4-dihydro-2H-qinazolin-3-yl)piperidine-1 -car- bonyl]- amino]-3-(7-methyl-1 H-indazol-5-yl)-propionic acid methyl ester;

( ± )-4-(6-Cyano-2-oxo-1 ,4-dihydro-2H-qinazolin-3-yl)-piperidine-1 -carbo- xylic acid{2-[1 ,4'bipiperidinyl-1 '-yl-1 -(7-methyl-1 H-indazol-5-yl methyl)-2-oxo-ethyl}-amide;

(±)-4-(2-Oxo-1 ,2,4,5-tetrahydro-benzo[d][1 ,3]diazepin-3-yl-1 -carboxyli- c acid{2- [1 , 4']bipiperid iny 1-1 '-yl-1 -(7-methyl-1 H-indazol-5-yl methyl)-2-oxo-ethyl}-amide;

( ± )-4-(6-Hydroxy-2-oxo-1 ,4-dihydro-2H-qinazolin-3-yl)-piperidine-1 -car- boxylic acid{2-[1 , 4']bipiperid iny 1-1 '-yl-1 -(7-methyl-1 H-indazol-5-yl methyl)-2-oxo-ethyl}-amide;

( ± )-4-(8-Methoxy-2-oxo-1 ,4-dihydro-2H-qinazolin-3-yl)-piperidine-1 -car- boxylic acid{2-[1 , 4']bipiperid iny 1-1 '-yl-1 -(7-methyl-1 H-indazol-5-yl methyl)-2-oxo-ethyl}-amide;

( ± )-4(8-Chloro-2-oxo-1 ,4-dihydro-2H-qinazolin-3-yl)-piperidine-1 -carbo- xylic acid{2- [1 , 4']bipiperid iny 1-1 '-yl-1 -(7-methyl-1 H-indazol-5-yl methyl)-2-oxo-ethyl}-amide;

( ± )-N-(3-(7-Ethyl-1 H-indazol-5-yl)-1 -(6,7-dihydro-1 H-pyrazolo[4,3-c]py- ridin-5(4H)- yl)-1 -oxopropan-2-yl)-4-(1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)- piperidine-1 - carboxamide;

( ± )-Methyl 2-(4-(8-fluoro-1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1 - carboxam- ide)-3-(7-methyl-1 H-indazol-5-yl)propanoate;

( ± )-4-(8-Fluoro-1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-methyl-1 - H-indazol-5- yl)-1 -oxo-1 -(4-(piperidi n-1 -y l)piperid in-1 -yl)propan-2-yl)piperidine-1 -carboxamide;

( ± )-4-(8-Fluoro-1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(1 -(- 4-(4- fluorophenyl)piperazin-1 -yl)-3-(7-methy-1 H-indazol-5-yl)-1 -oxopropan-- 2-y l)piperid ine-1 - carboxamide;

( ± )-4-(8-Fluoro-1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(1 -(4-(2-fluor- ophenyl)piperazin-1 -yl)-3-(7-methyl-1 H-indazol-5-yl)-1 -oxopropan-2-yl)pipe- rid ine-1 - carboxamide;

( ± )-4-(8-Fluoro-1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)-N-(3-(7-methyl-1 - H-indazol-5- yl)-1 -oxo-1 -(4-o-tolylpiperazin-1-yl)propan-2-yl)piperidine-1 -- carboxamide; ( ± )-Methyl 2-(4-(8-fluoro-1 ,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1 - carboxam- ide)-3-(7-ethyl -3-methyl-1 H-indazol-5-yl)propanoate;

( ± )-N-(3-(7-Ethyl-3-methyl-1 H-indazol-5-yl)-1 -oxo-1 -(4-(piperidin-1 -y l)piperidin-1 - yl)propan-2-yl)-4-(8-fluoro-1 ,2-dihydro-2-oxoquinazolin-3(4H)- -y l)piperid ine-1 - carboxamide;

(±)-4-(8-Fluoro-1 ,2-dihydro-2,4-dioxoquinazolin-3(4H)-yl)-N-(3-(7-meth- yl-1 H- indazol-5-yl)-1 -oxo-1 -(4-(piperid in-1 -y l)piperid in-1 -yl)propan-2-yl)- piperid ine-1 - carboxamide;

(R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid[2-(4- cyclohexyl-piperazin-1 -yl)-2-oxo-1 -(2-oxo-2,3-dihydro-benzooxaz- ol-6-ylmethyl)-ethyl]- amide;

(R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid[2-(4- isopropyl-piperazin-1 -yl)-2-oxo-1 -(2-oxo-2,3-dihydro-benzooxazo- l-6-y Im ethy l)-ethy I]- amide;

(R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid[2-

[1 , 4']bipiperid iny 1-1 '-yl-1 -(4-chloro-2-oxo-2,3-dihydro-benzooxazo- l-6-ylmethyl)-2-oxo- ethyl]-amide; (R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid[2-

(R)-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid[2-

( ± )-N-(1 -Benzyl-2-hydroxy-ethyl)-2-(7-methyl-1 H-indazol-5-ylmethyl)-4-- oxo-4-[4-(2- oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidin-1 -yl]-butyramide- ;

( ± )-1 -[1 , 4']B ipi perid iny 1-1 '-yl-4-[4-(8-fluoro-2-oxo-1 ,4-dihydro-2H-qu- inazolin-3-yl)- piperid in-1 -yl]-2-(7-methyl-1 H-indazol-5-ylmethyl)-butane-1 - ,4-dione;

( ± )1 -(4-Cyclohexyl-piperazin-1 -yl)-2-(2-oxo-2,3-dihydro-benzo- oxazol-6-ylmethyl)-

4-[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidin-1- -yl]-butane-1 ,4-dione;

( ± )-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)piperidine-1 -carboxylic acid[2-(4- cyclohexyl -piperazin-1 -yl)-1 -(7-methyl-1 H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide;

( ± )-4-(2-Oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid[2-[4-(4- fluoro-phenyl)-piperazin-1 -y l]-1 -(7-methyl-1 H-indazol-5-ylme- thyl)-2-oxo-ethyl]-amide;

( ± )-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino)}-propionic acid tert-butyl ester;

( ± )-3-(7-Methyl-1 H-indazol-5-yl)-2-}[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino}-propionic acid 1-methyl cyclohexyl ester;

( ± )-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-qu- inazolin-3-yl)- piperidine-1-carbonyl}-amino}-propionic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester;

( ± )-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino}-propionic acid piperidin-4-yl ester; (±)-4-(3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinaz- olin-3-yl)- piperidine-1-carbonyl[-amino}-propionyloxy)-piperidine-1 -carbox- ylic acid tert-butyl ester,

( ± )-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino}-propionic acid 3,4,5,6-tetrahydro-2H-[1 ,4']bipyridinyl-4-yl ester,

( ± )-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino)-propionic acid 1 -diethylamino-1 -methyl-ethyl ester;

( ± )-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino}-propionic acid 1 ,1 -dimethyl-2-phenyl-ethyl ester;

( ± )-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino)-propionic acid 1 ,1 -dimethyl-3-phenyl-propyl ester;

( ± )-3-(7-Methyl-1 H-indazol-5-yl)-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazoli- n-3-yl)- piperidine-1-carbonyl]-amino}-propionic acid ethyl ester; and

59. The method of claim 58, wherein the CGRP receptor antagonist is (R)-4-(2-Oxo- 1 ,4-dihydro-2H-quinazolin-3-yl)-piperidine-1 -carboxylic acid [2-[1 ,4']bipiperidinyl-1 '-yl-2- oxo-1 -(2-oxo-2,3-dihydro-benzooxazol~ 6-ylmethyl)-ethyl]-amide or a pharmaceutically acceptable salt thereof.

60. The method of claim 58, wherein the CGRP receptor antagonist is (R)-3-(1 H- Benzotriazol-5-yl-2-{[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-- y l)-piperidine-1 -carbonyljam ino}-propionic acid methyl ester or a pharmaceutically acceptable salt thereof.

61. A method of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, the method comprising administering to a subject in need thereof a CGRP receptor antagonistwherein the CGRP receptor antagonist is the compound (R)-N-(3-(7-methyl- 1 H-indazol-5-yl)-1 -(4-(1 -methylpiperidin-4-yl)piperazin-1 -yl)-1 -oxopropan-2-yl)-4-(2-oxo- 1 ,2-dihydroquinolin-3-yl)piperidine-1 -carboxamide, which has the following structure:

or a pharmaceutically acceptable salt thereof.

62. The method of any one of claims 26 - 61 , wherein the CGRP antagonist is administered in a unit dosage selected from the group consisting of about 5 mg, 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg

63. The method of any one of claims 26- 61 , wherein the CGRP antagonist is administered in a dosage of 0.01 -100 mg/kg body weight, or from .05 - 50 mg/kg body weight, or from 0.1 - 10 mg/kg body weight, or from 0.15 - 5 mg/kg body weight, or from 0.2 - 2 mg/kg body weight, or from 0.5 - 1 .5 mg/kg body weight, or from 1 - 1.5 mg/kg body weight.

64. The method of any one of claims 26 - 61 , wherein the CGRP antagonist is administered in an amount corresponding to an area under curve (AUC) within about 80 - 125 % of about 25, 50, 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000, 1300, 1600, 1900, 2500, 3500, 5000, 7500, 10,000, 15,000, 20,000, 30,000, 50,000, or 100,000 hr*ng/mL.

65. The method of any one of claims 26 - 61 , wherein the CGRP antagonist is administered in an amount corresponding to a Cmax value within about 80 - 125 % of about 1 , 2, 3, 4, 5, 8, 10, 20, 35, 50, 80,100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000, 1300, 1600, 1900, 2500, 3500, 5000, 7500, 10,000, 15,000, 20,000, 30,000, 50,000, and/or 100,000 ng/mL.

66. The method of any one of claims 64 and 65, wherein the CGRP antagonist is administered in an amount corresponding to a Cmax/AUC ratio within about 80 - 125 % of about 0.01 , 0.03, 0.05, 0.08, 0.1 , 0.13, 0.17, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, and 0.9

67. The method of any one of claims 26 - 66, wherein the CGRP antagonist is administered at an interval of daily, twice daily, once every other day, once every two days, once every three days, once every four days, once every five days, once every six days, or once weekly.

68. The method of any one of claims 26 - 67, wherein the CGRP antagonist is administered by a route selected from oral, intrabuccal, intranasal, inhalation, parenteral, intravenous, topical, injectable and/or transdermal.

69. The method of any one of claims 26 - 61 , wherein the CGRP antagonist is administered in a unit dosage of 5 mg, 10 mg, or 20 mg.

70. The method of claim 69, wherein the CGRP antagonist is administered intranasally.

71. A method of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, the method comprising administering to a subject in need thereof CGRP receptor antagonist according to Formula (III):

or a salt thereof or an optical isomer thereof, wherein

R¹ is H or Q-(Ci-C₆)alkyl; where Q is a bond, C(O) or C(O)O and where the (C-i- C₆)alkyl can be optionally substituted by N(C₁-C3alkyl)2 or CO2H;

R² is H or forms a spirocyclic heterocyclic ring with R³;

72. The method of claim 71 , wherein R⁴ is a substituted phenyl group wherein the substituents are selected from halo or hydroxy.

73. The method of claim 71 , wherein R⁴ is a moiety according to:

wherein X is halo.

74. The method of claim 73, wherein X is Br.

75. The method of claim 71 , wherein R⁴ is:

76. The method of claim 75, wherein R⁴ is

77. The method of claim 71 , wherein R² is H and R³ is:

78. The method of claim 71 , wherein R² forms a spirocyclic heterocyclic ring with R³ to form:

The method of claim 71 , wherein R² is H or forms a spirocyclic heterocyclic ring with R³ to form:

and wherein when R² is H, R³ is:

and R⁴ is:

80. The method of claim 71 , wherein R¹ is H, CC^Bu, CH2CH3, CH2CH2CH3, COCH2CH2CH2CH3, CH₂CH₂N(CH3)2, or COCH2CO2H.

81. The method of claim 80, wherein R¹ is H.

82. The method of claim 71 , wherein the CGRP antagonist is selected from the group consisting of:

N-[(2R)-3-(7-methyl-1 H-indazol-5-yl)-1 -oxo-1 -({(2S)-1 -oxo-3-(piperidin-4-yl)-1 -[4- (pyridin-4-yl)piperazin-1 -yl]propan-2-yl}amino)propan-2-yl]-4-(2-- oxo-2,3-dihydro-1 H- imidazo[4,5-b]pyridin-1 -yl)piperidine-1 -carboxamide; tert-butyl 4-{(2S)-2-{[(2R)-3-(7-methyl-1 H-indazol-5-yl)-2-({[[4-(2-oxo-1 ,2- dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoyl]amino}-3-oxo-3-[4-(py- rid in-4-y l)piperazin-1 -y l]propy I}piperid ine-1 -carboxylate;

3,5-dibromo-Na-{[4-(2-oxo-1 ,2-dihydroquinolin-3-yl)piperidin-1 -yl]carbonyl}-N- {(2S)-1 -oxo-3-(piperidin-4-yl)-1 -[4-(pyridin-4-yl)piperazin-1 -y- l]propan-2-yl}-D- tyrosinamide; N-[(2R)-3-(7-methyl-1 H-indazol-5-yl)-1 -oxo-1 -({(2S)-1 -oxo-3-(1 - pentanoylpiperidin-4-yl)-1-[4-(pyridin-4-yl)piperazin-1 -yl]propan-2-yl}amino)propan-2-yl]- 4-(2-oxo-1 ,2-dihydroquinolin-3-yl)piperidine-1 -carboxamide;

N-[(2R)-1-({(2S)-3-{1 -[2-(dimethylamino)ethyl]piperidin-4-yl}-1 -oxo-1 -[4-(pyridin-4- yl)piperazin-1-yl]propan-2-yl}amino)-3-(7-methyl-1 H-ind- azol-5-yl)-1 -oxopropan-2-yl]-4- (2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin- -1 -yl)piperidine-1 -carboxamide;

3-(4-{(2S)-2-{[(2R)-3-(7-methyl-1 H-indazol-5-yl)-2-({[4-(2-oxo-2,3-dihydro-1 H- imidazo[4,5-b]pyridin-1 -y l)piperid in-1 -yl]carbonyl}amino)propanoyl]am- ino}-3-oxo-3-[4- (pyridin-4-yl)piperazin-1 -yl]propyl}piperidin-1 -yl)-3-oxop- ropanoic acid, ammonium salt; and

3, 5-dibromo-Na-[(2'-oxo-1',2'-dihydro-1 H-spiro[piperidine-4,4'-pyrido- [2,3- d][1 ,3]oxazin]-1 -yl)carbonyl]-N-{(2S)-1 -oxo-3-(piperidin-4-yl)-1 -[4-(- pyridin-4- yl)piperazin-1 -yl]propan-2-yl}-D-tyrosinam ide; or a salt thereof or an optical isomer thereof.

83. The method of claim 82, wherein the CGRP antagonist is:

or a salt thereof or an optical isomer thereof. The method of claim 82, wherein the CGRP antagonist is:

or a salt thereof or an optical isomer thereof. A method of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, the method comprising administering to a subject in need thereof a CGRP receptor antagonist, wherein the CGRP receptor antagonist is the compound N-[(2R)-3-(7- methyl-1 H-indazol-5-yl)-1 -oxo-1 -({(2S)-1 -oxo-3-(piperidin-4-yl)-1 -[4-(py rid in-4- yl)piperazin-1-yl]propan-2-yl}amino)propan-2-yl]-2'-oxo-1 ',2'-dihydro-1 H- spiro[piperidine-4,4'-pyrido[2,3-d][1 ,3]oxazine]-1 -carboxamide, which has the following structure:

The method of any one of claims 71 - 85, wherein the CGRP antagonist is administered in a unit dosage selected from the group consisting of about 5 mg, 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg The method of any one of claims 71- 85, wherein the CGRP antagonist is administered in a dosage of 0.01 -100 mg/kg body weight, or from .05 - 50 mg/kg body weight, or from 0.1 - 10 mg/kg body weight, or from 0.15 - 5 mg/kg body weight, or from 0.2 - 2 mg/kg body weight, or from 0.5 - 1 .5 mg/kg body weight, or from 1 - 1.5 mg/kg body weight. The method of any one of claims 71 - 85, wherein the CGRP antagonist is administered in an amount corresponding to an area under curve (AUC) within about 80 - 125 % of about 25, 50, 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000, 1300, 1600, 1900, 2500, 3500, 5000, 7500, 10,000, 15,000, 20,000, 30,000, 50,000, or 100,000 hr*ng/mL. The method of any one of claims 71 - 85, wherein the CGRP antagonist is administered in an amount corresponding to a Cmax value within about 80 - 125 % of about 1 , 2, 3, 4, 5, 8, 10, 20, 35, 50, 80,100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000, 1300, 1600, 1900, 2500, 3500, 5000, 7500, 10,000, 15,000, 20,000, 30,000, 50,000, and/or 100,000 ng/mL. The method of any one of claims 88 and 89, wherein the CGRP antagonist is administered in an amount corresponding to a Cmax/AUC ratio within about 80 - 125 % of about 0.01 , 0.03, 0.05, 0.08, 0.1 , 0.13, 0.17, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, and 0.9 The method of any one of claims 71 - 90, wherein the CGRP antagonist is administered at an interval of daily, twice daily, once every other day, once every two days, once every three days, once every four days, once every five days, once every six days, or once weekly. The method of any one of claims 71 - 91 , wherein the CGRP antagonist is administered by a route selected from oral, intrabuccal, intranasal, inhalation, parenteral, intravenous, topical, injectable and/or transdermal. The method of any one of claims 71 - 85, wherein the CGRP antagonist is administered in a unit dosage of 5 mg, 10 mg, or 20 mg. The method of claim 93, wherein the CGRP antagonist is administered intranasally. The method of any one of claims 71 - 85, wherein the CGRP antagonist is administered in a unit dosage of 75 mg. The method of claim 95, wherein the CGRP antagonist is administered orally. A method of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, the method comprising administering to a subject in need thereof one or more CGRP receptor antagonists according to one or more of claims 1 - 96. A method of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising one or more CGRP receptor antagonists according to one or more of claims 1 - 96, and one or more pharmaceutically acceptable carriers.

99. The method of claim 98 wherein the composition is formulated for oral administration.

100. The method of claim 98 wherein the composition is formulated for injectable administration.

101. The method of claim 98 wherein the composition is formulated for topical administration.

102. The method of any one of claims 1 - 101 wherein the psoriasis is plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, and/or erythrodermic psoriasis.

103. The method of claim 102 wherein the psoriasis is plaque psoriasis.

104. The method of claim 103 wherein the plaque psoriasis is moderate plaque psoriasis.

105. A pharmaceutical composition for use in a method of treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising one or more CGRP receptor antagonists according to one or more of claims 1 - 96, and one or more pharmaceutically acceptable carriers.

106. The use of one or more CGRP antagonists of any one of claims 1 - 96 in the manufacture of a medicament for the treatment of psoriasis.

. The use of claim 104 wherein the treatment includes treating, ameliorating, alleviating, providing for prophylaxis or prevention of, halting the progression of, and/or reducing the risk of psoriasis.