JP2003505417A - Apicidin-derived cyclic tetrapeptides - Google Patents

Abstract

(57) Summary Acyclic tetrapeptide compounds derived from apicidin therapeutically inhibit histone deacetylase activity and are represented by formula (I). Embedded image

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to antiprotozoal agents. In particular, the invention relates to cyclic tetrapeptide compounds derived from apicidin that therapeutically inhibit histone deacetylase activity by protozoa.

BACKGROUND ART Parasitic protozoa are responsible for a wide variety of infections in humans and animals.
Many of the diseases are life-threatening for the host and create considerable economic loss in the livestock industry. Malaria poses a significant health threat to humans despite considerable international efforts to eradicate the disease. i) Chagas disease caused by Trypanosoma cruzi and ii) T.
Trypanosomiasis, such as African sleeping sickness caused by brucei, is not uncommon in Africa and South America. Moreover, opportunistic infections caused by Pneumocystis-carinii, Toxoplasma gondii and Cryptosporidium in immunocompromised hosts are becoming increasingly serious problems in developed countries.

A economically very important protozoal infection is coccidiosis, a disease of livestock that is endemic by infection with Eimeria protozoa. The most important Eimeria species are those of poultry. That is, E. tenella, E. acervulin
a, E. necatrix, E. praecox, E. mitis, E. brunetti and E. maxima. Coccidiosis can lead to high levels of morbidity and mortality in poultry, resulting in significant economic losses.

For some protozoal diseases such as Chagas disease, there is no satisfactory cure. In other protozoal diseases, drug-resistant strains of the protozoa may or have already occurred. Therefore, it is still desired to identify new and effective antiprotozoal agents. In most cases, however, the discovery of anthelmintic drugs was discovered by a random and cumbersome method of biological screening of natural and synthetic compounds against a group of parasites. If the specific target of the antiprotozoal drug could be identified and incorporated into the screening process, drug discovery could be greatly facilitated and made more direct.

Histone deacetylases (“HDA”) and histone acetyltransferases (“HAT”) synergistically regulate the net level of acetylation of histones. Inhibition of HDA action results in the accumulation of peracetylated histones, which is suggested in various cellular responses such as altered gene expression, cell differentiation and cell cycle arrest. Recently, trichostatin A and trapoxin (trap
oxin) A has been reported to be a reversible and irreversible inhibitor of mammalian HDA, respectively (eg Yoshida et al., BioAssays, 17 (5) , 423-430 (199 ) .
Five)). Trichostatin A has also been reported to inhibit partially purified yeast HDA (Sanchez del Pino et al., Biochem. J., 303, 723-729 (1994)).
Trichostatin A is an antifungal antibiotic and has i) anti-Trichomonas activity and cell differentiation activity in mouse erythroleukemia cells, and ii) si
having the ability to induce phenotypic reversion in s- transformed fibroblasts has been shown (e.g., U.S. Pat. No. 4218478;. Yoshida et al, BioAssays , 1 7 (5), 423-430 (1995) ; And references cited in these references). Trapoxin A, a cyclic tetrapeptide, induces morphological reversion of v-sis-transformed NIH3T3 cells (Yoshida and Sugita, Jap. J. Cancer Res., 83 (4) , 324-32.
8 (1992)).

HDA inhibition as a target for cancer research has been reported in the literature (Saito et al., Pr
oc. Natl Acad. Sci. USA, 96 , 4592-4597 (1999); Bernardi et al., Amino Ac
ids 6 , 315-318 (1994); and RE Shute et al., J. Med. Chem. 30 , 71-78.
(1987)).

US Pat. No. 5,620,953 describes novel cyclic tetrapeptides containing apicidin. Apicidin [cyclo (N-O-methyl-L-Trp-LI]
le-D-Pip-L-2-amino-8-oxo-decanoyl)] is a broad spectrum antiprotozoal, antifungal and antitumor drug isolated from fermentation cultures of Fusarium fungi.

[0008]

[Chemical 3]

Nevertheless, the development of new antiprotozoal compounds is desired. The present inventors have found that many cyclic tetrapeptides derived from apicidin, which are structurally related to trapoxin A, are inhibitors of histone deacetylase and have antiprotozoal activity.

DISCLOSURE OF THE INVENTION The present invention relates to novel cyclic tetrapeptides and pharmaceutical compositions containing the tetrapeptides. The invention further relates to a method of treating a protozoal infection by administering to a host suffering from a protozoal infection a therapeutically effective amount of a histone deacetylase inhibiting compound. The present invention also relates to the use of known cyclic tetrapeptides that inhibit histone deacetylase activity and are effective as antiprotozoal agents.

The present invention provides i) a novel antiprotozoal, antifungal and antitumor agent related to apicidin,
ii) methods of making such novel agents, iii) compositions containing such novel agents, iv) use of such novel agents in the treatment of parasitic infections such as malaria in humans and animals, v) cancer treatments. The use of such agents in.

In the treatment of cancer, the compound of the present invention can be used as a cytostatic agent, an agent for treating the differentiation or proliferation of abnormal cells, an agent for tumor formation, or an antimitotic agent in cancer chemotherapy.

BEST MODE FOR CARRYING OUT THE INVENTION According to one embodiment, in one embodiment, the present invention relates to a novel cyclic tetrapeptide represented by the following formula I or a pharmaceutically acceptable salt thereof. .

[0014]

[Chemical 4]   In the formula,   X is   (1) -CH_Two-,   (2) -C (O)-,   (3) -CH (OR^a)-,   (4) = CH- or   (5) Non-existence And   n is   (1) 1 or   (2) 2 And   R₁Is   (1) R₇,   (2) C (O) R₇,   (3) CN,   (4) CO_TwoR^b,   (5) C (O) N (OR^b) R^c,   (6) C (O) NR^cR^d,   (7) NHCO_TwoR^b,   (8) NHC (O) NR^cR^d,   (9) (C₀~ C_FourAlkyl) OR^a,   (10) (C₀~ C_FourAlkyl) OCO_TwoR^b,   (11) (C₀~ C_FourAlkyl) OC (O) NR^cR^d,   (12) C (O) NR^cNR^cR^d,   (13) C (O) NR^cSO_TwoR^b,   (14) OS (O)_niR₇,   (15) NR^bS (O)_niR₇(Ni is 0 to 2),   (16) 3 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C ₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono
, OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O
) NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr ha
Rogen, each substituent can be saturated, partially unsaturated or fully unsaturated
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R ^c Those which may have a substituent;   (17) 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
A benzene ring fused with a ~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C ₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino
, Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr with halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
The terror atoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^cSubstituent
And the benzene / heterocyclic fused ring has X or X at any position.
Bound to a tetrapeptide;   (18) Hete fused with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms
A 4- to 8-membered heterocycle having 1 to 4 atoms, each heterocycle being independently 1 to
It may be substituted with 4 groups, and each said substituent is independently C₁~ C₅Alkyl,
C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thi
Ono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each complex
The ring may be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cHas a substituent
Also good   And   R_TwoIs   (1) C which may be substituted_Two~ C₁₂Alkyl,   (2) C which may be substituted_Two~ C₁₂Alkenyl,   (3) C which may be substituted_Two~ C₁₂Alkynyl or   (4) (CH_Two)_nii-O- (CH_Two)_mii(Nii, mii = 0-7)
And the appropriate substituents on said alkyl, alkenyl and alkynyl are 1-8
Individual groups, each group independently   (A) CO_TwoR^a,   (B) C (O) R^b,   (C) C (O) N (OR^b) R^c,   (D) C (O) NR^cR^d,   (E) C (O) NR^cNR^cR^d,   (F) C (O) NR^cSO_TwoR₇,   (G) C_Three~ C₈Cycloalkyl,   (H) C_Two~ C₅Alkenyl,   (I) cyano,   (J) = NOR^a,   (K) = NNR^bR^c,   (L) = NNR^bS (O)_niR₇,   (M) N (OR^b) C (O) NR^bR^c,   (N) N (OR^b) C (O) R₇,   (O) NHC (O) N (OR^b) R^c,   (P) NR^cCO_TwoR^b,   (Q) NR^cC (O) NR^cR^d,   (R) NR^cC (S) NR^cR^d,   (S) NR^cC (O) R₇,   (T) NR^bS (O)_niR₇,   (U) NR^cCH_TwoCO_TwoR^a,   (V) NR^cC (S) R₇,   (X) NR^cC (O) CH_TwoOH,   (Y) NR^cC (O) CH_TwoSH,   (Z) NR^cCH_TwoCO_TwoR^a,   (Aa) NR^cCH_TwoCH (OH) R₇,   (Bb) NR^cP (O) (OR^a) R₇,   (Cc) NY¹Y^Two(Y¹And Y^TwoAre independently H or C₁~ C₁₀Alkyl
Is),   (Dd) NO_Two,   (Ee) N (OR^b) C (O) R^b,   (Ff) C₁~ C₁₀Alkanoylamino,   (Gg) OR^a,   (Hh) OS (O)_niR₇,   (Ii) oxo,   (Jj) OCO_TwoR^b,   (Kk) OC (O) NR^cR^d,   (Ll) P (O) (OR^a)_Two,   (Mm) P (O) (OR^a) R₇,   (Nn) SC (O) R₇,   (Oo) S (O)_niR₇,   (Pp) SR₇,   (Qq) S (O)_niNR^cR^d,   (Rr) NR^cCH_TwoCO_TwoR^a,   (Ss) diazo,   (Tt) C₁~ C₅Perfluoroalkyl,   (Uu) B (O) (OR^a) OR^a,   (Vv) halogen,   (Ww) Aryl (C₀~ C₅Alkyl) (aryl is substituted with 1 to 3 groups
Each group is independently R^fOr)   (Xx) a 3- to 8-membered heterocycle having 1 to 4 heteroatoms, each heterocycle
The atoms are independently oxygen, sulfur or nitrogen and the heterocycle is substituted with 1 to 3 groups
And each substituent is independently R^fAnd the heterocycle is saturated or partially
Things that can be unsaturated   And   R_ThreeEach independently,   (1) hydrogen,   (2) halogen,   (3) OR^a,   (4) C₁~ C_FourAlkyl or   (5) C₁~ C_FourAryl;   R₅Is   (1) Isopropyl or   (2) sec-butyl;   R₆Each independently,   (1) O,   (2) S or   (3) It is H;   R₇Is   (1) hydrogen,   (2) C which may be substituted_Two~ C₁₀Alkyl,   (3) C which may be substituted_Two~ C₁₀Alkenyl,   (4) C which may be substituted_Two~ C₁₀Alkynyl,   (5) C which may be substituted_Three~ C₈Cycloalkyl,   (6) C which may be substituted₅~ C₈Cycloalkenyl,   (7) optionally substituted aryl;   [The aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl
Suitable substituents on the aryl and aryl are 1 to 4 groups, each group being independently     (A) C₁~ C₅Alkyl,     (B) X¹-C₁~ C₁₀Alkyl (X¹Is O or S (O)_niIs)
,     (C) C_Three~ C₈Cycloalkyl,     (D) hydroxyl group,     (E) halogen,     (F) cyano,     (G) carboxy,     (H) NY¹Y^Two(Y¹And Y^TwoAre independently H or C₁~ C₁₀Alkyl
Is),     (I) nitro,     (J) C₁~ C₁₀Alkanoylamino,     (K) Aroylamino, wherein said aroyl is substituted with 1 to 3 groups
Each substituent is independently R^f1And R^f1Is (14), (26), (
R except 27) and (32)^fDefined by one of the following definitions for
What is done;     (L) Oxo,     (M) Aryl C₀~ C₅Alkyl, wherein the aryl is 1 to 3 groups
And each substituent is independently R.^f1What is;     (N) C₁~ C₅Perfluoroalkyl,     (O) N (OR^b) C (O) R_{7 '}And R_{7 '}Is (1)-(7) (n
) R₇Above for R and (8)-(12)₇About below
One of the definitions, or     (P) NR^cC (O) R_{7 '}Is. ];   (8) A 5- to 10-membered heterocycle having 1 to 4 heteroatoms, each heterocycle
The atoms are independently oxygen, sulfur or nitrogen and the heterocycle is substituted with 1 to 3 groups
And each substituent is independently R^f1And the heterocycle is saturated or
What may be unsaturated;   (9) Benzene ring fused with a 5- to 10-membered heterocycle having 1 to 4 heteroatoms
Wherein each heteroatom is independently oxygen, sulfur or nitrogen and said heterocycle is 1
~ 3 groups, each substituent being independently R^f1And said
Heterocycles which may be saturated or partially unsaturated;   (10) He condensed with a second 5- to 10-membered heterocycle having 1 to 4 heteroatoms.
A 5- to 10-membered heterocycle having 1 to 4 terror atoms, which is any of the above heterocycles
Where each heteroatom is independently oxygen, sulfur or nitrogen, said second heterocycle
May be substituted with 1 to 3 groups, and each substituent is independently R.^f1And
Each heterocycle independently being saturated or partially unsaturated;   (11) C_Three~ C₈A benzene ring fused to a cycloalkyl ring,
The chloroalkyl ring may be substituted with 1 to 3 groups, each substituent being independently
R^f1And the cycloalkyl ring may be saturated or partially unsaturated.
Of; or   (12) A 5- to 10-membered heterocycle having 1 to 4 heteroatoms, each heterocycle
The atoms are independently oxygen, sulfur or nitrogen and the heterocycle is C_Three~ C₈Cycloal
Fused with a kill ring, the cycloalkyl ring being substituted with 1 to 3 groups
And each substituent is independently R^f1And the cycloalkyl ring is saturated or
May be partially unsaturated;   R^aIs   (1) hydrogen,   (2) C which may be substituted₁~ C₁₀Alkyl,   (3) C which may be substituted_Three~ C₁₀Alkenyl,   (4) C which may be substituted_Three~ C₁₀Alkynyl,   (5) C which may be substituted₁~ C₁₀Alkanoyl,   (6) C which may be substituted_Three~ C₁₀Alkenoyl,   (7) C which may be substituted_Three~ C₁₀Alkinoyl,   (8) optionally substituted aroyl,   (9) optionally substituted aryl,   (10) C which may be substituted_Three~ C₇Cycloalkanoyl,   (11) C which may be substituted₅~ C₇Cycloalkenoyl,   (12) C which may be substituted₁~ C₁₀Alkylsulfonyl,   (13) C which may be substituted_Three~ C₈Cycloalkyl,   (14) C which may be substituted₅~ C₈Cycloalkenyl,   [The above C₁~ C₁₀Alkyl, C_Three~ C₁₀Alkenyl, C_Three~ C₁₀Archi
Nil, C₁~ C₁₀Alkanoyl, C_Three~ C₁₀Alkenoyl, C_Three~ C₁₀A
Ruquinoyl, aroyl, aryl, C_Three~ C₇Cycloalkanoyl, C₅~ C₇ Cycloalkenoyl, C₁~ C₁₀Alkylsulfonyl, C_Three~ C₈Cycloal
Kill and C₅~ C₈Suitable substituents on cycloalkenyl are 1-10 groups.
And each of the substituents is independently a hydroxyl group, C₁~ C₆Alkoxy, C_Three~ C₇Cyclo
Alkyl, aryl C₁~ C_ThreeAlkoxy, NR^xR^x, CO_TwoR^b, CONR ^c R^dOr halogen. ],   (15) C₁~ C₅Perfluoroalkyl,   (16) An arylsulfonyl which may be substituted with 1 to 3 groups,
Each substituent is independently C₁~ C₅Alkyl, C₁~ C₅Perfluoroalkyl,
Those which are nitro, halogen or cyano;   (17) a 5- or 6-membered heterocycle having 1 to 4 heteroatoms,
Each heteroatom is oxygen, sulfur or nitrogen and the heterocycle is substituted with from 1 to 4 groups
And each of the substituents is independently C₁~ C₅Alkyl, C₁~ C₅A
Lucenil, C₁~ C₅Perfluoroalkyl, amino, C (O) NR^cR^d, Shi
Ano, CO_TwoR^bOr halogen, wherein the heterocycle is saturated or partially unsaturated
What you may have; or   (18) OP (O) (OR^b)_TwoAnd   R^bIs   (1) H,   (2) optionally substituted aryl,   (3) C which may be substituted₁~ C₁₀Alkyl,   (4) C which may be substituted_Three~ C₁₀Alkenyl,   (5) C which may be substituted_Three~ C₁₀Alkynyl,   (6) C which may be substituted_Three~ C₁₅Cycloalkyl,   (7) C which may be substituted₅~ C₁₀Cycloalkenyl or   (8) an optionally substituted 5- to 10-membered compound having 1 to 4 heteroatoms
A prime ring in which each heteroatom is independently oxygen, sulfur or nitrogen;   The aryl, C₁~ C₁₀Alkyl, C_Three~ C₁₀Alkenyl, C_Three~ C_{1 0} Alkynyl, C_Three~ C₁₅Cycloalkyl and C₅~ C₁₀Cycloalkeni
Or a suitable substituent on the 5- to 10-membered heterocycle is 1 to 10 groups,
Each group is independently   (A) hydroxyl group,   (B) C₁~ C₆Alkyl,   (C) oxo,   (D) SO_TwoNR^xR^x,   (E) Aryl C₁~ C₆Alkoxy,   (F) Hydroxy C₁~ C₆Alkyl,   (G) C₁~ C₁₂Alkoxy,   (H) Hydroxy C₁~ C₆Alkoxy,   (I) Amino C₁~ C₆Alkoxy,   (J) cyano,   (K) mercapto,   (L) (C₁~ C₆Alkyl) -S (O)_ni-(C₀~ C₆Alkyl),   (M) C optionally substituted with 1 to 4 groups_Three~ C₇Cycloalkyl
And each substituent is independently R^eWhat is   (N) C₅~ C₇Cycloalkenyl,   (O) halogen,   (P) C₁~ C₅Alkanoyloxy,   (Q) C (O) NR^xR^x,   (R) CO_TwoRⁱ,   (S) formyl,   (T) -NR^xR^x,   (U) may be saturated or partially unsaturated, having 1 to 4 heteroatoms.
A 5- to 9-membered heterocycle in which each heteroatom is independently oxygen, sulfur or nitrogen.
, The heterocycle may be substituted with 1 to 5 groups, and each substituent is independent.
To R^eWhat is   (V) aryl which may be substituted, wherein the appropriate substituent is 1,2-
Methylenedioxy or 1 to 5 groups, each substituent of which is independently R^eIs
thing,   (X) optionally substituted aryl C₁~ C_ThreeAlkoxy, which is suitable
Convenient substituents are 1,2-methylenedioxy or 1-5 groups, each substitution
The groups are independently R^eOr   (Y) C₁~ C₅Perfluoroalkyl;   R^cAnd R^dIndependently R^bSelected from; or R^cAnd R^dGazo
Together with the N to which they are attached, 3 to 3 having 0 to 2 different heteroatoms
Forming a 10-membered ring, the other heteroatoms of which are independently oxygen, nitrogen or (O
)_niSubstituted sulfur, the ring of which may be substituted with 1 to 3 groups, each of which
The substituents are independently R^g, Hydroxyl, thioxo or oxo;   R^eIs   (1) halogen,   (2) C₁~ C₇Alkyl,   (3) C₁~ C_ThreePerfluoroalkyl,   (4) -S (O)_mRⁱ,   (5) Cyano,   (6) Nitro,   (7) RⁱO (CH_Two)_v-,   (8) RⁱCO_Two(CH_Two)_v-,   (9) RⁱOCO (CH_Two)_v-,   (10) The aryl which may be substituted, wherein the appropriate substituent is 1 to 3
Individual groups, wherein each substituent is independently halogen, C₁~ C₆Alkyl, C₁~
C₆Alkoxy or hydroxyl group,   (11) SO_TwoNR^xR^x,   (12) CO_TwoR^xOr   (13) NR^xR^xAnd   R^fIs   (1) C₁~ C_FourAlkyl,   (2) X¹-C₁~ C_FourAlkyl (X¹Is O or S (O)_miIs),   (3) C_Two~ C_FourAlkenyl,   (4) C_Two~ C_FourAlkynyl,   (5) C₁~ C_ThreePerfluoroalkyl,   (6) NY^ThreeY^Four(Y^ThreeAnd Y^FourAre independently hydrogen and C₁~ C₅Archi
LE or SO_TwoR^bIs),   (7) hydroxyl group,   (8) halogen,   (9) C₁~ C₅Alkanoylamino,   (10) (C₀~ C_FourAlkyl) CO_TwoR^a,   (11) (C₀~ C_FourAlkyl) C (O) NR^bR^c,   (12) (C₀~ C_FourAlkyl) NY⁵Y⁶(Y⁵And Y⁶But they combine
Together with N, forming a 3-7 membered ring having 0-2 different heteroatoms.
And the other heteroatom is independently oxygen, nitrogen or (O)_miSubstituted sulfur
And the ring may be substituted with 1 to 3 groups, each substituent being independently
R^eOr oxo),   (13) (C₀~ C_FourAlkyl) NO_Two,   (14) (C₀~ C_FourAlkyl) C (O) R₇,   (15) (C₀~ C_FourAlkyl) CN,   (16) Oxo,   (17) (C₀~ C_FourAlkyl) C (O) N (OR^b) R^c,   (18) (C₀~ C_FourAlkyl) C (O) NR^cR^d,   (19) (C₀~ C_FourAlkyl) NHC (O) OR^b,   (20) (C₀~ C_FourAlkyl) NHC (O) NR^cR^d,   (21) (C₀~ C_FourAlkyl) OR^a,   (22) (C₀~ C_FourAlkyl) OCO_TwoR^b,   (23) (C₀~ C_FourAlkyl) OC (O) NR^cR^d,   (24) (C₀~ C_FourAlkyl) C (O) NR^cNR^cR^d,   (25) (C₀~ C_FourAlkyl) C (O) NR^cSO_TwoR^b,   (26) (C₀~ C_FourAlkyl) OS (O)_niR₇,   (27) (C₀~ C_FourAlkyl) NR^bS (O)_niR₇,   (28) C₀~ C_FourAlkyl halogen,   (29) (C₀~ C_FourAlkyl) SR^a,   (30) P (O) (OR^a)_Two,   (31) C₀~ C_FourAlkyl azide,   (32) C substituted with 1 to 4 groups₀~ C_FourAryl, wherein each substituent is
Independently S (O)_TwoR₇Or   (33) C₀~ C_FourAryl, wherein the aryl group is substituted with 1 to 4 groups
And each of the substituents is independently CO._TwoR^b, C (O) NR^cR^d, N
O_Two, Halogen, OC (O) R^a, OR^aOr C₁~ C_FourWhat is an alkyl
And   R^gAnd R^hTogether with the N to which they are bound,
Forming a 3- to 7-membered ring having a terror atom, and each other heteroatom is independently oxygen,
Nitrogen or (O)_miA substituted sulfur, the ring of which is substituted by 1 to 3 groups
And each substituent is independently R^eOr oxo; or   R^gAnd R^hEach independently,   (1) Hydrogen.

[0015]   (2) Hydroxyl group, amino or CO_TwoRⁱC which may be replaced with₁~ C₆A
Luquil,   (3) halogen, 1,2-methylenedioxy, C₁~ C₇Alkoxy, C₁~
C₇Alkyl or C₁~ C_ThreeAn optionally substituted perfluoroalkyl
reel,   (4) Aryl C₁~ C₆An alkyl whose aryl is C₁~ C_ThreePar
What may be substituted with fluoroalkyl or 1,2-methylenedioxy
,   (5) C₁~ C₅Alkoxycarbonyl,   (6) C₁~ C₅Alkanoyl,   (7) C₁~ C₅Alkanoyl C₁~ C₆Alkyl,   (8) Aryl C₁~ C₅Alkoxycarbonyl,   (9) aminocarbonyl,   (10) (C₁~ C₅Monoalkyl) aminocarbonyl,   (11) (C₁~ C₅Dialkyl) aminocarbonyl or   (12) CO_TwoR^bAnd   RⁱIs   (1) hydrogen,   (2) C₁~ C_ThreePerfluoroalkyl,   (3) C₁~ C₆Alkyl or   (4) optionally substituted aryl C₀~ C₆Alkyl, as appropriate
The aryl substituents of are 1 to 3 groups, each of which is independently halogen, C₁~ C ₆ Alkyl, C₁~ C₆An alkoxy or hydroxyl group;   R^xIs C₁~ C_FourAlkyl;   m is 0 to 2;   mi is 0-2;   ni is 0 to 2;   mii is 0 to 7;   nii is 0 to 7;   v is 0-3;   However, apicidin, N-desmethoxyapicidin and the following chemical formula IIA
And compounds represented by formula IIB are excluded.

[0016]

[Chemical 5]

[0017]   Within the scope of this embodiment, the novel cyclic tetrapeptides of the invention include:   X is   (1) -CH_Two-,   (2) -C (O)-,   (3) -CH (OR^a)-,   (4) = CH- or   (5) Non-existence And   R₁But   (1) R₇,   (2) C (O) R₇,   (3) CN,   (4) CO_TwoR^b,   (5) C (O) N (OR^b) R^c,   (6) C (O) NR^cR^d,   (7) NHCO_TwoR^b,   (8) NHC (O) NR^cR^d,   (9) (C₀~ C_FourAlkyl) OR^a,   (10) (C₀~ C_FourAlkyl) OCO_TwoR^b,   (11) (C₀~ C_FourAlkyl) OC (O) NR^cR^d,   (12) C (O) NR^cNR^cR^d,   (13) C (O) NR^cSO_TwoR^b,   (13) OS (O)_niR₇,   (14) NR^bS (O)_niR₇(Ni is 0 to 2),   (15) 3 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C ₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono
, OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O
) NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr ha
Rogen, each substituent can be saturated, partially unsaturated or fully unsaturated
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R ^c Those which may have a substituent;   (16) 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
A benzene ring fused with a ~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C ₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino
, Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr with halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
The terror atoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^cSubstituent
And the benzene / heterocyclic fused ring has X or X at any position.
Bound to a tetrapeptide;   (17) Hete condensed with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms
A 4- to 8-membered heterocycle having 1 to 4 atoms, each heterocycle being independently 1 to
It may be substituted with 4 groups, and each said substituent is independently C₁~ C₅Alkyl,
C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thi
Ono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each complex
The ring may be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cHas a substituent
Also good   A genus of compounds represented by formula I or pharmaceutically acceptable compounds thereof
Included salt.

[0018]   The scope of this genus is   X is   (1) -CH_Two-,   (2) -C (O)-,   (3) -CH (OR^a)-,   (4) = CH- or   (5) Non-existence And   R₁But   (1) R₇,   (2) C (O) R₇,   (3) CN,   (4) CO_TwoR^b,   (5) C (O) N (OR^b) R^c,   (6) C (O) NR^cR^d,   (7) NHCO_TwoR^b,   (8) NHC (O) NR^cR^d,   (9) (C₀~ C_FourAlkyl) OR^a,   (10) (C₀~ C_FourAlkyl) OCO_TwoR^b,   (11) (C₀~ C_FourAlkyl) OC (O) NR^cR^d,   (12) C (O) NR^cNR^cR^d,   (13) C (O) NR^cSO_TwoR^b,   (14) OS (O)_niR₇,   (15) NR^bS (O)_niR₇(Ni is 0 to 2),   (16) 3 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C ₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono
, OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O
) NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr ha
Rogen, each substituent can be saturated, partially unsaturated or fully unsaturated
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R ^c Those which may have a substituent;   (17) 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
A benzene ring fused with a ~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C ₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino
, Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr with halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
The terror atoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^cSubstituent
And the benzene / heterocyclic fused ring has X or X at any position.
Bound to a tetrapeptide;   (18) Hete fused with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms
A 4- to 8-membered heterocycle having 1 to 4 atoms, each heterocycle being independently 1 to
It may be substituted with 4 groups, and each said substituent is independently C₁~ C₅Alkyl,
C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thi
Ono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each complex
The ring may be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cHas a substituent
Also good   And   R_TwoBut,   (1) C which may be substituted_Two~ C₁₂Alkyl,   (2) C which may be substituted_Two~ C₁₂Alkenyl,   (3) C which may be substituted_Two~ C₁₂Alkynyl or   (4) (CH_Two)_nii-O- (CH_Two)_mii(Nii, mii = 0-7)
And the above C_Two~ C₁₂Alkyl, C_Two~ C₁₂Alkenyl and C_Two~ C_{1 Two} Suitable substituents on alkynyl are 1-8 groups, each group being independently   (A) CO_TwoR^a,   (B) C (O) R^b,   (C) C (O) N (OR^b) R^c,   (D) C (O) NR^cR^d,   (E) C (O) NR^cNR^cR^d,   (F) C (O) NR^cSO_TwoR₇,   (G) C_Three~ C₈Cycloalkyl,   (H) C_Two~ C₅Alkenyl,   (I) cyano,   (J) = NOR^a,   (K) = NNR^bR^c,   (L) = NNR^bS (O)_niR₇,   (M) N (OR^b) C (O) NR^bR^c,   (N) N (OR^b) C (O) R₇,   (O) NHC (O) N (OR^b) R^c,   (P) NR^cCO_TwoR^b,   (Q) NR^cC (O) NR^cR^d,   (R) NR^cC (S) NR^cR^d,   (S) NR^cC (O) R₇,   (T) NR^bS (O)_niR₇,   (U) NR^cCH_TwoCO_TwoR^a,   (V) NR^cC (S) R₇,   (X) NR^cC (O) CH_TwoOH,   (Y) NR^cC (O) CH_TwoSH,   (Z) NR^cCH_TwoCO_TwoR^a,   (Aa) NR^cCH_TwoCH (OH) R₇,   (Bb) NR^cP (O) (OR^a) R₇,   (Cc) NY¹Y^Two(Y¹And Y^TwoAre independently H or C₁~ C₁₀Alkyl
Is),   (Dd) NO_Two,   (Ee) N (OR^b) C (O) R^b,   (Ff) C₁~ C₁₀Alkanoylamino,   (Gg) OR^a,   (Hh) OS (O)_niR₇,   (Ii) oxo,   (Jj) OCO_TwoR^b,   (Kk) OC (O) NR^cR^d,   (Ll) P (O) (OR^a)_Two,   (Mm) P (O) (OR^a) R₇,   (Nn) SC (O) R₇,   (Oo) S (O)_niR₇,   (Pp) SR₇,   (Qq) S (O)_niNR^cR^d,   (Rr) NR^cCH_TwoCO_TwoR^a,   (Ss) diazo,   (Tt) C₁~ C₅Perfluoroalkyl,   (Uu) B (O) (OR^a) OR^a,   (Vv) halogen,   (Ww) Aryl (C₀~ C₅Alkyl) (aryl is substituted with 1 to 3 groups
Each group is independently R^fOr)   (Xx) a 3- to 8-membered heterocycle having 1 to 4 heteroatoms, each heterocycle
The atoms are independently oxygen, sulfur or nitrogen and the heterocycle is substituted with 1 to 3 groups
And each substituent is independently R^fAnd the heterocycle is saturated or partially
Things that can be unsaturated   A group of compounds represented by Formula I or pharmaceutically acceptable compounds thereof
There is salt.

Within the above group of compounds are the subgroups of compounds represented by Formula I wherein n is 1 or 2 or pharmaceutically acceptable salts of the compounds.

[0020]   In this genus,   X is   (1) -CH_Two-,   (2) -C (O)-or   (3) Non-existence And   R₁But   (1) R₇,   (2) C (O) R₇,   (3) CN,   (4) CO_TwoR^b,   (5) C (O) N (OR^b) R^c,   (6) C (O) NR^cR^d,   (7) NHCO_TwoR^b,   (8) NHC (O) NR^cR^d,   (9) (C₀~ C_FourAlkyl) OR^a,   (10) (C₀~ C_FourAlkyl) OCO_TwoR^b,   (11) (C₀~ C_FourAlkyl) OC (O) NR^cR^d,   (12) C (O) NR^cNR^cR^d,   (13) C (O) NR^cSO_TwoR^b,   (14) OS (O)_niR₇,   (15) NR^bS (O)_niR₇(Ni is 0 to 2),   (16) 3 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C ₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono
, OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O
) NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr ha
Rogen, each substituent can be saturated, partially unsaturated or fully unsaturated
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R ^c Those which may have a substituent;   (17) 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
A benzene ring fused with a ~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C ₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino
, Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr with halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
The terror atoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^cSubstituent
And the benzene / heterocyclic fused ring has X or X at any position.
Bound to a tetrapeptide;   (18) Hete fused with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms
A 4- to 8-membered heterocycle having 1 to 4 atoms, each heterocycle being independently 1 to
It may be substituted with 4 groups, and each said substituent is independently C₁~ C₅Alkyl,
C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thi
Ono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each complex
The ring may be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cHas a substituent
Also good   Another group of compounds represented by Formula I or pharmaceutically acceptable compounds thereof
There is salt that can be used.

Within the above group of compounds are the subgroups of compounds represented by Formula I wherein n is 1 or 2 or pharmaceutically acceptable salts of the compounds.

[0022]   In this genus,   X is   (1) -CH_Two-,   (2) -C (O)-or   (3) Non-existence And   R₁But   (1) R₇,   (2) C (O) R₇,   (3) CO_TwoR^b,   (4) C (O) N (OR^b) R^c,   (5) C (O) NR^cR^d,   (6) 3 to 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
An 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono,
OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O)
NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr halo
Gen and each substituent can be saturated, partially unsaturated or fully unsaturated,
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^c Those which may have a substituent;   (7) 4 to 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
A benzene ring fused with an 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino,
Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
Each atom is independently oxygen, sulfur or nitrogen, and said nitrogen is R^cSubstituent
The benzene / heterocyclic fused ring may have X or the terephthalate at any position.
Bound to trapeptides;   (8) Hetero fused with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms.
4- to 8-membered heterocycle having 1 to 4 atoms, each said heterocycle being independently 1 to 4
Each of the above substituents may be independently substituted with C₁~ C₅Alkyl, C _Two ~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thio
No, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each heterocycle
Can be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cEven if it has a substituent
Good things   Yet another group of compounds represented by Formula I
There is an acceptable salt.

Within the above group of compounds are the subgroups of compounds represented by Formula I wherein n is 1 or 2 or pharmaceutically acceptable salts of the compounds.

[0024]   In this genus,   X is   (1) -CH_Two-,   (2) -C (O)-or   (3) Non-existence And   R₁But   (1) R₇,   (2) C (O) R₇,   (3) CO_TwoR^b,   (4) C (O) N (OR^b) R^c,   (5) C (O) NR^cR^d,   (6) 3 to 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
An 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono,
OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O)
NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr halo
Gen and each substituent can be saturated, partially unsaturated or fully unsaturated,
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^c Those which may have a substituent;   (7) 4 to 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
A benzene ring fused with an 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino,
Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
Each atom is independently oxygen, sulfur or nitrogen, and said nitrogen is R^cSubstituent
The benzene / heterocyclic fused ring may have X or the terephthalate at any position.
Bound to trapeptides;   (8) Hetero fused with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms.
4- to 8-membered heterocycle having 1 to 4 atoms, each said heterocycle being independently 1 to 4
Each of the above substituents may be independently substituted with C₁~ C₅Alkyl, C _Two ~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thio
No, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each heterocycle
Can be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cEven if it has a substituent
Good things   And   R_TwoBut,   (1) C which may be substituted_Two~ C₁₂Alkyl,   (2) C which may be substituted_Two~ C₁₂Alkenyl,   (3) C which may be substituted_Two~ C₁₂Alkynyl or   (4) (CH_Two)_nii-O- (CH_Two)_mii(Nii, mii = 0-7)
And the above C_Two~ C₁₂Alkyl, C_Two~ C₁₂Alkenyl and C_Two~ C_{1 Two} Suitable substituents on alkynyl are 1-5 groups, each group being independently   (A) CO_TwoR^a,   (B) C (O) R^b,   (C) C (O) N (OR^b) R^c,   (D) C (O) NR^cR^d,   (E) C (O) NR^cNR^cR^d,   (F) C (O) NR^cSO_TwoR₇,   (G) C_Three~ C₈Cycloalkyl,   (H) C_Two~ C₅Alkenyl,   (I) cyano,   (J) = NOR^a,   (K) = NNR^bR^c,   (L) = NNR^bS (O)_niR₇,   (M) N (OR^b) C (O) NR^bR^c,   (N) N (OR^b) C (O) R₇,   (O) NHC (O) N (OR^b) R^c,   (P) NR^cCO_TwoR^b,   (Q) NR^cC (O) NR^cR^d,   (R) NR^cC (S) NR^cR^d,   (S) NR^cC (O) R₇,   (T) NR^bS (O)_niR₇,   (U) NR^cCH_TwoCO_TwoR^a,   (V) NR^cC (S) R₇,   (X) NR^cC (O) CH_TwoOH,   (Y) NR^cC (O) CH_TwoSH,   (Z) NR^cCH_TwoCO_TwoR^a,   (Aa) NR^cCH_TwoCH (OH) R₇,   (Bb) NR^cP (O) (OR^a) R₇,   (Cc) NY¹Y^Two(Y¹And Y^TwoAre independently H or methyl),   (Dd) NO_Two,   (Ee) N (OR^b) C (O) R^b,   (Ff) C₁~ C_ThreeAlkanoylamino,   (Gg) OR^a,   (Hh) OS (O)_niR₇,   (Ii) oxo,   (Jj) OCO_TwoR^b,   (Kk) OC (O) NR^cR^d,   (Ll) P (O) (OR^a)_Two,   (Mm) P (O) (OR^a) R₇,   (Nn) SC (O) R₇,   (Oo) S (O)_niR₇,   (Pp) SR₇,   (Qq) S (O)_niNR^cR^d,   (Rr) NR^cCH_TwoCO_TwoR^a,   (Ss) diazo,   (Tt) C₁~ C₅Perfluoroalkyl,   (Uu) B (O) (OR^a) OR^a,   (Vv) halogen,   (Ww) Aryl (C₀~ C₅Alkyl) (aryl is substituted with 1 to 3 groups
Each group is independently R^fOr)   (Xx) a 3- to 6-membered heterocycle having 1 to 4 heteroatoms, each heterocycle
The atoms are independently oxygen, sulfur or nitrogen and the heterocycle is substituted with 1 to 3 groups
And each substituent is independently R^fAnd the heterocycle is saturated or partially
Things that can be unsaturated   Yet another group of compounds represented by Formula I
There is an acceptable salt.

Within the above group of compounds is a small group of compounds represented by Formula I wherein n is 1 or 2 or a pharmaceutically acceptable salt thereof.

[0026]   In this embodiment,   R_ThreeEach independently,   (1) hydrogen,   (2) halogen,   (3) OR^a,   (4) C₁~ C_FourAlkyl or   (5) C₁~ C_FourAryl;   R^aBut   (1) hydrogen,   (2) C which may be substituted₁~ C₆Alkyl,   (3) C which may be substituted_Three~ C₆Alkenyl,   (4) C which may be substituted_Two~ C_FourAlkanoyl,   (5) C which may be substituted_Three~ C_FourAlkenoyl,   (6) optionally substituted aroyl,   (7) optionally substituted aryl,   (8) C which may be substituted₅~ C₆Cycloalkanoyl,   (9) C which may be substituted₁~ C_FourAlkylsulfonyl,   (10) C which may be substituted₅~ C₆Cycloalkyl,   (11) C which may be substituted₅~ C₆Cycloalkenyl,   [The above C₁~ C₆Alkyl, C_Three~ C₆Alkenyl, C_Two~ C_FourAlkanoyl
, C_Three~ C_FourAlkenoyl, aroyl, aryl, C₅~ C₆Cycloalkanoy
Le, C₁~ C_FourAlkylsulfonyl, C₅~ C₆Cycloalkyl and C₅~ C ₆ Suitable substituents on cycloalkenyl are 1-10 groups, each substituent being
Independently hydroxyl group, methoxy, arylmethoxy, NR^xR^x, CO_TwoR^b, CO
NR^cR^dOr halogen. ],   (12) CF_Three,   (13) An arylsulfonyl which may be substituted with 1 to 3 groups,
Each of the substituents is independently methyl, CF_Three, Nitro, halogen or cyano too
Of; or   (14) a 5- or 6-membered heterocycle having 1 to 3 heteroatoms,
Each heteroatom is oxygen, sulfur or nitrogen and the heterocycle is substituted with from 1 to 3 groups
And each substituent is independently methyl, CF._Three, NMe_Two, C (O
) NR^cR^d, Cyano, CO_TwoR^bOr halogen, wherein the heterocycle is saturated or
Or may be partially unsaturated   A compound of the second genus represented by formula I or a pharmaceutically acceptable compound thereof
There is salt to be contained.

[0027]   In this second genus,   R_ThreeEach independently,   (1) hydrogen,   (2) halogen,   (3) OR^a,   (4) C₁~ C_FourAlkyl or   (5) C₁~ C_FourAryl;   R^aBut   (1) hydrogen,   (2) C which may be substituted₁~ C₆Alkyl,   (6) C which may be substituted_Three~ C₆Alkenyl,   (7) C which may be substituted_Two~ C_FourAlkanoyl,   (5) C which may be substituted_Three~ C_FourAlkenoyl,   (6) optionally substituted aroyl,   (7) optionally substituted aryl,   (8) C which may be substituted₅~ C₆Cycloalkanoyl,   (9) C which may be substituted₁~ C_FourAlkylsulfonyl,   (10) C which may be substituted₅~ C₆Cycloalkyl,   (11) C which may be substituted₅~ C₆Cycloalkenyl,   [The above C₁~ C₆Alkyl, C_Three~ C₆Alkenyl, C_Two~ C_FourAlkanoyl
, C_Three~ C_FourAlkenoyl, aroyl, aryl, C₅~ C₆Cycloalkanoy
Le, C₁~ C_FourAlkylsulfonyl, C₅~ C₆Cycloalkyl and C₅~ C ₆ Suitable substituents on cycloalkenyl are 1-10 groups, each substituent being
Independently hydroxyl group, methoxy, arylmethoxy, NR^xR^x, CO_TwoR^b, CO
NR^cR^dOr halogen. ],   (12) CF_Three,   (13) An arylsulfonyl which may be substituted with 1 to 3 groups,
Each of the substituents is independently methyl, CF_Three, Nitro, halogen or cyano too
Of; or   (14) a 5- or 6-membered heterocycle having 1 to 3 heteroatoms,
Each heteroatom is oxygen, sulfur or nitrogen and the heterocycle is substituted with from 1 to 3 groups
And each substituent is independently methyl, CF._Three, NMe_Two, C (O
) NR^cR^d, Cyano, CO_TwoR^bOr halogen, wherein the heterocycle is saturated or
Or may be partially unsaturated;   X is   (1) -CH_Two-,   (2) -C (O)-,   (3) = CH- or   (5) Non-existence And   R₁But   (1) R₇,   (2) C (O) R₇,   (3) CN,   (4) CO_TwoR^b,   (5) C (O) N (OR^b) R^c,   (6) C (O) NR^cR^d,   (7) NHCO_TwoR^b,   (8) NHC (O) NR^cR^d,   (9) (C₀~ C_FourAlkyl) OR^a,   (10) (C₀~ C_FourAlkyl) OCO_TwoR^b,   (11) (C₀~ C_FourAlkyl) OC (O) NR^cR^d,   (12) C (O) NR^cNR^cR^d,   (13) C (O) NR^cSO_TwoR^b,   (14) OS (O)_niR₇,   (15) NR^bS (O)_niR₇(Ni is 0 to 2),   (16) 3 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C ₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono
, OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O
) NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr ha
Rogen, each substituent can be saturated, partially unsaturated or fully unsaturated
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R ^c Those which may have a substituent;   (17) 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
A benzene ring fused with a ~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C ₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino
, Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr with halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
The terror atoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^cSubstituent
And the benzene / heterocyclic fused ring has X or X at any position.
Bound to a tetrapeptide;   (18) Hete fused with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms
A 4- to 8-membered heterocycle having 1 to 4 atoms, each heterocycle being independently 1 to
It may be substituted with 4 groups, and each said substituent is independently C₁~ C₅Alkyl,
C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thi
Ono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each complex
The ring may be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cHas a substituent
Also good   A group of compounds represented by Formula I or pharmaceutically acceptable compounds thereof
There is salt.

Within the above group of compounds are subgroups of compounds of formula I, wherein n is 1 or 2, or pharmaceutically acceptable salts of the compounds.

[0029]   In this second genus,   R_ThreeEach independently,   (1) hydrogen,   (2) halogen,   (3) OR^a,   (4) C₁~ C_FourAlkyl or   (5) C₁~ C_FourAryl;   R^aBut   (1) hydrogen,   (2) C which may be substituted₁~ C₆Alkyl,   (3) C which may be substituted_Three~ C₆Alkenyl,   (4) C which may be substituted_Two~ C_FourAlkanoyl,   (5) C which may be substituted_Three~ C_FourAlkenoyl,   (6) optionally substituted aroyl,   (7) optionally substituted aryl,   (8) C which may be substituted₅~ C₆Cycloalkanoyl,   (9) C which may be substituted₁~ C_FourAlkylsulfonyl,   (10) C which may be substituted₅~ C₆Cycloalkyl,   (11) C which may be substituted₅~ C₆Cycloalkenyl,   [The above C₁~ C₆Alkyl, C_Three~ C₆Alkenyl, C_Two~ C_FourAlkanoyl
, C_Three~ C_FourAlkenoyl, aroyl, aryl, C₅~ C₆Cycloalkanoy
Le, C₁~ C_FourAlkylsulfonyl, C₅~ C₆Cycloalkyl and C₅~ C ₆ Suitable substituents on cycloalkenyl are 1-10 groups, each substituent being
Independently hydroxyl group, methoxy, arylmethoxy, NR^xR^x, CO_TwoR^b, CO
NR^cR^dOr halogen. ],   (12) CF_Three,   (13) An arylsulfonyl which may be substituted with 1 to 3 groups,
Each of the substituents is independently methyl, CF_Three, Nitro, halogen or cyano too
Of; or   (14) a 5- or 6-membered heterocycle having 1 to 3 heteroatoms,
Each heteroatom is oxygen, sulfur or nitrogen and the heterocycle is substituted with from 1 to 3 groups
And each substituent is independently methyl, CF._Three, NMe_Two, C (O
) NR^cR^d, Cyano, CO_TwoR^bOr halogen, wherein the heterocycle is saturated or
Or may be partially unsaturated;   X is   (1) -CH_Two-,   (2) -C (O)-,   (3) = CH- or   (4) Non-existence And   R₁But   (1) R₇,   (2) C (O) R₇,   (9) CO_TwoR^b,   (10) C (O) N (OR^b) R^c,   (11) C (O) NR^cR^d,   (12) 3 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C ₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono
, OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O
) NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr ha
Rogen, each substituent can be saturated, partially unsaturated or fully unsaturated
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R ^c Those which may have a substituent;   (13) 4 having 1 to 4 heteroatoms which may be substituted with 1 to 4 groups
A benzene ring fused with a ~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C ₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino
, Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr with halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
The terror atoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^cSubstituent
And the benzene / heterocyclic fused ring has X or X at any position.
Bound to a tetrapeptide;   (14) Hete fused with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms.
A 4- to 8-membered heterocycle having 1 to 4 atoms, each heterocycle being independently 1 to
It may be substituted with 4 groups, and each said substituent is independently C₁~ C₅Alkyl,
C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thi
Ono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each complex
The ring may be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cHas a substituent
Also good   A group of compounds represented by Formula I or pharmaceutically acceptable compounds thereof
There is salt.

Within the above group of compounds are the subgroups of compounds represented by Formula I wherein n is 1 or 2 or pharmaceutically acceptable salts of the compounds.

[0031]   In this embodiment,   R₆Each independently,   (1) O,   (2) S or   (3) It is H;   X is   (1) -CH_Two-,   (2) -C (O)-,   (3) = CH- or   (4) Non-existence And   R₁But   (1) R₇,   (2) C (O) R₇,   (3) CN,   (4) CO_TwoR^b,   (5) C (O) N (OR^b) R^c,   (6) C (O) NR^cR^d,   (7) NHCO_TwoR^b,   (8) NHC (O) NR^cR^d,   (9) (C₀~ C_FourAlkyl) OR^a,   (10) (C₀~ C_FourAlkyl) OCO_TwoR^b,   (11) (C₀~ C_FourAlkyl) OC (O) NR^cR^d,   (12) C (O) NR^cNR^cR^d,   (13) C (O) NR^cSO_TwoR^b,   (14) OS (O)_niR₇,   (15) NR^bS (O)_niR₇(Ni is 0 to 2),   (16) 3 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C ₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono
, OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O
) NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr ha
Rogen, each substituent can be saturated, partially unsaturated or fully unsaturated
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R ^c Those which may have a substituent;   (17) 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
A benzene ring fused with a ~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C ₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino
, Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr with halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
The terror atoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^cSubstituent
And the benzene / heterocyclic fused ring has X or X at any position.
Bound to a tetrapeptide;   (18) Hete fused with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms
A 4- to 8-membered heterocycle having 1 to 4 atoms, each heterocycle being independently 1 to
It may be substituted with 4 groups, and each said substituent is independently C₁~ C₅Alkyl,
C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thi
Ono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each complex
The ring may be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cHas a substituent
Also good   A compound of the third genus represented by formula I or a pharmaceutically acceptable compound thereof
There is salt to be contained.

This third genus includes the group of compounds represented by Formula I wherein n is 1 or 2 or a pharmaceutically acceptable salt of the compound.

[0033]   In this third genus,   R_ThreeEach independently,   (1) hydrogen,   (2) halogen,   (3) OR^a,   (4) C₁~ C_FourAlkyl or   (5) C₁~ C_FourAryl;   R₆Each independently,   (1) O,   (2) S or   (3) It is H;   X is   (1) -CH_Two-,   (2) -C (O)-,   (3) = CH- or   (4) Non-existence And   R₁But   (1) R₇,   (2) C (O) R₇,   (3) CN,   (4) CO_TwoR^b,   (5) C (O) N (OR^b) R^c,   (6) C (O) NR^cR^d,   (7) NHCO_TwoR^b,   (8) NHC (O) NR^cR^d,   (9) (C₀~ C_FourAlkyl) OR^a,   (10) (C₀~ C_FourAlkyl) OCO_TwoR^b,   (11) (C₀~ C_FourAlkyl) OC (O) NR^cR^d,   (12) C (O) NR^cNR^cR^d,   (13) C (O) NR^cSO_TwoR^b,   (14) OS (O)_niR₇,   (15) NR^bS (O)_niR₇(Ni is 0 to 2),   (16) 3 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C ₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono
, OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O
) NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr ha
Rogen, each substituent can be saturated, partially unsaturated or fully unsaturated
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R ^c Those which may have a substituent;   (17) 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
A benzene ring fused with a ~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C ₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino
, Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr with halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
The terror atoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^cSubstituent
And the benzene / heterocyclic fused ring has X or X at any position.
Bound to a tetrapeptide;   (18) Hete fused with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms
A 4- to 8-membered heterocycle having 1 to 4 atoms, each heterocycle being independently 1 to
It may be substituted with 4 groups, and each said substituent is independently C₁~ C₅Alkyl,
C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thi
Ono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each complex
The ring may be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cHas a substituent
Also good   A group of compounds represented by Formula I or pharmaceutically acceptable compounds thereof
There is salt.

Within the above group of compounds are the subgroups of compounds represented by Formula I wherein n is 1 or 2 or pharmaceutically acceptable salts of the compounds.

In one aspect the invention provides a novel cyclic tetrapeptide represented by formula I wherein X is preferably —CH ₂ —.

In another aspect the invention provides a novel cyclic tetrapeptide represented by formula I, wherein X is preferably —C (O) —.

In yet another aspect, the invention provides a novel cyclic tetrapeptide represented by formula I, wherein X is preferably absent.

[0038]   In yet another aspect, the invention provides R₁Is preferably substituted with 1 to 4 groups
A 3- to 8-membered heterocycle having 1 to 4 heteroatoms, which may be
The substituents are independently C₁~ C₅Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfume
Oroalkyl, NR^cR^d, Oxo, thiono, OR^a, S (O)_niR^a(Ni
= 0, 1 or 2), C (O) R^a, C (O) NR^cR^d, Cyano, (C₀~ C ₆ Alkyl) aryl, CO_TwoR^bOr halogen, each substituent is saturated,
May be partially unsaturated or fully unsaturated, wherein the heteroatoms are
Oxygen, sulfur or nitrogen, wherein the nitrogen is R^cWhich may have a substituent
There is provided a novel cyclic tetrapeptide represented by certain Formula I.

In yet another aspect, the present invention provides a benzene ring fused with a 4-8 membered heterocycle wherein R ₁ preferably has 1 to 4 heteroatoms optionally substituted with 1 to 4 groups. Wherein each said substituent is independently C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₁ -C ₅ perfluoroalkyl, amino, oxo, thiono, C (O) NR ^c R ^d , cyano. , CO ₂ R ^b or halogen, each substituent can be saturated, partially unsaturated or fully unsaturated, said heteroatoms are each independently oxygen, sulfur or nitrogen and said nitrogen is R ^c substituted. There is provided a novel cyclic tetrapeptide represented by formula I, which may have a group, wherein said fused benzene / heterocyclic ring is attached to X or a tetrapeptide at any position.

In yet another aspect, the invention provides a 4-8 membered R ₁ having 1 to 4 heteroatoms fused with a second 4-8 membered heterocyclic ring, preferably having 1 to 4 heteroatoms. A heterocycle of, wherein each heterocycle may be independently substituted with 1 to 4 groups,
Wherein each substituent is _C 1 -C ₅ alkyl _{independently,} C 2 -C _{5 alkenyl,} C 1 -C ₅ perfluoroalkyl, amino, oxo, ^{thiono, C (O) NR c R} d, cyano, _CO 2 R ^b or halogen, each heterocycle may be saturated, partially unsaturated or fully unsaturated, said heteroatoms are each independently oxygen, sulfur or nitrogen, said nitrogen having an R ^c substituent. There is provided a novel cyclic tetrapeptide represented by Formula I, which is optional.

In yet another aspect, the present invention relates to Examples 2, 3a, 3b, 3d, 10, 11
, 12d, 12e, 17 or 18 are novel cyclic tetrapeptides represented by Formula I.

[0042]

[Chemical 6]

In yet another aspect, the present invention provides examples 22a, 22b, 23a, 23b,
There is provided a novel cyclic tetrapeptide represented by Formula I which is a compound of 145, 146c, 146d, 146e, 146f or 147.

[0044]

[Chemical 7]

In yet another aspect, the invention provides Examples 21a, 21b, 24a, 24b,
26, 27, 28, 29, 30, 32, 37, 39, 43, 44, 46, 51,
There is provided a novel cyclic tetrapeptide represented by Formula I which is a compound of 56a, 63, 64 or 67.

[0046]

[Chemical 8]

In yet another aspect, the invention provides Examples 69, 70, 72, 73, 74a,
74b, 74c, 74d, 74e, 74f, 74g, 74h, 74i, 74j,
Provided are novel cyclic tetrapeptides represented by Formula I which are compounds of 75, 79, 91, 93, 97, 98, 129a or 129b.

[0048]

[Chemical 9]

In yet another aspect, the invention provides embodiments 132a, 133, 135, 138.
, 139a, 139b, 139c, 139d, 139e, 139f, 139g,
139h, 139i, 139j, 140, 141, 142, 144b, 144d
, 144f, 158, 159, 160, 162a or 162b are novel cyclic tetrapeptides represented by Formula I.

In yet another aspect, the invention provides embodiments 102, 103, 108a or 1.
There is provided a novel cyclic tetrapeptide represented by Formula I which is a compound of 08b.

In yet another aspect, the invention provides a novel cyclic tetrapeptide represented by Formula I which is a compound of Example 109 or 110.

In yet another aspect, the invention provides a novel cyclic tetrapeptide represented by Formula I, which is a compound of Example 168.

In yet another aspect, the invention provides Examples 156, 157a, 157b, 15
There is provided a novel cyclic tetrapeptide represented by Formula I which is a compound of 7c or 157d.

In yet another aspect, the invention provides novel cyclic tetrapeptides represented by Formula I, which are the compounds below.

[0055]

[Chemical 10]

In yet another aspect, the invention provides novel cyclic tetrapeptides represented by Formula I, which are the compounds below.

[0057]

[Chemical 11]

In yet another aspect, the invention provides a novel cyclic tetrapeptide represented by Formula I, which is the compound of Example 153 or 154.

In yet another aspect, the invention provides a method of treating a protozoal infection, wherein a host having a protozoal infection is administered a therapeutically effective amount of a novel compound of the invention that inhibits histone deacetylase. A method having steps is provided. A therapeutically effective amount is an amount sufficient to suppress and overcome infection by inhibiting the histone deacetylase activity of the causative protozoan. The invention further provides a method of preventing protozoal infections, the method comprising administering to a host an effective prophylactic amount of a novel compound of the invention that inhibits histone deacetylase. An effective prophylactic amount is an amount sufficient to inhibit infection of the host.

In yet another aspect, the invention provides a composition useful in the treatment or prevention of a protozoal infection, the composition comprising an inert carrier and an effective amount of a compound of formula I.

As used herein, “alkyl” as well as other groups having the prefix “alk”, such as certain alkoxy, alkanoyl, alkenyl, alkynyl, etc., may be linear or branched or combinations thereof. Means a carbon chain capable of Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. “Alkenyl” and “alkynyl” and other like terms include carbon chains having one or more unsaturated C—C bonds.

The term “cycloalkyl” means carbocycles containing no heteroatoms, including saturated, monocyclic, bicyclic and tricyclic carbocycles, as well as fused ring systems. Such fused ring systems can include rings that are partially or fully unsaturated such as benzene rings to form fused ring systems such as benzofused carbocycles. Cycloalkyl includes fused rings such as spiro fused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthalene and the like. Similarly, “cycloalkenyl” means a carbocycle having no heteroatoms and having one or more non-aromatic C—C double bonds, monocyclic, bicyclic and tricyclic partially unsaturated. Examples include carbocyclic and benzo-fused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl and the like.

The term “halogen” includes fluorine, chlorine, bromine and iodine atoms.

Unless otherwise indicated, the term “heterocycle” is defined above for cycloalkyl and cycloalkenyl where one or more of the atoms in the atomic groups forming the backbone of the ring is a sulfur, oxygen or nitrogen atom. It means a ring system such as those described. Such heterocycles include saturated or partially unsaturated monocyclic or bicyclic compounds, and benzo or heteroaromatic ring fused saturated or partially unsaturated heterocycles, independent of oxygen, sulfur and nitrogen. And those having 1 to 4 heteroatoms selected for. Examples of saturated heterocycles include morpholine, thiomorpholine, piperidine, piperazi, tetrahydropyran, tetrahydrofuran, dioxane, tetrahydrothiophene, oxazolidine, pyrrolidine, and the like, and examples of partially unsaturated heterocycles include dihydropyran, dihydropyridazine, Examples include dihydrofuran, dihydrooxazole, dihydropyrazole, dihydropyridine and dihydropyridazine. Benzo or heteroaromatic fused heterocycles include 2,3-dihydrobenzofuranyl, benzopyranyl, tetrahydroquinoline, tetrahydroisoquinoline, benzomorpholinyl, 1,4-benzodioxanyl, 2,3-dihydrofuro (
2,3-b) pyridyl and the like.

The term “aryl” is 0 to independently selected from nitrogen, oxygen and sulfur.
It is intended to include monocyclic and bicyclic aromatic and heteroaromatic rings having 5 heteroatoms. The term "aryl" is also meant to include benzofused cycloalkyl, benzofused cycloalkenyl and benzofused heterocyclic groups. Examples of "aryl" groups are phenyl, pyrrolyl, isoxazolyl, pyrazinyl, pyridinyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidinyl, pyridazinyl,
Pyrazinyl, naphthyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furo (2,3-B) pyridyl, 2,3-dihydrofuro (2,3-b) pyridyl, benzoxazinyl, benzothiophenyl, quinolinyl , Indolyl, 2,3-dihydrobenzofuranyl, benzopyrazinyl, 1,4
-Benzodioxanyl, indanyl, indenyl, fluorenyl, 1,2,3,
4-tetrahydronaphthalene and the like.

Aroyl means arylcarbonyl in which aryl is as defined above.

3 having 0-2 additional heteroatoms selected from O, S (O) _m and N
Examples of NR ^c R ^d or NR ^g R ^h forming a 10-membered ring include aziridine, azetidine, pyrrolidine, piperidine, thiomorpholine, morpholine, piperazine, octahydroindole, tetrahydroisoquinoline and the like.

The term “C ₀ ” means that no carbon is present. Therefore, "C ₀ ~
C ₅ "is the presence of zero to five carbons, ie 5, 4, 3,
It means that there are 2, 1 or zero carbons.

The term “optionally substituted” is meant to include both substituted and unsubstituted. Thus, for example, an optionally substituted aryl could represent a pentafluorophenyl or phenyl ring.

The compounds described herein have one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. included. Formula I above is shown without definitive stereochemistry at certain positions. The present invention includes all stereoisomers of formula I. Also included are mixtures of stereoisomers as well as individual specific stereoisomers. During the synthetic procedures used to prepare such compounds, or when performing racemization or epimerization procedures known to those of skill in the art, the products of such procedures are mixtures of stereoisomers. May be.

The term “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (cupric and cuprous), ferric, ferrous,
Examples include salts of lithium, magnesium, manganese (secondary manganese and primary manganese), potassium, sodium, zinc and the like. Especially preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary salts.
Included are primary amines, and substituted amines such as cyclic amines and natural and synthetic substituted amines. Other salt-forming pharmaceutically acceptable organic non-toxic bases include ion exchange resins. Examples include arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, Glucamine,
Glucosamine, histidine, hydrabamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, such as inorganic and organic acids. Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, Examples include malic acid, mandelic acid, methanesulfonic acid, mucus acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like. Particularly preferred are citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid.

The idea of inhibition of histone deacetylase as a target for antiprotozoal compounds is
It is described in pending US patent application Ser. No. 09 / 296,834 filed April 22, 1999 and US patent application Ser. No. 08/716978 filed September 20, 1996. Known compounds that are considered to be useful in the treatment of protozoal diseases because they can be histone deacetylase inhibitors include trichostatin A, trapoxin A and B, HC-toxin, chlamidocin, Cly-2, WF-3161, T
an-1746, apicidin and their analogs. Trapoxin A was reported by Itazaki et al. (Itazaki et al., J. Antibiot. 43 , 1524-1532 (1990).
)), And HC-toxin is reported by Leish et al. (Liesch et al., Te
trahedron 38 , 45-48 (1982)), clamidosine is described in the report by Crosse et al. (Closse et al., Helv. Chim. Acta 57 , 533-545 (1974)), and Cly- 2 is a report by Hirota et al. (Hirota et al., Agri. Biol. Chem., 37 , 95
5-56 (1973)), and Tan-176 is described in Japanese Patent No. 7196686. Unlike the ethylketone side chain found in apicidin, HC toxin, clamidosine, trapoxin A and trapoxin B have C8α-keto epoxide functional groups.

Apicidin and its analogs referred to herein are represented by the following chemical formulas:

[0075]

[Chemical 12]

[0076]   For example:

[0077]

[Table 1]

These compounds are pending US patent application No. 0, filed July 27, 1994.
No. 08/4476 filed on Aug. 23, 1995 and May 23, 1995
64. These compounds are manufactured from the Fusarium strains disclosed in these applications.

The compounds of the present invention have been found to be histone deacetylase inhibitors. Therefore, the compounds may be useful in the treatment and prevention of protozoal diseases in humans and animals, including poultry. Examples of protozoal diseases for which a histone deacetylase inhibitor can be used include 1) amebiasis (dinuclear amoeba such as Entamoeba histolytica); and 2) giardia lamblia. 3) Malaria (P. vivax, P. falciparum, P. m)
Malaria parasites such as alariae and P. ovale); 4) Leishmaniasis (L. dono
Leishmanias such as vani, L. tropica, L. mexicana and L. braziliensis); 5) Trypanosomiasis and Chagas disease (T. brucei, T. theileri, T. r.
hodesiense, T. gambiense, T. evansi, T. equiperdum, T. equinum, T. congol
trypanosomes such as ense, T. vivax and T. cruzi); toxoplasmosis (
Toxoplasma gondii); 7) Neospora caninum; 8) Babesiosis (Babesia); 9) Cryptosporidiosis (Cryptosporidium);
10) Shigellosis (Valentinideum large intestine); 11) T. vaginitis and T. foetu
Trichomonas such as s); 12) Coccidiosis (E. tenella, E. necatrix,
E. acervulina, E. maxima and E. brunetti, E. mitis, E. bovis, E. melagr
Eimeria and isospora such as amatis); 13) Intestinal hepatitis (Histomonas g
allinarum); 14) Anaplasmas, vesnoitia, leucocytozones,
Included are infections caused by microspores, spores, theileria, and Pneumocystis carinii.

The histone deacetylase inhibitory compounds and compositions of the present invention are preferably used in the treatment or prevention of a protozoal infection caused by a protozoan of the subphylum Apicomplexans. More preferably the compounds and compositions are i
) Use in the treatment or prevention of malaria, toxoplasmosis, cryptosporidiosis and trypanosomiasis in humans and animals, and ii) in the management of coccidiosis, especially in poultry, for the purpose of treating coccidiosis or preventing the development of such infections. To be done.

When chronically administering the histone deacetylase-inhibiting compounds and compositions of the invention, such as in the prevention of coccidiosis in poultry, the histone deacetylase inhibitor is preferably more preferred than the host histone deacetylase. It is selective for protozoan histone deacetylases. Such selective inhibitors are believed to reduce the deleterious effects of histone deacetylase inhibition on the host over an extended period of time.

Two specific examples of the method for preventing the occurrence of protozoan infections in humans and animals by administering an effective preventive amount of a histone deacetylase inhibitor according to the present invention will be given below. 1) Malaria parasites in endemic areas (malaria) There is prevention of infection, and 2) prevention of coccidiosis in poultry. The histone deacetylase inhibiting compound may conveniently be administered continuously in feed or drinking water, or it may be administered orally or parenterally on a regular basis.

Malaria is the number one cause of death in the world. The disease is transmitted by mosquitoes in specific areas and the infection can progress very rapidly to life-threatening. Therefore, residents or visitors in areas where the mosquitoes that carry malaria routinely live receive prophylactic drugs to prevent infection. Thus, according to one embodiment of the invention, the histone deacetylase inhibitor is administered orally or parenterally, preferably in a dose range of about 0.01 mg / kg to about 100 mg / kg each, once or more daily. . The compound can be administered over the entire period of time that the patient or animal is at risk of developing a parasitic infection.

Coccidiosis is a disease that can occur in humans and animals and is caused by several coccidiosis. The economically most important coccidiosis is a disease of poultry. Coccidiosis in poultry is caused by a parasite protozoan of the genus Eimeria. The disease can spread very rapidly throughout the bird population via contaminated stools. This parasite destroys intestinal tissues and damages the intestinal lining, thereby inhibiting nutrient absorption. Since outbreaks of coccidiosis in poultry houses can pose a significant economic loss to poultry farmers, it has become standard practice to use anticoccidial agents prophylactically in poultry feed. Thus, according to another embodiment of the present invention, a histone deacetylase inhibitor is placed in the feed or drinking water over the life of the poultry or some portion thereof to obtain about 0.1 ppm to about 500 ppm of the feed or drinking water. It is administered in a range of doses.

To treat established parasitic infections in humans or animals, a histone deacetylase inhibitor is conveniently administered orally or parenterally when the infection is suspected or diagnosed. The duration of treatment will vary depending on the particular parasitic disease and the severity of its infection. Generally, treatment is continued until the parasite is effectively eradicated or the symptoms of the disease are resolved. Two specific examples of the method of the present invention for treating a protozoal infection by administering a therapeutically effective amount of a histone deacetylase inhibitor include: 1) treatment of Crytosporidium parvum infection in animals or humans and 2) humans. There is treatment for acute falciparum malaria in.

Crytosporidium parvum is a protozoan parasite that infects and destroys the cells that make up the lining of the human and animal intestinal tract. The infection takes root very rapidly, causing acute symptoms in the patient. In humans, patients develop severe dysentery over 5-7 days. In immunocompromised patients, C. parvum infection may persist,
May be life threatening. In animals, C. parvum infection is the leading cause of death in young dairy cows. C. parvum infection can be easily diagnosed by symptoms and stool sample examination. If the disease is suspected or diagnosed, administration of a histone deacetylase inhibitor according to the method of the present invention can be started. Dosages preferably range from about 0.01 mg / kg to about 500 mg / kg. Histone deacetylase is administered orally or parenterally once or more daily until the infection disappears. The dosing period typically ranges from about 1 to 3 weeks.

Plasmodium falciparum causes acute and life-threatening malaria infections in humans. If left untreated, infections often result in death of the patient. Malaria infections can be easily diagnosed by examination of symptoms and patient blood sample. It is thought that treatment will be started after the diagnosis. According to one embodiment of the present invention, the histone deacetylase inhibitor is administered orally or parenterally once or more times a day until the infection disappears. The dose is preferably about 0.01 mg / kg to about 20.
The range is 0 mg / kg.

The histone deacetylase inhibitory composition of the present invention can be administered to a host in need of treatment in a manner similar to the method used for other known antiprotozoal drugs. For example, the composition may be administered parenterally, orally, topically or rectally.
The dose administered will vary with the particular compound used, the infectious agent involved, the particular host, the severity of the disease, the physical condition of the host and the route of administration chosen. Appropriate doses can be readily determined by one of ordinary skill in the art. For treatment of protozoal diseases in humans and animals, the dose is preferably about 0.01 mg / kg to about 500 mg /
It is in the range of kg. For prophylactic use in humans and animals, the dose is preferably about 0.
． It ranges from 01 mg / kg to about 100 mg / kg. Especially for use as an anticoccidial drug in poultry, the compounds are preferably administered in animal feed or drinking water. Doses preferably range from about 0.1 ppm to about 500 ppm.

In one aspect, the composition of the invention comprises a histone deacetylase inhibitor and an inert carrier. Such compositions include pharmaceutical compositions for humans and animals and feed compositions for controlling coccidiosis in poultry.

The pharmaceutical composition of the present invention comprises a histone deacetylase inhibitor as an active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. The compositions include those suitable for oral, rectal, topical and parenteral (subcutaneous, muscular and intravenous, etc.). However, the most suitable route for a particular case is
It will depend on the particular host and the nature and severity of the condition for which the active ingredient is administered. The pharmaceutical composition is conveniently presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy.

In practice, the histone deacetylase inhibitors of the present invention can be combined as the active ingredient in direct admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, eg oral or parenteral (including intravenous). Therefore, the pharmaceutical composition of the present invention can be provided as individual units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of active ingredient. Furthermore, this composition is a powder, granule, liquid,
It can be provided as a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. In addition to the usual formulations described above, the histone deacetylase inhibitor can also be administered by sustained release means and / or administration devices. The composition may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both. The product can be easily shaped into the desired shape.

A simple pharmaceutical medium can be used in the production of the composition for oral formulation. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions. On the other hand, carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like can be used to form oral solid preparations such as powders, capsules and tablets. Tablets and capsules with solid pharmaceutical carriers are the preferred oral dosage units because of ease of administration. If desired, tablets may be coated by standard aqueous or non-aqueous methods.

A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets are obtained by compressing the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersant, on a suitable machine. It can be manufactured. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 1 mg to about 500 mg of the active ingredient and each cachet or capsule containing from about 1 mg to about 500 mg of the active ingredient.

Pharmaceutical compositions of the invention suitable for parenteral administration may be prepared as a solution or suspension of the active compound in water. Suitable surfactants can include, for example, hydroxypropyl cellulose. Dispersions can also be prepared in glycerin, liquid polyethylene glycols and their mixtures in oil. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the composition can be in the form of a sterile powder for the immediate preparation of such sterile aqueous solutions or dispersions. In all cases, the ultimate injectable form must be sterile and must be fluid to the extent that easy syringability exists. Since the pharmaceutical composition must be stable under the conditions of manufacture and storage, it must preferably 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, polyhydric alcohols (eg, glycerin, propylene glycol and liquid polyethylene glycol), vegetable oils and suitable mixtures thereof.

The pharmaceutical composition of the present invention may be in a form suitable for topical use such as aerosol, cream, ointment, lotion, dusting powder and the like. Further, the composition can be in a form suitable for use in transdermal devices. These formulations can be manufactured using the histone deacetylase inhibiting compounds of the invention by conventional processing methods. By way of example, a cream or ointment is prepared by mixing a hydrophilic material and water with about 5% to about 10% by weight of the compound to produce a cream or ointment having the desired viscosity.

The pharmaceutical composition of the present invention can be in a form suitable for rectal administration, in which the carrier is a solid. The mixture preferably forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and molding.

In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparations are appropriately added to the above-mentioned pharmaceutical preparations such as diluents, buffers, flavors, binders, surfactants, thickeners, lubricants, preservatives (antioxidants, etc.). One or more additional carrier components such as can be included. In addition, other adjuvants can be included to make the formulation isotonic with the intended recipient's blood.

As noted above, the histone deacetylase inhibitors of the present invention can be administered as a component of a feed composition to control coccidiosis in poultry. For poultry feed, preferably about 1 ppm to about 1000 ppm, more preferably about 10 ppm.
˜150 ppm of a histone deacetylase inhibitor of the present invention. The optimum level varies depending on the type of Eimeria involved and can be easily determined by those skilled in the art. The histone deacetylase inhibitor of the present invention is added to the feed at about 0.
It is preferably added to the poultry feed in an amount of 01% to about 0.1% by weight. The compositions of the present invention are particularly useful in controlling diseases associated with coccidia. A preferred concentration for similar inhibition of enteric species is from about 0.01% to about 0.1% by weight of the feed. About 0.
Amounts from 01% to about 0.1% by weight are advantageous in reducing the pathogenic effects of both fecal and enteric coccidiosis.

In the production of poultry feed incorporating the compositions of the present invention, the histone deacetylase inhibitor may be simply added, for example by i) mechanically admixing the poultry feed with fines, or ii) first It can be mixed with the formulation (to produce a premix) and then dispersed by mixing with other poultry feed ingredients. Typical poultry feed ingredients include molasses, fermentation residues, corn meal, oat flour and pressed oats, wheat bran and secondary products, alfalfa, clover, which are used with mineral supplements such as bone meal, calcium carbonate and vitamins. And meat powder.

Compositions containing a compound of formula I may be prepared in powder or liquid concentrate form. According to standard animal formulation practice, conventional water-soluble excipients such as lactose or sucrose can be incorporated into powders to improve their physical properties. It is preferred to include from about 50% to about 100%, more preferably from about 60% to about 80% by weight of the compound in the powder composition of the present invention. The dust can be added to the animal feed, for example by an intermediate premix, or it can be added to the animal drinking water by dilution.

The liquid concentrate of the present invention preferably contains a compounding agent of a water-soluble compound, and may further contain a veterinarily acceptable water-miscible solvent. For example polyethylene glycol, propylene glycol, glycerin or glycerin forearl (gl
A solvent such as ycerol formal) can be mixed with up to 30% by volume of ethanol. Liquid concentrates of the invention preferably contain from about 50% to about 100%, more preferably from about 60% to about 80% by weight of the compound. Liquid concentrates can be administered in addition to the drinking water of animals, especially poultry.

The following examples are provided to further illustrate the present invention, but they should not be construed as limiting the scope of the claims in any way.

[0104]   Preparation of side chain modified apicidin analog   Referring to Scheme I below, apicidin is substituted with an α-substituted analog 4 and
Can be converted to 5.

[0105]

[Chemical 13]

[0106]   First, LiN (iPr)_Two, NaN (SiMe_Three)_Two, KN (SiMe_Three) _Two -78 with a suitable amine base such as, but not limited to,
Apicidin is enolized in the temperature range of 0 ° C to 0 ° C to form the enolate.
The amine base is preferably KN (SiMe_Three)_TwoIs. Suitable solvents for this reaction
, Et_TwoO, dioxane, tetrahydrofuran (THF), dimethoxyethane
However, the present invention is not limited to these. The solvent is preferably THF
. The enolate is converted to MeI, EtI, allyl bromide, benzyl bromide, PhSeCl,
PhSCl, PhSSPh, (MeO)_TwoP (O) Cl, (CF_TwoSO_Two)_TwoO
, Et_ThreeSiCl, tBu (Me)_TwoSiCl, (nPr)_ThreeSiCl, Me_Three SiCl, Ph (Me)_TwoSuch as, but not limited to, SiCl
Reaction with a suitable electrophile RX to form a silyl enol ether. Electromotive
The agent is preferably Me_ThreeIt is SiCl.

[0107]   The silyl enol ether thus produced was converted to H_TwoO_Two, TBuOOH, M
e_ThreeSiOOH, AcOOH, dimethyldioxirane, etc., or MCPBA
With an oxidant such as (but not limited to) (metachloroperbenzoic acid)
, -78 ° C to RT (room temperature), preferably 0 ° C to RT.
Then, the corresponding α-silyloxyketone compound 4a / 5a is produced. Then CH _Two Cl_Two, CHCl_Three, MeOH, EtOH, iPrOH, THF, Et_TwoO oh
Protic or non-protonic, such as but not limited to, and dioxane
HCl, H in a protic solvent at a temperature of 0 ° C. to 50 ° C._TwoSO_Four, HBF_Four,vinegar
Acid, PPTS (pyridinium p-toluenesulfonate), TsOH (p-toluene)
Sulfonyl hydroxide), HF, HF / pyridine or nBu_FourNF etc.
(But not limited to these) silyl protecting groups using various acids or fluorine sources.
Is removed to form the α-hydroxyketone compound 4d / 5d.

The α-hydroxyketone compound 4d / 5d can be separated, if desired, or can be used without further separation. Compound 4d / 5
d is swell acid oxidation, Dess-Martin oxidation, PCC (pyridinium chlorochromate), PDC (pyridinium dichromate, moffat oxidation, etc.), or most preferably toluene, CH ₂ Cl ₂ , CHCl _3, etc. (limited to these. TPAP / NMO (tetrapropylammonium perruthenium (VII) / 4-methylmorpholine N at temperatures ranging from −78 ° C. to room temperature)
-Oxide) and the like (but not limited thereto) can oxidize to the corresponding diketone, compound 4e / 5e.

The α-hydroxyketone compound 4d / 5d can be obtained by converting Ph ₃ P / CBr ₄ at a temperature of −78 ° C. to room temperature in a solvent such as CH ₂ Cl ₂ , CHCl ₃ , benzene or toluene.
Ph ₃ P / I ₂ , PH ₃ P / CCl ₄ , Ph ₃ P / CHCl ₂ CHCl ₂ , DA
By treatment with ST (diethylaminosulfur trifluoride), morpholinyl sulfur trifluoride or the like, it can be converted into a corresponding α-haloketone compound such as 4f / 5f.

Α-Hydroxyketone compounds 4d / 5d are NaIO ₄ , HIO ₄ , Amberlite® IRA-904 ion exchange resin available from Aldrich Chemical Compan, Milwaukee, Wisconsin. , NaIO ₄ , KIO ₄ and nBu ₄ NIO ₄ , or most preferably P
treated with an oxidizing agent such as (but not limited to) b (OAc) ₄ ,
C7-aldehyde compound 6 and C8-methyl ester compound 7 can be obtained by oxidative cleavage reaction. This oxidative cleavage reaction is carried out with water, EtOH, iPrO.
H (isopropanol), tBuOH (tert-butanol), may be performed acetone, ether, THF, benzene, _{toluene, CH 2 Cl 2, CHCl 3} , or most preferably in various solvents or solvent mixture such as MeOH.
Generally, the oxidative cleavage reaction is conducted at a temperature of about -78 ° C to about 80 ° C. When using MeOH, the reaction should be run at -20 ° C to room temperature. This oxidative cleavage reaction can be improved by adding a base such as but not limited to NaHCO ₃ , Et ₃ N, EtN (iPr) ₂ , lutidine, or most preferably pyridine. The oxidative cleavage reaction is completed in about 5 minutes to about 24 hours.

Referring to Scheme II below, phenisulfide compound 4c / 5c or phenyl selenide compound 4b / 5b, which is an analog of apicidin, can be converted into toluene, CHCl ₃ , MeOH, water or most preferably CH ₂ Cl _2. Oxone, MCPBA, tBuOOH, AcOOH, NaIO ₄ , dimethyldioxirane, etc. in a solvent or solvent mixture of (but not limited to) -20 ° C to 50 ° C, or most preferably H. Oxidation with reagents such as (but not limited to) ₂ O ₂ to the corresponding sulfoxide or selenoxide compounds (not shown).

[0112]

[Chemical 14]

Although only the compound 4b / 5b is shown as the starting compound in the scheme II, the same scheme is directly applied when 4c / 5c is used as the starting compound. Sulfoxides and selenoxides can be converted to R in a solvent such as CH ₂ Cl ₂ , CHCl ₃ , MeOH or most preferably toluene (but not limited to).
Thermal desorption at temperatures ranging from T to 110 ° C. yields the corresponding enone compounds 8 and 9
To generate.

The enone compounds 8 and 9 are present in a solvent or solvent mixture such as but not limited to toluene, CHCl ₃ , MeOH or most preferably CH ₂ Cl _{2 in} the range of -20 ° C to RT. At temperature, dimethyldioxirane, H ₂ O ₂ ,
It can be epoxidized with a suitable epoxidizing agent such as (but not limited to) tBuOOH, AcOOH (not shown).

The enone compounds 8 and 9 can also be dihydroxylated with OsO ₄ under conditions known to those skilled in the art to form the corresponding diols. Osmium tetroxide can be used in stoichiometric or catalytic amounts in the presence of (but not limited to) oxidants such as morpholine N-oxide, triethylamine N-oxide, hydrogen peroxide, and tert-butyl hydroperoxide. Can be used.
The dihydroxylation reaction is carried out in various solvents or solvent mixtures. The solvent is
Included are both protic and aprotic solvents such as water, MeOH, EtOH, tert-butanol, ether, THF, benzene, pyridine, acetone. The dihydroxylation reaction is carried out at a temperature of -78 ° C to 80 ° C and is completed in 5 minutes to 24 hours. The diol product so obtained can be subjected to oxidative cleavage according to the methods described above for compounds 6 and 7 to afford C6-aldehyde compounds 10 and C8 methyl ester compounds from compounds 8 and 9, respectively.

Referring to Scheme III below, the C8-ketone group of apicidin can be the starting point for analog synthesis.

[0117]

[Chemical 15]

[0118] _{R 11b, R 11c, R 11d} , R 11f1, R 11f2, R 11g, R 11 h, independently to _{R 11i1,} R 11i2 and _{R 11k,} is an optionally substituted alkyl group or an aryl group .

According to Scheme III, the side chain C8-ketone group is represented by LiBH ₄ , LiAlH ₄ , D
IBAL-H (diisobutylaluminum hydride), K-Selectride (registered trademark; K-Selectride: potassium trisec-butyl borohydride) commercially available from Aldrich Chemical Company, Milwaukee, Wisconsin,
L-Selectride (registered trademark; lithium triborohydride-sec-butyl) commercially available from Aldrich, Alpine-Borane (registered trademark; Al) commercially available from Aldrich
pine-Borane: B-isopinocampheyl-9-borabicyclo [3.3.1]-
Nonane), or most preferably (but not limited to) NaBH _{4 and the} like, can be reduced using reagents known to those skilled in the art to provide C8 alcohol compound 11a. These reduction reactions may be performed on a protic or non-proton basis such as but not limited to THF, ether, dimethyl ether, dioxane, EtOH, CH ₂ Cl ₂ , EtOAc, CHCl ₃ , benzene, toluene or most preferably MeOH. It can be carried out in a protic solvent at a temperature of −78 ° C. to RT.

The side chain C8-ketone group of apicidin is RMgBr, RMgCl, RMgI, R
The substituted alcohol compound 11b can also be formed by treatment with Li, R ₂ CuLi, RCeCl ₂ Li, or the like. In these RLi, RLiX or RMgX type reactants, R is an alkyl group or an aryl group, and these alkyl group and aryl group may be substituted. These substitution reactions may be carried out with Et ₂ O, dioxane, HMPA (hexamethylphosphoramide), DMSO, NMP (1-methyl-2-pyrrolidinone), dimethoxyethane, etc. or most preferably THF.
In a solvent or solvent mixture such as (but not limited to) -78 ° C.
It can be carried out at a temperature of ~ RT and is completed in 5 minutes to 12 hours.

[0121]   The C8-alcohol compound 11a formed as described above is a known alcohol.
, Acylation using the acylation, sulfonylation and alkylation methods of
Alternatively, by sulfonylation, the apicidin derivative compound 11c or 11d
Obtainable. Acylation is then carried out according to general procedures known to those skilled in the art,
Acid anhydrides, acid chlorides, chloroformates, carbamoyl chlorides, Cl
C (S) OPh (F₅), Thiocarbonyldiimidazole, isocyanates
Any reagent and amine base can be used. Sulfonylation is sulfo
It can be carried out using nyl chlorides or sulfonic anhydrides. Alkyl
Cation is performed using alkyl halides or trichloroacetimidates
be able to. Suitable solvents for these reactions include benzene, toluene, CHCl. _Three , CH_TwoClCH_TwoCl etc. or most preferably CH_TwoCl_TwoAnd so on,
It can be performed at a temperature of -40 ° C to 80 ° C.

The hydroxyl group at the C8 position of the compound 11a is determined by the Burgess reagent, Martin (M
can be eliminated using the sulfuran reagent from Artin) or by treating compound 11d with a base to form a mixture of C6, C7- and C7, C8-olefin isomers. Suitable _{bases, CH 2 Cl 2, CHCl 3} , toluene, benzene, MeOH, EtOH, in a solvent such as pyridine, 0 ° C. to 110 ° C. of the temperature in _{Et 3 N, EtN (iPr)} 2, NaOMe, KOtBu , etc. Or most preferably, but not limited to, DBU and the like. Compound 11a
The C8-hydroxyl group of can also be eliminated by reduction via the intermediate compound 11c where R is OPh, OPh (F ₅ ), Set etc. or most preferably N-1-imidazolyl. Intermediate compound 11c can be prepared by oxidizing oxygen in a solvent such as but not limited to CH ₂ Cl ₂ , CHCl ₃ , benzene, MeOH, EtOH or most preferably toluene at a temperature of −78 ° C. to 110 ° C. / Et ₃ B
, AIBN (2,2'-azobisisobutyronitrile), a radical initiator such as benzoyl peroxide, and _{ii) Et 3 SiH, Me 3} SnH, Ph 3 SnH
, Ph ₃ AsH, nBu ₃ SnCl / NaBH _4, etc. or most preferably nB
treated with a hydride source such as (but not limited to) u ₃ SnH,
Compound 11e is formed.

Apicidin can be treated with a mono- or di-substituted amine, a hydride source and a proton source to form compound 11f. Suitable solvents include, but are not limited to, benzene, toluene, EtOH, iPrOH and the like or more preferably MeOH and the like. Suitable proton sources include TsOH, HCl
, HCO ₂ H, PPTS and the like or most preferably HOAc and the like, but not limited to. The intermediate imine, as produced, in situ,
Alternatively, it can be reduced after azeotropic removal of water using a Dean-Stark trap. Suitable reducing agents include LiAlH ₄ , NaBH ₄ , LiBH ₄ ,
H ₂ / (10% Pd / C) etc. or most preferably, but not limited to NaBH ₃ CN etc.

[0124] The oxime compound 11g and the hydrazone compound 11h are produced by treating apicidin with hydrazine in a solvent having a proton source. For example, apicidin can be treated with a mono- or di-substituted amine and a proton source.
Suitable solvents include, but are not limited to, benzene, toluene, EtOH, iPrOH and the like or more preferably MeOH and the like. Suitable proton sources include, but are not limited to, TsOH, HCl, HCO ₂ H, PPTS and the like or most preferably HOAc and the like.

Apicidin is treated with a stabilizing Wittig reagent, a destabilizing Wittig reagent or a Horner-Emmons reagent to form the unsaturated product, compound 11i. Suitable _{reagents, Ph 3 P = CH 2,} Ph 3 P = CHMe,
Ph ₃ P = CH (nPr), (MeO) ₂ P (O) CH ₂ CO ₂ Me, Ph ₃ P
═CH ₂ C (O) Me and the like, but are not limited thereto. These olefins are reacted with DMF (N, N-dimethylformamide), MeOH,
CH ₂ Cl _{2, toluene,} Et 2 O, MeCN, can be carried out in a solvent such as THF (but not limited to), it may be carried out at a temperature of -78 ° C. to 110 ° C.. Apicidin's C8 ketone is MeO at a temperature of -78 ° C to 50 ° C.
CH ₂ = N ₂ or Me ₃ SiCH = N ₂ in H, or Me ₃ S (O) I and tBuOK, nBuLi or more preferably in a solvent such as tBuOH, dimethoxyethane, THF, DMF, DMSO or more preferably HMPA. NaH
It can be converted into an epoxide (compound 11j) by treating with a strong base such as.

Introducing sulfur into C8 by treating compound 11d with a suitable sulfur-containing nucleophile,
Compound 11k can be formed. Suitable nucleophiles include NaSMe, KSAc
, HSPh / Et ₃ N, HSCH ₂ CH ₂ OH / EtN (iPr) _2, and the like. These reactions are based on MeOH, EtOH, DMF, DMSO, HMPA, NMP.
In a polar solvent such as, the reaction proceeds easily at a temperature of 0 ° C to 50 ° C.

Referring to Scheme IV below, the formation of compounds 12a and 12b by the Beckmann rearrangement is performed at temperatures of 0 ° C. to 50 ° C. such as POCl ₃ , SOCl ₂ , MeSO ₂ Cl, etc., or more preferably TsCl, etc. Can be induced by treating compound 11g with an acylating agent (not shown) and an amine base. Suitable amine bases include Et ₃ N, EtN (iPr) ₂ , lutidine,
DBU (1,8-diazabicyclo [5.4.0] undec-7-ene) and the like, or most preferably pyridine and the like. Pyridine may also serve as the solvent for this reaction or, alternatively, MeCN, benzene, toluene, dioxane and the like can be used.

[0128]

[Chemical 16]

Referring to Scheme V below, a C7-aldehyde compound 6 is prepared under conditions known in the art from a suitable such as NaOCl / HOAc / MeOH, tBuOCl / MeOH / pyridine, or most preferably PDC / DMF / MeOH. It is considered that the corresponding C7 methyl ester compound 13 can be oxidized by treatment with a different oxidizing agent. The C7 methyl ester compound 13 can be further used as a raw material for another derivative. Similarly, the C6-aldehyde compound 10 can be oxidized to its corresponding C6 methyl ester (not shown).

[0130]

[Chemical 17]

Referring to Scheme VI below, the methyl ester compounds 7 and 13 are
It can be converted into a series of esters, amides and ketones.

[0132]

[Chemical 18]

R _14a , R _14b1 and R _14b2 are each independently an _optionally substituted alkyl group or aryl group.

It is believed that saponification can be accomplished by treating compound 7 with a reagent such as but not limited to NaOH, KOH, Me ₃ SiOOK, LiOOH, or more preferably LiOH. . The solvent or solvent mixture includes
MeOH, EtOH, tBuOH, DMF, DMSO, HMPA, Et ₂ O, T
HF and water. The reaction proceeds at a temperature of 0 ° C to 100 ° C. Amide and ester formation was carried out using C8-carboxylic acid (compound 14a) so prepared using standard ester and amide forming reagents known to those skilled in the art.
Can be carried out by reacting. The esterification reaction is carried out with at least 1 equivalent of alcohol HOR. Preferably 10 to 100 equivalents of alcohol are used, but the esterification can be carried out using alcohol as the solvent. Esterification reagents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl), diisopropylcarbodiimide, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium.hexafluoro. Phosphate (BOP), bis (
2-oxo-3-oxazolidinyl) phosphine chloride (BOP-Cl),
Benzotriazol-1-yl-oxo-tris-pyrrolidino-phosphonium
Hexafluorophosphate (PyBOP), chloro-tris-pyrrolidino-phosphonium hexafluorophosphate (PyClOP), bromo-tris-
Pyrrolidino-phosphonium hexafluorophosphate (PyBrOP), diphenylphosphoryl azide (DPPA), 2- (1H-benzotriazole-1)
-Yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), O-benzotriazol-1-yl-N, N, N ', N'-
Examples include (but are not limited to) bis (pentamethylene) uronium hexafluorophosphate and 2-chloro-1-methylpyridinium iodide. This ester forming reaction is carried out using N-hydroxybenzotriazole, N-
Hydroxy-7-aza-benzotriazole, 4- (N, N-dimethylamino)
This can be promoted by adding pyridine or 4-pyrrolidinopyridine as appropriate. The ester forming reaction is generally carried out with at least one equivalent of amine bases such as triethylamine, diisopropylethylamine, pyridine and the like, although it is possible to use several equivalents. The carbonyl group can be activated for ester bond formation via its corresponding acid chloride or mixed anhydride using conditions known to those skilled in the art. The ester forming reaction is carried out at a temperature in the range of -20 ° C to 60 ° C in an aprotic solvent such as methylene chloride, tetrahydrofuran, diethyl ether, dimethylformamide, N-methylpyrrolidine, etc. for about 15 minutes to about 24 hours. Is completed. Using the appropriate amine HNR _14b1 R _14b2 and following the procedure described for the ester from the corresponding carboxylic acid (see above),
The amide (R ₁₂ is NR _14b1 R _14b2 ) is prepared.

The amide compound 14b (NR _14b1 R _14b2 is N (OMe) Me) can be treated with a nucleophile to give the corresponding aldehydes (compound 14c) and ketones (compounds 14d and 14e). . Suitable nucleophiles include compound 11a
And hydride reagents, such as, but not limited to, RLi or RMgX, described above for the preparation of and 11b. Furthermore, the aldehyde and ketone products 14c, 14b and 14e are further combined with a hydride reagent, RLi or RM.
It can be reacted with gX to form the corresponding alcohol adduct described above.

Referring to Scheme VII below, the aldehyde compounds 6, 10 and 14
c serves as a raw material for manufacturing various derivatives.

[0137]

[Chemical 19]

R _15a , R _15b , R _15d1 , R _15d2 and R _15e are each independently an optionally substituted alkyl group or aryl group.

Compound 15a (R _15a = H) was prepared by reducing the side chain aldehyde group in compounds 6, 10 and 14c with a hydride reagent. The side chain alcohol so obtained can be sulfonylated according to the method described above in Scheme III. Then, replacing the sulfonyl group with a suitable sulfur, nitrogen or phosphorus nucleophile,
Compounds 15b, 15c and 15e can be formed, respectively. Suitable nucleophiles _{include, NaSMe, KSAc, NaN 3,} (PhCH 2 O) 2 P (O) H,
(P (OCH ₂ Ph) ₃ , (MeO) ₂ P (O) H, P (OMe) ₃ and the like.

Further, the side chain azide compound 15c was added to H ₂ /10% Pd / C, HSAc / MeO 2.
H, SnCl ₂ , Ph ₃ P / H ₂ O, etc. (but not limited to) can be reduced using conditions known to those skilled in the art to form a side chain amine compound (not shown). ). The amine compound thus obtained can be acylated, alkylated or sulfonylated according to the methods described above. Alternatively, reductive amination of aldehyde compounds 6, 10 and 14c with a suitable amine as described above provides amine compound 15d.

Referring to Scheme VIII below, reaction of a stabilizing Wittig reagent, a destabilizing Wittig reagent or a Horner-Emmons reagent with an aldehyde extends the side chain of compounds 6, 10 and 14c to give compound 16a. Can be formed.

[0142]

[Chemical 20]

R _16a , R _16b , R _16d1 , R _16d2 and R _16e are each independently an _optionally substituted alkyl group or aryl group.

The side chain of compound 16a can be reduced by catalytic hydrogenation using conditions known to those skilled in the art. Suitable catalysts include 5% Pd / C, 10% Pd / C, Pd (
OH) ₂ , PtO ₂ , RhCl ₃ , RuCl ₂ (PPh ₃ ) ₃ and the like. The hydrogenation reaction is performed by CH ₂ Cl ₂ , CHCl ₃ , toluene, MeOH, EtOH, EtO.
It can be carried out in a solvent or solvent mixture such as Ac, acetone, THF, Et ₂ O, dimethoxyethane, DMF, DMSO. The reduction can be carried out at a hydrogen pressure of 1 to 10 atm, and the reaction is completed in 5 minutes to 24 hours. In the case of apicidin analogs _16a or _16b where R _16a or R _16b represents an ester moiety, the ester can be saponified and the resulting carboxylic acid converted to another ester or amide according to the methods described above.

Referring to Scheme IX below, the N-methoxy group of apicidin can be eliminated by hydrogenation according to the method described above, and the resulting free indole nitrogen compound is known to indoles. N-alkylation, acylation or sulfonylation can be performed using acylation, sulfonylation and alkylation methods to form apicidin derivative compound 17.

[0146]

[Chemical 21]

R ₁₇ is an optionally substituted alkyl group or aryl group.

Therefore, acylation can be carried out using reagents such as acid anhydrides, acid chlorides, chloroformates, carbamoyl chlorides, and isocyanates according to general procedures known to those skilled in the art. The sulfonylation can be performed using sulfonyl chlorides or sulfonic anhydrides. Alkylation can be performed with an alkyl halide. Suitable bases for these acylation, sulfonylation and alkylation reactions include KH, nBuLi, tBuLi, LiN (iPr
) ₂ , NaN (SiMe ₃ ) ₂ , KN (SiMe ₃ ) ₂ or the like or more preferably NaH or the like. Suitable solvents or solvent mixtures for these reactions are benzene, toluene, CHCl ₃ , CH ₂ ClCH ₂ Cl, CH ₂ Cl ₂ , DMSO, H.
There is MPA, NMP etc. or most preferably DMF etc. and the reaction is -40
It can be carried out at a temperature of from -80 ° C.

When the newly incorporated R ₁₇ group has an ester moiety, the apicidin derivative compound 17 can be saponified to the corresponding carboxylic acid and converted to a series of amides using the conditions described above.

If the newly incorporated R ₁₇ group carries an alcohol functional group, the apicidin derivative compound 17 can be acylated, alkylated, phosphorylated or sulfonylated according to the methods described above. Alternatively, the alcohol functionality can be converted to a leaving group such as a sulfonate or halide and replaced with a suitable sulfur, nitrogen or phosphorus nucleophile according to the methods described above.

Referring to Scheme X below, tryptophan of apicidin can be allylated to form β-oxoapicidin analog 18 using conditions known to those of skill in the art. (What is R ₁₈ ?).

[0152]

[Chemical formula 22]

R ₁₈ is an optionally substituted alkyl group or aryl group.

Suitable oxidants include tBuOOH, SeO ₂ , CrO ₃ , Na ₂ CrO ₄ , P.
CC or the like or more preferably DDQ (2,3-dichloro-5,6-dicyano-
1,4-benzoquinone) and the like, but are not limited thereto. Suitable solvents or solvent mixtures include DMF, toluene, benzene, CH ₂ Cl ₂ , C
HCl ₃ , HOAc, pyridine, THF, MeOH, EtOH, water and the like or more preferably MeCN and the like. These reactions are carried out at a temperature of -20 ° C to 50 ° C and are completed in 5 minutes to 24 hours. The stereochemistry of the β-oxo-tryptophan bond of compound 18 can be altered by treatment with a base such as pyridine, EtN (iPr) ₂ , NaH, KH, DBU, lutidine or most preferably Et ₃ N. The epimerization reaction is performed using CHCl ₃ , CH ₂ ClCH ₂ Cl, MeOH, EtO.
Proceed at a temperature of 0 ° C. to 50 ° C. in a solvent such as H, DMF, DMSO, NMP, etc. or most preferably CH ₂ Cl ₂ . The nitrogen of β-oxo-tryptophan is
It can be alkylated, acylated, sulfonylated or phosphorylated according to the methods described above.

The β-oxocarbonyl of compound 18 can be selectively reduced with a hydride source under radical conditions. Suitable hydride source, _Me 3 _SnH in the presence of a radical _{initiator, nBu 3 SnCl / NaBH 4,} Ph 3 SnH, Ph 3 As
H or the like or most preferably nBu ₃ SnH and the like. Suitable radical initiators include, for example, benzoyl peroxide, Et ₃ B / O ₂ etc. or most preferably AI.
BN etc. Suitable solvents for carbonyl reduction include MeOH, EtOH, water,
Benzene or most preferably toluene and the like. The reaction is 0 ℃ -110 ℃
Proceed at the temperature of.

Referring to Scheme XI below, carboxylic acid compound 19a (R ₂ OH) can be prepared by oxidative decomposition of indole of apicidin using conditions known to those skilled in the art.

[0157]

[Chemical formula 23]

R _19a , R _19b , R _19c and R _19d are each independently an optionally substituted alkyl group or aryl group.

Suitable oxidizing agents include KMnO ₄ , KMnO ₄ / NaIO ₄ , NaIO ₄ / Ru.
O _{4 and the} like, or most preferably NaIO ₄ / RuCl _{3 and the} like, are not limited thereto. Suitable solvents or solvent mixtures include CHCl ₃ , CH ₂ ClCH ₂ Cl, MeCN, MeOH, EtOH, tBuOH, etc. or most preferably CH ₂ Cl ₂ . This reaction proceeds at a temperature of 0 ° C to 50 ° C.
The carboxylic acid can be converted to an ester or amide according to the method described above.

Alternatively, first the methyl ester (eg compound 19 wherein R _19a is OMe) is used.
a) is prepared and reacted with LiN (OMe) Me, Me ₂ AlN (OMe) Me or most preferably BrMgN (OMe) Me, where R _19a is N (OMe) M.
Weinreb amide compound 19a, which is e, can be prepared. Suitable solvents for the reaction include Et ₂ O, dimethoxyethane, dioxane and the like or most preferably THF and the like. This reaction is carried out at a temperature of -78 ° C to 50 ° C for 30 minutes to 1
It will be completed in 2 hours.

Reduction of the side chain of the C8-ketone group of compound 19a to the corresponding alcohol proceeds according to the method described above. The Weinreb amide so formed can then be reacted with a hydride reagent, RLi or RMgX, according to the methods described above to produce the corresponding aldehyde or ketone (eg R _19a is H, alkyl or An aryl group 19a). At this point, the side chain C8-alcohol can be oxidized back according to the method described above to form the C8-ketone again.

When R _19a is OH in compound 19a, the carboxylic acid can be reduced with BH ₃ to form the alcohol compound 19c (R _19c is H). The alcohol can be acylated, sulfonylated or phosphorylated according to the methods described above. Treatment of alcohol compound 19c with an Ar ₃ Bi reagent _yields the corresponding aryl ether compound 1 wherein R _19c is an aryl group.
9c is formed. Both α and β stereochemistry on tetrapeptides can be obtained according to the methods described above.

Using the β-oxoapicidin derivative compound 18 in place of apicidin in Scheme XI above, cleaved apicidin analog compounds 19b and 19d are formed.

Referring to Scheme XII, the 2,3-indole bond in apicidin can be oxidatively cleaved to form compound 20 using conditions known to those of skill in the art.

[0165]

[Chemical formula 24]

R ₂₀ and R ₂₁ are each independently an optionally substituted alkyl group or aryl group.

Suitable oxidizers include KMnO ₄ , NaIO ₄ , Pb (OAc) ₄ etc. or most preferably ozone. This reaction is performed with CHCl ₃ , CH ₂ ClCH ₂ C
1 or more preferably in a solvent such as CH ₂ Cl ₂ at a temperature of −78 ° C. to RT and the reaction is complete in 1 minute to 2 hours. Treatment of compound 20 with a base induces aldol cyclization to form quinolone compound 21. Suitable bases for this reaction include Et ₃ N, EtN (iPr) ₂ , pyridine, DBU,
NaOMe, NaOEt, NaHCO _{3 and the} like or more preferably KOtBu and the like. Aldol cyclization can be performed with CH ₂ Cl ₂ , CHCl ₃ , MeOH, EtOH
, DMF, THF, Et ₂ O, DMSO, water etc. or more preferably tBuO.
It can be carried out in a solvent such as H or a solvent mixture. The reaction is completed within 10 minutes to 12 hours at a temperature of 0 ° C to RT. By using an N-substituted-N-desmethoxy-apicidin derivative (Compound 17) in place of apicidin in Scheme XII, an N-substituted quinolone derivative is formed.

Referring to Scheme XIII below, a compound 22 in which R ₂₂ is a sulfonate moiety is treated by treating the quinolone compound 21 with a sulfonylating agent according to the method described above.
Can be formed.

[0169]

[Chemical 25]

R ₂₂ and R ₂₃ are each independently an optionally substituted alkyl group or aryl group.

During this reaction, a partial conversion of the stereocompound at the tetrapeptide ring binding moiety occurs.
When R _{22 of} compound ₂₂ is OSO ₂ CF ₃ , the triflate is converted to NaBr,
_NaCl, KI, NaN 3, NaSMe, can be substituted KSAc, halogen such as pyridine (but not limited to), in a suitable nucleophile such as sulfur nucleophiles or nitrogen nucleophiles. The compound obtained is not shown. Suitable solvents for this displacement reaction include CH ₂ Cl ₂ , CHCl ₃ , DMF, DMSO, HMPA,
Examples include NMP and the like, but the invention is not limited thereto. The reaction is 0 ° C to 80 ° C
Proceed at the temperature of.

In the case of the apicidin derivative compound ₂₂ where R ₂₂ is N-1-pyridinium, the above-mentioned catalytic hydrogenation can be used to reduce the pyridinium group.

Furthermore, the C8-ketone group of the apicidin derivative compound 21 can be first reduced. The quinolone carbonyl thus formed can be reacted with a hydride reagent, a nucleophile such as RLi or RMgX according to the methods described above. The apicidin derivative compound 23 can be produced by re-oxidizing a C8-alcohol according to the method described above.

Referring to Scheme XIV below, the compound ₂₄ , wherein R ₂₄ is Br, is obtained by removing the N-methoxy group and then brominating the apicidin at the C2 position of the indole using conditions known to those skilled in the art. Can be formed.

[0175]

[Chemical formula 26]

Suitable brominating agents include Br ₂ , Hg (OAc) ₂ / Br ₂ , CBr ₄ , CuB
r ₂ , HOBr, Br ₂ / HOAc / NaOAc, etc. or most preferably N-
Examples include, but are not limited to, bromosuccinimide. The bromination reaction can be promoted by a radical initiator such as benzoyl peroxide, Et ₃ B / O ₂ or AIBN.

[0177]   The 2-bromo-indole thus obtained was further treated with a palladium catalyst, a base and
And ArX can induce an aryl coupling reaction.
Suitable palladium catalysts include Pd (OAc)_Two, Pd (OAc) / PPh_Three, P
dCl_Two(PPh_Three)_Two, Pd (dba)_Two/ PPh_ThreeOr most preferably
Is Pd (PPh_Three)_FourHowever, the present invention is not limited to these. This anti
Suitable bases are KOtBu, CsCO_ThreeOr most preferably NaHCO _Three However, the present invention is not limited to these. Suitable for this coupling reaction
Suitable solvents or solvent mixtures include toluene, DMF, MeCN, NMP, DMS.
O, H_TwoO, EtOH or most preferably dioxane / water and the like. Suitable
The ArX group contains PhB (OH)_Two, 2-naphthylboronic acid, (4-Me) PhB
(OH)_Two, (4-F) PhOTf and the like, but are not limited to these.
Absent. The reaction is completed within 30 minutes to 48 hours at a temperature of RT to 110 ° C.

[0178]   Synthesis of side chain modified apicidin derivatives   Unless stated otherwise specifically in the following examples and elsewhere in this specification.
As long as all percentages are by weight. In addition, specifically
Unless otherwise noted, all compound ratios are by volume. Room temperature (RT) is about 1
A temperature of 8 ° C. to about 25 ° C. is meant. If the temperature is not stated specifically, the condition
Is understood to be room temperature. It is noted that the component is used without specifically describing the amount.
For some of the listed steps, those of skill in the art can understand the desired results.
The amount can be easily determined. In general, pure example
The purity of the compound was higher than about 95%.

Example 1

[0180]

[Chemical 27]

The compound of Example 1 was prepared by the following procedure. I) 60% NaH at room temperature
5.6 mg and ii) Me ₃ S (O) I in a mixture of 0.35 mL HMPA.
27 mg was added. The resulting solution was left for 5 minutes. Next, Apicidin 12m
The reaction mixture was obtained by adding the mixture in g of DMF (95 μL). After 48 hours, quenched with water, extracted with EtOAc, dried over Na ₂ SO ₄ to produce 8 mg of the compound of Example 1. The compound of Example 1 so obtained was characterized by ¹ H NMR and MS [m / z: 638 (M ⁺ +1)] without further purification.

Example 2

[0183]

[Chemical 28]

The compound of Example 2 was prepared by the following procedure. 20m Apicidin at room temperature
To a solution of g in CH ₂ Cl ₂ (10 mL), HCl.H ₂ NOH 60 mg and E
181 μL of t ₃ N was added. The resulting solution was left for 12 hours. Volatiles were removed under reduced pressure. 1: 3 MeCN with a 60 min linear gradient without post-treatment:
Preparative RP-HPLC from H ₂ O using a gradient elution, wherein 100% MeCN
(Reverse phase high performance liquid chromatography) was performed to obtain the compound of Example 2. The pure compound of Example 2 thus obtained was analyzed by ¹ H NMR and MS [m / z: 6].
39.3 (M ⁺ +1)].

[0185]   Examples 3A-3M   For compounds 11f, 11g and 11h and for the compound of Example 2
The compounds of Examples 3a-3m were prepared according to the general procedure shown in Scheme III.
. The compounds of Examples 3a-3m are represented by the following chemical formula, NMR and mass
Characterized by analysis.

[0186]

[Chemical 29]

[0187]

[Table 2]

Examples 4A and 4B

[0189]

[Chemical 30]

The compounds of Examples 4a and 4b were prepared according to the following procedure. At 0 ° C., the compound of Example 2 (C8-ketoxime of apicidin) 3 mg of pyridine (0.5
(mL) solution, 4.5 mg of p-toluenesulfonyl chloride was added to form a solution. The solution was maintained at 0 ° C. for 10 minutes, warmed to RT and allowed to stand for 50 minutes. Then 1 mL each of saturated brine and saturated NaHCO ₃ (aq) was added. The solution was then extracted with EtOAc and dried over Na ₂ SO ₄ . Gradient elution (1
: 3MeCN: H ₂ O isocratic for 10 minutes, then linear gradient 100 over 75 minutes.
Preparative RP-HPLC with (% MeCN) provided a pure mixture of the compounds of Examples 4a and 4b. For the pure mixture so obtained, ¹ H
Characterization was done by NMR and MS [m / z: 639.2 (M ⁺⁺ 1)].

Example 5

[0192]

[Chemical 31]

The compound of Example 5 was prepared according to the following procedure. I) N at room temperature (RT)
16.8 mg dispersion of aH in 60% oil, ii) 2 mL DMF and iii
) Ph ₃ PCH ₃ ⁺ Br ⁻ 114 mg was added to 0.2 mL of HMPA to form a mixture. After the mixture stopped foaming, 20 mg of apicidin DMF (1 m
L) solution was added. The resulting solution was left for 4 hours. Without post-treatment, gradient elution (1: 3MeCN: _{H 2} O isocratic for 10 minutes, then a linear gradient to 75 minutes over 100% MeCN) performing preparative RP-HPLC using a pure implementation 14 mg of the compound of example 5 are obtained. For that, ¹ H NMR and MS [m / z: 62
2.3 (M ⁺ +1)].

Examples 6A to 6D

[0195]

[Chemical 32]

The compound of Example 6a was prepared according to the following procedure. At 0 ° C., THF 1.
To 15 mg of apicidin in a mixture of 75 mL and 0.25 mL of pyridine, (4
0.12 mL of 1.0 M Et ₂ O solution of —Cl) PhMgBr was added dropwise. 0 ° C
After 1 h at 0.1 h additional 0.1 M Et ₂ O solution of (4-Cl) PhMgBr 0.1.
2 mL was added. The resulting solution was aged at 0 ° C. for 1 hour and at RT for 1 hour. The solution was quenched by adding saturated NH ₄ Cl (aq). The quenched mixture was extracted with EtOAc and dried over Na ₂ SO ₄ . Gradient elution (1: 3 MeCN:
(H ₂ O isocratic for 10 minutes, then linear gradient for 75 minutes to 100% MeCN)
Preparative RP-HPLC was performed using to give 8 mg of pure compound of Example 6a. For that, ¹ H NMR and MS [m / z: 736.3 (M ⁺ +1)].
Was characterized by.

The compounds of Examples 6b, 6c and 6d are represented by the chemical structures shown below. Specific substituents are shown in Table 2 in tabular form. The compounds of Examples 6b, 6c and 6d were prepared according to the general procedure shown in Scheme III for compound 11b under conditions similar to those described above for the compound of Example 6a.

[0198]

[Chemical 33]

[0199]

[Table 3]

[0200]   Example 7   Cyclo (N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-a
Mino-8-hydroxy-decanoyl).

[0201]

[Chemical 34]

The compound of Example 7 was prepared by first treating at 0 ° C. with 300 mg apicidin MeOH.
18 mg of NaBH ₄ was added to the (12 mL) solution. Then the ice bath was immediately removed and the solution was stirred at RT for 4 hours. The reaction was quenched by adding acetone, and the solvent was removed under reduced pressure at room temperature. The residue was dissolved in CH ₂ Cl ₂ , poured into saturated NaHCO ₃ , extracted with 1: 9 iPrOH: CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . Flash chromatography on silica gel with 1: 1 acetone: hexane as eluent gave the pure product. The pure compound of Example 7, ¹ H
Characterized by NMR. TLC: _Rf = 0.32 (1: 1 acetone: hexane).

Example 8

[0204]

[Chemical 35]

The compound of Example 8 was prepared according to the procedure of Example 7 except that N-desmethoxy-apicidin was used as the starting material. The compound of Example 8 was characterized by ¹ H NMR and MS [m / z: 596 (M ⁺ +1)].

Example 9

[0207]

[Chemical 36]

The compound of Example 9 was prepared by the following method. At room temperature, cyclo (N-O-
Methyl -L-Trp-L-Ile- D-Pip-L-2- amino-8-hydroxy - in decanoyl) 40 mg of _CH 2 _Cl 2 (1.6mL) solution was added thiocarbonyl imidazole 57 mg. The resulting solution was heated at 75 ° C for 2 hours. Next, 1 mg of DMAP (4-dimethylaminopyridine) was added and the solution was added at 75 ° C.
For 48 hours at RT. The solvent was removed under reduced pressure. Pure intermediate product 8-OC (S) imidazolyl-apicidin (cyclo (N-O-methyl-LT)
rp-L-Ile-D- Pip-L-2- amino-8-imidazolylthio Bruno oxy - decanoyl) also referred), a developing solution _{1: 3: 96NH 4 OH:} MeO
Obtained by PTLC in H: CHCl ₃ (2 1500 μm plates) and characterized by ¹ H NMR and MS [m / z: 610 (M ⁺ +1)].

To 59 mg of the intermediate 8-OC (S) imidazoyl-apicidin in 1.6 mL of toluene prepared above, 2.6 mg AIBN and 53 μL nBu ₃ Sn were prepared.
H was added. The solution was concentrated under reduced pressure by heating under vacuum at 80 ° C. for 1 hour, M
Separated using eCN and hexane. The hexane layer was removed. The volatiles were removed under reduced pressure, gradient elution (4: 6 to _1: 0MeCN: _H 2 O) using a RP-HP
LC was performed to give the pure product of Example 9. ¹ H NMR and MS
It was characterized by [m / z: 610 (M ⁺ I)].

Example 10

[0211]

[Chemical 37]

Cyclo (N—O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-8-hydroxy-decanoyl) 100 mg of pyridine (2 mL) in R solution.
The compound of Example 10 was prepared by adding 10 mg of DMAP at T. Next, 94 mg of tosylic anhydride was added. After 3 h at RT, the solution was poured into saturated NaHCO ₃ , extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . Gradient elution (1: 1: 98 as eluent, then 1: 2: 97, then 1: 3: 96 NH ₄ OH: MeOH
Flash chromatography on silica gel with CHCl ₃ ) to give pure Example 10 compound. The compound of Example 10 was characterized by ¹ H NMR. _{TLC: R f = 0.36 (1} : 3: 96NH 4 OH: MeO
H: CHCl _3).

Example 11

[0214]

[Chemical 38]

The procedure for producing the compound of Example 11 was as follows. 1: 1 THF at room temperature
: The apicidin 100mg in MeOH (10 _mL), was added NaBH 4 50 mg. After 30 min at RT, the solution was poured into brine, extracted with _CH 2 Cl _2, N
It was dehydrated with a ₂ SO ₄ . To the residue so obtained was added pyridine 2 mL, then DMAP 10 mg and Ac ₂ O 10 drops. After an additional 15 minutes at RT, the solution was heated at 80 ° C. for 10 minutes and no reaction was noted. An additional 5 drops of fresh Ac ₂ O (from an unopened bottle) was added and the solution was stirred at RT for 24 hours. The solvent was removed under reduced pressure and the residue was freeze dried from dioxane. Gradient elution (3: 7 to _6: 4MeCN: _H 2 O) by preparative RP-HPLC using to give the product 69mg of pure Example 11. It was analyzed by ¹ H NMR and MS [m / z: 668
． 6 (M ⁺ +1)]. _HPLC: t R = 4.95 min (6:
_4MeCN: H 2 O, 1.5mL / min, Rainin Corporation available from (Rainin Co.) Zorbax (Zorbax; R) RX-8).

[0216]   Examples 12A-12E   Following the procedures described in Scheme III, compounds 11c and 11d, Example 10 and
And the compounds of Examples 12a-12f below were prepared in the same manner as in
Prepared and characterized by NMR and mass spectroscopy.

[0217]

[Chemical Formula 39]

[0218]

[Table 4]

Example 13

[0220]

[Chemical 40]

To prepare the compound of Example 13, apicidin 100 mg EtOAc (5
mL) solution at RT, (Me ₃ Si) ₂ NH 0.16 mL and ZnCl ₂
235 mg was added. The solution was heated at 55 ° C. for 12 hours. The solution was cooled to 0 ° C. and 12 mg NaBH ₄ was added. After 1 hour, the solution was warmed to RT and left for another 2 hours. The solution was poured into 1: 1 brine: saturated NaHCO ₃ , C
It was extracted with H ₂ Cl ₂ and dried over Na ₂ SO ₄ . Gradient elution (3: 7 to 6: 4M
_ECN: performing preparative RP-HPLC using a _H 2 O), to give the pure product of Example ^13, 1 H NMR and ^{MS [m / z: 625.3 (} M + +1)] by the characteristics Were determined. TLC: R _f = 0.22 min (1: 9: 90 NH ₄ OH: Me
OH: CHCl _3).

Example 14

[0223]

[Chemical 41]

To prepare the compound of Example 14, a solution of 8-amino-8-desoxoapicidin 14 mg in pyridine (2 mL) at 0 ° C. was added Ac ₂ O 2 drops and a catalytic amount of D.
MAP was added. The solution was stirred at 0 ° C. for 30 minutes and at RT for another 30 minutes. Next, 1 mL of methanol was added and the solution was concentrated under reduced pressure. Preparative RP-HPLC purification (25: 75MeCN: 100 with _{H 2} O and then at the 10 minutes, linear gradient of 70 min
(Gradient elution to% MeCN) to give pure Example 14 compound, ¹ H
It was characterized by NMR and MS [m / z: 667.4 (M ⁺⁺ 1)].
TLC: R _f = 0.67 min (1: 9: 90 NH ₄ OH: MeOH: CHCl ₃ ).
. _HPLC: t R = 4.60 _{min, 1: 1MeCN: H 2 O} , 1.5mL / min, Zorbax (R) RX-8).

Example 15

[0226]

[Chemical 42]

First, at RT, to a solution of 60 mg of apicidin in MeOH (0.5 mL), i) 1 mL of pyridine, ii) ethanolamine 40 μL, iii) ice HOAc (pH about 5.0) 60 μL and iv) powder 4Å sieves. The compound of Example 15 was prepared by addition. The solution was cooled to 0 ° C. and 7.9 mg NaCNBH ₃ was added. After 2 hours, the temperature of the solution was raised to RT and 12 hours passed. The solution as eluent _{1: 1CH} 2 Cl 2: Celite filter agent with MeOH (Aldrich Ch
(commercially available from emical Company, Milwaukee, Wisconsin), reduced volume under reduced pressure, poured into saturated NaHCO ₃ , extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . 1: 1MeCN: _{H 2} O from prep using an elution gradient of 100% MeCN R
P-HPLC gave 4.2 mg of the pure compound of Example 15. For the product so obtained, ¹ H NMR and MS [m / z: 669 (M ⁺ +1
)].

Example 16

[0229]

[Chemical 43]

The compound of Example 16 was prepared in the same manner as in Example 15. Apicidin 60 mg in MeOH (0.5 mL) solution at RT, i) pyridine 2 mL, ii) propylamine 0.5 mL, iii) ice HOAc (pH about 4.5) 1 mL and iv)
Powder 4Å sieves was added. The solution was cooled to 0 ° C. and NaCNBH ₃ 60 m
g was added. After 2 hours, the temperature of the solution was raised to RT and 12 hours passed. The solution was filtered through Celite with 1: 1 CH ₂ Cl ₂ : MeOH as eluent, reduced in volume under reduced pressure, poured into saturated NaHCO ₃ , extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . did. 2:18:80 NH ₄ OH: MeOH: CH as the developing solution
PTLC on silica gel with Cl ₃ (1500 μm plate 1) was performed to give pure compound of Example 16. The pure compound of Example 16 so obtained was characterized by ¹ H NMR and MS [m / z: 667 (M ⁺ +1)].

Example 17

[0232]

[Chemical 44]

To prepare the compound of Example 17, the C8-tosylate compound 1 of Example 10 was prepared.
32 mg of KSAc was added to a solution of 8.1 mg of 95% EtOH (3 mL).
The solution was heated at 70 ° C. for 3 hours. The solution was cooled to RT and sat. NH ₄ Cl (aq) was added. The solution was then extracted with EtOAc and dried over Na ₂ SO ₄ .
The solution was filtered, evaporated to dryness. PTLC (1 1000 μm plate) on silica gel using 3: 7 acetone: hexane as the developing solution gave 3.4 mg of pure Example 17 product. It was characterized by ¹ H NMR.

Example 18

[0235]

[Chemical formula 45]

To prepare the compound of Example 18, 3.4 mg of the C8-thioacetate compound of Example 17 was added at RT to 0.2 mL of NaOMe in 2M MeOH.
Time has passed. The solution was poured into saturated NH ₄ Cl (aq), extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . The solution is filtered, the solvent is evaporated to dryness, and RP-
The pure compound of Example 18 was obtained after HPLC. The compound of example 18 so obtained was characterized by ¹ H NMR.

Examples 19A and 19B

[0238]

[Chemical formula 46]

The compounds of Examples 19a and 19b were prepared by the following procedure. 50 mg of apicidin was heated at 50 ° C. in 5 mL of THF until the resulting solution was homogeneous. The solution was cooled to -78 ° C and immediately added to potassium hexamethyldisilazane
． 800 μL of 5M toluene solution was added. After 5 minutes, 40 L of TMSCl as a THF (1 mL) solution was added. After 10 minutes at −78 ° C., saturated NaHCO ₃ 5 m
The reaction was stopped by adding L. The solution was then first extracted with EtOAc, then CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . The crude mixture of the compound of Example 19a and the compound of Example 19b was used in the next reaction without further purification.
The crude yield was 74 mg (145%). The mixture was characterized by ¹ H NMR. TLC: _Rf = 0.52 (1: 2 acetone: hexane).

Examples 20A and 20B

[0241]

[Chemical 47]

To prepare the compounds of Examples 20a and 20b, the compound of Example 19a, cyclo (N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-
Amino-8-trimethylsiloxy-7-ene-decanoyl) and Example 19b.
Which is a compound of cyclo (N-O-methyl-L-Trp-L-Ile-D-Pip
-L-2-amino-8-trimethylsiloxy-8-ene-decanoyl) crude about 1
1 mixture at RT in 5 mL CH ₂ Cl ₂ and added to it solid NaHCO ₃
00 mg was added. To the solution was added 20 mg of 85% MCPBA. After 5 minutes, it was quenched with 1: 1 saturated Na ₂ S ₂ O ₃ : saturated NaHCO ₃ , extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . Thereby, the compound cyclo (N-O-methyl-L-Trp-L-Ile-D-Pip) of Example 20a was obtained after flash chromatography on silica gel with 4: 1 hexane: acetone as eluent.
-L-2-amino-8-oxo-7-trimethylsiloxy-decanoyl) and the compound of Example 20b cyclo (N-O-methyl-L-Trp-L-Ile-D-
Pip-L-2-amino-8-oxo-9-trimethylsiloxy-decanoyl)
43 mg of pure mixture of were obtained. The mixture was characterized by ¹ H NMR.
TLC: _Rf = 0.33 (1: 2 acetone: hexane).

Examples 21A and 21B

[0244]

[Chemical 48]

The compounds of Example 21a and Example 21b were prepared by the following procedure.
The compound of Example 20a cyclo (N-O-methyl-L-Trp-L-Ile-D-
Pip-L-2-amino-8-oxo-7-trimethylsiloxy-decanoyl)
And the compound of Example 20b cyclo (N-O-methyl-L-Trp-L-Ile
-D-Pip-L-2- amino-8-oxo-9- trimethylsiloxy - decanoyl) of 1: 1 mixture 43mg of THF (4 mL) solution in RT, _nBu 4 NF
120 μL of 1M THF was added. After 20 min at RT, the solvent was distilled off under reduced pressure, without workup, the crude mixture 6: 4MeCN: using _{H 2} O RP-HPL
Purified by C. The resulting pure mixture of Examples 21a and 21b was characterized by ¹ H NMR and MS [m / z: 657.2 (M ⁺ + NH ₄ )]. TLC: _Rf = 0.14 (1: 2 acetone: hexane).

Examples 22A and 22B

[0247]

[Chemical 49]

A 95% pure mixture of the compounds of Examples 22a and 22b was prepared according to the procedure of Examples 19-21 and characterized by ¹ H NMR.

Examples 23A and 23B

[0250]

[Chemical 50]

A 95% pure mixture of the compounds of Examples 23a and 23b was prepared according to the procedure of Examples 19-21 and characterized by ¹ H NMR.

Examples 24A and 24B

[0253]

[Chemical 51]

[0254]   Approximately 1: 1 mixture of the compounds of Examples 21a and 21b 10 mg MeOH (3
(mL) solution at 0 ° C. with 10 mL of pyridine and then Pb (OAc)._Four  10 mg
Was added to produce Examples 24a and 24b. After 10 minutes, add Na to the solution. _Two S_TwoO_Three  Quench with 2 mL and dilute with about 2 mL brine, CH_TwoC
l_TwoExtracted with Na_TwoSO_FourDehydrated in. As developing solution 1: 2 acetone: hexa
Separated after preparative TLC on silica gel (500 μm plate) using
Pure product was obtained.

The compound of Example 24a cyclo (N-O-methyl-L-Trp-L-Ile-D
-Pip-L-2-amino-7-oxo-heptanoyl) (5.5 mg) was characterized by ¹ H NMR and MS [m / z: 582.2 (M ⁺ +1)]. TLC: _Rf = 0.16 (1: 2 acetone: hexane).

The compound of Example 24b cyclo (N-O-methyl-L-Trp-L-Ile-D
-Pip-L-2-amino-7-carboxymethyl-heptanoyl) (6.5m
g) was characterized by ¹ H NMR and MS [m / z: 626.3 (M ⁺ +1)]. TLC: _Rf = 0.23 (1: 2 acetone: hexane).

[0257]   Examples 25A-25D   The compounds of Examples 25a-25d were prepared according to the procedure of Example 24b. Fruit
Starting from the compounds of Examples 21a and 21b and using a suitable alcohol as solvent
Then, the following derivatives were produced and analyzed by NMR and mass spectrometry.

[0258]

[Chemical 52]

[0259]

[Table 5]

Example 26

[0261]

[Chemical 53]

The compound of Example 26 was prepared by the following procedure. Cyclo (N-O-methyl -L-Trp-L-Ile- D-Pip-L-2- amino-7-carboxymethoxy - heptanoyl) 41 mg of 3: 1: 1 THF: MeOH : H 2 O (4
(mL) solution was added 100 μL of 1 M LiOH at 0 ° C. The solution was stirred for 1 hour and an additional 300 μL of 1M LiOH was added. After 12 hours, without workup, gradient elution (5: 95MeCN: In column equilibrated with _{H 2} O, 25: 75Me
CN: _{H 2} and 40 minutes at O, using the gradient to 100% MeCN over next 20 min, after preparative RP-HPLC using a flow rate of 10 mL / min), pure Example 26
33 mg of product was obtained. The compound of Example 26 was analyzed by ¹ H NMR and MS [m
/ Z ^: 629.2 (M ⁺ + NH ₄ )]. _{HPLC: t} R =
1.98 _{min, 45: 55MeCN: H 2 O} , 1.5mL / min, Zorbax (R) RX-8).

Example 27

[0264]

[Chemical 54]

[0265]   The compound of Example 27 was prepared by the following procedure. Cyclo (N-O-meth)
Le-L-Trp-L-Ile-D-Pip-L-2-amino-7-carboxy-
Heptanoyl) -lithium salt To a mixture of 15 mg in DMF (3 mL) at RT, H. _Two NOSi (Me)_TwotBu 5.4 mg and EDC.HCl 7 mg were added.
It was After 2 hours at RT, additional H_TwoNOSi (Me)_TwotBu 15 mg and E
DC.HCl 14 mg was added and the solution was stirred overnight. 5 drops of ice HOAc and M
The reaction was stopped by adding 1 mL of OH. Pour solution into brine, CH_Two Cl_TwoExtracted with Na_TwoSO_FourDehydrated in. For the crude product, gradient elution (1:
3:96 NH_FourOH: MeOH: CHCl_ThreeFrom 1: 4: 95 NH_FourOH: Me
OH: CHCl_Three, And 1: 9: 90 NH_FourOH: MeOH: CHCl_Three)
Chromatography on the silica gel used was carried out. Chromatographic material
The product to remove the small amount of EDU impurities present in_Three  2 mL
And dissolved in 2 mL of 10% HOAc aqueous solution. After 5 minutes, remove the water layer by decantation.
Removed and washed two more times to give 5.5 mg of pure Example 27 product.
It was The pure product of Example 27 is Fe (III) Cl_ThreeHydroxy with dyeing
Positive staining (purple-orange red) was obtained for samic acid. The product is¹1 H NMR
And MS [m / z: 627.3 (M⁺+1)]. TLC
: R_f= 0.26 (1: 9: 90 NH_FourOH: MeOH: CHCl_Three).

Example 28

[0267]

[Chemical 55]

[0268]   The compound of Example 28 was prepared by the following procedure. Cyclo (N-O-meth)
Le-L-Trp-L-Ile-D-Pip-L-2-amino-7-carboxy-
Heptanoyl) -lithium salt To a mixture of 30 mg in DMF (1 mL) at RT, H
Cl.HN (OMe) Me 47 mg, DMAP 2 mg, HOBT (1-hydr
Roxybenzotriazole hydrate) 7 mg and DIEA (Et_TwoNiPr)
90 μL was added, then EDCI (1- (3-dimethylaminopropyl) -3-E
12 mg of tylcarbodiimide hydrochloride) was added. After 36 hours, the solution was brined
Add pH, acidify with 2N HCl to pH about 4.0, CH_TwoCl_TwoExtracted with Na _Two SO_FourDehydrated in. 1: 3: 96 NH as eluent_FourOH: MeOH: CHC
l_ThreeAfter purification by flash chromatography on silica gel using
29.6 mg of the compound of Example 28 are obtained,¹1 H NMR and MS [m / z: 65
5.3 (M⁺+1)]. TLC: R_f= 0.39 (1: 3
: 96NH_FourOH: MeOH: CHCl_Three). HPLC: t_R= 3.90 minutes (6
2:38 MeCN: H_TwoO, 1.5 mL / min, Zorbax® RX-
8).

Example 29

[0270]

[Chemical 56]

The compound of Example 29 was prepared by the following procedure. Cyclo (N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-7-carboxy-
Heptanoyl) to a mixture in 150 mg CH ₂ Cl ₂ (14 mL) at 0 ° C. and HC
l · H ₂ NOCH ₂ Ph 78 mg, DIEA 0.13 mL, HOBT 33
mg, DMAP 2 mg and BOP 108 mg were added. 1 hour at 0 ° C, R
After 12 h at T, the solution was poured into saturated NaHCO ₃ , extracted with CH ₂ Cl ₂ , N ₂
It was dehydrated with a ₂ SO ₄ . Pure Example 29 after preparative TLC on silica gel with 5:95 MeOH: CHCl ₃ as developing solution (5 1000 μm plates).
137 mg of the compound of was obtained and characterized by ¹ H NMR. _{TLC: R f = 0.62 (5} : 95MeOH: CHCl 3). _HPLC: t R = 7.46 min (
45:55 MeCN: H ₂ O, 1.5 mL / min, Zorbax® RX
-8).

Example 30

[0273]

[Chemical 57]

The compound of Example 30 was prepared by the following procedure. Cyclo (N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-7- (N-benzyloxy-carboxamido) -heptanoyl) 130 mg MeOH (5 mL).
At RT, 5% Pd / C was added to the medium mixture to create an H ₂ atmosphere (balloon pressure). After 12 hours, 10 mg of Pd (OH) ₂ was added and the reaction was continued for another 2 hours. The catalyst
Celite was filtered using MeOH as an eluent, and the solution was concentrated under reduced pressure. Gradient elution (5: 95MeCN: 50 in the inclination of the over and between 5 minutes _{H 2} O, then 55 minutes
: 50 MeCN: H ₂ O) and pure Example 3 after RP-HPLC purification.
0 product was obtained. The pure compound of Example 30 was analyzed by ¹ H NMR and MS [m
/ Z ^: 597.5 (M ⁺ +1)]. TLC: R _f = 0.1
_{1 (1: 9: 90NH 4} OH: MeOH: CHCl 3). _HPLC: t R = 10
． 65 minutes (of over 2 minutes 5: 95MeCN: from _{H 2} O 1: 1MeCN: inclination in the _{H 2} O, 1.0 mL / min, Zorbax (R) RX-8).

Example 31

[0276]

[Chemical 58]

[0277]   The compound of Example 31 was prepared by the following procedure. Cyclo (N-O-meth)
Le-L-Trp-L-Ile-D-Pip-L-2-amino-7- (N-O-me
Tyl-N-methyl-carboxamido) -heptanoyl) 100 mg of THF (2
mL) at 0 ° C. to CH 2_Two= CHMgBr 1M Et_TwoO solution (150
μL) was added. After 15 minutes at 0 ° C, the solution was cooled to -78 ° C and saturated NH._FourC
The reaction was stopped by adding 1 mL. Pour solution into brine, CH_TwoCl _Two Extracted with Na_TwoSO_FourDehydrated in. Eluent 1: 2 acetone: hexane
The product was partially purified on a silica gel pipette layer using. As a developing solution 1:
3:96 NH_FourOH: MeOH: CHCl_ThreePreparative TLC on silica gel using
After (one 250 μm plate), 2.1 mg of the pure compound of Example 31 was obtained, ¹ 1 H NMR and MS [m / z: 596.3 (M⁺+1)] to determine the characteristics
did. TLC: R_f= 0.57 (1: 3: 96 NH_FourOH: MeOH: CHCl _Three ).

Example 32

[0279]

[Chemical 59]

[0280]   The compound of Example 32 was prepared by the following procedure. Cyclo (N-O-meth)
Le-L-Trp-L-Ile-D-Pip-L-2-amino-7- (N-methoxy)
Ci-N-methyl-carboxamido) -heptanoyl) 7 mg THF (1 mL)
To the medium mixture at 0 ° C., 1M Et in MeMgBr_TwoO solution (55 μL) was added.
Saturated NH solution_FourPut into Cl, CH_TwoCl_TwoExtracted with Na_TwoSO_FourDehydrated with
It was Preparative TLC on silica gel using 4: 6 acetone: hexane as the developing solution.
After (one 500 μm plate) 4.3 mg of pure Example 32 compound was obtained.
Pure compound of Example 32¹1 H NMR and MS [m / z: 610.3 (M ⁺ +1)]. TLC: R_f= 0.22 (1: 2 acetone:
Hexane). HPLC: t_R= 4.51 min (1: 1 MeCN: H_TwoO, 1.5m
L / min, Zorbax® RX-8).

[0281]   Examples 33A-33C   The following derivatives were prepared according to the procedure described in Examples 26-34.

[0282]

[Chemical 60]

[0283]

[Table 6]

Example 34

[0285]

[Chemical formula 61]

[0286]   The compound of Example 34 was prepared by the following procedure. Cyclo (N-O-meth)
Le-L-Trp-L-Ile-D-Pip-L-2-amino-7-oxo-hep
Tanoyl) 25 mg, anhydrous LiCl 11 mg and (MeO)_TwoP (O) CH _Two CO_TwoTo a solution of Me 21 mL MeCN (2.5 mL) at RT, DIEA 4
2 mL was added. After 2 hours, the solution was saturated with NaHCO 3._ThreeTo the CH_TwoCl_Twoso
Extract, Na_TwoSO_FourDehydrated in. Use 1: 2 acetone: hexane as eluent
Pure flash of Example 34 after flash chromatography on silica gel containing
I got a product. Pure compound of Example 34¹1 H NMR and MS [m / z: 6
38.2 (M⁺+1)]. TLC: R_f= 0.38 (1:
2 acetone: hexane). HPLC: t_R= 5.09 minutes (1: 1 MeCN: H_Two O, 1.5 mL / min, Zorbax® RX-8).

Example 35

[0288]

[Chemical formula 62]

The compound of Example 35 was prepared by the following procedure. Cyclo (N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-7,8-dehydro-8-carbomethoxy-octanoyl) 35 mg of 1: 1 THF: MeOH (4
(mL) solution, Pd (OH) ₂ was added to make H ₂ atmosphere (balloon pressure). After 12 hours the catalyst was filtered off and after flash chromatography on silica gel with 1: 2 acetone: hexane as eluent the pure product of Example 35 11.7m.
g was obtained. The pure compound of Example 35 was characterized by ¹ H NMR. T
LC: _Rf = 0.21 (1: 2 acetone: hexane). _HPLC: t R = 3.8
4 minutes _{(55: 45MeCN: H 2 O} , 1.5mL / min, Zorbax (R) RX-8).

Example 36

[0291]

[Chemical formula 63]

The compound of Example 36 was made by the following procedure. Cyclo (N-O-methyl -L-Trp-L-Ile- D-Pip-L-2- amino-8-methoxy - octanoyl) 10.6 mg of _{3: 1: 1THF: MeOH:} H 2 O (1m
L) To the mixture at 0 ° C. was added 15 mL of 1M LiOH. The solution was stirred at 0 ° C. for 1 h, RT for 6 h, 4 ° C. for 3 days, and an additional 30 mL of 1M LiOH was added. After a further 8 hours, the solvent was removed with a strong N ₂ stream and without work-up, preparative RP-HPLC (2: 8 MeCN: H ₂ O for 10 minutes, then 100% over 60 minutes). Purification using (gradient elution with a gradient of MeCN) gave the pure product of Example 36. Pure product was analyzed by ¹ H NMR and M
It was characterized by S [m / z: 596.3 (M ⁺ +1)]. _HPLC: t R = 2.89 min _{(3: 7MeCN: H 2 O} , 1.5mL / min, Zorbax (R) RX-8).

Example 37

[0294]

[Chemical 64]

The compound of Example 37 was prepared by the following procedure. Cyclo (N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-7-oxo-heptanoyl) 25 mg in DMF (1.25 mL) solution at RT, MeOH 0.2.
5 mL was added, followed by 67.5 mg PDC. The solution was stirred for 3.5 hours, then MeOH was used as an eluent and the top layer was about 1.27 cm (0.5 in).
Filtered through about 1 inch of silica gel as a Celite layer. Preparative TLC on silica gel using 5:95 MeOH: CHCl ₃ as developer (1
After two 000 μm plates) 9 mg of pure Example 37 product was obtained. The pure compound of Example 37 was characterized by ¹ H NMR and MS [m / z: 612.3 (M ⁺ +1)]. TLC: _Rf = 0.24 (1: 2 acetone: hexane). _HPLC: t R = 9.41 min _{(45: 55MeCN: H 2 O} , 1.5
mL / min, Zorbax® RX-8).

Example 38

[0297]

[Chemical 65]

Example 15 and Scheme III using methyl glycinate opened in ethylamine.
By performing the steps, to produce a compound of Example ^38, 1 H NMR and MS [
m / z: 655.0 (M ⁺ +1)].

Example 39

[0300]

[Chemical formula 66]

Following the procedure of Example 36 and using the methyl ester of Example 38 as the raw material.
Compound 9 was prepared and its ¹ H NMR and MS [m / z: 641.4 (M ⁺ +1) were prepared.
)].

Example 40

[0303]

[Chemical formula 67]

The compound of Example 40 was prepared according to the procedure of Example 7 by using the compound of Example 32 as a starting material, and ¹ H NMR and MS [m / z: 598.3 (M ⁺ +1)].
Characterized by

Example 41

[0306]

[Chemical 68]

The compound of Example 41 was prepared by converting the C7-aldehyde of the compound of Example 23 according to the procedure of Example 7, ¹ H NMR and MS [m / z: 584.
2 (M ⁺ +1)].

Example 42

[0309]

[Chemical 69]

[0310]   The compound of Example 42 was prepared by the following two methods.

[0311]   Method A   Following the procedure of Example 7, cyclo (N-O-methyl-L-Trp-L-Ile-
D-Pip-L-2-amino-6-oxo-heptanoyl) 64 mg of 1: 1T
HF: EtOH (1 mL) solution at 0 ° C. with NaBH_Four  By adding 2.1 mg
The C6-aldehyde of the compound of Example 58a was converted to the compound of Example 42.
After 1 hour, the resulting solution was saturated NH_FourPut into Cl, CH_TwoCl_TwoAnd 3: 7
iPrOH: CHCl_ThreeSufficiently extracted by (once). The organic layer is Na_TwoSO _Four Dehydrated in. On silica gel using 1: 1 acetone: hexane as the developing solution.
Pure compound of Example 42 is obtained according to PTLC (one 500 μm plate).
It was The compound of Example 42 is¹1 H NMR and MS [m / z: 570 (M⁺+
1)].

[0312]   Method B   6,7- and 9,1 of apicidin, a compound of Examples 55a and 55b
7.3 mg of a 1: 1 mixture of 0-enone was added to CH_TwoCl_Two  Enter 1 mL at -78 ° C
It was The solution was bubbled with ozone until the blue color disappeared. Use strong nitrogen gas
Excess ozone was removed. To the solution, add NaBH_Four  3.6 mg of 1: 1E
tOH: H_TwoAdd the mixture in O (120 μL), remove the cooling bath and let the solution stand overnight.
Let Saturated NH solution_FourPut into Cl (aqueous solution), CH_TwoCl_TwoExtracted with N
a_TwoSO_FourDehydrated in. Silica using 1: 1 acetone: hexane as a developing solution
PTLC purification on gel (one 500 μm plate) was performed to give pure Example 42
Was obtained.

Example 43

[0314]

[Chemical 70]

The compound of Example 43 was prepared by the following procedure. Cycloalkyl is a compound of Example 41 (N-O-methyl -L-Trp-L-Ile- D-Pip-L-2- amino-7-hydroxy - heptanoyl) 32 mg of _CH 2 _Cl 2 (2.5mL)
To the solution at 0 ° C. was added 27 μL of DIEA, catalytic amount of DMAP and 36 mg of anhydrous toluenesulfonic acid. After 1 hour at 0 ° C. and 12 hours at RT, the solution was saturated with N 2.
It was poured into aHCO ₃ , extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . Preparative TLC on silica gel using 1: 3: 96 NH ₄ OH: MeOH: CHCl ₃ as the eluent (2 1000 μm plates) gave 20 mg of pure Example 43 product, ¹ H NMR and MS [. m / z: 755.5 (M ⁺ + NH ₄ )]. TLC: R _f = 0.58 (1: 3: 96NH ₄ OH
: MeOH: CHCl _3).

Example 44

[0317]

[Chemical 71]

Following the procedure of Example 43, the compound of Example 42, cyclo (N—O-methyl-L)
-Trp-L-Ile-D-Pip-L-2-amino-6-hydroxy-hexanoyl) to prepare the compound of Example 44, ¹ H NMR and MS [m / z:
? ? ? (M ⁺ + NH ₄ )].

Example 45

[0320]

[Chemical 72]

The compound of Example 45 was prepared by the following procedure. (MeO) ₂ P (O) H
95% NaH in 9 μL of THF (350 μL) at room temperature using a syringe 2.
5 mg was added and the solution was heated to reflux for 20 minutes. The solution was cooled to RT and cyclo (N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-7 was used.
25 mg of-(paratoluenesulfonyl) -heptanoyl) in THF (350 μL)
) As a solution, heated under reflux for 2 hours, cooled to RT and stirred for 12 hours.
The solution was poured into saturated NaHCO ₃ , extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . Pure Example 4 by PTLC (1 1000 μm plate) on silica gel using 1: 3: 96 NH ₄ OH: MeOH: CHCl ₃ as developing solution.
4.1 mg of the product of 5 was obtained. The pure product was analyzed by ¹ H NMR and MS [
m / z: 676 (M ⁺ +1)].

Example 46

[0323]

[Chemical formula 73]

The compound of Example 46 was prepared by the following procedure. Cyclo (N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-7- (paratoluenesulfonyl) -heptanoyl) 5 mg in DMF (1 mL) in NaSM at RT.
e 5 mg was added. After 2 hours, the solution was poured into brine, extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . Preparative TLC on silica gel with 1: 2 acetone: hexane as developing solution (1 500 μm plate) gave the pure product of Example 46. The pure product was analyzed by ¹ H NMR and MS [m / z:
614.5 (M ⁺ +1)]. TLC: R _f = 0.33 (1
: 2 acetone: hexane).

Example 47

[0326]

[Chemical 74]

The compound of Example 47 was prepared by the following procedure. Cyclo (N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-7- (paratoluenesulfonyl) -heptanoyl) 5 mg in DMF (1 mL) solution at RT in NaSA.
c 5 mg was added. After 2 hours, the solution was poured into brine, extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . Preparative TLC on silica gel using 1: 2 acetone: hexane as a developing solution (one 500 μm plate) gave the pure product of Example 47. The pure product was analyzed by ¹ H NMR and MS [m / z:
642.5 (M ⁺ +1)]. TLC: R _f = 0.22 (1
: 2 acetone: hexane).

Example 48

[0329]

[Chemical 75]

Starting from the compound of Example 22b and following the procedure described for Example 7, the compound of Example 48 was prepared. Conversion of the C8 ketone group of the compound of Example 22b to a hydroxyl group formed the compound of Example 48, which was characterized by ¹ H NMR.

Example 49

[0332]

[Chemical 76]

The compound of Example 49 was prepared by the following procedure. Dibenzyl phosphate 63μ
A solution of L in THF (1 mL) was added to 7 mg of 95% NaH using a syringe and the solution was heated to reflux for 20 minutes. The mixture was cooled to RT and 70 mg of cyclo (N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-7- (paratoluenesulfonyl) -octanoyl) in THF (1 mL). It was added as a solution. The resulting white heterogeneous solution was heated at reflux for 2 hours, then at RT for 12 hours. The solution was added to water, extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . Pure product of Example 49 2 by PTLC (1500 μm plate) on silica gel using 1: 3: 96 NH ₄ OH: MeOH: CHCl ₃ as developing solution.
6 mg was obtained. The product was characterized by ¹ H NMR and MS [m / z: 828 (M ⁺ +1)].

Example 50

[0335]

[Chemical 77]

The compound of Example 50 was prepared by the following procedure. Cyclo (N-O-methyl -L-Trp-L-Ile- D-Pip-L-2- amino-7-dibenzylphosphono - octanoyl) 11 mg of _H 2 O 44 [mu] L and KHCO ₃ 1.3 m
To an iPrOH (2 mL) solution containing g was added 10 mg Pd / C 1 mg at RT. The atmosphere was hydrogen (balloon pressure). After 12 hours, 1: 1 MeO with catalyst as eluent
Removed by filtration through Celite with H: H ₂ O. The solution was concentrated under reduced pressure and the residue washed with CHCl ₃ and then EtOAc. The residual glass was lyophilized from water to give 3 mg of product. ¹ H NMR and MS of the product
It was characterized by [m / z: 738 (M ⁺ +1)].

Example 51

[0338]

[Chemical 78]

The compound of Example 51 was prepared by the following procedure. To a solution of cyclo (N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-7-dibenzylphosphono-octanoyl) 2 mg in iPrOH (2 mL), water 8 μL, KHC
O ₃ 0.25 mg and 10% Pd / C 0.5 mg were added, and the atmosphere of the balloon was made hydrogen. After 7 hours at RT, the catalyst was removed by filtration through Celite and washed with water. 3 mg of pure Example 51 product was analyzed by ¹ H NMR and MS [m / z: 6].
48 (M ⁺ +1)].

Examples 52A and 52B

[0341]

[Chemical 79]

[0342]   The compounds of Examples 52a and 52b were prepared by the following procedure. Cyclo (
N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-7-
Hydroxy-8-oxo-decanoyl) and cyclo (N-O-methyl-LT)
rp-L-Ile-D-Pip-L-2-amino-9-hydroxy-8-oxo
-Decanoyl) 3 mg) about 1: 1 mixture 3 mg CH_TwoCl_Two(0.25 mL
) To the solution at -78 ° C, add powder activated 4Å sieves, then Et._TwoNSF_Three  
1.5 μL was added. The solution was warmed to -10 ° C over 1 hour and saturated NaH
CO_ThreeThe reaction was stopped by adding. CH solution_TwoCl_TwoExtracted with Na_TwoSO _Four Dehydrated in. 1: 3: 96 NH as developing solution_FourOH: MeOH: CHCl_ThreeTo
By PTLC on silica gel used (one 500 μm plate),
An approximately 1: 1 mixture of Examples 52a and 52b was obtained. For 2.5 mg of the mixture, ¹ 1 H NMR and MS [m / z: 641 (M⁺+1)]
It was

Examples 53A and 53B

[0344]

[Chemical 80]

The compounds of Examples 53a and 53b were prepared by the following procedure. Example 2
Cyclo (N-O-methyl-L-Trp-LI) which is the compound of 0a and 20b.
le-D-Pip-L-2-amino-7-hydroxy-8-oxo-decanoyl) and cyclo (N-O-methyl-L-Trp-L-Ile-D-Pip-L-.
2-amino-9-hydroxy-8-oxo-decanoyl) about 1: 1 mixture 6m
At RT, powder activation 4Å sieves was added, then N-methylmorpholine-N
-Oxide 3 mg and TPAP 0.3 mg were added. After 1 hour, the mixture was diluted with _CH 2 Cl _2, and filtered through celite using _CH 2 Cl ₂ as eluent. The filtrate was extracted with 10% NaHSO ₃ (aq), washed with water, Na ₂ S
It was dehydrated with O ₄ . Pure product was obtained by PTLC (1 500 μm plate) using 1: 3: 96 NH ₄ OH: MeOH: CHCl ₃ as the developing solution.
3.5 mg of each pure Example 53a and 53b compound was characterized by ¹ H NMR and MS [m / z: 637 (M ⁺ +1)].

Examples 54A and 54B

[0347]

[Chemical 81]

The compounds of Examples 54a and 54b were prepared by the following procedure. To a solution of 2 g of apicidin in THF (32 mL) was added at 0 ° C. 14 mL of a 0.5 M toluene solution of potassium hexamethyldisilazane. The solution was aged at 0 ° C. for 30 minutes. Then solid PhSeCl 25. g was added and the solution was warmed to RT and left for 2 hours. The reaction was quenched by adding saturated NaHCO ₃ (aq) and CH ₂ C
extracted with l _2, dried over _Na 2 SO _4, from gradient elution (hexane 1: 1EtOA
8 of silica gel with (c: hexane, and then 1: 1 acetone: hexane)
Filtration was performed on a × 14 cm layer. The product was used in the preparation of the compounds of Examples 55a and 55b without further purification. 2.3 g of the mixture thus obtained were treated with ¹ H 2 N
Characterized by MR and MS [m / z: 780.3 (M ⁺ +1)]. T
_{LC: R f = 0.60 (1} : 3: 96NH 4 OH: MeOH: CHCl 3).

Examples 55A and 55B

[0350]

[Chemical formula 82]

The compounds of Examples 55a and 55b were prepared by the following procedure. Cyclo (
N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-8-
Oxo-7-phenylselenyl-decanoyl) and cyclo (N-O-methyl-)
L-Trp-L-Ile-D-Pip-L-2-amino-8-oxo-9-phenylselenyl-decanoyl) about 1: 1 mixture to a solution of 2.2 g of THF (40 mL) at 0 ° C. 7.3 mL of 30% H ₂ O ₂ was added. The solution was warmed to 50 ° C., cooled after 10 minutes to 0 ° C., quenched with saturated Na ₂ S ₂ O ₃ , CH ₂ C.
extracted with l _2, and dried over _Na 2 SO _4. Pure 2 mixture of Examples 55a and 55b after purification on silica gel using 4: 6 acetone: hexane as eluent.
For 30 mg, ¹ H NMR and MS [m / z: 622.3 (M ⁺ +1).
] To determine the characteristics. _{TLC: R f = 0.38 (1} : 3: 96NH 4 OH
: MeOH: CHCl _3).

Examples 56A and 56B

[0353]

[Chemical 83]

The compounds of Examples 56a and 56b were prepared by the following procedure. Cyclo (
N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-8-
Oxo-6,7-dehydro-decanoyl) and cyclo (N-O-methyl-L-
Trp-L-Ile-D-Pip-L-2-amino-8-oxo-9,10-dehydro-decanoyl) about 1: 1 mixture 5.6 mg THF (0.225 mL).
To the solution at RT was added 0.8 mL of PhCH ₂ N (Me) ₃ (40% MeOH solution) and then 1.5 mL of 70% t-BuOOH (aq). 4.5 hours later, E
tOAc and a little water were added and the aqueous layer was extracted well with EtOAc. The organic layer was washed with cold 1N HCl (1 ×) and immediately again with saturated NaHCO ₃ ,
It was dehydrated with a ₂ SO ₄ . PTL using 4: 6 acetone: hexane as a developing solution
The pure product was separated by C (one 500 μm plate). The pure compounds of Examples 56a and 56b were characterized by ¹ H NMR. By this procedure, cyclo (N-O-methyl-L-Trp-L-Ile-D-Pip-L-
1.4 mg of 2-amino-6,7-oxiranyl-decanoyl) was obtained (MS [m
/ Z: 638 (M ⁺⁺ 1)]; TLC: _Rf = 0.4 (4: 6 acetone: hexane)). By this procedure, cyclo (N-O-methyl-L-Trp-L-Ile
-D-Pip-L-2-amino-9,10-oxiranyl-decanoyl) 1.4
mg (MS [m / z: 638 (M ⁺ +1)]; TLC: R _f = 0.3 (4
: 6 acetone: hexane)).

Examples 57A and 57B

[0356]

[Chemical 84]

The compounds of Examples 57a and 57b were prepared by the following procedure. Cyclo (
N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-8-
Oxo-6,7-dehydro-decanoyl) and cyclo (N-O-methyl-L-
Trp-L-Ile-D-Pip-L-2-amino-8-oxo-9,10-dehydro-decanoyl) about 1: 1 mixture 115 mg of 8: 1 acetone: water (4 m
L) solution at 0 ° C. with 45 mg of triethylamine-N-oxide and then 0.02
0.77 mL of 4M OsO ₄ (aq) was added. The temperature of the solution is raised to RT,
It was allowed to stand for 3 hours and then at 4 ° C. for 12 hours. 10% NaHSO ₃ (aqueous solution) 2
The reaction of the brown homogeneous solution was stopped by adding mL at 0 ° C. After 10 minutes, brine was added and the solution was thoroughly extracted with 3: 7 iPrOH: CHCl ₃ (9 times), N 2.
It was dehydrated with a ₂ SO ₄ . The solvent was removed under reduced pressure to give 230 mg of crude product (theoretical 121 mg). It was used without further purification. A small amount of the regioisomeric diol was separated by PTLC on silica gel (1 1000 μm plate) using 1: 1 acetone: hexane as a developing solution, and the product was subjected to ¹ H NMR.
And characterized by MS.

Cyclo (N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-8-oxo-6,7-dihydroxy-decanoyl): MS [m / z: 65
6 (M ⁺⁺ 1)]; TLC: _Rf = 0.5 (4: 6 acetone: hexane).

Cyclo (N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-8-oxo-9,10-dihydroxy-decanoyl): MS [m / z: 6
56 (M ⁺⁺ 1)]; TLC: _Rf = 0.25 (4: 6 acetone: hexane).

Examples 58A and 58B

[0361]

[Chemical 85]

The compounds of Examples 58a and 58b were prepared by the following procedure. Cyclo (
N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-8-
Oxo-6,7-dihydroxy-decanoyl) and cyclo (N-O-methyl-)
L-Trp-L-Ile-D-Pip-L-2-amino-8-oxo-9,10
-Dihydroxy-decanoyl) about 1: 1 mixture 121 mg MeOH (6 mL)
) To the solution at 0 ° C. was added 75 mL of pyridine and then 184 mg of Pb (OAc) ₄ . After 40 minutes, the solution was poured into saturated Na ₂ S ₂ O ₃ and extracted with CH ₂ Cl ₂ , N ₂
It was dehydrated with a ₂ SO ₄ . As a developing solution, 1: 3: 96 NH ₄ OH: MeOH: CH
PTLC on silica gel with Cl ₃ (3 1500 μm plates) gave pure isolated compounds of Examples 58a and 58b. The pure product obtained was characterized by ¹ H NMR and MS.

The compound of Example 58a cyclo (N-O-methyl-L-Trp-L-Ile-D
-Pip-L-2-amino-6-oxo-hexanoyl): Yield: 30 mg, M
S [m / z: 568 (M ⁺⁺ 1)]; TLC: _Rf = 0.45 (1: 1 acetone: hexane).

The compound of Example 58b cyclo (N-O-methyl-L-Trp-L-Ile-D
-Pip-L-2-amino-7-carboxymethyl-heptanoyl): Yield: 2
0 mg.

Example 59

[0366]

[Chemical 86]

The compound of Example 59 was prepared by the following procedure. Cyclo (N-O-methyl -L-Trp-L-Ile- D-Pip-L-2- amino-6-hydroxy - hexanoyl) 4 mg of _CH 2 _Cl 2 (0.14mg) and pyridine (1 mL)
To the solution at 0 ° C. was added 1 mL of ethyl chloroformate. The temperature of the solution is raised to RT,
After 3 hours, the solvent was removed under reduced pressure. PTLC (1 500 μm plate) on silica gel using 4: 6 acetone: hexane as the developing solution gave 1.3 mg of pure Example 59 compound. The pure product was characterized by ¹ H NMR and MS [m / z: 659 (M ⁺ + NH ₄ )].

Example 60

[0369]

[Chemical 87]

The compound of Example 60 was prepared by the following procedure. The C6- alcohol 7.5mg of Example 64 was placed in _CH 2 Cl ₂ to about 1mL at 0 ° C., it _(4-NO 2)
To 3.2 mg PhOC (O) Cl was added, followed by 1.3 μL pyridine. 0
After 2 hours at ℃, the volatile components were removed under reduced pressure without post-treatment, and the developing solution was 1: 1.
PTLC on silica gel with acetone: hexanes (1 500 μm plate) gave 9 mg of pure Example 60 compound. The so obtained pure compound of Example 60 was subjected to ¹ H NMR and MS [m / z: 735 (M ⁺ +1).
] Was characterized.

Example 61

[0372]

[Chemical 88]

The compound of Example 61 was prepared by the following procedure. Anhydrous ammonia was bubbled into 2 mL of dioxane at 0 ° C. to give an approximately 0.5 M solution. This solution was added to 6 mg of solid cyclo (N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-6-paranitrophenoxycarbonyloxy-hexanoyl) at 0 ° C. The ice bath was removed and the solution was allowed to stand at RT for 2 hours. The solution is concentrated under reduced pressure,
PTLC using 1: 9: 90 NH ₄ OH: MeOH: CHCl ₃ as a developing solution
(1 500 μm plate) afforded 1.7 mg of the pure compound of Example 61, which was characterized by ¹ H NMR and MS [m / z: 613 (M ⁺ +1)].

Example 62

[0375]

[Chemical 89]

The compound of Example 62 was prepared by the following procedure. Ph ₃ P 4 mg TH
F (0.2 mL) solution at 0 ° C. with DEAD (diethylazodicarboxylate)
2.4 mL was added and left for 30 minutes. The resulting solution was added to the solid cyclo (
N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-6-
4 mg of hydroxy-hexanoyl) was added at 0 ° C. After 1 hour at 0 ° C., the solution was warmed to RT and left for 1 hour. The solvent was removed under reduced pressure. PTLC (1 250 μm plate) using 1: 1 acetone: hexanes as the developing solution gave 2 mg of pure Example 62 product, ¹ H NMR and MS [m / z.
: 628 (M ⁺ +1)].

Example 63

[0378]

[Chemical 90]

The compound of Example 63 was prepared by the following procedure. Cyclo (N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-6-acetylthio-
Hexanoyl) in a solution of 1.5 mg MeOH (0.2 mL) at 0 ° C., NaOMe
0.3 wt.% 25 wt% MeOH solution was added. After 5 hours, water was added to stop the reaction. The solution was extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . 1 as developing solution
PTLC (1 250 μm plate) with 1: 1 acetone: hexanes gave 0.5 mg of pure Example 63 product. The compound of Example 63 was treated with ¹ H
It was characterized by NMR and MS [m / z: 588 (M ⁺⁺ 1)].

Example 64

[0380]

[Chemical Formula 91]

Following the procedure of Example 63, the C7 thiol was prepared from the corresponding thioacetate of Example 47. The compound of Example 64 was analyzed by ¹ H NMR and MS [m / z:
599 (M ⁺ +1)].

Example 65

[0384]

[Chemical Formula 92]

The compound of Example 65 was prepared by the following procedure. Cyclo - the (N-O-methyl -L-Trp-L-Ile- D-Pip-L-2- amino-6-hydroxy-hexanoyl) 1.6 mg of _CH 2 _Cl 2 (0.28mL) solution at 0 ℃ , DMA
0.2 mg P and then 2 mg TsCl were added. After 16 hours, let the solution stand
For 16 hours. The solvent was removed under reduced pressure. 1: 3: 96N as developing solution
PTLC with H ₄ OH: MeOH: CHCl ₃ (one 250 μm plate)
Gave 0.3 mg of the pure compound of Example 65. The pure ^product, 1 H
It was characterized by NMR and MS [m / z: 724 (M ⁺ +1)].

Example 66

[0387]

[Chemical formula 93]

[0388]   The compound of Example 66 was prepared by the following procedure. Cyclo (N-O-methyl
-L-Trp-L-Ile-D-Pip-L-2-amino-6-hydroxy-f
Xanoyl) 4 mg of CH_TwoCl_Two(0.35 mL) solution at 0 ° C., i) PPh _Three   3.7 mg, ii) imidazole 1 mg and iii) Zn (N_Three)_Two・ (
Pyridine)_TwoThen, iv) 2.2 μL of DEAD was added. Raise the temperature of the solution
It was set to RT and left for 12 hours. 1: 3: 96 NH as developing solution_FourOH: MeO
H: CHCl_ThreePure by PTLC (1 500 μm plate) using
2 mg of the compound of Example 66 was obtained. The compound of Example 66¹1 H NMR and
MS [m / z: 595 (M⁺+1)].

Example 67

[0390]

[Chemical 94]

[0391]   The compound of Example 67 was prepared by the following procedure. Cyclo (N-O-methyl
-L-Trp-L-Ile-D-Pip-L-2-amino-6-azido-hexa
Noyl) in a solution of 1 mg of THF (0.1 mL) at 0 ° C. and 0.1 mL of thiolacetic acid
Was added. After 1 hour, the solution was warmed to RT and left for 1 hour. Strong nitrogen
The solvent was removed with a stream of air. Dissolve the residue in 0.2 mL neat thiolacetic acid,
After the passage of time, the mixture was concentrated with a strong nitrogen stream. 1: 3: 96 NH as developing solution_FourOH
: MeOH: CHCl_ThreeBy PTLC (one 250 μm plate)
The pure product of Example 67 was obtained. The pure product obtained (0.7 mg) ¹ 1 H NMR and MS [m / z: 611 (M⁺+1)]
.

Example 68

[0393]

[Chemical 95]

The compound of Example 68 was prepared by the following procedure. To a solution of 500 mg apicidin in 1: 1 THF: MeOH (40 mL) was added 40 mg Pd (OH) ₂ . The atmosphere was H ₂ (balloon pressure). After 12 hours, the palladium catalyst was removed by filtration through Celite with MeOH as the eluent. After flash chromatography on silica gel using 4: 6 acetone: hexane as eluent,
467 mg of pure Example 68 product were obtained and characterized by ¹ H NMR. TLC: _Rf = 0.18 (1: 2 acetone: hexane). _{HPLC: t} R =
7.54 min _{(1: 1MeCN: H 2 O} , 1.5mL / min, Zorbax (R) RX-8).

Example 69

[0396]

[Chemical 96]

[0397]   The compound of Example 69 was prepared by the following method.

[0398]   Method C   30 mg of N-desmethoxyapicidin in DMF (500 μL) at RT,
4 drops MeI were added followed by 11 mg tBuOK. Solution at RT for 2 hours at 4 ° C
For 12 hours and at RT for a further 4 hours. Heat the solution at 60 ° C. for 1.5 hours,
It was cooled again to RT. Add an additional 20 mg of tBuOK and stir the solution for 1 hour.
I stirred. Solution 1: 2 saturated NaHCO_Three: Pour into 3 mL of saturated brine, CH_Two Cl_TwoExtracted with Na_TwoSO_FourDehydrated in. As developing solution 1: 2 acetone: hex
By preparative TLC on silica gel with Sun (2 1500 μm plates)
To obtain 19 mg of the pure compound of Example 69,¹1 H NMR and MS [m / z
: 625.3 (M⁺+ NH_Four)]. TLC: R_f= 0.3
1 (1: 2 acetone: hexane). HPLC: t_R= 3.90 minutes (62: 38M
eCN: H_TwoO, 1.5 mL / min, Zorbax® RX-8).

[0399]   Method D   20 mg of N-desmethoxyapicidin in DMF (0.35 mL) at RT
1.3 mg of 60% NaH was added. After 30 minutes, add 4 μL of MeI and add the solution.
Stir for 10 hours. Saturated NH solution_FourPut into Cl, CH_TwoCl_TwoExtracted with N
a_TwoSO_FourDehydrated in. Silica using 1: 2 acetone: hexane as a developing solution
Preparative TLC on gel (one 500 μm plate) was performed and a linear gradient (1:
1 to 1: 0 MeCN: H_TwoPurification by preparative RP-HPLC using O)
To give 5 mg of the pure compound of Example 69,¹1 H NMR and MS [
m / z: 608.5 (M⁺+1)].

Example 70

[0401]

[Chemical 97]

The compound of Example 70 was prepared by the following method. At RT, 467 mg of N-desmethoxyapicidin was placed in 16 mL of DMF, into which 60% NaH 63 m
g was added. After 10 minutes, 206 μL BrCH ₂ CO ₂ Me and nBu ₄ NI.
871 mg was added and the solution was heated to 80 ° C. After 15 minutes, the solution was poured into water, extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . Flash chromatography on silica gel with 1: 1 acetone: hexanes as eluent gave 401 mg of the pure compound of Example 70, which was analyzed by ¹ H NMR and MS.
Characterized by [m / z: 666 (M ⁺ +1)]. TLC: R _f = 0.4
6 (1: 1 acetone: hexane). _HPLC: t R = 7.21 min (1: 1MeC
_N: H 2 O, 1.0mL / minute, Zorbax (R) RX-8).

Example 71

[0404]

[Chemical 98]

The compound of Example 71 was prepared by the following method. At 0 ° C., to a DMF solution of N-desmethoxy-N- (paracarboxyphenylmethyl) apicidin 3.5 mg was added HOBT 0.65 mg, NaHCO ₃ 1.6 mg, 5-aminotetrazole 0.5 mg and EDCI 1 mg. . After 12 hours, the solution was saturated with NH
It was poured into Cl ₄ , extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . Gradient elution (
RP-HPLC with 4: 6 to 1: 0 MeCN: water acetone) yielded 1.6 mg of the pure compound of Example 71, which was analyzed by ¹ H NMR and MS [m.
/ Z: 795 (M ⁺ +1)].

Example 72

[0407]

[Chemical 99]

[0408]   The compound of Example 72 was prepared by the following method. At RT, N-Desmetoki
50 mg of siapicidin dissolved in DMF (0.2 mL) and HMPA (0.2 ml)
To the liquid, 3.4 mg of 60% NaH was added. After gas generation stops (PhO) _Two 35 μL of P (O) Cl was added. After 24 hours, pour the solution into water and wash with EtOA.
Extract with c, Na_TwoSO_FourDehydrated in. Eluent 1: 2 acetone: hexane
Of pure Example 72 by chromatotron TLC using
To obtain 16 mg of compound¹1 H NMR and MS [m / z: 826 (M⁺ +1)].

Example 73

[0410]

[Chemical 100]

The compound of Example 73 was prepared by the following method. In RT, the N- desmethoxy Api chlorhexidine 10mg of _CH 2 _Cl 2 (0.17mL) _solution, Et 3 N 7m
1 mL of L and DMAP was added. 3.9 μL MeSO ₂ Cl was added. Two
After 0 h, the solution was poured into water, extracted with EtOAc, dried over Na ₂ SO ₄ .
Linear gradient (4: 6 to _1: 0MeCN: _H 2 O) by preparative RP-HPLC using to give the compound 0.6mg of pure Example 73 _(R f = 0.4,4: 6 acetone: hexane), it ¹ H NMR and ^{MS [m / z: 672 (} M + +
1)].

[0412]   Examples 74A to 74J   Examples 69-7 using the appropriate electrophile (R-X), which will be readily determined by one of ordinary skill in the art.
The following compounds were prepared according to the procedure of 2.

[0413]

[Chemical 101]

[0414]

[Table 7]

Example 75

[0416]

[Chemical 102]

The compound of Example 75 was prepared by the following method. At RT, N-desmethoxy-N- (paraaminophenoxycarbonyl) apicidin 9 mg DMF (0.
22 mL) solution, 0.1 mL of pyridine was added, and then 22 μL of HOCH ₂ CH ₂ NMe ₂ was added. After 15 hours, the solution was poured into saturated NaHCO ₃ and CH ₂ C.
extracted with l _2, and dried over _Na 2 SO _4. Preparative Chromatotron TLC (1000 μm plate) using 1: 2 Acetone: Hexane as the developing solution gave the pure compound of Example 75, which was subjected to ¹ H NMR and MS [m / z: 709.
(M ⁺ +1)].

Example 76

[0419]

[Chemical 103]

The compound of Example 76 was prepared by the following method. At 0 ° C., N-desmethoxy-N- (paracarboxymethylphenylmethyl) apicidin 3.8 mg TH
To a F: MeOH: H ₂ O 3: 1: 1 mixture (0.13 mL) solution, 1N Li was added.
7.8 μL of OH was added. After 2 hours at 0 ° C. and 17 hours at RT, the volatiles were removed with a strong stream of nitrogen. The aqueous layer was extracted with EtOAc and the aqueous layer was pH adjusted with 2N HCl.
The acidity was about 4. The aqueous layer was further extracted 5 times with a 3: 7 mixture of iPrOH: CHCl ₃ and finally dried over Na ₂ SO ₄ . Linear gradient (2: 8 to 1: 0 MeCN
: By RP-HPLC using _H 2 O), a compound of pure Example 76 2.5
mg was obtained, which was characterized by ¹ H NMR and MS [m / z: 728 (M ⁺ +1)].

Example 77

[0422]

[Chemical 104]

[0423]   The compound of Example 77 was prepared by the following method. N-Desme at -10 ℃
Toxy-N- (paraacetoxyphenylcarbonyl) apicidin 3.3 mg T
HF: MeOH: H_TwoO 3: 1: 1 mixture (0.11 mL) solution to 1 M L
6.5 μL of iOH was added. After 1 hour, the volatiles were removed with nitrogen. Next, water
And about 2 mL each of EtOAc were added. Pour the resulting solution with 2N HCl
The pH was approximately 7 after neutralization. The solution is extracted with EtOAc, Na_TwoSO_FourWith
Watered PTLC using 6: 4 acetone: hexane as a developing solution (500 μm
(1 plate) gave 1.7 mg of the pure compound of Example 77, which was ¹ 1 H NMR and MS [m / z: 714 (M⁺+1)]
.

Example 78

[0425]

[Chemical 105]

The compound of Example 78 was prepared by the following method. At RT, 0.5 mg of 10% Pd / C catalyst was added to a CH ₂ Cl ₂ (0.2 mL) solution of ₂ mg of N-desmethoxy-N- (paranitrophenoxycarbonyl) apicidin to make a hydrogen atmosphere (balloon pressure). ). After 6.5 hours, the catalyst was removed by Celite filtration using 1: 1 MeOH: CH ₂ Cl ₂ as eluent. 1.8 mg of the obtained compound of Example 78 was subjected to ¹ H NMR and MS [m / z: 729 (M ⁺⁺⁾ without further purification.
1)].

Example 79

[0428]

[Chemical formula 106]

The compound of Example 79 was prepared by the following method. At 0 ° C., N-desmethoxy -N- carbomethoxymethyl Api chlorhexidine 89mg of _THF: MeOH: _H 2 O
To a 1: 1: 1 mixed solution (3.5 mL) solution, 200 μL of 1M LiOH was added. After 45 minutes at 0 ° C., the slightly cloudy solution was warmed to RT and became homogeneous. After an additional 20 minutes, it was removed using a strong stream of _{N 2} and MeOH and THF.
Next, ethyl acetate was added to the solution and removed to discard the residual organic soluble matter. Solution 2
Acidify to pH ˜4.0 with N HCl and add 3 mL of brine to the aqueous layer,
It was extracted with a 1: 4 mixture of PrOH: CHCl ₃ . The organic layer was dried over Na ₂ SO ₄ to give 51 mg of pure Example 79 compound. ¹ H NMR and M
It was characterized by S [m / z: 652.5 (M ⁺ +1)]. _HPLC: t R = 1.21 min _{(1: 1MeCN: H 2 O} , 1.5mL / min, Zorbax (R) RX-8).

Example 80

[0431]

[Chemical formula 107]

The compound of Example 80 was prepared by the following method. In RT, N-desmethoxy-N-- of _CH 2 _Cl 2 (6-amino hexylamino carbonyl methyl) Apicidin 6 mg (1 mL) solution was added TEA 2.6 mL. Next, NBD-
4 mg Cl was added and the vial was wrapped in foil. After 3 hours at RT, pure Example 80 compound was obtained by flash chromatography on silica gel without workup using 1: 1 hexane: acetone as eluent. The pure product was characterized by ¹ H NMR. TLC: _Rf = 0.19 (1:
1 acetone: hexane).

Example 81

[0434]

[Chemical 108]

[0435]   The compound of Example 81 was prepared by the following method. N-Desmetoki at 0 ° C
50 mg of Ci-N-carbomethoxymethylapicidin, CBZ-HN (CH_Two)₆ NH_Two  29 mg, HOBT 10 mg and DIEA 19 μL CH_TwoCl _Two To the (5 mL) solution was added 19 mg of EDCI. 15 min at 0 ° C and RT
After 1 hour, 3 mg of DMAP was added. After another two hours, a strong N_TwoUsing airflow
CH_TwoCl_TwoWas removed and 2 mL of DMF was added. After 2 hours, add 2: 1H to the solution._Two O: Pour into 20 μL of brine, acidify to pH about 3.0 with 2N HCl, then add C
H_TwoCl_Two  Extraction was performed 5 times with 15 mL each. The organic layer is Na_TwoSO_FourDehydrated in.
54 mg of pure Example 81 compound were obtained without further purification and¹H N
MR and MS [m / z: 884.6 (M⁺+1)]. T
LC: R_f= 0.72 (1: 9: 90 NH_FourOH: MeOH: CHCl_Three). H
PLC: t_R= 5.38 minutes (6: 4 MeCN: H_TwoO, 1.5 mL / min, Solva
X (registered trademark) RX-8).

Example 82

[0437]

[Chemical 109]

The compound of Example 82 was prepared by the following method. A solution of N-desmethoxy-N-carboxymethylapicidin (5.7 mg) in DMF (0.1 mL) at 0 ° C.,
2.9 mg NaHCO ₃ and 1.2 m EtSCH ₂ CH ₂ NH ₂ .HCl.
To g, 1.2 mg of HOBT was added. To it was added 1.8 mg of EDCI.
The solution was warmed to RT and left for 16 hours. The aged solution is saturated with NaHC
It was poured into O ₃ , extracted with EtOAc and dried over Na ₂ SO ₄ . Gradient elution (4:
6 from _1: 0MeCN: by RP-HPLC using _H 2 O), to give a compound 3.3mg of pure Example 82, it ¹ H NMR and MS [m / z: 7
39 (M ⁺ +1)].

Example 83

[0440]

[Chemical 110]

The compound of Example 83 was prepared by the following method. At RT, to a solution of N-desmethoxy-N- [6- (benzyloxycarbonylamino) -hexylaminocarbonylmethyl] -apicidin 54 mg in DMF (3 mL) was added 5% Pd / C catalyst 10 mg, and H ₂ atmosphere was added. Yes (balloon pressure). After 2 hours, additional 5% Pd / C
40 mg was added and the solution was stirred overnight. The catalyst was filtered off and the solvent was removed under reduced pressure. Gradient elution (first with undiluted CHCl ₃ , then 1: 3: 96 as eluent,
Flash chromatography on silica gel with 1: 4: 95 then 1: 9: 90 NH ₄ OH: MeOH: CHCl ₃ ) gives pure Example 83 compound, ¹ 1 H NMR and MS [m / z: 750
． 4 (M ⁺ +1)]. TLC: R _f = 0.12 (1: 9:
_{90NH 4 OH: MeOH: CHCl 3} ).

Example 84

[0443]

[Chemical 111]

[0444]   The compound of Example 84 was prepared by the following method. At RT, N-Desmetoki
4 mg of cy-N- (6-aminohexylaminocarbonylmethyl) -apicidin
CH_TwoCl_Two(0.5 mL) NHS-SS-biotin 3.2 mg was added to the solution,
Then 2 μL of DIEA was added. Let the solution stand at RT for 1 hour and then at 4 ° C for 12 hours.
And stirred at RT for 2 hours. Additional NHS-SS-Biotin 3.2 mg and DI
2 μL of EA was added, followed by 100 μL of DMF. After another hour, the solution
Gradient elution (1: 3: 96 to 1: 9: 90 NH as eluent)_FourOH: MeOH
: CHCl_ThreeA) to a pure silica gel pipette column carrying out
4 mg of the compound of It¹It was characterized by 1 H NMR. TLC: R _f = 0.26 (1: 9: 90 NH_FourOH: MeOH: CHCl_Three).

Example 85

[0446]

[Chemical 112]

The compound of Example 85 was prepared by the following method. In RT, N-desmethoxy-N-(6- aminohexyl aminocarbonylmethyl) - to Apicidin 2mg of _CH 2 _Cl 2 (0.5mL) solution, HOBT 0.5mg, Fmoc-Phe
(4-Bz) -OH (Fmoc = 9-fluorenylmethyloxycarbonyl) 2
． 6 mg and 1 mg EDCI were added. Then 3 μL of DIEA was added. R
After 2 h at T, without workup, the crude product was subjected to pipette column purification on silica gel with gradient elution (1: 1 acetone: hexane and then 5:95 MeOH: CHCl ₃ as eluent). It was The partially purified compound of Example 85 was characterized by ¹ H NMR. TLC: _Rf = 0.26 (1: 9: 90
_{NH 4 OH: MeOH: CHCl 3} ). TLC: R _f = 0.53 (5:95 Me
OH: CHCl _3).

Example 86

[0449]

[Chemical 113]

The compound of Example 86 was prepared by the following method. At RT, a solution of 15 mg of the Fmoc-protected compound of Example 85 in CH ₂ Cl ₂ (2 mL) was added with piperidine 0.
2 mL was added. After 3 hours at RT, the volatiles were removed under reduced pressure to produce the compound of Example 86. The material was used in Example 87 without further purification.

Example 87

[0452]

[Chemical 114]

[0453]   2 mg of the crude product of Example 86 CH_TwoCl_TwoEt solution (0.2 mL) at 0 ° C. _Three N 5 μL was added, then MeSO_Two2 μL of Cl was added. 30 minutes later, NH_Four OH: MeOH: CHCl_ThreeReaction was stopped by adding 3 drops of 1: 9: 90 mixture
did. 1: 3: 96 NH as eluent_FourOH: MeOH: CHCl_ThreeUsing
By flash chromatography on lica gel, the pure
The compound of Example 87 was obtained. It¹It was characterized by 1 H NMR.

Example 88

[0455]

[Chemical 115]

[0456]   The compound of Example 88 was prepared by the following procedure. First, HOBT 6
mg, (4-Bz) PhCO_TwoH 10 mg, DIEA 23 μL and BOP
  CH at 19.6 mg at RT_TwoCl_Two  In addition to 250 mL, (4-Bz) Ph
CO (OBT) was obtained. Then, in a vial, N-desmethoxy-N- (6-a
Minohexylaminocarbonylmethyl) -apicidin 1 mg CH_TwoCl_Two(2
To the (00 μL) solution, add the freshly prepared (4-Bz) PhCO (OBT) solution.
I got it. The vial was wrapped in foil and stirred overnight at RT. 1: 9: 9 as the developing solution
0 NH_FourOH: MeOH: CHCl_ThreePreparative TLC on silica gel using
The partially purified product was obtained by 0 μm plate 1). As a developing solution 1: 3:
96 NH_FourOH: MeOH: CHCl_ThreePreparative TLC (2
Pure 50 μm plate) gave pure compound of Example 88. It¹ It was characterized by 1 H NMR. TLC: R_f= 0.27 (1: 3: 96 NH _Four OH: MeOH: CHCl_Three).

Example 89

[0458]

[Chemical formula 116]

The compound of Example 89 was prepared by the following procedure. 9 mg N-desmethoxy-N- (6-aminohexylaminocarbonylmethyl) -apicidin at RT
HOBT 3 mg, Et ₃ N 6 μL and (4-Bz) PhCH═CHCO ₂ H 4.1 mg were added to a CH ₂ Cl ₂ (1 mL) solution of BOP 13m.
g was added. After 4 hours, without post-treatment, 1: 3: 96 NH ₄ OH: MeOH.
The crude material was purified by flash chromatography on silica gel with: CHCl ₃ . This gave 13.4 mg of the pure compound of Example 89, which was characterized by ¹ H NMR. TLC: _Rf = 0.29 (1: 3
_{: 96NH 4 OH: MeOH: CHCl} 3). _HPLC: t R = 4.90 min (7
_{: 3MeCN: H 2 O, 1.5mL} / min, Zorbax (R) RX-8)
.

Example 90

[0461]

[Chemical 117]

The compound of Example 90 was prepared by the following procedure. At RT, 3 mg of 5% Pd / C catalyst was added to a solution of 4 mg of the compound of Example 89 in 1: 1 MeOH: CH ₂ Cl ₂ and a deuterium gas atmosphere was added (balloon pressure). After 1 hour, 1: 9: 9 as eluent
The solution was purified on a silica gel pipette column with 0 NH ₄ OH: MeOH: CHCl ₃ to give 2.9 mg of pure Example 90 compound. ¹ H NMR
Was characterized. TLC: R _f = 0.34 (1: 3: 96 NH ₄ OH: MeOH
: CHCl _{3). HPLC:} t R = 4.66 min _{(7: 3MeCN: H 2 O} , 1.
5 mL / min, Zorbax® RX-8).

Example 91

[0464]

[Chemical 118]

The compound of Example 91 was prepared by the following procedure. A solution of 9 mg of the compound of Example 74d, which is a silyl ether, in pyridine (0.2 mL) was added at 0 ° C. to an HF / pyridine solution (HF / pyridine 25 mg, pyridine 10 mL, and THF 25 m).
(Prepared from L) 0.2 mL was added. After 1.5 h, it was quenched by addition of saturated NaHCO ₃ , extracted with CH ₂ Cl ₂ and the combined organic layers were dried over Na ₂ SO ₄ . 7.4 mg of the alcohol so obtained was used without further purification in Example 92 below and was characterized by ¹ H NMR and MS [m / z: 638 (M ⁺ +1)].

Example 92

[0467]

[Chemical formula 119]

[0468]   Example 91 alcohol 7.4 mg CH_TwoCl_Two(4 mL) solution at RT,
422 mg of 1,2,4-triazole was added, followed by (PhCH_TwoO)_TwoPNEt _Two   The compound of Example 92 was prepared by adding 610 μL. Allow the solution to pass for 3 hours
After passing, the volatiles were removed under reduced pressure to give a yellow residue. Then THF
  7 mL was added to the yellow residue to give a solution which was cooled to -40 ° C. So
30% H in the solution of_TwoO_Two  4.6 mL was added and the temperature was raised to RT. 30 minutes
After passing 10% Na_TwoS_TwoO_ThreeThe reaction is stopped by adding (aqueous solution)
Japanese NaHCO_ThreeDiluted with (aqueous solution) and water, CH_TwoCl_TwoExtracted with Na_TwoS
O_FourDehydrated in. Chromatography using 1: 2 acetone: hexane as the developing solution
255 m pure Example 92 compound by purification (1000 μm plate)
g and get it¹1 H NMR and MS [m / z: 898 (M⁺+1)]
I decided the characteristics.

Example 93

[0470]

[Chemical 120]

245 mg of the compound of Example 92 iPrOH (40 mL) and water (1 mL)
The compound of Example 93 was prepared by adding 27 mg of KHCO ₃ and 25 mg of 10% Pd / C catalyst to the solution of. A hydrogen atmosphere was applied for 12 hours (balloon pressure). The catalyst was removed by filtration through Celite with 1: 1 MeOH: H ₂ O as eluent, followed by removal of volatiles under reduced pressure. 214 mg of the compound of Example 93 were obtained without further purification. It was analyzed by ¹ H NMR and MS [
m / z: 718 (M ⁺ +1)].

Example 94

[0473]

[Chemical 121]

[0474]   The compound of Example 94 was prepared by the following procedure. Apicidin al at 0 ° C
Call 20mg CH_TwoCl_Two(2 mL) to the solution, add 2 mg of DMAP, then
Ts_Two26 mg O was added. After 10 minutes, the temperature of the solution was raised to RT and 3 hours passed.
Let Then 10 mg of TsCl was added and the solution was left for 16 hours. Solvent
Removed under reduced pressure, and developing solution from 4: 6 acetone: hexane to 1: 9: 90 NH _Four OH: MeOH: CHCl_ThreePure Example 94 by centrifugal TLC using
1 mg of the compound of The product¹1 H NMR and MS [m / z: 792 (
M⁺+1)].

Example 95

[0476]

[Chemical formula 122]

[0477]   The compound of Example 95 was prepared by the following procedure. N-Desmetoki at 0 ° C
Ci-N- (2-hydroxyethyl) -apicidin 300 mg CH_TwoCl_Two(2
5 mL) solution to Ph_ThreeP 247 mg and Zn (N_Three)_Three・ Pyridine 217m
g and then 150 μL DEAD. The temperature of the solution was raised to RT.
After 12 hours, the volatile matter was removed under reduced pressure. 1: 3: 96 as developing solution
NH_FourOH: MeOH: CHCl_ThreeChromatotron TL on silica gel using
C (2 mm plate) provided 311 mg of pure Example 95 compound (
R_f= 0.32, 1: 9: 90 NH_FourOH: MeOH: CHCl_Three). It ¹ 1 H NMR and MS [m / z: 663 (M⁺+1)]
.

Example 96

[0479]

[Chemical 123]

[0480]   The compound of Example 96 was prepared by the following procedure. At RT, N-Desmetoki
Ci-N- (2-azidoethyl) apicidin 311 mg CH_TwoCl_Two10 in solution
60 mg of a% Pd / C catalyst was added, and a hydrogen atmosphere was created (balloon pressure). Elution after 8 hours
3: 7 iPrOH: CHCl as liquid_ThreeThe catalyst was filtered through Celite using
The desired product was obtained. 1: 3: 96 NH as developing solution_FourOH: MeOH: CHCl _Three Chromatotron PTLC (2000 μm 1 plate) using
The compound of smart Example 96 (200 mg, R_f= 0.21 (1: 3: 96 NH_FourO
H: MeOH: CHCl_Three) Got. It¹1 H NMR and MS [m / z
: 637 (M⁺+1)].

Example 97

[0482]

[Chemical formula 124]

[0483]   The compound of Example 97 was prepared by the following procedure. N-Desmetoki at 0 ° C
Ci-N- (2-aminoethyl) apicidin 10 mg CH_TwoCl_Two(0.5 mL
) To the solution, Et_ThreeN 9 μL was added, then MeSO_Two3.6 μL of Cl was added
. The solution was warmed to RT and stirred for 30 minutes. Saturated NaHCO_ThreeAdd
Stop the reaction of the solution with and CH_TwoCl_TwoExtracted with Na_TwoSO_FourDehydrated in.
PTLC on silica gel using 1: 1 acetone: hexane as a developing solution (25
A 0 μm plate) provided 9 mg of pure compound of Example 97. It
To¹1 H NMR and MS [m / z: 732 (M⁺+ NH_Four)]
Decided TLC: R_f= 0.26 (1: 1 acetone: hexane). HPLC: t _R = 4.7 minutes (1: 1 MeCN: H_TwoO, 1.5 mL / min, Zorbax (register
(Trademark) RX-C8).

Example 98

[0485]

[Chemical 125]

The compound of Example 98 was prepared by the following procedure. At RT, N-desmethoxy-N-2-methanesulfonamidoethylapicidin 4 mg THF (0.28
mL) solution, add 7 μL of NaN (TMS) ₂ (1M THF solution), and then add M
1.5 μL of eI was added. After 16 hours, the reaction was quenched by adding water, extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . 1: 3: 9 as developing solution
PTLC on silica gel with 6NH ₄ OH: MeOH: CHCl ₃ (250
(1 μm plate) gave 2.2 mg of pure compound of Example 98. It was characterized by ¹ H NMR and MS [m / z: 746.6 (M ⁺ + NH ₄ )]. _{TLC: R f = 0.42 (1} : 3: 96NH 4 OH: MeOH:
CHCl _3).

Example 99

[0488]

[Chemical formula 126]

[0489]   The compound of Example 99 was prepared by the following procedure. At RT, N-Desmetoki
Ci-N- (2-aminoethyl) -apicidin 16 mg CH_TwoCl_Two(1 mL)
To the solution, HOBT 5 mg, TEA 7 μL and Fmoc-Phe (4-Bz
) -OH 18.4 mg was added, followed by BOP 16 mg. 3 hours at RT
Later, 1: 3: 96 NH as eluent_FourOH: MeOH: CHCl_ThreeSiri using
The solution was purified by flash chromatography on kagel to give a pure run.
The compound of Example 99 was obtained. It¹It was characterized by 1 H NMR. TLC: R _f = 0.50 (1: 3: 96 NH_FourOH: MeOH: CHCl_Three).

Example 100

[0491]

[Chemical 127]

To a solution of the Fmoc-protected amine of Example 99 15 mg in CH ₂ Cl ₂ (2 mL) was R
The compound of Example 100 was prepared by adding 50 μL of piperidine at T. RT
After 2 h at rt the solution was concentrated under reduced pressure and freeze dried from dioxane to remove residual piperidine. The crude deprotected amine product was dissolved in ₂ mL CH ₂ Cl 2 at 0 ° C.,
5.6 μL of Et ₃ N was added, followed by 62 μL of MeSO ₂ Cl (0.26M CH ₂ Cl ₂ solution). After 1 hour, the reaction was quenched by adding saturated NaHCO ₃ (aq), extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . PTL on silica gel using 1: 4: 95 NH ₄ OH: MeOH: CHCl ₃ as developing solution
C (1 1000 μm plate) gave pure Example 100 compound. It was characterized by ¹ H NMR and MS [m / z: 1080 (M ⁺ +1)].

Example 101

[0494]

[Chemical 128]

[0495]   The compound of Example 101 was prepared by the following procedure. At RT, N-Desmet
20 mg xy-N- (2-aminoethyl) apicidin in MeOH (2 mL)
To NaBH_Four  8 mg was added. After 2 hours at RT, add acetone to the solution and mix.
Stop the reaction and add saturated NaHCO 3 solution._ThreeTo the CH_TwoCl_TwoExtracted with Na_TwoS
O_FourDehydrated in. 1: 9: 90 NH as eluent_FourOH: MeOH: CHCl_Three Pure Example by flash chromatography on silica gel using
101 compounds are obtained. It¹It was characterized by 1 H NMR. TLC: R _f = 0.28 (1: 9: 90 NH_FourOH: MeOH: CHCl_Three).

Example 102

[0497]

[Chemical formula 129]

The compound of Example 102 was prepared by the following procedure. In RT, the N- desmethoxy Api hepcidin 20 mg _9: 1 MeCN: in H 2 O (1.1mL) solution, DD
Q 16.1 mg was added to give a dark purple solution which turned red like blood over 30 minutes. The solution was aged at 0 ° C. for 12 hours. Without post-treatment, as the eluent 4: 6MeCN: The solution was purified by RP-HPLC using _{H 2} O. This gave 15 mg of the compound of example 102, which was characterized by ¹ H NMR and MS [m / z: 608 (M ⁺ +1)].

Example 103

[0500]

[Chemical 130]

The compound of Example 103 was prepared by the following procedure. At RT, cyclo (β-
Oxo-L-Trp-L-Ile-D-Pip-L-2-amino-8-oxo-
Decanoyl) 6 mg in CH ₂ Cl ₂ (0.5 mL) solution, Et ₃ N 1.5 μ
L was added. After 10 minutes, 1: 1 MeCN: H ₂ O as eluent without workup.
The solution was purified by RP-HPLC using. This gives pure Example 1
3 mg of the compound of 03 was obtained, which was subjected to ¹ H NMR and MS [m / z: 608 (
M ⁺ +1)].

Examples 104A and 104B

[0503]

[Chemical 131]

[0504]   The compounds of Examples 104a and 104b were prepared by the following procedure. RT
, Β-oxo-N-desmethoxyapicidin 300 mg HMPA 0.25
BrCH in DMF (0.5 mL) solution containing mL_TwoCH_TwoCH_TwoCH_TwoCl 0
． 14 mL, nBu_Four0.5 g NI and 25 mg 95% NaH were added.
Solution for 4 minutes N_TwoIt was degassed by blowing and heated at 100 ° C. for 90 minutes. Melting
Cool the solution to RT and saturate brine / sat NaHCO 3._ThreeTo the CH_TwoCl _Two Extracted with Na_TwoSO_FourDehydrated in. 1: 3: 96 NH as developing solution_Three: Me
OH: CHCl_ThreePTLC on silica gel using 2 (1500 μm plates 2
), A pure mixture of the compounds of Examples 104a and 104b was obtained. So
Pure product of¹1 H NMR and MS [m / z: 698.
5 (M⁺+1)]. The yield is 150 mg of D-Trp isomer.
And L-Trp isomer 120 mg. TLC: R_f= D-Trp isomer
0.42 and 0.25 for L-Trp isomer (2: 3 acetone: hexane).

Examples 105A and 105B

[0506]

[Chemical 132]

At RT, β-oxo-N-desmethoxyapicidin 300 mg HMPA 0
． 25 mL DMF (0.5 mL) solution at RT, BrCH ₂ CH ₂ CH ₂ CH ₂ Cl 0.12 mL, nBu ₄ NI 0.5 g and 95% NaH 25.
The compounds of Examples 105a and 105b were prepared by adding mg. The solution was degassed by bubbling N ₂ for 4 minutes and heated at 100 ° C. for 90 minutes. The solution was cooled to RT, poured into 1: 1 saturated brine: saturated NaHCO ₃ , CH ₂ C.
extracted with l _2, and dried over _Na 2 SO _4. As a developing solution, 1: 3: 96 NH ₃ : M
PTLC on silica gel with MeOH: CHCl ₃ (1500 μm plate 2
To obtain a pure mixture of the compounds of Examples 105a and 105b.
It was analyzed by ¹ H NMR and MS [m / z: 684.5 (M ⁺⁺ for each isomer).
1)]. Yield: 120 mg D-Trp isomer and LT
80 mg of rp isomer. TLC: _Rf = 0.55 for the D-Trp isomer and L-
0.27 for Trp isomer (2: 3 acetone: hexane).

Examples 106A and 106B

[0509]

[Chemical 133]

Cyclo (N- (4-chloro-n-butyl) -β-oxo-D-Trp-LI
Example 1 by adding 516 mg of NaI to a solution of 120 mg of le-D-Pip-L-2-amino-8-oxo-decanoyl) in dry MeCN (2.2 mL).
The compounds of 06a and 106b were prepared. The resulting solution was heated at 60 ° C for 12 hours. The solution was cooled to RT, diluted with 1: 1 brine: saturated NaHCO ₃ , extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . Thereby, Example 10
100 mg of a mixture of compounds of 6a and 106b was obtained. It was characterized by ¹ H NMR and MS [m / z: 790.5 (M ⁺ +1) for each isomer]. _TLC: R f = D-Trp isomer 0.58 and 0.41 with L-Trp isomers _{(1: 3: 96NH 4 OH} : MeOH: CHCl 3).

Examples 107A and 107B

[0512]

[Chemical 134]

Cyclo (N- (4-chloro-n-propyl) -β-oxo-D-Trp-L-
Example 1 by adding 350 mg of NaI to a solution of 80 mg of Ile-D-Pip-L-2-amino-8-oxo-decanoyl) in dry MeCN (1.5 mL).
The compounds of 07a and 107b were prepared. The resulting solution was heated at 60 ° C for 12 hours. The solution was cooled to RT, diluted with 1: 1 brine: saturated NaHCO ₃ , extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . Thereby, Example 10
70 mg of a mixture of the compounds of 7a and Example 107b was obtained. ¹ H NM
R and MS [m / z: 776.5 (M ⁺ +1) for each isomer] were characterized. _TLC: R f = D-Trp isomer 0.53 and 0.42 with L-Trp isomers _{(1: 3: 96NH 4 OH} : MeOH: CHCl 3).

Examples 108A and 108B

[0515]

[Chemical 135]

Cyclo (N- (3-iodo-n-propyl) -β-oxo-D-Trp-L-
Ile-D-Pip-L-2-amino-8-oxo-decanoyl) and cyclo (N- (3-iodo-n-propyl) -β-oxo-L-Trp-L-Ile-
D-Pip-L-2-amino-8-oxo-decanoyl) about 1: 1 mixture 40
The compounds of Examples 108a and 108b were prepared by adding 30 mg of MgBr ₂ .H ₂ O and 30 μL of nBu ₃ SnH to a solution of mg in CH ₂ Cl ₂ (0.5 mL). The resulting solution was cooled to -78 ° C. Then Et ₃ B 1
00 μL was added, and then 500 μL of oxygen gas was added from a syringe over 2 hours. 1
The reaction was quenched by adding 1: 1 brine: saturated NaHCO ₃ at -78 ° C. The solution was warmed to RT, partitioned with CH ₂ Cl ₂ and the organic layer dried over Na ₂ SO ₄ . The solution was concentrated under reduced pressure and the residue was partitioned between hexane: MeCN (1: 3). The MeCN layer was washed with hexane (3 times), and the MeCN layer was concentrated under reduced pressure. The pure product was obtained by PTLC (1 1000 μm plate) on silica gel using 1: 3: 96 NH ₄ OH: MeOH: CHCl ₃ as the developing solution. Pure product was analyzed by ¹ H NMR and MS [m / z: 650.
6 (M ⁺ +1)]. TLC: _Rf = 0 for D-Trp isomer
． 69 and 0.51 with L-Trp isomers _{(1: 3: 96NH 4 OH} : MeO
H: CHCl _3).

Example 109

[0518]

[Chemical 136]

The compound of Example 109 was prepared by the following procedure. Cyclo (N- (3-iodo-n-propyl) -β-oxo-D- (and L, about 1: 1) -Trp-L
-Ile-D-Pip-L-2-amino-8-oxo-decanoyl) mixture 2
To a solution of 2 mg of toluene (0.6 mL), 5 mg of 2,2′-azobisisobutyronitrile and 38 μL of nBu ₃ SnH were added. The solution was sparged with nitrogen for 5 minutes and it was heated at 100 ° C. for 2 hours. The solution was cooled to RT, concentrated under reduced pressure and the residue partitioned between hexane: MeCN (1: 3). The MeCN layer was washed with hexane (3 times), and the MeCN layer was concentrated under reduced pressure. Pure Example 10 by PTLC on silica gel with 4: 6 acetone: hexane as the developing solution.
10 mg of the compound of 9 were obtained. It was analyzed by ¹ H NMR and MS [m / z: 652].
． 7 (M ⁺ +1)]. TLC: R _f = 0.50 and 0.
43 (mixture of β-hydroxy isomers) (1: 3: 96 NH ₄ OH: MeOH:
CHCl _3).

Example 110

[0521]

[Chemical 137]

[0522]   The compound of Example 110 was prepared by the following procedure. At RT, cyclo (N-
(4-iodo-n-butyl) -β-oxo-D-Trp-L-Ile-D-Pi
p-L-2-amino-8-oxo-decanoyl) and cyclo (N- (4-ioo)
Do-n-butyl) -β-oxo-L-Trp-L-Ile-D-Pip-L-2
-Amino-8-oxo-decanoyl) about 1: 1 mixture 31 mg of toluene (0
． 8 mL) solution, 6 mg of 2,2'-azobisisobutyronitrile and nBu _Three 52 μL of SnH was added. The solution is sparged with nitrogen for 5 minutes and at 100 ° C
Heated for 2 hours. The solution is cooled to RT, concentrated under reduced pressure and the residue is taken up in hexane.
Partitioned between: MeCN (1: 3). Wash the MeCN layer with hexane (3 times)
The MeCN layer was concentrated under reduced pressure. The compound of Example 110 was prepared without purification.¹ It was characterized by 1 H NMR. TLC: R_f= 0.66 (1: 3: 96 NH _Four OH: MeOH: CHCl_Three).

Examples 111A and 111B

[0524]

[Chemical 138]

[0525]   β-oxo-N-desmethoxyapicidin 3 mg EtOH (0.25 mL)
NaBH in solution at 0 ° C_Four  1 mg was added to give Example 111a and 111
The compound of b was prepared. Saturate the solution after 2.5 hours at RT and 10 hours at 0 ° C.
NH_FourCl and extracted with 3: 1 EtOAc: iPrOH, Na_TwoSO_Fourso
Dehydrated. Gradient elution (2: 3 to 1: 1 MeCN: H_TwoRP-HP using O)
LC provided a pure mixture of the compounds of Examples 111a and 1112b.
,¹1 H NMR and MS [m / z: 594 (M for both isomers⁺-H_Two O)]. TLC: R_f= If D-Trp isomer is 0.50
And 0.28 (1: 9: 90 NH in L-Trp isomer)_FourOH: MeOH: CHC
l_Three). TLC: R_f= 0.26 (1: 1 acetone: hexane). HPLC: t _R = 3.9 min with D-Trp isomer and 3.5 min with L-Trp isomer (1: 1M
eCN: H_TwoO, 1.5 mL / min, Zorbax® RX-C8).

Examples 112A and 112B

[0527]

[Chemical 139]

Cyclo (β-oxo-L-Trp-L-Ile-D-Pip-L-2-amino-8-oxo-decanoyl) 10 mg in MeOH (0.2 mL) at RT C.
The addition of eCl ₃ · 6H ₂ O, were prepared compounds of Examples 112a and 112b. After 5 minutes, the solution was cooled to 0 ° C. and 0.6 mg NaBH ₄ was added. The solution was poured into saturated _NH 4 Cl, extracted with EtOAc, dried over _Na 2 SO _4. As eluent 1: 1 MeCN: by RP-HPLC using _{H 2} O, to give a pure mixture of compound 1.3mg of compound 0.7mg and Example 112b Example ^112a, 1 H NMR and MS [m / z: 609 for each isomer
(M ⁺ +1)].

Examples 113A and 113B

[0530]

[Chemical 140]

Cyclo (β-oxo-L-Trp-L-Ile-D-Pip-L-2-amino-8-hydroxy-decanoyl) 700 mg in dichloroethane (115 mL) was added at RT to DMAP 14 mg and Ac ₂ O 0. The compounds of Examples 113a and 113b were prepared by adding 0.533 mL. After 8 hours, the mixture was poured into saturated _NH 4 Cl, extracted with _CH 2 Cl _2, and dried over _Na 2 SO _4. A preparative chromatotron (4 μm plate) using a gradient elution of 2: 8 to 4: 6 acetone: hexane as the developing solution gave 8 mg of a mixture of the compounds of Example 113a and Example 113b. Pure epimeric isomers were analyzed by ¹ H NMR and MS [m
/Z:694.4(M ⁺ +1)] was characterized by. D-Trp isomer: yield 140 mg; TLC: _Rf = 0.71 (1: 1 acetone: hexane); MS [
m / z: 694.4 (M ⁺⁺ 1)]. L-Trp isomer: yield 110 mg; TL
C: R _f = 0.57 (1: 1 acetone: hexane); MS [m / z: 694.5.
(M ⁺ +1)].

Example 114

[0533]

[Chemical 141]

The compound of Example 114 was prepared by the following procedure. At RT, apicidin 1
N-bromosuccinimide 28.5 was added to a solution of 00 mg of CCl ₄ (5.3 mL).
mg and 1.2 mg benzoyl peroxide were added. Next, nitrogen was bubbled through the solution for 5 minutes, the solution was refluxed for 15 minutes and cooled to RT. 1: 3 as developing solution
: 96NH ₃ : MeOH: CHCl ₃ (1 development) and then by PTLC (3 1000 μm plates) on silica gel with 4: 6 acetone: hexane (2 developments) for pure compound of Example 114. to give 62 mg, it ¹ H N
It was characterized by MR and MS [m / z: 704 (M ⁺ +1)]. RP-
_HPLC: t R = 5.02 min _(apicidin: t R = 4.82 min), 6: 4MeC
_N: H 2 O, 1.5mL / min.

Examples 115A and 115B

[0536]

[Chemical 142]

The compound of Example 115a (mobile product A) was prepared by Methods E and F below.
And the compound of Example 115b (polar product B) was prepared.

[0538]   Method E   AgBH at 0 ° C_Four  4 mg of 3: 1 DMSO: CH_TwoCl_Two(250 μL)
10 mg of the compound of Example 114 was added to the solution. After 10 minutes (at this time
At that point, TLC showed that the raw material bromide had disappeared), Et_ThreeN 10
μL was added and the solution was allowed to pass for an additional hour. The reaction was stopped by adding water.
CH the mixture_TwoCl_TwoExtracted with Na_TwoSO_FourDehydrated in. 1: 1 as developing solution
PTLC on silica gel with acetone: hexane (one 250 μm plate
), To obtain a pure mixture of the compounds of Examples 115a and 115b,¹ 1 H NMR and MS [m / z: 640 (M for both isomers⁺+1)]
Therefore, it was determined. TLC: R_f= The compound of Example 115a (mobile product A
)) And 0.41 with the compound of Example 115b (polar product B).
1 acetone: hexane.

[0539]   Method F   At RT, apicidin 43 mg CH_TwoCl_TwoIn solution, NaHCO_Three  12 mg
Was added, followed by 18 mg of 85% MCPBA. Increase the resulting solution for 12 hours
It was stirred. Saturated NaHCO 3 solution_Three(Water solution), CH_TwoCl_TwoExtracted with
, Na_TwoSO_FourDehydrated in. On silica gel with 1: 1 acetone: hexane
Pure compound of Example 115a by PTLC (1 250 μm plate)
Got This is in all respects the compound of Example 115a from Method E above, ie
Identical to mobile product A.

Example 116

[0541]

[Chemical 143]

The compound of Example 116 was prepared according to the procedure of Example 115a Method E. Using the compound of Example 114 (10 mg) as a starting material, the compound of Example 116 (4 mg) was obtained.
It was characterized by ¹ H NMR and MS [m / z: 718.6 (M ⁺ +1)].

Example 117

[0544]

[Chemical 144]

The compound of Example 117 was prepared by adding 4 μL of Ac ₂ O to a solution of 5.4 mg of the compound of Example 115b in ClCH ₂ CH ₂ Cl (375 μL) and then adding 0.3 mg of DMAP. After 1.5 hours, the volatile matter was removed under a nitrogen stream.
PTLC on silica gel using 1: 1 acetone: hexane as a developing solution (25
6 mg of pure Example 117 compound were obtained by means of a 0 μm plate). It was characterized by ¹ H NMR and MS [m / z: 762 (M ⁺ +1)].

Example 118

[0547]

[Chemical 145]

The compound of Example 118 was prepared by the following procedure. To a solution of the compound of Example 117 (5 mg) in CH ₂ Cl ₂ at RT was added Pd (OH) ₂ (1 mg), and a hydrogen atmosphere was generated (balloon pressure). After 2 hours, the solution was filtered and concentrated under reduced pressure.
Flash chromatography on silica gel with 1: 9: 90 NH ₄ OH: MeOH: CHCl ₃ afforded 3.5 mg of pure Example 118 compound. It was characterized by ¹ H NMR and MS [m / z: 652 (M ⁺ +1)].

Example 119

[0550]

[Chemical 146]

The compound of Example 119 was prepared by the following procedure. To a solution of 25 mg of β-oxo-N-desmethoxy-apicidin in MeOH (1.5 mL) was added 15 μL of pyridine at RT, followed by 126 mg of Pb (OAc) ₄ . After 48 hours, the solution was cooled to 0 ° C. and saturated Na ₂ S ₂ O ₃ (aq) was added. The solution was poured into saturated NH ₄ Cl (aq): brine (1: 1), iPrOH: C.
It was extracted with HCl ₃ (3: 7) and dried over Na ₂ SO ₄ . The solution was filtered and concentrated under reduced pressure. _{1: 9: 90NH 4 OH:} MeOH: by flash chromatography on silica gel using CHCl _3, compound of pure Example 119 3
6 mg was obtained. It was subjected to ¹ H NMR and MS [m / z: 638 (M ⁺ +1)].
Characterized by

Example 120

[0553]

[Chemical 147]

The compound of Example 120 was prepared by the following procedure. To a solution of 81 mg of the compound of Example 114 in THF: H ₂ O (6 mL) at RT, basic Al ₂ O ₃ 141.
mg and 191 mg Ag ₂ CO ₃ were added. Raise the temperature of the solution to 50 ° C.,
After 5 hours, cooled to RT. The mixture was partitioned between water and _CH 2 Cl _2, to carry out a liquid separation, the organic layer was dried over _Na 2 SO _4, and filtered through Celite. PTLC using a 1: 3: 96 NH ₄ OH: MeOH: CHCl ₃ as a developing solution (500
(1 μm plate) gave pure Example 120 compound. It ¹ h
It was characterized by NMR and MS [m / z: 640.5 (M ⁺⁺ 1)].

Example 121

[0556]

[Chemical 148]

Following the procedure of Example 120 and using the dibromide of Example 126 as a starting material, the compound of Example 121 was prepared. The product thus obtained was treated with ¹ H 2 N
It was characterized by MR and MS [m / z: 720 (M ⁺ +1)].

Example 122

[0559]

[Chemical 149]

[0560]   The compound of Example 122 was prepared by the following procedure. CH at -78 ° C_TwoCl _Two   To 200 μL, 6 μL of oxalyl chloride (2M CH_TwoCl_Twosolution),
Then 2 μL of DMSO was added. After 5 minutes, 3.3 mg of the compound of Example 120 (C
H_TwoCl_Two  50 μL of the solution) as described above in DMSO / oxalyl chloride
Added to the solution. After 15 minutes, Et_ThreeAdd 14 μL of N and raise the temperature of the solution
To 0 ° C. The reaction is stopped by adding water, and CH_TwoCl_TwoExtracted with Na _Two SO_FourDehydrated in. 1: 3: 96 NH as developing solution_FourOH: MeOH: CHC
l_ThreePure by PTLC on silica gel (1 500 μL plate) using
Obtaining the trendy Example 122 compound,¹1 H NMR and MS [m / z: 658 (
M⁺+1)].

Example 123

[0562]

[Chemical 150]

A solution of 28 mg of the compound of Example 126 in DMF (1.5 mL) and NaSMe 1
The compound of Example 123 was prepared by mixing 3 mg with RT. The mixture was heated to 50 ° C. After 1 hour, the solution was poured into water, extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . PTLC (1 500 μL plate) on silica gel using 4: 6 acetone: hexanes as developing solution (twice development) gave pure compound of Example 123, ¹ H NMR and MS [m / z: 748 (
M ⁺ +1)].

Example 124

[0565]

[Chemical 151]

To a solution of 11 mg of the compound of Example 114 in DMF (260 μL) was added KSAc 5.
The compound of Example 124 was prepared by adding 4 mg at 0 ° C. After allowing the solution to stand for 48 hours, the temperature was raised to RT and a further 20 hours passed. The solution was poured into water, extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . 4: 6 as developing solution
After PTLC on silica gel with acetone: hexane, the product so obtained was characterized by ¹ H NMR and MS [m / z: 622 (M ⁺ +1)].

Example 125

[0568]

[Chemical 152]

The compound of Example 125 was prepared by adding 5 mg of DDQ to a solution of 5 mg of the compound of Example 115a (mobile product A) in THF (200 μL) at RT.
The resulting solution was heated to 65 ° C. After 20 hours, additional DDQ 5m
g was added. After a further 6 hours, the volatiles were removed under reduced pressure at room temperature. Methylene chloride was added, the solution was filtered, and the filtrate was collected by preparative TLC plate (one 250 μm plate,
Silica gel). PT using 4: 6 acetone: hexane as a developing solution
After LC purification, the so obtained pure compound of Example 125 was characterized by ¹ H NMR and MS [m / z: 608.6 (M ⁺ +1)].

Example 126

[0571]

[Chemical 153]

The compound of Example 126 was prepared by the following procedure. Apicidin 100mg
86 mg of N-bromosuccinimide was added to a CCl ₄ (5.3 mL) solution of, and then 1.2 mg of benzoyl peroxide was added. The resulting solution was purged by vigorous nitrogen bubbling for 5 minutes. The solution was heated to reflux for 45 minutes and cooled to RT. Volatiles were removed under reduced pressure, and the developing solution was 1: 3: 96NH ₃ : MeOH: CH.
PTLC purification on silica gel with Cl ₃ (1500 μm plate) gave pure Example 126 compound. The thus obtained dibromide compound of Example 126 was analyzed by ¹ H NMR and MS [m / z: 780 (M ⁺ +1)].
Characterized by _{TLC: R f = 0.49 (1} : 3: 96NH 3: MeO
H: CHCl _{3). HPLC:} t R = 10.02 min, 1.0mL / minute, 6: 4M
_{eCN: H} 2 O, Zorbax (R) RX-8).

Examples 127A and 127B

[0574]

[Chemical 154]

To 10 mg of the compound of Example 126, 0.32 mL of DMF and 1: 1 saturated Na
HCO _{3: H} 2 O 0.32mL was added, followed by addition of _Na 2 _S 2 _O 4 4.5mg, to prepare the compound of Example 127a and 127b. The milky white solution thus obtained was allowed to age for 24 hours at RT. Next, 2m of acetonitrile
L was added and the solid was removed by filtration. Thereby, 1: 1M as eluent
ECN: _{H 2} O after RP-HPLC using a compound of pure Example 127a (
1 mg of mobile product A) and pure compound of Example 127b (polar product B).
4 mg was obtained. Both products were characterized by 1H NMR and MS.

Example 127a Mobile Product A: MS: [m / z: 704 (M ⁺ +1)]; T
_{LC: R f = 0.75 (1} : 1 acetone: hexane); _{HPLC: t} R = 8 min,
2 mL / _{min, 1: 1MeCN: H 2 O} , Zorbax (R) RX-8).

Example 127b Polar product B: MS: [m / z: 702 (M ⁺ +1)]; TL
_{C: R f = 0.60 (1} : 1 acetone: hexane); _{HPLC: t} R = 7 min, 2
mL / _{min, 1: 1MeCN: H 2 O} , Zorbax (R) RX-8).

Example 128

[0579]

[Chemical 155]

The compound of Example 128 was prepared by the following procedure. Apicidin 1 at 0 ° C
To 3mg of _CH 2 _Cl 2 (1mL) and MeOH (0.5 mL) solution was added N- bromosuccinimide 6 mg. After 4 minutes, saturated Na ₂ SO ₃ (aq) 1 m
L was added, followed by 1 mL brine. The solution is extracted with EtOAc, Na ₂ S
It was dehydrated with O ₄ . Partially purified product was obtained by PTLC on silica gel (1 × 1500 μm plate) using 1: 2 acetone: hexane as the developing solution.
Then, flash chromatography on silica gel using 1: 2 acetone: hexane as the eluent gave the pure compound of Example 128. The thus obtained compound of Example 128 was analyzed by ¹ H NMR and MS [m / z: 670.4 (
M ⁺ +1)].

Examples 129A and 129B

[0582]

[Chemical 156]

The compounds of Examples 129a and 129b were prepared by the following procedure. N-
Desmethoxyapicidin 10 mg in DMF (0.1 mL) solution at RT, 37%
3 μL formaldehyde (aq) and 3 μL pyrrolidine were added. After 48 h, quenched with saturated NaHCO ₃ , extracted with EtOAc, dried over Na ₂ SO ₄ . P using 1: 3: 96 NH ₄ OH: MeOH: CHCl ₃ as a developing solution
By TLC (R _f = 0.2) 2 mg of the compound of Example 129a which is a pyrrolidino compound (R _f = 0.2) and Example 129 which is a hydroxymethyl compound.
2 mg of the compound of b (R _f = 0.1) was obtained. ¹ H NMR of the pure product
And MS [m / z: 624 (M ⁺ +1) with the pyrrolidino compound of Example 129a.
And the hydroxymethyl compound of Example 129b by 677 (M ⁺ +1)].

Example 130

[0585]

[Chemical 157]

The compound of Example 130 was prepared by the following procedure. N-desmethoxy-N
To a solution of 5 mg of -hydroxymethylapicidin in pyridine (0.16 mL) at RT was added 0.63 mL of acetyl chloride and one DMAP crystal. After 12 h, it was quenched with sat. NH ₄ Cl, extracted with EtOAc, dried over Na ₂ SO ₄ . 4 as eluent: 6 from 1: 0MeCN: using a linear gradient of _{H 2} O RP-HPL
C gives the pure compound of Example 130, which is subjected to ¹ H NMR and MS.
Characterized by [m / z: 666 (M ⁺ +1)].

Example 131

[0588]

[Chemical 158]

[0589]   The compound of Example 131 was prepared by the following procedure. N-desmethoxy-N
-Hydroxymethylapicidin 9 mg CH_TwoCl_TwoThe solution was added with EtN (i
Pr)_Two  Add 13 μL, then (PhCH_TwoO)_Two43 μL of Cl was added.
After 30 minutes at 0 ° C, 0.4 mg of DMAP was added and the solution was allowed to stand at 0 ° C for 1.5 hours.
And then at RT for 2.5 hours. Stop the reaction by adding water, CH_TwoCl_Twoso
Extract, Na_TwoSO_FourDehydrated in. 4: 6 to 1: 0 MeCN: H as eluent _Two Compound 0 of Example 131 pure by RP-HPLC using a linear O gradient.
． I got 3 mg and¹1 H NMR and MS [m / z: 884 (M⁺+1)
] Was characterized.

Examples 132A and 132B

[0591]

[Chemical 159]

The compounds of Examples 132a and 132b were prepared by Methods G, H and I below.

[0593]   Method G   Apicidin 100 mg MeCN (4 mL) and CH_TwoCl_Two(3mL) dissolved
Liquid at RT, NaIO_Four  Add 800 mg aqueous solution (10 mL water), then Ru
Cl_Three  10 mg was added. The solution was allowed to pass overnight. Pour the solution into brine,
Acidified with glacial acetic acid and filtered to remove particulates. CH solid_TwoCl_TwoWashed with
, CH solution_TwoCl_TwoIt was extracted with. The combined organic layers are Na_TwoSO_FourDehydrated and filtered
And concentrated under reduced pressure. Gradient elution (1: 4 to 1: 1 MeCN: H_TwoO, 50
Pure carboxylic acid after preparative RP-HPLC (linear gradient of minutes).
52 mg of the compound of Example 132a were obtained. The compound of Example 132a obtained was¹ 1 H NMR and MS [m / z: 523.2 (M⁺+1)]
It was Further from that reaction is the implementation of a nitrophenyl ketone apicidin analog.
The compound of Example 132b is also obtained, which is¹1 H NMR and MS [m / z: 628
． 2 (M⁺+1)].

[0594]   Method H   RuCl_Three・ XH_TwoO 0.3 mg and N-desmethoxyapicidin 50 m
1: 1 MeCN: CCl containing g_Four(2 mL) solution, NaIO_Four(H2O 1
324 mg was added (as a solution in mL). After 45 hours, the resulting green solution was 1:
1 brine: saturated NH_FourCl and 3: 7 iPrOH: CHCl_ThreeDistributed between
. Next, the organic layer is Na_TwoSO_FourDehydrated in. The solution was concentrated under reduced pressure to give the crude product.
60 mg was obtained.

[0595]   Method I   Cyclo (L-Asp-L-Ile-D-Pip-2-amino-8-oxo-de
Canoyl) -methyl ester 9 mg 3: 1: 1 THF: MeOH: H_TwoO (1
(mL) solution at 0 ° C. was added 50 μL of 1M LiOH. 1 hour at 0 ° C, then
After 2 days at RT, the solution was loaded onto a reverse phase layer (C-18.
5 g), concentrated under reduced pressure and gradient elution without workup (5:10 min:
95MeCN: H_Two25:75 MeCN: H from O_TwoTilt to O, then 60 minutes
Purified by RP-HPLC using 100% MeCN gradient).

Example 133

[0597]

[Chemical 160]

12 mg of the carboxylic acid product of Example 132a, 2: 1 MeOH: Et ₂ O (4
The compound of Example 133 was prepared by adding 1 mL of Me ₃ SiCH = N ₂ (0.5 M hexane solution) to the (mL) solution at RT. After 20 minutes, the solution became homogeneous and 0.25 mL of glacial acetic acid was added. The solution was poured into brine, extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . The solution was filtered and concentrated under reduced pressure. PTLC on silica gel with 1: 1 acetone: hexanes as developing solution (one 1000 μm plate) gave pure Example 133 compound. The thus obtained methyl ester compound of Example 133 was analyzed by ¹ H NMR and MS [m / z
: 537.5 (M ⁺ +1)].

Example 134

[0600]

[Chemical 161]

The compound of Example 134 was prepared by adding 9.6 mg of NaBH ₄ at 0 ° C. to a solution of 120 mg of the compound of Example 133 in THF (7 mL). After 3 hours, the reaction was quenched by adding NH ₄ Cl (aq), extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . As a developing solution, 4: 6 acetone: hexane (R _f = 0
． PTLC with 53) gave 117 mg of the pure compound of Example 134, which was characterized by ¹ H NMR.

Example 135

[0603]

[Chemical 162]

[0604]   The compound of Example 135 was made by Methods J and K below.

[0605]   Method J   50 mg CH 2 compound of Example 132a_TwoCl_Two(2 mL) solution at RT, E
t_ThreeN 14 μL and then MeSO_Two8 μL of Cl was added sequentially. Let 2 hours pass
After that, solid HCl.HN (OMe) Me 18 mg was added. After another hour,
Volatiles were removed under reduced pressure. 1: 2: 97 NH as eluent_FourOH: MeOH:
CHCl_ThreePure by flash chromatography on silica gel using
1.9 mg of the pure example compound 135 are obtained. It¹For 1 H NMR and MS
Therefore, it was determined.

[0606]   Method K   To a solution of the compound of Example 132a, 20 mg, in THF (1 mL) at -78 ° C, HC.
1 · HN (OMe) Me 10.6 mg was added, and then iPrMgBr (2M T
HF solution) 112 μL was added. The temperature of the resulting solution was gradually raised to 4 ° C., 1
Two hours have passed. Saturated NH_FourThe reaction was stopped by adding 1 mL of Cl (aqueous solution)
, CH_TwoCl_TwoExtracted with Na_TwoSO_FourDehydrated in. 1: 2: 97 as eluent
NH_FourOH: MeOH: CHCl_ThreeFlash chromatography on silica gel using
By chromatography, 11 mg of pure Example 135 compound was obtained. It¹H
  Characterized by NMR and MS.

Example 136

[0608]

[Chemical formula 163]

Compound 1 of Example 134 using Method K according to the method described in Example 135.
The compound of Example 136 was prepared from 17 mg. This gave 76 mg of the compound of Example 136 (R _f = 0.46, 1: 9: 90 NH ₄ OH: MeOH: C.
HCl ₃ ), ¹ H NMR and MS [m / z: 568 (M ⁺ +1)].

Example 137

[0611]

[Chemical 164]

The compound of Example 137 was prepared by the following procedure. Cyclo (N-O-methyl-N-methyl-L-Asp-L-Ile-D-Pip-L-2-amino-8-
Hydroxy-decanoyl) 11 mg THF (0.39 mL) and HMPA (
80 μL) solution at 0 ° C. and n-C ₁₀ H ₂₁ MgBr (1M Et ₂ O solution) 3
88 μL was added. The solution was immediately warmed to RT and left for 12 hours. The solution was poured into saturated NH ₄ Cl (aq), partitioned with THF and dried over Na ₂ SO ₄ . Pure Example 13 by PTLC (1 500 μm plate) on silica gel using 1: 9: 90 NH ₄ OH: MeOH: CHCl ₃ as developing solution.
2.5 mg of the compound of 7 was obtained and characterized by ¹ H NMR and MS [m / z: 649 (M ⁺ +1)].

Example 138

[0614]

[Chemical 165]

To a solution of ₂ mg of the compound of Example 137 in CH ₂ Cl ₂ (0.35 mL) at 23 ° C. was added 5 μL of pyridine and then Dess-Martin periodinane (Dess-Martin pe).
The compound of Example 138 was prepared by adding 7 mg of riodinane). 1.5
After time, the solution 1: 1 saturated NaHCO _3: was added to 10% NaHSO _3, then after 10 minutes, and extracted with _CH 2 Cl _2, dried over _Na 2 SO _4. 1 as developing solution
: PTLC on silica gel with 3:96 NH ₄ OH: MeOH: CHCl ₃
1.5 mg of pure Example 138 compound (1 250 μm plate)
Obtained and characterized by ¹ H NMR and MS [m / z: 647 (M ⁺ +1)].

[0616]   Examples 139A-139J   Following the procedures described in Examples 137 and 138 are considered obvious to one of ordinary skill in the art.
Suitable starting compounds and reactants obtained, in particular R₁Using a suitable nucleophile for the group,
The following compounds were prepared.

[0617]

[Chemical 166]

[0618]

[Table 8]

Example 140

[0620]

[Chemical 167]

The compound of Example 140 was prepared by the following procedure. Cyclo (β-oxo-
L-Trp-L-Ile- D-Pip-L-2- amino-8-oxo - of _{decanoyl) 100mg 1: 1: 1MeCN:} CCl 4: H 2 O (6mL) solution to RT
At this point, 0.7 mg of RuCl ₃ .2H ₂ O was added, followed by NaIO ₄ (H ₂ O 2 m
634 mg (as a sonicated solution in L) was added. After 30 hours, the resulting tan-white heterogeneous solution was treated with 1: 1 brine: NH ₄ Cl and 3: 7 iPrOH: CH.
Partitioned with Cl ₃ . The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure,
100 mg of the compound of Example 140 are obtained. The resulting crude product was characterized by ¹ H NMR and MS [m / z: 526 (M ⁺ + NH ₄ )] without further purification.

Example 141

[0623]

[Chemical 168]

[0624]   The compound of Example 141 was prepared by the following procedure. Cyclo (D-2-ami
No-2-carboxy-ethanoyl-L-Ile-D-Pip-L-2-amino-
8-oxo-decanoyl) 80 mg 2: 1 MeOH: Et_TwoO (3.3 mL)
Solution at RT, TMSCHN_Two1 mL of (2M hexane solution) was added. 1.5 o'clock
After a while, ice HOAc was added until bubbling ceased and the solution was 1: 1 brine: saturated NH. _Four Cl and CH_TwoCl_TwoDistributed between and. The organic layer is Na_TwoSO_FourDehydrated in. Exhibition
PTLC on silica gel using 3:97 HOAc: EtOAc as the opening (1
A 500 μm plate) gives 28 mg of pure compound of Example 141.
It was It¹1 H NMR and MS [m / z: 540 (M⁺+ NH_Four)]
And determined the characteristics.

Example 142

[0626]

[Chemical 169]

The compound of Example 142 was prepared by the following procedure. To a solution of the compound of Example 140 26.5 mg in CH ₂ Cl ₂ (2 mL) at RT, HCl.HN (OMe).
Add Me 51 mg, then DMAP 13 mg, and then BOP 46 mg
Was added. After 8 hours at RT, the solution was heated to 40 ° C. and 12 hours. After removal of volatiles, PTLC on silica gel with 1: 1 acetone: hexanes as the eluent gave 2 mg of pure Example 142 compound. ¹ H NMR and MS [m / z: 522 (M ⁺ +1) for the product.
)].

Example 143

[0629]

[Chemical 170]

The compound of Example 143 was prepared using the compound of Example 141 as a starting material. First, the side chain carbonyl of the compound of Example 141 was reduced according to the method described in Example 134. The resulting intermediate compound was processed by the procedure described in Example 135. The so obtained pure compound of Example 143 was characterized by ¹ H NMR.

[0631]   Examples 144A to 144G   The procedure described in Examples 142 and 143 (see Example 142 for Example 144g).
The procedure of Example 143 was used for Examples 144a-144f).
The following compounds were prepared using suitable materials that would be apparent to one of ordinary skill in the art.
Manufactured.

[0632]

[Chemical 171]

[0633]

[Table 9]

Example 145

[0635]

[Chemical 172]

The compound of Example 145 was prepared according to the following procedure. N-desmethoxy-N
- at -78 ° C. in _CH 2 _Cl 2 (2.5mL) solution of methyl Api chlorhexidine 10 mg,
O ₃ was bubbled in until the solution turned light blue. The resulting solution was stirred for 10 minutes and the solution was sparged with N ₂ for 5 minutes. Next, 250 μL of dimethyl sulfide was added, the temperature of the solution was gradually raised to RT, and the solution was concentrated under reduced pressure. The resulting residue is 1:
It was dissolved in 1THF: tBuOH at 0 ° C., and 3.7 mg of tBuOK was added. 0 ° C
After 2 h at rt the solution was poured into 1: 1 water: saturated NaHCO ₃ , extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . As a developing solution, 1: 3: 96 NH ₄ OH: MeOH
: By preparative TLC on silica gel using CHCl ₃ (500 [mu] m one plate) to give the pure compound of Example 145. It was analyzed by ¹ H NMR and MS [
m / z: 622.7 (M ⁺ +1)]. TLC: R _f = 0.
_{15 (1: 3: 96NH 4} OH: MeOH: CHCl 3).

[0637]   Examples 146A-146F   The following compounds were prepared according to the general ozonolysis reaction described in Example 145.
It was

[0638]

[Chemical 173]

[0639]

[Table 10]

Example 147

[0641]

[Chemical 174]

The compound of Example 147 was prepared by the following procedure. Cyclo (L-2-amino-2- (3 '-(quinol-4'-onyl))-ethanoyl-L-Ile-D
-Pip-L-2- amino-8-oxo - decanoyl) 10 mg of ClCH ₂ C
To the H ₂ Cl (1 mL) solution at RT was added 4 mg DMAP and 19 μL TEA, followed by 5 μL MeSO ₂ Cl. After 15 minutes at RT, the solution is saturated with Na.
It was poured into HCO ₃ , extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . Preparative TLC on silica gel using 1: 1 acetone: hexane as a developing solution (500 μm
One plate) gave pure compound of Example 147. ¹ H N
It was characterized by MR and MS [m / z: 608.5 (M ⁺ +1)]. T
LC: _Rf = 0.43 (1: 1 acetone: hexane).

Examples 148A and 148B

[0644]

[Chemical 175]

Cyclo (L-2-amino-2- (3 ′-(N—O-methyl-quinol-4′-onyl))-ethanoyl-L-Ile-D-Pip-L-2-amino-8 - oxo - decanoyl) to 20mg of MeOH (5 mL) solution at 0 ℃, NaBH ₄ 3
The compounds of Examples 148a and 148b were prepared by adding mg. The cooling bath was immediately removed. After 20 minutes, acetone was added to stop the reaction, and the solution was saturated with NaH.
It was poured into CO ₃ , extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . Initial purification was performed by flash chromatography on silica gel with 1: 1 acetone: hexane as the eluent. It should be noted that the product obtained was an approximately 1: 1 mixture of two compounds with similar TLC R _f values (
Product A: 0.39 and product B: 0.28 with 1: 1 acetone: hexane).
Purify again by preparative TLC on silica gel (one 500 μm plate),
Two pure products were obtained. It was subjected to ¹ H NMR and MS [m / z: 640.6 (M ⁺ +1) for the compound of Example 148a and 6 for the compound of Example 148b.
10.5 (M ⁺ +1)].

Example 148a: Cyclo (L-2-amino-2- (3 ′-(N—O-methyl-
Quinor-4'-onyl))-ethanoyl-L-Ile-D-Pip-L-2-
Amino-8-hydroxy-decanoyl); TLC: _Rf = 0.55 (1: 3: 9).
_{6NH 4 OH: MeOH: CHCl 3} ); HPLC: t R = 7.17 min (1: 1
_MeCN: H 2 O, 1.0mL / minute, Zorbax (R) RX-8).

Example 148b: Cyclo (L-2-amino-2- (3'-quinol-4'-onyl) -ethanoyl-L-Ile-D-Pip-L-2-amino-8-hydroxy-decanoyl. ); TLC: R _f = 0.18 (1: 3: 96 NH ₄ OH: MeO
H: CHCl ₃ ); HPLC: t _R = 5.86 min (1: 1 MeCN: H ₂ O, 1
． 0 mL / min, Zorbax® RX-8).

Example 149

[0649]

[Chemical 176]

The compound of Example 149 was prepared by the following procedure. A solution of 25 mg apicidin in CH ₂ Cl ₂ (2.5 mL) was bubbled with ozone at −78 ° C. until the pale blue color of the resulting solution did not disappear. After 10 minutes, the solution was purged with a strong stream of nitrogen and then Me ₂ S was added. The temperature of the solution was raised to RT. Remove volatiles under reduced pressure,
PTLC on silica gel using 1: 2 acetone: hexane as a developing solution (20
A pure 00 μm plate) gave the pure compound of Example 149. The pure compound of Example 149 thus obtained was analyzed by ¹ H NMR and MS [m / z: 6].
62.5 (M ⁺ + Li)].

Example 150

[0652]

[Chemical 177]

The compound of Example 150 was prepared by the following procedure. A solution of 470 mg of N-desmethoxy-apicidin in CH ₂ Cl ₂ (40 mL) was bubbled with ozone at −78 ° C. for about 10 minutes until the blue color disappeared. The solution was purged with a strong stream of nitrogen, then 1 mL of dimethyl sulfide was added. The temperature of the obtained solution was raised to RT, and volatile components were removed under reduced pressure. Gradient elution (2: 3 to 1: 1 acetone:
Flash chromatography on silica gel with (hexane) provided 320 mg of the pure Example 150 compound. It was analyzed by ¹ H NMR and MS [
m / z: 626 (M ⁺ +1)].

Example 151

[0655]

[Chemical 178]

Example 150 was carried out using β-oxo-N-desmethoxy-apicidin as a raw material.
The compound of Example 151 was prepared according to the procedure described in 1. The compound of Example 151 thus obtained was analyzed by ¹ H NMR and MS [m / z: 640 (M ⁺ +1.
)].

Examples 152A and 152B

[0658]

[Chemical 179]

Cyclo (L-2-amino-2- (3'-quinol-4'-onyl) -ethanoyl-L-Ile-D-Pip-L-2-amino-8-oxo-decanoyl) 43
The compounds of Examples 152a and 152b were prepared by adding 30 μL of pyridine to a solution of mg in CH ₂ Cl ₂ (1.2 mL). The mixture was cooled to 0 ° C. 14 μL of (CF ₃ SO ₂ ) ₂ O was added to the resulting solution. After 40 minutes, the solvent was removed under reduced pressure. The crude pyridinium salt thus obtained was analyzed by ¹ H NMR and M
It was characterized by S [m / z: 740 (M ⁺ +1)].

Example 153

[0661]

[Chemical 180]

[0662]   The compound of Example 153 was prepared by Methods L and M below.

[0663]   Method L   Cyclo (L-2-amino-2- (3 '-(4'-pyridinium-quinolyl) -e
Tanoyl-L-Ile-D-Pip-L-2-amino-8-oxo-decanoyl
) 52 mg of CH_TwoCl_Two(4 mL) solution at RT, 20% Pd (OH)_TwoDeg
1 mg of Sassa catalyst was added. The atmosphere was hydrogen (balloon pressure). After 12 hours, the catalyst
It was removed by celite filtration using acetone as the eluent. As a developing solution
1: 3: 96 NH_FourOH: MeOH: CHCl_ThreeWith silica gel using PTL
Compound C of Example 153 pure by C (1 1000 μm plate)
get g,¹1 H NMR and MS [m / z: 675 (M⁺+1)]
Sex determined.

[0664]   Method M   Cyclo (L-2-amino-2- (3'-quinol-4'-onyl) -ethanoi
Ru-L-Ile-D-Pip-L-2-amino-8-oxo-decanoyl) 20
mg CH_TwoCl_Two(0.6 mL) solution at 0 ° C. with 2,6-di-t-butyl-4
-Methyl-pyridine 8 mg and then (CF_ThreeSO_Two)_TwoO 7 μL was added. 3.
After 5 hours, 7 μL of piperidine was added, the solution was allowed to stand for 2.5 hours, and the temperature was raised to R
T was 12 hours. 1: 3: 96N as developing solution without post-treatment
H_FourOH: MeOH: CHCl_ThreePTLC on silica gel (500 μm
(1 plate) gave 6 mg of the pure compound of Example 153,¹H N
MR and MS [m / z: 675 (M⁺+1)].

Example 154

[0666]

[Chemical 181]

The compound of Example 154 was prepared by the following procedure. Example 14 at 23 ° C
13 mg of the compound of 6a was placed in 360 μL of DMF. 5.3 mg of 2,6-di-t-butyl-4-methyl-pyridine was added, followed by 6.9 mg of 2,4-dinitrobenzenesulfonyl chloride. After 6 hours, LiCl 2.7
mg was added and the temperature of the solution was raised to 60 ° C. for 12 hours. The reaction was cooled to RT, quenched by adding water, extracted with CH ₂ Cl ₂ , Na ₂ S
It was dehydrated with O ₄ . PTLC (1 500 μm plate) on silica gel using 1: 9: 90 NH ₄ OH: MeOH: CHCl ₃ as eluent gave 5 mg of the pure compound of Example 154, ¹ H NMR and MS [m / z. : 626
(M ⁺ +1)].

Example 155

[0669]

[Chemical 182]

1.2 g of N-desmethoxy-apicidin, 360 m of N-bromosuccinimide
The compound of Example 155 was prepared by mixing g and 15 mg of benzoyl peroxide in 70 mL of CCl ₄ . The resulting mixture was heated to 80 ° C. for 15 minutes. The solvent was removed under reduced pressure and the crude product was eluted with 4: 6 MeC.
N: Purification by two batches by RP-HPLC using _{H 2} O, to give the compound 400mg of pure Example 155. It was analyzed by ¹ H NMR and MS [m / z
: 674 (M ⁺ +1)].

Example 156

[0672]

[Chemical 183]

[0673]   Cyclo (2-bromo-L-Trp-L-Ile-D-Pip-L-2-amino
-8-oxo-decanoyl) 100 mg dioxane 3 mL and EtOH 3
The compound of Example 156 was prepared by dissolving in mL. Next, LiCl 63m
g, (3,5-diMeO) PhB (OH)_Two  270 mg and 1M NaHC
O_Three  1.5 mL was added. Pd (PPh_Three)_Four  17 mg
In addition, the resulting solution is 90 ° C. for 90 minutes, 100 ° C. for 15 minutes and 80 ° C. for 1 minute.
It heated in order of 2 hours. Solution 1: 1 saturated NaHCO_Three: Put in brine, C
H_TwoCl_TwoExtracted with Na_TwoSO_FourDehydrated in. 1: 3: 96 NH as developing solution _Four OH: MeOH: CHCl_ThreePreparative TLC on silica gel using (500 μm
1 plate) (4 developments) gave pure Example 156 compound 67
It was It¹1 H NMR and MS [m / z: 730 (M⁺+1)]
Sex determined.

[0674]   Examples 157A-157D   The compounds of Examples 157a-157d were prepared according to the procedure described in Example 156.
I made it.

[0675]

[Chemical 184]

[0676]

[Table 11]

Example 158

[0678]

[Chemical 185]

[0679]   To a solution of 100 mg of the compound of Example 141 in THF (6 mL) at 0 ° C. was added NaBH _Four   The compound of Example 158 was prepared by adding 9 mg. 2 hours later, aceto
And then saturated NaHCO 3._ThreeThe reaction is stopped by adding (aqueous solution), and CH_Two Cl_TwoExtracted with Na_TwoSO_FourDehydrated in. As a result, the developing solution is 3: 7.
Pure diol after PTLC on silica gel with acetone: hexane.
Example 158 compound (R_f= 0.37) 10 mg was obtained. It¹H NM
Characterized by R.

Example 159

[0681]

[Chemical 186]

[0682]   The compound of Example 159 was prepared by Methods N and O below.

[0683]   Method N   A solution of the compound of Example 133 (100 mg) in THF (3.5 mL) was added with Li at 0 ° C.
BH_Four  11.6 mg was added. After 4 hours at 0 ° C., raise the temperature of the reaction solution.
It was RT. After another 2 hours, add acetone, then saturated brine.
The reaction was stopped with and 3: 7 iPrOH: CHCl_ThreeExtracted with Na_TwoSO_FourDehydrated with
did. 1: 3: 96 NH as developing solution_FourOH: MeOH: CHCl_ThreeUse
Pure diol compound of Example 159 by PTLC on silica gel
60 mg was obtained. It¹1 H NMR and MS [m / z: 511 (M⁺+1)
] Was characterized.

[0684]   Method O   To a solution of 250 mg of the compound of Example 133 in THF (11 mL) at 0 ° C., DIB
2.65 mL of AL-H (1M toluene solution) was added. 4 hours at 0 ° C
After that, the reaction was stopped by adding acetone and then saturated brine, and the reaction was stopped at 3: 7 iP.
rOH: CHCl_ThreeExtracted with Na_TwoSO_FourDehydrated in. Eluent 1: 3:
96 to 1: 9: 90 NH_FourOH: MeOH: CHCl_ThreeUsing gradient elution
By flash chromatography on a Rica gel, the pure diol
The compound of Example 159 (R_f= 0.41, 1: 9: 90 NH_FourOH: MeOH:
CHCl_Three) 100 mg was obtained. It¹It was characterized by 1 H NMR.

Example 160

[0686]

[Chemical 187]

[0687]   The compound of Example 160 was prepared by the following procedure. CH_TwoCl_Two(1 mL
) Ph dissolved in_ThreeBi 27 mg at RT, CH_ThreeCO_ThreeAdd 0.5 μL of H
I got it. 10 minutes later, Ph_ThreeBi / CH_ThreeCO_ThreeAn H solution was obtained. In that solution, the example
159 compound 22 mg CH_TwoCl_Two(1 mL) solution, then Cu (
OAc)_Two  3.5 mg was added. The resulting solution is heated to 60 ° C. for 3 hours
Let it pass. After cooling to RT, saturated NaHCO 3_ThreeAdding (aqueous solution)
The reaction was stopped at 3: 7 iPrOH: CHCl_ThreeExtracted with Na_TwoSO_FourDehydrated with
It was PTLC on silica gel using 4: 6 acetone: hexane as the developer (
R_f= 0.66) yielded 4 mg of the pure compound of Example 160. It ¹ 1 H NMR and MS [m / z: 587 (M⁺+1)]
.

Example 161

[0689]

[Chemical 188]

The compound of Example 161 was prepared by oxidizing 3 mg of the compound of Example 160 using the Dess-Martin reagent in a similar manner to that described for Example 138.
This gave 2 mg of the compound of example 161, which was characterized by ¹ H NMR and MS [m / z: 585 (M ⁺ +1)].

[0692]   Examples 162A and 162B   Following the procedures of Examples 160 and 161, the following Examples 162a and 16
The compound of 2b was prepared and characterized by NMR and MS.

[0692]

[Chemical 189]

[0693]

[Table 12]

Example 163

[0695]

[Chemical 190]

The compound of Example 163 was prepared by the following procedure. 2 mL of PhMgBr (2M THF solution) was added to a solution of 68 mg of the compound of Example 148a in THF (6 mL) at RT. After 20 hours at RT, the reaction was quenched by adding saturated NH ₄ Cl (aq), extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . Pure intermediate compound with side chain alcohol (R _f = 0.49, 1: 1 by PTLC on silica gel with 1: 9: 90 NH ₄ OH: MeOH: CHCl ₃ as developing solution (1500 μm plate). 9:90 NH ₄ OH: MeOH
: CHCl ₃ ) was obtained and it was characterized by ¹ H NNMR. The intermediate side chain alcohol was then oxidized using the Dess-Martin reagent according to the method described in Example 138. PTLC (1 500 μm plate) on silica gel using 1: 9: 90 NH ₄ OH: MeOH: CHCl ₃ as developing solution gave 13 mg of pure compound of Example 163 (R _f = 0.66, 1 _{: 9: 90 NH 4 OH:} MeOH: CHCl 3). It was analyzed by ¹ H NMR and MS [m / z: 68
4 (M ⁺ +1)].

[0697]   Examples 164a and 164b   Following the procedure of Example 163, the compounds of the following Examples 164a and 164b
Was manufactured.

[0698]

[Chemical 191]

[0699]

[Table 13]

Example 165

[0701]

[Chemical 192]

The compound of Example 165 was prepared by the following procedure. To a solution of 20 mg apicidin in DMF (321 μL) at RT was added 16 μL MeI, followed by NaH (6
3.8 mg of 0% suspension in mineral oil) was added. After 20 hours, add water and add solution to EtO.
It was extracted with Ac and dried over Na ₂ SO ₄ . 1: 3: 96 NH ₄ O as a developing solution
PTLC on silica gel with 1 H: MeOH: CHCl ₃ (1 1000 μm plate) gave 9.9 mg of the pure compound of Example 165. It was characterized by ¹ H NMR and MS [m / z: 666 (M ⁺ +1)].

[0703]   Examples 166A-166C   Similarly to the procedure described in Example 165, the compounds of Examples 166a-166c
Was manufactured. The apicidin was replaced by the methyl bromide in Example 165, and the benzyl bromide was replaced.
Treatment with ruthenium gave a mixture of mono-, di- and tribenzylated derivatives. And then
The obtained compounds of Examples 166a to 166c, which are three kinds of compounds, were¹H NM
Characterized by R and MS. Regiochemistry of mono- and dibenzylated derivatives
Was unknown.

[0704]

[Chemical formula 193]

[0705]

[Table 14]

Examples 167A-167D

[0707]

[Chemical 194]

Examples 167a-167d were made by the following procedure. Apicidin 10
13 mg of Lawesson's reagent was added to a solution of mg in toluene (2 mL). The resulting solution was heated at 80 ° C. for 25 minutes and cooled to RT. The entire solution was loaded directly onto a silica gel flash chromatography column and purified by gradient elution (1 column of 100% CHCl ₃ followed by 1: 3: 96NH ₄ OH: MeOH: CHCl ₃ ) to give two fractions. Obtained. That is, Example 167a that is a monothiono compound
(Fraction 1-Product A; R _f = 0.83, 1: 3: 96 NH ₄ OH: Me
OH: CHCl ₃ ) and less pure bis and tristhiono forms of Examples 167b-167d (fractions 2-products B, C and D, R _f = 0.68, 1: 3.
: 96NH ₄ OH: MeOH: obtain a CHCl _3). Fraction 2 was decanted (2:
3MeCN: linear gradient from _{H 2} O 100% MeCN, 70 minutes) was further purified by preparative RP-HPLC using a. The product thus obtained was added to ¹ H NM
Characterized by R and MS. The following retention times were obtained for these four products during the preparative RP-HPLC operation.

[0709] t _R = 34.2 min (product A- Example 167a); 39.9 min (product B- Example 167b); 45.6 min (product C- Example 167c); 48. 8 min (product D- example 167d); (2: 3MeCN: 100% from _{H 2} O MeCN, 7
0 minute straight slope).

Table 15

[0711]

[Table 15]

Example 168

[0713]

[Chemical 195]

To a solution of apicidin 10 mg in THF (2 mL) at 0 ° C. was added BH ₃ · THF (1M
The compound of Example 168 was prepared by adding 0.160 mL of a THF solution). After 30 minutes, the temperature of the resulting solution was raised to RT and 12 hours were allowed to elapse. 12 in total
． After 5 hours, at that point, the solution was heated at 60 ° C. for 30 minutes and cooled to RT. Then add 1 mL of methanol, then Me ₂ NCH ₂ CH ₂ OH 0.15 m
L was added and the solution was stirred for 2 hours. The stirred solution was poured into saturated brine and EtO
It was extracted with Ac and dried over Na ₂ SO ₄ . The volatiles were removed under reduced pressure and the crude product as eluent _{1: 3: 96NH 4 OH /} MeOH / CHCl 3 with about 3.
Baseline contaminants were removed by filtration through a 81 cm (1.5 inch) silica gel layer. The filtered solution was concentrated under reduced pressure and the pure product was obtained by preparative RP-HPLC with 1/3 MeCN / H ₂ O isocratic for 20 minutes, then 100% MeCN with a linear gradient over 60 minutes. The pure compound of Example 168 thus obtained was converted into ¹ H
It was characterized by NMR and MS [m / z: 612.4 (M ⁺⁺ 1)].
_HPLC: t R = 6.69 _{min, 1 / 1MeCN: H 2 O} , 1.5mL / min, Zorbax (R) RX-8 column. TLC: _Rf = 0.50, 1: 3: 96
_{NH 4 OH / MeOH / CHCl 3} .

Examples 169 and 170

[0716]

[Chemical 196]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 33/02 173 A61P 33/06 33/06 35/00 35/00 43/00 105 43/00 105 111 111 A61K 37/02 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, B , BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ , NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Shimatsutsu, Dennis United States, New Jersey 07065-0907, Lowway, East Lincoln Avenue 126 (72) Inventor Fitzcher, Michael E. United States, New Jersey 07065-0907, Low Way, East Lincarn Aveniryu 126 (72) Inventor Rattray, Sandra Giay USA, New Jersey 07065-0907, Lowway, East Lincarn Avenyu 126 (72) Inventor Collecti, Stephen El United States, New Jersey 07065-0907, Lowway, East Lincoln Avenue 126 (72) Inventor Weibratt, Mathieu Jay Ray United States, New Jersey 07065-0907, Lowway, East Lincoln Avenue 126 (72) Inventor Meyers, Robert D'Abri, United States, New Jersey 07065-0907, Lowway, East Lincoln Avenue 126 (72) Inventor Garnett, Anne M, United States New Jersey 07065-0907, B Way, East Li Nkan-Abeniyu · 126 F term (reference) 4C084 AA02 AA07 BA01 BA16 BA24 BA32 CA05 DA27 DA43 DC32 NA14 ZB261 ZB351 ZB371 ZB381 ZC202 ZC611 ZC641 4H045 AA10 AA30 BA13 BA30 BA50 CA15 DA55 EA29 FA10

Claims (28)

[Claims] 1. A compound having the structure of the following formula I or a pharmaceutically acceptable compound thereof:
Salt to be contained.     [Chemical 1]   [In the formula,   X is   (1) -CH_Two-,   (2) -C (O)-,   (3) -CH (OR^a)-,   (4) = CH- or   (5) Non-existence And   n is   (1) 1 or   (2) 2 And   R₁Is   (1) R₇,   (2) C (O) R₇,   (3) CN,   (4) CO_TwoR^b,   (5) C (O) N (OR^b) R^c,   (6) C (O) NR^cR^d,   (7) NHCO_TwoR^b,   (8) NHC (O) NR^cR^d,   (9) (C₀~ C_FourAlkyl) OR^a,   (10) (C₀~ C_FourAlkyl) OCO_TwoR^b,   (11) (C₀~ C_FourAlkyl) OC (O) NR^cR^d,   (12) C (O) NR^cNR^cR^d,   (13) C (O) NR^cSO_TwoR^b,   (14) OS (O)_niR₇,   (15) NR^bS (O)_niR₇(Ni is 0 to 2),   (16) 3 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C ₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono
, OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O
) NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr ha
Rogen, each substituent can be saturated, partially unsaturated or fully unsaturated
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R ^c Those which may have a substituent;   (17) 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
A benzene ring fused with a ~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C ₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino
, Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr with halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
The terror atoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^cSubstituent
And the benzene / heterocyclic fused ring has X or X at any position.
Bound to a tetrapeptide;   (18) Hete fused with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms
A 4- to 8-membered heterocycle having 1 to 4 atoms, each heterocycle being independently 1 to
It may be substituted with 4 groups, and each said substituent is independently C₁~ C₅Alkyl,
C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thi
Ono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each complex
The ring may be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cHas a substituent
Also good   And   R_TwoIs   (1) C which may be substituted_Two~ C₁₂Alkyl,   (2) C which may be substituted_Two~ C₁₂Alkenyl,   (3) C which may be substituted_Two~ C₁₂Alkynyl or   (4) (CH_Two)_nii-O- (CH_Two)_mii(Nii, mii = 0-7)
And the above C_Two~ C₁₂Alkyl, C_Two~ C₁₂Alkenyl and C_Two~ C_{1 Two} Suitable substituents on alkynyl are 1-8 groups, each group being independently   (A) CO_TwoR^a,   (B) C (O) R^b,   (C) C (O) N (OR^b) R^c,   (D) C (O) NR^cR^d,   (E) C (O) NR^cNR^cR^d,   (F) C (O) NR^cSO_TwoR₇,   (G) C_Three~ C₈Cycloalkyl,   (H) C_Two~ C₅Alkenyl,   (I) cyano,   (J) = NOR^a,   (K) = NNR^bR^c,   (L) = NNR^bS (O)_niR₇,   (M) N (OR^b) C (O) NR^bR^c,   (N) N (OR^b) C (O) R₇,   (O) NHC (O) N (OR^b) R^c,   (P) NR^cCO_TwoR^b,   (Q) NR^cC (O) NR^cR^d,   (R) NR^cC (S) NR^cR^d,   (S) NR^cC (O) R₇,   (T) NR^bS (O)_niR₇,   (U) NR^cCH_TwoCO_TwoR^a,   (V) NR^cC (S) R₇,   (X) NR^cC (O) CH_TwoOH,   (Y) NR^cC (O) CH_TwoSH,   (Z) NR^cCH_TwoCO_TwoR^a,   (Aa) NR^cCH_TwoCH (OH) R₇,   (Bb) NR^cP (O) (OR^a) R₇,   (Cc) NY¹Y^Two(Y¹And Y^TwoAre independently H or C₁~ C₁₀Alkyl
Is),   (Dd) NO_Two,   (Ee) N (OR^b) C (O) R^b,   (Ff) C₁~ C₁₀Alkanoylamino,   (Gg) OR^a,   (Hh) OS (O)_niR₇,   (Ii) oxo,   (Jj) OCO_TwoR^b,   (Kk) OC (O) NR^cR^d,   (Ll) P (O) (OR^a)_Two,   (Mm) P (O) (OR^a) R₇,   (Nn) SC (O) R₇,   (Oo) S (O)_niR₇,   (Pp) SR₇,   (Qq) S (O)_niNR^cR^d,   (Rr) NR^cCH_TwoCO_TwoR^a,   (Ss) diazo,   (Tt) C₁~ C₅Perfluoroalkyl,   (Uu) B (O) (OR^a) OR^a,   (Xx) halogen,   (Yy) aryl (C₀~ C₅Alkyl) (aryl is substituted with 1 to 3 groups
Each group is independently R^fOr)   (Xx) a 3- to 8-membered heterocycle having 1 to 4 heteroatoms, each heterocycle
The atoms are independently oxygen, sulfur or nitrogen and the heterocycle is substituted with 1 to 3 groups
And each substituent is independently R^fAnd the heterocycle is saturated or partially
Things that can be unsaturated   And   R_ThreeEach independently,   (1) hydrogen,   (2) halogen,   (3) OR^a,   (4) C₁~ C_FourAlkyl or   (5) C₁~ C_FourAryl;   R₅Is   (1) Isopropyl or   (2) sec-butyl;   R₆Each independently,   (1) O,   (2) S or   (3) It is H;   R₇Is   (1) hydrogen,   (2) C which may be substituted_Two~ C₁₀Alkyl,   (3) C which may be substituted_Two~ C₁₀Alkenyl,   (4) C which may be substituted_Two~ C₁₀Alkynyl,   (5) C which may be substituted_Three~ C₈Cycloalkyl,   (6) C which may be substituted₅~ C₈Cycloalkenyl,   (7) optionally substituted aryl;   [The above C_Two~ C₁₀Alkyl, C_Two~ C₁₀Alkenyl, C_Two~ C₁₀Archi
Nil, C_Three~ C₈Cycloalkyl, C₅~ C₈Cycloalkenyl and aryl
The above optional substituents are 1 to 4 groups, each group independently being     (A) C₁~ C₅Alkyl,     (B) X¹-C₁~ C₁₀Alkyl (X¹Is O or S (O)_niIs)
,     (C) C_Three~ C₈Cycloalkyl,     (D) hydroxyl group,     (E) halogen,     (F) cyano,     (G) carboxy,     (H) NY¹Y^Two(Y¹And Y^TwoAre independently H or C₁~ C₁₀Alkyl
Is),     (I) nitro,     (J) C₁~ C₁₀Alkanoylamino,     (K) Aroylamino, wherein said aroyl is substituted with 1 to 3 groups
Each substituent is independently R^f1And R^f1Is (14), (26), (
R except 27) and (32)^fDefined by one of the following definitions for
What is done;     (L) Oxo,     (M) Aryl C₀~ C₅Alkyl, wherein the aryl is 1 to 3 groups
And each substituent is independently R.^f1What is;     (Q) C₁~ C₅Perfluoroalkyl,     (R) N (OR^b) C (O) R_{7 '}And R_{7 '}Is (1)-(7) (n
) R₇Above for R and (8)-(12)₇About below
One of the definitions, or     (S) NR^cC (O) R_{7 '}Is. ];   (8) A 5- to 10-membered heterocycle having 1 to 4 heteroatoms, each heterocycle
The atoms are independently oxygen, sulfur or nitrogen and the heterocycle is substituted with 1 to 3 groups
And each substituent is independently R^f1And the heterocycle is saturated or
What may be unsaturated;   (9) Benzene ring fused with a 5- to 10-membered heterocycle having 1 to 4 heteroatoms
Wherein each heteroatom is independently oxygen, sulfur or nitrogen and said heterocycle is 1
~ 3 groups, each substituent being independently R^f1And said
Heterocycles which may be saturated or partially unsaturated;   (10) He condensed with a second 5- to 10-membered heterocycle having 1 to 4 heteroatoms.
A 5- to 10-membered heterocycle having 1 to 4 terror atoms, which is any of the above heterocycles
Where each heteroatom is independently oxygen, sulfur or nitrogen, said second heterocycle
May be substituted with 1 to 3 groups, and each substituent is independently R.^f1And
Each heterocycle independently being saturated or partially unsaturated;   (11) C_Three~ C₈A benzene ring fused to a cycloalkyl ring,
The chloroalkyl ring may be substituted with 1 to 3 groups, each substituent being independently
R^f1And the cycloalkyl ring may be saturated or partially unsaturated.
Of; or   (12) A 5- to 10-membered heterocycle having 1 to 4 heteroatoms, each heterocycle
The atoms are independently oxygen, sulfur or nitrogen and the heterocycle is C_Three~ C₈Cycloal
Fused with a kill ring, the cycloalkyl ring being substituted with 1 to 3 groups
And each substituent is independently R^f1And the cycloalkyl ring is saturated or
May be partially unsaturated;   R^aIs   (1) hydrogen,   (2) C which may be substituted₁~ C₁₀Alkyl,   (3) C which may be substituted_Three~ C₁₀Alkenyl,   (4) C which may be substituted_Three~ C₁₀Alkynyl,   (5) C which may be substituted₁~ C₁₀Alkanoyl,   (6) C which may be substituted_Three~ C₁₀Alkenoyl,   (7) C which may be substituted_Three~ C₁₀Alkinoyl,   (8) optionally substituted aroyl,   (9) optionally substituted aryl,   (10) C which may be substituted_Three~ C₇Cycloalkanoyl,   (11) C which may be substituted₅~ C₇Cycloalkenoyl,   (12) C which may be substituted₁~ C₁₀Alkylsulfonyl,   (13) C which may be substituted_Three~ C₈Cycloalkyl,   (14) C which may be substituted₅~ C₈Cycloalkenyl,   [The above C₁~ C₁₀Alkyl, C_Three~ C₁₀Alkenyl, C_Three~ C₁₀Archi
Nil, C₁~ C₁₀Alkanoyl, C_Three~ C₁₀Alkenoyl, C_Three~ C₁₀A
Ruquinoyl, aroyl, aryl, C_Three~ C₇Cycloalkanoyl, C₅~ C₈ Cycloalkenyl, C₁~ C₁₀Alkylsulfonyl, C_Three~ C₈Cycloalk
Le and C₅~ C₈Suitable substituents on cycloalkenyl are 1-10 groups
, Each of the substituents is independently a hydroxyl group, C₁~ C₆Alkoxy, C_Three~ C₇Cycloa
Rukiru, Aryl C₁~ C_ThreeAlkoxy, NR^xR^x, CO_TwoR^b, CONR^c R^dOr halogen. ],   (15) C₁~ C₅Perfluoroalkyl,   (16) An arylsulfonyl which may be substituted with 1 to 3 groups,
Each substituent is independently C₁~ C₅Alkyl, C₁~ C₅Perfluoroalkyl,
Those which are nitro, halogen or cyano;   (17) a 5- or 6-membered heterocycle having 1 to 4 heteroatoms,
Each heteroatom is oxygen, sulfur or nitrogen and the heterocycle is substituted with from 1 to 4 groups
And each of the substituents is independently C₁~ C₅Alkyl, C₁~ C₅A
Lucenil, C₁~ C₅Perfluoroalkyl, amino, C (O) NR^cR^d, Shi
Ano, CO_TwoR^bOr halogen, wherein the heterocycle is saturated or partially unsaturated
What you may have; or   (18) OP (O) (OR^b)_TwoAnd   R^bIs   (1) H,   (2) optionally substituted aryl,   (3) C which may be substituted₁~ C₁₀Alkyl,   (4) C which may be substituted_Three~ C₁₀Alkenyl,   (5) C which may be substituted_Three~ C₁₀Alkynyl,   (6) C which may be substituted_Three~ C₁₅Cycloalkyl,   (7) C which may be substituted₅~ C₁₀Cycloalkenyl or   (8) an optionally substituted 5- to 10-membered compound having 1 to 4 heteroatoms
A prime ring in which each heteroatom is independently oxygen, sulfur or nitrogen;   The aryl, C₁~ C₁₀Alkyl, C_Three~ C₁₀Alkenyl, C_Three~ C_{1 0} Alkynyl, C_Three~ C₁₅Cycloalkyl and C₅~ C₁₀Cycloalkeni
Or a suitable substituent on the 5- to 10-membered heterocycle is 1 to 10 groups,
Each group is independently   (A) hydroxyl group,   (B) C₁~ C₆Alkyl,   (C) oxo,   (D) SO_TwoNR^xR^x,   (E) Aryl C₁~ C₆Alkoxy,   (F) Hydroxy C₁~ C₆Alkyl,   (G) C₁~ C₁₂Alkoxy,   (H) Hydroxy C₁~ C₆Alkoxy,   (I) Amino C₁~ C₆Alkoxy,   (J) cyano,   (K) mercapto,   (L) (C₁~ C₆Alkyl) -S (O)_ni-(C₀~ C₆Alkyl),   (M) C optionally substituted with 1 to 4 groups_Three~ C₇Cycloalkyl
And each substituent is independently R^eWhat is   (N) C₅~ C₇Cycloalkenyl,   (O) halogen,   (P) C₁~ C₅Alkanoyloxy,   (Q) C (O) NR^xR^x,   (R) CO_TwoRⁱ,   (S) formyl,   (T) -NR^xR^x,   (U) may be saturated or partially unsaturated, having 1 to 4 heteroatoms.
A 5- to 9-membered heterocycle in which each heteroatom is independently oxygen, sulfur or nitrogen.
, The heterocycle may be substituted with 1 to 5 groups, and each substituent is independent.
To R^eWhat is   (V) aryl which may be substituted, wherein the appropriate substituent is 1,2-
Methylenedioxy or 1 to 5 groups, each substituent of which is independently R^eIs
thing,   (X) optionally substituted aryl C₁~ C_ThreeAlkoxy, which is suitable
Convenient substituents are 1,2-methylenedioxy or 1-5 groups, each substitution
The groups are independently R^eOr   (Y) C₁~ C₅Perfluoroalkyl;   R^cAnd R^dIndependently R^bSelected from; or R^cAnd R^dGazo
Together with the N to which they are attached, 3 to 3 having 0 to 2 different heteroatoms
Forming a 10-membered ring, the other heteroatoms of which are independently oxygen, nitrogen or (O
)_niSubstituted sulfur, the ring of which may be substituted with 1 to 3 groups, each of which
The substituents are independently R^g, Hydroxyl, thioxo or oxo;   R^eIs   (1) halogen,   (2) C₁~ C₇Alkyl,   (3) C₁~ C_ThreePerfluoroalkyl,   (4) -S (O)_mRⁱ,   (5) Cyano,   (6) Nitro,   (7) RⁱO (CH_Two)_v-,   (8) RⁱCO_Two(CH_Two)_v-,   (9) RⁱOCO (CH_Two)_v-,   (10) The aryl which may be substituted, wherein the appropriate substituent is 1 to 3
Individual groups, wherein each substituent is independently halogen, C₁~ C₆Alkyl, C₁~
C₆Alkoxy or hydroxyl group,   (11) SO_TwoNR^xR^x,   (12) CO_TwoR^xOr   (13) NR^xR^xAnd   R^fIs   (1) C₁~ C_FourAlkyl,   (2) X¹-C₁~ C_FourAlkyl (X¹Is O or S (O)_miIs),   (3) C_Two~ C_FourAlkenyl,   (4) C_Two~ C_FourAlkynyl,   (5) C₁~ C_ThreePerfluoroalkyl,   (6) NY^ThreeY^Four(Y^ThreeAnd Y^FourAre independently hydrogen and C₁~ C₅Archi
LE or SO_TwoR^bIs),   (7) hydroxyl group,   (8) halogen,   (9) C₁~ C₅Alkanoylamino,   (10) (C₀~ C_FourAlkyl) CO_TwoR^a,   (11) (C₀~ C_FourAlkyl) C (O) NR^bR^c,   (12) (C₀~ C_FourAlkyl) NY⁵Y⁶(Y⁵And Y⁶But they combine
Together with N, forming a 3-7 membered ring having 0-2 different heteroatoms.
And the other heteroatom is independently oxygen, nitrogen or (O)_miSubstituted sulfur
And the ring may be substituted with 1 to 3 groups, each substituent being independently
R^eOr oxo),   (13) (C₀~ C_FourAlkyl) NO_Two,   (14) (C₀~ C_FourAlkyl) C (O) R₇,   (15) (C₀~ C_FourAlkyl) CN,   (16) Oxo,   (17) (C₀~ C_FourAlkyl) C (O) N (OR^b) R^c,   (18) (C₀~ C_FourAlkyl) C (O) NR^cR^d,   (19) (C₀~ C_FourAlkyl) NHC (O) OR^b,   (20) (C₀~ C_FourAlkyl) NHC (O) NR^cR^d,   (21) (C₀~ C_FourAlkyl) OR^a,   (22) (C₀~ C_FourAlkyl) OCO_TwoR^b,   (23) (C₀~ C_FourAlkyl) OC (O) NR^cR^d,   (24) (C₀~ C_FourAlkyl) C (O) NR^cNR^cR^d,   (25) (C₀~ C_FourAlkyl) C (O) NR^cSO_TwoR^b,   (26) (C₀~ C_FourAlkyl) OS (O)_niR₇,   (27) (C₀~ C_FourAlkyl) NR^bS (O)_niR₇,   (28) C₀~ C_FourAlkyl halogen,   (29) (C₀~ C_FourAlkyl) SR^a,   (30) P (O) (OR^a)_Two,   (31) C₀~ C_FourAlkyl azide,   (32) C substituted with 1 to 4 groups₀~ C_FourAryl, wherein each substituent is
Independently S (O)_TwoR₇Or   (33) C₀~ C_FourAryl, wherein the aryl group is substituted with 1 to 4 groups
And each of the substituents is independently CO._TwoR^b, C (O) NR^cR^d, N
O_Two, Halogen, OC (O) R^a, OR^aOr C₁~ C_FourWhat is an alkyl
And   R^gAnd R^hTogether with the N to which they are bound,
Forming a 3- to 7-membered ring having a terror atom, and each other heteroatom is independently oxygen,
Nitrogen or (O)_miA substituted sulfur, the ring of which is substituted by 1 to 3 groups
And each substituent is independently R^eOr oxo; or   R^gAnd R^hEach independently,   (1) Hydrogen.   (2) Hydroxyl group, amino or CO_TwoRⁱC which may be replaced with₁~ C₆A
Luquil,   (3) halogen, 1,2-methylenedioxy, C₁~ C₇Alkoxy, C₁~
C₇Alkyl or C₁~ C_ThreeAn optionally substituted perfluoroalkyl
reel,   (4) Aryl C₁~ C₆An alkyl whose aryl is C₁~ C_ThreePar
What may be substituted with fluoroalkyl or 1,2-methylenedioxy
,   (5) C₁~ C₅Alkoxycarbonyl,   (6) C₁~ C₅Alkanoyl,   (7) C₁~ C₅Alkanoyl C₁~ C₆Alkyl,   (8) Aryl C₁~ C₅Alkoxycarbonyl,   (9) aminocarbonyl,   (10) (C₁~ C₅Monoalkyl) aminocarbonyl,   (11) (C₁~ C₅Dialkyl) aminocarbonyl or   (12) CO_TwoR^bAnd   RⁱIs   (1) hydrogen,   (2) C₁~ C_ThreePerfluoroalkyl,   (3) C₁~ C₆Alkyl or   (4) optionally substituted aryl C₀~ C₆Alkyl, as appropriate
The aryl substituents of are 1 to 3 groups, each of which is independently halogen, C₁~ C ₆ Alkyl, C₁~ C₆An alkoxy or hydroxyl group;   R^xIs C₁~ C_FourAlkyl;   m is 0 to 2;   mi is 0-2;   ni is 0 to 2;   mii is 0 to 7;   nii is 0 to 7;   v is 0-3;   However, apicidin, N-desmethoxyapicidin and chemical formula IIA and
Formula IIB     [Chemical 2] Compounds represented by are excluded. ] 2.   X is   (1) -CH_Two-,   (2) -C (O)-,   (3) -CH (OR^a)-,   (4) = CH- or   (5) Non-existence And   R₁But   (1) R₇,   (2) C (O) R₇,   (3) CN,   (4) CO_TwoR^b,   (5) C (O) N (OR^b) R^c,   (6) C (O) NR^cR^d,   (7) NHCO_TwoR^b,   (8) NHC (O) NR^cR^d,   (9) (C₀~ C_FourAlkyl) OR^a,   (10) (C₀~ C_FourAlkyl) OCO_TwoR^b,   (11) (C₀~ C_FourAlkyl) OC (O) NR^cR^d,   (12) C (O) NR^cNR^cR^d,   (13) C (O) NR^cSO_TwoR^b,   (21) OS (O)_niR₇,   (22) NR^bS (O)_niR₇(Ni is 0 to 2),   (23) 3 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C ₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono
, OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O
) NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr ha
Rogen, each substituent can be saturated, partially unsaturated or fully unsaturated
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R ^c Those which may have a substituent;   (24) 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
A benzene ring fused with a ~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C ₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino
, Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr with halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
The terror atoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^cSubstituent
And the benzene / heterocyclic fused ring has X or X at any position.
Bound to a tetrapeptide;   (25) Hete fused with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms
A 4- to 8-membered heterocycle having 1 to 4 atoms, each heterocycle being independently 1 to
It may be substituted with 4 groups, and each said substituent is independently C₁~ C₅Alkyl,
C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thi
Ono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each complex
The ring may be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cHas a substituent
Also good   The compound of claim 1 or a pharmaceutically acceptable salt of the compound. 3.   X is   (1) -CH_Two-,   (2) -C (O)-,   (3) -CH (OR^a)-,   (4) = CH- or   (5) Non-existence And   R₁But   (1) R₇,   (2) C (O) R₇,   (3) CN,   (4) CO_TwoR^b,   (5) C (O) N (OR^b) R^c,   (6) C (O) NR^cR^d,   (7) NHCO_TwoR^b,   (8) NHC (O) NR^cR^d,   (9) (C₀~ C_FourAlkyl) OR^a,   (10) (C₀~ C_FourAlkyl) OCO_TwoR^b,   (11) (C₀~ C_FourAlkyl) OC (O) NR^cR^d,   (12) C (O) NR^cNR^cR^d,   (25) C (O) NR^cSO_TwoR^b,   (26) OS (O)_niR₇,   (27) NR^bS (O)_niR₇(Ni is 0 to 2),   (28) 3 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C ₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono
, OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O
) NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr ha
Rogen, each substituent can be saturated, partially unsaturated or fully unsaturated
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R ^c Those which may have a substituent;   (29) 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
A benzene ring fused with a ~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C ₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino
, Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr with halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
The terror atoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^cSubstituent
And the benzene / heterocyclic fused ring has X or X at any position.
Bound to a tetrapeptide;   (30) Hete condensed with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms
A 4- to 8-membered heterocycle having 1 to 4 atoms, each heterocycle being independently 1 to
It may be substituted with 4 groups, and each said substituent is independently C₁~ C₅Alkyl,
C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thi
Ono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each complex
The ring may be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cHas a substituent
Also good   And   R_TwoBut,   (1) C which may be substituted_Two~ C₁₂Alkyl,   (2) C which may be substituted_Two~ C₁₂Alkenyl,   (3) C which may be substituted_Two~ C₁₂Alkynyl or   (4) (CH_Two)_nii-O- (CH_Two)_mii(Nii, mii = 0-7)
And the above C_Two~ C₁₂Alkyl, C_Two~ C₁₂Alkenyl and C_Two~ C_{1 Two} Suitable substituents on alkynyl are 1-8 groups, each group being independently   (A) CO_TwoR^a,   (B) C (O) R^b,   (C) C (O) N (OR^b) R^c,   (D) C (O) NR^cR^d,   (E) C (O) NR^cNR^cR^d,   (F) C (O) NR^cSO_TwoR₇,   (G) C_Three~ C₈Cycloalkyl,   (H) C_Two~ C₅Alkenyl,   (I) cyano,   (J) = NOR^a,   (K) = NNR^bR^c,   (L) = NNR^bS (O)_niR₇,   (M) N (OR^b) C (O) NR^bR^c,   (N) N (OR^b) C (O) R₇,   (O) NHC (O) N (OR^b) R^c,   (P) NR^cCO_TwoR^b,   (Q) NR^cC (O) NR^cR^d,   (R) NR^cC (S) NR^cR^d,   (S) NR^cC (O) R₇,   (T) NR^bS (O)_niR₇,   (U) NR^cCH_TwoCO_TwoR^a,   (V) NR^cC (S) R₇,   (X) NR^cC (O) CH_TwoOH,   (Y) NR^cC (O) CH_TwoSH,   (Z) NR^cCH_TwoCO_TwoR^a,   (Aa) NR^cCH_TwoCH (OH) R₇,   (Bb) NR^cP (O) (OR^a) R₇,   (Cc) NY¹Y^Two(Y¹And Y^TwoAre independently H or C₁~ C₁₀Alkyl
Is),   (Dd) NO_Two,   (Ee) N (OR^b) C (O) R^b,   (Ff) C₁~ C₁₀Alkanoylamino,   (Gg) OR^a,   (Hh) OS (O)_niR₇,   (Ii) oxo,   (Jj) OCO_TwoR^b,   (Kk) OC (O) NR^cR^d,   (Ll) P (O) (OR^a)_Two,   (Mm) P (O) (OR^a) R₇,   (Nn) SC (O) R₇,   (Oo) S (O)_niR₇,   (Pp) SR₇,   (Qq) S (O)_niNR^cR^d,   (Rr) NR^cCH_TwoCO_TwoR^a,   (Ss) diazo,   (Tt) C₁~ C₅Perfluoroalkyl,   (Uu) B (O) (OR^a) OR^a,   (Xx) halogen,   (Yy) aryl (C₀~ C₅Alkyl) (aryl is substituted with 1 to 3 groups
Each group is independently R^fOr)   (Xxi) is a 3- to 8-membered heterocycle having 1 to 4 heteroatoms, each heterocycle
B atom is independently oxygen, sulfur or nitrogen, and the heterocycle is substituted with 1 to 3 groups.
And each substituent is independently R^fAnd the heterocycle is saturated or
What may be unsaturated   The compound of claim 1 or a pharmaceutically acceptable salt of the compound. 4. The compound according to claim 3, wherein n is 1 or 2, or a pharmaceutically acceptable salt of the compound. 5.   X is   (1) -CH_Two-,   (2) -C (O)-or   (3) Non-existence And   R₁But   (1) R₇,   (2) C (O) R₇,   (3) CN,   (4) CO_TwoR^b,   (5) C (O) N (OR^b) R^c,   (6) C (O) NR^cR^d,   (7) NHCO_TwoR^b,   (8) NHC (O) NR^cR^d,   (9) (C₀~ C_FourAlkyl) OR^a,   (10) (C₀~ C_FourAlkyl) OCO_TwoR^b,   (11) (C₀~ C_FourAlkyl) OC (O) NR^cR^d,   (12) C (O) NR^cNR^cR^d,   (19) C (O) NR^cSO_TwoR^b,   (20) OS (O)_niR₇,   (21) NR^bS (O)_niR₇(Ni is 0 to 2),   (22) 3 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C ₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono
, OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O
) NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr ha
Rogen, each substituent can be saturated, partially unsaturated or fully unsaturated
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R ^c Those which may have a substituent;   (23) 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
A benzene ring fused with a ~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C ₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino
, Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr with halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
The terror atoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^cSubstituent
And the benzene / heterocyclic fused ring has X or X at any position.
Bound to a tetrapeptide;   (24) Hete fused with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms
A 4- to 8-membered heterocycle having 1 to 4 atoms, each heterocycle being independently 1 to
It may be substituted with 4 groups, and each said substituent is independently C₁~ C₅Alkyl,
C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thi
Ono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each complex
The ring may be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cHas a substituent
Also good   The compound of claim 2 or a pharmaceutically acceptable salt of the compound. 6. The compound according to claim 5, wherein n is 1 or 2, or a pharmaceutically acceptable salt of the compound. 7.   X is   (1) -CH_Two-,   (2) -C (O)-or   (3) Non-existence And   R₁But   (1) R₇,   (2) C (O) R₇,   (15) CO_TwoR^b,   (16) C (O) N (OR^b) R^c,   (17) C (O) NR^cR^d,   (18) 3 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C ₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono
, OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O
) NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr ha
Rogen, each substituent can be saturated, partially unsaturated or fully unsaturated
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R ^c Those which may have a substituent;   (19) 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
A benzene ring fused with a ~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C ₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino
, Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr with halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
The terror atoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^cSubstituent
And the benzene / heterocyclic fused ring has X or X at any position.
Bound to a tetrapeptide;   (20) Hete condensed with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms
A 4- to 8-membered heterocycle having 1 to 4 atoms, each heterocycle being independently 1 to
It may be substituted with 4 groups, and each said substituent is independently C₁~ C₅Alkyl,
C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thi
Ono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each complex
The ring may be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cHas a substituent
Also good   The compound of claim 2 or a pharmaceutically acceptable salt of the compound. 8. The compound according to claim 7, wherein n is 1 or 2, or a pharmaceutically acceptable salt of the compound. 9.   X is   (1) -CH_Two-,   (2) -C (O)-or   (3) Non-existence And   R₁But   (1) R₇,   (9) C (O) R₇,   (10) CO_TwoR^b,   (11) C (O) N (OR^b) R^c,   (12) C (O) NR^cR^d,   (13) 3 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C ₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono
, OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O
) NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr ha
Rogen, each substituent can be saturated, partially unsaturated or fully unsaturated
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R ^c Those which may have a substituent;   (14) 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
A benzene ring fused with a ~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C ₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino
, Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr with halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
The terror atoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^cSubstituent
And the benzene / heterocyclic fused ring has X or X at any position.
Bound to a tetrapeptide;   (15) Hete condensed with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms
A 4- to 8-membered heterocycle having 1 to 4 atoms, each heterocycle being independently 1 to
It may be substituted with 4 groups, and each said substituent is independently C₁~ C₅Alkyl,
C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thi
Ono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each complex
The ring may be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cHas a substituent
Also good   And   R_TwoBut,   (1) C which may be substituted_Two~ C₁₂Alkyl,   (2) C which may be substituted_Two~ C₁₂Alkenyl,   (3) C which may be substituted_Two~ C₁₂Alkynyl or   (4) (CH_Two)_nii-O- (CH_Two)_mii(Nii, mii = 0-7)
And the above C_Two~ C₁₂Alkyl, C_Two~ C₁₂Alkenyl and C_Two~ C_{1 Two} Suitable substituents on alkynyl are 1-5 groups, each group being independently   (A) CO_TwoR^a,   (B) C (O) R^b,   (C) C (O) N (OR^b) R^c,   (D) C (O) NR^cR^d,   (E) C (O) NR^cNR^cR^d,   (F) C (O) NR^cSO_TwoR₇,   (G) C_Three~ C₈Cycloalkyl,   (H) C_Two~ C₅Alkenyl,   (I) cyano,   (J) = NOR^a,   (K) = NNR^bR^c,   (L) = NNR^bS (O)_niR₇,   (M) N (OR^b) C (O) NR^bR^c,   (N) N (OR^b) C (O) R₇,   (O) NHC (O) N (OR^b) R^c,   (P) NR^cCO_TwoR^b,   (Q) NR^cC (O) NR^cR^d,   (R) NR^cC (S) NR^cR^d,   (S) NR^cC (O) R₇,   (T) NR^bS (O)_niR₇,   (U) NR^cCH_TwoCO_TwoR^a,   (V) NR^cC (S) R₇,   (X) NR^cC (O) CH_TwoOH,   (Y) NR^cC (O) CH_TwoSH,   (Z) NR^cCH_TwoCO_TwoR^a,   (Aa) NR^cCH_TwoCH (OH) R₇,   (Bb) NR^cP (O) (OR^a) R₇,   (Cc) NY¹Y^Two(Y¹And Y^TwoAre independently H or methyl),   (Dd) NO_Two,   (Ee) N (OR^b) C (O) R^b,   (Ff) C₁~ C_ThreeAlkanoylamino,   (Gg) OR^a,   (Hh) OS (O)_niR₇,   (Ii) oxo,   (Jj) OCO_TwoR^b,   (Kk) OC (O) NR^cR^d,   (Ll) P (O) (OR^a)_Two,   (Mm) P (O) (OR^a) R₇,   (Nn) SC (O) R₇,   (Oo) S (O)_niR₇,   (Pp) SR₇,   (Qq) S (O)_niNR^cR^d,   (Rr) NR^cCH_TwoCO_TwoR^a,   (Ss) diazo,   (Tt) C₁~ C₅Perfluoroalkyl,   (Uu) B (O) (OR^a) OR^a,   (Zz) halogen,   (Aaa) aryl (C₀~ C₅Alkyl) (aryl is substituted with 1 to 3 groups
And each group is independently R^fOr)   (Xxii) a 3 to 6 membered heterocycle having 1 to 4 heteroatoms, each heterocycle
The terror atom is independently oxygen, sulfur or nitrogen and the heterocycle is substituted with 1 to 3 groups
Each substituent is independently R^fAnd the heterocycle is saturated or
What may be partially unsaturated   The compound of claim 2 or a pharmaceutically acceptable salt of the compound. 10. The compound according to claim 9, wherein n is 1 or 2, or a pharmaceutically acceptable salt of the compound. 11.   R_ThreeEach independently,   (1) Hydrogen or   (2) halogen,   (3) OR^a,   (4) C₁~ C_FourAlkyl or   (5) C₁~ C_FourAryl;   R^aBut   (1) hydrogen,   (2) C which may be substituted₁~ C₆Alkyl,   (8) C which may be substituted_Three~ C₆Alkenyl,   (9) C which may be substituted_Two~ C_FourAlkanoyl,   (5) C which may be substituted_Three~ C_FourAlkenoyl,   (6) optionally substituted aroyl,   (7) optionally substituted aryl,   (8) C which may be substituted₅~ C₆Cycloalkanoyl,   (9) C which may be substituted₁~ C_FourAlkylsulfonyl,   (10) C which may be substituted₅~ C₆Cycloalkyl,   (15) C which may be substituted₅~ C₆Cycloalkenyl,   [The above C₁~ C₆Alkyl, C_Three~ C₆Alkenyl, C_Two~ C_FourAlkanoyl
, C_Three~ C_FourAlkenoyl, aroyl, aryl, C₅~ C₆Cycloalkanoy
Le, C₁~ C_FourAlkylsulfonyl, C₅~ C₆Cycloalkyl and C₅~ C ₆ Suitable substituents on cycloalkenyl are 1-10 groups, each substituent being
Independently hydroxyl group, methoxy, arylmethoxy, NR^xR^x, CO_TwoR^b, CO
NR^cR^dOr halogen. ],   (16) CF_Three,   (17) An arylsulfonyl which may be substituted with 1 to 3 groups,
Each of the substituents is independently methyl, CF_Three, Nitro, halogen or cyano too
Of; or   (18) A 5- or 6-membered heterocycle having 1 to 3 heteroatoms,
Each heteroatom is oxygen, sulfur or nitrogen and the heterocycle is substituted with from 1 to 3 groups
And each substituent is independently methyl, CF._Three, NMe_Two, C (O
) NR^cR^d, Cyano, CO_TwoR^bOr halogen, wherein the heterocycle is saturated or
Or may be partially unsaturated   The compound of claim 1 or a pharmaceutically acceptable salt of the compound. 12. The method according to claim 12,   R_ThreeEach independently,   (1) hydrogen,   (2) halogen,   (3) OR^a,   (4) C₁~ C_FourAlkyl or   (5) C₁~ C_FourAryl;   R^aBut   (1) hydrogen,   (2) C which may be substituted₁~ C₆Alkyl,   (10) C which may be substituted_Three~ C₆Alkenyl,   (11) C which may be substituted_Two~ C_FourAlkanoyl,   (5) C which may be substituted_Three~ C_FourAlkenoyl,   (6) optionally substituted aroyl,   (7) optionally substituted aryl,   (8) C which may be substituted₅~ C₆Cycloalkanoyl,   (9) C which may be substituted₁~ C_FourAlkylsulfonyl,   (10) C which may be substituted₅~ C₆Cycloalkyl,   (15) C which may be substituted₅~ C₆Cycloalkenyl,   [The above C₁~ C₆Alkyl, C_Three~ C₆Alkenyl, C_Two~ C_FourAlkanoyl
, C_Three~ C_FourAlkenoyl, aroyl, aryl, C₅~ C₆Cycloalkanoy
Le, C₁~ C_FourAlkylsulfonyl, C₅~ C₆Cycloalkyl and C₅~ C ₆ Suitable substituents on cycloalkenyl are 1-10 groups, each substituent being
Independently hydroxyl group, methoxy, arylmethoxy, NR^xR^x, CO_TwoR^b, CO
NR^cR^dOr halogen. ],   (16) CF_Three,   (17) An arylsulfonyl which may be substituted with 1 to 3 groups,
Each of the substituents is independently methyl, CF_Three, Nitro, halogen or cyano too
Of; or   (18) A 5- or 6-membered heterocycle having 1 to 3 heteroatoms,
Each heteroatom is oxygen, sulfur or nitrogen and the heterocycle is substituted with from 1 to 3 groups
And each substituent is independently methyl, CF._Three, NMe_Two, C (O
) NR^cR^d, Cyano, CO_TwoR^bOr halogen, wherein the heterocycle is saturated or
Or may be partially unsaturated;   X is   (1) -CH_Two-,   (2) -C (O)-,   (3) = CH- or   (5) Non-existence And   R₁But   (1) R₇,   (2) C (O) R₇,   (3) CN,   (4) CO_TwoR^b,   (5) C (O) N (OR^b) R^c,   (6) C (O) NR^cR^d,   (7) NHCO_TwoR^b,   (8) NHC (O) NR^cR^d,   (9) (C₀~ C_FourAlkyl) OR^a,   (10) (C₀~ C_FourAlkyl) OCO_TwoR^b,   (11) (C₀~ C_FourAlkyl) OC (O) NR^cR^d,   (12) C (O) NR^cNR^cR^d,   (19) C (O) NR^cSO_TwoR^b,   (20) OS (O)_niR₇,   (21) NR^bS (O)_niR₇(Ni is 0 to 2),   (22) 3 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C ₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono
, OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O
) NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr ha
Rogen, each substituent can be saturated, partially unsaturated or fully unsaturated
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R ^c Those which may have a substituent;   (23) 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
A benzene ring fused with a ~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C ₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino
, Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr with halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
The terror atoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^cSubstituent
And the benzene / heterocyclic fused ring has X or X at any position.
Bound to a tetrapeptide;   (24) Hete fused with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms
A 4- to 8-membered heterocycle having 1 to 4 atoms, each heterocycle being independently 1 to
It may be substituted with 4 groups, and each said substituent is independently C₁~ C₅Alkyl,
C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thi
Ono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each complex
The ring may be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cHas a substituent
Also good   The compound of claim 11, which is: or a pharmaceutically acceptable salt of the compound. 13. The compound according to claim 12, wherein n is 1 or 2, or a pharmaceutically acceptable salt of the compound. 14.   R_ThreeEach independently,   (1) hydrogen,   (2) halogen,   (3) OR^a,   (4) C₁~ C_FourAlkyl or   (5) C₁~ C_FourAryl;   R^aBut   (1) hydrogen,   (5) C which may be substituted₁~ C₆Alkyl,   (6) C which may be substituted_Three~ C₆Alkenyl,   (7) C which may be substituted_Two~ C_FourAlkanoyl,   (5) C which may be substituted_Three~ C_FourAlkenoyl,   (6) optionally substituted aroyl,   (7) optionally substituted aryl,   (8) C which may be substituted₅~ C₆Cycloalkanoyl,   (9) C which may be substituted₁~ C_FourAlkylsulfonyl,   (10) C which may be substituted₅~ C₆Cycloalkyl,   (15) C which may be substituted₅~ C₆Cycloalkenyl,   [The above C₁~ C₆Alkyl, C_Three~ C₆Alkenyl, C_Two~ C_FourAlkanoyl
, C_Three~ C_FourAlkenoyl, aroyl, aryl, C₅~ C₆Cycloalkanoy
Le, C₁~ C_FourAlkylsulfonyl, C₅~ C₆Cycloalkyl and C₅~ C ₆ Suitable substituents on cycloalkenyl are 1-10 groups, each substituent being
Independently hydroxyl group, methoxy, arylmethoxy, NR^xR^x, CO_TwoR^b, CO
NR^cR^dOr halogen. ],   (16) CF_Three,   (17) An arylsulfonyl which may be substituted with 1 to 3 groups,
Each of the substituents is independently methyl, CF_Three, Nitro, halogen or cyano too
Of; or   (18) A 5- or 6-membered heterocycle having 1 to 3 heteroatoms,
Each heteroatom is oxygen, sulfur or nitrogen and the heterocycle is substituted with from 1 to 3 groups
And each substituent is independently methyl, CF._Three, NMe_Two, C (O
) NR^cR^d, Cyano, CO_TwoR^bOr halogen, wherein the heterocycle is saturated or
Or may be partially unsaturated;   X is   (1) -CH_Two-,   (5) -C (O)-,   (6) = CH- or   (7) Non-existence And   R₁But   (1) R₇,   (2) C (O) R₇,   (21) CO_TwoR^b,   (22) C (O) N (OR^b) R^c,   (23) C (O) NR^cR^d,   (24) 3 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C ₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono
, OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O
) NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr ha
Rogen, each substituent can be saturated, partially unsaturated or fully unsaturated
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R ^c Those which may have a substituent;   (25) 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
A benzene ring fused with a ~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C ₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino
, Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr with halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
The terror atoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^cSubstituent
And the benzene / heterocyclic fused ring has X or X at any position.
Bound to a tetrapeptide;   (26) Hete condensed with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms
A 4- to 8-membered heterocycle having 1 to 4 atoms, each heterocycle being independently 1 to
It may be substituted with 4 groups, and each said substituent is independently C₁~ C₅Alkyl,
C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thi
Ono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each complex
The ring may be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cHas a substituent
Also good   The compound of claim 11, which is: or a pharmaceutically acceptable salt of the compound. 15. The compound according to claim 14, wherein n is 1 or 2, or a pharmaceutically acceptable salt of the compound. 16.   R₆Each independently,   (1) O,   (2) S or   (3) It is H;   X is   (1) -CH_Two-,   (2) -C (O)-,   (5) = CH- or   (6) Non-existence And   R₁But   (1) R₇,   (2) C (O) R₇,   (3) CN,   (4) CO_TwoR^b,   (5) C (O) N (OR^b) R^c,   (6) C (O) NR^cR^d,   (7) NHCO_TwoR^b,   (8) NHC (O) NR^cR^d,   (9) (C₀~ C_FourAlkyl) OR^a,   (10) (C₀~ C_FourAlkyl) OCO_TwoR^b,   (11) (C₀~ C_FourAlkyl) OC (O) NR^cR^d,   (12) C (O) NR^cNR^cR^d,   (13) C (O) NR^cSO_TwoR^b,   (19) OS (O)_niR₇,   (20) NR^bS (O)_niR₇(Ni is 0 to 2),   (21) 3 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C ₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono
, OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O
) NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr ha
Rogen, each substituent can be saturated, partially unsaturated or fully unsaturated
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R ^c Those which may have a substituent;   (22) 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
A benzene ring fused with a ~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C ₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino
, Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr with halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
The terror atoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^cSubstituent
And the benzene / heterocyclic fused ring has X or X at any position.
Bound to a tetrapeptide;   (23) Hete condensed with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms
A 4- to 8-membered heterocycle having 1 to 4 atoms, each heterocycle being independently 1 to
It may be substituted with 4 groups, and each said substituent is independently C₁~ C₅Alkyl,
C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thi
Ono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each complex
The ring may be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cHas a substituent
Also good   The compound of claim 1 or a pharmaceutically acceptable salt of the compound. 17. The compound according to claim 16, wherein n is 1 or 2, or a pharmaceutically acceptable salt of the compound. 18.   R_ThreeEach independently,   (1) hydrogen,   (2) halogen,   (3) OR^a,   (4) C₁~ C_FourAlkyl or   (5) C₁~ C_FourAryl;   R₆Each independently,   (1) O,   (2) S or   (3) It is H;   X is   (1) -CH_Two-,   (2) -C (O)-,   (3) = CH- or   (5) Non-existence And   R₁But   (1) R₇,   (2) C (O) R₇,   (3) CN,   (4) CO_TwoR^b,   (5) C (O) N (OR^b) R^c,   (6) C (O) NR^cR^d,   (7) NHCO_TwoR^b,   (8) NHC (O) NR^cR^d,   (9) (C₀~ C_FourAlkyl) OR^a,   (10) (C₀~ C_FourAlkyl) OCO_TwoR^b,   (11) (C₀~ C_FourAlkyl) OC (O) NR^cR^d,   (12) C (O) NR^cNR^cR^d,   (19) C (O) NR^cSO_TwoR^b,   (20) OS (O)_niR₇,   (21) NR^bS (O)_niR₇(Ni is 0 to 2),   (22) 3 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C₅Alkyl, C_Two~ C ₅ Alkenyl, C₁~ C₅Perfluoroalkyl, NR^cR^d, Oxo, thiono
, OR^a, S (O)_niR^a(Ni = 0, 1 or 2), C (O) R^a, C (O
) NR^cR^d, Cyano, (C₀~ C₆Alkyl) aryl, CO_TwoR^bOr ha
Rogen, each substituent can be saturated, partially unsaturated or fully unsaturated
The heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R ^c Those which may have a substituent;   (23) 4 having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups
A benzene ring fused with a ~ 8-membered heterocycle, wherein each said substituent is independently C₁~ C ₅ Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino
, Oxo, thiono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr with halogen
And each substituent can be saturated, partially unsaturated or fully unsaturated,
The terror atoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is R^cSubstituent
And the benzene / heterocyclic fused ring has X or X at any position.
Bound to a tetrapeptide;   (24) Hete fused with a second 4- to 8-membered heterocycle having 1 to 4 heteroatoms
A 4- to 8-membered heterocycle having 1 to 4 atoms, each heterocycle being independently 1 to
It may be substituted with 4 groups, and each said substituent is independently C₁~ C₅Alkyl,
C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl, amino, oxo, thi
Ono, C (O) NR^cR^d, Cyano, CO_TwoR^bOr halogen, each complex
The ring may be saturated, partially unsaturated or fully unsaturated, said heteroatom being
Each independently oxygen, sulfur or nitrogen, said nitrogen being R^cHas a substituent
Also good   17. The compound of claim 16 or a pharmaceutically acceptable salt of the compound. 19. The compound according to claim 18, wherein n is 1 or 2, or a pharmaceutically acceptable salt of the compound. 20. The compound according to claim 1, wherein X is preferably —CH ₂ — or a pharmaceutically acceptable salt of the compound. 21. The compound according to claim 1 or a pharmaceutically acceptable salt of the compound, wherein X is preferably -C (O)-. 22. A compound according to claim 1 or a pharmaceutically acceptable salt of said compound, wherein X is preferably absent. 23. R₁Is preferably a group which may be substituted with 1 to 4 groups.
A 3- to 8-membered heterocycle having 1 to 4 terror atoms, wherein each said substituent is independently C ₁ ~ C₅Alkyl, C_Two~ C₅Alkenyl, C₁~ C₅Perfluoroalkyl,
NR^cR^d, Oxo, thiono, OR^a, S (O)_niR^a(Ni = 0, 1 or
2), C (O) R^a, C (O) NR^cR^d, Cyano, (C₀~ C₆Alkyl)
Reel, CO_TwoR^bOr halogen, each substituent is saturated, partially unsaturated or
It can be fully unsaturated, wherein each heteroatom is independently oxygen, sulfur or
Is nitrogen, and the nitrogen is R^cIn Claim 1, which may have a substituent.
The described compound. 24. R ₁ is preferably a benzene ring fused with a 4-8 membered heterocycle having 1 to 4 heteroatoms optionally substituted with 1 to 4 groups, each said substitution The groups are independently C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₁ -C ₅ perfluoroalkyl, amino, oxo, thiono, C (O) NR ^c R ^d , cyano,
CO ₂ R ^b or halogen, each substituent can be saturated, partially unsaturated or fully unsaturated, the heteroatoms are each independently oxygen, sulfur or nitrogen, and the nitrogen is an R ^c substituent. 2. The benzene / heterocyclic fused ring may be attached to X or a tetrapeptide at any position.
Or a pharmaceutically acceptable salt of the compound. 25. A second 4 to 4 in which R ₁ preferably has 1 to 4 heteroatoms.
A 4- to 8-membered heterocycle having 1 to 4 heteroatoms fused with an 8-membered heterocycle, wherein each said heterocycle may be independently substituted with 1 to 4 groups, said each The substituents are independently C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₁ -C ₅ perfluoroalkyl, amino, oxo, thiono, C (O) NR ^c R ^d , cyano, CO ₂ R ^b or Halogen, each heterocycle can be saturated, partially unsaturated or fully unsaturated, said heteroatoms are each independently oxygen, sulfur or nitrogen, said nitrogen having an R ^c substituent. The compound according to claim 1, which is also good, or a pharmaceutically acceptable salt of the compound. 26. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. 27. A method for treating a protozoal infection, which is effective in inhibiting the histone deacetylase activity of the protozoan in a host in need thereof, in a nontoxic amount. A method comprising administering the described composition. 28. A method of preventing protozoal infections, the method comprising administering to a host a non-toxic, effective prophylactic amount of the composition of claim 1.