# US 2013/0157976 A1 · Novel pyridopyrazines and their use as modulators of kinases

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2013/0157976 A1
- Document ID: US20130157976A1
- Status: Published application
- Kind: A1
- Application number: 13/770,470
- Filed: 2013-02-19
- Published: 2013-06-20
- Earliest claimed: 2005-11-11
- Inventors: Eckhard CLAUS; Irene Seipelt; Eckhard Guenther; Emmanuel Polymeropoulos; Michael Czech; Tilmann Schuster
- Web page: https://patentgrep.com/patent/US20130157976A1

## CPC

- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 31/695: Silicon compounds
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 17/06: Antipsoriatics
- C07D 487/04: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention relates to novel pyrido[2,3-b]pyrazine derivatives of the general formulae (I) and (II), and to their preparation and use as medicaments, especially for the treatment of malignant disorders and other disorders based on pathological cell proliferations.

## Claims

### Claim at position 1

1-60. (canceled)

### Claim 61

A method of treating a physiological and/or pathological condition in a mammal mediated by two or more enzymes, the method comprising administering an effective amount of at least one pyrido[2,3-b]pyrazine derivative to the mammal;
wherein said physiological and/or pathophysiological states are selected from the group consisting of malignant tumours, inflammatory disorders, inflammations, rheumatic disorders, arthritic disorders, HIV infections, rheumatism, arthritis, AIDS, ARC (AIDS related complex), Kaposi's sarcoma, tumours emanating from the brain and/or nervous system and/or meninges, dementia, Alzheimer's, hyperproliferative disorders, colon tumour, stomach tumour, intestine tumour, lung tumour, pancreas tumour, ovarial tumour, prostate tumour, leukaemia, melanoma, liver tumour, kidney tumour, head tumour, throat tumour, glioma, breast tumour, uterine cancer, endometrial cancer, cervical cancer, brain tumour, adenocanthoma, bladder cancer, colorectal tumour, oesophageal cancer, gynaecological tumour, ovarian tumour, thyroid cancer, lymphoma, chronic leukaemia, acute leukaemia, diabetes, disorders of the metabolism, solid tumours, rheumatoid arthritis, allergies, allergic disorders, atherosclerosis, cardiac disorders, cardiovascular disorders, angiogenetic disorders, ischaemia, cardiac hypertrophy, obesity, excess weight, hypertension,
wherein said mediation by two or more enzymes is an inhibition of two or more enzymes, wherein at least one enzyme is selected from the group consisting of: “Erk, Erk1, Erk2” and at least one enzyme is selected from the group consisting of: “PI3K, PI3Kalpha, PI3Kbeta, PI3Kgamma, PI3Kdelta, PI3K-C2alpha, PI3K-C2beta, PI3K-Vps34p,
wherein said pyrido[2,3-b]pyrazine derivative is selected according to formula II
where the substituents R1-R4 have the following meaning:
R2 and R4: hydrogen
R1 is substituted heteroaryl, where:
the heteroaryl radical has one or more, identical or different, substituents selected from the group consisting of
(i) NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH2, NH-alkyl-OH, N(alkyl)2, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO2-alkyl, NHSO2-cycloalkyl, NHSO2-heterocyclyl, NHSO2-aryl, NHSO2-heteroaryl, NHSO2-alkyl-aryl, NHSO2-alkyl-heteroaryl, S-alkyl, S-aryl, S-heteroaryl, O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl, OC(O)-alkyl-heteroaryl, OSO2-alkyl, OSO2-cycloalkyl, OSO2-heterocyclyl, OSO2-aryl, OSO2-heteroaryl, OSO2-alkyl-aryl, OSO2-alkyl-heteroaryl, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO2-alkyl, CO2-cycloalkyl, CO2-heterocyclyl, CO2-aryl, CO2-heteroaryl, CO2-alkyl-cycloalkyl, CO2-alkyl-heterocyclyl, CO2-alkyl-aryl, CO2-alkyl-heteroaryl, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)2, C(O)N(cycloalkyl)2, C(O)N(aryl)2, C(O)N(heteroaryl)2, SO2NH-alkyl, SO2NH-aryl, SO2NH-heteroaryl, SO2NH-alkyl-aryl, SO2O-alkyl, SO2O-aryl, SO2O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,
with the proviso that
the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl substituents from group (i) in turn themselves have one or more, identical or different, substituents selected from the group consisting of:
(ii) NH-cycloalkyl, NH-heterocyclyl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH2, NH-alkyl-OH, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO2-alkyl, NHSO2-cycloalkyl, NHSO2-heterocyclyl, NHSO2-aryl, NHSO2-heteroaryl, NHSO2-alkyl-aryl, NHSO2-alkyl-heteroaryl, S-aryl, S-heteroaryl, O-cycloalkyl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl, OC(O)-alkyl-heteroaryl, OSO2-alkyl, OSO2-cycloalkyl, OSO2-heterocyclyl, OSO2-aryl, OSO2-heteroaryl, OSO2-alkyl-aryl, OSO2-alkyl-heteroaryl, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO2-alkyl, CO2-cycloalkyl, CO2-heterocyclyl, CO2-aryl, CO2-heteroaryl, CO2-alkyl-cycloalkyl, CO2-alkyl-heterocyclyl, CO2-alkyl-aryl, CO2-alkyl-heteroaryl, C(O)—NH2, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)2, C(O)N(cycloalkyl)2, C(O)N(aryl)2, C(O)N(heteroaryl)2, SO2NH2, SO2NH-alkyl, SO2NH-aryl, SO2NH-heteroaryl, SO2NH-alkyl-aryl, SO2O-alkyl, SO2O-aryl, SO2O-alkyl-aryl, cycloalkyl, heterocyclyl, aryl or heteroaryl,
where the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl radicals listed in group (ii) may in turn themselves have one or more, same or different, substituents selected from the group consisting of:
(iii) H, F, Cl, Br, I, CF3, CHF2, CN, NH2, NH-alkyl, N(alkyl)2, NO2, SH, S-alkyl, OH, OCF3, OCHF2, O-alkyl, alkyl, alkyl-O—[(CH2)n—O]m (n=1, 2 or 3, m=1, 2 or 3), CH(O), C(O)-alkyl, CO2H, CO2-alkyl, C(O)—NH2, C(O)NH-alkyl, C(O)N(alkyl)2, SO3H, SO2-alkyl, SO2NH2, SO2NH-alkyl, SO2N(alkyl)2,
R3 is NR9R10,
where R9 may be
(iv) hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl or alkyl-heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl radicals listed in group
(iv) may in turn themselves have one or more, same or different, substituents selected from the group consisting of
(v) H, F, Cl, Br, I, CF3, CHF2, CN, NH2, NH-alkyl, N(alkyl)2, NO2, SH, S-alkyl, OH, OCF3, OCHF2, O-alkyl, alkyl, alkyl-O—[(CH2)n—O]m (n=1, 2 or 3, m=1, 2 or 3), CH(O), C(O)-alkyl, CO2H, CO2-alkyl, C(O)—NH2, C(O)NH-alkyl, C(O)N(alkyl)2, SO3H, SO2NH2, SO2NH-alkyl, SO2N(alkyl)2,
and R10 may be
(A) —C(Y)NR11R12, where Y is O or S
and R11 and R12 may be independently of one another
(vi) hydrogen,
(vii) unsubstituted or substituted alkyl, where the alkyl radical may have one or more, identical or different, substituents selected from the group consisting of F, Cl, Br, I, CF3, CN, NH2, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl)2, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO2-alkyl, NHSO2-cycloalkyl, NHSO2-heterocyclyl, NHSO2-aryl, NHSO2-heteroaryl, NHSO2-alkyl-aryl, NHSO2-alkyl-heteroaryl, NO2, SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF3, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl, OC(O)-alkyl-heteroaryl, OSO3H, OSO2-alkyl, OSO2-cycloalkyl, OSO2-heterocyclyl, OSO2-aryl, OSO2-heteroaryl, OSO2-alkyl-aryl, OSO2-alkyl-heteroaryl, OP(O)(OH)2, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO2H, CO2-alkyl, CO2-cycloalkyl, CO2-heterocyclyl, CO2-aryl, CO2-heteroaryl, CO2-alkyl-cycloalkyl, CO2-alkyl-heterocyclyl, CO2-alkyl-aryl, CO2-alkyl-heteroaryl, C(O)—NH2, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)2, C(O)N(cycloalkyl)2, C(O)N(aryl)2, C(O)N(heteroaryl)2, SO-alkyl, SO-aryl, SO2-alkyl, SO2-aryl, SO2NH2, SO2NH-alkyl, SO2NH-aryl, SO2NH-heteroaryl, SO2NH-alkyl-aryl, SO3H, SO2O-alkyl, SO2O-aryl, SO2O-alkyl-aryl, cycloalkyl, heterocyclyl, aryl or heteroaryl,
(viii) unsubstituted or substituted cycloalkyl, where the cycloalkyl radical may have one or more, identical or different, substituents selected from the group consisting of F, Cl, Br, I, NH2, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl)2, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO2-alkyl, NHSO2-cycloalkyl, NHSO2-heterocyclyl, NHSO2-aryl, NHSO2-heteroaryl, NHSO2-alkyl-aryl, NHSO2-alkyl-heteroaryl, OH, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl, OC(O)-alkyl-heteroaryl, OSO3H, OSO2-alkyl, OSO2-cycloalkyl, OSO2-heterocyclyl, OSO2-aryl, OSO2-heteroaryl, OSO2-alkyl-aryl, OSO2-alkyl-heteroaryl, OP(O)(OH)2, CO2H, CO2-alkyl, CO2-cycloalkyl, CO2-heterocyclyl, CO2-aryl, CO2-heteroaryl, CO2-alkylcycloalkyl, CO2-alkyl-heterocyclyl, CO2-alkyl-aryl, CO2-alkyl-heteroaryl, C(O)—NH2, C(O)NH-aryl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)2, C(O)N(cycloalkyl)2, C(O)N(aryl)2, C(O)N(heteroaryl)2, alkyl or aryl,
(ix) unsubstituted or substituted heterocyclyl, where the heterocyclyl radical may have one or more, identical or different, substituents selected from the group consisting of OH, O-alkyl, O-aryl, NH2, NH-alkyl, NH-aryl, alkyl, alkyl-aryl or aryl,
(x) unsubstituted or substituted aryl, where the aryl radical may have one or more, identical or different, substituents selected from the group consisting of F, Cl, Br, I, CF3, CN, NH2, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH2, NH-alkyl-OH, N(alkyl)2, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO2-alkyl, NHSO2-cycloalkyl, NHSO2-heterocyclyl, NHSO2-aryl, NHSO2-heteroaryl, NHSO2-alkyl-aryl, NHSO2-alkyl-heteroaryl, NO2, SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF3, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH, O—(CH2)n—O (n=1, 2 or 3), OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl, OC(O)-alkyl-heteroaryl, OSO3H, OSO2-alkyl, OSO2-cycloalkyl, OSO2-heterocyclyl, OSO2-aryl, OSO2-heteroaryl, OSO2-alkyl-aryl, OSO2-alkyl-heteroaryl, OP(O)(OH)2, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO2H, CO2-alkyl, CO2-cycloalkyl, CO2-heterocyclyl, CO2-aryl, CO2-heteroaryl, CO2-alkyl-cycloalkyl, CO2-alkyl-heterocyclyl, CO2-alkyl-aryl, CO2-alkyl-heteroaryl, C(O)—NH2, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)2, C(O)N(cycloalkyl)2, C(O)N(aryl)2, C(O)N(heteroaryl)2, SO-alkyl, SO-aryl, SO2-alkyl, SO2-aryl, SO2NH2, SO2NH-alkyl, SO2NH-aryl, SO2NH-heteroaryl, SO2NH-alkyl-aryl, SO3H, SO2O-alkyl, SO2O-aryl, SO2O-alkylaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl,
(xi) unsubstituted or substituted heteroaryl, where the heteroaryl radical may have one or more, identical or different, substituents selected from the group consisting of F, Cl, Br, I, CF3, CN, NH2, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH2, NH-alkyl-OH, N(alkyl)2, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO2-alkyl, NHSO2-cycloalkyl, NHSO2-heterocyclyl, NHSO2-aryl, NHSO2-heteroaryl, NHSO2-alkyl-aryl, NHSO2-alkyl-heteroaryl, NO2, SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF3, O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl, OC(O)-alkyl-heteroaryl, OSO3H, OSO2-alkyl, OSO2-cycloalkyl, OSO2-heterocyclyl, OSO2-aryl, OSO2-heteroaryl, OSO2-alkyl-aryl, OSO2-alkyl-heteroaryl, OP(O)(OH)2, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO2H, CO2-alkyl, CO2-cycloalkyl, CO2-heterocyclyl, CO2-aryl, CO2-heteroaryl, CO2-alkyl-cycloalkyl, CO2-alkyl-heterocyclyl, CO2-alkyl-aryl, CO2-alkyl-heteroaryl, C(O)—NH2, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)2, C(O)N(cycloalkyl)2, C(O)N(aryl)2, C(O)N(heteroaryl)2, SO2NH2, SO2NH-alkyl, SO2NH-aryl, SO2NH-heteroaryl, SO2NH-alkyl-aryl, SO3H, SO2O-alkyl, SO2O-aryl, SO2O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl,
(xii) —C(O)—R17, where R17 may be alkyl, aryl or heteroaryl, and where alkyl and aryl may in turn themselves have one or more, same or different, substituents selected from the group consisting of
F, Cl, Br, I, CN, CF3, NH2, NH-alkyl, NH-aryl, N(alkyl)2, NO2, SH, S-alkyl, OH, OCF3, O-alkyl, O-aryl, OSO3H, OP(O)(OH)2, CHO, CO2H, SO3H or alkyl.
(xiii) or R11 and R12 together may be cycloalkyl or heterocyclyl.

### Claim 62 (depends on 61)

The method of claim 61, wherein
R1 is selected from the group consisting of
(i) pyrrolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, phthalazinyl, indolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl, acridinyl,
where the heteroaryl radicals listed in group (i) are substituted once with a radical selected from the group consisting of
(ii) C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, SO2NH-alkyl, SO2NH-aryl, SO2NH-heteroaryl, SO2NH-alkyl-aryl, SO2O-alkyl, SO2O-aryl, SO2O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, with the proviso, that
the heteroaryl radicals listed in group (ii) in turn themselves have one or more, same or different, substituents selected from the group consisting of
(iii) NH-alkyl, N(alkyl)2, S-alkyl, O-alkyl, alkyl, alkyl-OH, alkyl-NH2, alkyl-SH, alkyl-O-alkyl, alkyl-O—[(CH2)n—O]m, (n=1, 2 or 3, m=1, 2 or 3), alkyl-NH-alkyl, alkyl-N-(alkyl)2, alkyl-S-alkyl, C(O)-alkyl, CO2-alkyl, C(O)—NH2, C(O)NH-alkyl, C(O)N(alkyl)2, SO2-alkyl, SO2NH-alkyl, SO2N(alkyl)2, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl,
and where the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl radicals listed in group (iii) may in turn themselves have one or more, same or different, substituents selected from the group consisting of
(iv) H, F, Cl, Br, I, CF3, CHF2, CN, NH2, NH-alkyl, N(alkyl)2, NO2, SH, S-alkyl, OH, OCF3, OCHF2, O-alkyl, alkyl, alkyl-OH, alkyl-O-alkyl, alkyl-O—[(CH2)n—O]m, (n=1, 2 or 3, m=1, 2 or 3), alkyl-NH2, alkyl-NH-alkyl, alkyl-N(alkyl)2, CH(O), C(O)-alkyl, CO2H, CO2-alkyl, C(O)—NH2, C(O)NH-alkyl, C(O)N(alkyl)2, SO3H, SO2-alkyl, SO2NH2, SO2NH-alkyl, SO2N(alkyl)2,
R3 is NHC(O)NH-alkyl or NHC(S)NH-alkyl
where the alkyl radical may be selected from the group consisting of
(v) methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-hexyl, n-heptyl, n-octyl, ethylenyl (vinyl), ethynyl, propenyl (—CH2CH═CH2, —CH═CH—CH3, —C(═CH2)—CH3), propynyl (—CH2—C≡CH, —C≡C—CH3), butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, heptenyl, heptynyl, octenyl, octynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and where the radicals listed in group (v) may in turn themselves have one or more, same or different, substituents selected from the group consisting of
(vii) F, Cl, Br, I, CF3, CHF2, CN, NH2, NH-alkyl, N(alkyl)2, NO2, SH, S-alkyl, OH, OCF3, OCHF2, O-alkyl, alkyl, alkyl-OH, alkyl-O—[(CH2)n—O]m (n=1, 2 or 3, m=1, 2 or 3), alkyl-NH2, alkyl-NH-alkyl, alkyl-N(alkyl)2, CH(O), C(O)-alkyl, CO2H, CO2-alkyl, C(O)—NH2, C(O)NH-alkyl, C(O)N(alkyl)2, SO3H, SO2-alkyl, SO2NH2, SO2NH-alkyl, SO2N(alkyl)2.

### Claim 63 (depends on 61)

The method of claim 61, wherein
R1 is pyrazolyl,
with the proviso that
the pyrazolyl radical is substituted one or more times with an alkyl-aryl substituent,
where the alkyl-aryl radicals in turn themselves may have one or more, same or different, substituents selected from the group consisting of
(i) H, F, Cl, Br, I, CF3, CHF2, CN, NH2, NH-alkyl, N(alkyl)2, NO2, SH, S-alkyl, OH, OCF3, OCHF2, O-alkyl, alkyl, alkyl-OH, alkyl-O—[(CH2)n—O]m (n=1, 2 or 3, m=1, 2 or 3), alkyl-NH2, alkyl-NH-alkyl, alkyl-N(alkyl)2, CH(O), C(O)-alkyl, CO2H, CO2-alkyl, C(O)—NH2, C(O)NH-alkyl, C(O)N(alkyl)2, SO3H, SO2-alkyl, SO2NH2, SO2NH-alkyl, SO2N(alkyl)2,
R3 is NHC(O)NH-alkyl or NHC(S)NH-alkyl
where the alkyl radical may be selected from the group consisting of
(ii) methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, ethylenyl (vinyl), ethynyl, propenyl (—CH2CH═CH2, —CH═CH—CH3, —C(═CH2)—CH3), propynyl (—CH2—C|CH, —C≡C—CH3), butenyl, butynyl, cyclopropyl, cyclobutyl,
and where the radicals listed in group (ii) may in turn themselves have one or more, same or different, substituents selected from the group consisting of
(iii) F, Cl, Br, I, CF3, CHF2, CN, NH2, NH-alkyl, N(alkyl)2, NO2, SH, S-alkyl, OH, OCF3, OCHF2, O-alkyl, alkyl, alkyl-OH, alkyl-O-alkyl, alkyl-O—[(CH2)n—O]m (n=1, 2 or 3, m=1, 2 or 3), alkyl-NH2, alkyl-NH-alkyl, alkyl-N(alkyl)2, CH(O), C(O)-alkyl, CO2H, CO2-alkyl, C(O)—NH2, C(O)NH-alkyl, C(O)N(alkyl)2, SO3H, SO2-alkyl, SO2NH2, SO2NH-alkyl, SO2N(alkyl)2.

### Claim 64 (depends on 61)

The method of claim 61, wherein
R1 is (1-benzyl)pyrazol-4-yl
where the 1-benzyl radical in turn itself may have one or more, same or different, substituents selected from the group consisting of
(i) F, Cl, Br, I, CF3, CHF2, CN, NH2, NH-alkyl, N(alkyl)2, NO2, SH, S-alkyl, OH, OCF3, OCHF2, O-alkyl, alkyl, alkyl-OH, alkyl-O-alkyl, alkyl-O—[(CH2)n—O]m (n=1, 2 or 3, m—1, 2 or 3), alkyl-NH2, alkyl-NH-alkyl, alkyl-N(alkyl)2, CH(O), C(O)-alkyl, CO2H, CO2-alkyl, C(O)—NH2, C(O)NH-alkyl, C(O)N(alkyl)2, SO3H, SO2NH2, SO2NH-alkyl, SO2N(alkyl)2,
R3 is NHC(O)NH-alkyl or NHC(S)NH-alkyl
where the alkyl radical may be selected from the group consisting of
(i) methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, ethylenyl (vinyl), ethynyl, propenyl (—CH2CH═CH2, —CH═CH—CH3, —C(═CH2)—CH3), propynyl (—CH2—C≡CH, —C≡C—CH3), cyclopropyl, cyclobutyl
and where the radicals listed in group (i) may in turn themselves have one or more, same or different, substituents selected from the group consisting of
(ii) F, Cl, Br, I, CF3, CHF2, CN, NH2, NH-alkyl, N(alkyl)2, NO2, SH, S-alkyl, OH, OCF3, OCHF2, O-alkyl, alkyl, alkyl-OH, alkyl-O-alkyl, alkyl-O—[(CH2)n—O]m (n=1, 2 or 3, m=1, 2 or 3), alkyl-NH2, alkyl-NH-alkyl, alkyl-N(alkyl)2, CH(O), C(O)-alkyl, CO2H, CO2-alkyl, C(O)—NH2, C(O)NH-alkyl, C(O)N(alkyl)2, SO3H, SO2NH2, SO2NH-alkyl, SO2N(alkyl)2.